Summary: development and regulatory status

As of September 2026, the axitinib intravitreal implant (AXPAXLI, OTX-TKI) is investigational and is not approved in any country. It is in phase 3 development for neovascular age-related macular degeneration (nAMD) in three trials: SOL-1 (superiority versus a single injection of aflibercept 2 mg; conducted under an FDA Special Protocol Assessment), SOL-R (non-inferiority versus aflibercept 2 mg every 8 weeks; 640 participants randomized), and the open-label extension SOL-X. The sponsor completed a pre-NDA meeting in September 2026 and plans to submit a New Drug Application under section 505(b)(2) in the fourth quarter of 2026, based on SOL-1 Week 52 efficacy and safety data, interim Week 52 safety data from a subset of SOL-R participants, and confirmatory evidence. The sponsor plans to submit SOL-1 Year 2 safety data at the 120-day safety update to support repeat dosing, and describes a potential launch in 2027 if approved. No FDA expedited program designation, European Medicines Agency submission, or other ex-U.S. regulatory filing was identified.

Investigational status and product name

“AXPAXLI is a trade name which we use to refer to our OTX-TKI product candidate.” (opens the source at this quote in a new tab)
“Food and Drug Administration, or FDA, has not approved AXPAXLI as a product name.” (opens the source at this quote in a new tab)

Current development phase in nAMD

“AXPAXLI is currently being evaluated in a Phase 3 registrational program for wet age-related macular degeneration, or wet AMD, which we refer to as the SOL program.” (opens the source at this quote in a new tab)

Special Protocol Assessment agreement and modifications for SOL-1

“We received an agreement letter regarding the overall trial design from the FDA under the SPA agreement on October 30, 2023.” (opens the source at this quote in a new tab)
“We received an agreement letter regarding the first SPA agreement modification from the FDA on January 22, 2024.” (opens the source at this quote in a new tab)
“We received an agreement letter regarding the second SPA agreement modification from the FDA on February 24, 2025.” (opens the source at this quote in a new tab)

FDA feedback on the SOL-R trial and a one superiority plus one non-inferiority trial package

“At the time, the FDA also noted that the use of one superiority trial and one non-inferiority trial is generally acceptable as the basis of an eventual NDA in wet AMD.” (opens the source at this quote in a new tab)

Planned NDA content after the May 2026 Type C meeting

“The NDA is expected to include the Week 52 efficacy and safety data from the SOL-1 trial, together with interim Week 52 safety data for a subset of subjects in the SOL-R trial and confirmatory evidence.” (opens the source at this quote in a new tab)
“To provide safety information for a minimum of 300 subjects in the aggregate with at least one year of treatment with AXPAXLI in accordance with FDA guidance and to supplement the 170 subjects who received AXPAXLI in the SOL-1 trial, we plan to conduct an interim safety analysis of the SOL-R trial during the fourth quarter of 2026 assessing all subjects who have completed the Week 52 time point at the time of analysis.” (opens the source at this quote in a new tab)
“SOL-R efficacy data is not part of our planned NDA submission.” (opens the source at this quote in a new tab)

Repeat-dosing data planned for the 120-day safety update

“At the standard 120-day safety update following the submission of our NDA, we plan to submit Year 2 safety data from the SOL-1 trial to the FDA to support the potential inclusion of repeat dosing on a label for AXPAXLI, if approved.” (opens the source at this quote in a new tab)

Regulatory submission: NDA planned for the fourth quarter of 2026

“Based on the Pre-NDA Meeting, the Company’s expectations for the AXPAXLI NDA package remain consistent with prior FDA communications, including the May 2026 Type C Meeting. Ocular remains on track to submit the NDA in the fourth quarter of 2026.” (opens the source at this quote in a new tab)
“The September 2026 Pre-NDA Meeting further confirmed alignment with the FDA on the content and format of the planned NDA submission under the 505(b)(2) pathway, which has the potential to shorten the FDA review timeline by up to 60 days as compared to the traditional 505(b)(1) pathway for a new molecular entity.” (opens the source at this quote in a new tab)

Basis for the 505(b)(2) pathway

“Because axitinib is FDA-approved for non-ophthalmic indications, we plan to submit an NDA under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, or FDCA, which has the potential to shorten the review timeline for AXPAXLI by up to two months compared to the traditional review pathway for new molecular entities” (opens the source at this quote in a new tab)

SOL-R protocol amendment and revised topline timing

“Following these changes, topline SOL-R results are now expected in the first quarter of 2028. The trial's primary endpoint, non-inferiority of AXPAXLI to aflibercept (2 mg) at Week 56, remains unchanged.” (opens the source at this quote in a new tab)

Launch: Anticipated in 2027

“Commercial readiness accelerates ahead of potential 2027 launch as AXPAXLI is well positioned to potentially be the first TKI approved for wet AMD” (opens the source at this quote in a new tab)

FDA expedited program designations, EMA submissions, and other ex-U.S. regulatory filings

No evidence found.

Manufacturer: Ocular Therapeutix

“Sponsor Ocular Therapeutix, Inc.” (opens the source at this quote in a new tab)

Product names and development code

“AXPAXLI™ (also known as OTX-TKI), Ocular’s investigational product candidate for retinal disease, is an axitinib intravitreal hydrogel based on its ELUTYX™ proprietary bioresorbable hydrogel-based formulation technology.” (opens the source at this quote in a new tab)

Intervention name in trial registrations

“Drug: OTX-TKI (axitinib implant)” (opens the source at this quote in a new tab)

Therapeutic class

“Our product candidate AXPAXLI is an investigational, bioresorbable hydrogel implant, based on our ELUTYX technology, incorporating axitinib, a small molecule, multi-target, tyrosine kinase inhibitor, or TKI, with anti-angiogenic properties.” (opens the source at this quote in a new tab)

Class context: approved oral axitinib

“INLYTA (axitinib) is a kinase inhibitor.” (opens the source at this quote in a new tab)

Nonproprietary name for the implant

No evidence found.

Dosage form: polyethylene glycol hydrogel containing micronized axitinib

“Our intravitreal hydrogel product candidates, such as AXPAXLI, consist of a PEG-based hydrogel, which contains embedded micronized particles of” (opens the source at this quote in a new tab)

“OTX-TKI is a dried polyethylene glycol-based hydrogel fiber containing dispersed microcrystals of a small molecule tyrosine kinase inhibitor (TKI).” (opens the source at this quote in a new tab)

Strength in phase 3 trials: 450 µg (0.45 mg), second-generation formulation

“We are currently conducting the SOL-1, SOL-R and HELIOS-3 trials, and we plan to conduct the SOL-X trial and, if needed, the HELIOS-2 trial with a 450 µg axitinib dose of AXPAXLI, or AXPAXLI 450 µg, which is a different formulation than we used in either of the two Phase 1 trials of AXPAXLI that we have completed for the treatment of wet AMD.” (opens the source at this quote in a new tab)
“This optimized configuration provides for an increased daily release of the drug and improved synchronization of axitinib drug release with hydrogel bioresorption.” (opens the source at this quote in a new tab)

Second-generation formulation: more soluble form of axitinib

“Optimized in same hydrogel but with a more soluble form of axitinib, delivering the targeted daily release rate in a 0.45-mg dose” (opens the source at this quote in a new tab)

Strengths studied in phase 1 trials: first-generation 200, 400, and 600 µg implants

“In the clinical trial, intravitreal injections of AXPAXLI at 200 μg, 400 μg, and 600 μg, with and without concurrent administration of anti-VEGF, were generally well tolerated.” (opens the source at this quote in a new tab)

Delivery device: single-use applicator

“IVT administration with single-use applicator (25G needle)” (opens the source at this quote in a new tab)

Commercial presentation, packaging, and storage conditions

No evidence found.

WHO ATC classification of axitinib (oral antineoplastic)

ATC code	Name	DDD	Unit	Route
“L01EK01”	“axitinib”	“10”	“mg”	“O”

“L01EK Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors” (opens the source at this quote in a new tab)

WHO ATC ophthalmic antineovascularisation agents (S01LA): listed substances

“S01LA Antineovascularisation agents” (opens the source at this quote in a new tab)
“S01LA05 aflibercept” (opens the source at this quote in a new tab)
“S01LA09 faricimab” (opens the source at this quote in a new tab)

AHFS classification and ophthalmic ATC code for the axitinib intravitreal implant

No evidence found.

Indication under development

“today announced the successful completion of its Pre-New Drug Application (NDA) Meeting with the U.S. Food and Drug Administration (FDA) for its investigational product candidate AXPAXLI™ (also known as OTX-TKI) for the treatment of wet age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)

Label sought by the sponsor

“Based on the SOL-1 trial results, we believe AXPAXLI has the potential to receive a superiority label as compared to a single injection of aflibercept 2 mg, with redosing potentially as infrequently as every 12 months, if approved.” (opens the source at this quote in a new tab)

“We believe the design of the SOL-1 trial enhances the potential for a 6 - 12 month dosing label for AXPAXLI for the treatment of wet AMD and also provides insights into the long-term durability of AXPAXLI.” (opens the source at this quote in a new tab)

Population studied in the pivotal superiority trial

“In December 2024, the trial completed randomization of 344 treatment-naïve subjects with a diagnosis of wet AMD in the study eye. Two randomized subjects withdrew from the trial prior to receiving Day 1 treatment.” (opens the source at this quote in a new tab)

Other indications in development

“AXPAXLI is currently in Phase 3 clinical trials for wet age-related macular degeneration (wet AMD), and diabetic retinal disease, including non-proliferative diabetic retinopathy (NPDR).” (opens the source at this quote in a new tab)

Intracellular VEGF receptor tyrosine kinase inhibition

“TKIs bind the intracellular tyrosine kinase domains of VEGF receptors, inhibiting ATP binding and preventing activation of pro-angiogenic signaling” (opens the source at this quote in a new tab)

Receptor targets of axitinib: review

“Axitinib is a second-generation TKI that potently targets the VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase receptors.” (opens the source at this quote in a new tab)
“It also inhibits the PDGFR α and PDGFR β tyrosine kinases and c-Kit receptors at higher concentrations.” (opens the source at this quote in a new tab)

Class context: mechanism of action in the oral axitinib (INLYTA) label

“Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations.” (opens the source at this quote in a new tab)

Contrast with extracellular anti-VEGF ligand binding

“Anti-VEGFs act on the extracellular side by binding selective ligands, like VEGF-A, to prevent receptor binding and pro-angiogenic activity” (opens the source at this quote in a new tab)

Hydrogel drug-release mechanism

“Cross-linked multi-arm PEG hydrogel network with hydrolyzable ester linkages” (opens the source at this quote in a new tab)
“Micronized axitinib entrapped in hydrogel steadily dissolves into vitreous, then diffuses into ocular tissues” (opens the source at this quote in a new tab)
“Hydrogel degrades via hydrolysis (like dissolvable sutures), implant bioresorbs, and remaining axitinib is released for continued delivery” (opens the source at this quote in a new tab)

ELUTYX hydrogel platform chemistry

“We create our hydrogels by cross-linking PEG molecules to form a network that resembles a three-dimensional mesh on a molecular level.” (opens the source at this quote in a new tab)
“We design these hydrogels to slowly degrade in the presence of water, a process called hydrolysis, by inserting a biodegradable linkage between the PEG molecule and the cross-linked molecule.” (opens the source at this quote in a new tab)

Rationale for sustained delivery of a tyrosine kinase inhibitor

“In the absence of a sophisticated drug delivery system, TKIs have been difficult to deliver to the eye for acceptable time frames at therapeutic levels without causing local and systemic toxicity due to low drug solubility, very short half-lives in solution, and off-target effects.” (opens the source at this quote in a new tab)

Combined VEGF and PDGF pathway inhibition: in vitro and rat choroidal neovascularization models

“Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD.” (opens the source at this quote in a new tab)

Intracellular kinase inhibition and hydrogel delivery of axitinib: independent review

“Tyrosine kinase inhibitors (TKIs) are small molecules that act at the intracellular level to inhibit receptor tyrosine kinase by preventing tyrosine kinase phosphorylation and the downstream signaling cascade.” (opens the source at this quote in a new tab)
“Notably, TKIs are capable of inhibiting all isoforms of VEGF as well as other receptor tyrosine kinases including fibroblast growth factor receptor and platelet-derived growth factor receptor.” (opens the source at this quote in a new tab)
“Axitinib binds to the intracellular ATP-binding site of VEGFR-1, VEGFR-2, and VEGFR-3, thereby inhibiting receptor phosphorylation” (opens the source at this quote in a new tab)
“Cross-linked polyethylene glycol polymer chains form a hydrogel, allowing diffusion of the micronized molecule.” (opens the source at this quote in a new tab)

Rationale for single-agent dual VEGF and PDGF receptor inhibition in choroidal neovascularization

“Axitinib is a small molecule tyrosine kinase inhibitor mainly targeting VEGFR1-3 and PDGFR.” (opens the source at this quote in a new tab)
“Targeting VEGFR1-3, axitinib offers an anti-VEGF spectrum as broad as aflibercept, but also adds PDGFR and c-Kit inhibition” (opens the source at this quote in a new tab)
“In our hands, axitinib was not only capable of a modulation of VEGF-mediated endothelial cellular function, but also expanded current treatment options by inhibition of pericytes attributable to its impact on PDGF-signaling, as pericytes do not express c-Kit” (opens the source at this quote in a new tab)
“From a future perspective, axitinib as a single substance offering dual anti-VEGF/PDGF inhibition might allow for an easier, better-tolerated application.” (opens the source at this quote in a new tab)

Kinase selectivity and potency: sponsor cell-based and biochemical assays

Compound	VEGFR2 IC50 (nM)	PDGFR-β IC50 (nM)	FGFR2 IC50 (nM)	TIE2 IC50 (nM)
Axitinib	“0.032”	“1.6”	“72”	“1500”
Sunitinib	“2.900”	“11.0”	“>10000”	“1400”
Vorolanib	“3.300”	“16.0”	“1400”	“>10000”

“Kinome profiling demonstrated VEGFR-1, -2, -3 and PDGFR- α, -β are the top 5 axitinib kinase targets exhibiting >85% inhibition.” (opens the source at this quote in a new tab)
“Cellular assay data demonstrated no TIE2 inhibition within physiological drug solubility range at cell ATP levels via the gold standard cell phosphorylation assay.” (opens the source at this quote in a new tab)

TIE2 inhibition: comparative study sponsored by a competitor developer

“HotSpot™ assay and TIE2 IC 50 values showed that only axitinib potently inhibited TIE2 (up to 89%).” (opens the source at this quote in a new tab)
“Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability.” (opens the source at this quote in a new tab)

VEGFR2 potency above IC50: comparative in vivo angiogenesis findings

“This experiment demonstrates that in a VEGF-dependent study, any of the three TKIs when used at the VEGFR2 IC 50 value will achieve the desired efficacy and when levels higher than IC 50 are utilized the result is little to no enhancement in the effect; hence, the higher potency for VEGFR2 inhibition reported for axitinib relative to vorolanib and sunitinib appears to be of no benefit when compounds are present at concentrations at or above the receptor IC 50 value for that particular TKI.” (opens the source at this quote in a new tab)

Melanin binding

“Both vorolanib and axitinib showed little or no binding to melanin, so the K d and B max values of these two TKIs could not be determined” (opens the source at this quote in a new tab)

Vascular leakage in a VEGF challenge rabbit model: 0.45 mg second-generation implant

“OTX-TKI maintained low leakage scores throughout the study period” (opens the source at this quote in a new tab)
“Bevacizumab had a marked reduction in efficacy after day 31” (opens the source at this quote in a new tab)
“At day 73, bevacizumab had similar scores to untreated control” (opens the source at this quote in a new tab)

Endothelial cells and pericytes in vitro

“Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro.” (opens the source at this quote in a new tab)

Pericyte phenotype with combined VEGF and PDGF receptor inhibition

“Combined anti-VEGF/PDGF inhibition seems to induce a proto-myofibroblast-like phenotype in human pericytes in vitro, but reduce profibrotic cellular mechanisms due to prolonged anti-PDGF inhibition.” (opens the source at this quote in a new tab)

Preclinical ocular tolerability: 6-month GLP toxicology study in non-human primates

“No signs of inflammation or clinically significant changes in IOP were observed following intravitreal injection with OTX-TKI implant” (opens the source at this quote in a new tab)
“OTX-TKI 700 μg dose represents a human equivalent dose of 1400 μg axitinib and 2.3X ocular dose safety margin when normalized to the vitreous volume between humans and monkeys” (opens the source at this quote in a new tab)

Preclinical repeat dosing every 6 months in non-human primates

“Repeated IVT dosing of OTX-TKI in NHPs was generally well tolerated over an 18-month period with no inflammation and no IOP elevations, supporting the favorable safety profile of repeat doses of OTX-TKI every 6 months in NHPs (~8-9 months in humans)” (opens the source at this quote in a new tab)

Exposure-response in humans: clinical activity relative to preclinical tissue concentrations

“This preclinical PK data aligns with the pharmacodynamics data we observed in our U.S. clinical trial, namely the high proportion of rescue-free subjects up to Month 10 and suggests that AXPAXLI may provide continuous VEGF receptor inhibition.” (opens the source at this quote in a new tab)

Onset of anatomic activity: Australian phase 1 trial

“Some subjects showed a decrease in intraretinal or subretinal fluid by two months in cohorts 2 (400 µg) and 3a (600 µg).” (opens the source at this quote in a new tab)
“We observed extended duration of activity of six months or more for over 60% of subjects across all cohorts and for over 80% of subjects in cohort 3a, in which we administered a 600 μg dose.” (opens the source at this quote in a new tab)

Kinase selectivity of axitinib compared with sunitinib: independent review

“In vitro, individual TKIs differ in their VEGFR-binding affinity, receptor selectivity profiles, and off-target inhibition.” (opens the source at this quote in a new tab)
“Axitinib, for example, is a potent and selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 with minimal activity against other kinases, whereas sunitinib has broader activity, also targeting platelet-derived growth factor receptors (PDGFRs), c-Kit, and FLT3.” (opens the source at this quote in a new tab)
“These differences in molecular selectivity may influence not only efficacy and durability but also safety profiles when these agents are applied to ocular tissues via sustained-release platforms.” (opens the source at this quote in a new tab)

Concentration-dependent inhibition of endothelial cell and pericyte proliferation and migration by axitinib in vitro

“Human endothelial cells (HUVEC) and human pericytes (hPC-PL) were treated with axitinib doses ranging from 1.0 ng/ml to 10 μg/ml.” (opens the source at this quote in a new tab)
“In HUVEC, a significant decrease in cellular proliferation compared to untreated controls could be observed from 0.1 to 10 μg/ml axitinib” (opens the source at this quote in a new tab)
“In pericytes, stimulation with 20 ng PDGF-BB resulted in an approximately 6-fold migratory increase” (opens the source at this quote in a new tab)
“On regular Cultrex, treatment with 0.5, 1, and 2.5 μg/ml axitinib showed a significant decrease of vessel-associated area by 48, 50, and 62% respectively” (opens the source at this quote in a new tab)
“IC50 values of antiproliferative activity were generally lower on endothelial cells than on pericytes. This correlates well with the pharmacological profile of axitinib, which offers VEGFR2-inhibition with an IC50 of 0.2 nM versus 1.6 nM for PDGFR” (opens the source at this quote in a new tab)

In vitro tolerability range of axitinib on endothelial cells and pericytes

“In HUVEC, no statistically significant decrease of metabolic activity and cell count compared to controls treated with vehicle could be observed from 1.0 ng/ml to 7.5 μg/ml axitinib” (opens the source at this quote in a new tab)
“In pericytes, no reduction of metabolic activity could be observed within the range of solubility of axitinib up to 10 μg/ml” (opens the source at this quote in a new tab)
“All effects on both cell lines were observed in non-toxic concentrations of axitinib.” (opens the source at this quote in a new tab)

Designed release duration

“AXPAXLI is delivered by intravitreal injection and is designed for a duration of six months or longer.” (opens the source at this quote in a new tab)
“Our prolonged constant rate of axitinib delivery over a nine-to-twelve-month period could make it possible to reduce patients’ treatment burden by reducing the frequency of treatment for wet AMD.” (opens the source at this quote in a new tab)

Implant bioresorption in humans

“Implant observed to bioresorb consistently at about eight to nine months in trial, informing potential redosing timeline” (opens the source at this quote in a new tab)

“In addition, the AXPAXLI doses in cohort 1 (200 µg single dose) were observed to have biodegraded in all subjects within nine to 10.5 months of injection.” (opens the source at this quote in a new tab)

Systemic exposure in humans: Australian phase 1 trial

“Plasma levels of the active drug, axitinib, were below the limit of quantification at all doses, indicating that systemic exposure to intravitreal delivery of axitinib by AXPAXLI up to 600 μg was negligible.” (opens the source at this quote in a new tab)

Ocular tissue concentrations in non-human primates: first-generation implants

“Median axitinib concentrations in the retina and choroid/RPE were substantially greater than the inhibitory concentration (IC50) of VEGF receptor-2 (0.08 ng/mL) from after Month 3” (opens the source at this quote in a new tab)
“Hydrogel degradation was observed at approximately 5 to 6 months with released axitinib particles visible in the vitreous at Month 9 and localized at Month 12” (opens the source at this quote in a new tab)
“Plasma samples showed axitinib levels were below the lower limit of quantification (LLOQ=0.1 ng/mL) up to Month 3, then slightly above LLOQ (0.1 – 0.2 ng/mL) in Month 6 samples and returned to below LLOQ at Month 9” (opens the source at this quote in a new tab)

Ocular tissue concentrations through 12 months in non-human primates: sponsor summary

“That data showed that clinically representative formulations of AXPAXLI delivered sustained axitinib concentrations through 12 months that were well above the IC50 for VEGFR-2 (vascular endothelial growth factor receptor) in cynomolgus monkey retina tissue and choroid/RPE tissues.” (opens the source at this quote in a new tab)

First-generation versus second-generation implant pharmacokinetics in monkeys and rabbits

“Rapidly achieved higher initial axitinib concentrations in the target tissues, suggesting a potential earlier onset of action” (opens the source at this quote in a new tab)
“Maintained steady-state concentrations better than OTX-TKI due to drug left behind following hydrogel bioresorption at 6 months” (opens the source at this quote in a new tab)

Interspecies scaling of implant bioresorption

“Implant bioresorption at ~5-6 months in NHPs is equivalent to ~8-9 months in humans” (opens the source at this quote in a new tab)

Terminal release after bioresorption

“Hydrogel remains intact until final resorption event, which occurs over a span of about 3-4 weeks. In humans, the resorption occurs 8-9 months after implantation.” (opens the source at this quote in a new tab)

Release kinetics: independent review

“Axitinib concentrations were above the half-maximum inhibitory concentration of VEGF receptor 2 in the retina, choroid, and retinal pigment epithelium consistently through 9 months.” (opens the source at this quote in a new tab)

“Axpaxli is an investigational intravitreal, hydrogel implant that delivers axitinib with 0-order kinetics for 6–12 months, reducing the need for frequent intravitreal injections.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) absorption, distribution, and half-life

“The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.” (opens the source at this quote in a new tab)
“Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein.” (opens the source at this quote in a new tab)
“The plasma half-life of INLYTA ranges from 2.5 to 6.1 hours.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) metabolism and excretion

“Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.” (opens the source at this quote in a new tab)
“Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine.” (opens the source at this quote in a new tab)

Vitreous and plasma concentrations of the 450 µg implant in humans

No evidence found.

Vitreous clearance of tyrosine kinase inhibitors and the rationale for sustained release: independent review

“Rapid vitreous clearance of existing VEGF inhibitors limits durability to 1-4 months.” (opens the source at this quote in a new tab)
“Combining TKIs with sustained release platforms, such as hydrogel or polyvinyl alcohol, allow for the sustained release of the molecules and the potential for extended durability.” (opens the source at this quote in a new tab)
“OTX-TKI is administered via a 25-gauge intravitreal injection and is designed to be completely bioresorbable and have biologic activity over 9-12 months.” (opens the source at this quote in a new tab)

FDA-approved prescribing information, contraindications, boxed warnings, and REMS

Not applicable.

Key safety findings in the pivotal trial through Week 52

“No treatment-related ocular or systemic serious adverse events were observed.” (opens the source at this quote in a new tab)
“No cases of endophthalmitis, occlusive retinal vasculitis, non-occlusive retinal vasculitis, retinal detachment, or implant migration to the anterior chamber were observed in the AXPAXLI arm.” (opens the source at this quote in a new tab)

Vitreous floaters and relation to hydrogel bioresorption

“Appearance of floaters likely corresponds to hydrogel dissolution and drug elution” (opens the source at this quote in a new tab)
“No evidence of IOI” (opens the source at this quote in a new tab)
“No case observed to be associated with cataract formation” (opens the source at this quote in a new tab)

“For all AXPAXLI subjects with a vitreous floater adverse event reported, drug particles are no longer visible (mean time of 20 weeks).” (opens the source at this quote in a new tab)

Intraocular inflammation

“Nine events observed in study eyes of 7 subjects in the OTX-TKI arm” (opens the source at this quote in a new tab)
“All cases were mild or moderate in severity and resolved” (opens the source at this quote in a new tab)

Injection-procedure endophthalmitis in the U.S. phase 1 trial

“One SAE of endophthalmitis was observed in the AXPAXLI arm which occurred following the aflibercept injection required by the clinical trial protocol at month one and was assessed by the investigator as related to the injection procedure.” (opens the source at this quote in a new tab)

Implant retrieval

“Our hydrogel implants and inserts are designed to fully dissipate and can be removed if necessary by a healthcare professional.” (opens the source at this quote in a new tab)

Class context: retinal vein occlusion with systemic tyrosine kinase inhibitors, including oral axitinib

“Three patients were on imatinib, five patients on axitinib, two on ibrutinib, and one patient on regorafenib.” (opens the source at this quote in a new tab)
“This series highlights a possible association between TKI therapy and RVO, underscoring the need for awareness in patients with vascular risk factors.” (opens the source at this quote in a new tab)

Age range studied

Study	Quoted criterion
SOL-1	“50 Years and older (Adult, Older Adult )”

“Ages Eligible for Study 50 Years and older (Adult, Older Adult )” (opens the source at this quote in a new tab)

“50 Years to 100 Years (Adult, Older Adult )” (opens the source at this quote in a new tab)

Age of randomized participants in SOL-1

“Age, years, mean (SD) 75.7 (8.3) 76.3 (7.4)” (opens the source at this quote in a new tab)

Pregnancy, breastfeeding, and contraception: SOL-X exclusion criterion

“Female participants who are pregnant (had a positive urine test at the Baseline visit [Day 1]) or breastfeeding or intend to become pregnant during the study, who are unwilling to use 2 forms of highly effective contraception from baseline until they exit the study or at least 3 months after the last study treatment, whichever is later.” (opens the source at this quote in a new tab)

Contraception in the Australian phase 1 trial

“Are female who is postmenopausal for at least 12 months prior to screening or surgically sterile; or male or female of childbearing potential willing to use two forms of adequate contraception” (opens the source at this quote in a new tab)

Monocular patients and fellow-eye vision: exclusion criteria

“Monocular subjects or a Best Corrected Visual Acuity (BCVA) score of 20/200 in fellow eye at screening.” (opens the source at this quote in a new tab)

Advanced lesions with scar, fibrosis, or atrophy: exclusion criterion

“Have evidence of a scar, fibrosis, or atrophy of > 50% of the total lesion in the study eye.” (opens the source at this quote in a new tab)

Prior intraocular inflammation: SOL-X exclusion criterion

“History of intraocular inflammation in the study eye” (opens the source at this quote in a new tab)

Pediatric use, renal or hepatic impairment, and lactation data for the implant

No evidence found.

Clinical drug interaction studies with the intravitreal implant

No evidence found.

Systemic exposure after intravitreal administration as context for interaction potential

“Plasma levels of the active drug, axitinib, were below the limit of quantification at all doses, indicating that systemic exposure to intravitreal delivery of axitinib by AXPAXLI up to 600 μg was negligible.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) with strong CYP3A4/5 inhibitors

“Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) with strong CYP3A4/5 inducers

“Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) pH-dependent solubility

“Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility.” (opens the source at this quote in a new tab)

Clinical drug interaction studies with the intravitreal implant

No evidence found.

Class context: oral axitinib (INLYTA) effects on CYP enzymes and transporters

“In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.” (opens the source at this quote in a new tab)
“Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, INLYTA is not expected to inhibit P-gp at therapeutic plasma concentrations.” (opens the source at this quote in a new tab)

Preclinical systemic exposure with repeat intravitreal dosing

“Plasma samples revealed minimal to no systemic axitinib exposure over the study duration” (opens the source at this quote in a new tab)

SOL-1: single dose after aflibercept loading, with redosing at Weeks 52 and 76

“Subjects who achieve best corrected visual acuity (BCVA) of 20/20 at Day 1 (baseline) or gain at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at Day 1 along with a CSFT of ≤350 μm were then randomized to receive a single dose of AXPAXLI (0.45 mg) or a single dose of aflibercept (2 mg). At Week 52 and at Week 76, all subjects are re-dosed with their respective initial treatment of AXPAXLI (0.45 mg) or aflibercept (2 mg).” (opens the source at this quote in a new tab)

SOL-R: dosing every 24 weeks

“Subjects in the first arm of the SOL-R trial received a single dose of AXPAXLI 450 μg at Day 1 and are re-dosed with AXPAXLI 450 μg at Weeks 24, 48, and 72.” (opens the source at this quote in a new tab)

SOL-X: long-term dosing every 24 weeks

“According to the trial design, all subjects will be given AXPAXLI every 24 weeks, starting at Day 1 (after completion of the Week 104 visit in SOL-1, or Week 96 visit in SOL-R), and again at Weeks 24, 48, 72, 96, and 120.” (opens the source at this quote in a new tab)

U.S. phase 1 trial: single 600 µg first-generation implant with one aflibercept injection

“The U.S.-based Phase 1 clinical trial is a prospective, multi-center, randomized, controlled study in subjects previously treated with anti-VEGF therapy that is evaluating a 600 μg dose of OTX-TKI in a single implant, with a 2 mg aflibercept injection four weeks after the implant, compared to 2 mg aflibercept injections administered every 8 weeks.” (opens the source at this quote in a new tab)

Redosing interval informed by bioresorption and disease reactivation

“Four subjects received rescue therapy for the first time at Month 12, indicating the waning of OTX-TKI’s therapeutic effect and potential disease reactivation, which helps establish a re-dosing timeline for patients.” (opens the source at this quote in a new tab)

“Terminal drug release at bioresorption creates a flexible redosing period” (opens the source at this quote in a new tab)

Proposed labeled dose, dosing interval, and dose modification

No evidence found.

Route: intravitreal injection

“Experimental: OTX-TKI (axitinib implant) Drug: OTX-TKI (axitinib implant) Intravitreal Injection of OTX-TKI (axitinib implant)” (opens the source at this quote in a new tab)

Needle gauge and applicator

“Familiar IVT injection with 25g needle” (opens the source at this quote in a new tab)

Administration by a healthcare professional

“Our hydrogel implants and inserts are placed by a healthcare professional and are designed to provide local programmed-release of drug to the ocular surface, intracameral space or intravitreal space.” (opens the source at this quote in a new tab)

Injection site in preclinical studies

“Inferior-temporal injection” (opens the source at this quote in a new tab)

Monitoring the implant after injection

“It has also been observed in the trial that the hydrogels were able to be adequately monitored and that there was limited to no movement of the hydrogel and no migration into the anterior chamber has occurred.” (opens the source at this quote in a new tab)

Visit schedule in the long-term extension

“Subjects are assessed at Week 4, Week 12, and then every 12 weeks thereafter. Additional visits can be conducted with supplemental anti-VEGF injection administered based on investigator discretion.” (opens the source at this quote in a new tab)

Aseptic technique, pre-injection preparation, and post-injection monitoring instructions

No evidence found.

Current access through clinical trials

“Subjects who have completed their two-year follow-up in either SOL-1 or SOL-R have an opportunity to enroll in the SOL-X study for an additional three years.” (opens the source at this quote in a new tab)

Manufacturing

“We have a single-site manufacturing facility for DEXTENZA, and we have a separate single-site manufacturing facility for product candidates that we use in our clinical trials and other research and development activities, including AXPAXLI.” (opens the source at this quote in a new tab)
“For example, we depend on a sole source supplier for the supply of our PEG.” (opens the source at this quote in a new tab)

Commercial readiness and payer engagement

“Ocular's payer team has also engaged 100% of Tier 1 Medicare Advantage and commercial payers, who have indicated that a label demonstrating superior durability could command premium pricing.” (opens the source at this quote in a new tab)

Commercial field and reimbursement team

“~50-person Field Team” (opens the source at this quote in a new tab)
“~15-person Reimbursement Team” (opens the source at this quote in a new tab)

Reimbursement risk stated by the sponsor

“For instance, if DEXTENZA ceases to be eligible for reimbursement separate from ophthalmic surgery in the ambulatory surgical center setting or if we are not able to achieve the pricing and reimbursement coverage we anticipate for AXPAXLI, if approved, our net product revenues would be impacted significantly” (opens the source at this quote in a new tab)

Patent protection

“AXPAXLI (axitinib intravitreal hydrogel) We own an issued patent in the United States that covers this product candidate, with a current expiration date in 2044 as well as corresponding pending U.S. and foreign counterpart applications, together with other issued patents in the United States and patents in certain foreign jurisdictions that cover this product candidate, with current expiration dates in 2041, as well as corresponding pending U.S. and foreign counterpart applications.” (opens the source at this quote in a new tab)

Expanded access program, HCPCS code, distribution channel, and REMS

No evidence found.

Coverage restrictions on anti-VEGF agents in United States commercial and Medicare Advantage plans

“A recent assessment of US commercial and MA health plans as of 2024 revealed substantial heterogeneity in coverage restrictions for these agents, including requirements for step therapy protocols, prescriber type, and patient subgroup criteria, with approximately 65% of commercial plans imposing restrictions beyond US Food and Drug Administration labeling.” (opens the source at this quote in a new tab)
“Notably, some plans excluded coverage for specific agents, such as brolucizumab, and varying reauthorization criteria further complicate access.” (opens the source at this quote in a new tab)
“These payer-driven differences likely reinforce the geographic disparities observed in Medicare utilization patterns in 2023.” (opens the source at this quote in a new tab)

SOL-1: aflibercept loading doses before randomization

“Under the study protocol, after initial screening, every enrolled subject received two aflibercept 2 mg loading doses between the screening visit and Day 1: one at Week -8 and another at Week -4.” (opens the source at this quote in a new tab)

SOL-1: supplemental aflibercept rescue

“Our pre-specified rescue criteria are a loss of 15 or more letters on the ETDRS chart compared to baseline due to wet AMD, or a new hemorrhage that is deemed to be likely to cause irreversible vision loss due to progression of wet AMD.” (opens the source at this quote in a new tab)

“The protocol provides that after the first rescue injection, rescue therapy may be provided at investigator discretion per their clinical judgement.” (opens the source at this quote in a new tab)

SOL-R: anti-VEGF screening doses, aflibercept loading, and rescue criteria

“Over the six month screening and lead-in period prior to Baseline (Day 1) randomization, enrolled subjects were given three screening doses of any anti-VEGF therapy, excluding brolucizumab-dbll, and two monthly loading doses of aflibercept 2 mg prior to Day 1, and monitored to exclude subjects demonstrating early persistent fluid or significant retinal fluid fluctuations.” (opens the source at this quote in a new tab)

“The pre-specified rescue criteria include a loss of more than 5 ETDRS letters in BCVA from best recorded prior visit (baseline or later) due to wet AMD, combined with an increase of 75 microns or more in CSFT from prior lowest measurement (baseline or later) due to wet AMD.” (opens the source at this quote in a new tab)

Phase 1 trials: concomitant anti-VEGF injection

“Experimental: Cohort 3 (Anti-VEGF) Subjects will receive OTX-TKI plus a single anti-VEGF injection” (opens the source at this quote in a new tab)

U.S. phase 1 trial: prior anti-VEGF treatment requirement

“Must have received at least 3 anti-VEGF injections in the past year.” (opens the source at this quote in a new tab)

Topical corticosteroids for intraocular inflammation in SOL-1

“8 events treated with topical corticosteroids and resolved” (opens the source at this quote in a new tab)

Prophylactic corticosteroids with implant administration

“Most importantly, retina specialists would not need to change anything about how they treat patients today – no surgery, no concomitant steroids, no new procedures.” (opens the source at this quote in a new tab)

Concomitant systemic medication use in studied participants

No evidence found.

IRIS Registry QCDR measure IRIS63: exudative AMD gain of visual acuity

“Percentage of patients with a diagnosis of exudative age-related macular degeneration, being treated with anti-VEGF agents, with a gain of 1 Snellen line or more” (opens the source at this quote in a new tab)
“Measure Type: Outcome” (opens the source at this quote in a new tab)

IRIS63 denominator: treatments counted as anti-VEGF agents

“Rate 1: All patients aged 50 years of older with a diagnosis of exudative age-related macular degeneration and documentation of laterality (OD, OS, OU) with 5 or more treatments with Anti-VEGF Agents over the reporting year.” (opens the source at this quote in a new tab)
“Ranibizumab (Lucentis®) injections (CPT: 67028 and HCPCS: J2778) Aflibercept (EYLEA®) injections (CPT: 67028 and HCPCS: J0178)” (opens the source at this quote in a new tab)

Product-specific effect on quality measures

No evidence found.

Summary

No head-to-head trial has compared the axitinib intravitreal implant with aflibercept 8 mg, faricimab, the ranibizumab port delivery system, vorolanib intravitreal insert (DURAVYU, EYP-1901), or gene therapies. The only randomized comparisons are with aflibercept 2 mg: a single implant versus a single aflibercept 2 mg injection in SOL-1 (superiority), and implant every 24 weeks versus aflibercept 2 mg every 8 weeks in SOL-R (non-inferiority, results expected in the first quarter of 2028); SOL-R also includes an aflibercept 8 mg every 24 weeks arm with a planned Week 96 superiority comparison. Approved extended-durability comparators reached approval through non-inferiority trials against aflibercept 2 mg every 8 weeks (aflibercept 8 mg in PULSAR, 1009 treated participants; faricimab in TENAYA and LUCERNE, 1329 randomized participants) or monthly ranibizumab (port delivery system in Archway, 418 participants). Labeled maintenance intervals are every 8 weeks for aflibercept 2 mg, every 8 to 16 weeks for aflibercept 8 mg (every 20 weeks may be considered after one year), up to every 16 weeks for faricimab after 4 monthly doses, and refills every 24 weeks for the port delivery system, which carries a boxed warning for endophthalmitis and requires prior response to at least two anti-VEGF injections. SOL-1 enrolled participants selected for response to two aflibercept loading doses, with mean baseline BCVA of 80.8 and 79.2 letters, whereas the comparators' pivotal trials enrolled participants with lower baseline vision; cross-trial comparisons of durability or treatment burden are therefore limited, and the sponsor's own cross-trial treatment burden table is labeled as illustrative. Among other sustained-delivery tyrosine kinase inhibitors, the phase 3 LUGANO trial of vorolanib intravitreal insert did not meet its non-inferiority primary endpoint in the full dataset (August 2026). Gene therapies surabgene lomparvovec (ABBV-RGX-314) and 4D-150 are in phase 3, with topline data expected in the fourth quarter of 2026 and in 2027, respectively. Preclinical kinase-profiling studies sponsored by the developers of axitinib and vorolanib products reached different conclusions about axitinib inhibition of TIE2.

Competitive landscape described by the sponsor

“Anti-VEGF products that are currently approved by the FDA for the treatment of wet AMD include Vabysmo (faricimab), Eylea HD (aflibercept 8 mg), Lucentis (ranibizumab), Eylea (aflibercept 2 mg), Beovu (brolicizumab), and Susvimo (ranibizumab Port Delivery System).” (opens the source at this quote in a new tab)
“In addition, there are several companies pursuing gene therapies to treat wet AMD including, 4D Molecular Therapeutics, Adverum Biotechnologies, which was acquired by Eli Lilly and Company in 2025, and RegenxBio.” (opens the source at this quote in a new tab)

Aflibercept 2 mg (EYLEA): labeled nAMD dosing

“The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).” (opens the source at this quote in a new tab)
“Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy.” (opens the source at this quote in a new tab)

Aflibercept 8 mg (EYLEA HD): labeled nAMD dosing

“The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week.” (opens the source at this quote in a new tab)
“Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: PULSAR phase 3 results at Week 48

“Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters).” (opens the source at this quote in a new tab)

Faricimab (VABYSMO): labeled nAMD dosing

“The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44.” (opens the source at this quote in a new tab)

Faricimab: TENAYA and LUCERNE phase 3 results

“BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]).” (opens the source at this quote in a new tab)

Ranibizumab port delivery system (SUSVIMO): indication, dosing, and boxed warning

“Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a VEGF inhibitor (1.1).” (opens the source at this quote in a new tab)
“The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately 6 months). (2.2)” (opens the source at this quote in a new tab)
“The SUSVIMO implant has been associated with an up to 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: Archway phase 3 results

“Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters).” (opens the source at this quote in a new tab)
“Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions.” (opens the source at this quote in a new tab)

Vorolanib intravitreal insert (DURAVYU, EYP-1901): LUGANO phase 3 topline results

“Despite the outperformance in key secondary endpoints, the primary endpoint of change from baseline in best corrected visual acuity (BCVA) versus 2 mg aflibercept on-label control was not achieved in the full dataset, confounded by this asymmetric cohort.” (opens the source at this quote in a new tab)
“54% of DURAVYU patients were supplement-free up to Week 56” (opens the source at this quote in a new tab)
“The Company anticipates potentially filing an NDA for DURAVYU for the potential treatment of wet AMD in the first half of 2027.” (opens the source at this quote in a new tab)

Suprachoroidal axitinib (CLS-AX): phase 1/2a OASIS trial

“Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST.” (opens the source at this quote in a new tab)

Axitinib-based products in development

“Several axitinib-based therapies are in development for wet AMD and other retinal diseases, including Axpaxli (also known as Ocular Therapeutix-TKI, Ocular Therapeutix), CLS-AX (Clearside Biomedical), AR-14034 (Alcon), and GLK-401 (Glaukos).” (opens the source at this quote in a new tab)

Gene therapy: surabgene lomparvovec (ABBV-RGX-314) pivotal trial timing

“REGENXBIO expects to announce topline data with AbbVie from the ATMOSPHERE® and ASCENT® pivotal trials of sura-vec using subretinal delivery in Q4 2026.” (opens the source at this quote in a new tab)

Gene therapy: 4D-150 pivotal trial timing

“Completed enrollment for 4D-150 4FRONT-2 wet AMD Phase 3; topline data expected in H2 2027” (opens the source at this quote in a new tab)

Sponsor cross-trial treatment burden comparison at approximately 1 year

Product and trial	Reduction versus aflibercept 2 mg, loading doses included	Reduction versus aflibercept 2 mg, loading doses not included
Faricimab, TENAYA/LUCERNE phase 3	“14% (6.4 vs 7.4)”	“46% (2.4 vs 4.4)”
Aflibercept 8 mg, PULSAR phase 3	“29% (5.49 vs 7.7)”	“47% (2.49 vs 4.7)”
4D-150, PRISM phase 2b	“50% (3.97 vs 8)”	“51% (2.97 vs 6)”
Axitinib intravitreal implant, SOL-1 with SOL-R rescue criteria	“56% (3.95 vs 9)”	“72% (1.95 vs 7)”

“Results intended to be illustrative as the analysis is subject to the limitations of cross-trial comparisons, including different enrollment and rescue criteria.” (opens the source at this quote in a new tab)

Baseline vision in SOL-1 compared with other nAMD phase 3 trials

“SOL-1 Evaluates a Distinct nAMD Cohort with Excellent Baseline Vision” (opens the source at this quote in a new tab)
“mean BCVA: 52 to 62 letters” (opens the source at this quote in a new tab)

Hydrogel compared with other polymer implant platforms

“Hydrogel PLA/PLGA PVA” (opens the source at this quote in a new tab)
“Redosing interval 6-12 months1 N/A 6 months3” (opens the source at this quote in a new tab)
“Vehicle persistence 8-9 months1 Months to years2 18 to 24 months4” (opens the source at this quote in a new tab)

Durability and treatment burden across sustained-delivery TKIs: independent reviews

“Out of all the drugs explored in this section, thus far, EYP 1901, OTX-TKI and CLS-AX have shown good safety but moderate durability signals on PhI/IIa studies on nAMD patients who are sub-optimal responders to standard of care.” (opens the source at this quote in a new tab)

“Tyrosine kinase inhibitors delivered via intravitreal or suprachoroidal implants (e.g. EYP-1901, OTX-TKI, and CLS-AX) show potential for twice-yearly or less frequent dosing.” (opens the source at this quote in a new tab)

Proportion of PULSAR participants maintaining extended aflibercept 8 mg intervals to week 48

“A total of 251 (79%) of 316 patients in the aflibercept 8q12 group and 239 (77%) of 312 patients in the aflibercept 8q16 group maintained their assigned dosing regimen up to week 48. Overall, 523 (83%) of 628 patients who received aflibercept 8 mg maintained at least 12-week dosing intervals up to week 48.” (opens the source at this quote in a new tab)
“The minimum interval for all patients was 8 weeks, and dosing intervals could not be extended within the first year of treatment.” (opens the source at this quote in a new tab)

Baseline vision and eligibility differences that limit cross-trial comparison with PULSAR

“the mean baseline BCVA ETDRS letter score was 59·6 (SD 13·3), approximately Snellen equivalent 20/63” (opens the source at this quote in a new tab)
“Furthermore, the PULSAR study enrolled patients with a larger total lesion size of up to 12 disc areas and required foveal involvement, whereas patient eligibility in TENAYA and LUCERNE was restricted to those with lesion sizes of up to 9 disc areas without foveal involvement.” (opens the source at this quote in a new tab)
“Differences between trials in the criteria used to implement regimen modifications, the timepoints at which dose-modification criteria were assessed, and in study populations, limit cross-trial comparisons.” (opens the source at this quote in a new tab)

Faricimab dosing-interval distribution at week 48 in TENAYA and LUCERNE

“At week 48, approximately 80% of faricimab-treated patients in both TENAYA and LUCERNE were on 12-week or 16-week dosing intervals, with 107 (34·0%) patients in TENAYA and 104 (32·9%) patients in LUCERNE on extended dosing regimens of every 12 weeks, and 144 (45·7%) patients in TENAYA and 142 (44·9%) patients in LUCERNE on 16-week dosing” (opens the source at this quote in a new tab)

Comparator choice and masking-related limits on durability comparison in the faricimab trials

“The registrational phase 3 trials of faricimab for nAMD were not designed for head-to-head comparison of faricimab’s durability versus aflibercept because extended fixed 12-week or fixed 16-week dosing regimens have not been studied in double-masked phase 3 registrational trials for aflibercept.” (opens the source at this quote in a new tab)
“Fixed 8-week aflibercept dosing, which was used in the pivotal phase 3 trials of aflibercept, was therefore the most appropriate regimen against which to evaluate noninferiority of a new treatment, especially considering the potential for extended dosing with faricimab at up to 16-week repeating intervals.” (opens the source at this quote in a new tab)
“Finally, the assessment of the potential for faricimab to reduce treatment burden and improve quality of life might also be limited by the fact that at the time of the primary analysis, all patients returned for monthly visits to maintain masking.” (opens the source at this quote in a new tab)

Injections and treatment completion over 2 years in TENAYA and LUCERNE

“Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment” (opens the source at this quote in a new tab)
“Moving to the T&E regimen during year 2 resulted in significantly fewer injections of faricimab compared with aflibercept Q8W dosing (median, 10 injections vs. 15 injections from baseline through year 2; 3 injections vs. 6 injections during the year 2 T&E phase); however, per the design of the study, aflibercept was given at fixed intervals throughout the 2-year study period.” (opens the source at this quote in a new tab)

Sustained-delivery tyrosine kinase inhibitor platforms compared: independent review

“EYP-1901 is a sustained-delivery implant that combines Durasert E with a multikinase pan-VEGF inhibitor vorolanib. The implant is designed to release vorolanib at near zero order kinetics for 9 months and to be completely bioerodible.” (opens the source at this quote in a new tab)
“Among these emerging therapies, platforms combining intravitreal sustained-release technology with pan-VEGF inhibition (eg, EYP-1901, OTX-TKI, CLS-AX) currently appear the most balanced in terms of efficacy, safety, and durability. However, the clinical value of pan-VEGF inhibition remains uncertain.” (opens the source at this quote in a new tab)
“Despite evidence suggestive of the beneficial biologic effect of X-82, the phase 2 trial was terminated early because of concerns regarding elevated liver enzyme elevations and high study discontinuation rate because of AEs.” (opens the source at this quote in a new tab)
“At this time, the sponsor has discontinued further investigation of GB-102.” (opens the source at this quote in a new tab)

Endophthalmitis risk attributed to the implantation procedure and to indwelling devices

“Review of the case details including surgical videos identified 8 cases where the surgical procedures may have contributed to the risk of developing endophthalmitis.” (opens the source at this quote in a new tab)
“A large scleral incision (>3.5 mm) resulting in an inadequate seal around the implant, may increase the risk of endophthalmitis occurring soon after the PDS surgery.” (opens the source at this quote in a new tab)
“Notably, these rates are similar to what has been observed for FA implants versus systemic therapy (1.3% vs. 0%, respectively) over 24 months in patients with noninfectious uveitis.” (opens the source at this quote in a new tab)

Vision course after implantation in Archway

“Patients treated with the PDS Q24W experienced a transient and reversible postsurgical drop of approximately 1 ETDRS line in vision after implant insertion, with vision returning to baseline by week 8.” (opens the source at this quote in a new tab)
“A similar proportion of patients in the PDS Q24W arm (80.5%) and the monthly ranibizumab arm (82.2%) showed a BCVA of 69 letters or better at the average of weeks 36 and 40 (Table S5, available at www.aaojournal.org).” (opens the source at this quote in a new tab)

AMD definition: AAO Preferred Practice Pattern

“Age-related macular degeneration (AMD) is a spectrum of disorders of the macula characterized by one or more of the following:” (opens the source at this quote in a new tab)
“Presence of at least medium-size drusen (≥ 63 μm in diameter)” (opens the source at this quote in a new tab)
“Retinal pigment epithelium (RPE) abnormalities such as hypopigmentation or hyperpigmentation” (opens the source at this quote in a new tab)
“Patients are typically aged 50 years or older, with or without visual symptoms.” (opens the source at this quote in a new tab)

AMD definition: CONAN consensus nomenclature

“A condition in patients, typically beyond 50 years of age, in which the structure and function of the macula deteriorates. A salient characteristic is the accumulation of extracellular deposits including subretinal drusenoid deposits, basal linear, and basal laminar deposit. These eyes may demonstrate neovascularization or atrophy.” (opens the source at this quote in a new tab)
“In AMD, the neovascularization may start in the outer retina, and therefore, the term choroidal neovascularization is not appropriate for the class.” (opens the source at this quote in a new tab)

Clinical classification: Beckman Initiative for Macular Research

“Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD.” (opens the source at this quote in a new tab)
“Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group.” (opens the source at this quote in a new tab)

Clinical classification: AREDS categories used by the AAO Preferred Practice Pattern

“Early AMD (AREDS category 2) is characterized by a combination of multiple small drusen, few intermediate drusen (> 63–124 μm in diameter), or mild RPE abnormalities.” (opens the source at this quote in a new tab)
“Advanced AMD (AREDS category 4) is characterized by one or more of the following (in the absence of other causes) in one eye:” (opens the source at this quote in a new tab)
“Macular neovascularization (MNV) historically referred to as CNV and includes the following:” (opens the source at this quote in a new tab)

Late-stage classification: geographic atrophy and exudative neovascular AMD

“In the late stages of AMD, 2 distinct manifestations emerge. One is the development of confluent areas of atrophy involving photoreceptors and retinal pigment epithelium, known as geographic atrophy. The other is the growth of abnormal blood vessels in the macular region, referred to as neovascular AMD.” (opens the source at this quote in a new tab)
“Neovascular AMD causes visual change when these new blood vessels leak, which may cause subretinal and intraretinal fluid accumulation, hemorrhages, and fibrosis. This condition is known as exudative neovascular AMD.” (opens the source at this quote in a new tab)

Macular neovascularization subtypes: CONAN definitions

Term	Quoted definition
Type 1 MNV	“Ingrowth of vessels initially from the choriocapillaris into and within the sub-RPE space. Leads to varying types of PEDs.”
Polypoidal choroidal vasculopathy	“A variant of type 1 MNV commonly seen in Asian persons. Indocyanine green angiography imaging shows a branching vascular network and aneurysmal dilations of varying number at the outer edge of the expanding lesion.”
Type 2 MNV	“Neovascularization that originates from the choroid that traverses Bruch’s membrane and the RPE monolayer and then proliferates in the subretinal space.”
Type 3 MNV	“Neovascularization that originates from the retinal circulation, typically the deep capillary plexus, and grows toward the outer retina.”

Macular neovascularization subtypes: AAO Preferred Practice Pattern

“Type 1 MNV: a neovascular complex located in the sub-RPE space originating from the choroid through a defect in Bruch’s membrane” (opens the source at this quote in a new tab)
“Polypoidal choroidal vasculopathy (PCV) lesions, similar to Type 1 MNV, characterized by branching vascular networks with dilated vascular elements (historically referred to as polyps)” (opens the source at this quote in a new tab)
“Type 2 MNV: a neovascular complex located in the subretinal space above the RPE originating from the choroid” (opens the source at this quote in a new tab)
“Type 3 MNV: pathologic angiogenesis originating from the deep retinal capillary plexus and extending to the outer retina (historically referred to as retinal angiomatous proliferation)” (opens the source at this quote in a new tab)

Polypoidal choroidal vasculopathy: frequency by population and presentation

“Although a minority subtype in white populations, it accounts for approximately half of MNV seen in Asia.” (opens the source at this quote in a new tab)
“In Asian persons, the typical presentation comprises isolated macular involvement, unilateral, and male preponderance, whereas in white persons, bilateral involvement, female preponderance, and the neovascular lesion originating from the peripapillary region are more common.” (opens the source at this quote in a new tab)

Type 3 neovascularization: origin and terminology

“The neovascularization in RAP may originate not only from deep retinal capillaries but also from the choroid. We therefore propose the more descriptive term "Type 3 neovascularization" for this entity to emphasize the intraretinal location of the vascular complex and distinguish this type from the two types of neovascularization previously described by J. Donald Gass in his classic text.” (opens the source at this quote in a new tab)

Distribution of neovascular subtypes at diagnosis: US single-physician cohort

“A total of 232 patients (266 eyes) fit the inclusion criteria. Mean age was 86.3 years; 67.7% of eyes (180/266) were from female patients, and 95.5% (254/266) were from white patients.” (opens the source at this quote in a new tab)
“With FA+OCT, 39.9% (106/266), 9.0% (24/266), 34.2% (91/266), and 16.9% (45/266) were type 1 (sub-retinal pigment epithelium), type 2 (subretinal), type 3 (intraretinal), and mixed neovascularization (NV), respectively.” (opens the source at this quote in a new tab)

Etiology: multifactorial disease

“AMD is a multifactorial disease related to aging, genetic susceptibility, and environmental risk factors such as cigarette smoking; it develops as a consequence of disruption of the normal homeostatic mechanisms of the retina.” (opens the source at this quote in a new tab)

“Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids).” (opens the source at this quote in a new tab)

Risk factors: AAO Preferred Practice Pattern summary

“Risk factors for the development of advanced AMD include smoking, increasing age, northern European ancestry, and genetic factors. Cigarette smoking has been identified as the primary modifiable risk factor in numerous studies on advanced AMD. It is strongly recommended to advise patients with AMD or those at risk for AMD to stop smoking. Routine genetic testing is not currently recommended.” (opens the source at this quote in a new tab)

Risk factors: age

“A meta-analysis of AMD incidence in 10 populations of White individuals from Europe, Australia, and the United States with approximately 135 000 person-years of follow-up reported that late-stage AMD was associated with an incidence of 0.3 per 1000 in those aged 55to 59 years, 5.7 per 1000 in those aged 75 to 79 years, and 36.7 per 1000 in those aged 90 years or older.” (opens the source at this quote in a new tab)

Risk factors: cigarette smoking

“Cigarette smoking is an independent risk factor for AMD” (opens the source at this quote in a new tab)
“increasing the risk of AMD by twofold to fourfold” (opens the source at this quote in a new tab)
“Smoking cessation reduces the risk of AMD, and after 20 years of cessation, the risk of AMD is similar to that in non-smokers” (opens the source at this quote in a new tab)

“In a large prospective cohort study of 61 862 women over a 12-year follow-up period, 1 case of AMD developed per 1708 person-years among women who currently smoked 25 or more cigarettes per day compared with 1 case per 3740 person-years among those who had never smoked.” (opens the source at this quote in a new tab)

Risk factors: meta-analysis of clinical risk factors for late AMD

“A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors.” (opens the source at this quote in a new tab)
“Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen.” (opens the source at this quote in a new tab)

Risk factors: heritability and major genetic loci (CFH and ARMS2-HTRA1)

“Estimated heritability of late-stage AMD is approximately 71% (estimate for additive risk, 0.71 [95% CI, 0.18-0.88] in 840 participants from a US twin study of AMD” (opens the source at this quote in a new tab)
“indicating that approximately 71% of the risk of AMD is genetic.” (opens the source at this quote in a new tab)

“Patients who are homozygous for the Y402H risk allele of CFH possess a 7.4-fold increased risk of AMD.” (opens the source at this quote in a new tab)
“Strong linkage disequilibrium has been shown across the ARMS2-HTRA1 region, and these two genes are also strongly associated with AMD.” (opens the source at this quote in a new tab)

Risk factors: genome-wide association study and a genetic signal specific to neovascular AMD

“Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants” (opens the source at this quote in a new tab)
“While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9” (opens the source at this quote in a new tab)

Risk factors: race and ancestry

“Findings from the Multi-ethnic Study of Atherosclerosis also suggest that neovascular AMD may be more common in Caucasian individuals than in African American individuals.” (opens the source at this quote in a new tab)

United States: annual incidence of neovascular AMD in White adults aged 50 years and older

“Annual incidence (estimated from prevalence) of late AMD in American whites was 3.5 per 1000 aged ≥50 years (95% credible interval 2.5, 4.7 per 1000), equivalent to 293 000 new cases in American whites per year (95% credible interval 207 000, 400 000). Incidence rates approximately quadrupled per decade in age. Annual incidence GA rates were 1.9 per 1000 aged ≥50 years, NVAMD rates were 1.8 per 1000. Late AMD incidence was 38% higher in women vs men (95% credible interval 6%, 82%).” (opens the source at this quote in a new tab)

United States: 3-year incidence of exudative AMD in Medicare beneficiaries

“Overall, the 3-year incidence of exudative AMD is estimated to be between 9.4 per 1000 and 11.4 per 1000 Americans age 65 and older (depending on ascertainment criteria), based on those diagnosed and treated by ophthalmologists for the condition.” (opens the source at this quote in a new tab)
“Women were found to have a slightly higher incidence of AMD than men using all ascertainment criteria (P < 0.001), and white Americans were found to have a fivefold-to-sixfold higher ascertainment criteria than black Americans (P < 0.001).” (opens the source at this quote in a new tab)

United States: 15-year cumulative incidence in the Beaver Dam Eye Study

“The 15-year cumulative incidence was 14.3% for early AMD (the presence of either soft indistinct drusen or the presence of pigmentary abnormalities together with any type of drusen) and 3.1% for late AMD (presence of exudative AMD or geographic atrophy).” (opens the source at this quote in a new tab)
“Individuals > or = 75 years of age at baseline had significantly (P<0.01) higher 15-year incidences of the following characteristics than people 43 to 54 years of age: larger drusen (125 mum in diameter, 24.1% vs 10.6%), soft indistinct drusen (18.7% vs 6.5%), retinal pigmentary abnormalities (20.2% vs 3.7%), exudative macular degeneration (4.4% vs 0.4%), and pure geographic atrophy (3.2% vs 0%).” (opens the source at this quote in a new tab)

United States: 8-year incidence of late AMD by race and ethnicity

“A prospective cohort study of 3811 participants aged 46 to 86 years residing in the US reported an 8-year incidence of late-stage AMD of 0.4% for people who were Black, 2.2% for people who were Chinese, 0.8% for people who were Hispanic, and 4.1% for people who were White.” (opens the source at this quote in a new tab)

United States: newly diagnosed neovascular AMD in the IRIS Registry, 2016 to 2021

“Among the 918 759 patients with nAMD (61.5% female, 82.3% White), male, Black, and Hispanic patients demonstrated nAMD at younger ages (P < 0.001).” (opens the source at this quote in a new tab)
“Overall, the mean ± standard deviation (SD) age at nAMD presentation was 80.2 ± 9.1) years.” (opens the source at this quote in a new tab)

Europe: pooled annual incidence of late AMD

“In the meta-analysis of incidence, the pooled annual incidence of any late AMD was 1.4 per 1 000 individuals (95% CI 0.8 to 2.6).” (opens the source at this quote in a new tab)
“Incident late AMD is estimated to increase from 400 000 per year today to 700 000 per year in 2050.” (opens the source at this quote in a new tab)

Progression to late AMD: AREDS simplified severity scale

“Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases in this easily remembered sequence: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%.” (opens the source at this quote in a new tab)

Progression to late AMD: updated simplified severity scale incorporating reticular pseudodrusen

“As the final Simplified Severity Scale, the five-year progression rates for levels 0–4, respectively, were 0.3%, 4.3%, 11.6%, 26.7%, and 50.0%, for participants without RPD at baseline, and 2.8%, 8.0%, 29.0%, 58.7%, and 72.2%, for participants with RPD at baseline.” (opens the source at this quote in a new tab)

Progression to neovascular AMD: AREDS eyes free of late AMD at baseline

“In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss.” (opens the source at this quote in a new tab)

Progression from early AMD in the AREDS

“Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD.” (opens the source at this quote in a new tab)

Fellow-eye conversion: AAO Preferred Practice Pattern summary

“In the AREDS, the risk of progression for patients with advanced AMD in one eye to an advanced stage in the fellow eye ranged from 35% to 50% at 5 years, depending largely on the phenotype in the better eye.” (opens the source at this quote in a new tab)

Fellow-eye conversion: CATT participants receiving anti-VEGF therapy

“Among 1185 CATT participants, 727 (61%) had no CNV in the fellow eye at enrollment. At two years, CNV had developed in 75 (20.6%) of 365 patients treated with ranibizumab and 60 (16.6%) of 362 patients treated with bevacizumab (absolute difference 4.0%, 95% confidence interval (−1.7%, 9.6%); p=0.17).” (opens the source at this quote in a new tab)
“Incidence was not associated with genotype on rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3) (p > 0.35).” (opens the source at this quote in a new tab)

Fellow-eye conversion: UK National Health Service database

“When fellow eyes with baseline VA worse than 20/200 were excluded to restrict analyses to eyes at risk of nAMD, the rate of second-eye involvement was 14.0% per year (42%/3 years).” (opens the source at this quote in a new tab)

Fellow-eye conversion: Fight Retinal Blindness! registry

“The cumulative incidence of second eye involvement was 54% over 5 years.” (opens the source at this quote in a new tab)

Fellow-eye conversion: untreated neovascular AMD

“Neovascular AMD developed in the fellow eye in 12.2% of patients by 12 months and in 26.8% by 4 years.” (opens the source at this quote in a new tab)

United States: annual incidence of neovascular AMD in White adults aged 65 years and older and 80 years and older

“In those aged 65 years and older the annual incidence rate for late AMD is 7.8 per 1000 (95% credible interval 5.5, 10.6), 4.3 per 1000 for GA (95% credible interval 2.9, 6.2), and 3.9 per 1000 for NVAMD (95% credible interval 2.7, 5.5).” (opens the source at this quote in a new tab)
“In those aged 80 years and older the annual incidence rates per 1000 are 19.4 (95% credible interval 13.8, 26.2), 10.9 (95% credible interval 7.2, 16.1), and 9.9 (95% credible interval 6.8, 14.0), respectively.” (opens the source at this quote in a new tab)
“This corresponds to approximately 293 000 new cases of late AMD each year (95% credible interval 207 000, 400 000), and 160 000 (95% credible interval 107 000, 234 000) and 148 000 (95% credible interval 103 000, 207 000) for GA and NVAMD, respectively.” (opens the source at this quote in a new tab)

United States: late AMD and neovascular AMD incidence rates in women compared with men

“For all age groups (except the youngest), women have a slightly higher annual incidence rate of late AMD (4 per 1000, 95% credible interval 2.3, 6.6) than men (2.4 per 1000, 95% credible interval 1.4, 4.2; Table 3).” (opens the source at this quote in a new tab)
“In those aged 65 years and older the incidence rates of NVAMD within each 5-year age group are higher in women than in men.” (opens the source at this quote in a new tab)
“Under 70 years of age the number of incident cases is similar in men and women.” (opens the source at this quote in a new tab)

United States: rate of increase in late AMD incidence per decade of age by estimation method

“A meta-analysis of incidence studies showed that the incidence rate for late AMD triples per decade increase in age (rate ratio 2.9; 95% credible interval 2.6, 3.2, Table 2).” (opens the source at this quote in a new tab)
“In proportionate terms, annual incidence rates from prevalent studies suggest a quadrupling in risk per decade, whereas the meta-analysis of incidence studies suggests a tripling.” (opens the source at this quote in a new tab)
“Although late AMD incidence increases log-linearly with age, the absolute number of incident cases of late AMD decreases beyond the age of about 85 years because of increased mortality.” (opens the source at this quote in a new tab)

United States: 3-year incidence of exudative AMD in Medicare beneficiaries by ascertainment criterion

“As shown in Table 4, the 3-year estimated incidence of exudative macular degeneration in the Medicare population ranges from 0.37% (95% confidence interval [CI], 0.35, 0.38) to 1.14% (95% CI, 1.12, 1.16), depending on the ascertainment criteria chosen.” (opens the source at this quote in a new tab)
“Extrapolating from the published report, the 5-year incidence of exudative AMD in persons aged 65 and older is 1.48% (95% CI, 0.80%, 2.16%).” (opens the source at this quote in a new tab)

United States: person-level rather than eye-level counting in the Medicare incidence estimate

“In this study, we have attempted to measure the 3-year per-person incidence, as opposed to the per-eye incidence of exudative AMD.” (opens the source at this quote in a new tab)
“The lack of information on laterality in the Medicare database makes it impossible to estimate the incidence of exudative AMD per eye.” (opens the source at this quote in a new tab)

United States: age gradient and coverage limits of the Medicare claims-based estimate

“As shown in Figure 2, the incidence of exudative AMD increases linearly with age, but seems to level off at the oldest age group. There is no biological basis to suggest a decrease in true incidence.” (opens the source at this quote in a new tab)
“Approximately 20% of Medicare beneficiaries aged 65 to 74 years and 18% of beneficiaries aged 75 to 85 years join Medicare HMOs.” (opens the source at this quote in a new tab)

United States: prevalence of early and late AMD in 2019

“For 2019, we estimated that there were 18.34 million people 40 years and older (95% uncertainty interval [UI], 15.30-22.03) living with early-stage AMD, corresponding to a crude prevalence rate of 11.64% (95% UI, 9.71-13.98). We estimated there were 1.49 million people 40 years and older (95% UI, 0.97-2.15) living with late-stage AMD, corresponding to a crude prevalence rate of 0.94% (95% UI, 0.62-1.36).” (opens the source at this quote in a new tab)
“Prevalence of late-stage AMD increased with age from 0.02% (95% UI, 0.01-0.05) among those 40 to 44 years (Figure 3) to 11.39% (95% UI, 6.45-18.46) among people 85 years or older.” (opens the source at this quote in a new tab)
“The gender- and age-standardized rate of late AMD for non-Hispanic White individuals 40 years and older was 1.03% (95% UI, 0.65-1.52).” (opens the source at this quote in a new tab)

United States: late AMD definition used in 2019 prevalence estimates

“late-stage (defined as choroidal neovascularization and/or geographic atrophy in either eye) manifestations of AMD.” (opens the source at this quote in a new tab)

United States: prevalence in 2000 and projection to 2020

“The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy.” (opens the source at this quote in a new tab)
“Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020.” (opens the source at this quote in a new tab)

United States: NHANES 2005 to 2008

“In the civilian, noninstitutionalized, US population aged 40 years and older, the estimated prevalence of any AMD was 6.5% (95% confidence interval, 5.5-7.6) and the estimated prevalence of late AMD was 0.8% (95% confidence interval, 0.5-1.3).” (opens the source at this quote in a new tab)

United States: projection to 2050 and share of AMD that is neovascular

“Aging is the greatest risk factor; therefore, the prevalence of AMD in the United States is anticipated to increase to 22 million by the year 2050, whereas the global prevalence is expected to increase to 288 million by the year 2040.” (opens the source at this quote in a new tab)
“Although an estimated 80% of patients with age-related macular degeneration (AMD) have non-neovascular or atrophic AMD, the neovascular form is responsible for most of the severe vision loss associated with AMD.” (opens the source at this quote in a new tab)

Global: pooled prevalence and projections to 2040

“Analysis of 129,664 individuals (aged 30-97 years), with 12,727 cases from 39 studies, showed the pooled prevalence (mapped to an age range of 45-85 years) of early, late, and any age-related macular degeneration to be 8.01% (95% CrI 3.98-15.49), 0.37% (0.18-0.77), and 8.69% (4.26-17.40), respectively.” (opens the source at this quote in a new tab)
“The projected number of people with age-related macular degeneration in 2020 is 196 million (95% CrI 140-261), increasing to 288 million in 2040 (205-399).” (opens the source at this quote in a new tab)

Global: prevalence by ancestry

“The pooled prevalence of any AMD is approximately 8.69% (95% credible interval [CrI], 4.26-17.40) in persons aged 45 to 85 years, with a prevalence in people who are of European origin of 12.33% (95% CrI, 6.46-22.75), 10.43% (95% CrI, 5.27-20.01) in people who are of Hispanic origin, 7.53% (95% CrI, 3.80-14.89) in people who are of African origin, and 7.38% (95% CrI, 3.80-14.89) in people who are of Asian origin.” (opens the source at this quote in a new tab)

Europe: pooled prevalence in adults aged 60 years and older

“Our pooled prevalence estimate of early or intermediate AMD and any late AMD in those 60 years and older was 25.3% (95% CI 18.0% to 34.4%) and 2.4% (95% CI 1.8% to 3.3%), respectively.” (opens the source at this quote in a new tab)

Global: prevalence of vision impairment due to AMD, 1990 to 2021, with forecasts to 2050

“Globally, the number of individuals with vision impairment due to AMD more than doubled, rising from 3·64 million (95% uncertainty inverval [UI] 3·04-4·35) in 1990 to 8·06 million (6·71-9·82) in 2021.” (opens the source at this quote in a new tab)
“The burden of vision impairment due to AMD is projected to increase to about 21·34 million in 2050.” (opens the source at this quote in a new tab)

Untreated neovascular AMD: systematic review and meta-analysis of visual acuity loss

“Four thousand three hundred sixty-two untreated neovascular AMD patients from published interventional studies.” (opens the source at this quote in a new tab)
“The mean VA change in logMAR progressed from 0.1 (1 line lost) at 3 months to 0.3 (2.7 lines lost) after 12 months and 0.4 (4 lines lost) after 24 months. The proportion of patients who developed severe vision loss (>6 lines) from baseline increased from 21.3% at 6 months to 41.9% by 3 years. The proportion of patients with VA worse than logMAR 1.0 (20/200 Snellen) increased from 19.7% at baseline to 75.7% by 3 years.” (opens the source at this quote in a new tab)
“A doubling of the visual angle of presenting VA may be expected to occur in the year after initial presentation in eyes with untreated neovascular AMD.” (opens the source at this quote in a new tab)

Untreated neovascular AMD: MARINA sham-injection arm

“Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons).” (opens the source at this quote in a new tab)
“At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons).” (opens the source at this quote in a new tab)

Untreated neovascular AMD: severe vision loss in the MARINA sham-injection arm through 24 months

“At 12 months, very few patients receiving ranibizumab had severe vision loss (30 letters or more) from baseline (0.8% of the 0.3-mg ranibizumab group and 1.2% of the 0.5-mg ranibizumab group compared with 14.3% of the sham-injection group); at 24 months, 3.4% of the 0.3-mg ranibizumab group and 2.5% of the 0.5-mg ranibizumab group had severe vision loss compared with 22.7% of the sham injection group” (opens the source at this quote in a new tab)

Untreated neovascular AMD: VISION sham-injection arm

“In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001).” (opens the source at this quote in a new tab)

Neovascular AMD without anti-VEGF therapy: ANCHOR verteporfin photodynamic therapy arm

“Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P<0.001 for each comparison).” (opens the source at this quote in a new tab)

End stage of untreated exudative disease: fibrosis and disciform scar

“Without treatment, exudative MNV typically results in extensive fibrosis with severe central vision loss.” (opens the source at this quote in a new tab)

“Disciform scar: Subretinal fibrovascular tissue that usually becomes more fibrous within a few years and that is often the end result of CNV.” (opens the source at this quote in a new tab)
“the neovascular form is responsible for nearly 90% of the severe VA loss (20/200 or worse) from AMD because of its natural history.” (opens the source at this quote in a new tab)

Natural history before neovascularization: 5-year and 10-year risk by simplified severity score

“The following scores enable the clinician to communicate with the patient about the approximate 5-year risk for developing advanced AMD: four factors, 45%; three factors, 26%; two factors, 9%; one factor, 4%; and zero factors, 0.5%. The approximate 10-year risks were 71%, 53%, 28%, 8%, and 1.5%, respectively.” (opens the source at this quote in a new tab)
“Advanced AMD in one eye is counted as two risk factors.” (opens the source at this quote in a new tab)

Nonexudative macular neovascularization preceding exudation

“found OCT evidence of neovascularization in 88% of eyes before the development of exudation, with conversion occurring up to 35.5 months after initial entry in the study.” (opens the source at this quote in a new tab)

Mortality: systematic review and meta-analysis (10 studies)

“Late AMD was associated with elevated rates of all-cause (nine studies, hazard ratio (HR) 1.20, 95% confidence interval, CI, 1.02-1.41) and cardiovascular mortality (six studies, HR 1.46, 95% CI 1.13-1.98), but early AMD was not (all-cause mortality, 10 studies, HR 1.06, 95% CI 0.98-1.14; cardiovascular mortality, five studies, HR 1.12, 95% CI 0.96-1.31).” (opens the source at this quote in a new tab)

Mortality: meta-analysis of 13 population-based cohort studies

“The risk of all-cause mortality and cardiovascular mortality associated with early AMD were 1.08 (1.00-1.18) and 1.05 (0.89-1.24), and the associations with late AMD were 1.23 (1.11-1.36) and 1.28 (1.04-1.57), respectively.” (opens the source at this quote in a new tab)

Mortality: neovascular AMD and anti-VEGF therapy in AREDS2

“During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared to participants with no or few drusen (hazard ratio [HR] 1.56, 95% confidence interval [CI], 1.21–2.01; p-value [p]<0.001).” (opens the source at this quote in a new tab)
“Participants who received anti-vascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR: 0.71, 95% CI 0.57–0.88; p=0.002).” (opens the source at this quote in a new tab)

Mortality: advanced AMD in the AREDS

“During median follow-up of 6.5 years, 534 (11%) of 4753 AREDS participants died. In fully adjusted models, participants with advanced age-related macular degeneration (AMD) compared with participants with few, if any, drusen had increased mortality (relative risk [RR], 1.41; 95% confidence interval [CI], 1.08-1.86). Advanced AMD was associated with cardiovascular deaths.” (opens the source at this quote in a new tab)

Retinal structures affected in AMD

“In AMD, important neural, structural, and vascular layers undergo degenerative changes leading to cell death. These include the photoreceptors, which are specialized neurons that convert light into electrical signals that are processed in the visual cortex to form images; the retinal pigment epithelium, a cell layer that is adjacent to the photoreceptors; the Bruch membrane, a collagenous layer that supports and separates the retinal pigment epithelium from the choroid; and the choriocapillaris, which is a fine meshwork of capillaries located in the innermost aspect of the choroid.” (opens the source at this quote in a new tab)

Drusen formation: aging, inflammation, lipid deposition, and oxidative stress

“These aging-related alterations, combined with chronic inflammation, altered lipid and lipoprotein deposition, increased oxidative stress, and impaired extracellular matrix maintenance, lead to extracellular deposits in the neurosensory retina, retinal pigment epithelium, and Bruch membrane” (opens the source at this quote in a new tab)

VEGF-A and VEGFR2 signaling in neovascularization

“Neovascularization is thought to be induced by increased expression of hypoxia-driven vascular endothelial growth factor A (VEGF-A), which is released in response to stimuli such as oxidative stress and complement activation.” (opens the source at this quote in a new tab)
“VEGF promotes angiogenesis by binding to its receptor VEGFR2 and activating downstream pathways that promote endothelial cell proliferation.” (opens the source at this quote in a new tab)

VEGF expression in surgically excised choroidal neovascular membranes

“Surgically removed subfoveal fibrovascular membranes from 18 eyes were analyzed for the expression of VEGF mRNA and protein using in situ hybridization and immunohistochemistry, respectively.” (opens the source at this quote in a new tab)
“Most specimens expressed both VEGF mRNA and protein.” (opens the source at this quote in a new tab)
“Results indicate that VEGF may be of pathogenetic importance for the development of the choroidal neovascularization (age-related macular degeneration)” (opens the source at this quote in a new tab)

“All three choroidal neovascular membranes and all seven epiretinal membranes stained positive for vascular endothelial growth factor.” (opens the source at this quote in a new tab)
“Because expression of some growth factors is stimulated by hypoxia, their localization within choroidal neovascular membranes suggests that hypoxia may be an etiologic factor for choroidal as well as for retinal neovascularization.” (opens the source at this quote in a new tab)

Signaling model: oxidized lipoprotein debris, RPE-derived VEGF, and choroidal endothelial activation

“One predominant component of oxidized lipoprotein debris that accumulates in BrM in neovascular AMD is 7-ketocholesterol, which can induce angiogenesis” (opens the source at this quote in a new tab)
“7-Ketocholesterol is thought to activate microglia to release cytokines, such as TNF, which mediates VEGF expression in RPE cells and its release preferentially from the basal aspects” (opens the source at this quote in a new tab)
“Furthermore, the generated ROS presumably also diminish the RPE barrier integrity and permit secreted VEGF entry into the retina, which promotes choroidal endothelial cell migration, proliferation and eventually MNV formation” (opens the source at this quote in a new tab)

Transition from nonexudative to exudative MNV: PDGF, angiopoietin, and VEGF signaling

“The conversion of non-exudative MNV to exudative MNV is likely to be a major disease transition point in neovascular AMD. Signalling pathways that contribute to this transition may include alterations in MNV pericyte coverage (as potentially regulated by PDGF and TIE2–ANG1 signalling)” (opens the source at this quote in a new tab)
“changes in the local balance of vascular trophic factors (such as VEGF and PEDF)” (opens the source at this quote in a new tab)
“or modulation of complement function” (opens the source at this quote in a new tab)

PDGF-mediated pericyte stabilization and combined VEGF and PDGF receptor inhibition in vitro

“Platelet-derived growth factor (PDGF) signaling is pivotal to pericyte-induced stabilization of choroidal neovascularizations (CNV), and causes partial anti-VEGF resistance.” (opens the source at this quote in a new tab)
“Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro.” (opens the source at this quote in a new tab)

Exudation: leakage, fluid, and breakdown of the blood-retinal barrier

“However, in many eyes, increased intralesional hydrostatic pressure coupled with breakdown of the outer blood–retinal barrier leads to exudation into the subretinal space. Intraretinal fluid accumulation may occur in conjunction with breakdown of the external limiting membrane, or VEGF expression may induce intraretinal leakage independently.” (opens the source at this quote in a new tab)

Fibrosis: wound-healing response and the VEGF to connective tissue growth factor balance

“Fibrosis is a part of the wound-healing response” (opens the source at this quote in a new tab)
“that results from numerous cytokines and factors such as transforming growth factor β1, pigment epithelial growth factor, and connective tissue growth factor.” (opens the source at this quote in a new tab)
“Higher levels of VEGF in relation to connective tissue growth factor may promote vascular growth, whereas decreases in the ratio may lead to increased fibrosis, scarring, and contracture of that tissue.” (opens the source at this quote in a new tab)

Complement dysregulation: CFH Y402H

“The CFH gene product is involved in regulation of the complement system through binding to factor C3b.” (opens the source at this quote in a new tab)
“An alteration of regulation that occurs from modification at the C3b site leads to a defective regulation of the alternative complement pathway and results in an up-regulation of inflammation to host cells that are mediated by the membrane attack complex.” (opens the source at this quote in a new tab)

Causes of vision loss in neovascular AMD: leakage, hemorrhage, fibrosis, and atrophy

“The main causes of vision loss in neovascular AMD include those directly related to the new vessels such as leakage, hemorrhage, and fibrosis. Another important cause of vision loss, particularly in treated cases, is atrophy.” (opens the source at this quote in a new tab)
“In the Age-Related Eye Disease Study 2, 40% of patients demonstrating MNV also showed atrophy at baseline.” (opens the source at this quote in a new tab)

Pericyte recruitment and anti-VEGF resistance in choroidal neovascularization

“While VEGF mainly regulates endothelial cells, PDGF signaling is crucial for cells of the vascular wall, i.e., pericytes and smooth muscle cells” (opens the source at this quote in a new tab)
“Pericytes migrate along a PDGF gradient towards neovessels, proliferate, and associate with the endothelial tubes, leading to vascular stabilization via physical contact, VEGF, and the Ang1/Tie2 system” (opens the source at this quote in a new tab)
“However, PDGF-recruited pericytes are known to support endothelial cells with paracrine VEGF and other pro-survival factors which cannot be complexed as effectively by current anti-VEGF agents” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: history and examination

“Metamorphopsia” (opens the source at this quote in a new tab)
“Decreased vision” (opens the source at this quote in a new tab)
“Scotoma” (opens the source at this quote in a new tab)
“Photopsia” (opens the source at this quote in a new tab)
“Difficulties in dark adaptation” (opens the source at this quote in a new tab)
“Binocular slit-lamp biomicroscopy of the ocular fundus is often necessary to detect subtle clinical signs of MNV. These include small areas of hemorrhage, hard exudates, subretinal fluid, macular edema, subretinal fibrosis, or pigment epithelial elevation.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: optical coherence tomography

“Optical coherence tomography defines the cross-sectional architecture of the retina, which is not possible with any other imaging technology. It may reveal the presence of fluid that is not apparent on biomicroscopy alone.” (opens the source at this quote in a new tab)
“Newer-generation OCT modalities, including SD-OCT and swept-source (SS) OCT, are preferred technologies.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: optical coherence tomography angiography

“Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality that provides evaluation of the retinal and choroidal vasculature; it is becoming more commonly applied in the evaluation and management of AMD, but it has not replaced other angiographic methods.” (opens the source at this quote in a new tab)
“A meta-analysis of OCTA for detection of MNV revealed a sensitivity of 0.87 and specificity of 0.97.” (opens the source at this quote in a new tab)
“Optical coherence tomography angiography may detect subclinical MNV, which needs close monitoring and not treatment.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: fluorescein angiography indications and risks

“To detect the presence of and determine the extent, type, size, and location of MNV.” (opens the source at this quote in a new tab)
“The role and indications for fluorescein angiography are evolving as continued advances in OCT occur.” (opens the source at this quote in a new tab)
“Even death from anaphylaxis has been reported (approximately 1 in 200,000 patients).” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: indocyanine green angiography for polypoidal choroidal vasculopathy

“Indocyanine green angiography has been shown to be useful in evaluating specific forms of AMD, such as PED, poorly defined MNV, occult MNV, and lesions including retinal angiomatous proliferation or idiopathic PCV.” (opens the source at this quote in a new tab)
“An indocyanine green (ICG) angiogram is often useful in confirming the diagnosis. Multicolor fundus imaging and optical coherence tomography (OCT) can be used to detect some PCV cases as well.” (opens the source at this quote in a new tab)

Imaging modalities for diagnosis and management

Imaging modality	Quoted considerations
Optical coherence tomography	“Most suitable for monitoring treatment effects in exudative neovascular AMD”
Fluorescein angiography	“Gold standard for assessing exudative neovascular AMD due to visualization of dye leakage”
Fluorescein angiography	“Invasive with intravenous dye injection and risk of anaphylaxis”
Optical coherence tomography angiography	“Noninvasive and a potential replacement for fluorescein angiography in detecting neovascular AMD”

Sensitivity and specificity of monitoring tests for exudative neovascular AMD in fellow eyes

Diagnostic test	Quoted sensitivity and specificity, % (95% CI)
Self-reported vision changes	“Sensitivity: 4.2 (1.6-9.8); specificity: 97.0 (94.6-98.5)”
Amsler chart	“Sensitivity: 33.7 (25.1-43.5); specificity: 81.4 (76.4-85.5)”
Visual acuity	“Sensitivity: 30.0 (22.5-38.7); specificity: 66.3 (61.0-71.1)”
Biomicroscopic examination	“Sensitivity: 53.8 (44.8-62.5); specificity: 97.6 (95.3-98.9)”
Optical coherence tomography	“Sensitivity: 91.7 (85.2-95.6); specificity: 87.8 (83.8-90.9)”

Optical coherence tomography versus fluorescein angiography: systematic review

“Twenty-two studies (2 abstracts and 20 articles) enrolling 2124 participants were identified” (opens the source at this quote in a new tab)
“In a meta-analysis of TD-OCT studies, sensitivity and specificity (95% CI) were 88% (46-98%) and 78% (64-88%), respectively.” (opens the source at this quote in a new tab)
“Diagnosis of nAMD should not rely solely on OCT.” (opens the source at this quote in a new tab)

Optical coherence tomography angiography versus fluorescein angiography: meta-analyses

“The total population included in the meta-analysis comprised 553 eyes, with a cumulative sensitivity and specificity of 85.9% (95% CI 81.9-89.3%) and 89% (95% CI 83.5-93.2%), respectively” (opens the source at this quote in a new tab)
“The evidence obtained does not demonstrate the superiority of OCTA over FA.” (opens the source at this quote in a new tab)

“We found a pooled sensitivity of 0.90 (95% confidence intervals (CIs): 0.82-0.95) and a pooled specificity of 0.97 (95% CI: 0.89-0.99).” (opens the source at this quote in a new tab)

Detection of new-onset MNV in high-risk fellow eyes: AMD DOC study

“The sensitivity of each modality for detecting CNV was: OCT 0.40 (95% confidence interval [CI], 0.16-0.68), supervised Amsler grid 0.42 (95% CI, 0.15-0.72), and PHP 0.50 (95% CI, 0.23-0.77).” (opens the source at this quote in a new tab)
“Among fellow eyes of individuals with unilateral CNV, FA remains the best method to detect new-onset CNV.” (opens the source at this quote in a new tab)

Home monitoring for earlier detection: HOME study

“Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013.” (opens the source at this quote in a new tab)
“The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: self-monitoring and prompt evaluation of new symptoms

“Patients with a high-risk AMD phenotype are at increased risk of progression to advanced AMD and should be educated about methods of detecting new symptoms of MNV, including self-monitoring.” (opens the source at this quote in a new tab)
“Electronic monitoring devices are now available to aid in the detection of neovascularization at an early stage.” (opens the source at this quote in a new tab)

Polypoidal choroidal vasculopathy: OCT-based diagnostic criteria without indocyanine green angiography

“For the diagnosis of PCV, the combination of 3 OCT-based major criteria (sub-retinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation, and sharp-peaked PED) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset 80 eyes achieved an accuracy of 82%.” (opens the source at this quote in a new tab)

Diagnosis in US practice: ICD-10 coding of active choroidal neovascularization

“The nAMD diagnosis was based on the International Classification of Diseases, Tenth Revision, codes of H35.3211, H35.3221, H35.3231, and H35.3291.” (opens the source at this quote in a new tab)

Visual distortion: metamorphopsia as a presenting symptom

“A retrospective survey including 217 patients revealed that about 40% sought assistance due to visual distortion (straight lines appearing curved); approximately 38% of patients reported a decline in vision, characterized by blurred vision, loss of visual acuity, or difficulty focusing.” (opens the source at this quote in a new tab)

Onset: sudden symptoms with rapid worsening

Stage	Quoted clinical manifestation
Intermediate-stage AMD	“Difficulties in low-light and low-contrast surroundings, distortion, blurriness; typically no decrease in visual acuity at this stage”
Geographic atrophy	“Symptom onset and progression rather slow: distortion, decline in vision, and/or central visual field defects”
Exudative neovascular AMD	“Symptoms may occur suddenly with rapid worsening: distortion, decline in vision, and/or central visual field defects”

Central vision loss: visual acuity at presentation in the IRIS Registry

“Overall, 25.9% of patients with nAMD demonstrated normal or near-normal vision (20/40 or better) at presentation. Most patients (60.0%) showed mild to moderate vision impairment (VA between 20/40 and 20/200), and 14.1% of patients showed severe vision impairment (VA worse than 20/200; Table 1).” (opens the source at this quote in a new tab)
“Among Hispanic patients with nAMD, 20.5% showed normal or near-normal vision and 19.6% showed severe vision impairment at presentation.” (opens the source at this quote in a new tab)

Central visual field loss: scotoma

“patients with the onset of new symptoms suggestive of AMD (e.g., new visual loss, metamorphopsia, or scotoma) should be examined promptly.” (opens the source at this quote in a new tab)

“The exudative stage of neovascular AMD (also known as ‘wet AMD’) becomes apparent when these new vessels leak or rupture, resulting in fluid accumulation and/or haemorrhages, and distortion and deterioration in vision.” (opens the source at this quote in a new tab)

Low-luminance and contrast symptoms: difficulty in dim light

“An early symptom of AMD is difficulty performing tasks under low light conditions and in low-contrast surroundings,” (opens the source at this quote in a new tab)
“such as in poorly illuminated rooms. Patients typically seek help when experiencing more pronounced symptoms.” (opens the source at this quote in a new tab)

Functional symptoms: reading, driving, and face recognition

“When AMD becomes symptomatic in both eyes, or if there is already reduced vision in one eye when the other eye becomes symptomatic, patients are more likely to report a loss in their ability to read, drive, or perceive fine details, including facial expressions. Having good vision in one eye, however, may mask symptoms in the other eye.” (opens the source at this quote in a new tab)

Entoptic symptoms: photopsia

“The top 16 included posterior vitreous detachment (PVD) in 39.7% of eyes; retinal tear in 8.9% of eyes; neovascular age-related macular degeneration (AMD) in 7.9% of eyes” (opens the source at this quote in a new tab)
“The photopsias from neovascular AMD are more centrally located (83%), quick and repetitive (79%), seen in light (73%) and dark (63%) environments, have no inciting stimuli (84%), and are more likely to be nonwhite (40%).” (opens the source at this quote in a new tab)

Visual hallucinations: Charles Bonnet syndrome

“We identified 18 studies with data on >4303 patients with AMD. We found an overall prevalence of CBS of 15.8% (95% confidence interval: 11.0%-21.2%). When looking at consecutively recruited patients with neovascular AMD from the clinic, prevalence of CBS was 7.2% (95% confidence interval: 4.3%-10.6%). Among visitors to visual rehabilitation centres, prevalence of CBS was 31.6% (95% confidence interval: 21.7%-42.3%).” (opens the source at this quote in a new tab)

“Twenty-five (8.3%) patients of 300 had hallucinations attributable to CBS.” (opens the source at this quote in a new tab)

“Patients who have Charles Bonnet syndrome and their family members should be informed that visual symptoms are not unusual and do not represent a sign of psychosis or mental deterioration.” (opens the source at this quote in a new tab)

Fundus signs: hemorrhage, exudation, fluid, and pigment epithelial detachment

“Macular neovascularization can lead to the following:” (opens the source at this quote in a new tab)
“Serous detachment of the neurosensory retina or RPE” (opens the source at this quote in a new tab)
“Hard exudates (a secondary phenomenon resulting from chronic vascular leakage)” (opens the source at this quote in a new tab)
“Subretinal fibrosis (formerly known as disciform scar)” (opens the source at this quote in a new tab)

Fundus signs: polypoidal choroidal vasculopathy

“which should be suspected in patients with orange polypoid lesions and especially in African or Asian individuals.” (opens the source at this quote in a new tab)
“The lesions are often located in the peripapillary region, but may also present in the central macula or the macular arcades initially as large hemorrhagic retinal PED, lipid exudation, and subretinal fluid.” (opens the source at this quote in a new tab)

Fundus signs: type 3 macular neovascularization

“Scattered flecks of intraretinal hemorrhage (always outside the foveal avascular zone) and cystoid spaces are present, both of which may appear before the neovascularization.” (opens the source at this quote in a new tab)

Asymptomatic disease: symptom-based detection in fellow eyes

“Patients who check monocular near vision (reading/Amsler grid/Amsler-grid equivalent) may be more likely to become aware of subtle visual symptoms due to MNV, increasing the likelihood of detecting MNV at an early stage which, on average, yields better long-term visual outcomes with treatment compared with neovascular disease detected at a more advanced stage.” (opens the source at this quote in a new tab)

Blindness: leading cause among White adults in the United States

“Based on demographics from the 2000 US Census, an estimated 937 000 (0.78%) Americans older than 40 years were blind (US definition). An additional 2.4 million Americans (1.98%) had low vision. The leading cause of blindness among white persons was age-related macular degeneration (54.4% of the cases), while among black persons, cataract and glaucoma accounted for more than 60% of blindness.” (opens the source at this quote in a new tab)

Blindness: share of severe visual loss in the United States

“Overall, AMD is responsible for an estimated 46% of cases of severe visual loss (visual acuity [VA] 20/200 or worse) in people over age 40 in the United States.” (opens the source at this quote in a new tab)

Blindness and moderate to severe vision impairment: global estimates for 2020

“In 2020, 1.85 million (95%UI: 1.35 to 2.43 million) people were estimated to be blind due to AMD, and another 6.23 million (95%UI: 5.04 to 7.58) with MSVI globally. High-income countries had the highest number of individuals with AMD-related blindness (0.60 million people; 0.46 to 0.77).” (opens the source at this quote in a new tab)

“The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7-18·0]), followed by glaucoma (3·6 million cases [2·8-4·4]), undercorrected refractive error (2·3 million cases [1·8-2·8]), age-related macular degeneration (1·8 million cases [1·3-2·4]), and diabetic retinopathy (0·86 million cases [0·59-1·23]).” (opens the source at this quote in a new tab)

Legal blindness: incidence before and after introduction of anti-VEGF therapy

“The incidence rate of legal blindness attributable to AMD in citizens aged ≥50 years decreased from 52.2 cases per year per 100 000 in 2000 to 25.7 cases per year per 100 000 in 2010, corresponding to a reduction of 50% (95% confidence interval [CI(95)]: 45%-56%, P < .0001, adjusted for age), the bulk of the reduction occurring after 2006.” (opens the source at this quote in a new tab)

Visual acuity after 5 years of anti-VEGF therapy: CATT

“VA was obtained for 647 (71%) of 914 living patients with average follow-up time 5.5 years.” (opens the source at this quote in a new tab)
“At the 5-year visit, 50% of study eyes had VA 20/40 or better and 20% had VA 20/200 or worse. Mean change in VA was −3 letters from baseline and −11 letters from 2 years.” (opens the source at this quote in a new tab)

Visual acuity and macular atrophy 7 years after ranibizumab: SEVEN-UP

“At a mean of 7.3 years (range, 6.3-8.5 years) after entry into ANCHOR or MARINA, 37% of study eyes met the primary end point of 20/70 or better BCVA, with 23% achieving a BCVA of 20/40 or better. Thirty-seven percent of study eyes had BCVA of 20/200 or worse.” (opens the source at this quote in a new tab)
“Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing ocular anti-VEGF treatments. Macular atrophy was detected by FAF in 98% of eyes, with a mean area of 9.4 mm(2); the area of atrophy correlated significantly with poor visual outcome (P<0.0001).” (opens the source at this quote in a new tab)

Visual acuity after up to 7 years of treatment: Fight Retinal Blindness! registry

“After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years.” (opens the source at this quote in a new tab)
“Treatment was discontinued for 663 eyes (53%) within the first 5 years.” (opens the source at this quote in a new tab)

Visual acuity after 10 years of treatment: real-world meta-analysis

“Our search produced 12 observational studies encompassing 7509 eyes, with 1274 completing 10-years of follow-up.” (opens the source at this quote in a new tab)
“On average, there was a decline of 8.11 letters in VA after 10 years from baseline (95% CI -10.83 to -5.39, p < 0.01).” (opens the source at this quote in a new tab)

Geographic atrophy after anti-VEGF therapy: CATT 5-year incidence

“Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years.” (opens the source at this quote in a new tab)

Macular atrophy after anti-VEGF therapy: IVAN trial and long-term follow-up

“Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%.” (opens the source at this quote in a new tab)

“Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years).” (opens the source at this quote in a new tab)
“Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively).” (opens the source at this quote in a new tab)

Fibrotic and nonfibrotic scar: CATT through 2 years

“Scar developed in 480 of 1059 eyes (45.3%) by 2 years.” (opens the source at this quote in a new tab)
“Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes.” (opens the source at this quote in a new tab)

Fibrotic scar and associated atrophy: CATT through 5 years

“Cumulative proportion of eyes with scar was 32%, 46% and 56% at year 1, 2 and 5, respectively.” (opens the source at this quote in a new tab)
“Among 68 eyes that developed fibrotic scar at year 1, visual acuity decreased by a mean of additional 13 letters between year 1 and 5.” (opens the source at this quote in a new tab)

Atrophy and fibrosis as causes of long-term vision loss despite treatment

“Long-term follow-up studies have identified that the gains made in the first 2 years are not maintained in the long term” (opens the source at this quote in a new tab)
“Besides patients dropping out of treatment, evidence shows that atrophy and fibrosis are important causes of vision loss despite good early results” (opens the source at this quote in a new tab)

Falls and fractures: population-based cohort in England

“Compared with comparators, there was an increased risk of falls in those with cataract (adjusted hazard ratio [HR], 1.36; 95% CI, 1.35-1.38), AMD (HR, 1.25; 95% CI, 1.23-1.27), and glaucoma (HR, 1.38; 95% CI, 1.35-1.41). Likewise for fractures, there were increased risks in all eye diseases, with an HR of 1.28 (95% CI, 1.27-1.30) in the cataract cohort, an HR of 1.18 (95% CI, 1.15-1.21) for AMD, and an HR of 1.31 (95% CI, 1.27-1.35) for glaucoma.” (opens the source at this quote in a new tab)

Falls and injuries: prospective diary study in older adults with AMD

“Overall, 74% of participants reported having either a fall or a non-fall-related injury. Fifty-four percent of participants reported a fall and 30% reported more than one fall; of the 102 falls reported, 63% resulted in an injury.” (opens the source at this quote in a new tab)

Hip fracture: Medicare beneficiaries with exudative and atrophic AMD

“In adjusted analyses, the risk of hip fractures was similar in cases that were coded with exudative AMD (odds ratio, 1.03; 95% confidence interval (CI), 0.95, 1.12) compared with cases with no AMD but was significantly higher in cases that were coded with atrophic AMD (odds ratio, 1.11; 95% CI, 1.06, 1.16).” (opens the source at this quote in a new tab)

Depression and anxiety: systematic review

“The prevalence estimates, taken from nine cross-sectional and cohort studies, ranged from 15.7%-44% for depressive symptoms and 9.6%-30.1% for anxiety symptoms in people with AMD. The seven case-control studies found that people with AMD were more likely to experience symptoms of depression compared with those without AMD, but not more likely to experience symptoms of anxiety.” (opens the source at this quote in a new tab)

Depression: recent-onset bilateral AMD

“Seventeen patients (33%) were depressed at baseline and had worse visual acuity (P =.04) and greater levels of vision-specific (P =.03) and general (P =.002) physical disability than nondepressed patients.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: falls, depression, and vision rehabilitation

“Loss of VA increases the risk of frequent falls.” (opens the source at this quote in a new tab)
“Depression and visual hallucinations (Charles Bonnet syndrome) frequently accompany severe central vision loss.” (opens the source at this quote in a new tab)
“Patients can be informed that while central visual loss is common, total visual loss is extremely rare.” (opens the source at this quote in a new tab)

PDGF-driven extracellular matrix deposition and macular scarring in neovascular AMD

“In the CATT trial, macular scarring was the most frequent anatomical correlate of impaired visual acuity, affecting every second patient at year two” (opens the source at this quote in a new tab)
“Scar tissue in nAMD has been shown to consist largely of endothelial cells, dedifferentiated RPE, fibrin, and extracellular matrix (ECM)” (opens the source at this quote in a new tab)
“This notion is also supported by the fact that a longer time interval between diagnosis and start of treatment is associated with more fibrosis, and invasion of the supra-RPE space by classic CNV is associated with a six times higher hazard ratio of developing macular scarring when compared to minimally classic or occult CNV” (opens the source at this quote in a new tab)

Summary: vision-related quality of life, mental health, and treatment burden

Health utility in age-related macular degeneration depends on visual acuity in the better-seeing eye. In a time trade-off study of 80 participants, mean utility fell from 0.89 with 20/20 to 20/25 vision to 0.40 with counting fingers to light perception. In the MARINA and ANCHOR trials, a 15-letter change in best corrected visual acuity corresponded to a 4- to 6-point change in NEI VFQ-25 scores. In a five-country study, 401 participants with bilateral nAMD reported 45% worse vision-related functioning, 30% more anxiety symptoms, and 42% more depression symptoms than 471 controls, with a fall rate of 16% versus 8%. Among Medicare beneficiaries with nAMD (n = 1228), 26% reported a lot of trouble seeing or blindness compared with 5% of controls. Published prevalence of depressive symptoms in AMD ranges from 15.7% to 44%, and in a French nationwide cohort treated nAMD was associated with a 19% higher risk of both disability and mood disorders.

Treatment with repeated intravitreal injections carries its own burden. In a U.S. time-and-motion study, participants reported almost 12 hours per visit including recovery, and in a 2024 multinational survey 24.2% of participants needed 1 day or more to recover from an injection. In a UK survey of 300 participants receiving anti-VEGF therapy, 56% of participants (n = 132) reported anxiety related to treatment. In the U.S. IRIS Registry, 11.6% of 156,327 treatment-naive participants were lost to follow-up within 12 months of the last injection, and in a single urban U.S. practice the proportion was 22.2% of 9007 participants. Risk of loss to follow-up increased with age, Black race, Medicaid insurance, lower regional income, and greater distance from the clinic.

Utility values by visual acuity in the better-seeing eye: time trade-off and standard gamble

“Eighty white patients with unilateral or bilateral age-related macular degeneration in 1 or both eyes, and visual loss to a minimum of the 20/40 level in at least 1 eye.” (opens the source at this quote in a new tab)
“The mean utility value for the total group with age-related macular degeneration was 0.72 (95% confidence interval [CI], 0.66-0.78) using the time trade-off method and 0.81 (95% CI, 0.76-0.86) using the standard gamble method.” (opens the source at this quote in a new tab)
“Using the time trade-off method correlated with the visual acuity in the better-seeing eye, the results were as follow: group 1, 0.89 (95% CI, 0.82-0.96), group 2, 0.81 (95% CI, 0.73-0.89), group 3, 0.57 (95% CI, 0.47-0.67), group 4, 0.52 (95% CI, 0.38-0.66), and group 5, 0.40 (95% CI, 0.29-0.50).” (opens the source at this quote in a new tab)
“Thus, those patients in group 1 were willing to trade 11% of their remaining lifetime in return for perfect vision in each eye, whereas those in group 5 were willing to trade 60% of their remaining lifetime in return for perfect vision in each eye.” (opens the source at this quote in a new tab)

Visual acuity group, better-seeing eye	Quoted definition
Group 1	“1 (20/20 to 20/25)”
Group 2	“2 (20/30 to 20/ 50)”
Group 3	“3 (20/60 to 20/100)”
Group 4	“4 (20/200 to 20/400)”
Group 5	“5 (counting fingers to light perception)”

Utility values: visual acuity rather than underlying disease as the determinant

“No difference was found between the utility value means of the diabetic retinopathy (n = 333) and ARMD (n = 246) subgroups stratified according to visual acuity levels” (opens the source at this quote in a new tab)
“A 2-way analysis of variance demonstrated that, among the variables of ocular disease, sex, age, and visual acuity in the better-seeing eye, only visual acuity was significantly associated with utility values (P =.003).” (opens the source at this quote in a new tab)

Quality-of-life decrement by AMD severity: value-based medicine analysis

“Mild ARMD caused a 17% decrement in the quality of life of the average patient, similar to that encountered with moderate cardiac angina or symptomatic human immunodeficiency virus syndrome.” (opens the source at this quote in a new tab)
“Moderate ARMD caused a 32% decrease in the average patient's quality of life, similar to that associated with severe cardiac angina or a fractured hip.” (opens the source at this quote in a new tab)
“Severe ARMD caused a 53% decrease in quality, more than that of dialysis, and very severe ARMD caused a 60% decrease in the average ARMD patient's quality of life” (opens the source at this quote in a new tab)
“Patients with varying degrees of severity of ARMD were found to have quality-of-life impairment ranging from 96% to 750% greater than that estimated by treating ophthalmologists for the same condition.” (opens the source at this quote in a new tab)

Utility instruments in AMD: HUI-3, SF-6D, EQ-5D, and time trade-off

“Two hundred nine patients were recruited with substantial loss of visual function as obtained by visual tests (mean decimal VA in the better-seeing eye: 0.2) and self-report (mean VF-14 score: 41.5).” (opens the source at this quote in a new tab)
“The mean (+/-SD) utilities were 0.34 +/- 0.28 for HUI-3, 0.66 +/- 0.14 for SF-6D, 0.72 +/- 0.22 for EQ-5D, and 0.64 +/- 0.31 for TTO.” (opens the source at this quote in a new tab)
“ARMD is associated with a substantial impact on patients' health status, but this was not reflected in two of the generic preference-based measures used.” (opens the source at this quote in a new tab)

Utility weights in wet AMD: systematic literature review

“Of 2415 articles identified from the searches, 212 articles were reviewed in full, and 17 selected for data extraction.” (opens the source at this quote in a new tab)
“HUI3 estimates were most highly correlated with VA changes, followed by TTO; no trend was observed between VA and EQ-5D or SF-6D utility weights.” (opens the source at this quote in a new tab)
“The EQ-5D and SF-6D were poor indicators of the impact of VA on HRQL.” (opens the source at this quote in a new tab)

NEI VFQ-25 responsiveness to visual acuity change: MARINA and ANCHOR

“According to the regression models, the difference associated with a 15-letter change was 4 to 6 points for the composite score and the three pre-specified subscales.” (opens the source at this quote in a new tab)
“Based on MARINA and ANCHOR data, a 4- to 6-point change in NEI VFQ-25 scores represents a clinically meaningful change corresponding to a 15-letter change in BCVA.” (opens the source at this quote in a new tab)

NEI VFQ-25 change by better- or worse-seeing study eye: MARINA and ANCHOR

“We included 646 MARINA and 379 ANCHOR patients.” (opens the source at this quote in a new tab)
“At the 24-month follow-up visit, mean change in composite scores with ranibizumab seemed to be better than control for both better-seeing eyes (8.4 [95% confidence interval (CI), 5.2-11.6], 7.5 [95% CI, 3.7-11.4], and -9.4 [95% CI, -12.5 to -6.3] for the 0.3-mg, 0.5-mg, and sham groups, respectively)” (opens the source at this quote in a new tab)

Bilateral nAMD versus controls: vision-related functioning, anxiety, depression, and falls (five countries)

“A cross-sectional study of 401 patients with bilateral NV-AMD and 471 elderly control subjects without AMD was conducted in 5 countries.” (opens the source at this quote in a new tab)
“The patients reported 45% worse vision-related functioning, 13% worse overall well-being, and 30% more anxiety and 42% more depression symptoms than controls after adjusting for covariates (all, P < .001).” (opens the source at this quote in a new tab)
“The effect of NV-AMD was also observed as a doubled fall rate (16% vs 8% [P < .001]) and a quadrupled need for assistance with daily activities (29% vs 7% [P < .001]) in the patients compared with controls.” (opens the source at this quote in a new tab)

NEI VFQ-25, EQ-5D, and HADS depression versus controls: UK cohort

“Patients with NV-AMD reported substantially worse vision-related functioning and overall well-being, including higher depression scores, than controls after adjusting for age, gender and co-morbidities (adjusted mean scores: NEI-VFQ-25 overall 52.7 vs 90.7, p<0.0001; EQ-5D 0.67 vs 0.77, p = 0.0273; HADS depression 6.8 vs 4.0, p = 0.0026).” (opens the source at this quote in a new tab)
“Significantly more patients reported a need for assistance with daily activities compared with controls (25.3% vs 6.6%, p = 0.003).” (opens the source at this quote in a new tab)

Vision impairment and functional status: Medicare Current Beneficiary Survey linked to claims

“Outcomes between community-dwelling beneficiaries with nAMD (n = 1228), DME (n = 101), or RVO (n = 251) were compared with community-dwelling beneficiaries without any VTRDs (n = 104 088), controlling for baseline demographic and clinical differences.” (opens the source at this quote in a new tab)
“Compared with those without VTRDs, beneficiaries with nAMD had higher odds of diagnosed vision loss (odds ratio [OR], 5.39; 95% confidence interval, 4.06-7.16; P < .001) and difficulties with iADLs (odds ratio, 1.41; 95% confidence interval, 1.11-1.80; P = .005)” (opens the source at this quote in a new tab)
“After adjusting for age, sex, race/ethnicity, poverty status, comorbidities, and other relevant covariates, nAMD, DME, and RVO were not significantly associated with anxiety/depression, falls, or fractures.” (opens the source at this quote in a new tab)
“Patients with nAMD continue to experience more vision impairment and worse functional status compared with a similar population of Medicare beneficiaries despite availability of therapies like antivascular endothelial growth factor to treat retinal disease.” (opens the source at this quote in a new tab)

Disability and mood disorders after treated nAMD: French nationwide cohort

“During the study period, 1662 cases of incident nAMD were identified.” (opens the source at this quote in a new tab)
“After adjustment for age, sex, Charlson comorbidity index and number of drugs, nAMD was significantly associated with the occurrence of ADL disability (Hazard ratio (HR): 1.19, 95% confidence interval (CI): 1.08-1.30; p = 0.0002) and of mood disorders (HR: 1.19, 95%CI: 1.07-1.32; p = 0.002).” (opens the source at this quote in a new tab)
“Treated neovascular AMD remains associated with a 19% increased risk of disability and mood disorders, while no association was detected with falls, fractures and head trauma.” (opens the source at this quote in a new tab)

Depression and anxiety prevalence in AMD: systematic review

“The prevalence estimates, taken from nine cross-sectional and cohort studies, ranged from 15.7%-44% for depressive symptoms and 9.6%-30.1% for anxiety symptoms in people with AMD.” (opens the source at this quote in a new tab)
“The seven case-control studies found that people with AMD were more likely to experience symptoms of depression compared with those without AMD, but not more likely to experience symptoms of anxiety.” (opens the source at this quote in a new tab)

Depressive disorder in advanced AMD: structured clinical interview

“Participants were 151 adults aged 60 and older (mean age, 80 years) with advanced macular degeneration whose vision was 20/60 or worse in their better eye.” (opens the source at this quote in a new tab)
“Of the participants, 32.5% (n = 49) met SCID-IV criteria for depressive disorder, twice the rate observed in previous studies of community-dwelling elderly.” (opens the source at this quote in a new tab)

Depression and anxiety by visual acuity severity: France, Germany, and Italy

“The prevalence of severe depression increased from 0% (BE:VA > or = 20/40+WE:VA > or = 20/200) to 7.6% (BE:VA < 20/40+WE:VA < 20/200), whereas anxiety was unrelated to VA loss.” (opens the source at this quote in a new tab)
“Moreover, total depression scores were strongly associated with VA severity (P = 0.006), but not total anxiety scores (P = 0.840).” (opens the source at this quote in a new tab)

Incident depression after AMD diagnosis: Korean nationwide cohort

“A total of 3 599 589 individuals older than 50 years participated in the Korean National Health Screening Program in 2009.” (opens the source at this quote in a new tab)
“Patients with previous diagnoses of AMD showed a greater risk of new-onset depression, with a hazard ratio of 1.15 (95% CI, 1.13-1.17) compared with the control group in the fully adjusted model.” (opens the source at this quote in a new tab)
“Patients with AMD and accompanying VD showed a further increased risk of depression, with a hazard ratio of 1.23 (95% CI, 1.16-1.30).” (opens the source at this quote in a new tab)

Treatment-related anxiety and clinical depression during anti-VEGF therapy: UK

“Three hundred patients with wAMD receiving anti-VEGF treatment and 100 patient carers were recruited.” (opens the source at this quote in a new tab)
“Qualitative data showed that 56% of patients (n = 132) reported anxiety related to anti-VEGF treatment.” (opens the source at this quote in a new tab)
“The main sources of anxiety were fear of going blind owing to intravitreal injections and concerns about treatment effectiveness, rather than around pain.” (opens the source at this quote in a new tab)
“From validated questionnaires, 17% of patients (n = 52) showed clinical levels of anxiety and 12% (n = 36) showed clinical levels of depression.” (opens the source at this quote in a new tab)

Patient-reported outcomes and mental health in routine anti-VEGF care: systematic review

“Of 856 records identified, 63 met inclusion criteria.” (opens the source at this quote in a new tab)
“Depression or depressive symptoms were reported in up to 42% of patients with nAMD.” (opens the source at this quote in a new tab)
“Of these, seven reported a statistically significant improvement at the earliest time point measured (Month 3-12) and approximately 50% reported sustained QoL benefits at 12 months.” (opens the source at this quote in a new tab)

Time burden per visit: U.S. time-and-motion study

“Fifty-six physicians provided data for 221 patients with neovascular AMD.” (opens the source at this quote in a new tab)
“An average patient visit for neovascular AMD was 90 minutes (range: 13 minutes to >4 hours).” (opens the source at this quote in a new tab)
“Patients reported an average time per visit of almost 12 hours, including preappointment preparation (16 minutes), travel (66 minutes), waiting time (37 minutes), treatment time (43 minutes), and postappointment recovery (9 hours).” (opens the source at this quote in a new tab)

Treatment barriers, recovery time, and work absenteeism: multinational patient survey including the United States

“This multinational, non-interventional, quantitative, cross-sectional, observational survey assessed treatment barriers/burden, patient-reported visual functioning, and treatment satisfaction in DME and nAMD patients in the USA, the UK, Canada, France, Italy, and Spain.” (opens the source at this quote in a new tab)
“The survey was completed by 183 DME and 391 nAMD patients.” (opens the source at this quote in a new tab)
“Most patients reported ≥1 barrier (66.1% DME, 49.2% nAMD patients) related to treatment (35.0%), clinic (32.6%), and COVID-19 (21.1%).” (opens the source at this quote in a new tab)
“Nearly one-quarter (24.2%) of patients needed ≥1 day to recover from intravitreal injections; most reported ≥30 min of travel time (73.7%) and clinic wait time (54.2%).” (opens the source at this quote in a new tab)

Patient and ophthalmologist perceptions of injection burden: U.S. survey

“In June 2024 a survey of 101 patients (50 with DME and 51 with nAMD) and 100 ophthalmologists who treat these conditions completed surveys.” (opens the source at this quote in a new tab)
“Sixty-six percent and 86% of patients with DME and nAMD, respectively, reported receiving intravitreal injections at least once every 8 weeks.” (opens the source at this quote in a new tab)
“Eighty-two percent required a caregiver and/or public transportation to get to their appointments.” (opens the source at this quote in a new tab)
“They overestimated the extent to which patients became less nervous with subsequent injections after the first (3.40 vs 2.94; P < 0.01) and underestimated their difficulty of getting to appointments (2.30 vs 2.64; P < 0.01).” (opens the source at this quote in a new tab)

Pre-injection anxiety, stress, and discomfort: Norway survey

“In total, 130 patients responded to the survey.” (opens the source at this quote in a new tab)
“The majority of patients reported to receive nine or more injections per year (48.8%), and many patients needed caregiver support for every treatment appointment (37.7%).” (opens the source at this quote in a new tab)
“Patients reported to be anxious one day (25.4%), two days (8.5%), one week (10.8%) or more than one week (3.1%) prior to treatment.” (opens the source at this quote in a new tab)
“The week before the treatment, 33.1% of patients reported to be stressed and 15.4% struggled to sleep.” (opens the source at this quote in a new tab)

Time per treatment visit and caregiver assistance: Sweden

“The study included 93 patients with an average age of 79.9 years, 68% were women.” (opens the source at this quote in a new tab)
“On average, patients had to spend 2.7 h (2.4-2.9: 95% CI) per treatment and a caregiver assisted the patient in 58% of cases.” (opens the source at this quote in a new tab)

Psychosocial and practical burden of repeated injections: qualitative study

“Patients recognised the importance of treatment to preserve eyesight, yet experienced significant psychosocial and practical burden from the treatment schedule.” (opens the source at this quote in a new tab)
“Important issues included treatment-related anxiety, financial considerations and transport burden placed on relatives or carers.” (opens the source at this quote in a new tab)
“Patients prioritised treatment, often sacrificing family, travel and social commitments owing to a fear of losing eyesight if treatment was not received.” (opens the source at this quote in a new tab)

Challenges in nAMD management: global survey of patients, providers, and staff

“There were 6425 responses; 4558 patients with neovascular age-related macular degeneration, 659 providers, and 1208 clinic staff.” (opens the source at this quote in a new tab)
“Challenges identified included concern about patient burden to family/friends, high frequency of treatment, difficulties in traveling to appointments, long waiting times, and insufficient comprehension of neovascular age-related macular degeneration.” (opens the source at this quote in a new tab)

Obstacles to treatment and missed clinic visits: nine-country patient survey

“Most patients (65.4%; n=595/910) and caregivers (77.0%; n=685/890) reported a number of obstacles in managing wAMD (Figure 2).” (opens the source at this quote in a new tab)
“For patients, the main barrier was the treatment itself (34.8%; n=317/910)” (opens the source at this quote in a new tab)
“Other barriers included treatment costs (27.8%; n=253/910) and finding the right treatment option (27.4%; n=249/910)” (opens the source at this quote in a new tab)
“For the 15.7% (n=143/910) of patients who missed a clinic appointment, the main obstacles were that the caregiver was unable to take them to the appointment (25.9%; n=37/143), fear about receiving an injection (21.0%; n=30/143), and patient illness (reason not stated) (18.9%; n=27/143).” (opens the source at this quote in a new tab)

Loss to follow-up and nonpersistence: U.S. IRIS Registry

“One hundred fifty-six thousand three hundred twenty-seven treatment-naive patients with neovascular AMD who subsequently were treated with anti-VEGF therapy from 2013 through 2015 and followed up through 2019.” (opens the source at this quote in a new tab)
“For neovascular AMD, 11.6% of patients (95% CI, 11.4%-11.7%) were LTFU, and 88.4% of patients were followed up within 12 months.” (opens the source at this quote in a new tab)
“Odds of being LTFU were higher for patients with Medicaid insurance (OR, 1.27; 95% CI, 1.01-1.60; P = 0.04) and lower for patients with Medicare Fee-For-Service insurance (OR, 0.69; 95% CI, 0.64-0.74; P < 0.001) than for patients with private insurance.” (opens the source at this quote in a new tab)
“Furthermore, 14.3% (95% CI, 14.1-14.4) of patients were nonpersistent, and 85.7% of patients underwent follow-up within 6 months.” (opens the source at this quote in a new tab)

Loss to follow-up by age, income, and distance: U.S. urban retina practice

“Among the 9007 patients (mean [SD] age, 81.2 [8.8] years; 5917 [65.7%] female; 7905 [87.8%] white), 2003 (22.2%) were LTFU.” (opens the source at this quote in a new tab)
“Odds of LTFU were greater among patients with regional adjusted gross income of $50 000 or less (OR, 1.52; 95% CI, 1.30-1.79; P < .001), $51 000 to $75 000 (OR, 1.35; 95% CI, 1.17-1.56; P < .001), and $76 000 to $100 000 (OR, 1.28; 95% CI, 1.08-1.50; P = .004) compared with patients with incomes greater than $100 000.” (opens the source at this quote in a new tab)
“Odds of LTFU for patients living 21 to 30 miles (OR, 1.33; 95% CI, 1.05-1.69; P = .02) and more than 30 miles (OR, 1.55; 95% CI, 1.28-1.88; P < .001) from clinic were greater compared with patients who lived 10 miles or less from the clinic.” (opens the source at this quote in a new tab)

Nonadherence and nonpersistence: mixed-methods systematic review

“Of the 1284 abstract results screened, 124 articles were assessed in full and 37 studies met the inclusion criteria.” (opens the source at this quote in a new tab)
“Nonpersistence occurred early, with up to 50% of patients stopping treatment by 24 months.” (opens the source at this quote in a new tab)
“High rates of nonadherence were similarly reported, occurring in 32% to 95% of patients.” (opens the source at this quote in a new tab)

Visual outcomes after loss to follow-up of more than 6 months

“A total of 169 patients were classified into 43 in the long-term LTFU group, 57 in the short-term LTFU group, and 69 in the CFU group.” (opens the source at this quote in a new tab)
“The final visual acuity was significantly lower in the long-term LTFU group (1.12 ± 0.79) compared with the short-term LTFU group (0.65 ± 0.62) and the CFU group (0.65 ± 0.56) (P < 0.001)” (opens the source at this quote in a new tab)

Maintenance of driving vision over 4 years by first-year injection count

“In year 1, the nAMD and DME cohorts gained 8.5 and 9.5 ETDRS letters, respectively.” (opens the source at this quote in a new tab)
“Between years 1 and 4, patients with nAMD and DME lost 6.6 and 2.7 ETDRS letters, respectively.” (opens the source at this quote in a new tab)
“The probability of maintaining driving vision over 4 years was 56% (nAMD) and 72% (DME); among patients who received 1 to 5, 6 to 7, and ≥ 8 anti-VEGF injections in year 1, corresponding probabilities were 50%, 56%, and 65% (nAMD; P < 0.001)” (opens the source at this quote in a new tab)

Injection frequency and duration of treatment before loss to follow-up: U.S. IRIS Registry

“Among patients who were LTFU, the average number of anti-VEGF injections was 14 (average frequency, every 2.1 months), whereas the average number of anti-VEGF injections for those not LTFU during the same period was 12 (average frequency, every 2.5 months; Table 4).” (opens the source at this quote in a new tab)
“Among patients who were LTFU, the average time from the first intravitreal injection to the last visit was 2.4 years and was 4.4 years for patients not LTFU.” (opens the source at this quote in a new tab)

Visual acuity at the last visit among nonpersistent participants: U.S. IRIS Registry

“Compared with patients without nonpersistence during the same follow-up period, a lower percentage of patients with nonpersistence showed VA of 20/40 or better (35% vs. 43%; P < 0.001) at the last visit (Table 5) in the treated eye.” (opens the source at this quote in a new tab)
“Compared with patients without nonpersistence during the same follow-up period, a higher percentage of patients with nonpersistence lost > 5 ETDRS letters (40% vs. 36%; P < 0.001; Table 5) in the treated eye.” (opens the source at this quote in a new tab)

Return to care after loss to follow-up or nonpersistence: U.S. IRIS Registry

“Twelve percent of patients who were LTFU did later undergo follow-up (defined as after the first year and within 4 years of the last anti-VEGF intravitreal injection).” (opens the source at this quote in a new tab)
“Twenty-eight percent of patients who were nonpersistent did later undergo follow-up (defined as after the first 6 months and within 4 years of the last anti-VEGF intravitreal injection).” (opens the source at this quote in a new tab)

Travel time, clinic waiting time, and appointment duration of 1 hour or more

“Overall, 41.3% (n = 237) reported having ≥1 h of travel time to their appointment and 29.4% (n = 169) had ≥1 h of waiting time.” (opens the source at this quote in a new tab)
“Approximately equal proportions of patients experienced a combined (injection and examination) appointment duration of <1 h (29.4%; n = 169) and ≥1 h (32.9%; n = 198).” (opens the source at this quote in a new tab)

Impairment in activities of daily living and work absenteeism attributed to treatment

“Nearly half of patients (n = 258, 44.9%) reported some level of impairment in their ADL due to treatment.” (opens the source at this quote in a new tab)
“Among working patients (n = 42 DME; n = 24 nAMD), 62.1% experienced some level of absenteeism at work.” (opens the source at this quote in a new tab)

Elements of treatment burden associated with lower treatment satisfaction

“Treatment satisfaction scores were worse with higher time-related impacts of treatment (both nAMD and DME), higher impacts on finances and daily life (nAMD), and negative impacts on employment and lower expectations for treatment effectiveness (DME).” (opens the source at this quote in a new tab)
“Moreover, patients reporting a higher treatment burden (e.g., longer wait times) had worse treatment satisfaction scores.” (opens the source at this quote in a new tab)
“Patients were generally satisfied with their current treatment (MacTSQ, mean total score = 59.2, SD = 9.6; RetTSQ, mean total score = 61.3, SD = 12.8).” (opens the source at this quote in a new tab)

Visit length and post-injection recovery reported by U.S. participants

“More than one-third (36%, 27 of 75) of patients reported that their most recent visit took 90 minutes or more, and 79% (59 of 75) reported spending at least 3 hours recovering following injections.” (opens the source at this quote in a new tab)
“The average age was 79 years (range 55–98 years) and 89% (67 of 75) of patients had a concomitant medical condition.” (opens the source at this quote in a new tab)

Monthly injection and monitoring visits as the stated driver of extended-interval development

“The risk of rare but serious adverse events resulting from the intravitreal procedure, together with the significant burden of making monthly visits to their retinal specialist, have led to extensive efforts to decrease injection and monitoring frequency.” (opens the source at this quote in a new tab)
“By halving the need for monthly visits, the every-2-month regimen of aflibercept may markedly decrease the treatment burden experienced by patients and their families.” (opens the source at this quote in a new tab)

Strength of and reasons for patient preference for continuous delivery over injections

“A fairly or very strong preference for the PDS was expressed by 88% (22/25) of respondents (Fig 8), with fewer treatments (72% [18/25]) and less discomfort (64% [16/25]) being the most frequently cited reasons for preference.” (opens the source at this quote in a new tab)

Patient preference for continuous delivery over monthly injections in Archway

“At week 40, 218 of 234 PDS-treated patients (93.2%) preferred ranibizumab as delivered via the PDS compared with intravitreal injection, as assessed by the PDS Patient Preference Questionnaire; 3 patients (1.3%) preferred intravitreal injections and 13 patients (5.6%) reported no preference.” (opens the source at this quote in a new tab)

Summary: Medicare spending, per-patient costs, and real-world utilization

Anti-VEGF agents for macular degeneration account for a large share of Medicare Part B drug spending. In 2024, fee-for-service Medicare spent $3.0 billion on Eylea (including Eylea HD) for 329,500 users and $1.9 billion on Vabysmo for 173,300 users; Eylea ranked second and Vabysmo sixth among all Part B products, with average spending per user of $9,200 and $11,100. Across 2014 to 2023, Medicare fee-for-service beneficiaries received 36,398,293 intravitreal anti-VEGF injections, and aflibercept use increased from 618,796 injections in 2014 to 1,713,729 in 2023.

In U.S. commercial claims (6,076 participants), mean annual all-cause cost was $24,520 per patient, and nAMD-related outpatient visit costs were $8,658 for active choroidal neovascularization compared with $2,406 for inactive disease. A prevalence-based model estimated per-annum costs of $55,752 per person with nAMD in the United States when productivity and well-being losses are included. Vision loss of all causes cost the United States an estimated $134.2 billion in 2017.

Real-world injection counts are lower than in registration trials: a mean of 7.3 injections in year 1 in the Vestrum database (49,485 eyes), 6.0 in U.S. electronic health records, and 7.2 in year 1 falling to 4.2 to 4.6 per year in years 3 to 6 in the IRIS Registry. In these data, visual acuity outcomes increased with injection count, and in the IRIS Registry mean visual acuity was 4.6 letters below baseline after 6 years.

Medicare Part B spending on macular degeneration drugs, 2024

Product	Total drug spending, billions	Number of users	Average spending per user	Percent change in total spending, 2023 to 2024
Eylea (includes Eylea HD)	“3.0”	“329,500”	“9,200”	“–4”
Vabysmo	“1.9”	“173,300”	“11,100”	“48”

“Medicare spending (including beneficiary cost sharing) on the top 10 products accounted for $22.4 billion, or 34 percent of total Part B drug spending.” (opens the source at this quote in a new tab)
“The top 20 also include 3 products for arthritis, autoimmune disease, or inflammatory bowel disease and 2 products for macular degeneration.” (opens the source at this quote in a new tab)
“Average spending per user ranged from $13,000 to $39,000 for three drugs used to treat arthritis, autoimmune disease, or inflammatory bowel disease, and from $9,000 to $11,000 for two drugs used to treat macular degeneration.” (opens the source at this quote in a new tab)
“Between January 2025 and 2026, four products experienced a price decrease: Eylea, Vabysmo, Rituxan, and Entyvio.” (opens the source at this quote in a new tab)

Medicare Part B spending on macular degeneration drugs, 2023

Product	Total drug spending, billions	Number of users	Average spending per user	Percent change in total spending, 2022 to 2023
Eylea	“3.1”	“341,800”	“9,200”	“–11”
Vabysmo	“1.3”	“112,600”	“11,500”	“N/A”
Avastin (indications include macular degeneration)	“0.6”	“161,500”	“3,700”	“–14”
Lucentis	“0.5”	“91,600”	“5,900”	“–32”

Medicare anti-VEGF injection volume and reimbursement per injection, 2014 to 2023

“From 2014 to 2023, a total of 36 398 293 intravitreal anti-VEGF injections were administered to Medicare beneficiaries.” (opens the source at this quote in a new tab)
“Aflibercept use increased significantly (618 796 injections in 2014 vs. 1 713 729 in 2023; τ = 0.91; P < 0.001).” (opens the source at this quote in a new tab)
“Faricimab demonstrated rapid early uptake after its introduction in 2022 (65 052-556 512 injections).” (opens the source at this quote in a new tab)
“Standardized Medicare reimbursement per injection declined significantly for ranibizumab ($1234.35-$724.74; τ = -1.00; P < 0.001) and aflibercept ($1527.37-$1379.54; τ = -0.82; P = .001), remained stable for brolucizumab, and increased for bevacizumab ($46.76-$300.73; τ = 0.69; P < 0.01).” (opens the source at this quote in a new tab)

On-label versus off-label anti-VEGF use and Part B spending by community, 2013 to 2023

“From 2013-2023, 5,178 providers billed Part B for 34.5 million anti-VEGF injections.” (opens the source at this quote in a new tab)
“Equalizing anti-VEGF mix to that of the highest-poverty quartile would have resulted in approximately $4.2 billion lower spending.” (opens the source at this quote in a new tab)

Anti-VEGF injection trends in Medicare Part B, 2013 to 2021

“Among 26 602 816 total injections performed from 2013 to 2021, relative usage of aflibercept increased by 158.3%, while relative usage decreased by 27.5% for ranibizumab and 49.6% for bevacizumab.” (opens the source at this quote in a new tab)
“Step therapy has not significantly increased bevacizumab usage on an aggregate level.” (opens the source at this quote in a new tab)

Medicare Part B spending per beneficiary on ranibizumab and aflibercept, 2011 to 2015

“During this 5-year period, associated Medicare drug costs averaged $1.3 billion annually.” (opens the source at this quote in a new tab)
“Annual Medicare drug expenditure for aflibercept was $1.4 billion on average.” (opens the source at this quote in a new tab)
“On average, Medicare spent $9719 and $9934 annually on each beneficiary receiving ranibizumab and aflibercept injections, respectively.” (opens the source at this quote in a new tab)
“Ranibizumab and aflibercept costs account for 12% of the Medicare Part B budget annually.” (opens the source at this quote in a new tab)

Estimated Medicare and patient savings from bevacizumab use, 2008 to 2015

“The use of bevacizumab from 2008 to 2015 resulted in an estimated savings of $17.3 billion, which corresponded to a $13.8 billion savings to Medicare and a $3.5 billion savings to patients.” (opens the source at this quote in a new tab)

Manufacturer payments to ophthalmologists and Medicare Part B spending, 2013 to 2019

“Ophthalmologists who accepted manufacturer payments were significantly less likely to prescribe bevacizumab (28.0% [95% CI, 24.6%-42.5%] of patients) compared with those who did not accept manufacturer payments (45.8% [95% CI, 44.5%-47.1%]).” (opens the source at this quote in a new tab)
“Had ophthalmologists who accepted manufacturer payments prescribed ARMD drugs as those who did not accept payments, Medicare spending on these treatments would have been $642 779 703.08 lower from 2013 to 2019, a 2.0% savings.” (opens the source at this quote in a new tab)

Direct costs and resource use by disease activity: U.S. commercial claims

“A total of 6,076 patients with nAMD were identified for the prevalent cohort; 60.1%, 17.2%, and 5.9% had active CNV, inactive CNV, and inactive scar disease stage at index, respectively.” (opens the source at this quote in a new tab)
“The nAMD-related outpatient visit costs were roughly 4 and roughly 7 times higher, respectively, for the active CNV group ($8,658 [SD = $11,612]) compared with the inactive CNV ($2,406 [SD = $5,510]) and inactive scar ($1,198 [SD = $3,035]) groups (P < 0.0001).” (opens the source at this quote in a new tab)
“About 10% of prevalent patients had a fall/fracture claim over 12 months of follow-up.” (opens the source at this quote in a new tab)
“A total of 3,623 prevalent patients (59.6%) were eligible for the anti-VEGF treatment patterns analysis (mean [SD] duration of therapy = 7.7 [4.5] months; mean [SD] number of injections = 6.0 [3.7]).” (opens the source at this quote in a new tab)

“Mean (SD) annual total all-cause cost for the prevalent cohort was $24,520 ($43,950) with outpatient costs as the largest cost component (63.5%; Supplementary Figure 2 (577KB, pdf) , available in online article).” (opens the source at this quote in a new tab)
“Multivariate GLM results revealed an increasing trend in costs with increasing anti-VEGF injection frequency; there were 73% higher costs for patients with 4-6 injections to 342% higher costs for those with 10 or more injections compared with those with 1-3 injections over 1 year of follow-up (P < 0.0001).” (opens the source at this quote in a new tab)

Outpatient visit type, prevalent cohort	All patients	Active CNV	Inactive CNV	Inactive scar
All-cause visits, mean (SD)	“30.6 (26.4)”	“31.0 (25.5)”	“27.5 (25.3)”	“27.1 (25.9)”
nAMD-related visits, mean (SD)	“6.6 (4.8)”	“7.7 (4.6)”	“4.1 (3.5)”	“2.9 (2.9)”
Anti-VEGF-related visits, mean (SD)	“3.9 (4.2)”	“5.1 (4.2)”	“1.3 (2.5)”	“0.5 (1.6)”

Real-world injection frequency and per-patient cost: ranibizumab and aflibercept in U.S. claims

“After adjusting for patient demographics and clinical characteristics, per-patient injection frequency and cost were not significantly different between treatment-naive patients with nAMD who received ranibizumab versus aflibercept over 12 months (5.62 vs. 5.54; P = 0.52, and $11,351 vs. $10,702; P = 0.06, respectively) and 24 months (7.86 vs. 8.37; P = 0.16, and $16,286 vs. $16,666; P = 0.69, respectively).” (opens the source at this quote in a new tab)
“Most patients received fewer injections than any FDA-indicated dosing schedule, suggesting potential undertreatment that may result in suboptimal vision outcomes.” (opens the source at this quote in a new tab)

Medicare Part B payments in the first year after nAMD diagnosis, 1994 to 2006 cohorts

“Overall yearly Part B payments per beneficiary increased significantly from $3,567 for the 1994 to $5,991 for the 2006 cohort (p<0.01) in constant 2008 dollars.” (opens the source at this quote in a new tab)
“Payments for eye care alone doubled from $1,504 for the 1994 cohort to $3,263 for the 2006 cohort (p<0.01).” (opens the source at this quote in a new tab)
“Most of the increase in payments for eye care in 2006 reflected payments for anti-VEGF injections, which were $1,609 over 1 year.” (opens the source at this quote in a new tab)

Societal cost of late-stage AMD in the United States, Germany, and Bulgaria

“Estimated per-annum total costs attributable to late-stage AMD were €449.5 million ($512.5 million) in Bulgaria, €7.6 billion ($8.6 billion) in Germany, and €43.2 billion ($49.4 billion) in the US.” (opens the source at this quote in a new tab)
“Across all countries, 10% to 13% of the total cost incurred was attributed to direct medical costs.” (opens the source at this quote in a new tab)
“In Germany and Bulgaria, the biggest contributor to the total economic burden was reduced well-being (67% and 76%, respectively), whereas in the US, loss of productivity (42%) was the biggest contributor.” (opens the source at this quote in a new tab)

“In nAMD, the loss of productivity accounted for 46% of the total cost, and in GA, it accounted for 36%.” (opens the source at this quote in a new tab)
“The financial costs incurred due to nAMD amounted to €17.2 billion ($19.7 billion) and totaled €13.4 billion ($15.3 billion) for GA (Table 3).” (opens the source at this quote in a new tab)
“Per-annum individual costs incurred due to nAMD and GA were estimated at €48 895 ($55 752) and €39 250 ($44 755), respectively (Table 4).” (opens the source at this quote in a new tab)

Economic burden of vision loss and blindness in the United States (2017)

“We estimated an economic burden of VL of $134.2 billion: $98.7 billion in direct costs and $35.5 billion in indirect costs.” (opens the source at this quote in a new tab)
“The largest burden components were NH ($41.8 billion), other medical care services ($30.9 billion), and reduced labor force participation ($16.2 billion), all of which accounted for 66% of the total.” (opens the source at this quote in a new tab)
“Those with VL incurred $16 838 per year in incremental burden.” (opens the source at this quote in a new tab)
“Informal care was the largest burden component for people 0 to 18 years of age, reduced labor force participation was the largest burden component for people 19 to 64 years of age, and NH costs were the largest burden component for people 65 years of age or older.” (opens the source at this quote in a new tab)

Lost gross domestic product attributable to AMD in the United States

“An economic analysis based upon losses to the gross domestic product suggests that ARMD has approximately a $30 billion annual negative impact.” (opens the source at this quote in a new tab)

“The total yearly loss to the GDP due to lost wages from neovascular ARMD among all affected people is therefore $2.866 billion + $2.530 billion = $5.396 billion.” (opens the source at this quote in a new tab)

Work productivity loss in AMD: meta-analysis

“Seven studies consisting of 3,060,864 subjects from 5 different countries were included in this systematic review.” (opens the source at this quote in a new tab)
“Mean wages lost due to impaired work productivity ranged from $1,395 to $55,180.” (opens the source at this quote in a new tab)
“The mean unemployment rate attributed to AMD ranged from 5.50% to 77.00%.” (opens the source at this quote in a new tab)

Modeled direct and indirect costs of extended-interval agents: aflibercept 8 mg versus faricimab (United States)

“Direct costs were estimated based on modeled mean injection numbers and 2025 wholesale acquisition costs per injection (aflibercept 8 mg: 2677.50 USD; faricimab: 2289.65 USD) plus medical monitoring costs.” (opens the source at this quote in a new tab)
“Over a 3-year time horizon, the mean number of injections was lower with aflibercept 8 mg versus faricimab for nAMD (12.25 vs. 14.80 injections) and DME (11.80 vs. 15.65 injections).” (opens the source at this quote in a new tab)
“Total costs (direct and indirect) associated with aflibercept 8 mg were 1978.74 USD lower than faricimab for nAMD and 6032.90 USD lower than faricimab for DME.” (opens the source at this quote in a new tab)

Real-world injection frequency and visual acuity: Vestrum Health Retina Database (United States)

“In this analysis, 49 485 eyes were included.” (opens the source at this quote in a new tab)
“At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001).” (opens the source at this quote in a new tab)
“There was a linear relationship between mean letters gained and mean number of injections, between 4 and 10 injections over 1 year, with 4 or fewer or 10 or more injections associated with loss of vision or a plateau, respectively.” (opens the source at this quote in a new tab)
“Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials.” (opens the source at this quote in a new tab)

Visits, injections, and visual acuity in U.S. electronic health records

“Over the first 12 months, patients made a mean of 8.1 (range, 1-39) ophthalmologist visits, received a mean of 6.0 (range, 1-27) anti-VEGF injections, and underwent 7.2 OCT and 5.3 FA examinations per study eye.” (opens the source at this quote in a new tab)
“Mean change from baseline VA at 12 months increased linearly with cumulative anti-VEGF injection count: +1.79 versus -0.95 approximate ETDRS letters for eyes receiving 7 or more injections versus fewer than 7 injections.” (opens the source at this quote in a new tab)

Six-year injection frequency, discontinuation, and visual acuity: U.S. IRIS Registry

“A cohort of 254 655 eyes (226 767 patients) with first anti-VEGF injection and at least 2 years of follow-up; 160 423 eyes had visual acuity (VA) data.” (opens the source at this quote in a new tab)
“After a mean VA increase of 3.0 ETDRS letters at year 1, annual decreases led to a net loss from baseline of 4.6 letters after 6 years.” (opens the source at this quote in a new tab)
“From a mean of 7.2 in year 1 and 5.6 in year 2, mean injections plateaued between 4.2 to 4.6 in years 3 through 6.” (opens the source at this quote in a new tab)
“Treatment was discontinued in 38.8% of eyes and switched in 32.3%.” (opens the source at this quote in a new tab)
“Of the patients, 58.5% lost ≥ 10 letters VA at least once during follow-up, with 14.5% of patients experiencing sustained poor vision after a median of 3.4 years.” (opens the source at this quote in a new tab)

First-year injection counts by agent: U.S. IRIS Registry

“Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year.” (opens the source at this quote in a new tab)
“The mean number of injections (standard deviation) at 1 year was higher in the ranibizumab (6.4 [±2.4]) and aflibercept groups (6.2 [±2.4]) compared to bevacizumab group (5.9 [±2.4]; P < 0.0001).” (opens the source at this quote in a new tab)

Real-world injection frequency and visual acuity: eight-country AURA study

“2227 patients who received ≥1 anti-VEGF injection with a baseline visual acuity assessment and ≥1 postbaseline visual acuity assessment for the treated eye were evaluated.” (opens the source at this quote in a new tab)
“Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively.” (opens the source at this quote in a new tab)
“Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively.” (opens the source at this quote in a new tab)

Causes of undertreatment in routine practice: literature review

“In real-world practice, patients are usually undertreated, accounting for the VA decline over time.” (opens the source at this quote in a new tab)
“Reasons for undertreatment include the burden of injections and monitoring visits imposed on patients/caregivers.” (opens the source at this quote in a new tab)

Blindness incidence and healthcare system impact after anti-VEGF introduction: systematic review

“Population-based analyses reported reduction in incidence among the general population of 47% (9.1 cases/100,000 in 2006 to 4.8 cases/100,000 in 2011).” (opens the source at this quote in a new tab)
“The introduction of anti-VEGF led to increased overall treatment costs due to replacement of existing less frequently administered treatments (e.g. photodynamic therapy) and increased number of patients treated (prior to anti-VEGF, only ~ 20% of patients were eligible for treatment).” (opens the source at this quote in a new tab)

Societal cost of bilateral nAMD: five-country observational study (2005 euros)

“In the previous 12 months, 12-22% of patients fell, and half of these patients required medical treatments.” (opens the source at this quote in a new tab)
“The average annual societal cost per bilateral NV-AMD patient treated was estimated to be euro 7879 in Canada, euro 7349 in France, euro 12 445 in Germany, euro 5732 in Spain and euro 5300 in the UK, and direct vision-related medical costs accounted for 23-63% of the total cost.” (opens the source at this quote in a new tab)

Annual healthcare utilization costs versus controls: UK cohort

“Total annual healthcare utilisation costs were more than sevenfold higher for patients with AMD compared with controls (£3,823.89 vs £517.05, respectively; p<0.0001)” (opens the source at this quote in a new tab)

Patient-centered incremental costs, including out-of-pocket costs: South Korea

“We identified 931 patients with exudative AMD and matched 783 (84.1%) with 2918 patients with nonexudative AMD.” (opens the source at this quote in a new tab)
“In the exponential conditional model, the total medical, reimbursement, nonreimbursement, and out-of-pocket incremental costs were estimated at US $3426, US $3130, US $366, and US $561, respectively, in the first year and US $1829, US $1461, US $373, and US $507, respectively, in the second year.” (opens the source at this quote in a new tab)

Vision impairment due to AMD: Global Burden of Disease 2021

“Globally, the number of individuals with vision impairment due to AMD more than doubled, rising from 3·64 million (95% uncertainty inverval [UI] 3·04-4·35) in 1990 to 8·06 million (6·71-9·82) in 2021.” (opens the source at this quote in a new tab)
“Similarly, DALYs increased by 91% over the same period, from 0·30 million (95% UI 0·21-0·42) to 0·58 million (0·40-0·80).” (opens the source at this quote in a new tab)

Five-year trend in first-year injection numbers by initial anti-VEGF agent, United States

“In 2012, there were 6.7 yearly injections, 7.3 yearly injections, and 7.2 yearly injections on average in the groups initially treated with bevacizumab, aflibercept, and ranibizumab, respectively.” (opens the source at this quote in a new tab)
“By 2016, the mean number of yearly injections in the groups initially treated with bevacizumab and ranibizumab had increased by approximately 1, to 7.8 and 8.0 yearly injections, respectively.” (opens the source at this quote in a new tab)

Injection visits and dosing schedules in routine care: multinational survey including the United States

“Within 12 months, nAMD patients attended more visits where anti-VEGF injections were administered (nAMD: mean = 7.74, SD = 3.63; DME: mean = 6.54, SD = 3.40).” (opens the source at this quote in a new tab)
“One-third of DME (33.9%) and one-quarter of nAMD patients (25.8%) were on a fixed treatment schedule, with 73.6% (n = 120 of 163) receiving injections every ≤8 weeks.” (opens the source at this quote in a new tab)
“About one-third of nAMD (38.1%) and one-quarter of DME (26.8%) patients were on a treat-and-extend (T&E) regimen, with 69.7% (n = 138 of 198) receiving injections every ≤8 weeks.” (opens the source at this quote in a new tab)

Retina practice staff time devoted to neovascular AMD management: U.S. time-and-motion study

“The results of the retina specialist survey showed that on average, 23 staff members were involved in the management of neovascular AMD patients, including the receptionist, the office manager, the billing manager, technicians, and other physicians or staff (Table).” (opens the source at this quote in a new tab)
“The management of patients with neovascular AMD accounted for an average of 20% of the staff’s time per work week: most technicians (68%) spent more than 20% of their time, one-quarter of office managers spent more than 10% of their time, and more than one-third (37%) of billing managers spent more than 20% of their time managing patients with neovascular AMD (Figure 2).” (opens the source at this quote in a new tab)
“Although these preparatory steps were typically performed concurrently, the average total staff time spent on all preparation steps was 43 minutes.” (opens the source at this quote in a new tab)

State-level variation in Medicare anti-VEGF injection rates, 2023

“West Virginia had the lowest overall injection rate at 5723/100 000 Medicare beneficiaries, whereas Alaska had the highest rate at 180 838/ 100 000, representing a 31.6-fold difference.” (opens the source at this quote in a new tab)
“For aflibercept, Alaska recorded the highest injection rate at 68 241/100 000, whereas Hawaii had the lowest at 2602/100 000, resulting in a 26.2-fold difference.” (opens the source at this quote in a new tab)
“Faricimab utilization ranged from 207/100 000 in Vermont to 10 247/100 000 in Nebraska, a 49.4-fold difference.” (opens the source at this quote in a new tab)
“Bevacizumab use was the highest in Alaska at 93 497/100 000 and lowest in West Virginia at 630/100 000, representing a 148.3-fold difference.” (opens the source at this quote in a new tab)

Total Medicare anti-VEGF expenditure and per-beneficiary utilization, 2014 to 2023

“From an economic perspective, total Medicare expenditures for anti-VEGF therapy rose from approximately $2.5 billion USD in 2014 to $3.7 billion USD in 2023, despite declining reimbursement per injection for aflibercept and ranibizumab.” (opens the source at this quote in a new tab)
“This increase was primarily driven by rising injection volumes and the introduction of newer branded agents (faricimab and brolucizumab).” (opens the source at this quote in a new tab)
“To summarize per-100 000-beneficiary utilization, aflibercept increased from 1864/100 000 to 5997/100 000 beneficiaries (221% rise)” (opens the source at this quote in a new tab)
“Faricimab increased from 219/100 000 to 1947/100 000 between 2022 and 2023 (789% rise), whereas brolucizumab declined from 142 to 18 per 100 000 (87% decline).” (opens the source at this quote in a new tab)

Summary: caregiver time, lost work, and transport

Most people receiving anti-VEGF therapy for nAMD rely on an informal caregiver to attend appointments. In a nine-country survey, 82.1% of 910 participants received caregiver support and 56.7% were usually taken to appointments by a caregiver. In a U.S. time-and-motion study, participants reported that caregivers took time away from work (22%) and personal activities (28%) to provide transport. In a 2024 multinational survey including U.S. caregivers, 70.5% of working caregivers (n = 44) reported absenteeism due to treatment or monitoring appointments. In a UK survey of 250 caregivers, 24.8% took time off work and 70% spent at least half a day on each clinic visit. An Australian study estimated caregiver time accompanying the patient at 6.2 hours per month and an annual caregiver cost of AU$5,333.58. A U.S. economic model applied an indirect cost of $289.98 per injection for patient and caregiver time and travel. In a 2006 U.S. survey, annual caregiving costs ranged from $225 to $47,086 depending on visual acuity.

Caregiver time away from work for transport: U.S. time-and-motion study

“A survey was administered to 75 neovascular AMD patients aged ≥50 years who received ≥1 anti-VEGF injection in the past 6 months.” (opens the source at this quote in a new tab)
“Telephone interviews were conducted with 13 neovascular AMD patient caregivers.” (opens the source at this quote in a new tab)
“Patients stated that caregivers took time away from work (22%) and personal activities (28%) to provide transportation to appointments.” (opens the source at this quote in a new tab)

Caregiving use and cost by visual acuity: U.S. survey

“Of 803 respondents, 56% were male, and the mean age was 73 years.” (opens the source at this quote in a new tab)
“Use of paid and unpaid help significantly increased as visual acuity decreased.” (opens the source at this quote in a new tab)
“Using a national average for caregiver time, annual costs for caregiving ranged from 225 to 47,086 US dollar depending on visual acuity.” (opens the source at this quote in a new tab)

Caregiver time and work absenteeism: multinational caregiver survey including the United States

“Caregivers for patients with DME (n = 30) and nAMD (n = 95) completed surveys.” (opens the source at this quote in a new tab)
“Mean ± SD length of time as a caregiver was 9.1 ± 10.0 years.” (opens the source at this quote in a new tab)
“Caregivers estimated they provided support for 4.2 ± 2.9 days/week and 6.0 ± 7.1 h/day on average.” (opens the source at this quote in a new tab)
“Nearly half of caregivers (45.6%) reported some impairment in daily activities, and more than two-thirds (70.5%) of working caregivers (n = 44) reported work absenteeism due to anti-VEGF treatment/monitoring appointments.” (opens the source at this quote in a new tab)

Caregiver burden, time off work, and loss of income: UK

“This is a cross-sectional questionnaire survey of 250 matched patient caregiver dyads across three large ophthalmic treatment centres in United Kingdom.” (opens the source at this quote in a new tab)
“The mean CRA score was 3.2±0.5, similar to the score reported by caregivers for atrial fibrillation who require regular hospital appointments for monitoring their thromboprophylaxis.” (opens the source at this quote in a new tab)
“Ranibizumab therapy for nAMD is associated with significant caregiver burden. Both disease impact and treatment frequency contributed to the overall burden.” (opens the source at this quote in a new tab)

“The most common eye-related care activity undertaken was accompanying patients for their eye clinic appointments, with 70.8% carers having attended ≥10 appointments over the last year.” (opens the source at this quote in a new tab)
“On an average, the caregivers reported that 70% spent at least half a day and 43.6% spent most of the day assisting their patient with their clinic visit every 4–6 weeks.” (opens the source at this quote in a new tab)
“24.8% of caregivers required time off work to support patients with their eye treatment, and 10% of them reported that this led to a loss of income.” (opens the source at this quote in a new tab)

Caregiver roles and attendance at appointments: nine-country patient and caregiver survey

“A total of 910 patients with wAMD and 890 caregivers completed the questionnaire.” (opens the source at this quote in a new tab)
“The majority of patients (82.1%; n=747/910) received support from a caregiver.” (opens the source at this quote in a new tab)
“Only 6.5% (n=58/890) were professional (paid) caregivers.” (opens the source at this quote in a new tab)
“Most caregivers always attended appointments (60.1%; n=535/890) and were involved in discussions about the treatment plan (83.3%; n=555/666; Table 3).” (opens the source at this quote in a new tab)
“Most patients (56.7%; n=516/910) were usually taken to the appointment by a caregiver; however, 20.4% (n=186/910) went by public transport, 12.4% (n=113/910) drove themselves, 8.1% (n=74/910) used a taxi, and 2.3% (n=21/910) were taken by an ambulance.” (opens the source at this quote in a new tab)

Caregiver time and costs: Australia (Australian dollars)

“The caregivers reported the time they spent accompanying the patient to their medical appointments specifically for intravitreal injections took an average of 6.2±1.1 hours per month, which equates to a loss of $262.45±$46.60 in income based on the national average hourly wage.” (opens the source at this quote in a new tab)
“Several caregivers indicated indirect costs due to lost productivity in the workplace, having to take considerable time off work in order to bring the patient in for monthly appointments and injections.” (opens the source at this quote in a new tab)

Cost or time item	Mean ± SD
Number of visits per year	“10.4±0.8”
Travel and parking costs, AU$	“64.80±79.70”
Travel time per visit, hours	“2.4±1.6”
Caregiver time spent accompanying patient to appointment, hours	“6.2±1.1”
Hours per week needing assistance	“4.3±3.2”
Annual mean cost of caregivers, AU$	“5,333.58±2,184.20”

Caregiver time off work per treatment visit: Sweden

“Caregivers spent on average 2.6 h (2.5-2.8: 95% CI) per visit, and 19% needed to take time off work.” (opens the source at this quote in a new tab)
“The majority (91%) of patients did not experience any transportation problems associated with treatment.” (opens the source at this quote in a new tab)

Indirect cost per injection for patients and caregivers: U.S. economic model

“Indirect costs per injection for patients and carers were calculated using multiple parameters, including caregiver time taken for an injection appointment [31], the average US wage per working hour [32], reduction in hourly wage for nonworking people’s time [33], hours of lost productivity for a patient due to the injection and appointment [34], percentage of carers’ time taken from activities [34], percentage of patients who require a caregiver [34], the average distance, in miles, traveled to get to an appointment [34, 35], and cost per mile traveled [36], for an indirect total cost of 289.98 USD per injection for patient and carer” (opens the source at this quote in a new tab)
“Indirect costs represent a relatively small proportion of the overall costs compared with the drug costs.” (opens the source at this quote in a new tab)

Caregiver share of productivity losses: late-stage AMD in the United States

“Parameters included patient job loss, patient job reduction, caregiver job reduction due to caregiving responsibilities, caregiver job reduction due to providing transport to eye health care appointments, and caregiver loss of leisure time due to providing transport.” (opens the source at this quote in a new tab)
“In nAMD, 99% of the total cost attributed to the loss of productivity was due to the impact on patients, with caregivers contributing to the remaining 1% of the cost.” (opens the source at this quote in a new tab)

Hospital appointments as a driver of caregiver burden: systematic review

“The need to attend hospital appointments was identified in various studies as an important contributor to caregiver burden (Gohil et al., 2015; Varano et al., 2015; Spooner et al., 2018).” (opens the source at this quote in a new tab)
“Approximately two‐thirds of patients required an accompanying person for travel to/from the clinic (Droege et al., 2013; Varano et al., 2015; Muller et al., 2017).” (opens the source at this quote in a new tab)
“In another (n = 100 caregivers), approximately 75% of caregivers reported little or no burden associated with supporting patients with nAMD, as evaluated on the Burden Assessment Scale (Senra et al., 2017).” (opens the source at this quote in a new tab)

Caregiver perceptions of the impact of caring: survey of 643 caregivers

“A cross-sectional, self-administered survey of 643 caregivers of people with neovascular AMD, comprising 27 closed-response questions and 2 open ended questions.” (opens the source at this quote in a new tab)
“Very few seek or receive respite and this added burden can have a negative impact upon the relationship between caregiver and care recipient.” (opens the source at this quote in a new tab)

Who transports participants to injection visits, and out-of-pocket transport costs

“The majority of patients (72%, 54 of 75) were driven to their appointment by a caregiver.” (opens the source at this quote in a new tab)
“Their caregiver was a spouse or partner (65%, 35 of 54), an adult child or grandchild (22%, 12 of 54), a friend (7%, 4 of 54), or another person (6%, 3 of 54).” (opens the source at this quote in a new tab)
“Few patients experienced direct out-of-pocket transportation costs. Eighty-nine percent (67 of 75) reported that they did not pay any transportation costs for their latest clinic visit.” (opens the source at this quote in a new tab)

Household income of U.S. participants receiving anti-VEGF injections

“The average income was $40 000. The majority of patients (62%, 46 of 75) reported an income of less than or equal to $50 000.” (opens the source at this quote in a new tab)
“Seventeen percent (13 of 75) reported an income between $50 001 and $75 000 while 10% (8 of 75) had an income greater than $75 000.” (opens the source at this quote in a new tab)

Summary: imaging for diagnosis and treatment monitoring

Diagnosis and retreatment decisions in nAMD rely on retinal imaging, principally optical coherence tomography (OCT), with fluorescein angiography used mainly at diagnosis. A 2025 U.S. model priced an initial visit with office visit, OCT, and fluorescein angiography at $534.15 and each subsequent office visit with OCT at $184.58. In U.S. electronic health records, eyes underwent a mean of 7.2 OCT and 5.3 fluorescein angiography examinations in the first 12 months of treatment, and in commercial claims 88.1% of participants had at least one OCT visit per year (mean 4.5 visits). Among Medicare retina specialists, OCT increased from 61.5% of imaging in 2012 to 70.5% in 2016 while fluorescein angiography fell from 20.9% to 15.1%. OCT-guided as-needed and treat-and-extend dosing was estimated to have saved the U.S. government $9.0 billion and patients $2.2 billion from 2008 to 2015, net of about $0.8 billion in OCT imaging costs. In UK economic evaluations, SD-OCT monitoring of the fellow eye had lower lifetime costs than other monitoring tests, and strategies using OCT alone for diagnosis or monitoring were unlikely to be cost-effective.

Cost of monitoring visits with OCT and fluorescein angiography: U.S. model inputs (2025)

“The direct medical monitoring costs (2025, in USD) [29, 30] included office visits, fluorescein angiography, and optical coherence tomography (OCT) (Table S1 in the electronic supplementary material).” (opens the source at this quote in a new tab)
“Monitoring cost for initial visit in year 1 = (initial office visit + OCT + fluorescein angiography) = 534.15 USD.” (opens the source at this quote in a new tab)
“Direct medical monitoring costs in year 2 and thereafter (year ≥ 2) were equal to the adjusted number of injections (taking discontinuation and mortality into account) in year ≥ 2 multiplied by 184.58 USD (i.e., subsequent office visit + OCT).” (opens the source at this quote in a new tab)

OCT and fluorescein angiography use among Medicare retina specialists, 2012 to 2016

“National relative utilization of OCT increased from 61.5% in 2012 to 70.5% in 2016 (P < .001), while IVFA fell from 20.9% to 15.1% over the same interval (P < .001).” (opens the source at this quote in a new tab)
“Fundus photography decreased from 14.6% in 2012 to 11.7% in 2016 (P < .001).” (opens the source at this quote in a new tab)

Retinal imaging volume and anti-VEGF injection volume in Medicare, 2013 to 2021

“For anti-VEGF injections, a positive association in annual volume was observed with ocular coherence tomography ( P < 0.001, R 2 = 0.84), whereas negative associations were observed with FA ( P < 0.001, R 2 = 0.89) and FA + indocyanine-green angiography ( P < 0.001, R 2 = 0.90).” (opens the source at this quote in a new tab)
“Ocular coherence tomography continues to rise as a percentage of all retinal imaging ordered, whereas FA has declined.” (opens the source at this quote in a new tab)

Medicare and patient savings from OCT-guided anti-VEGF therapy, 2008 to 2015

“From 2008 – 2015, the United States government and nvAMD patients have accrued an estimated savings of $9.0 billion and $2.2 billion, respectively, from the use of OCT to guide personalized anti-VEGF treatment.” (opens the source at this quote in a new tab)

“Using the meta-analysis and survey data, we calculated the cost of using OCT imaging to guide anti-VEGF treatment decisions from 2008– 2015 was $0.8 billion.” (opens the source at this quote in a new tab)
“Anti-VEGF drugs, their injection and OCT imaging are covered under Medicare Part B, which requires beneficiaries to copay 20% of the Medicare-approved amount in the absence of supplementary Medigap insurance.” (opens the source at this quote in a new tab)

Imaging studies per beneficiary in Medicare, 1994 to 2006 cohorts

“There were significant increases in the mean yearly number of visits (2.1 vs. 3.5, p<0.0001), OCTs (0 vs. 2.1, <0.0001), and anti-VEGF injections (0 vs. 2.0, p<0.0001) between 1994 and 2006.” (opens the source at this quote in a new tab)
“From 1994 to 2006, payments for fluorescein angiography remained essentially stable, while those for OCT increased significantly.” (opens the source at this quote in a new tab)

OCT-related visits by disease activity: U.S. commercial claims

OCT test-related visits, prevalent cohort	All patients	Active CNV	Inactive CNV	Inactive scar
Patients with at least 1 visit, n (%)	“5,350 (88.1)”	“3,384 (92.6)”	“893 (85.4)”	“253 (70.7)”
Number of unique visits, mean (SD)	“4.5 (3.5)”	“5.4 (3.6)”	“2.9 (2.6)”	“1.6 (1.9)”

Monitoring frequency in routine practice: U.S. claims, 2006 to 2011

“In the 2008-2010 cohorts (n = 10 259), mean annual number of injections remained low (bevacizumab: 4.6, 5.1, and 5.5; ranibizumab: 6.1, 6.6, and 6.9), as did mean numbers of ophthalmologist visits (bevacizumab only) and OCT examinations (both agents), but there was no such trend in FA examinations.” (opens the source at this quote in a new tab)

“In the 2010 cohort, among bevacizumab- and ranibizumab-treated patients, respectively, less than 23% and less than 40% had at least 10 ophthalmologist visits, and less than 4% and less than 21% had at least 10 optical coherence tomography scans.” (opens the source at this quote in a new tab)

OCT examinations per year and vision-related quality of life: Germany (ALBATROS)

“1478 patients (74.5 ± 10.9 years, 54.9% female) were included in the analysis.” (opens the source at this quote in a new tab)
“8.8 ± 2.6 OCT examinations and 6.1 ± 3.2 intravitreal injections were performed within 12 months.” (opens the source at this quote in a new tab)
“After twelve months, an increase in visual acuity and visual functional scale was observed for nAMD, DME, and BRVO, while in DME only, there was an association between number of OCT examinations and VRQoL.” (opens the source at this quote in a new tab)

Cost-effectiveness of OCT for diagnosis and monitoring: UK Health Technology Assessment

“For monitoring, the pooled sensitivity and specificity (95% CI) was 85% (72% to 93%) and 48% (30% to 67%) respectively.” (opens the source at this quote in a new tab)
“The FFA for diagnosis and nurse-technician-led monitoring strategy had the lowest cost (£ 39,769; QALYs 10.473) and dominated all others except FFA for diagnosis and ophthalmologist-led monitoring (£ 44,649; QALYs 10.575; incremental cost-effectiveness ratio £ 47,768).” (opens the source at this quote in a new tab)
“Strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective.” (opens the source at this quote in a new tab)

Monitoring tests for nAMD in the fellow eye: EDNA economic evaluation (UK)

“SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests.” (opens the source at this quote in a new tab)
“Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS.” (opens the source at this quote in a new tab)

“The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)]” (opens the source at this quote in a new tab)

Community optometrist versus hospital monitoring of quiescent nAMD: cost per assessment (UK)

“The mean cost per assessment, including the subsequent care pathway, was £411 for optometrists and £397 for ophthalmologists: a cost difference of £13 (95% CI -£18 to £45).” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: anti-VEGF therapy as first-line treatment

“Anti-VEGF therapies have become first-line therapy for treating and stabilizing most cases of neovascular AMD, and a Cochrane systematic review demonstrates the effectiveness of these agents to maintain VA.” (opens the source at this quote in a new tab)
“(I++, Good quality, Strong recommendation)” (opens the source at this quote in a new tab)
“Adverse events for all anti-VEGF agents include rare risks of arterial thromboembolic events, endophthalmitis, and elevated intraocular pressure.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: management options and agent selection

“Anti-VEGF agents are cost-effective for the management of neovascular AMD, and the choice of which agent to use should be individually tailored based on discussion between the patient and physician.” (opens the source at this quote in a new tab)
“Management options for AMD include observation, antioxidant vitamin and mineral supplements, intravitreal injection of anti-VEGF agents, PDT, and laser photocoagulation surgery.” (opens the source at this quote in a new tab)

Cochrane systematic review of anti-VEGF agents versus control and bevacizumab versus ranibizumab

“We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial.” (opens the source at this quote in a new tab)
“Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95% CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95% CI 0.98 to 1.02; high-certainty evidence)” (opens the source at this quote in a new tab)
“Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups.” (opens the source at this quote in a new tab)

Ranibizumab: FDA-approved dosing in neovascular AMD

“LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).” (opens the source at this quote in a new tab)
“Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment.” (opens the source at this quote in a new tab)
“Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Patients should be assessed regularly.” (opens the source at this quote in a new tab)

Ranibizumab: label efficacy in the pivotal trials

“Almost all LUCENTIS-treated patients (approximately 95%) maintained their visual acuity. Among LUCENTIS-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months.” (opens the source at this quote in a new tab)

Ranibizumab: warnings and precautions

“Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be monitored following the injection (5.1).” (opens the source at this quote in a new tab)
“There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors (5.3).” (opens the source at this quote in a new tab)

Ranibizumab: MARINA sham-controlled trial

“We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons).” (opens the source at this quote in a new tab)
“During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.” (opens the source at this quote in a new tab)

Ranibizumab: ANCHOR trial versus verteporfin photodynamic therapy

“Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison).” (opens the source at this quote in a new tab)
“Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P<0.001 for each comparison).” (opens the source at this quote in a new tab)

Bevacizumab: off-label intravitreal use

“Bevacizumab is a full-length monoclonal antibody that binds all isoforms of VEGF. It is FDA approved for intravenous use in the treatment of metastatic colorectal, metastatic breast, and non-small cell lung cancer.” (opens the source at this quote in a new tab)
“Because preliminary reports appeared favorable, ophthalmologists began using intravitreal bevacizumab off-label to treat MNV.” (opens the source at this quote in a new tab)
“The off-label status of bevacizumab for neovascular AMD should be included in the discussion; information and a consent form are available from the Ophthalmic Mutual Insurance Company.” (opens the source at this quote in a new tab)

Bevacizumab versus ranibizumab: CATT 1-year results

“In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation.” (opens the source at this quote in a new tab)
“Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively.” (opens the source at this quote in a new tab)
“The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66)” (opens the source at this quote in a new tab)

Bevacizumab versus ranibizumab: CATT 2-year results

“Among patients following the same regimen for two years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference: −1.4 letters; 95% confidence interval (CI): [−3.7, 0.8]; p=0.21).” (opens the source at this quote in a new tab)
“The proportion of patients with ≥1 systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio 1.30; CI [1.07, 1.57]; p=0.009).” (opens the source at this quote in a new tab)

Bevacizumab versus ranibizumab: IVAN 2-year results

“610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses.” (opens the source at this quote in a new tab)
“For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26).” (opens the source at this quote in a new tab)
“Ranibizumab and bevacizumab have similar efficacy.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: comparative efficacy and safety of bevacizumab and ranibizumab

“Presently, there does not appear to be a significant difference in efficacy between ranibizumab and bevacizumab.” (opens the source at this quote in a new tab)
“The systemic safety data in the CATT and IVAN studies are inconclusive and two Cochrane systematic reviews have also concluded that if a difference in safety between these anti-VEGF drugs exists, it is minimal.” (opens the source at this quote in a new tab)

Bevacizumab, ranibizumab, and aflibercept: IRIS Registry real-world comparison

“Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year.” (opens the source at this quote in a new tab)
“There was no statistical difference in the age-adjusted or multivariate-adjusted mean logMAR VA change (standard deviation) at 1 year among treatment groups (-0.048 [0.44] bevacizumab, -0.053 [0.46] ranibizumab, -0.040 [0.39] aflibercept; P = 0.46).” (opens the source at this quote in a new tab)

Bevacizumab: EURETINA guideline recommendation on regimen

“Bevacizumab, as needed, failed to meet NI equivalence to monthly ranibizumab, that is, bevacizumab used in a PRN regimen did not reach the superior visual outcome achievable with monthly ranibizumab. Therefore, choice of the proper (fixed monthly) regimen is relevant when off-label bevacizumab is used.” (opens the source at this quote in a new tab)

NICE guideline NG82: anti-VEGF agents considered equivalent

“Offer intravitreal anti-vascular endothelial growth factor (VEGF) treatment for late AMD (wet active) for eyes with visual acuity within the range specified in recommendation 1.5.6.” (opens the source at this quote in a new tab)
“Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: cost-effectiveness of bevacizumab and ranibizumab

“This study estimated the cost utility of bevacizumab treatment (relative to no treatment) at approximately $2,700 per quality-adjusted life year ([QALY] for monthly dosing) and $3,300 per QALY (for PRN dosing). In contrast, the cost-effectiveness of ranibizumab was estimated as $63,300/QALY for monthly dosing and $18,600 per QALY for PRN dosing.” (opens the source at this quote in a new tab)
“Wholesale prices of anti-VEGF medications range from $50 to $1,950 per dose, depending on the medication.” (opens the source at this quote in a new tab)

Brolucizumab: description and approved dosing

“Brolucizumab 6 mg is a single-chain variable fragment (the smallest functional portion of an antibody) that binds VEGF-A and was approved by the FDA for the treatment of neovascular AMD.” (opens the source at this quote in a new tab)

“The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately every 25-31 days) for the first three doses, followed by one dose of 6 mg (0.05 mL) every 8-12 weeks (2.2).” (opens the source at this quote in a new tab)

Brolucizumab: HAWK and HARRIER 48-week results

“Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.” (opens the source at this quote in a new tab)
“At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison).” (opens the source at this quote in a new tab)
“Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]).” (opens the source at this quote in a new tab)

Brolucizumab: HAWK and HARRIER 96-week results

“At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively.” (opens the source at this quote in a new tab)

“The proportion of patients who were maintained on every 12-week dosing through Week 96 was 45% and 39% in HAWK and HARRIER, respectively.” (opens the source at this quote in a new tab)

Brolucizumab: retinal vasculitis and retinal vascular occlusion warning

“Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of BEOVU. These immune-mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with BEOVU in patients who develop these events.” (opens the source at this quote in a new tab)

Brolucizumab: Safety Review Committee analysis of intraocular inflammation in HAWK and HARRIER

“On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%).” (opens the source at this quote in a new tab)
“Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%.” (opens the source at this quote in a new tab)

Brolucizumab: MERLIN every-4-week dosing terminated for intraocular inflammation

“Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% (0.8% and 2.0%) for brolucizumab versus 4.5% (0% and 0%) for aflibercept, respectively.” (opens the source at this quote in a new tab)
“However, incidences of IOI, including retinal vasculitis and retinal vascular occlusion, also were higher, leading to study termination.” (opens the source at this quote in a new tab)

“Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, was 11.5% (0.8% and 2.2%) for brolucizumab versus 6.1% (0% and 0.6%) for aflibercept.” (opens the source at this quote in a new tab)
“therefore, brolucizumab should not be used more frequently than every 8 weeks after the loading regimen.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: brolucizumab safety

“After FDA approval, several cases of occlusive retinal vasculitis occurred after intravitreal brolucizumab injection.” (opens the source at this quote in a new tab)
“Brolucizumab is approved for use every 8 to 12 weeks after the loading period, and more frequent administration should be avoided.” (opens the source at this quote in a new tab)
“Although HAWK and HARRIER found a 2.1% incidence of retinal vasculitis with retinal vascular occlusion, postmarketing surveillance revealed a higher incidence of intraocular inflammation.” (opens the source at this quote in a new tab)

Medicare Advantage step therapy for Part B drugs: CMS policy

“issuing new guidance that recognizes Medicare Advantage (MA) plans may use step therapy for Part B drugs, beginning January 1, 2019, as part of a patient-centered care coordination program.” (opens the source at this quote in a new tab)

Medicare Advantage step therapy: bevacizumab-first payer policy example

“Repackaged Avastin, then Eylea or Eylea HD or Pavblu” (opens the source at this quote in a new tab)
“History of a trial of at least 3 consecutive doses given monthly, resulting in minimal clinical response to repackaged Avastin (bevacizumab); or History of contraindication or adverse event(s) to repackaged Avastin (bevacizumab); or Continuation of prior therapy within the past 365 days.” (opens the source at this quote in a new tab)

Step therapy: bevacizumab-first policies and supply disruption

“Following the 2019 Centers for Medicare and Medicaid Services (CMS) decision permitting Medicare Advantage plans to impose step therapy for Part B drugs, many insurers adopted a bevacizumab (Avastin, Genentech/Roche)-first approach.” (opens the source at this quote in a new tab)
“In addition, with rigid fail-first protocols, patients are often required to receive three monthly bevacizumab injections before a switch can be approved.” (opens the source at this quote in a new tab)
“the problem intensified in 2024 with the discontinuation of bevacizumab production from Optum Specialty Pharmacy, the facility responsible for 45% of bevacizumab repackaging in the United States.” (opens the source at this quote in a new tab)

Step therapy: AAO position

“The Academy opposes the adoption of step therapy in Medicare Advantage, which now covers over half of all Medicare beneficiaries, and commercial payer policies.” (opens the source at this quote in a new tab)

ASRS Preferences and Trends survey: agent switching after suboptimal bevacizumab response

“The survey was given electronically to 2,971 members of the society (2,615 regular members and 356 fellows); 1,057 respondents completed the survey (35-percent response rate).” (opens the source at this quote in a new tab)
“For wet AMD patients who have a suboptimal response to Avastin (bevacizumab, Genentech) treatment, 88.4 percent of the physicians say they’ll switch to Eylea (aflibercept, Regeneron).” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: aflibercept 2 mg

“the 2-mg dose has been documented to be of similar efficacy to ranibizumab in the head-to-head phase-3 VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials.” (opens the source at this quote in a new tab)
“Aflibercept was found to have a 0% to 0.16% rate of intraocular inflammation (not counting endophthalmitis).” (opens the source at this quote in a new tab)

Aflibercept 2 mg: FDA-approved dosing

“The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).” (opens the source at this quote in a new tab)
“Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.” (opens the source at this quote in a new tab)

Aflibercept 2 mg: VIEW 1 and VIEW 2 trials

“Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.” (opens the source at this quote in a new tab)
“All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies).” (opens the source at this quote in a new tab)

Aflibercept 2 mg: label efficacy and warnings

“Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1.” (opens the source at this quote in a new tab)
“Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: FDA-approved dosing

“The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week.” (opens the source at this quote in a new tab)
“Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: PULSAR 48-week results

“Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment” (opens the source at this quote in a new tab)
“Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters).” (opens the source at this quote in a new tab)
“The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]).” (opens the source at this quote in a new tab)

Aflibercept 8 mg: PULSAR interval maintenance at week 48

“At 48 weeks, 79% of eyes maintained 12-week dosing intervals and 77% maintained 16-week dosing intervals.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: label injection counts and intervals through week 96

“In patients completing week 48, the mean number of injections administered was 5.2 in the HDq16 group (n=312), 6.1 in the HDq12 group (n=316) and 6.9 in the EYLEA q8 group (n=309).” (opens the source at this quote in a new tab)
“During the second year of treatment in patients who completed week 96, the mean number of injections administered was 3 in the HDq16 group (n=292), 3.7 in the HDq12 group (n=291) and 5.8 in the 2q8 group (n=286).” (opens the source at this quote in a new tab)
“In the pooled HDq12 and HDq16 groups, patients maintained their visual and anatomic outcomes through week 96, with 71% and 46.8% of patients attaining treatment intervals of ≥16 weeks and ≥20 weeks, respectively, at week 96.” (opens the source at this quote in a new tab)
“6.2% of total EYLEA HD treated patients who met protocol-defined criteria to be treated every 8 weeks did not maintain a response with every 8 weeks dosing after successful response to the 3 initial monthly doses.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: PULSAR 96-week outcomes by baseline disease severity

“Overall, 869 patients completed treatment through week 96.” (opens the source at this quote in a new tab)
“Patients in the aflibercept 8q12 and 8q16 arms achieved visual and anatomic outcomes at week 96 comparable to those in the aflibercept 2q8 arm within subgroups defined by baseline disease severity.” (opens the source at this quote in a new tab)

NICE guideline NG82: aflibercept recommendation

“Aflibercept solution for injection is recommended as an option for treating wet age-related macular degeneration only if: it is used in accordance with the recommendations for ranibizumab in NICE's technology appraisal guidance on ranibizumab and pegaptanib for the treatment of age-related macular degeneration” (opens the source at this quote in a new tab)

Injections received in VIEW 1 and VIEW 2 through weeks 52 and 96

“The mean number of active injections received by patients in all monthly treatment arms, which were scheduled to receive 13 monthly injections, was 12.1 to 12.5 in VIEW 1 and 12.2 to 12.4 in VIEW 2.” (opens the source at this quote in a new tab)
“The total number of active injections (baseline to week 96) was 16.0 to 16.2 in the monthly intravitreal aflibercept groups, 16.5 in the monthly ranibizumab group, and 11.2 in the original 2q8 group.” (opens the source at this quote in a new tab)

Monitoring schedule in year 1 and the modified quarterly protocol in year 2 of VIEW 1 and VIEW 2

“Patients were examined on the day of treatment initiation and every 4 weeks thereafter through 52 weeks, as well as 1 week after first treatment for safety assessment (subsequent safety assessments occurred by telephone).” (opens the source at this quote in a new tab)
“After the 1-year primary end point of VIEW 1/VIEW 2 presented in this article, all treatment groups’ dosing intervals were changed to a common protocol of modified quarterly dosing with their originally randomized dose and drug (all patients were monitored monthly and received a minimum of dosing every 12 weeks with interim as-needed monthly intravitreal injections).” (opens the source at this quote in a new tab)

Injection-related serious ocular adverse events per 1000 injections in VIEW 1 and VIEW 2

“The combined data for both studies showed a rate of events/1000 injections of 1.1, 0.8, 0.1, and 0.2 for the ranibizumab 0.5q4 and intravitreal aflibercept 2q4, 0.5q4, and 2q8 groups, respectively.” (opens the source at this quote in a new tab)
“These events included eye disorders, endophthalmitis, procedural complications, and increased intraocular pressure.” (opens the source at this quote in a new tab)

PULSAR criteria for shortening the aflibercept 8 mg dosing interval

“Beginning at week 16, patients receiving aflibercept 8 mg were assessed and the dosing interval was shortened if the following DRM criteria were met: BCVA loss of more than 5 letters from week 12 and either a more than 25 μm increase in central retinal thickness (CRT) from week 12 or new foveal haemorrhage or neovascularisation” (opens the source at this quote in a new tab)
“Patients in the aflibercept 8q12 and 8q16 groups who met the DRM criteria at week 16 or week 20 had their interval shortened and subsequently received aflibercept 8 mg every 8 weeks.” (opens the source at this quote in a new tab)

Ocular and systemic safety in PULSAR through week 48

“Serious ocular TEAEs in the study eye occurred in 13 (1·3%) of 1009 patients” (opens the source at this quote in a new tab)
“In PULSAR, rates of intraocular inflammation with aflibercept were low, and there were no cases of endophthalmitis or retinal vasculitis up to week 48.” (opens the source at this quote in a new tab)
“All cases of intraocular inflammation were mild or moderate in severity.” (opens the source at this quote in a new tab)
“Eight cases of arteriothrombotic events, assessed and categorised by an Anti-Platelet Trialists’ Collaboration adjudication committee, were reported, with no clinically relevant differences observed across groups” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: faricimab

“Faricimab-svoa, a humanized bispecific monoclonal antibody for intravitreal use that acts through dual inhibition of both angiopoietin-2 and VEGF-A, was approved by the FDA for the treatment of patients with neovascular AMD.” (opens the source at this quote in a new tab)
“Approximately 80% of eyes could be dosed every 12 weeks or more, and 45% could be dosed every 16 weeks in year 1 and increased to 63% in year 2. Through year 2, the median number of injections in the faricimab group was 10, compared with 15 for aflibercept.” (opens the source at this quote in a new tab)

Faricimab: FDA-approved dosing

“The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44.” (opens the source at this quote in a new tab)

Faricimab: TENAYA and LUCERNE primary results

“Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept).” (opens the source at this quote in a new tab)
“BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]).” (opens the source at this quote in a new tab)

Faricimab: TENAYA and LUCERNE 2-year results with treat-and-extend dosing

“At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing.” (opens the source at this quote in a new tab)
“Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112.” (opens the source at this quote in a new tab)

Faricimab: label dosing-interval distribution and FDA caveats

“At week 48, after 4 initial monthly doses in the VABYSMO arm, 45% of patients received the Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the remaining 22% of patients received dosing every 8 weeks.” (opens the source at this quote in a new tab)
“The disease activity criteria, which was instrumental in determining dose frequency, is unvalidated.” (opens the source at this quote in a new tab)
“The clinical efficacy for the second year of the study has not been reviewed.” (opens the source at this quote in a new tab)

Faricimab: safety

“The most common adverse reactions (≥ 5%) reported in patients receiving VABYSMO were cataract (15%) and conjunctival hemorrhage (8%).” (opens the source at this quote in a new tab)

“Recently, case reports of intraocular inflammation (excluding endophthalmitis) with faricimab were as high as 2% and retinal vasculitis with or without occlusion were 0.17 per 10,000 injections (vasculitis) and 0.06 per 10,000 for occlusive vasculitis.” (opens the source at this quote in a new tab)

Faricimab: real-world use in previously treated eyes (TRUCKEE)

“Six-month results included 376 eyes, 337 of which had been previously treated with other anti-VEGF agents with an average of 31.1 prior injections.” (opens the source at this quote in a new tab)

NICE technology appraisal TA800: faricimab

“If patients and their clinicians consider faricimab to be 1 of a range of suitable treatments (including aflibercept and ranibizumab), choose the least expensive treatment.” (opens the source at this quote in a new tab)
“Evidence from clinical trials shows that faricimab is as effective as aflibercept. An indirect comparison of faricimab with ranibizumab also suggests similar clinical effectiveness.” (opens the source at this quote in a new tab)

Network meta-analysis of anti-VEGF agents and regimens

“Forty‐nine RCTs including 23 257 eyes of 23 257 patients were included. No anti‐VEGF drug or treatment regimen provided a better BCVA response compared to the reference.” (opens the source at this quote in a new tab)
“When results are considered simultaneously, faricimab 6.0 mg or aflibercept 8.0 mg in a treatment regimen with an LD followed by either a treat‐and‐extend regimen or a fixed 12‐ or 16‐week regimen appears to provide the optimal balance between visual outcomes, anatomical outcomes and the lowest treatment burden.” (opens the source at this quote in a new tab)

Fixed dosing without rescue treatment in TENAYA and LUCERNE

“From day 1, patients randomly assigned to the faricimab group initially received intravitreal faricimab 6·0 mg every 4 weeks up to week 12 (four injections) and patients in the aflibercept group received intravitreal aflibercept 2·0 mg, per its international label guidance, every 4 weeks up to week 8 (three injections), followed by fixed 8-week dosing to study end, without allowing rescue or additional treatments during the study.” (opens the source at this quote in a new tab)
“Patients in the faricimab group who did not have active disease at weeks 20 and 24 received faricimab at week 28 and continued a 16-week regimen up to week 60.” (opens the source at this quote in a new tab)

Intraocular inflammation and endophthalmitis in TENAYA and LUCERNE at week 48

“Rates of intraocular inflammation were low across both trials.” (opens the source at this quote in a new tab)
“In TENAYA and LUCERNE, at week 48, rates of intraocular inflammation were low and on average reported in 2·0% of patients receiving faricimab and 1·2% of patients receiving aflibercept” (opens the source at this quote in a new tab)
“There was one report of endophthalmitis in the aflibercept group of LUCERNE, which was culture negative.” (opens the source at this quote in a new tab)

Treat-and-extend interval rules and maintenance of extended intervals in year 2

“In brief, dosing intervals could be extended by 4 weeks (up to Q16W) if the patient achieved stable anatomic features, vision, and no new macular hemorrhage.” (opens the source at this quote in a new tab)
“The interval was reduced by 4- or 8-week increments (as low as Q8W) if worsening vision or anatomic features were found, or new macular hemorrhage occurred” (opens the source at this quote in a new tab)
“On average, 71% of patients who achieved the extended dosing interval of Q12W or longer during the fixed-dosing phase in year 1 maintained Q12W or longer dosing without a reduction to Q8W dosing during the T&E PTI dosing phase through year 2” (opens the source at this quote in a new tab)
“Similarly, 69% of patients receiving Q16W dosing during the fixed-dosing phase in year 1 continued to receive that treatment interval without deviation during the T&E PTI dosing phase” (opens the source at this quote in a new tab)

Serious ocular adverse events and intraocular inflammation through week 112

“The proportion of patients with serious ocular AEs in the study eye through week 112 was low and comparable across study arms in TENAYA (faricimab up to Q16W, 14 patients [4.2%]; aflibercept Q8W, 13 patients [3.9%]) and LUCERNE (faricimab up to Q16W, 15 patients [4.5%]; aflibercept Q8W, 16 patients [4.9%]).” (opens the source at this quote in a new tab)
“The incidence of intraocular inflammation (IOI) events through week 112 was low and comparable between patients receiving faricimab up to Q16W (TENAYA, 11 events [3.3%]; LUCERNE, 9 events [2.7%]) and aflibercept Q8W (TENAYA, 5 events [1.5%]; LUCERNE, 10 events [3.1%]; Table 5)” (opens the source at this quote in a new tab)
“All IOI events except 1 were nonserious.” (opens the source at this quote in a new tab)
“Also, no new retinal vasculitis or noninflammatory occlusive events were reported, in line with their absence at the primary analysis.” (opens the source at this quote in a new tab)

FDA-approved ranibizumab and aflibercept biosimilars

Nonproprietary name	Biosimilar product	Approval date	Reference product
Ranibizumab-nuna	“Byooviz (ranibizumab-nuna)”	“September 2021”	“Lucentis (ranibizumab)”
Ranibizumab-eqrn	“Cimerli (ranibizumab-eqrn)”	“August 2022”	“Lucentis (ranibizumab)”
Ranibizumab-leyk	“Nufymco (ranibizumab-leyk)”	“December 2025”	“Lucentis (ranibizumab)”
Ranibizumab-hkdz	“Ranluspec (ranibizumab-hkdz)”	“June 2026”	“Lucentis (ranibizumab)”
Aflibercept-yszy	“Opuviz (aflibercept-yszy)”	“May 2024”	“Eylea (aflibercept)”
Aflibercept-jbvf	“Yesafili (aflibercept-jbvf)”	“May 2024”	“Eylea (aflibercept)”
Aflibercept-mrbb	“Ahzantive (aflibercept-mrbb)”	“June 2024”	“Eylea (aflibercept)”
Aflibercept-abzv	“Enzeevu (aflibercept-abzv)”	“August 2024”	“Eylea (aflibercept)”
Aflibercept-ayyh	“Pavblu (aflibercept-ayyh)”	“August 2024”	“Eylea (aflibercept)”
Aflibercept-boav	“Eydenzelt (aflibercept-boav)”	“October 2025”	“Eylea (aflibercept)”

AAO Preferred Practice Pattern: biosimilar approval standard and product choice

“Ophthalmic biosimilars require one comparative trial of 9 months or more for AMD demonstrating safety and efficacy compared with the reference product.” (opens the source at this quote in a new tab)
“They have no clinically meaningful differences from the reference product except in inactive components, or excipients, which can have implications for safety.” (opens the source at this quote in a new tab)
“There are no prospective long-term clinical data comparing ranibizumab biosimilars to ranibizumab.” (opens the source at this quote in a new tab)
“When used, the choice of biologic product (reference, biosimilar, or interchangeable) should be that of the treating ophthalmologist and the patient because patients may respond more favorably to one biologic over another.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: aflibercept biosimilar dosing

“All are injected intravitreally as a 2-mg solution, and the adverse events appear comparable to aflibercept. The recommended dose for all five agents is 2 mg every 4 weeks for the first 12 weeks, followed by 2 mg every 8 weeks.” (opens the source at this quote in a new tab)

Ranibizumab-nuna: biosimilar labeling and dosing

“BYOOVIZ (ranibizumab-nuna) is biosimilar 1 to LUCENTIS (ranibizumab injection)” (opens the source at this quote in a new tab)
“BYOOVIZ 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month (approximately 28 days).” (opens the source at this quote in a new tab)

Ranibizumab-eqrn and aflibercept-ayyh: biosimilar labeling

“CIMERLI (ranibizumab-eqrn) is biosimilar* to LUCENTIS® (ranibizumab injection).” (opens the source at this quote in a new tab)

“PAVBLU (aflibercept-ayyh) is biosimilar* to EYLEA® (aflibercept).” (opens the source at this quote in a new tab)

Ranibizumab biosimilar SB11: phase 3 equivalence trial

“This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions.” (opens the source at this quote in a new tab)
“Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of −0.8 letter (90% CI, −1.8 to 0.2 letters).” (opens the source at this quote in a new tab)
“Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group.” (opens the source at this quote in a new tab)

Ranibizumab biosimilar FYB201: COLUMBUS-AMD equivalence trial

“A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239).” (opens the source at this quote in a new tab)
“The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was -0.4 ETDRS letters with a 90% confidence interval (CI) of -1.6 to 0.9.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: Medicare prices and modeled savings from biosimilars

“Medicare Part B average sales prices for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept 2 mg were $776, $1,292, and $1,806, respectively, as of October 2022.” (opens the source at this quote in a new tab)
“The model predicted that a bevacizumab biosimilar priced at $500 would increase Medicare Part B costs by $457 million annually, and one priced at $900 would increase costs by $897 million annually. However, switching from ranibizumab and aflibercept 2 mg to their biosimilars could lead to total cost savings of $132 million for Medicare.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: boxed warning for endophthalmitis

“The SUSVIMO implant has been associated with an up to 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab. Many of these events were associated with conjunctival retractions or erosions.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: indication and dosing

“Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a VEGF inhibitor (1.1).” (opens the source at this quote in a new tab)
“The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately 6 months).” (opens the source at this quote in a new tab)
“Supplemental treatment with 0.5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: Archway phase 3 trial

“Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab.” (opens the source at this quote in a new tab)
“Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters).” (opens the source at this quote in a new tab)
“Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: label supplemental treatment and endophthalmitis rates

“In the first 24 weeks, 1.6% of patients assessed for supplemental treatment received 1 or more supplemental treatment(s) and in the following 24 weeks, 5.4% of patients assessed for supplemental treatment received 1 or more supplemental treatment(s).” (opens the source at this quote in a new tab)
“In the active comparator period of controlled clinical trials in AMD, the ranibizumab implant has been associated with a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab (1.7% in the SUSVIMO arm vs 0.5% in the intravitreal arm). When including extension phases of clinical trials, 2% (11/555) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: septum dislodgement

“In clinical trials, a type of implant damage where the septum has dislodged into the implant body has been reported.” (opens the source at this quote in a new tab)
“The benefits and risks of retaining, removing, or removing and replacing an implant with a dislodged septum are not well characterized.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: endophthalmitis case series across clinical trials

“Twelve endophthalmitis events were reported in 11 patients (11/555 [2.0%]) through March 12, 2021.” (opens the source at this quote in a new tab)
“Seven cases (7/11 [63.6%]) had preceding/concurrent conjunctival complications. At last follow-up, 7 patients recovered vision to study baseline levels or ≥20/40; 4 patients experienced vision loss of ≥15 ETDRS letters.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: Portal extension trial

“In the All-PDS safety population (mean follow-up, 111 weeks), 137 (24.7%) patients had ≥1 ocular AESI; most common were cataract (11.4%), vitreous hemorrhage (6.1%), and conjunctival thickening (bleb)/filtering bleb leak (6.3%). Endophthalmitis occurred in 11 of 555 (2.0%) patients.” (opens the source at this quote in a new tab)
“Approximately 95% of patients did not need supplemental treatment before each refill-exchange for >2 years since Portal enrollment.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: 5-year Portal results

“In the Susvimo cohort, best-corrected visual acuity (BCVA) was 74.4 letters at baseline and 67.6 letters at 5 years. In the IVT-Susvimo cohort, BCVA was 76.3 letters at baseline and 68.6 at 5 years.” (opens the source at this quote in a new tab)

Ranibizumab port delivery system: voluntary recall and reintroduction

“Susvimo was approved by the FDA in 2021. The following year, Genentech voluntarily recalled the ocular implant, insertion tool and initial fill kit in the U.S. following test results that showed some implants did not perform to Genentech’s standards.” (opens the source at this quote in a new tab)
“The U.S. Food and Drug Administration (FDA) has approved a post-approval supplement to the Biologics License Application for Susvimo, reflecting component-level updates made to the ocular implant and refill needle.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: port delivery system risks and cost-effectiveness

“Importantly, after using the implant, there was a 2% risk of endophthalmitis in clinical trials (a rate three times higher than monthly intravitreal injections of ranibizumab).” (opens the source at this quote in a new tab)
“They found that although the implant seemed to compare favorably at $21,825 with two ranibizumab 100-mg/ml fills at 1 year compared with $18,405 for 11.8 injections of ranibizumab 0.5 mg over that same time period, this benefit did not seem to extend to 5- and 12-year time points.” (opens the source at this quote in a new tab)

Timing of endophthalmitis after port delivery system implantation

“There were 2 cases (2/555 [0.4%]) of postoperative endophthalmitis consistent with acute postoperative endophthalmitis.” (opens the source at this quote in a new tab)
“The range of onset for all other cases was 57 to 853 days after the PDS implant insertion procedure (Table 3), including 6 cases occurring in the first year after the PDS implant insertion procedure and 1 case occurring >2 years after the PDS implant insertion procedure (Fig 2).” (opens the source at this quote in a new tab)
“The retraction cases presented relatively earlier in the first year after surgery, with onset ranging between 2 to 6 months after implantation surgery, whereas the erosion cases presented later, with onset ranging from 20 to 28 months after implantation surgery.” (opens the source at this quote in a new tab)

Severity, organisms, and management of port delivery system endophthalmitis cases

“all patients experienced moderate (4/11 [36.4%]) or severe (7/11 [63.6%]) endophthalmitis when events were analyzed by greatest intensity.” (opens the source at this quote in a new tab)
“Three cases of endophthalmitis were culture positive (1 case each of Streptococcus pneumoniae, Enterococcus faecalis, Staphylococcus aureus; the case positive for E. faecalis reported history of exposure to a septic tank 1 week prior).” (opens the source at this quote in a new tab)
“Vitrectomy was performed for endophthalmitis in 5 cases; vitrectomy and a scleral wound revision was performed after endophthalmitis had resolved for 1 additional case to treat a subsequent event of wound leak/hypotony.” (opens the source at this quote in a new tab)
“Six patients had the PDS implant removed after their endophthalmitis episode per surgeon's preference, and 1 patient with endophthalmitis associated with E. faecalis discontinued refills but retained the implant at the surgeon's discretion.” (opens the source at this quote in a new tab)

Serious ocular adverse events of special interest in the pooled port delivery system population

“Other important ocular AESIs included conjunctival erosion (reported in 4.0% [22/555] of patients), conjunctival retraction (1.8% [10/555]), endophthalmitis (2.0% [11/555]), hyphema (1.6% [9/555]), implant dislocation (1.1% [6/555]), rhegmatogenous retinal detachment (0.7% [4/555]), and septum dislodgement (0.5% [3/555]) (Table 6).” (opens the source at this quote in a new tab)
“Among ocular AESIs reported as serious, the most common were endophthalmitis (1.8% [10/555]), conjunctival erosion (1.3% [7/555]), and conjunctival retraction (0.9% [5/555]; Table 6).” (opens the source at this quote in a new tab)
“Overall, 73.0% (27/37) of vitreous hemorrhage events were mild; most (91.9% [34/37]) resolved with observation.” (opens the source at this quote in a new tab)
“The majority of conjunctival bleb events involved fluid and most resolved after approximately 11 (mean, 11.21) weeks, without the need for additional procedures.” (opens the source at this quote in a new tab)

Septum dislodgement and the 2022 voluntary recall

“Since the March 2021 data cut used for the current analysis, there were an additional 30 septum dislodgements to August 2022 across the PDS clinical trials.” (opens the source at this quote in a new tab)
“Due to additional testing conducted during an investigation into septum dislodgement cases in phase III clinical trials, Roche/Genentech initiated a voluntary recall of the PDS Ocular Implant and Insertion Tool Assembly in October 2022 and paused all new implantations.” (opens the source at this quote in a new tab)

Number and timing of supplemental injections between refill-exchanges in Portal

“Across all treatment arms, 39 supplemental treatments were administered in 21 patients (data not shown).” (opens the source at this quote in a new tab)
“Of these, 32 supplemental treatments occurred 8 weeks before a refill-exchange, and 7 occurred 4 weeks before a refill-exchange.” (opens the source at this quote in a new tab)
“Of the 21 patients, 9 received 1 treatment, 9 received 2 treatments, 2 received 3 treatments, and 1 received 5 treatments.” (opens the source at this quote in a new tab)

Ocular adverse events associated with persistent vision loss and their timing

“Six of 7 episodes of conjunctival erosion that occurred across the analysis period were associated with significant persistent vision loss, of which 2 were repeat events.” (opens the source at this quote in a new tab)
“One episode of endophthalmitis occurred 2.3 years after implantation in Ladder and was attributed to the refill-exchange procedure.” (opens the source at this quote in a new tab)
“As shown by the distribution of ocular AESIs over time, all events that occurred >2 years after PDS implantation were in patients who received the PDS implant earlier in the PDS clinical trial program, and surgical procedures have since been further optimized.” (opens the source at this quote in a new tab)

Supplemental treatment before the first refill-exchange in Archway

“Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure.” (opens the source at this quote in a new tab)
“In total, 4 PDS-treated patients (1.6%) who were assessed for supplemental treatment received supplemental treatment before the first refill-exchange procedure.” (opens the source at this quote in a new tab)

Timing and surgical management of ocular adverse events in Archway

“Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation.” (opens the source at this quote in a new tab)
“endophthalmitis occurred in 4 patients (1.6%) in the PDS Q24W arm; all events were serious and occurred outside of the postoperative period at days 57, 59, 161, and 282. Three of the 4 events were associated with conjunctival retraction.” (opens the source at this quote in a new tab)
“Conjunctival erosion and conjunctival retraction events occurred in 6 patients (2.4%) and 5 patients (2.0%) in the PDS Q24W arm, respectively.” (opens the source at this quote in a new tab)
“In total, 9 of 11 patients required additional surgery, and events were addressed with conjunctival flap revisions; 3 repairs were performed using split-thickness corneal graft.” (opens the source at this quote in a new tab)

Vitreous hemorrhage, conjunctival bleb, and unscheduled visits in Archway

“Vitreous hemorrhage occurred in 13 patients (5.2%) in the PDS Q24W arm; 1 event was serious and 12 of 13 events occurred in the postoperative period.” (opens the source at this quote in a new tab)
“Eleven of 13 hemorrhages (84.6%) were grade 1 or 2 based on functional impact (Table S2, available at www.aaojournal.org), and all events resolved spontaneously without vitrectomy.” (opens the source at this quote in a new tab)
“Conjunctival bleb or conjunctival filtering bleb leak events were reported in 16 patients (6.5%) in the PDS Q24W arm. All events were nonserious.” (opens the source at this quote in a new tab)
“Of these 47 PDS patients, 16 underwent at least 1 unscheduled visit within 7 days of occurrence of an ocular adverse event of special interest, and 18 underwent at least 1 unscheduled visit within 14 days of occurrence.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: role of verteporfin photodynamic therapy

“Although current practice patterns support anti-VEGF monotherapy for exudative neovascular AMD, verteporfin PDT remains approved for the treatment of subfoveal lesions and can be used in certain situations.” (opens the source at this quote in a new tab)
“The DENALI and MONT BLANC studies (ranibizumab and verteporfin PDT compared with ranibizumab alone) did not show a significant benefit of adding PDT to anti-VEGF therapy in new-onset neovascular AMD.” (opens the source at this quote in a new tab)
“However, the EVEREST study demonstrated that fewer anti-VEGF injections were needed in combination therapy compared with anti-VEGF monotherapy in eyes with the PCV variant of neovascular AMD.” (opens the source at this quote in a new tab)

Verteporfin: FDA-approved indication

“VISUDYNE (verteporfin for injection) therapy is a photoenhancer indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.” (opens the source at this quote in a new tab)

Verteporfin photodynamic therapy: TAP trials

“Six hundred nine patients were randomly assigned (2: 1) to verteporfin (6 mg per square meter of body surface area) or placebo (5% dextrose in water) administered via intravenous infusion of 30 mL over 10 minutes.” (opens the source at this quote in a new tab)
“At the month-12 examination, 246 (61%) of 402 eyes assigned to verteporfin compared with 96 (46%) of 207 eyes assigned to placebo had lost fewer than 15 letters of visual acuity from baseline (P<.001).” (opens the source at this quote in a new tab)

Verteporfin photodynamic therapy: complications

“A severe decrease in central vision occurred within 1 week following treatment in 1% to 4% of patients, which may be permanent” (opens the source at this quote in a new tab)
“Verteporfin is contraindicated in patients with porphyria or a known allergy or sensitivity to the drug.” (opens the source at this quote in a new tab)

NICE guideline NG82: photodynamic therapy

“Do not offer photodynamic therapy alone for late AMD (wet active).” (opens the source at this quote in a new tab)
“Do not offer photodynamic therapy as an adjunct to anti-VEGF as first-line treatment for late AMD (wet active).” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: thermal laser photocoagulation

“There still remains a role for laser photocoagulation surgery in eyes with extrafoveal and peripapillary CNV lesions as defined by the MPS.” (opens the source at this quote in a new tab)
“The current trend is to use anti-VEGF agents in preference to laser photocoagulation surgery.” (opens the source at this quote in a new tab)
“Thermal laser is no longer recommended for subfoveal MNV.” (opens the source at this quote in a new tab)

Macular Photocoagulation Study: 5-year results for extrafoveal lesions

“In eyes with senile (age-related) macular degeneration as the underlying cause, the relative risk of losing six or more lines of visual acuity from the baseline level among untreated eyes (n = 117) compared with laser-treated eyes (n = 119) was 1.5 from 6 months through 5 years after entry (P = .001).” (opens the source at this quote in a new tab)
“Recurrent neovascularization had been observed in 54% of laser-treated eyes by the end of the 5-year follow-up period.” (opens the source at this quote in a new tab)

Summary

Current therapies control exudation but do not cure neovascular AMD, and all FDA-approved options require ongoing intravitreal injections or, for the port delivery system, surgery and refills every 24 weeks. Efficacy observed in registration trials is not reproduced in routine practice. In a US database of 49,485 treatment-naive eyes, participants received a mean of 7.3 injections in year 1 and gained a mean of 0.95 letters, and in SIERRA-AMD (98,821 eyes) mean visual acuity change was -5.2 letters by year 4. In the 1,208-participant CATT trial, 5-year mean change was -3 letters from baseline and -11 letters from year 2, and in SEVEN-UP 34% of study eyes had declined by 15 letters or more at a mean of 7.3 years. Treatment burden contributes to undertreatment: a systematic review of 37 studies reported nonpersistence in up to 50% of patients by 24 months and nonadherence in 32% to 95%; loss to follow-up was 22.2% among 9,007 participants in one US practice cohort; and 48.8% of 130 Norwegian survey respondents received 9 or more injections per year, with 37.7% requiring caregiver support at every appointment. Response is heterogeneous, and there is no consensus definition of non-response. Safety constraints limit some options: brolucizumab carries warnings for retinal vasculitis and retinal vascular occlusion, and the port delivery system carries a boxed warning for an up to 3-fold higher rate of endophthalmitis. Payer step therapy requiring bevacizumab first can delay access to FDA-approved agents.

Real-world visual outcomes and injection frequency: US database of 49,485 eyes

“At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001).” (opens the source at this quote in a new tab)
“Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials.” (opens the source at this quote in a new tab)

Real-world visual outcomes over 4 years: SIERRA-AMD

“A total of 98 821 eyes from 79 885 patients receiving intravitreal anti-VEGF therapy.” (opens the source at this quote in a new tab)
“In eyes with 4-year follow-up, VA changes from baseline (ETDRS letters) were least squares means of +1.1 (95% confidence interval [CI], 1.0;1.3), -1.3 (95%CI, -1.5;-1.0), and -3.1 (95%CI, -3.5;-2.7), and -5.2 (95%CI, -6.0;-4.3) for years 1-4. Mean±SD number of injections was 7.5±1.9, 6.7±2.1, 6.6±2.3, and 6.4±2.3 for years 1-4.” (opens the source at this quote in a new tab)

Undertreatment in real-world practice: literature review

“In real-world practice, patients are usually undertreated, accounting for the VA decline over time. Reasons for undertreatment include the burden of injections and monitoring visits imposed on patients/caregivers.” (opens the source at this quote in a new tab)

Real-world injection number and outcomes: AURA and LUMINOUS

“Patients who received >7 injections (in 1 year) or >14 injections (over 2 years) gained more letters and demonstrated greater vision maintenance (loss of <15 letters) than patients who received fewer injections.” (opens the source at this quote in a new tab)

“At Year 1 (n = 10,168), the mean (SD) VA change was −1.6 (12.6) letters (baseline VA: 58.3 [19.0] letters) with a mean (SD) of 4.7 (3.1) ranibizumab injections.” (opens the source at this quote in a new tab)

Real-world outcomes in the United Kingdom: systematic review

“Twenty-six studies (n=25,761 eyes) were included” (opens the source at this quote in a new tab)
“Longer-term studies reported that the visual gains achieved in the first year of treatment were rarely maintained, with under-treatment a likely contributing factor.” (opens the source at this quote in a new tab)

Long-term visual decline: CATT 5-year follow-up

“VA was obtained for 647 (71%) of 914 living patients with average follow-up time 5.5 years.” (opens the source at this quote in a new tab)
“Mean change in VA was -3 letters from baseline and -11 letters from 2 years.” (opens the source at this quote in a new tab)
“Vision gains during the first 2 years of the trial were not maintained at 5 years.” (opens the source at this quote in a new tab)

Long-term visual decline: SEVEN-UP 7-year follow-up

“Forty-three percent of study eyes had a stable or improved letter score (≥0-letter gain) compared with ANCHOR or MARINA baseline measurements, whereas 34% declined by 15 letters or more, with overall a mean decline of 8.6 letters (P<0.005).” (opens the source at this quote in a new tab)
“Macular atrophy was detected by FAF in 98% of eyes, with a mean area of 9.4 mm(2); the area of atrophy correlated significantly with poor visual outcome (P<0.0001).” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: real-world treatment and loss to follow-up

“Real-world treatment tends to fall short of clinical trial guidelines and protocols, and it results in worse outcomes.” (opens the source at this quote in a new tab)
“Loss to follow-up is not uncommon in patients with neovascular AMD.” (opens the source at this quote in a new tab)
“Risk factors included increased age, male sex, unilateral involvement, diabetes, Medicaid insurance, and race and ethnicity.” (opens the source at this quote in a new tab)

Loss to follow-up: US retina practice cohort

“Among the 9007 patients (mean [SD] age, 81.2 [8.8] years; 5917 [65.7%] female; 7905 [87.8%] white), 2003 (22.2%) were LTFU.” (opens the source at this quote in a new tab)

Loss to follow-up: systematic review and meta-analysis

“We included 52 studies.” (opens the source at this quote in a new tab)
“LTFU rates ranged from <5% to >75% over up to 10 years.” (opens the source at this quote in a new tab)
“Patients who were LTFU had worse visual outcomes even after resuming care.” (opens the source at this quote in a new tab)

Nonadherence and nonpersistence: systematic review

“Nonpersistence occurred early, with up to 50% of patients stopping treatment by 24 months. High rates of nonadherence were similarly reported, occurring in 32% to 95% of patients.” (opens the source at this quote in a new tab)

Nonadherence increases with treatment duration

“NA with gaps of >56 days after the scheduled appointment was detected in 39%, 89%, and 100% of patients in group 1, 2, and 3, respectively (groups 1 and 2 vs group 3, p < 0.001).” (opens the source at this quote in a new tab)

Treatment burden: patient-reported survey

“In total, 130 patients responded to the survey. The majority of patients reported to receive nine or more injections per year (48.8%), and many patients needed caregiver support for every treatment appointment (37.7%).” (opens the source at this quote in a new tab)

“Responders included 910 patients and 890 caregivers” (opens the source at this quote in a new tab)
“Most patients and caregivers reported a number of obstacles in managing wAMD, including the treatment itself (35% and 39%, respectively). Sixteen percent of patients also missed a clinic visit.” (opens the source at this quote in a new tab)

ASRS Preferences and Trends survey: reasons for real-world undertreatment

“The most popular reason given was patient non-compliance with visits, at 35 percent” (opens the source at this quote in a new tab)

Heterogeneous response and lack of a consensus definition of non-response

“Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies.” (opens the source at this quote in a new tab)

NICE guideline NG82: limited benefit of switching agents

“Consider switching anti-VEGF treatment for people with late AMD (wet active) if there are practical reasons for doing so (for example, if a different medicine can be given in a regimen the person prefers), but be aware that clinical benefits are likely to be limited.” (opens the source at this quote in a new tab)

Injection counts associated with vision loss, linear gain, and plateau in United States practice

“At the lower range, those patient eyes that received 4 anti-VEGF injections or fewer in the first year of treatment generally lost vision, approximately 2 to 3 letters at 1 year.” (opens the source at this quote in a new tab)
“In the mid range, a linear relationship was found between mean letters gained and mean number of anti-VEGF injections, up to 10 injections over 1 year, after which the relationship plateaued at approximately 3 to 4 letters gained.” (opens the source at this quote in a new tab)

Older age and worse baseline visual acuity among eyes receiving the fewest injections

“Patient eyes that received 4 anti-VEGF injections or fewer over 1 year generally showed worse mean baseline VA than those patient eyes that received a greater number of injections over 1 year.” (opens the source at this quote in a new tab)
“Those who received 1 anti-VEGF injection had a mean baseline age of 81.1 years, whereas those who received 13 injections over 1 year had a mean baseline age of 78.4 years (Fig 3; Table 3).” (opens the source at this quote in a new tab)

One-year visual acuity change by baseline visual acuity at similar injection frequency

“Specifically, patients with baseline VA of 20/200 or worse, 20/70 to 20/200, 20/40 to 20/70, and 20/40 or better received 6.5, 7.4, 7.5, and 7.3 anti-VEGF injections, respectively, over 1 year.” (opens the source at this quote in a new tab)
“Patients with baseline VA of 20/40 or better tended to lose VA at 1 year, regardless of anti-VEGF injection frequency.” (opens the source at this quote in a new tab)

Adherence, missed visits, and visual acuity in routine anti-VEGF care

“In unadjusted univariable analyses, treatment adherence was related to a higher most recent VA (β = 8.98 letters; CI, 1.34–16.62) and lower odds of VA below driving vision (≤69 letters vs. ≥ 70 letters) (OR = 0.50; CI, 0.25–1.00) among nAMD patients.” (opens the source at this quote in a new tab)
“Number of missed visits was associated with lower most recent VA and lower odds of VA below driving vision in nAMD patients.” (opens the source at this quote in a new tab)
“nAMD patients who received more injections had better self-reported NEIVFQ-25 composite scores in unadjusted analyses.” (opens the source at this quote in a new tab)

Retina specialist views on monitoring and injection frequency as a resource burden

“When asked about the impact of activities for monitoring and injection administration on staff time, the majority of the surveyed retina specialists (62%, 35 of 57) felt that frequency of patient monitoring placed a significant burden on staff time.” (opens the source at this quote in a new tab)
“Forty-nine percent (28 of 57) of retina specialists reported that the frequency of injections was an impactful burden on office space, including waiting rooms and examination rooms.” (opens the source at this quote in a new tab)
“Over one-third of physicians (35%, 20 of 57) considered frequency of patient monitoring to be an important motivator in choosing a treatment to prescribe. Two-thirds of physicians (38 of 57) stated they would find it very desirable to reduce office visits.” (opens the source at this quote in a new tab)

Summary

The axitinib intravitreal implant is investigational and has no established place in therapy. If approved, it would be the first tyrosine kinase inhibitor marketed for nAMD. Its pivotal evidence comes from adults aged 50 years or older with newly diagnosed nAMD: SOL-1 randomized 344 treatment-naive participants who, after two aflibercept 2 mg loading doses, reached a BCVA of about 20/20 or gained at least 10 letters with CSFT of 350 µm or less; SOL-R randomized 640 treatment-naive or recently diagnosed participants after a 6-month lead-in that excluded eyes with early persistent fluid or significant fluid fluctuation. No pivotal trial has enrolled previously treated participants with established disease; only the 21-participant U.S. phase 1 trial enrolled previously treated, anti-VEGF-responsive participants, using a different formulation. The sponsor anticipates a label allowing redosing every 6 to 12 months and positions the product as a maintenance treatment after anti-VEGF loading. Anticipated administration is an intravitreal injection with a 25-gauge needle by retina specialists in the office setting, the same care setting as current anti-VEGF injections, without concomitant corticosteroids. Sponsor-funded market research reports that about 80% of surveyed retina specialists would be likely to use a product with this profile; these data have not been independently published. Independent reviewers state that larger controlled trials are needed to define the role of sustained-release tyrosine kinase inhibitors in clinical practice.

Anticipated position as the first tyrosine kinase inhibitor for nAMD

“If approved, AXPAXLI would be the first tyrosine kinase inhibitor commercialized for the treatment of wet AMD.” (opens the source at this quote in a new tab)

Studied population: SOL-1 treatment-naive participants responding to aflibercept loading

“Under the trial protocol, subjects were eligible for enrollment in the SOL-1 trial if they were treatment-naïve for wet AMD in the study eye; had central subfield thickness, or CSFT, of less than or equal to 500” (opens the source at this quote in a new tab)
“Subjects reaching either a BCVA of greater than or equal to 84 ETDRS letters (approximately 20/20 Snellen equivalent vision) or experiencing an improvement of at least 10 ETDRS letters with a reduction in CSFT to no greater than 350 microns in the study eye after these injections were randomized in the trial on Day 1 (Baseline).” (opens the source at this quote in a new tab)

Studied population: sponsor description of SOL-1 enrollment

“Subjects were randomized in SOL-1 after showing a peak response to two aflibercept (2 mg) injections, reaching approximately 20/20 vision or experiencing an improvement of at least 10 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters of best corrected visual acuity (BCVA), in addition to satisfying other criteria. This is a population that was specifically selected to lose vision.” (opens the source at this quote in a new tab)

Studied population: SOL-R treatment-naive or recently diagnosed participants

“The SOL-R trial is designed as a multi-center, double-masked, randomized (2:2:1), three-arm trial requiring subjects that were either treatment naïve or have been diagnosed with wet AMD in the study eye within about four months prior to screening.” (opens the source at this quote in a new tab)
“To qualify for screening in the SOL-R trial, a subject’s study eye must have had a BCVA of at least 34 ETDRS letters (approximately 20/200 Snellen equivalent vision).” (opens the source at this quote in a new tab)

Previously treated population: U.S. phase 1 trial only

“The trial enrolled a total of 21 subjects at six clinical sites, comprising two arms consisting of subjects previously treated with, and who were responsive to, standard of care anti-VEGF therapy: a 16-subject arm receiving AXPAXLI in combination with a single anti-VEGF injection at month one and a five-subject arm receiving on-label aflibercept at eight-week intervals.” (opens the source at this quote in a new tab)

Anticipated dosing interval: sponsor projection

“Potential AXPAXLI Label up to 12 Months” (opens the source at this quote in a new tab)
“NDA filing pending – does not reflect labeled dosing” (opens the source at this quote in a new tab)

“AXPAXLI is being developed to address this unmet need with the potential to extend dosing intervals to every 6 to 12 months and potentially provide superior and sustainable long-term visual outcomes.” (opens the source at this quote in a new tab)

Sponsor rationale for early initiation

“By starting AXPAXLI treatment early and sustaining disease control over multiple years, we have the opportunity to potentially improve long-term outcomes, reduce treatment burden, and significantly expand the number of patients who remain on therapy.” (opens the source at this quote in a new tab)

Care setting: office-based intravitreal injection by retina specialists

“It is the same intravitreal injection procedure we use every day, but with the potential for the therapy to last far longer, with possibly better long-term outcomes.” (opens the source at this quote in a new tab)

“Pre-filled intravitreal injection facilitates smooth practice integration” (opens the source at this quote in a new tab)

Prescriber base: retina specialists

“2.5 – 3K Retina Specialists in U.S.” (opens the source at this quote in a new tab)
“~600 HCPs account for 80% of claims volume” (opens the source at this quote in a new tab)

Anticipated uptake: sponsor-funded market research

“Following SOL-1's results, market research found that approximately 80% of retina specialists surveyed would likely use a product with AXPAXLI’s profile based on SOL-1 data alone, with more than 90% expected to adopt such a product within its first year, if approved.” (opens the source at this quote in a new tab)

“Ocular Therapeutix Market Research (n=53 Retina Specialists) Conducted February-May 2026, Retina Specialists surveyed at Medical Presentations of SOL-1 Data” (opens the source at this quote in a new tab)

Role of sustained-release tyrosine kinase inhibitors: independent review

“Continued evaluation through larger, controlled clinical trials is essential to validate these early findings and define the role of these agents in clinical practice.” (opens the source at this quote in a new tab)

Use in previously treated or anti-VEGF-refractory nAMD, fellow eyes, and switching from other agents

No evidence found.

Uptake of longer-interval agents in Medicare as an indicator of clinician preference for durability

“The increasing preference for aflibercept and faricimab suggests that clinicians are gravitating toward agents that balance efficacy with reduced injection frequency.” (opens the source at this quote in a new tab)
“The significant growth in faricimab use, despite its relatively high cost, suggests clinicians value extended treatment durability and reduced patient burden.” (opens the source at this quote in a new tab)
“The consistent escalation in total Medicare spending underscores the financial impact of intravitreal therapy on the US health care system, a trend that may be tempered by the introduction of biosimilars and alternative delivery systems.” (opens the source at this quote in a new tab)

Independent assessment of the evidence still needed for sustained-release tyrosine kinase inhibitors

“Intravitreal agents such as OTX-TKI and EYP-1901 have demonstrated encouraging durability and safety profiles in early-phase trials.” (opens the source at this quote in a new tab)
“Sustained delivery of VEGF receptor TKIs represents a promising frontier in the management of retinal and choroidal vascular diseases. The ability to reduce treatment burden while maintaining safety and efficacy addresses a significant unmet need in this space.” (opens the source at this quote in a new tab)
“Ongoing phase 2 and 3 trials will be critical in determining which of these novel delivery systems can meaningfully reduce treatment burden while preserving vision outcomes” (opens the source at this quote in a new tab)

Stratification by baseline visual acuity in SOL-1

“In addition, the subjects were stratified between the two treatment groups at randomization based on BCVA category (≤ 71 and >71 ETDRS letters) as of the initial screening visit.” (opens the source at this quote in a new tab)

Distribution of the SOL-1 population across the stratification category

“>71 letters (~ 20/40)*, n (%) 145 (85.3) 136 (79.1)” (opens the source at this quote in a new tab)

Visual acuity outcomes by screening BCVA quartile: post hoc analysis

“The magnitude of vision improvements was influenced by BCVA at screening. For example, AXPAXLI subjects in the lowest vision quartile group at screening had the greatest visual gains with +11.8 ETDRS letters compared to +8.5 letters in the aflibercept (2 mg) arm at Week 52.” (opens the source at this quote in a new tab)
“In comparison, subjects in the best vision quartile at screening had essentially no change in vision at Week 52 (-0.5 vs +1.1 letters; AXPAXLI vs aflibercept) as they started with almost 20/20 vision.” (opens the source at this quote in a new tab)

Outcomes restricted to rescue-free participants: post hoc analysis

“Observed difference for change in BCVA from baseline at Week 24 in the rescue-free subjects was -1.9 ETDRS letters in the AXPAXLI arm (+7.5 letters from screening) vs -2.6 letters in the aflibercept arm (+6.0 letters from screening).” (opens the source at this quote in a new tab)

Rescue criteria as a source of variation in estimated durability

“In a prespecified exploratory analysis applying the SOL-R protocol rescue criteria to the SOL-1 results, AXPAXLI demonstrated a 77.1% rescue-free rate at Week 24.” (opens the source at this quote in a new tab)

Enriched SOL-R population and expected differences in response

“We expect these rescue-free rates to be even higher in populations such as the one randomized in SOL-R, given SOL-R’s patient enrichment strategy over the six months prior to randomization that excluded subjects with early persistent fluid or significant fluid fluctuations.” (opens the source at this quote in a new tab)

Differences between phase 1 populations

“The population we studied in this U.S.-based clinical trial was different than the population we studied in our Phase 1 clinical trial of AXPAXLI in Australia.” (opens the source at this quote in a new tab)
“In this trial, we evaluated how long we are able to maintain subjects who have been previously treated with anti-VEGF therapy without the need for retreatment.” (opens the source at this quote in a new tab)

Baseline vision of SOL-1 compared with other nAMD trial populations

“mean BCVA: 81 letters (~20/25)” (opens the source at this quote in a new tab)
“mean BCVA: 52 to 62 letters” (opens the source at this quote in a new tab)

Subgroup efficacy results by age, sex, race or ethnicity, lesion type, or baseline fluid

No evidence found.

AAO Preferred Practice Pattern: dosing regimens and follow-up

“Initial treatment and follow-up with intravitreal anti-VEGF therapy should be at approximately 4-week intervals.” (opens the source at this quote in a new tab)
“There are numerous protocols: monthly or bimonthly injections, treat-and-extend, PRN, or personalized treatment interval. There is no consensus about the ideal treatment intervals with anti-VEGF agents, and the physician can tailor treatment on an individual patient basis.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: treat-and-extend and as-needed (PRN) regimens

“The PRN regimens using ranibizumab appear to have efficacy and safety comparable to fixed monthly regimens over 1 year of treatment, but they do not maintain the initial visual gains with longer follow-up.” (opens the source at this quote in a new tab)
“A continuous, variable dosing regimen that attempts to individualize therapy, commonly referred to as treat-and-extend, is frequently used in clinical practice as an alternative to the two treatment approaches above.” (opens the source at this quote in a new tab)
“Caution should be used when dosing PRN bevacizumab, as it may be slightly less effective than other monthly anti-VEGF regimens and other PRN anti-VEGF regimens.” (opens the source at this quote in a new tab)

As-needed dosing: CATT and IVAN regimen comparisons

“Mean gain was greater for monthly than for as-needed treatment (difference: −2.4 letters; CI: [−4.8, −0.1]; p=0.046).” (opens the source at this quote in a new tab)
“Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (−2.2 letters, p=0.03) and a lower proportion without fluid (−19%, p<0.0001).” (opens the source at this quote in a new tab)

“Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18).” (opens the source at this quote in a new tab)
“Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug.” (opens the source at this quote in a new tab)

Treat-and-extend: TREX-AMD 2-year results

“Sixty patients were enrolled and 50 completed month 24, at which point mean ETDRS BCVA letter gains were similar: 10.5 and 8.7 for the monthly and TREX cohorts, respectively (P = 0.64).” (opens the source at this quote in a new tab)
“Through month 24, the mean number of injections administered was 25.5 (range, 22-27) and 18.6 (range, 10-25) for the monthly and TREX cohorts, respectively (P < 0.001).” (opens the source at this quote in a new tab)

Treat-and-extend: TREX-AMD third-year results

“Transition from Monthly to PRN was associated with a decline in best corrected visual acuity (BCVA) (+10.5 letters (month 24) to +5.4 (M36, p=0.09))” (opens the source at this quote in a new tab)
“Outcomes among subjects continued on TREX were more favourable, with a mean gain of +5.0 letters at M36.” (opens the source at this quote in a new tab)

Treat-and-extend: CANTREAT 24-month results

“Participants included 580 patients with treatment-naive choroidal neovascularization secondary to AMD.” (opens the source at this quote in a new tab)
“By the end of month 24, 466 of the 580 randomized patients (80.3%) had completed the study and participants in the T&E arm received a mean of 17.6 injections compared with 23.5 injections for the monthly arm, for a difference of 5.9 injections and visits over 2 years (95% CI, 5.4-6.5; P < .001). The mean (SD) BCVA improvement was not worse with the T&E arm, 6.8 (14.1) letters vs 6.0 (12.6) letters, compared with the monthly arm (difference, 0.9; 95% CI, −1.6 to 3.3; P = .21).” (opens the source at this quote in a new tab)

Treat-and-extend with aflibercept: ALTAIR and ARIES

“Over 52 weeks, mean number of injections was 7.2 and 6.9 and mean last injection interval was 10.7 and 11.8 weeks, for the 2- and 4-week groups, respectively.” (opens the source at this quote in a new tab)
“Last injection interval before week 52 was at least 12 weeks in 42.3% and 49.6% of patients and 56.9% and 60.2% before week 96.” (opens the source at this quote in a new tab)

“Two-hundred seventy-one patients were randomized.” (opens the source at this quote in a new tab)
“The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients.” (opens the source at this quote in a new tab)

Treat-and-extend and loss to follow-up

“Treat-and-extend (T&E) regimens showed lower LTFU than pro re nata.” (opens the source at this quote in a new tab)

EURETINA guideline: monitoring schedules after treatment

“Patients who have received treatment should be monitored at regular intervals, according to a standardised strategy, either monthly or following an individualised pro-re-nata (PRN) or treat-and-extend regimen.” (opens the source at this quote in a new tab)

NICE guideline NG82: timely treatment and OCT monitoring

“For eyes with confirmed late AMD (wet active) for which antiangiogenic treatment is recommended (see the section on pharmacological management of AMD), offer treatment as soon as possible (within 14 days of referral to the macular service).” (opens the source at this quote in a new tab)
“Offer people with late AMD (wet active) ongoing monitoring with OCT for both eyes.” (opens the source at this quote in a new tab)

Home monitoring for fellow-eye conversion: HOME study of the ForeseeHome device

“763 participants were randomized to device monitoring and 757 to standard care, and followed for a mean of 1.4 years between July 2010-December 2013.” (opens the source at this quote in a new tab)
“The primary analysis achieved statistical significance with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median (interquartile range [IQR]):−4 [−11.0, −1.0] letters) compared with standard care (median [IQR]:−9 [−14.0, −4.0] letters) (p=0.021), resulting in better visual acuity at CNV detection in the device arm.” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: self-monitoring and electronic monitoring devices

“Electronic monitoring devices are now available to aid in the detection of neovascularization at an early stage. Such devices use hyperacuity perimetry (or vernier acuity) to create a quantified central visual map of metamorphopsia.” (opens the source at this quote in a new tab)

Home OCT self-imaging: prospective study

“The mean weekly scan frequency was 5.7 ± 0.9 scans per week, and 93% of the scans were eligible for NOA analyses. The median scan time was 42 seconds.” (opens the source at this quote in a new tab)
“The NVHO scans analyzed using NOA and the in-office OCT scans graded by human experts agreed on the fluid status in 96% of the cases.” (opens the source at this quote in a new tab)

Home OCT: FDA De Novo authorization

“Digital healthcare provider, Notal Vision, announced today that the US Food and Drug Administration (FDA) has granted De Novo authorization for its patient self-operated SCANLY® Home OCT device.” (opens the source at this quote in a new tab)
“97% of all participants were able to successfully obtain OCT images at home.” (opens the source at this quote in a new tab)

AREDS2 supplements for the fellow eye

“For patients with unilateral disease, the fellow eye without MNV remains at high risk of developing advanced AMD.” (opens the source at this quote in a new tab)
“The risk can be lowered by as much as 36% over a 10-year period by taking the AREDS/AREDS2 supplements.” (opens the source at this quote in a new tab)

AREDS2 randomized trial

“The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 × 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye.” (opens the source at this quote in a new tab)
“However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.” (opens the source at this quote in a new tab)

AREDS2 10-year follow-up

“The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91 (95% CI, 0.84-0.99; P = .02)” (opens the source at this quote in a new tab)
“At 10 years, the odds ratio (OR) of having lung cancer was 1.82 (95% CI, 1.06-3.12; P = .02) for those randomly assigned to beta carotene and 1.15 (95% CI, 0.79-1.66; P = .46) for lutein/zeaxanthin.” (opens the source at this quote in a new tab)

Vision rehabilitation and counseling: AAO Preferred Practice Pattern

“An important component of care for a patient with AMD is referral for vision rehabilitation as well as continued follow-up for general eye care.” (opens the source at this quote in a new tab)
“Patients should be told that these are treatments not cures for neovascular AMD and ongoing follow-up is essential to maintain the best possible vision.” (opens the source at this quote in a new tab)
“Patients who are currently smoking should be advised to stop.” (opens the source at this quote in a new tab)

Low vision rehabilitation: LOVIT randomized trial

“A total of 126 patients were included, 98% of whom were white and male.” (opens the source at this quote in a new tab)
“The difference in mean changes was 2.43 logits (95% confidence interval [CI], 2.07-2.77; P < .001; effect size, 2.51) for visual reading ability” (opens the source at this quote in a new tab)
“Because the waiting-list control patients demonstrated a decline in functional ability, low-vision services should be offered as early as possible.” (opens the source at this quote in a new tab)

Integrated low vision and mental health care: depression prevention trial

“At 4 months, 11 BA+LVR subjects (12.6%) and 18 ST+LVR subjects (23.4%) developed a depressive disorder (relative risk [RR], 0.54; 95% CI, 0.27–1.06; P = 0.067). In planned adjusted analyses the RR was 0.51 (95% CI, 0.27–0.98; P = 0.04).” (opens the source at this quote in a new tab)

NICE guideline NG82: support for people with visual impairment

“Be aware that people with AMD are at an increased risk of depression.” (opens the source at this quote in a new tab)
“Consider referring people with AMD causing visual impairment to low-vision services.” (opens the source at this quote in a new tab)
“Consider a group-based rehabilitation programme in addition to a low-vision service to promote independent living for people with AMD.” (opens the source at this quote in a new tab)

Conjunctival monitoring and patient education after port delivery system implantation

“Ongoing assessment of conjunctival health during follow-up visits via slit-lamp assessment is critical in monitoring for potential AEs.” (opens the source at this quote in a new tab)
“Use of fluorescein in conjunction with a cobalt blue light may aid in identifying areas of conjunctival thinning or erosion, and serial review of longitudinal clinical images of the implantation site may be helpful in identifying new clinical findings or assessing the progression of existing ones.” (opens the source at this quote in a new tab)
“In addition, patients treated with the PDS should be educated for eye hygiene and to avoid environmental exposure, which may potentially increase the risk of endophthalmitis.” (opens the source at this quote in a new tab)

Summary

Expected outcomes are based on one completed phase 3 trial (SOL-1, Week 52) and two phase 1 trials; no peer-reviewed publication of phase 3 results and no repeat-dosing efficacy data are available. In SOL-1, among treatment-naive participants who responded to aflibercept loading, 74.1% of participants treated with a single 450 µg implant maintained vision (loss of fewer than 15 letters) at Week 36 versus 55.8% with a single aflibercept 2 mg injection, and 65.9% versus 44.2% at Week 52; 68.8% versus 47.7% were rescue-free at Week 52 under the SOL-1 rescue criteria. In a post hoc analysis applying SOL-R rescue criteria, the sponsor estimated a 72% reduction in injection burden (56% including loading doses) versus projected on-label aflibercept 2 mg every 8 weeks over 60 weeks. In the U.S. phase 1 trial of the first-generation 600 µg implant in previously treated participants, 60% were rescue-free through Month 12 and treatment burden was reduced by 89%. Expected adverse effects include vitreous floaters (12.4% versus 1.2% with aflibercept through Week 52), which the sponsor attributes to hydrogel bioresorption, and mild or moderate intraocular inflammation (9 events in 7 participants); no endophthalmitis or retinal vasculitis was reported in the implant arm. Long-term effects on fibrosis, macular atrophy, and vision beyond 2 years are unknown and are being evaluated in SOL-X (estimated 850 participants, primary completion 2030) and at Week 96 in SOL-R.

Vision maintenance with a single implant: SOL-1 primary and key secondary endpoints

“The superiority primary endpoint was met with 74.1% of subjects in the AXPAXLI (0.45 mg) arm maintaining vision at Week 36, a 17.5% risk difference (p=0.0006), compared to the aflibercept (2 mg) arm. A key secondary endpoint was met with 65.9% of subjects treated with AXPAXLI (0.45 mg) maintaining vision at Week 52, a 21.1% risk difference (p<0.0001), compared to the aflibercept (2 mg) arm.” (opens the source at this quote in a new tab)

Rescue-free rates through Week 52

“The rescue-free rates in the AXPAXLI arm were 80.6%, 74.7%, and 68.8% at Weeks 24, 36, and 52, respectively, compared to 72.1%, 56.4%, and 47.7% in the aflibercept 2 mg arm at the same time periods.” (opens the source at this quote in a new tab)

Anatomic control: time to CSFT increase, post hoc analysis

“The median time to ≥30 uM Central Subfield Thickness (CSFT) increase from Week 8 was 39 weeks in the AXPAXLI group and 16 weeks in the aflibercept (2 mg) group, a 23-week difference.” (opens the source at this quote in a new tab)

Estimated treatment burden reduction: post hoc analysis

“The total estimated mean injection burden with AXPAXLI represents a 72% reduction counting from the first screening visit at Week -8 excluding loading doses and a 56% reduction when loading doses are included, as compared to a projected on-label dosing regimen of aflibercept (2 mg) with no rescues.” (opens the source at this quote in a new tab)

Previously treated participants: U.S. phase 1 outcomes at 12 months

“60% of OTX-TKI subjects were rescue-free up to Month 12.” (opens the source at this quote in a new tab)
“Overall, an 89% reduction in treatment burden was observed in OTX-TKI treated subjects at 12 months.” (opens the source at this quote in a new tab)

Expected adverse effects: ocular adverse events through Week 52

“Vitreous floaters 21 (12.4) 2 (1.2)” (opens the source at this quote in a new tab)
“Cataract 12 (7.1) 5 (2.9)” (opens the source at this quote in a new tab)
“Conjunctival hemorrhage 11 (6.5) 5 (2.9)” (opens the source at this quote in a new tab)

Expected long-term outcomes: fibrosis and macular atrophy hypothesis

“Ocular believes sustained VEGF suppression with AXPAXLI may reduce the incidence of fibrosis and atrophy in wet AMD, thereby improving long-term outcomes.” (opens the source at this quote in a new tab)

Long-term outcome measures in the SOL-X extension

“Incidence and severity of treatment-emergent adverse events (TEAEs) from Baseline (Day 1) through Week 144” (opens the source at this quote in a new tab)
“Proportion of participants with severe vision loss (defined as ≥ 30 Early Treatment Diabetic Retinopathy Study [ETDRS] letters loss) from Baseline (Day 1) through Week 144” (opens the source at this quote in a new tab)

Uncertainty in expected long-term outcomes: independent review

“Long-term safety, efficacy, and durability will determine which of these candidates redefine standard care.” (opens the source at this quote in a new tab)

Patient-reported outcomes, quality of life, and repeat-dosing efficacy

No evidence found.