Investigational status

“All of the Company’s product candidates are in clinical or preclinical development and have not yet been approved for marketing by the U.S. Food and Drug Administration or any other regulatory authority.” (opens the source at this quote in a new tab)

Current development phase and indications

“The Company’s lead indication for 4D-150 is wet age-related macular degeneration, which is currently in Phase 3 development, and second indication is diabetic macular edema.” (opens the source at this quote in a new tab)

FDA regenerative medicine advanced therapy designation

“the U.S. Food and Drug Administration (FDA) has granted the RMAT designation for the investigational genetic medicine candidate 4D-150 for intravitreal treatment of wet age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)
“Receiving RMAT designation offers sponsor companies all the benefits of the fast track and breakthrough therapy designation programs, allowing for early, close and frequent interactions with the FDA with the goal of expediting drug development.” (opens the source at this quote in a new tab)

EMA PRIME designation

“the European Medicines Agency (EMA) has granted Priority Medicine (PRIME) designation for the investigational genetic medicine candidate 4D-150 for intravitreal treatment of wet age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)

Designations covering both wet AMD and diabetic macular edema

“and RMAT designation for 4D-150 for treatment of DME, which highlights recognition from regulatory bodies of the potential of 4D-150 to address significant unmet medical needs for both wet AMD and DME.” (opens the source at this quote in a new tab)

4FRONT-1 enrollment completion and expected topline data

“The 4D-150 4FRONT-1 Phase 3 trial enrolled in 11 months in a treatment-naïve large market patient population.” (opens the source at this quote in a new tab)

“Enrollment completed in February 2026 and randomization completed (N=523) in March 2026; topline data expected in Q2 2027” (opens the source at this quote in a new tab)

4FRONT-2 enrollment completion and expected topline data

“Enrollment completed in June 2026 with N>500 expected to be randomized; topline data expected in H2 2027” (opens the source at this quote in a new tab)

“4FRONT-2 52-week topline data is expected in H2 2027.” (opens the source at this quote in a new tab)

Phase 3 design alignment with FDA, EMA, and Japan Pharmaceuticals and Medical Devices Agency

“Target enrollment per study is 480 patients randomized 1:1 to 4D-150 or the aflibercept comparator arm, providing approximately 90% power with a noninferiority margin of 4 letters as aligned with the Japan Pharmaceuticals and Medical Devices Agency and EMA and over 90% power with a noninferiority margin of 4.5 letters per FDA guidance.” (opens the source at this quote in a new tab)

“Study design has been aligned with feedback from U.S. Food and Drug Administration (FDA) under RMAT designation” (opens the source at this quote in a new tab)

Licensure pathway in the second indication

“In January 2025, we also announced alignment with the FDA that a single Phase 3 clinical trial would be acceptable as the basis of a biologics license application (“BLA”) submission for 4D-150 in DME.” (opens the source at this quote in a new tab)

Biologics license application submission date, marketing authorization application, and approval dates

No evidence found.

Regulatory submission

No evidence found.

Launch

No evidence found.

Manufacturer: 4D Molecular Therapeutics

“ClinicalTrials.gov ID NCT06864988 Sponsor 4D Molecular Therapeutics Information provided by 4D Molecular Therapeutics (Responsible Party)” (opens the source at this quote in a new tab)

“4DMT retains full development and commercialization rights for 4D-150 outside the APAC region, including the U.S., Latin America and Europe.” (opens the source at this quote in a new tab)

Nonproprietary name, brand name, and code name

No evidence found.

Therapeutic class: intravitreal AAV gene therapy expressing anti-VEGF biologics

“4D-150 utilizes our customized and evolved intravitreal AAV vector, R100, which was invented at 4DMT through our proprietary Therapeutic Vector Evolution platform.” (opens the source at this quote in a new tab)

“Our lead product candidate 4D-150 utilizes our proprietary R100 vector and a transgene encoding anti-VEGF biologics: aflibercept and an RNA interference (RNAi) approach targeting VEGF-C.” (opens the source at this quote in a new tab)

Phase 3 dose and route

“Experimental: 4D-150 IVT (3E10 vg/eye) Biological: 4D-150 IVT (3E10 vg/eye) If randomized to the 4D-150 treatment arm, 4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1” (opens the source at this quote in a new tab)

Doses studied in clinical trials

“PRISM enrolled patients with severe, recalcitrant disease with high anti-VEGF treatment burden (Phase 1/2a, 25 patients dosed with Phase 3 dose of 3E10 vg/eye) and with broad disease activity and treatment burden (Phase 2b, 30 patients dosed with Phase 3 dose).” (opens the source at this quote in a new tab)
“In total, 71 patients have been dosed with the Phase 3 dose of 3E10 vg/eye.” (opens the source at this quote in a new tab)

“Synthetic R100 capsid optimized for IVT; Dose: 6 × 10⁹ –3 × 10¹⁰ vg/eye” (opens the source at this quote in a new tab)

Dose levels evaluated in the diabetic macular edema trial

“In the Dose Confirmation cohort, patients were sequentially enrolled to one of three dose arms of 4D-150 (5E9, 1E10 and 3E10 vg/eye).” (opens the source at this quote in a new tab)

Commercial formulation, container, and storage conditions

No evidence found.

Summary: comparator Medicare Part B payment limits

No price, average sales price, or wholesale acquisition cost has been announced for 4D-150. For intravitreal anti-VEGF comparators, Medicare Part B payment limits effective July 1 to September 30, 2026 (based on first-quarter 2026 ASP data) were $743.605 per 1 mg for aflibercept (J0178), $298.683 per 1 mg for aflibercept HD (J0177), $803.255 per 1 mg for aflibercept-ayyh (Q5147), $32.381 per 0.1 mg for faricimab-svoa (J2777), $51.090 per 0.1 mg for ranibizumab (J2778), $240.972 per 0.1 mg for ranibizumab-nuna (Q5124), $82.528 per 0.1 mg for ranibizumab-eqrn (Q5128), $74.795 per 0.1 mg for ranibizumab via the Susvimo implant (J2779), $359.713 per 1 mg for brolucizumab-dbll (J0179), and $74.823 per 10 mg for bevacizumab (J9035), each with 20% coinsurance. At labeled nAMD doses these limits correspond to $1,487.21 per aflibercept 2 mg injection, $1,606.51 per aflibercept-ayyh 2 mg injection, $2,389.46 per aflibercept 8 mg injection, $1,942.86 per faricimab 6 mg injection, $255.45 per ranibizumab 0.5 mg injection, and $2,158.28 per brolucizumab 6 mg injection (calculated).

Sponsor statements on anticipated pricing of 4D-150

“Pricing was not disclosed, but the company said 4D-150 would likely be priced well above a single intravitreal anti-VEGF injection.” (opens the source at this quote in a new tab)

“In addition, we expect the relatively low doses required to allow for favorable manufacturing scalability, cost of goods sold, and pricing flexibility compared to conventional IV genetic medicines.” (opens the source at this quote in a new tab)

Comparator wholesale acquisition costs: aflibercept 8 mg and faricimab, 2025

“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)

Comparator Medicare Part B average spending per claim, 2025

HCPCS code	Brand name	Average spending per claim, 2025 (Q1-Q4)
J0178	“EYLEA”	“1792.4254857”
J0177	“EYLEA HD”	“3006.5947467”
Q5147	“PAVBLU”	“2010.6720252”
J2777	“VABYSMO”	“2390.9037697”
J2778	“LUCENTIS”	“542.43913909”
Q5128	“CIMERLI”	“880.821349”
Q5124	“BYOOVIZ”	“706.41442336”
J2779	“SUSVIMO”	“7460.7805379”
J0179	“BEOVU”	“2267.6140542”

Wholesale acquisition cost of a one-time ocular gene therapy: voretigene neparvovec

“On January 3, 2018, Spark Therapeutics, Inc., announced that the wholesale acquisition cost for LUXTURNA™ (voretigene neparvovec-rzyl) is $425,000 per dose or per eye.” (opens the source at this quote in a new tab)

Average sales price methodology for physician-administered agents under Medicare Part B

“Under Medicare Part B, physician-administered drugs are reimbursed based on an average sales price methodology (average sales price + 6%, effectively reduced by sequestration).” (opens the source at this quote in a new tab)

Effect of billing code attribution on reported reimbursement per bevacizumab injection

“In our primary analysis, unspecified codes (e.g., J3490, J3590, and J7999) were attributed to bevacizumab based on established billing precedent. Sensitivity analyses excluding these codes demonstrated that mean reimbursement remained stable at approximately $50 per injection, consistent with historical pricing patterns.” (opens the source at this quote in a new tab)
“Thus, the observed increase in reimbursement in later years likely reflects coding attribution and billing structure rather than true changes in drug cost, clinical demand, or therapeutic preference.” (opens the source at this quote in a new tab)

WHO ATC classification of ocular antineovascularisation agents

ATC code	Quoted entry
S01L	“OCULAR VASCULAR DISORDER AGENTS”
S01LA	“Antineovascularisation agents”
S01LA05	“aflibercept”
S01LA09	“faricimab”

AHFS class and ATC code assigned to 4D-150

No evidence found.

Indication under investigation

“4D-150 is being developed for wet AMD and diabetic macular edema (DME), which both affect millions of patients globally, with the goal of freeing patients from burdensome injections while preserving vision.” (opens the source at this quote in a new tab)

Population studied in 4FRONT-1

“Treatment naïve MNV secondary to nAMD in the study eye” (opens the source at this quote in a new tab)
“BCVA between 25 and 78 ETDRS letters, inclusive (20/320-20/32 Snellen equivalent) in the study eye at the Screening Visit” (opens the source at this quote in a new tab)

Population studied in 4FRONT-2

“Previously treated with no more than 4 IVT anti-VEGF injections due to nAMD and received diagnosis of nAMD no more than 6 months prior to the Screening Visit AND documented evidence of anatomical improvement and visual stability/improvement in response to previous IVT anti-VEGF treatment, as determined by the Investigator” (opens the source at this quote in a new tab)

Approved indication and labeled population

Not applicable.

Dual-transgene payload delivered by an evolved AAV capsid

“We then engineered 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA sequence that inhibits expression of VEGF-C.” (opens the source at this quote in a new tab)

Inhibition of four members of the VEGF family

“In addition, to our knowledge, 4D-150 is the first genetic medicine product candidate for the eye designed to directly inhibit four different angiogenic growth factor targets, VEGF A, B, and C plus PlGF.” (opens the source at this quote in a new tab)

Directed evolution of the R100 capsid in nonhuman primates

“We implemented a directed evolution strategy that used genetic diversification and selection processes to invent a novel AAV capsid (R100) with the capacity to transduce all major cell types across all regions of the primate retina, including the macula, following IVT administration at relatively low doses.” (opens the source at this quote in a new tab)
“After round 6, the R100 peptide insertion sequence motif represented approximately 70% of all remaining capsid sequences” (opens the source at this quote in a new tab)

Capsid structure and mechanism of inner limiting membrane penetration

“Structure–function analyses demonstrated that the 10-amino-acid peptide insertion at position R588 in the R100 capsid reduces heparin binding affinity and facilitates transit through the heparan sulfate-rich ILM, suggesting a putative mechanism for enhanced delivery to cells within the retina.” (opens the source at this quote in a new tab)

“4D-R100 was similarly engineered from an AAV2 backbone through in vivo screening in NHPs, incorporating a 10–amino acid insertion (LAISDQTKHA) at residue 588 and a VP1 point mutation at position 34 (Pro→Ala).” (opens the source at this quote in a new tab)

Rationale for targeting VEGF-C

“In addition, VEGF-C concentrations are reportedly elevated in the eye following treatment with VEGF-A inhibitors, suggesting that VEGF-A suppression induces compensatory upregulation of VEGF-C.” (opens the source at this quote in a new tab)

Promoter used in the 4D-150 transgene cassette

No evidence found.

Glycan interactions and the retinal cell types transduced by the R100 capsid

“These modifications reduce HSPG affinity and promote alternative glycan interactions (notably sialic acid), facilitating enhanced ILM penetration and efficient retinal transduction across RPE, photoreceptors, and RGCs from macula to periphery following IVT administration.” (opens the source at this quote in a new tab)

Human retinal pigment epithelial cells in vitro: VEGF-A neutralization and VEGF-C suppression

“Transduction of human retinal pigment epithelial cells in vitro by 4D-150 resulted in dose-dependent transgene expression and corresponding reductions in VEGF-A and VEGF-C.” (opens the source at this quote in a new tab)
“The 4D-150 plasmid cassette significantly reduced endothelial cell proliferation compared to the CAG-GFP plasmid and shock controls (1-way ANOVA, P < 0.01), whereas CAG-AFLB alone did not” (opens the source at this quote in a new tab)

Nonhuman primates: intraocular aflibercept and microRNA expression

“Mean 4D-150 aflibercept transgene product levels were nearly 8-fold higher in the retina/choroid (mean ±SD = 22,518 ± 24,981 ng aflibercept/g of tissue) compared to the aqueous humor (2,919 ± 2,366 ng aflibercept/mL).” (opens the source at this quote in a new tab)
“In addition, VEGF-C miRNA expression was detected (up to 91,910 copies per input RNA) from RNA isolated throughout the retina, including the superior, nasal, central, temporal, and inferior regions.” (opens the source at this quote in a new tab)

Nonhuman primates: aqueous aflibercept concentrations by dose and construct

“Analysis of free aflibercept protein concentration in aqueous humor samples collected 21 days after dosing showed a dose response between the highest dose (1 × 1012 vg/eye) and the 2 lower doses (3 × 1011 and 1 × 1011 vg/eye) of 4D-150” (opens the source at this quote in a new tab)
“Interestingly, IVT administration of 4D-150 to NHPs resulted in significantly higher levels of aflibercept protein in aqueous humor samples compared to an equivalent dose of the single-transgene construct (R100.CAG-AFLB), suggesting that the VEGF-C RNAi transgene or its position within the transgene cassette promotes aflibercept expression.” (opens the source at this quote in a new tab)

Nonhuman primate laser-induced choroidal neovascularization model

“At 2 weeks post laser administration, a significant reduction in the incidence of grade IV CNV lesions was observed at all tested doses of 4D-150 compared to vehicle (Fisher's Exact Prob test, P < 0.005 for all comparisons).” (opens the source at this quote in a new tab)
“The CNV complex area was significantly smaller in the 4D-150–treated groups compared to the vehicle group (52%–62% reduction; 2-way ANOVA followed by Tukey-Kramer Honestly Significant Difference (HSD), P < 0.005 for all comparisons; Fig. 7C).” (opens the source at this quote in a new tab)
“The lowest tested dose of 4D-150 (1 × 1011 vg/eye) conferred equivalent protection against CNV compared to the highest dose (1 × 1012 vg/eye).” (opens the source at this quote in a new tab)

Duration of transgene expression in nonhuman primates

“Transgene expression was detected as early as week 1 and increased markedly by week 3. Expression increased further between weeks 3 and 8 and was stably maintained until the final assessment 6 months after administration.” (opens the source at this quote in a new tab)

Aqueous aflibercept concentrations and VEGF suppression measured in participants

No evidence found.

Systemic exposure to the transgene product in nonhuman primates

“Serum aflibercept concentrations were below the lower limit of quantitation in all animals and at all time points in the 1 × 1011 vg/eye dose group.” (opens the source at this quote in a new tab)
“Low concentrations of aflibercept were detected in serum in 2 of 7 animals in both the 3 × 1011 and 1 × 1012 vg/eye dose groups; of these, only one animal in the 3 × 1011 vg/eye treatment group had quantifiable levels at more than one time point” (opens the source at this quote in a new tab)

Intraocular distribution assessed in nonhuman primates

“Cynomolgus macaques (age = 6 years) received bilateral IVT injections of 4D-150 1 × 1012 vg/eye.” (opens the source at this quote in a new tab)
“Secreted free aflibercept was detected in all tissue samples from all ocular compartments.” (opens the source at this quote in a new tab)

Vector shedding assessment in the PRISM clinical trial

“Vector Shedding sub-study: Approximately 15 subjects will receive an open-label IVT injection of 4D-150 to evaluate vector shedding.” (opens the source at this quote in a new tab)

Clinical pharmacokinetics, shedding results, and immunogenicity results in participants

No evidence found.

Cell-based infectivity assay for transduction-competent vector in serum

“Assessment of AAV vector shedding post-administration is required by regulatory health agencies and has traditionally been characterized by qPCR, a method that detects both transduced and encapsidated, potentially transduction-competent vector DNA, but does not discriminate between the two.” (opens the source at this quote in a new tab)
“The advantage of a cell-based infectivity assay is that it will only detect material that is potentially transduction competent.” (opens the source at this quote in a new tab)
“NAb(-) Serum Sensitivity: 3E4 vg/mL serum at MRD10” (opens the source at this quote in a new tab)
“NAb(+) Serum Sensitivity: 3E8 vg/mL serum at MRD10” (opens the source at this quote in a new tab)

Assay readout targeted to the transgene cassette

“The forward primer sits in the chicken beta actin Exon1 from the CAG promoter, while the reverse primer sits in the transgene (Tg) Exon 2.” (opens the source at this quote in a new tab)

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

Not applicable.

Intraocular inflammation observed in the PRISM clinical trial

“As previously reported, within approximately the first 6 months (28 weeks) post-4D-150 dosing, 2.8% (2 of 71) of patients had 4D-150-related 1+ (mild) intraocular inflammation (IOI) (SUN/NEI scales), which were transient 1+ vitreous cells noted at a single timepoint” (opens the source at this quote in a new tab)
“Following the first 28 weeks post-4D-150 dosing, no new cases of inflammation with 2 to more than 4 years of follow-up on all patients as of the data cutoff” (opens the source at this quote in a new tab)

Events not observed in the clinical program to date

“No 4D-150-related hypotony, endophthalmitis, vasculitis, occlusive/non-occlusive retinal vasculitis or choroidal effusions observed to date” (opens the source at this quote in a new tab)

“Supplemental aflibercept injection-related case of endophthalmitis (presumed bacterial infection), resolved over following 2 visits” (opens the source at this quote in a new tab)

Dose-related ocular inflammation in nonhuman primates

“A dose response was observed for white blood cells in the aqueous and vitreous humor.” (opens the source at this quote in a new tab)
“At 1 × 1011 vg/eye, no inflammation was observed in any eyes (0/14) in either the aqueous or vitreous humor.” (opens the source at this quote in a new tab)
“Hypotony was not observed in any 4D-150–treated eyes” (opens the source at this quote in a new tab)

Class risks described for AAV gene therapy in neovascular AMD

“Potential risks of gene therapy include a potential immune response that may be elicited by the vector, accidental activation of oncogenes or inactivation of tumor suppresor genes leading to malignant transformation via insertational mutagenesis and integration of the viral DNA inserts into the host's DNA.” (opens the source at this quote in a new tab)

“Although AAV vectors typically support long-term and well-tolerated protein production, excessive or ectopic expression can disrupt retinal homeostasis or trigger immune-mediated inflammation” (opens the source at this quote in a new tab)
“One of the most significant limitations is the presence of preexisting NAbs against AAV capsids in the human population” (opens the source at this quote in a new tab)

Dependence of intraocular inflammation on vector dose and route of delivery

“Inflammation is dependent on the dose and delivery routes of the vector.” (opens the source at this quote in a new tab)
“The AAV capsid leads to a dose-related humoral immunity response and antigen-specific T cell activation.” (opens the source at this quote in a new tab)
“In terms of injection sites, the subretinal space is the least immunogenic followed by the suprachoroidal and ending with the vitreous cavity.” (opens the source at this quote in a new tab)

“Moreover, because IVT administration inherently relies on passive diffusion of AAV particles within the vitreous, achieving therapeutically relevant transduction generally necessitates the use of high vector doses. This requirement, in turn, increases the likelihood of dose-dependent ocular inflammation and systemic immune activation, which remain key safety considerations in the clinical application of this route” (opens the source at this quote in a new tab)

Dilution of the vector in the vitreous and the dose required for intravitreal delivery

“First, once the vector and its cargo are injected into the vitreous, dilution of the vector occurs. Therefore a higher dose has to be injected to compensate for this dilution effect. A higher dose may elicit a stronger immune response.” (opens the source at this quote in a new tab)

Episomal persistence of the AAV genome and the risk of insertional mutagenesis

“In addition, AAV genomes rarely integrate into the host genome, thereby minimizing the risk of insertional mutagenesis, and instead persist as stable episomal forms that enable long-term transgene expression” (opens the source at this quote in a new tab)

Transgene overexpression as a dose-related risk and the limits on expression control

“Another important consideration is the risk of toxicity from transgene overexpression, especially when high vector doses are needed to reach therapeutic levels” (opens the source at this quote in a new tab)
“This risk is heightened by the limited packaging capacity of AAV vectors, which constrains the use of complex regulatory elements that could otherwise fine-tune expression” (opens the source at this quote in a new tab)

Preexisting capsid antibodies, treatment eligibility, and re-dosing

“These antibodies, which may arise from natural exposure to wild-type AAVs, can neutralize the vector before it reaches target tissues, reducing transduction efficiency and potentially rendering patients ineligible for treatment” (opens the source at this quote in a new tab)
“Furthermore, a single exposure to an AAV vector can prime the immune system, complicating future re-dosing efforts and raising safety concerns” (opens the source at this quote in a new tab)

Ocular compartmentalization and the age of the treated population as modifiers of immune risk

“Fortunately in ocular gene therapy, the therapeutic gene is compartmentalized to the eye. Smaller doses of genetic material need to be delivered minimizing systemic side effects.” (opens the source at this quote in a new tab)
“In addition, the patient population affected by NV-AMD is typically an older population. This may represent an advantage since aging individuals may not mount an exuberant immune response” (opens the source at this quote in a new tab)

Dose-related inflammation after intravitreal AAV aflibercept delivery in nonhuman primates

“Intravitreal injection of ixo-vec caused a dose related ocular inflammatory response consisting of anterior chamber cells, keratic precipitates, lens deposits and vitreous cells.” (opens the source at this quote in a new tab)

Age eligibility in the Phase 3 trials

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

Ocular comorbidity exclusions

“History of retinal detachment in the study eye” (opens the source at this quote in a new tab)
“History of or presence of active inflammation in either eye” (opens the source at this quote in a new tab)
“Glaucoma or intraocular hypertension requiring more than 2 topical medications for control” (opens the source at this quote in a new tab)

Systemic condition exclusions relevant to immune and cardiovascular risk

“Acute coronary syndrome, myocardial infarction or coronary artery revascularization, cerebrovascular accident, transient ischemic attack within 6 months of the Screening Visit” (opens the source at this quote in a new tab)
“History of autoimmune condition that may predispose to the development of uveitis” (opens the source at this quote in a new tab)

Pediatric use, pregnancy and lactation, renal and hepatic impairment, and use in participants with pre-existing antibodies to the capsid

No evidence found.

Prophylactic corticosteroids administered with 4D-150

“Durezol® taper (both arms) starting Day -3” (opens the source at this quote in a new tab)

“Prophylactic corticosteroid (~20 weeks)” (opens the source at this quote in a new tab)

Formal drug interaction studies

No evidence found.

Formal drug interaction studies

No evidence found.

Single administration at the Phase 3 dose

“4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1” (opens the source at this quote in a new tab)

Dose selection across the clinical program

“In the Phase I/II PRISM trial, patients with nAMD received a single IVT administration across three dose cohorts (6 × 10⁹, 1 × 10¹⁰, and 3 × 10¹⁰ vg/eye).” (opens the source at this quote in a new tab)

“In addition, a consistent dose response was observed between 3E10 vg/eye, the selected Phase 3 dose, and the lower dose of 1E10 vg/eye.” (opens the source at this quote in a new tab)

Supplemental anti-VEGF injections after dosing

“Patients in both arms will be eligible for supplemental aflibercept injections.” (opens the source at this quote in a new tab)

Redosing, dose modification, and dosing of the fellow eye

No evidence found.

Route and care setting

“The product candidate combines our proprietary R100 vector designed for efficient intravitreal delivery to the retina with a dual transgene payload expressing aflibercept and VEGF-C RNAi.” (opens the source at this quote in a new tab)
“Intravitreal delivery of biologics into the eye is a routine in-office injection, which we believe allows for seamless adoption into retina clinic workflows.” (opens the source at this quote in a new tab)

Topical corticosteroid prophylaxis regimen in the PRISM clinical trial

“14/15 participants did not require steroids after completion of the protocol-mandated 20-week prophylactic topical steroid taper” (opens the source at this quote in a new tab)

“97% (38 of 39) completed the 20-week topical corticosteroid taper on schedule; no participant restarted steroids during up to 48 weeks of follow up” (opens the source at this quote in a new tab)

“99% (70 of 71) completed steroid prophylaxis taper on schedule” (opens the source at this quote in a new tab)

Aflibercept loading doses administered around 4D-150 dosing

“All patients randomized to receive 3 total loading doses per aflibercept label” (opens the source at this quote in a new tab)

“Aflibercept 2mg dosed at Day -7 and Day 28. 4D-150 dosed at Day 0.” (opens the source at this quote in a new tab)

Current availability

“All of the Company’s product candidates are in clinical or preclinical development and have not yet been approved for marketing by the U.S. Food and Drug Administration or any other regulatory authority.” (opens the source at this quote in a new tab)

Manufacturing capabilities and commercial supply

“Our current in-house manufacturing capabilities include GMP manufacturing (upstream, downstream and fill/finish), production capabilities for late-phase clinical trials, IND-enabling Good Laboratory Practice (“GLP”) toxicology studies, and research candidate production.” (opens the source at this quote in a new tab)
“In addition to our in-house facilities, we have established a partnership with a leading global commercial CDMO for potential commercialization of 4D-150. We have successfully completed the tech transfer of produced and released Phase 3 batches using our intended commercial processes at this CDMO.” (opens the source at this quote in a new tab)

Commercial rights in Asia-Pacific markets

“Under the terms of the agreement, 4DMT will grant Otsuka exclusive rights to develop and commercialize 4D-150 for retinal vascular diseases, including wet AMD and DME, in Japan, China, Australia and other Asia-Pacific markets. Otsuka will lead all regulatory and commercialization activities in its licensed territories.” (opens the source at this quote in a new tab)
“4DMT retains full development and commercialization rights for 4D-150 outside the APAC region, including the U.S., Latin America and Europe.” (opens the source at this quote in a new tab)

Preparation for commercialization

“As CTO, Dr. Barglow will continue to oversee 4DMT’s transition to commercial manufacturing, with responsibility for CMC quality, supply chain, and technical operations.” (opens the source at this quote in a new tab)

Expanded access program, specialty distribution, and site qualification requirements

No evidence found.

Supplemental aflibercept in the Phase 3 trials

“The key secondary endpoint is treatment burden reduction comparing the number of aflibercept injections received in the 4D-150 arm versus the aflibercept comparator arm over 52 weeks. Patients in both arms are eligible for supplemental aflibercept injections.” (opens the source at this quote in a new tab)

Supplemental injection criteria

“Supplemental aflibercept injection criteria for 4D-150 arm optimized to protect primary BCVA endpoint and to maximize reduction of supplemental treatment burden; no supplemental injections allowed in control arm” (opens the source at this quote in a new tab)

Concomitant ocular treatments excluded in 4FRONT-2

“Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, other than allowed prior IVT anti-VEGF in the study eye” (opens the source at this quote in a new tab)

Corticosteroid use after the prophylactic taper

“99% (70 of 71) remained completely off steroids” (opens the source at this quote in a new tab)

Medicare quality measure for age-related macular degeneration

“Percentage of patients aged 50 years and older with a diagnosis of age-related macular degeneration (AMD) who had a dilated macular examination performed which included documentation of the presence or absence of macular thickening or geographic atrophy or hemorrhage AND the level of macular degeneration severity during one or more office visits within the 12 month performance period” (opens the source at this quote in a new tab)

Effect of 4D-150 on quality measures

No evidence found.

Summary: comparison with other gene therapies and long-acting anti-VEGF agents in neovascular AMD

No head-to-head trial has compared 4D-150 with another gene therapy for neovascular AMD. The three most advanced AAV programs differ in capsid, route, and dose. 4D-150 uses the synthetic R100 capsid, is given as a single intravitreal injection at 3E10 vg/eye in the Phase 3 4FRONT trials, and carries two transgenes, a codon-optimized aflibercept sequence and a microRNA targeting VEGF-C. ABBV-RGX-314 (surabgene lomparvovec) uses an AAV8 vector encoding an anti-VEGF antibody fragment and is delivered by subretinal surgery in the ATMOSPHERE (671 participants enrolled) and ASCENT (735 participants enrolled) trials, with suprachoroidal delivery in earlier-phase studies. Ixoberogene soroparvovec uses the AAV2.7m8 capsid and intravitreal delivery of aflibercept, with 6E10 vg/eye selected for the Phase 3 ARTEMIS trial (311 participants enrolled). All three Phase 3 programs use a noninferiority comparison against a bolus anti-VEGF comparator: aflibercept 2 mg every 8 weeks for 4FRONT-1, 4FRONT-2, ASCENT, and ARTEMIS, and ranibizumab 0.5 mg monthly for ATMOSPHERE. Reported intraocular inflammation differs by program and prophylaxis: 2 of 71 participants (2.8%) dosed with 4D-150 at 3E10 vg/eye had mild inflammation within 28 weeks and none thereafter, while inflammation with ixoberogene soroparvovec was managed with topical corticosteroids and drove selection of a lower dose with topical-only prophylaxis, and about 23% of participants in a suprachoroidal ABBV-RGX-314 cohort had mild inflammation. Approved long-acting comparators remain repeat-administration products: aflibercept 8 mg is dosed every 4 weeks for three doses then every 8 to 16 weeks, faricimab 6 mg is dosed every 4 weeks for four doses then at intervals up to 16 weeks, and ranibizumab delivered by the Susvimo ocular implant requires surgical implantation and refill-exchange every 24 weeks, with a boxed warning for endophthalmitis.

Sponsor view of competing late-stage gene therapy programs

“We consider our most direct competitors in late-stage development with respect to 4D-150 for the treatment of retinal vascular diseases including wet AMD and DME to be late-stage AAV-based anti-VEGF genetic medicine programs including ABBV-RGX-314 from AbbVie Inc. and REGENXBIO Inc. (subretinal delivery in Phase 3 for wet AMD; suprachoroidal delivery initiating Phase 3 for diabetic retinopathy and in Phase 2 for wet AMD) and Ixo-Vec from Adverum Biotechnologies Inc., now a subsidiary of Eli Lilly and Company (intravitreal delivery in Phase 3 for wet AMD, previously discontinued in diabetic populations).” (opens the source at this quote in a new tab)
“AAV genetic medicine approaches are being developed by several companies to treat wet AMD by delivering a copy of a transgene encoding an anti-VEGF biologic by either subretinal surgery or suprachoroidal injection with a conventional AAV vector, or intravitreal administration with a mouse-evolved vector.” (opens the source at this quote in a new tab)

Comparison with interval-extension approaches

“In addition to genetic medicine approaches, other product candidates designed for extended durability are in development, with the potential to extend dosing intervals by several weeks. We believe a backbone therapy, like 4D-150, designed to provide potentially lifelong benefit with a one-time treatment, would be paradigm-shifting and highly differentiated from interval extension approaches.” (opens the source at this quote in a new tab)

Capsid, route, and transgene of competing AAV programs

“RGX-314 is one of the most advanced candidates, employing an AAV8 vector to deliver a transgene encoding an anti-VEGF antibody fragment analogous to ranibizumab” (opens the source at this quote in a new tab)
“ADVM-022 (ixoberogene soroparvovec; Ixo-vec) employs an engineered AAV2.7m8 capsid for IVT delivery of aflibercept to suppress multiple angiogenic pathways” (opens the source at this quote in a new tab)
“Based on these findings, the 6 × 10¹⁰ vg/eye dose combined with topical-only prophylaxis was selected for the pivotal Phase III program” (opens the source at this quote in a new tab)

Inflammation reported with suprachoroidal and intravitreal competitor programs

“Early interim data from Cohorts 1 and 2 (2.5 × 10¹¹ and 5.0 × 10¹¹ vg/eye) showed no drug-related serious ocular adverse events, with mild intraocular inflammation occurring in approximately 23% of patients and resolving with topical corticosteroids.” (opens the source at this quote in a new tab)
“The most common adverse event was mild-to-moderate anterior segment inflammation, generally responsive to topical corticosteroids, underscoring the need for steroid co-administration and vector dose or formulation optimization” (opens the source at this quote in a new tab)

Registered design of the ixoberogene soroparvovec Phase 3 trial

“This is a multi-center, randomized, double-masked, active-comparator-controlled, Phase 3 study in a broad participant population (treatment-naïve and treatment-experienced) with neovascular (wet) age-related macular degeneration (nAMD). The study will evaluate a single intravitreal (IVT) injection of Ixo-vec compared to an active comparator.” (opens the source at this quote in a new tab)

Registered design of the ABBV-RGX-314 Phase 3 trials

“ABBV-RGX-314 (also known as RGX-314 and surabgene lomparvovec (sura-vec)) is being developed as a novel one-time gene therapy for the treatment of neovascular (wet) age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)

“Ranibizumab (LUCENTIS®) 0.5 mg (0.05 mL of 10 mg/mL solution) administered by intravitreal injection approximately every 28 days” (opens the source at this quote in a new tab)

Approved long-acting anti-VEGF agents: labeled 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)

“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)

Port delivery system: labeled administration and boxed warning

“The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 24 weeks (approximately 6 months).” (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)

Vorolanib intravitreal insert: mechanism, delivery, and Phase 3 LUGANO and LUCIA design

“DURAVYU brings a potential new multi-mechanism of action and treatment paradigm for retinal diseases beyond existing anti-VEGF large molecule ligand blocking therapies, as vorolanib acts intracellularly to suppress angiogenesis through the inhibition of all VEGF receptors and PDGFR, while also suppressing inflammation through the inhibition of interleukin 6 (IL-6)/JAK1 signaling.” (opens the source at this quote in a new tab)
“DURAVYU is delivered via a standard intravitreal injection in the physician's office, similar to current practice with FDA approved anti-VEGF treatments.” (opens the source at this quote in a new tab)
“LUGANO and LUCIA are identical, randomized, double-masked, aflibercept controlled, non-inferiority Phase 3 trials assessing the efficacy and safety of DURAVYU in patients with active wet AMD including both treatment naïve and treatment experienced patients.” (opens the source at this quote in a new tab)
“Enrollment is complete in both trials with over 900 patients enrolled.” (opens the source at this quote in a new tab)
“At Day 1, patients are randomized 1:1 to receive either DURAVYU 2.7mg every six months or on-label aflibercept as control.” (opens the source at this quote in a new tab)
“The primary endpoint of the Phase 3 pivotal trials is non-inferiority in the average change in best corrected visual acuity (BCVA) at weeks 52 and 56 compared to baseline.” (opens the source at this quote in a new tab)

“A 2-year Phase 3, Multicenter, Prospective, Randomized, Double-Masked, Parallel-Group Study of EYP-1901, a Tyrosine Kinase Inhibitor (TKI), Compared to Aflibercept in Subjects With Wet AMD” (opens the source at this quote in a new tab)

LUGANO Phase 3 results: primary endpoint, treatment burden, safety, and LUCIA data timing

“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)
“42% reduction in treatment burden, achieving superiority versus on-label aflibercept (nominal p-value<0.0001) compared to a maximum possible reduction of 60%” (opens the source at this quote in a new tab)
“This reduction translates to two fewer injections on average in DURAVYU patients versus on-label aflibercept up to Week 56” (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)
“79% of DURAVYU patients received zero or one supplement up to Week 56” (opens the source at this quote in a new tab)
“No difference in cataracts, elevated intraocular pressure, or intraocular inflammation between study and control group” (opens the source at this quote in a new tab)
“No observed occurrences of insert migration, anterior chamber opacities, free-floating drug particles, retinal vasculitis, or severe intraocular inflammation (IOI)” (opens the source at this quote in a new tab)
“The Company remains on track to report topline data from the second wet AMD pivotal Phase 3 LUCIA trial in the fourth quarter of 2026. 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)

Axitinib intravitreal implant: mechanism, delivery, and Phase 3 SOL-1 and SOL-R design

“AXPAXLI™ (also known as OTX-TKI) is an investigational, bioresorbable, intravitreal hydrogel incorporating axitinib, a small molecule, multi-target, tyrosine kinase inhibitor with anti-angiogenic properties, being evaluated for the treatment of wet AMD and diabetic retinal disease.” (opens the source at this quote in a new tab)
“The registrational Phase 3 SOL-1 trial (NCT06223958) is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (1:1), parallel group trial that involves more than 100 clinical trial sites located in the U.S. and Argentina. In December 2024, the trial completed randomization of 344 treatment-naïve subjects with a diagnosis of wet AMD in the study eye.” (opens the source at this quote in a new tab)
“The registrational Phase 3 SOL-R trial (NCT06495918) is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (2:2:1), three-arm trial that includes sites located in the U.S., Argentina, India, and Australia in subjects who are treatment-naïve or were diagnosed with wet AMD in the study eye within about four months prior to enrollment.” (opens the source at this quote in a new tab)
“In December 2025, the trial completed the randomization of 631 subjects.” (opens the source at this quote in a new tab)
“Subjects in the first arm receive a single dose of AXPAXLI (0.45 mg) at Day 1 and are re-dosed at Weeks 24, 48, and 72.” (opens the source at this quote in a new tab)
“The primary endpoint of SOL-R is to demonstrate non-inferiority in mean BCVA change from baseline between the AXPAXLI and on-label aflibercept (2 mg) arms at Week 56.” (opens the source at this quote in a new tab)

“A Phase 3, Multicenter, Double-Masked, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Intravitreal OTX-TKI (Axitinib Implant) in Subjects With Neovascular Age-Related Macular Degeneration (nAMD)” (opens the source at this quote in a new tab)

SOL-1 Phase 3 results: primary endpoint, rescue-free rates, safety, and SOL-R data timing

“AXPAXLI met its primary endpoint at Week 36 with high statistical significance. The proportion of subjects with <15 ETDRS letters lost from baseline at Week 36 was 74.1% in the AXPAXLI arm compared to 55.8% in the aflibercept (2 mg) arm, with a risk difference of 17.5% and p-value of 0.0006 per the pre-specified statistical model, and with an observed difference of 18.3%.” (opens the source at this quote in a new tab)
“The proportion of subjects who maintained vision at Week 52 was 65.9% in the AXPAXLI arm compared to 44.2% in the aflibercept (2 mg) arm, with a risk difference of 21.1% and a p-value of <0.0001 per the pre-specified statistical model compared to aflibercept (2 mg) subjects, and with an observed difference of 21.7%.” (opens the source at this quote in a new tab)
“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% for the aflibercept (2 mg) arm at the same time periods.” (opens the source at this quote in a new tab)
“As of the Week 52 database lock on February 5, 2026, AXPAXLI was generally well-tolerated in SOL-1 with no observed treatment-related ocular or systemic serious adverse events (SAEs). There were no events of endophthalmitis, occlusive or non-occlusive retinal vasculitis, retinal detachment, or implant migration to the anterior chamber observed in the AXPAXLI arm.” (opens the source at this quote in a new tab)
“The complementary SOL-R Phase 3 non-inferiority trial of AXPAXLI in wet AMD will continue as planned, with topline data expected in 1Q 2027.” (opens the source at this quote in a new tab)

Procedural requirements and complications of the subretinal and intravitreal routes

“However, this method is inherently invasive, requiring pars plana vitrectomy, a surgical procedure in which the vitreous gel inside the eye is removed to access the retina, and specialized surgical expertise, and may lead to serious complications such as vitreous hemorrhage and retinal detachment when performed under nonstandard conditions” (opens the source at this quote in a new tab)

“For instance, intravitreal injections have a safer profile than subretinal injections. They can be performed in out patient clinics with topical anesthesia. Panretinal transduction with the genetic vector is also possible. The main disadvantages of an intravitreal injection include a potential immune response and incomplete vector penetration through the ILM.” (opens the source at this quote in a new tab)

Dose thresholds for expression and burden reduction in the subretinal ABBV-RGX-314 program

“In the Phase I/IIa SR dose-escalation trial, higher-dose cohorts (≥6 × 10¹⁰ vg/eye) maintained protein expression for up to 2 years, with stable best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and required 59–85% fewer anti-VEGF injections compared with baseline” (opens the source at this quote in a new tab)
“Subsequent dose expansion to 1.0 × 10¹² vg/eye (dose level 3) maintained a consistent safety profile and yielded an ≈80% reduction in annualized injection frequency, with 50% of eyes remaining injection-free at 6 months” (opens the source at this quote in a new tab)

Retinal pigmentary changes after subretinal delivery of ABBV-RGX-314

“Almost 70% of patients developed retinal pigmentary changes.” (opens the source at this quote in a new tab)
“These retinal pigmentary changes typically were seen in the inferior retinal periphery.” (opens the source at this quote in a new tab)

Intraocular aflibercept concentration after AAV delivery compared with bolus injection

“The aflibercept levels in the aqueous humor 7 months after an ixo-vec injection were comparable to those found in humans one month after a bolus monthly or bimonthly 2 mg aflibercept injection” (opens the source at this quote in a new tab)

Ocular adverse events reported in the ixoberogene soroparvovec Phase 1 trial

“The most common adverse events recorded was a dose dependent intraocular inflammatory response manifested by cellularity in the anterior chamber and the vitreous cavity.” (opens the source at this quote in a new tab)
“Some eyes developed asymptomatic pigment dispersion, segmental iris atrophy and transillumination iris defects.” (opens the source at this quote in a new tab)
“There was no clinical, tomographic or angiographic evidence of retinal vasculitis, retinitis or choroiditis” (opens the source at this quote in a new tab)

Onset window for inflammation and its control in the ixoberogene soroparvovec Phase 2 trial

“Both doses were well tolerated, and inflammation was effectively controlled with topical corticosteroids, with no new onset beyond week 30.” (opens the source at this quote in a new tab)

Definition: spectrum of macular disorders with neovascular and atrophic late stages

“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)
“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)

“Age-related macular degeneration is a process by which the structure and function of the macula deteriorates over time in association with distinguishing signs and symptoms that typically become evident clinically beyond 50 years of age and do not seem to be secondary to other processes such as pathologic myopia, central serous chorioretinopathy, monogenetic inherited retinal disease, chorioretinal uveitic syndromes or infections, or trauma.” (opens the source at this quote in a new tab)

Multifactorial etiology: complement, lipid, angiogenic, and inflammatory pathways

“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: age, smoking, ancestry, and genetic factors

“The main unmodifiable risk factors for the development of advanced AMD are increasing age, Northern European ancestry, and genetic factors. Although a number of modifiable risk factors have been investigated, cigarette smoking is the main one that has been consistently identified in numerous studies.” (opens the source at this quote in a new tab)
“Smoking cessation is associated with a reduced risk of AMD progression; the risk of developing AMD in individuals who have not smoked for more than 20 years is comparable to the risk in nonsmokers.” (opens the source at this quote in a new tab)
“Routine genetic testing is not currently recommended.” (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)

Genetic risk: CFH Y402H and ARMS2 A69S genotypes

“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)

“Overall, we included 6676 neovascular AMD cases and 7668 controls. Pooled overall odds ratios (ORs) (95% CI) for neovascular AMD/control were ARMS2 A69S: OR = 2.35 (2.01-2.75) for GT versus GG; OR = 8.57 (6.91-10.64) for TT versus GG; CFH Y402H: OR = 1.94 (1.73-2.18) for CT versus TT; OR = 4.89 (3.96-6.05) for CC versus TT.” (opens the source at this quote in a new tab)

Tobacco as a modifiable contributor to global burden

“The global contribution of tobacco to age-standardised DALYs decreased by 20%, declining from 12·45% (95% UI 7·73-17·37) in 1990 to 9·96% (6·12-14·06) in 2021.” (opens the source at this quote in a new tab)

Hallmark lesion and etiologic interplay of ageing, environment, and genetic susceptibility

“AMD is characterized by accumulation of extracellular deposits, namely drusen, along with progressive degeneration of photoreceptors and adjacent tissues.” (opens the source at this quote in a new tab)
“AMD is a multifactorial disease encompassing a complex interplay between ageing, environmental risk factors and genetic susceptibility.” (opens the source at this quote in a new tab)

United States incidence: meta-analysis in White Americans aged 50 years or 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.” (opens the source at this quote in a new tab)
“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 incidence: Medicare beneficiaries aged 65 years or older

“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)

Europe incidence: systematic review and meta-analysis

“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)

Fellow-eye incidence in untreated unilateral disease

“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 incident cases by subtype, age, and sex

“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)
“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). 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)
“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)

Share of incident cases expected to be eligible for and able to receive treatment

“Although our overall estimates of NVAMD incidence are high (owing to the inclusion of those at older ages, especially in women), this does not reflect the number in need of treatment.” (opens the source at this quote in a new tab)
“Of note, the inclusion of older ages in our estimates may include a large number who are unwilling or too frail to undergo treatment.” (opens the source at this quote in a new tab)
“Approximately 89% of the US population aged 80 years and older is white.” (opens the source at this quote in a new tab)

Sensitivity of the fellow-eye incidence estimate to outlier studies

“These cumulative incidence rates were influenced by significant heterogeneity in the studies caused by outliers.” (opens the source at this quote in a new tab)
“If outliers were not included in the analysis, the 12-month incidence rate changed considerably, from 12.2% to 8.1% (95% CI, 4.9–11.9).” (opens the source at this quote in a new tab)

Global prevalence: systematic review and meta-analysis of 39 population-based studies

“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)

United States prevalence of late-stage AMD in 2019: Vision and Eye Health Surveillance System

“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)
“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).” (opens the source at this quote in a new tab)

United States prevalence of neovascular AMD or geographic atrophy in 2000

“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)

United States projections and share of severe vision loss

“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)
“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)
“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)

Europe prevalence: systematic review and meta-analysis

“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 AMD-related vision impairment: Global Burden of Disease Study 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)
“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)

Global prevalence of the neovascular subtype and of geographic atrophy

“Eight (21%) of the 39 studies provided information on geographic atrophy and neovascular subtypes. Subgroup analysis showed similar overall prevalence of geographic atrophy (0·44%, 95% CrI 0·15–1·36) and neovascular age-related macular degeneration (0·46%, 0·18–1·08).” (opens the source at this quote in a new tab)
“Europeans had a higher prevalence of geographic atrophy (1·11%, 95% CrI 0·53–2·08) than Africans (0·14%, 0·04–0·45), Asians (0·21%, 0·04–0·87), and Hispanics (0·16%, 0·05–0·46).” (opens the source at this quote in a new tab)

Projected cases by world region in 2040

“Europe is expected to be second to Asia in the number of projected cases (69 million [40–109] in 2040), followed by Africa (39 million [12–93]), Latin America and the Caribbean (39 million [15–82]), North America (25 million [15–38]), and Oceania (2 million [1–5]).” (opens the source at this quote in a new tab)

Age at which late-stage prevalence rises most steeply

“Prevalence of late disease in populations with European ancestry increased most rapidly after age 75 years, with a similar trend seen in Europe and Oceania regions.” (opens the source at this quote in a new tab)

Neovascular share of prevalent late-stage disease

“Although neovascular AMD accounts for only two thirds of prevalent late-stage cases, it is responsible for over 80% of legal blindness due to AMD.” (opens the source at this quote in a new tab)

Natural history: visual acuity loss in untreated eyes

“Mean baseline VA among study patients was 0.64 logarithm of the minimum angle of resolution (logMAR) (approximately 20/87 Snellen). 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)

Natural history: macular atrophy after untreated neovascular AMD

“The cumulative risks of incident macular atrophy after untreated NV were 9.6% (standard error 1.2%), 31.4% (2.2%), 43.1% (2.6%), and 61.5% (4.3%) at two, five, seven, and 10 years, respectively. This corresponded to a linear risk of 6.5%/year.” (opens the source at this quote in a new tab)

Global blindness attributable to AMD

“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 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 at diagnosis in United States clinical practice

“The study included 162,902 eyes. Among all included eyes, 34.3% presented with 20/40 VA or better at diagnosis. Patients with 20/40 vision or better at baseline maintained a mean VA of 20/40 or better for 2 years after treatment initiation.” (opens the source at this quote in a new tab)

Mortality: late AMD and all-cause and cardiovascular mortality

“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)

“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)

Proportion of untreated eyes with stable and with worsening acuity

“Several studies reported the proportion of patients categorized as stable (defined as improved or unchanging acuity).” (opens the source at this quote in a new tab)
“The proportion of patients whose VA worsened (defined generally as any deterioration from baseline) increased from 45.0% at 3 months to 81.1% by 2 years” (opens the source at this quote in a new tab)

Progression to legal blindness within three months of presentation

“In 19.7%, VA was worse than 20/200 (legal blindness) at study inception, and this proportion increased to 50.3% by 3 months and to 77.6% by 3 years” (opens the source at this quote in a new tab)

Lesion location and visual prognosis by angiographic subtype in untreated eyes

“In the 41 treatment arms reporting the location of choroidal neovascularization relative to the fovea, most patients had subfoveal disease (81.4%).” (opens the source at this quote in a new tab)
“Based on these studies, at 12 months 33.2% (95% CI, 19.3%–48.7%) of patients with occult choroidal neovascularization had lost between 3 and 6 lines of VA, compared with 43.7% (95% CI, 28.0%–60.1%) of patients with classic choroidal neovascularization.” (opens the source at this quote in a new tab)
“This difference was not significant, as reflected by the overlapping CIs.” (opens the source at this quote in a new tab)

Generalizability of the untreated natural history estimates

“The lack of data on ethnicity and the fact that the vast majority of studies are North American and European limit the generalizability of the data to Western Caucasian populations.” (opens the source at this quote in a new tab)

Mean visual acuity at diagnosis in first and second eyes

“The mean VA at diagnosis was 0.62 ± 0.52 (mean ± standard deviation) logMAR (20/83) for all eyes, 0.63 ± 0.53 (20/85) for first eyes, and 0.60 ± 0.50 (20/79), for second eyes” (opens the source at this quote in a new tab)

Mortality over three and a half years in a treated trial cohort

“Among the 1117 patients alive at the end of the clinical trial (end of Year 2), 203 (18.2%) died before the end of the Follow-up Study.” (opens the source at this quote in a new tab)

Macular neovascularization types 1, 2, and 3

“Type 3 neovascularization is to be used when the vascular complex originates in the retina. Type 1 neovascularization is applied when the vessels originate from the choroid and remain under the RPE. Type 2 neovascularization is denoted if neovascularization that originates in the choroid breaks through the RPE to reach the subretinal space.” (opens the source at this quote in a new tab)
“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)

“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)
“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)

VEGF-A and VEGF-C in choroidal neovascularization

“With nAMD, immune cells are recruited to the macula, where they secrete proangiogenic cytokines (e.g., VEGF-A and VEGF-C) and proinflammatory cytokines (e.g., IL-31, LIF, and SDF1α)” (opens the source at this quote in a new tab)
“These VEGF ligand molecules stimulate endothelial cell proliferation and migration, angiogenesis, and increased vascular permeability, ultimately resulting in leakage of blood vessel fluid that damages the photoreceptor layer and impairs vision” (opens the source at this quote in a new tab)
“Interestingly, hypoxia-induced retinal expression of VEGF-C can induce pathological retinal neovascularization to an extent similar to that of VEGF-A” (opens the source at this quote in a new tab)

Compensatory VEGF-C and VEGF-D upregulation after VEGF-A inhibition

“Other ligand angiogenic mediators, VEGF-C and VEGF-D, are important in the pathogenesis of cancer and retinal vascular diseases; and evidence shows they are upregulated after VEGF-A suppression.” (opens the source at this quote in a new tab)
“In a laser-induced mouse model of CNV (a major cause of visual loss in patients with nAMD), the ability of anti-VEGF-C/-D monotherapy to reduce vascular leakage and CNV area was similar to that of aflibercept (which targets VEGF-A/-B and PIGF); and when used in combination, the efficacy was superior to that of either therapeutic approach alone” (opens the source at this quote in a new tab)

Complement dysregulation linked to CFH

“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)

Pathogenic processes implicated in drusen formation and photoreceptor degeneration

“Chronic inflammation, lipid deposition, oxidative stress and impaired extracellular matrix maintenance are strongly implicated in AMD pathogenesis.” (opens the source at this quote in a new tab)
“However, the exact interactions of pathophysiological events that culminate in drusen formation and the associated degeneration processes remain to be elucidated.” (opens the source at this quote in a new tab)

Disease spectrum of distinct phenotypes with different pathogenic mechanisms

“Compelling progress in high-resolution retinal imaging has enabled refined phenotyping of AMD in vivo.” (opens the source at this quote in a new tab)
“Hence, our current understanding promotes the view that AMD represents a disease spectrum comprising distinct phenotypes with different mechanisms of pathogenesis.” (opens the source at this quote in a new tab)

Optical coherence tomography in diagnosis and management

“Optical coherence tomography is important in diagnosing and managing AMD, particularly with respect to determining the presence of subretinal and intraretinal fluid and in documenting the degree of retinal thickening.” (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)

Optical coherence tomography angiography: diagnostic accuracy for macular neovascularization

“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)

Fluorescein angiography indications

“If MNV is suspected on the basis of new symptoms or ocular findings, fluorescein angiography should be performed and interpreted expeditiously by an individual experienced in managing patients with neovascular AMD.” (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)

Monitoring during anti-VEGF treatment and of high-risk fellow eyes

“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)
“Subsequent examinations, OCT, OCTA, and fluorescein angiography should be performed as indicated depending on the clinical findings and the judgment of the treating ophthalmologist.” (opens the source at this quote in a new tab)
“Optical coherence tomography is useful and OCTA may be useful for evaluating the status of high-risk fellow eyes.” (opens the source at this quote in a new tab)

Consensus nomenclature for imaging-based classification

“The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed.” (opens the source at this quote in a new tab)

Pooled accuracy of optical coherence tomography angiography against fluorescein angiography in 553 eyes

“Seven primary studies were included. The quality of the evidence was good.” (opens the source at this quote in a new tab)
“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, cumulative positive and negative likelihood ratios of 8.36 and 0.15, respectively (95% CI of 3.05-22.890 and 0.09-0.24, respectively), and a cumulative diagnostic odds ratio of 67.21 (95% CI 22.58-200.05).” (opens the source at this quote in a new tab)
“The evidence obtained does not demonstrate the superiority of OCTA over FA. Its use as a support technique could improve patient flow and reduce the number of FA.” (opens the source at this quote in a new tab)

Visual symptoms: metamorphopsia, decreased vision, and scotoma

Symptom listed for initial history	Quoted text
Distortion	“Metamorphopsia”
Reduced acuity	“Decreased vision”
Central field loss	“Scotoma”
Light flashes	“Photopsia”
Low-luminance function	“Difficulties in dark adaptation”

“Ophthalmologists, optometrists, and ancillary clinical personnel should be aware that 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)

Clinical signs: hemorrhage, exudates, subretinal fluid, and fibrosis

“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)

Care-seeking after onset of visual symptoms

“Most (73%) patients visited a health care professional within 1 month of experiencing vision changes and 54% began treatment immediately.” (opens the source at this quote in a new tab)

Functional impairment: activities of daily living

“The prevalence of impaired basic, instrumental and total ADL was 37.76%, 67.82% and 39.59%, respectively. In multivariate-adjusted models, moderate visual impairment [OR 5.65, 95% CI (2.31-13.83) and blindness [OR 5.43, 95% CI (2.09-14.12)] were associated with greater odds of impaired total ADL.” (opens the source at this quote in a new tab)

Psychological effects: depressive and anxiety symptoms

“The prevalence of depressive symptoms was 42.04% and 31.78% as per the CES-D-10 and MHI scales, respectively.” (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. The main sources of anxiety were fear of going blind owing to intravitreal injections and concerns about treatment effectiveness, rather than around pain. 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)

“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)

Perceptual symptoms: Charles Bonnet syndrome visual hallucinations

“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%).” (opens the source at this quote in a new tab)

“Depression and visual hallucinations (Charles Bonnet syndrome) frequently accompany severe central vision loss. 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)

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

Visual outcomes 5 years after starting anti-VEGF therapy: CATT

“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)
“Geographic atrophy was present in 213 (41%) of 515 gradable eyes and was subfoveal in 85 (17%). Among 555 eyes with spectral domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium).” (opens the source at this quote in a new tab)

Geographic atrophy under anti-VEGF treatment

“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)
“The overall GA growth rate was 0.33 (SE, 0.02) mm/year.” (opens the source at this quote in a new tab)

Subretinal fibrosis and scar formation

“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)
“Most fibrotic scars and accompanying macular atrophy expanded over time, reducing visual acuity.” (opens the source at this quote in a new tab)

Seven-year outcomes after intensive ranibizumab therapy: 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)

Falls and fractures

“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)

“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)

“Loss of VA increases the risk of frequent falls.” (opens the source at this quote in a new tab)

Hip fractures: Medicare beneficiaries

“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)

Atrophy in eyes treated with anti-VEGF agents: systematic review findings

“All studies confirmed the occurrence of atrophy, and when available, longitudinal data from the included studies demonstrated an increase in atrophy incidence over time.” (opens the source at this quote in a new tab)
“In addition, visual acuity loss was noted with foveal atrophy.” (opens the source at this quote in a new tab)

Uncertainty about whether anti-VEGF treatment causes atrophy

“All studies demonstrated that atrophy occurs in the context of MNV treated with anti-VEGF therapy; however, it is not clear whether anti-VEGF treatment is causative of atrophy versus being associated with atrophy development.” (opens the source at this quote in a new tab)
“The included studies were not designed or powered to assess atrophy as a primary outcome.” (opens the source at this quote in a new tab)
“Continued VEGF inhibition also may increase atrophy development.” (opens the source at this quote in a new tab)

Atrophy in eyes without macular neovascularization

“For example, more than 20% of fellow eyes (without GA or MNV at baseline) in the HARBOR study demonstrated evidence of atrophy at only 2 years.” (opens the source at this quote in a new tab)

Contribution of atrophy to long-term vision loss

“It is also noteworthy that atrophy represents only approximately 10% of vision loss related to AMD.” (opens the source at this quote in a new tab)
“Further, in a real-world analysis of anti-VEGF therapy for nAMD, fovea-involved atrophy was the most common cause of long-term vision loss, but represented only 37% of the cases.” (opens the source at this quote in a new tab)

Terminology for atrophy in the presence and absence of neovascularization

“According to Classification of Atrophy Meetings group recommendations, the term geographic atrophy should be used strictly to describe atrophy in the absence of MNV.” (opens the source at this quote in a new tab)
“In the presence of MNV, complete RPE and outer retinal atrophy is preferred when atrophy is defined using OCT, whereas macular atrophy is preferred when atrophy is observed clinically or defined on CFP (with GA being reserved for atrophy in the absence of MNV).” (opens the source at this quote in a new tab)

Retinal thinning and lesion growth accompanying the five-year decline in acuity

“The proportion of eyes with an abnormally thin retina increased from 22% at the end of Year 2 to 36% at 5 years.” (opens the source at this quote in a new tab)
“Worse VA outcomes have also been associated with increased lesion size, and in the Follow-up Study, mean lesion size increased more than 50% over the 3.5 year period” (opens the source at this quote in a new tab)
“These data highlight the need for agents that can prevent or minimize geographic atrophy and expansion of the total neovascular lesion.” (opens the source at this quote in a new tab)

Selection of returning participants in the five-year follow-up cohort

“Non-participants had a mean age 2.3 years older (p<0.001) and a mean baseline visual acuity score 3.1 letters worse than participants (p=0.001).” (opens the source at this quote in a new tab)
“Thus, the Follow-up Study results are likely better than would have been observed if 100% of CATT patients had returned.” (opens the source at this quote in a new tab)

Health utility values by visual acuity in the better-seeing eye

“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)

Vision-related quality of life: NEI VFQ-25 in a treated clinic cohort

“Individuals with mild or moderate visual impairment or blindness at baseline had significantly lower NEI-VFQ-25 scores at follow-up.” (opens the source at this quote in a new tab)
“Those with impaired instrumental ADLs scored 11.62 (p = 0.02), 13.13 (p < 0.0001) and 15.8 (p = 0.0012) points lower in the NEI-VFQ-25, SF-36 physical component score and EQ-5D-5L summary score, respectively.” (opens the source at this quote in a new tab)

Quality of life and mental health during anti-VEGF treatment: systematic reviews

“Depression or depressive symptoms were reported in up to 42% of patients with nAMD. Of 25/63 (40%) studies evaluating quality of life (QoL) and using various tools, eight studies reported composite National Eye Institute Visual Functioning Questionnaire scores following anti-VEGF treatment. 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)

“Change on National Eye Institute 25-Item Visual Function Questionnaire score from baseline to month 12 ranged from 0.7 to 4.4.” (opens the source at this quote in a new tab)

Depression and vision-related quality of life in guideline recommendations

“Age-related macular degeneration is associated with depression and reduced vision-related quality of life.” (opens the source at this quote in a new tab)
“Referrals for counseling, vocational rehabilitation, and or peer support groups for patients with depression, anxiety, and loss of independence or employment should be considered.” (opens the source at this quote in a new tab)

Disability-adjusted life-years attributable to AMD

“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)

Direct healthcare costs: commercially insured United States population

“Mean (SD) annual total all-cause cost for the prevalent cohort was $24,520 ($43,950) with outpatient costs as the largest cost component” (opens the source at this quote in a new tab)
“The nAMD-related outpatient costs represented 28% of total costs and 44% of total outpatient costs, respectively, and were driven primarily by anti-VEGF injection-related costs” (opens the source at this quote in a new tab)
“Annual all-cause cost was lower for the incident cohort compared to the prevalent cohort (mean [SD] = $18,943 [$29,236] vs mean [SD] = $24,520 [$43,950], respectively).” (opens the source at this quote in a new tab)
“Patients with active choroidal neovascularization (CNV) incurred at least $7,000 higher all-cause annual costs than patients with inactive CNV or inactive scar, largely driven by higher outpatient/anti-vascular endothelial growth factor (anti-VEGF) costs.” (opens the source at this quote in a new tab)

Annual visit and injection burden: commercially insured United States population

“Mean (SD) annual nAMD-related outpatient burden was 6.6 (4.8) visits overall; patients with active CNV had the highest utilization compared with patients with inactive CNV or inactive scar (P < 0.0001). Overall mean (SD) annual anti-VEGF–related outpatient visit burden was 3.9 (4.2) visits, with the highest utilization seen in active CNV group compared with inactive CNV and inactive scar groups (P < 0.0001).” (opens the source at this quote in a new tab)

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

“From 2014 to 2023, a total of 36 398 293 intravitreal anti-VEGF injections were administered to Medicare beneficiaries. 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)
“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)

Medicare Part B anti-VEGF spending per beneficiary

“During this 5-year period, associated Medicare drug costs averaged $1.3 billion annually. The number of Medicare Part B claims for aflibercept increased from 518 836 in 2013 to 866 749 in 2015. Annual Medicare drug expenditure for aflibercept was $1.4 billion on average. 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)

“Age-related macular degeneration (ARMD) therapies aflibercept and ranibizumab are among the highest-cost Medicare Part B drugs, even though off-label use of lower-cost bevacizumab is clinically noninferior.” (opens the source at this quote in a new tab)

AMD treatment costs per Medicare fee-for-service beneficiary, 2004 to 2018

“Annual costs among Medicare fee-for-service (FFS) beneficiaries increased from $261 per patient in 2004 to $1290 per patient in 2018.” (opens the source at this quote in a new tab)

Societal costs by visual acuity in the better-seeing eye

“The mean annual societal cost for the Control Cohort was $6,116 and for the Study Cohort averaged $39,910 (P < 0.001). Study Subcohort 1 costs averaged $20,339, while Subcohort 4 costs averaged $82,984.” (opens the source at this quote in a new tab)
“Total societal ophthalmic costs associated with neovascular age-related macular degeneration dramatically increase as vision in the better-seeing eye decreases.” (opens the source at this quote in a new tab)

Costs of vision loss and blindness in the United States

“We estimated an economic burden of VL of $134.2 billion: $98.7 billion in direct costs and $35.5 billion in indirect costs. 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. 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)

Clinic time burden for staff and patients

“Patients accounted for 20% of the health care staff's time per week, with an average of 23 staff members. 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)

Estimated Medicare savings from bevacizumab use

“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)

Anti-VEGF agent use across United States payers, 2017 to 2023

“Patients with Medicare B or C were significantly more likely to receive aflibercept over bevacizumab.” (opens the source at this quote in a new tab)

Total Medicare expenditure on anti-VEGF therapy, 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)

Annual Medicare drug cost per treated beneficiary by agent, 2022

“Bevacizumab, despite its widespread use in cost-sensitive settings, contributed minimally to total Medicare expenditures because of its low average cost per dose ($241 USD annually per beneficiary treated for wet age-related macular degeneration in 2022), compared with $8219 USD for aflibercept and $6143 USD for ranibizumab.” (opens the source at this quote in a new tab)

Injection rates per 100,000 Medicare beneficiaries by agent, 2014 to 2023

“aflibercept increased from 1864/100 000 to 5997/100 000 beneficiaries (221% rise)” (opens the source at this quote in a new tab)
“Ranibizumab declined overall by 44%, decreasing from 2437/100 000 to 1359/100 000 between 2014 and 2023, with an interim peak of 2591/100 000 in 2019.” (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)

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

“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)
“Because the MPUPD data set captures only FFS claims, states with higher MA enrollment have smaller captured FFS denominators, which may inflate calculated per-capita injection rates.” (opens the source at this quote in a new tab)

Staff time devoted to neovascular age-related macular degeneration care in retina practices

Staff type	Average number involved in neovascular AMD care (range)	Average share of a 40-hour work week spent in neovascular AMD care (range)	Average time per staff member per week	Average hours per week, all staff members
Receptionist	“5 (1–18 people)”	“20% (1%–75%)”	“8 hours”	“28 hours”
Office manager	“2 (0–10 people)”	“13% (0%–75%)”	“4 hours”	“10 hours”
Billing manager	“2 (0–6 people)”	“22% (0%–80%)”	“8 hours”	“18 hours”
Technician	“8 (1–50 people)”	“34% (3%–90%)”	“14 hours”	“112 hours”
Physicians other than retina specialists	“2 (0–18 people)”	“15% (0%–65%)”	“6 hours”	“12 hours”
Other staff members	“4 (1–12 people)”	“25% (5%–70%)”	“10 hours”	“40 hours”

Practice total	Quoted value
Staff members involved in neovascular AMD care	“23 people”
Office time per week across all staff members	“225 hours”

“The present study demonstrated that practices are highly invested in the management of patients with neovascular AMD, with an average retina practice consisting of 23 staff members involved in the disease management for every 1 treating retina specialist.” (opens the source at this quote in a new tab)
“In total, the management of patients with neovascular AMD accounts for one-fifth of the staff’s working week, and this estimate may likely underestimate the true workflow based on less structured communications with retina specialists.” (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” (opens the source at this quote in a new tab)

Retina specialist views on monitoring and injection frequency as burdens on staff, materials, and office space

“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. A large percentage of retina specialists (58%, 33 of 57) felt that billing and filing for reimbursement was also a significant burden on staff resources.” (opens the source at this quote in a new tab)
“In addition, 42% (24 of 57) of retina specialists considered monitoring frequency to be very impactful on material resources such as drugs and other supplies.” (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. 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)

Visit preparation time and post-injection recovery time

“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)
“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)

Practice setting and monthly injection volume of the surveyed retina specialists

“There were 57 retina specialists involved in the survey, 68% (39 of 57) were in a group practice, 14% (8 of 57) practiced in an academic setting, and 18% (10 of 57) were solo practitioners.” (opens the source at this quote in a new tab)
“The average total number of patients treated per month in these 3 settings was 556, and the average number of neovascular AMD patients treated per month was 201.” (opens the source at this quote in a new tab)
“The quantitative research section of this study was conducted between July and November 2011; additional sampling of respondents from Midwest and Great Plains states was carried out from June through August 2012, as these regions were underrepresented in the original sample.” (opens the source at this quote in a new tab)

Caregiver time and transportation to injection visits

“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). 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)

“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)

Caregiver work absenteeism: multinational survey including United States caregivers

“Caregivers estimated they provided support for 4.2 ± 2.9 days/week and 6.0 ± 7.1 h/day on average. 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 scores and contributors

“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. Caregiver tasks including accompanying for hospital appointments for eye treatment and patient's visual acuity in the better eye were the biggest contributors to the caregiver burden hierarchical model explaining 18% and 11% of the variance respectively.” (opens the source at this quote in a new tab)

Caregiver costs as a share of societal costs

“Direct nonmedical costs, primarily caregiver, comprised 67.1% of Study Cohort societal ophthalmic costs, versus 21.3% ($1,302/$6,116) of Control Cohort costs (P < 0.001) and 74.1% of 20/800 to no light perception subcohort costs.” (opens the source at this quote in a new tab)

Caregiver relationships and treatment barriers

“Many caregivers were a child/grandchild (47%) or partner (23%) of the patient; only 7% were professional 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)

“Consequences of untreated neovascular AMD include a substantial economic burden on patients, their family, and society.” (opens the source at this quote in a new tab)

Transportation to injection visits and the relationship of the accompanying person

“The majority of patients (72%, 54 of 75) were driven to their appointment by a caregiver. 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)
“Twenty percent (15 of 75) of patients drove themselves, while 8% (6 of 75) took a car service or public or government transportation.” (opens the source at this quote in a new tab)

Out-of-pocket transportation costs reported by participants

“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. Among those who had out-of-pocket transportation cost, 12% (8 of 67) paid for parking, 6% (4 of 67) paid tolls, and 3% (2 of 67) paid bus fare.” (opens the source at this quote in a new tab)

Age, comorbidity, and household income of surveyed participants

“The average age was 79 years (range 55–98 years) and 89% (67 of 75) of patients had a concomitant medical condition. 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)

Medicare Physician Fee Schedule payment for OCT, OCTA, and fluorescein angiography, 2025

CPT code and procedure	2025 total RVU	2025 MPFS national average
92134 OCT of retina	“0.97”	“$31.38”
92137 OCTA of retina	“1.76”	“$56.93”
92235 Fluorescein angiography	“4.72”	“$152.68”

“CPT code 92137 has been assigned a greater total of relative value units (RVUs) and a higher Medicare Physician Fee Schedule (MPFS) payment than 92134 to account for the additional work component and practice expenses associated with performing and interpreting OCTA.” (opens the source at this quote in a new tab)
“This means that you cannot bill for more than one of those procedures when they are performed by the same clinician on the same patient on the same day.” (opens the source at this quote in a new tab)

Frequency of OCT testing: commercially insured United States population

Annual OCT test-related visits	Overall cohort	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)”

Medicare savings from OCT-guided anti-VEGF treatment

“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)

Diagnostic testing patterns in Medicare and claims populations

“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)

Diffusion of diagnostic tests among Medicare beneficiaries in the first year after diagnosis

“A total of 23 941 Medicare beneficiaries with exudative AMD newly diagnosed during 1992-2009.” (opens the source at this quote in a new tab)
“Current Procedural Technology (CPT-4) billing codes were used to identify use of diagnostic tests (optical coherence tomography, fluorescein angiography, and fundus photography) and therapeutic interventions (argon laser photocoagulation, photodynamic therapy, intravitreal corticosteroids, and anti-vascular endothelial growth factor [VEGF] agents) used by these beneficiaries during the first year following diagnosis.” (opens the source at this quote in a new tab)
“Diffusion was rapid for each successive new diagnostic and treatment modality, with use of newer procedures quickly replacing existing ones.” (opens the source at this quote in a new tab)
“Although improving patient outcomes, rapid diffusion raises important public policy issues for Medicare and other payers to consider.” (opens the source at this quote in a new tab)

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

“Intravitreal injection therapy using anti-vascular endothelial growth factor (VEGF) agents, which may or may not target other factors such as placental growth factor or angiopoietin-2, is the most effective way to manage neovascular AMD and is the first-line treatment.” (opens the source at this quote in a new tab)
“The choice of biologic product (reference, biosimilar, or interchangeable) should be that of the treating ophthalmologist and the patient whenever possible.” (opens the source at this quote in a new tab)
“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)

NICE guideline NG82: anti-VEGF treatment and equivalence of agents

“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)
“Be aware that no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials considered by the guideline committee.” (opens the source at this quote in a new tab)

Ranibizumab: MARINA sham-controlled phase 3 trial

“We enrolled 716 patients in the study.” (opens the source at this quote in a new tab)
“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)
“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

“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)

Ranibizumab: FDA-labeled dosing intervals

“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 also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average.” (opens the source at this quote in a new tab)

Bevacizumab (off-label): CATT comparison with ranibizumab

“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.” (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), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.” (opens the source at this quote in a new tab)

Bevacizumab: off-label status and comparative efficacy in the AAO Preferred Practice Pattern

“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)
“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)

Ranibizumab biosimilars

“There are several biosimilar ranibizumab molecules approved by the FDA and others are available in numerous other countries.” (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)

Brolucizumab: HAWK and HARRIER phase 3 trials

“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)
“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 was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48.” (opens the source at this quote in a new tab)

Brolucizumab: retinal vasculitis and retinal vascular occlusion

“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)
“The interval between two BEOVU doses during maintenance treatment should not be less than 8 weeks.” (opens the source at this quote in a new tab)

“Retinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss.” (opens the source at this quote in a new tab)

“After FDA approval, several cases of occlusive retinal vasculitis occurred after intravitreal brolucizumab injection.” (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)

Brolucizumab: real-world incidence of intraocular inflammation

“The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively.” (opens the source at this quote in a new tab)

Brolucizumab: MERLIN every-4-week dosing in persistent fluid

“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)
“The incidence of IOI, including retinal vasculitis and retinal vascular occlusion, was higher with brolucizumab versus aflibercept; 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)

Brolucizumab intraocular inflammation through 96 weeks: rates and reported event terms

“The incidence of ocular adverse events (AEs) was similar across all treatment groups in both HAWK and HARRIER up to week 96 (Table 1), with the exception of combined intraocular inflammation (IOI) (iritis and uveitis), which was higher in the brolucizumab 6 mg group of HAWK compared with the aflibercept group (4.7% vs. 0.6%).” (opens the source at this quote in a new tab)
“The AEs related to IOI reported in both studies were iritis, uveitis, anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye inflammation, iridocyclitis, keratic precipitates, retinal vasculitis, vitreous haze, and vitreitis; among these, the most frequently reported were iritis and uveitis.” (opens the source at this quote in a new tab)
“Compared with week 48, the incidence of these AEs from week 48 through week 96 was low, with additional cases in HAWK only (2 cases of iritis in the brolucizumab 3 mg group, 1 case in the brolucizumab 6 mg group, and 1 case in the aflibercept group and 1 case of uveitis in the brolucizumab 6 mg group).” (opens the source at this quote in a new tab)

“Disparities between treatment arms were observed in the rates of IOI, 4.4% with brolucizumab versus 0.8% with aflibercept, and of endophthalmitis, 0.7% with brolucizumab versus 0.1% with aflibercept.” (opens the source at this quote in a new tab)

Retinal artery occlusion with concomitant inflammation in HAWK and HARRIER

“More specifically in relation to ATEs, across both studies, 4 brolucizumab 3 mg patients and 6 brolucizumab 6 mg patients experienced a RAO event that was reported as a SAE in 3 patients in the brolucizumab 3 mg group and in 0 patients in the brolucizumab 6 mg group.” (opens the source at this quote in a new tab)
“All brolucizumab 6 mg patients and 1 of the brolucizumab 3 mg patients showed concomitant IOI either before or after the RAO event.” (opens the source at this quote in a new tab)
“Of patients with RAO and concomitant IOI, 6 patients lost letters (2, 15, 21, 55, 55, and 62 letters) and 1 patient gained 18 letters by the end of the study.” (opens the source at this quote in a new tab)

Endophthalmitis onset relative to injection in HAWK and HARRIER

“All but 1 of the brolucizumab endophthalmitis patients showed onset within 5 days from the last injection.” (opens the source at this quote in a new tab)
“The time to onset since the last active injection and the investigator assessments suggest that it is likely that these endophthalmitis cases were related to the injection procedure.” (opens the source at this quote in a new tab)

Interval from injection to diagnosis of brolucizumab-associated retinal vasculitis

“Retinal vasculitis and IOI on a per-eye basis were diagnosed at a mean of 30.3 days after brolucizumab IVI.” (opens the source at this quote in a new tab)
“The interval to seeking treatment with vasculitis after the second brolucizumab IVI seemed to be shorter, ranging between 7 and 26 days.” (opens the source at this quote in a new tab)
“In eyes with retinal vasculitis after the first brolucizumab injection, this presentation could be delayed as long as 8 weeks after the injection, making a direct toxic or infectious cause unlikely and pointing to an autoimmune event, possibly leading to ischemia as a more likely cause.” (opens the source at this quote in a new tab)

Clinical findings and visual acuity at diagnosis in the postmarketing case series

“All eyes showed vitreous cells or opacities, and most (11 eyes [73.3%]) showed anterior chamber cells.” (opens the source at this quote in a new tab)
“Fine, nongranulomatous keratic precipitates, conjunctival injection, and Descemet folds also were reported, and no case of hypopyon occurred in this series.” (opens the source at this quote in a new tab)
“Of the 15 eyes, 9 eyes (60%) lost 0.3 logMAR of VA or more (the equivalent of 3 lines or more of ETDRS acuity)” (opens the source at this quote in a new tab)
“Five eyes (33%) showed a VA of less than 20/200.” (opens the source at this quote in a new tab)

Management of brolucizumab-associated inflammation and examination before repeat injection

“Treatment consisted of corticosteroids administered by a variety of methods (topical, sub-Tenon, oral, intravitreal, or a combination thereof).” (opens the source at this quote in a new tab)
“Two patients underwent vitrectomy without improvement of vision.” (opens the source at this quote in a new tab)
“Repeat brolucizumab IVI is contraindicated in an eye with active IOI.” (opens the source at this quote in a new tab)
“It also means that a clinical examination should be considered (rather than using a direct-to-injection protocol) before repeating brolucizumab injections to confirm that no IOI or vasculitis are present.” (opens the source at this quote in a new tab)
“Continued examinations are indicated in eyes demonstrating solely IOI because the occlusive vasculitis may develop after the initial examination.” (opens the source at this quote in a new tab)

Prior anti-VEGF exposure and the reason for switching in affected eyes

“The number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab.” (opens the source at this quote in a new tab)
“Nine patients were switched to brolucizumab for persistent intraretinal fluid, subretinal fluid (SRF), or both, and 3 patients were switched for potential increased durability of brolucizumab.” (opens the source at this quote in a new tab)

Inflammation with other approved anti-VEGF agents and the limits of incidence estimates

“Although IOI has been reported with the other FDA-approved anti-VEGF agents, most notably aflibercept, it typically is mild and sterile and resolves with corticosteroid eye drops.” (opens the source at this quote in a new tab)
“The incidence of retinal vasculitis cannot be ascertained because it is also not known how many injections of brolucizumab have been administered nationwide.” (opens the source at this quote in a new tab)

IVAN two-year comparison of ranibizumab with bevacizumab and of continuous with discontinuous dosing

“Between March 27, 2008, and Oct 15, 2010, we randomised 628 patients to ranibizumab or bevacizumab.” (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)
“It is now established that bevacizumab is not inferior to ranibizumab after 2 years of either continuous or discontinuous treatment with respect to visual acuity” (opens the source at this quote in a new tab)
“Safety was worse when treatment was administered discontinuously.” (opens the source at this quote in a new tab)

Aflibercept 2 mg: VIEW 1 and VIEW 2 phase 3 trials

“Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).” (opens the source at this quote in a new tab)
“In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures.” (opens the source at this quote in a new tab)
“These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.” (opens the source at this quote in a new tab)

Aflibercept 2 mg: FDA-labeled 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 12 weeks (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: PULSAR 48-week results

“PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide.” (opens the source at this quote in a new tab)
“Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: PULSAR 96-week results

“Least squares (LS) mean change from baseline in BCVA at week 96 was +5.6 (95% confidence interval [Cl], 4.1-7.1), +5.5 (95% Cl, 4.0-7.0), and +6.6 (95% Cl, 5.2-8.0) letters in the 8q12, 8q16, and 2q8 groups, respectively” (opens the source at this quote in a new tab)
“Patients completing 96 weeks of treatment in the 8q12, 8q16, and 2q8 groups received a mean of 9.7, 8.2, and 12.8 active injections, respectively.” (opens the source at this quote in a new tab)
“Of these, 87% of patients in the 8q12 group had last assigned dosing intervals of 12 weeks or more, whereas 78%, 53%, and 31% of patients in the 8q16 group qualified for last assigned dosing intervals of ≥ 16 weeks, ≥ 20 weeks, and 24 weeks, respectively.” (opens the source at this quote in a new tab)

Aflibercept 8 mg: FDA-labeled 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)

Aflibercept 2 mg biosimilars

“In 2024, the FDA approved five biosimilars to aflibercept 2 mg as of November 2024” (opens the source at this quote in a new tab)
“All are injected intravitreally as a 2-mg solution, and the adverse events appear comparable to aflibercept.” (opens the source at this quote in a new tab)

Faricimab: TENAYA and LUCERNE primary results

“Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A.” (opens the source at this quote in a new tab)
“Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks.” (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: two-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)
“Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals.” (opens the source at this quote in a new tab)

Faricimab: injection counts and inflammation in the AAO Preferred Practice Pattern

“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)
“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: FDA-labeled dosing and retinal vasculitis warning

“Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses.” (opens the source at this quote in a new tab)
“Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of VABYSMO” (opens the source at this quote in a new tab)

Archway phase 3 trial: refill-exchange every 24 weeks versus monthly ranibizumab

“Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy.” (opens the source at this quote in a new tab)
“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)
“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)
“Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.” (opens the source at this quote in a new tab)

FDA-labeled indication and boxed warning for endophthalmitis

“SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.” (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)
“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)

Surgical implantation, voluntary recall, and market reintroduction

“The implant is surgically inserted into the eye in the operating room and can be refilled every 6 months with an office procedure.” (opens the source at this quote in a new tab)
“In 2022, the implant was voluntarily recalled due to concerns about septum dislodgment. The implant was re-introduced to the market in 2024.” (opens the source at this quote in a new tab)

Portal extension trial: long-term safety

“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%).” (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)

Endophthalmitis cases across PDS clinical trials

“Seven cases (7/11 [63.6%]) had preceding/concurrent conjunctival complications.” (opens the source at this quote in a new tab)
“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)

Verteporfin photodynamic therapy: TAP trials

“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: FDA-labeled 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)
“There is insufficient evidence to indicate VISUDYNE for the treatment of predominantly occult subfoveal CNV.” (opens the source at this quote in a new tab)

Current role of photodynamic therapy and thermal laser in the AAO Preferred Practice Pattern

“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)
“Thermal laser is no longer recommended for subfoveal MNV.” (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)

Photodynamic therapy combined with ranibizumab in polypoidal choroidal vasculopathy: EVEREST II

“At 12 months, mean improvement from baseline was 8.3 letters with combination therapy vs 5.1 letters with monotherapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indicating that combination therapy met the predefined criterion for noninferiority as well as being superior to monotherapy (P = .01).” (opens the source at this quote in a new tab)
“Over 12 months, the combination therapy group received a median of 4.0 ranibizumab injections compared with 7.0 in the monotherapy group.” (opens the source at this quote in a new tab)

Summary

Current standard of care for neovascular AMD consists of repeated intravitreal anti-VEGF injections that suppress, but do not cure, the disease. Labeled maintenance intervals range from every 4 weeks (ranibizumab) to every 8 to 16 weeks (aflibercept 8 mg, faricimab); in PULSAR, participants completing 96 weeks received a mean of 8.2 to 12.8 injections, and through year 2 of TENAYA and LUCERNE the median number of faricimab injections was 10. Outcomes in routine practice are lower than in trials. In 49,485 treatment-naive eyes in a United States retina database, a mean of 7.3 injections in year 1 produced a mean gain of 0.95 letter, and in an 8-country study of 2,227 patients, mean injections fell from 5.0 in year 1 to 2.2 in year 2, with mean gains of +2.4 and +0.6 letters. In one United States practice, 2,003 of 9,007 patients (22.2%) were lost to follow-up after anti-VEGF injections, and a systematic review reported that up to 50% of patients stopped treatment by 24 months. Visits are time intensive: a time-and-motion study reported an average of almost 12 hours per visit from the patient perspective, including recovery. Long-term vision declines despite treatment: in the CATT cohort, mean visual acuity at 5 years was 3 letters below baseline and 11 letters below the 2-year value, and in SEVEN-UP macular atrophy was present in 98% of study eyes at a mean of 7.3 years. Longer-acting options carry specific risks: brolucizumab labeling warns of retinal vasculitis and retinal vascular occlusion, and the port delivery system requires surgical implantation, carries a boxed warning for an up to 3-fold higher rate of endophthalmitis than monthly ranibizumab (11 of 555 patients, 2%), and was voluntarily recalled in 2022 before reintroduction in 2024. Branded anti-VEGF agents account for a large share of Medicare Part B drug spending; ranibizumab and aflibercept accounted for 12% of the Part B budget in 2011 to 2015.

Real-world undertreatment and visual outcomes in the United States

“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)
“Older patients and those with poor baseline VA may be particularly prone to undertreatment.” (opens the source at this quote in a new tab)

Real-world injection frequency and loss of initial visual gains: multi-country study

“Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. 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)
“In clinical practice, fewer injections are administered than in clinical trials.” (opens the source at this quote in a new tab)

Real-world treatment falls short of trial protocols

“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)

“The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance.” (opens the source at this quote in a new tab)

Nonadherence, nonpersistence, and loss to follow-up

“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)

“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)

“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)

Time burden on patients, caregivers, and practices

“An average patient visit for neovascular AMD was 90 minutes (range: 13 minutes to >4 hours). 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)
“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)

Long-term decline in vision despite treatment

“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)
“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)

“Macular atrophy was present in 98% of study eyes, the mean area increasing from 0.83 ± 0.96 mm(2) at the ANCHOR or MARINA year 2 exit to 2.22 ± 1.6 mm(2) at the SEVEN-UP visit, a growth rate of 0.28 mm(2)/year.” (opens the source at this quote in a new tab)

Sponsor-described limitations of bolus anti-VEGF injections

“Each anti-VEGF injection requires an in-office visit, which carries significant burden and discomfort to patients, and when patients miss injections, they may experience vision decline due to undertreatment.” (opens the source at this quote in a new tab)
“Based on real world data for wet AMD, approximately 40% of patients discontinue treatment by year one, and early vision gains are followed by steady long-term vision decline, which is associated with declining injection frequency.” (opens the source at this quote in a new tab)

Cost to Medicare Part B

“Ranibizumab and aflibercept costs account for 12% of the Medicare Part B budget annually.” (opens the source at this quote in a new tab)

“Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019.” (opens the source at this quote in a new tab)

Unresolved challenges for gene therapy approaches

“Although promising, challenges including long-term safety, complex delivery procedures, immune responses, regulatory hurdles, and the need for optimized vectors and clinical protocols must be addressed before widespread adoption and integration into standard care.” (opens the source at this quote in a new tab)

Injection frequency and atrophy: conflicting analyses across trials

“The 2-year CATT analysis revealed an increased association between atrophy incidence and frequent treatment and also demonstrated a reduced incidence from year 1 to 2 among patients switched from monthly to PRN treatment; at the 5-year visit, the differences were no longer significant.” (opens the source at this quote in a new tab)
“Importantly, follow-up analyses of HARBOR and IVAN revealed no difference in atrophy incidence with monthly or continuous versus PRN or discontinuous treatment, in contrast with initial findings.” (opens the source at this quote in a new tab)
“For example, when images from HARBOR were analyzed with SD OCT, no difference in atrophy with monthly versus PRN was noted, in contrast with previous findings on CFP or FA.” (opens the source at this quote in a new tab)

Reducing injection frequency because of atrophy concern carries a risk of vision loss

“Reducing the frequency of anti-VEGF therapy to allay concerns of atrophy could lead to vision loss; however, titration, or dose adjustment, could be used to mitigate concerns about atrophy development.” (opens the source at this quote in a new tab)
“Because undertreatment of MNV is deleterious to vision, caution should be taken when extending treatment intervals because of concern regarding atrophy.” (opens the source at this quote in a new tab)
“No treatment for atrophy currently exists; therefore, physicians rely on cues from atrophy phenotype and risk factors when making treatment decisions.” (opens the source at this quote in a new tab)

Summary

4D-150 is investigational and has no established place in therapy. The sponsor describes its intended role as a single, in-office intravitreal "backbone therapy" that would replace repeated anti-VEGF injections rather than extend dosing intervals. The phase 3 4FRONT trials define the population studied for registration: 4FRONT-1 (North America) enrolls adults aged 50 years or older with treatment-naive macular neovascularization secondary to AMD, and 4FRONT-2 (global) enrolls treatment-naive participants and participants previously treated with no more than 4 anti-VEGF injections who were diagnosed no more than 6 months before screening. Both trials require a demonstrated clinical response to aflibercept, BCVA of 25 to 78 ETDRS letters, and central subfield thickness of 500 microns or less, with aflibercept 2 mg as the comparator; target enrollment is 480 participants per trial. By comparison, the approved sustained-delivery option (the port delivery system) is labeled for patients who previously responded to at least 2 anti-VEGF injections and requires surgical implantation, whereas 4D-150 is given by intravitreal injection, the same route used for current anti-VEGF agents. In the PRISM phase 1/2 trial, the sponsor also enrolled participants with severe, recalcitrant disease and high injection burden, a population in which use could be considered if approved. Current anti-VEGF care is delivered by ophthalmologists, predominantly retina specialists, in the office setting and billed under Medicare Part B; 36,398,293 intravitreal anti-VEGF injections were administered to Medicare beneficiaries from 2014 to 2023. Payer utilization management already applies to this class: after step therapy implementation in Medicare, relative use of aflibercept increased by 32.0% and bevacizumab decreased by 33.2%, and in 9 retina practices 96.2% of 2,225 prior authorization requests were approved but 59.6% of approvals delayed care by more than 24 hours. The sponsor reports that CMS has not established a uniform coverage and reimbursement policy for genetic medicine products.

Sponsor-intended role: in-office backbone therapy

“The goal for our development and potential commercialization of 4D-150 is to transform the standard of care for large market retinal vascular diseases with a safe, in-office, and durable lifelong backbone therapy, substantially reducing treatment burden and improving long-term vision outcomes.” (opens the source at this quote in a new tab)
“Intravitreal delivery of biologics into the eye is a routine in-office injection, which we believe allows for seamless adoption into retina clinic workflows.” (opens the source at this quote in a new tab)
“We believe a backbone therapy, like 4D-150, designed to provide potentially lifelong benefit with a one-time treatment, would be paradigm-shifting and highly differentiated from interval extension approaches.” (opens the source at this quote in a new tab)

Studied populations: 4FRONT phase 3 program and PRISM

“The first trial 4FRONT-1 is being conducted in North America and is enrolling a treatment-naïve population and the second trial 4FRONT-2 is being conducted globally and is enrolling both treatment-naïve and previously treated, recently diagnosed population.” (opens the source at this quote in a new tab)
“PRISM enrolled patients with severe, recalcitrant disease with high anti-VEGF treatment burden (Phase 1/2a, 25 patients dosed with Phase 3 dose of 3E10 vg/eye) and with broad disease activity and treatment burden (Phase 2b, 30 patients dosed with Phase 3 dose).” (opens the source at this quote in a new tab)

4FRONT-1 eligibility: treatment-naive disease with response to aflibercept

“Treatment naïve MNV secondary to nAMD in the study eye” (opens the source at this quote in a new tab)
“Demonstrated clinical response to aflibercept and functional stability in the study eye as confirmed by the Reading Center” (opens the source at this quote in a new tab)

4FRONT-2 eligibility: treatment-naive or recently diagnosed, previously treated disease

“Previously treated with no more than 4 IVT anti-VEGF injections due to nAMD and received diagnosis of nAMD no more than 6 months prior to the Screening Visit AND documented evidence of anatomical improvement and visual stability/improvement in response to previous IVT anti-VEGF treatment, as determined by the Investigator” (opens the source at this quote in a new tab)

Comparator positioning: sustained-delivery implant labeled after response to prior injections

“SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.” (opens the source at this quote in a new tab)

Care setting: ophthalmologist-administered office care

“The ophthalmologist should perform the examination, order appropriate testing, and administer all treatment and anti-VEGF injections, and certain aspects of the testing may be conducted by other trained individuals under the ophthalmologist's supervision.” (opens the source at this quote in a new tab)

Medicare Part B utilization of intravitreal anti-VEGF agents

“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)
“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)

“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)

Payer utilization management: step therapy and prior authorization

“After step therapy implementation, relative usage of aflibercept increased by 32.0%, while there was a decrease in relative usage of bevacizumab by 33.2% and ranibizumab by 4.3%.” (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)

“Overall, 2140 (96.2%) requests were approved.” (opens the source at this quote in a new tab)
“Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service.” (opens the source at this quote in a new tab)

Coverage uncertainty for genetic medicines

“Decisions regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis.” (opens the source at this quote in a new tab)

Care setting and payer mix of anti-VEGF injection encounters, 2017 to 2023

“Encounters where a patient received an intravitreal injection in an ophthalmology clinic were categorized by intravitreal medication ordered, visit diagnosis, and primary insurance payor.” (opens the source at this quote in a new tab)
“NAMD was the most common diagnosis at 53.2% (311672/585056 total diagnoses across all encounters), followed by diabetic eye diseases at 26.9% (157187/585056), retinal vascular occlusion at 14.4% (84442/585056)” (opens the source at this quote in a new tab)
“53.7% of encounters listed Medicare as the primary payor (309130/575256 total primary payors), while commercial/miscellaneous insurance covered 40.2% (231570/575256), and Medicaid covered 3.44% (19780/575256).” (opens the source at this quote in a new tab)

Agent selection rates in neovascular age-related macular degeneration and by payer

“In patients with nAMD, aflibercept 2 mg was used at a mean rate of 353.5 per 100000 OE (SD = 101.8) followed by bevacizumab at 202.8 (SD = 32.3) [t(6)=5.35, p = 0.002] and ranibizumab 0.5 mg at 62.9 per 100000 OE (SD = 16.6) [t(6) = 6.62, p < 0.001] from 2017–2023.” (opens the source at this quote in a new tab)
“Patients with Medicare (including both Medicare Advantage and part B [traditional fee-for-service Medicare]) insurance most often received aflibercept 2 mg at significantly higher rates than bevacizumab (M = 364.3/100000 OE, SD = 109.7 vs M = 187.1/100000 OE, SD = 28.4, respectively) [t(6) = 5.67, p = 0.001].” (opens the source at this quote in a new tab)
“For patients with commercial insurance, there was no significant difference in the average rate of use of aflibercept 2 mg (M = 233.9/100000 OE, SD = 94.9) and bevacizumab (M = 197.9/100000 OE, SD = 56.2) [t(6)=2.07, p > 0.05].” (opens the source at this quote in a new tab)

Adoption of a newly approved agent and stated demand for reduced treatment burden

“We observed a rapid adoption of faricimab, which surpassed the utilization of ranibizumab after less than 2 years following FDA approval in January 2022.” (opens the source at this quote in a new tab)
“While our results demonstrate that aflibercept 2 mg and bevacizumab remain the most utilized agents overall across all indications, there is a strong demand for the development of agents with greater or equivalent therapeutic efficacy with less treatment and/or financial burden.” (opens the source at this quote in a new tab)

Billing code availability as a constraint on use of a high-cost agent

“Aflibercept 8 mg was approved late in our study and does not have a permanent J code as of March 1, 2024 for billing, which limits physicians from utilizing a high-cost medication for concerns of denied reimbursement.” (opens the source at this quote in a new tab)

Step therapy under Medicare Advantage: treatment switching and injection frequency in a single practice

“CMS started allowing Medicare Advantage (MA) plans to implement step therapy for physician-administered Part B drugs in 2019.” (opens the source at this quote in a new tab)
“Eyes that had been previously treated were excluded, which narrowed the study to 1,794 eyes.” (opens the source at this quote in a new tab)
“Of the eyes in the study, treatment for 1,248 (almost 70%) was covered by traditional Medicare, 357 (almost 20%) by Medicare Advantage plans, and 189 (10.5%) by other types of insurance.” (opens the source at this quote in a new tab)
“Among the eye treatments covered by traditional Medicare, 31% were switched to a different anti-VEGF treatment within the first year of the diagnosis compared with 47% among those covered by Medicare Advantage plans that required step therapy.” (opens the source at this quote in a new tab)
“The average number was 6.04 in the traditional Medicare patients compared with 6.49 in the Medicare Advantage patients, although he noted that the difference was not statistically significant.” (opens the source at this quote in a new tab)

Variability in response to anti-VEGF therapy and definitions of response

“There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations.” (opens the source at this quote in a new tab)
“The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles.” (opens the source at this quote in a new tab)
“Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently.” (opens the source at this quote in a new tab)

Baseline predictors of visual outcome and injection need: HARBOR

“Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF).” (opens the source at this quote in a new tab)

Genetic background and choice of agent

“However, a systematic review published in 2015 looked at the association between anti-VEGF response and variations in AMD-associated genes; it concluded that genetic background may influence an individual’s response to treatment, however further studies are needed to better understand the contribution of various genes to treatment response.” (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)

Polypoidal choroidal vasculopathy subtype

“Polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative age-related macular degeneration among Asian individuals.” (opens the source at this quote in a new tab)
“Combination therapy was also superior to monotherapy in achieving complete polyp regression at month 12 (69.3% vs 34.7%; P < .001).” (opens the source at this quote in a new tab)

“Mean (95% CI) change from baseline to weeks 40/44/48 average was +8.9 (7.3-10.5) letters for BCVA and -126.5 (-144.8 to -108.3) μm for CST.” (opens the source at this quote in a new tab)
“At week 48, 83.4% (105/126) of patients were on ≥ Q12W dosing and 53.2% (67/126) were assigned to Q20W dosing.” (opens the source at this quote in a new tab)

Baseline disease severity and extended dosing with aflibercept 8 mg

“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)

Real-world differences in treatment intensity by age and baseline vision

“Greater mean 1-year change in VA also trended with worse baseline VA; those patients with better VA at presentation tended to be particularly vulnerable to vision loss. Those who received the fewest injections tended to be older and have worse baseline VA.” (opens the source at this quote in a new tab)

Subgroup differences in brolucizumab inflammation risk

“Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets).” (opens the source at this quote in a new tab)

4D-150 PRISM: treatment burden reduction by disease population

Cohort	Through year 1	Through year 1.5 (phase 2b) or year 2 (phase 1/2a)
Phase 2b subgroup: recently diagnosed	“94%”	“92%”
Phase 2b: broad	“83%”	“82%”
Phase 1/2a: severe, recalcitrant	“83%”	“79%”

4D-150 PRISM: comparators used for burden reduction differ by cohort

“Within the Phase 2b Phase 3 dose arm, a subgroup of 15 recently diagnosed patients were enrolled, which is most comparable to our Phase 3 population.” (opens the source at this quote in a new tab)

Subgroup efficacy results for 4D-150 by lesion subtype, genotype, or race

No evidence found.

Preexisting neutralizing antibody titers as a determinant of response and eligibility

“A critical consideration in future clinical development is the establishment of NAb threshold cutoffs to refine patient selection and increase trial success rates” (opens the source at this quote in a new tab)
“The implementation of standardized assays and validated NAb titer thresholds, exemplified by AAV6 enrollment assays that, through analyses of clinical trial data, demonstrate a correlation between preexisting NAb levels and transgene expression, enables more precise stratification of patients into likely responders and non-responders, thereby optimizing trial enrollment and minimizing variability in clinical outcomes” (opens the source at this quote in a new tab)

Transient immunosuppression to broaden eligibility in antibody-positive participants

“Combination therapy, such as transient systemic or local immunosuppression, represents a promising approach to enhance efficacy and expand patient eligibility in AAV-based gene therapy.” (opens the source at this quote in a new tab)
“This strategy can attenuate anti-capsid immune responses and has shown potential to enable transduction in NAb-positive subjects, and its use is increasingly explored in clinical settings” (opens the source at this quote in a new tab)

Lesion phenotype and risk factors for atrophy during anti-VEGF treatment

“Key risk factors or phenotypes associated with atrophy were fellow eye atrophy, reticular pseudodrusen, increased injections, and type 3 lesion.” (opens the source at this quote in a new tab)
“These phenotypes may explain why not all patients with AMD have the same atrophy-related outcomes.” (opens the source at this quote in a new tab)
“For example, patients with type 3 lesions typically demonstrate atrophy in parallel with anti-VEGF treatment; however, those with other lesion types may not demonstrate atrophy as readily with anti-VEGF therapy.” (opens the source at this quote in a new tab)

Sex distribution among reported cases of brolucizumab-associated retinal vasculitis

“From review of patient characteristics, all 12 patients in this series were women.” (opens the source at this quote in a new tab)
“Although this may be chance, a greater preponderance of noninfectious uveitis and autoimmune disorders occur in women, and this may play a role.” (opens the source at this quote in a new tab)

Two-year visual outcomes by baseline visual acuity in United States registry practice

“In all groups, eyes with better VA at baseline retained better VA at both Years 1 and 2” (opens the source at this quote in a new tab)
“Only groups of eyes with a mean VA of 20/40 or better at baseline maintained 20/40 or better vision 2 years after treatment initiation.” (opens the source at this quote in a new tab)
“Eyes with baseline VA of 37 to 23 letters (20/200-20/320) showed the greatest gain in VA at Year 1, improving to 0.37 ± 0.64 logMAR (20/160), and to 0.38 ± 0.68 logMAR (20/160) at Year 2.” (opens the source at this quote in a new tab)
“In contrast, mean VA declined slightly in the those with greater than 82 letters at baseline, from 0.03 ± 0.08 logMAR (> 20/25) to 0.14 ± 0.25 logMAR (20/32) at Year 1 and 0.18 ± 0.31 logMAR at Year 2 (20/32).” (opens the source at this quote in a new tab)

Racial composition and follow-up completeness of the registry cohort

“It should be noted that 97.5% of the evaluated population was white (which may not reflect the current racial makeup of the United States); the overwhelming percentage of white patients in this analysis suggests white patients may be more likely to seek diagnosis and treatment, or it may be reflective of socioeconomics and access to eye care in more racially diverse locations.” (opens the source at this quote in a new tab)
“Further, our 2-year data included only 54% of those included at baseline” (opens the source at this quote in a new tab)

AAO Preferred Practice Pattern: treatment 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)
“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)
“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)

Monthly versus as-needed dosing: CATT

“Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive.” (opens the source at this quote in a new tab)

Monthly versus as-needed dosing: HARBOR

“However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3).” (opens the source at this quote in a new tab)

Treat-and-extend versus monthly dosing: CANTREAT

“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).” (opens the source at this quote in a new tab)
“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 versus PRN in the third year: TREX-AMD

“Upon transition to PRN, subjects randomised to monthly dosing experienced a decline in BCVA.” (opens the source at this quote in a new tab)

Regimen and long-term outcomes in routine practice

“Eyes from ANZ patients received more injections than eyes from Swiss subjects over 10 years (a median of 53 vs 42, respectively) from fewer visits with better disease control (proportion of visits with active disease: 38% vs 69%, respectively), suggesting a treat-and-extend regimen versus a pro re nata regimen (treatment given only when the lesion is active).” (opens the source at this quote in a new tab)

Structured regimens and retention in care

“Treat-and-extend (T&E) regimens showed lower LTFU than pro re nata.” (opens the source at this quote in a new tab)
“Interventions to improve access and personalize support are essential to reduce LTFU and preserve visual outcomes.” (opens the source at this quote in a new tab)

NICE guideline NG82: switching, observation, and stopping treatment

“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)
“Consider observation without giving anti-VEGF treatment if the disease appears stable” (opens the source at this quote in a new tab)
“Stop anti-VEGF treatment if the eye develops late AMD (wet inactive) with no prospect of functional improvement.” (opens the source at this quote in a new tab)

Management of poor or non-response

“Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT).” (opens the source at this quote in a new tab)

Home monitoring devices

“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)

Supplemental aflibercept in the 4FRONT trials

“Eylea (aflibercept) will be administered at applicable visits” (opens the source at this quote in a new tab)

Visits and injections in years three through five after treatment initiation

“The mean (SD) number of visits for AMD care between the end of the clinical trial and the Follow-up Study visit was 25.3 (13.3); with 8.0 (4.0) in Year 3, 7.2 (4.0) in Year 4, and 6.5 (4.0) in Year 5. The mean (SD) number of treatments was 15.4 (12.5) with 4.8 (4.0) in Year 3, 4.5 (3.8) in Year 4, and 4.0 (3.6) in Year 5.” (opens the source at this quote in a new tab)
“There were 96 (14.8%) patients who had no treatments between the end of the clinical trial and the Follow-up Study visit, with a mean (SD) of 12.5 (8.4) visits.” (opens the source at this quote in a new tab)

Treatment intensity and five-year visual outcome across cohorts

“In the Australian retrospective review, the mean number of injections over 5 years was 25 with mean visual acuity decreasing to 20/63.” (opens the source at this quote in a new tab)
“In contrast, the mean number of injections was 11 over 5 years in the Pan-American Study and the mean visual acuity at 5 years was 20/250.” (opens the source at this quote in a new tab)
“Thus, more frequent treatment, both in the initial 2 years and in later years appears associated with better long-term outcomes, and many patients require treatment through 5 years and beyond.” (opens the source at this quote in a new tab)

Switching between anti-VEGF agents after release from a trial protocol

“After release from the clinical trial protocol, more than half of the patients received a treatment other than the drug assigned to them in the clinical trial.” (opens the source at this quote in a new tab)
“Among the 328 patients assigned to ranibizumab, 46 (14.0%) had no treatments, 64 (19.5%) had treatments with only ranibizumab, and 218 (66.5%) had at least 1 other type of treatment” (opens the source at this quote in a new tab)

Injection burden of continuous compared with discontinuous dosing over two years

“Participants assigned to the continuous regimen were treated monthly thereafter.” (opens the source at this quote in a new tab)
“If retreatment was needed, a further cycle of three doses was given monthly.” (opens the source at this quote in a new tab)

Regimen	Median number of treatments over 2 years (interquartile range)
Continuous, every month	“23 (21 to 24)”
Discontinuous, as needed	“13 (8 to 17)”
Overall	“18 (12 to 23)”

Trade-offs between continuous and discontinuous dosing

“Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22–1·03; p=0·05)” (opens the source at this quote in a new tab)
“Pooled data from the two trials shows that discontinuous treatment was inferior to continuous treatment for best corrected visual acuity.” (opens the source at this quote in a new tab)
“Conversely, the risk of geographic atrophy increased with continuous treatment.” (opens the source at this quote in a new tab)
“The increased risk of systemic SAEs and death with discontinuous treatment should probably outweigh the increased risk of new geographic atrophy that was recorded with monthly treatment.” (opens the source at this quote in a new tab)
“Continuous treatment also avoids the need to monitor disease activity on every visit.” (opens the source at this quote in a new tab)
“However, in the context of biological therapies, the possibility of immunological sensitisation with intermittent dosing needs to be considered.” (opens the source at this quote in a new tab)

“The association of monthly treatment with an increased rate of development of geographic atrophy was more consistent.” (opens the source at this quote in a new tab)
“In the IVAN study, 34% of eyes that received continuous (monthly) treatment developed geographic atrophy as compared with 26% in the discontinuous (PRN) group” (opens the source at this quote in a new tab)

Summary

With current anti-VEGF therapy, the expected outcome in pivotal trials is prevention of moderate vision loss in most treated eyes and a mean BCVA gain in the first year, followed by maintenance with continued treatment. In MARINA, mean BCVA increased by 7.2 letters with monthly ranibizumab 0.5 mg versus a 10.4-letter decrease with sham at 12 months; in ANCHOR, 96.4% of eyes receiving ranibizumab 0.5 mg lost fewer than 15 letters versus 64.3% with verteporfin. Newer agents achieve similar mean gains with fewer injections: at 2 years, adjusted mean BCVA change with faricimab was +3.7 and +5.0 letters in TENAYA and LUCERNE, with 59.0% and 66.9% of participants on every-16-week dosing at week 112, and at 96 weeks in PULSAR, least squares mean BCVA change was +5.6 and +5.5 letters with aflibercept 8 mg every 12 and 16 weeks versus +6.6 letters with aflibercept 2 mg every 8 weeks. The port delivery system maintained vision with 98.4% of participants needing no supplemental injection in the first 24-week interval, and Portal interim data suggest maintenance for 4 years in a small cohort. Long-term outcomes are lower. At 5 years in CATT, 50% of eyes had visual acuity of 20/40 or better and mean acuity was 3 letters below baseline; at 7.3 years in SEVEN-UP, mean acuity was 54 letters; and in the Fight Retinal Blindness! registry, eyes in Australia and New Zealand that completed 10 years of treatment lost a mean of 0.9 letters with a median of 53 injections, whereas Swiss eyes lost 14.9 letters with a median of 42. In routine care, outcomes are closer to maintenance than gain (mean +0.95 letter at 1 year in a United States database). The sponsor's stated goals for 4D-150 are maintenance of vision with substantially reduced treatment burden after a single injection, and the 4FRONT primary endpoint is noninferiority of BCVA change to aflibercept 2 mg every 8 weeks at 52 weeks.

Prevention of vision loss and first-year gains in pivotal ranibizumab trials

“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)
“The benefit in visual acuity was maintained at 24 months.” (opens the source at this quote in a new tab)

“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)

Maintenance of vision with extended dosing: faricimab and aflibercept 8 mg

“The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]).” (opens the source at this quote in a new tab)

“Aflibercept 8 mg delivered sustained disease control in patients with nAMD, maintaining improvements in visual and anatomic outcomes through week 96 with extended dosing intervals and similar safety profile to aflibercept 2 mg.” (opens the source at this quote in a new tab)

Durability with continuous delivery: port delivery system

“Interim results from Portal suggest 4-year maintenance of visual/anatomic outcomes with PDS 100 mg/mL, with the PDS preferred to monthly injections.” (opens the source at this quote in a new tab)
“Of Ladder-to-Portal previous monthly ranibizumab patients, 92% preferred the PDS over injections.” (opens the source at this quote in a new tab)

Long-term visual outcomes: CATT at 5 years

“At the 5-year visit, 50% of study eyes had VA 20/40 or better and 20% had VA 20/200 or worse.” (opens the source at this quote in a new tab)
“However, 50% of eyes had VA 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for neovascular AMD.” (opens the source at this quote in a new tab)

Long-term visual outcomes: SEVEN-UP at 7 years

“At a mean 7.3 years after ANCHOR or MARINA enrollment, mean visual acuity was 54 letters, study eyes having received a mean 1.6 injections per year since the HORIZON study.” (opens the source at this quote in a new tab)

Long-term visual outcomes: 10-year registry data

“The mean VA in 132 eyes (28%) from ANZ patients who completed 10 years of treatment dropped by 0.9 letters from baseline (95% confidence interval [CI], -4.9 to 3.1; P = 0.7) with 42% achieving ≥20/40, whereas the 37 eyes (12%) from Swiss subjects lost 14.9 letters (95% CI, -24 to -5.7; P < 0.001) with 35% achieving ≥20/40.” (opens the source at this quote in a new tab)
“Eyes with nAMD may achieve satisfactory long-term visual outcomes if they receive adequate treatment.” (opens the source at this quote in a new tab)

Long-term outcomes in polypoidal choroidal vasculopathy

“At 6 years, initial visual gains from aflibercept therapy were not maintained; however, nearly half of the eyes had BCVA ≥ 69 letters, and a large proportion achieved polypoidal lesion regression.” (opens the source at this quote in a new tab)

Expected outcomes for 4D-150: phase 3 primary endpoint

“The 4FRONT global Phase 3 registration program consists of two multicenter, randomized, double masked, aflibercept Q8W comparator-controlled trials, with the primary endpoint of BCVA noninferiority of 4D-150 3E10 vg/eye to aflibercept 2mg Q8W at 52 weeks.” (opens the source at this quote in a new tab)
“4D-150 demonstrated consistent and durable benefit across all three patient cohorts as evidenced by maintenance of visual acuity, control of retinal anatomy and reduction of treatment burden at all time points with up to 2 years of follow-up.” (opens the source at this quote in a new tab)

Maintenance of every-12-week brolucizumab dosing through 96 weeks

“The probability that an eye could be maintained on an q12w interval after loading to the DAA at week 92 was 39.7% and 45.4% for the brolucizumab 3 mg and 6 mg treatment groups in HAWK, respectively, and 38.6% for the brolucizumab 6 mg group in HARRIER.” (opens the source at this quote in a new tab)
“In those eyes receiving treatment q12w at the week 44 DAA in HAWK, an 80.5% (brolucizumab 3 mg) and 81.5% (brolucizumab 6 mg) probability of remaining on an q12w interval until the final DAA at week 92 was found, whereas the probability was 75.4% for the brolucizumab 6 mg group in HARRIER.” (opens the source at this quote in a new tab)
“Starting at week 16 (the first DAA), and up to week 92 (the last DAA), HAWK had 8 DAAs and HARRIER had 14 DAAs at which patients could only be adjusted from q12w to q8w therapy.” (opens the source at this quote in a new tab)

Visual acuity maintained to week 96 and the effect of high baseline acuity

“These BCVA gains, comparable across treatment arms and studies, were maintained until week 96, with both the brolucizumab 6 mg group and the aflibercept group gaining between 5.3 and 6.6 ETDRS letters from baseline.” (opens the source at this quote in a new tab)
“These visual acuity gains may have been influenced by a ceiling effect resulting from a high mean baseline BCVA of 60 ETDRS letters (60.6 letters [HAWK] and 61.2 letters [HARRIER], resulting from the upper limit of 78 letters for the BCVA inclusion criterion).” (opens the source at this quote in a new tab)

Interpretation limit on the reported every-12-week proportion

“Unlike real-world clinical practice, eyes in the brolucizumab treatment group that were switched from q12w to q8w therapy based on a DAA were not permitted to move back to q12w treatment.” (opens the source at this quote in a new tab)
“As a consequence, the probability for patients to remain on an q12w regimen at week 96 may be underestimated.” (opens the source at this quote in a new tab)

Duration of anti-VEGF expression reported across AAV gene therapy programs

“Collectively, these programs demonstrate that AAV gene therapy can provide durable anti-VEGF expression for up to 24 months post-injection, significantly reducing treatment burden” (opens the source at this quote in a new tab)

Visual outcomes before anti-VEGF therapy as a benchmark

“Two years after diagnosis, fewer than 10% of patients retained vision of 20/40 or better with no treatment and fewer than 15% of patients treated with photodynamic therapy retained 20/40 or better.” (opens the source at this quote in a new tab)

Mean acuity relative to baseline at five years

“Mean visual acuity at 5 years was 3 letters worse than baseline, highlighting an unmet need for further therapeutic advances.” (opens the source at this quote in a new tab)

Expected gain in eyes with poor baseline vision

“Only eyes with 20/200 or less at baseline exhibited a gain in mean VA following treatment, yet these groups were only able to reach the still significantly limited VA of 20/160 after 2 years of treatment.” (opens the source at this quote in a new tab)