Regulatory submission: BLA approved July 2026

“Please refer to your biologics license application (BLA) dated and received August 29, 2022, and your amendments, submitted under section 351(a) of the Public Health Service Act for Lytenava (bevacizumab-vikg) injection. We acknowledge receipt of your resubmission dated May 29, 2026, which constituted a complete response to our December 30, 2025, action letter.” (opens the source at this quote in a new tab)
“We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.” (opens the source at this quote in a new tab)

“Initial U.S. Approval: 2026” (opens the prescribing information at this quote)

Launch: Anticipated before the end of 2026

“Outlook Therapeutics expects to make LYTENAVA™ available to eligible patients in the United States before year-end.” (opens the source at this quote in a new tab)

“The Company continues to advance preparations for the U.S. commercial launch of LYTENAVA, the only FDA-approved ophthalmic bevacizumab for the treatment of wet age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)
“Outlook Therapeutics is advancing preparations for the U.S. commercial launch of LYTENAVA, planned before the end of calendar 2026.” (opens the source at this quote in a new tab)

Regulatory history: first Complete Response Letter

“the U.S. Food and Drug Administration (FDA) has issued a CRL to the Company's BLA for ONS-5010, an investigational ophthalmic formulation of bevacizumab under development to treat wet AMD. While the FDA acknowledged the NORSE TWO pivotal trial met its safety and efficacy endpoints, the Agency concluded it could not approve the BLA during this review cycle due to several CMC issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.” (opens the source at this quote in a new tab)
“The FDA accepted Outlook Therapeutics' BLA submission for ONS-5010 to treat wet AMD with an initial PDUFA goal date of August 29, 2023; FDA did not approve the BLA during this review cycle and the Company is working with the FDA to address the issues that have been raised so that the BLA may be re-submitted.” (opens the source at this quote in a new tab)

Regulatory history: NORSE EIGHT trial, second and third Complete Response Letters

“In the fourth quarter of calendar 2023, the Company agreed to conduct an additional adequate and well-controlled clinical trial to support its Biologics License Application (“BLA”) for LYTENAVA. The Company submitted a Special Protocol Assessment (“SPA”) for the NORSE EIGHT study in December 2023, and in January 2024 the U.S. Food and Drug Administration (the “FDA”) agreed that the protocol, if successful, would satisfy the requirement for a second adequate and well-controlled trial. The Company also identified approaches to address the Chemistry, Manufacturing, and Controls (“CMC”) comments in the Complete Response Letter (“CRL”). In November 2024, the Company announced that NORSE EIGHT did not meet the pre-specified non-inferiority endpoint; however, results demonstrated improvements in vision, evidence of biologic activity, and a favorable safety profile, which were further supported by the full week 12 data set. The Company resubmitted the BLA in February 2025. On August 27, 2025, the FDA issued a second CRL citing a single deficiency related to substantial evidence of effectiveness and recommended submission of confirmatory efficacy data, while reaffirming that the NORSE TWO trial met its primary endpoint. Following a Type A meeting in September 2025, the Company resubmitted the BLA on November 3, 2025, and received a third CRL on December 31, 2025.” (opens the source at this quote in a new tab)
“Following receipt of the CRL in December 2025, the Company engaged with the FDA on multiple occasions, including a formal Type A meeting held on March 2, 2026, which led to the submission of a formal dispute resolution meeting request. In April 2026, the meeting with the deciding official was conducted as part of the Company's ongoing efforts to align with the FDA regarding the regulatory pathway for LYTENAVA™ (bevacizumab-vikg).” (opens the source at this quote in a new tab)

Regulatory history: resubmission acceptance and final approval

“the U.S. Food and Drug Administration (FDA) has acknowledged receipt of the resubmission of the Biologics License Application (BLA) for ONS-5010/LYTENAVA™ for the treatment of neovascular age-related macular degeneration (nAMD), or wet AMD. The Company has been informed that the resubmission is a Class 1 review, with a PDUFA target action date of July 29, 2026.” (opens the source at this quote in a new tab)
“Outlook Therapeutics has initiated pre-launch activities in anticipation of the pending BLA approval.” (opens the source at this quote in a new tab)

“today announced that the U.S. Food and Drug Administration (FDA) has approved LYTENAVA™ (bevacizumab-vikg) for the treatment of neovascular age-related macular degeneration (nAMD), commonly known as wet AMD.” (opens the source at this quote in a new tab)
“The approval establishes LYTENAVA™ as the first and only FDA-approved ophthalmic formulation of bevacizumab for the treatment of wet AMD in the United States.” (opens the source at this quote in a new tab)
“the Company anticipates that the approval will provide LYTENAVA with 12 years of Reference Product Exclusivity under the BPCIA.” (opens the source at this quote in a new tab)

Regulatory history: European Union and United Kingdom approval and launch

“In May 2024 the Company received Marketing Authorization from the European Commission for LYTENAVA (bevacizumab gamma), an ophthalmic formulation of bevacizumab for the treatment of wet age-related macular degeneration (“AMD”) in the European Union (“EU”). Additionally, in July 2024 the Company also received marketing authorization for LYTENAVA (bevacizumab gamma) in the United Kingdom (“UK”) from the UK Medicines and Healthcare products Regulatory Agency (“MHRA”). LYTENAVA (bevacizumab gamma) is the first and only authorized ophthalmic formulation of bevacizumab for use in treating wet AMD in the EU and UK. In June 2025, the Company launched LYTENAVA commercially in both Germany and the UK, and commenced commercial sales in those countries.” (opens the source at this quote in a new tab)

“In Europe, Outlook Therapeutics continues to expand the commercialization of LYTENAVA in Germany, Austria and the United Kingdom. The Company is also preparing for a planned launch in the Netherlands later in 2026 following its Netherlands submission. In Switzerland, the Company's partner, Mediconsult, is leading regulatory and commercial activities in support of an anticipated launch in 2027.” (opens the source at this quote in a new tab)

Manufacturer: Outlook Therapeutics

“LYTENAVA™ (bevacizumab-vikg) Manufactured by: LYTENAVA is a trademark of Outlook Therapeutics, Inc. Outlook Therapeutics, Inc. ©2026 Outlook Therapeutics Inc. 111 S. Wood Ave, Unit #100 Iselin, NJ 08830 U.S. U.S. License No.: 2292” (opens the prescribing information at this quote)

Generic and brand names, therapeutic class

“LYTENAVA™ (bevacizumab-vikg) injection, for intravitreal use” (opens the prescribing information at this quote)
“LYTENAVA is a vascular endothelial growth factor (VEGF) inhibitor” (opens the prescribing information at this quote)
“LYTENAVA is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (nAMD).” (opens the prescribing information at this quote)

Development code name and prior identity

“ONS-5010 is an investigational ophthalmic formulation of bevacizumab under development as an intravitreal injection for the treatment of wet AMD and other retinal diseases.” (opens the source at this quote in a new tab)

Dosage form and strength

“Injection: 1.25 mg (0.05 mL of 25 mg/mL) colorless to light brown, opalescent solution for intravitreal injection in a single-dose vial.” (opens the prescribing information at this quote)

How supplied

“LYTENAVA (bevacizumab-vikg) injection is a colorless to light brown, opalescent solution. Each carton (NDC 82491-025-10) contains LYTENAVA 1.25 mg (0.05 mL of 25 mg/mL bevacizumab-vikg solution) in a single-dose glass vial with a BLUE CAP.” (opens the prescribing information at this quote)
“EACH CARTON IS FOR SINGLE-EYE USE ONLY.” (opens the prescribing information at this quote)

Storage and handling

“Store LYTENAVA refrigerated at 2oC to 8oC (36oF to 46oF) in the original carton until use to protect from light. DO NOT FREEZE.” (opens the prescribing information at this quote)
“Prior to use, the unopened glass vial of LYTENAVA may be kept at room temperature, 20oC to 25oC (68oF to 77oF), for up to 12 hours. Ensure the injection is given immediately after preparation of the dose.” (opens the prescribing information at this quote)

Composition

“LYTENAVA is supplied in a single-dose vial designed to deliver 0.05 mL of 25 mg/mL (1.25 mg) aqueous solution that also contains dibasic sodium phosphate (0.06 mg), monobasic sodium phosphate (0.29 mg), polysorbate 20 (0.02 mg), trehalose (2.71 mg), and Water for Injection. The pH is 6.” (opens the prescribing information at this quote)
“LYTENAVA (bevacizumab-vikg) injection is a sterile, colorless to light brown, opalescent solution for intravitreal use. LYTENAVA does not contain an anti-microbial preservative.” (opens the prescribing information at this quote)

Wholesale acquisition cost

“On September 16, 2026, Outlook Therapeutics, Inc. established the wholesale acquisition cost for LYTENAVA™ in the United States of $485 per vial.” (opens the source at this quote in a new tab)

Average sales price

No evidence found.

Indication

“LYTENAVA is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (nAMD).” (opens the prescribing information at this quote)

Mechanism of action

“Bevacizumab is a human vascular endothelial growth factor (VEGF) inhibitor. Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells.” (opens the prescribing information at this quote)
“LYTENAVA binds to all isoforms of VEGF-A, thereby preventing interaction with receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A, LYTENAVA suppresses endothelial cell proliferation, neovascularization, and vascular permeability. Inhibition of such activity targets a pathophysiologic process that contributes to vision loss.” (opens the prescribing information at this quote)

Central foveal thickness as a pharmacodynamic marker

“Increased retinal thickness (e.g., central foveal thickness (CFT)) and leakage of blood and fluid from choroidal neovascularization is associated with nAMD. CFT is known to be a reproducible, early indication of pharmacodynamic response to anti-VEGF treatments.” (opens the prescribing information at this quote)
“Changes in CFT were assessed using optical coherence tomography in NORSE TWO and NORSE EIGHT [see Clinical Studies (14)]. Increasingly greater reductions in CFT were observed at Weeks 4, 8, and 12 across both treatment arms.” (opens the prescribing information at this quote)
“Anatomic data were not used to influence LYTENAVA treatment decisions.” (opens the prescribing information at this quote)

Systemic pharmacokinetics after intravitreal injection

“Following intravitreal administration of LYTENAVA, the systemic exposure to bevacizumab-vikg is minimal.” (opens the prescribing information at this quote)
“In 14 subjects who received a single 1.25 mg dose of LYTENAVA, the serum bevacizumab-vikg concentration was assessed up to Day 4. The serum bevacizumab-vikg concentrations gradually increased over time, so the highest concentrations observed were approximately at Day 4 (the last collection time) ranging from 33 to 270 ng/mL, which was <1% of the Cmax after intravenous infusion of 2 mg/kg bevacizumab-vikg. However, due to the limited sample collection, Cmax or AUC could not be adequately characterized.” (opens the prescribing information at this quote)

Immunogenicity

“The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of LYTENAVA or of other bevacizumab products.” (opens the prescribing information at this quote)
“In a 52-week study, a total of 14 subjects who received LYTENAVA and were subsequently evaluated for immunogenicity did not show detectable ADA at any timepoint but the ADA assay sensitivity data in the presence of free drug was insufficient. However, due to the minimal systemic exposure to LYTENAVA following intravitreal injection, the risk of immunogenicity is not expected to be clinically significant.” (opens the prescribing information at this quote)

Contraindications

“LYTENAVA is contraindicated in patients with ocular or periocular infections.” (opens the prescribing information at this quote)
“LYTENAVA is contraindicated in patients with active intraocular inflammation.” (opens the prescribing information at this quote)
“LYTENAVA is contraindicated in patients with known hypersensitivity to bevacizumab products or any of the ingredients in LYTENAVA. Hypersensitivity reactions may manifest as severe intraocular inflammation.” (opens the prescribing information at this quote)

Warning: endophthalmitis and retinal detachments

“Intravitreal injections have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering LYTENAVA. In addition, patients should be monitored following the injection to permit early treatment should an infection occur [see Dosage and Administration (2.3) and Patient Counseling Information (17)].” (opens the prescribing information at this quote)

Warning: increases in intraocular pressure

“Increases in intraocular pressure have been noted post-injection (up to 60 minutes) while being treated with LYTENAVA. Monitor intraocular pressure prior to and following intravitreal injection with LYTENAVA and manage appropriately [see Dosage and Administration (2.4)].” (opens the prescribing information at this quote)

Warning: thromboembolic events

“Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LYTENAVA clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).” (opens the prescribing information at this quote)

Adverse reactions: clinical trial exposure and most common reaction

“The data described below reflect exposure to LYTENAVA in 601 patients, in five clinical trials [see Clinical Studies (14)].” (opens the prescribing information at this quote)
“Most common adverse reaction (≥ 4%) reported in patients receiving LYTENAVA was conjunctival hemorrhage (4%) (6.1).” (opens the prescribing information at this quote)

Adverse reactions: common ocular events versus ranibizumab

Adverse Reactions	LYTENAVA 1.25 mg (N = 601)	Ranibizumab 0.5 mg (N = 345)
Conjunctival hemorrhage	“4%”	“3%”
Eye pain	“2%”	“1%”
Vitreous floaters	“2%”	“1%”

Adverse reactions: less common ocular events

“Less common ocular adverse reactions reported in the study eye in <1% of patients treated with LYTENAVA were corneal abrasion, dry eye, eye irritation, and intraocular pressure increased.” (opens the prescribing information at this quote)

Pregnancy

“Based on the anti-VEGF mechanism of action for bevacizumab products [see Clinical Pharmacology (12.1)], treatment with LYTENAVA may pose a risk to human embryofetal development.” (opens the prescribing information at this quote)
“There are no adequate and well-controlled studies of LYTENAVA administration in pregnant women or pregnant animals. It is not known whether bevacizumab-vikg can cause fetal harm when administered to a pregnant woman. LYTENAVA should be given to a pregnant woman only if clearly needed.” (opens the prescribing information at this quote)
“All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.” (opens the prescribing information at this quote)

Lactation

“There are no data available on the presence of bevacizumab-vikg in human milk, the effects of bevacizumab-vikg on the breastfed infant or the effects of bevacizumab-vikg on milk production/excretion.” (opens the prescribing information at this quote)
“Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when LYTENAVA is administered to a nursing woman.” (opens the prescribing information at this quote)
“The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LYTENAVA and any potential adverse effects on the breastfed child from bevacizumab-vikg.” (opens the prescribing information at this quote)

Females and males of reproductive potential

“Females of reproductive potential should use effective contraception during treatment with LYTENAVA and for at least 3 months after the last dose when stopping treatment with LYTENAVA.” (opens the prescribing information at this quote)
“There are no data regarding the effects of LYTENAVA on human fertility. Based on the anti-VEGF mechanism of action LYTENAVA may pose a risk to reproductive capacity [see Clinical Pharmacology (12.1)].” (opens the prescribing information at this quote)

Pediatric use

“The safety and effectiveness of LYTENAVA in pediatric patients have not been established.” (opens the prescribing information at this quote)

Geriatric use

“In the three completed Phase 3 clinical studies, approximately 70% (238/341) of patients treated with LYTENAVA were ≥ 65 years of age and approximately 47 % (160/341) were ≥ 75 years of age. No overall differences in efficacy or safety were seen with increasing age in these studies [see Clinical Studies (14)].” (opens the prescribing information at this quote)

Recommended dose and dosing interval

“FOR OPHTHALMIC INTRAVITREAL INJECTION. LYTENAVA must only be administered by a qualified physician.” (opens the prescribing information at this quote)
“The recommended dose for LYTENAVA is 1.25 mg (0.05 mL of 25 mg/mL) administered by intravitreal injection once monthly (approximately 28 days).” (opens the prescribing information at this quote)

Required devices and preparation

“A 5-micron sterile filter needle (18-gauge x 1½-inch), a 1-mL syringe (with marking to measure 0.05 mL), and a 30-gauge x ½-inch sterile injection needle are needed.” (opens the prescribing information at this quote)
“The glass vial is for one-time use in one eye only.” (opens the prescribing information at this quote)
“Using aseptic technique, the total vial volume of a LYTENAVA vial should be withdrawn through a 5-micron (18-gauge x 1½-inch) sterile filter needle attached to a 1 mL syringe. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection. The filter needle should be replaced with a sterile 30-gauge x ½-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.” (opens the prescribing information at this quote)

Injection procedure and post-injection monitoring

“The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to injection.” (opens the prescribing information at this quote)
“Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in intraocular pressure using tonometry. Monitoring may also consist of a check for perfusion of the optic nerve head immediately after the injection [see Warnings and Precautions (5.2)]. Patients should also be monitored for and instructed to report any symptoms suggestive of endophthalmitis without delay following the injection [see Warnings and Precautions (5.1)].” (opens the prescribing information at this quote)
“Each single-dose vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter needle, and injection needles should be changed before LYTENAVA is administered to the other eye.” (opens the prescribing information at this quote)

Pre-launch preparation and planned launch timing

“Outlook Therapeutics has initiated pre-launch activities in anticipation of the pending BLA approval.” (opens the source at this quote in a new tab)

“Outlook Therapeutics expects to make LYTENAVA™ available to eligible patients in the United States before year-end. The Company is committed to providing broad patient access support services through comprehensive reimbursement and patient assistance programs designed to help physicians integrate LYTENAVA™ into routine clinical practice for wet AMD.” (opens the source at this quote in a new tab)

Distribution and logistics partner

“As part of the Company's multi-year commercial planning process, Outlook Therapeutics and AmerisourceBergen entered into a strategic commercialization agreement to expand the Company's reach for connecting to retina specialists and their patients. AmerisourceBergen will provide third-party logistics (3PL) services and distribution, as well as pharmacovigilance services and other services in the United States.” (opens the source at this quote in a new tab)

Reimbursement coding and payer access strategy

“Advancing the U.S. launch strategy for LYTENAVA, including broad market access, reimbursement, pricing, medical affairs, and supply capabilities” (opens the source at this quote in a new tab)
“As part of these efforts, the Company plans to submit an application for a permanent Healthcare Common Procedure Coding System or HCPCS code by October 1, 2026, to support reimbursement following launch.” (opens the source at this quote in a new tab)
“The Company's launch and go-to-market strategy is designed to reflect the evolving biosimilar landscape, affordability considerations, and the potential for additional market entrants, while supporting broad patient access and reimbursement.” (opens the source at this quote in a new tab)
“Our launch strategy reflects a deep understanding of the retina market and the needs of patients, physicians, practices, and payers” (opens the source at this quote in a new tab)
“We are taking a targeted approach to customer engagement, pricing, and reimbursement, while building the commercial and supply capabilities needed to support the introduction of LYTENAVA in the United States.” (opens the source at this quote in a new tab)

NORSE TWO: LYTENAVA versus ranibizumab, dosing regimens and primary endpoint at Month 11

“In NORSE TWO, adult patients with nAMD were randomized to LYTENAVA 1.25 mg (N=113) administered once monthly for 1 year or ranibizumab 0.5 mg (N=115) administered once monthly for 3 months (Days 0, 30, and 60) followed by once every 3 months for 1 year (Days 150 and 240). Patient ages ranged from 54 to 98 years, with a median age of 79 years.” (opens the prescribing information at this quote)
“The primary efficacy endpoint was the proportion of patients who gained ≥ 15 Best Corrected Visual Acuity (BCVA) letters from baseline to Month 11 as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. The difference observed between the study drug groups was significant, in favor of LYTENAVA (see Table 2).” (opens the prescribing information at this quote)

NORSE TWO: patients gaining 15 or more ETDRS letters at 11 months

Field	LYTENAVA 1.25 mg once monthly (N = 113)	Ranibizumab 0.5 mg once monthly x 3 months then every 3 months (N = 115)
Number of subjects, n/N (%)	“45/108 (41.7)”	“24/104 (23.1)”

NORSE TWO: risk difference between LYTENAVA and ranibizumab

“Risk difference 0.1859 95% CI 0.0442, 0.3086” (opens the prescribing information at this quote)

NORSE EIGHT: LYTENAVA versus ranibizumab, non-inferiority at Week 8

“In a multicenter, randomized, masked, controlled study (NORSE EIGHT – NCT06190093), 400 adult patients with nAMD were randomized (1:1) to LYTENAVA 1.25 mg or ranibizumab 0.5 mg, administered every 4 weeks for 3 total doses (Day 0, Week 4, and Week 8). The primary efficacy endpoint was the mean change in baseline BCVA as measured by ETDRS score at Week 8 using a non-inferiority (NI) margin of -3.5 letters.” (opens the prescribing information at this quote)
“NORSE EIGHT did not meet its pre-specified NI margin of -3.5 letters in mean change from baseline BCVA at Week 8 compared to ranibizumab.” (opens the prescribing information at this quote)
“At Week 8, the LYTENAVA group had a mean increase in BCVA of 3.3 compared to a mean increase of 4.5 in the ranibizumab group. The LS mean difference and 95% CI was -2.3 (-4.0, -0.5).” (opens the prescribing information at this quote)
“LYTENAVA showed an increase from baseline in BCVA at Week 12 consistent with NORSE TWO.” (opens the prescribing information at this quote)

Comparison with unapproved compounded bevacizumab

“Because no FDA-approved ophthalmic formulations of bevacizumab are available currently, clinicians wishing to treat retinal patients with bevacizumab have had to use unapproved repackaged IV bevacizumab provided by compounding pharmacies—products that have known risks of contamination and inconsistent potency and availability. If approved, ONS-5010 would provide an FDA-approved option for physicians that currently have no choice but to prescribe unapproved repackaged oncologic IV bevacizumab from compounding pharmacies for the treatment of wet AMD.” (opens the source at this quote in a new tab)

“Rather than relying on repackaged formulations originally intended for intravenous use, physicians now have access to a purpose-built ophthalmic formulation of bevacizumab designed specifically for intravitreal administration that delivers the manufacturing consistency, product quality, and regulatory oversight patients deserve.” (opens the source at this quote in a new tab)
“Bevacizumab already accounts for the majority of first-line anti-VEGF treatment in wet AMD, underscoring its important role in retina care.” (opens the source at this quote in a new tab)

Market size and competitive landscape

“The U.S. anti-VEGF retina market is estimated at approximately $8.5 billion annually, with millions of intravitreal injections administered every year.” (opens the source at this quote in a new tab)

“The Company's launch and go-to-market strategy is designed to reflect the evolving biosimilar landscape, affordability considerations, and the potential for additional market entrants, while supporting broad patient access and reimbursement.” (opens the source at this quote in a new tab)

Definition of age-related macular degeneration

“Age-related macular degeneration (AMD) is an eye disease that can blur your central vision.” (opens the source at this quote in a new tab)

Dry and wet forms of AMD

“Most people with AMD have dry AMD (also called atrophic AMD). This is when the macula gets thinner with age.” (opens the source at this quote in a new tab)
“Wet AMD (also called advanced neovascular AMD), is a less common type of late AMD that usually causes faster vision loss.” (opens the source at this quote in a new tab)
“It happens when abnormal blood vessels grow in the back of the eye and damage the macula.” (opens the source at this quote in a new tab)

Neovascular AMD as a distinct clinical entity

“Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid” (opens the source at this quote in a new tab)

Etiology: age as the leading risk factor

“Your risk for AMD increases as you get older. People age 55 and older are more likely to have AMD.” (opens the source at this quote in a new tab)

“Increasing age is the strongest demographic and leading risk factor associated with AMD” (opens the source at this quote in a new tab)

Etiology: family history, race, and smoking

“The risk for AMD is also higher for people who: Have a family history of AMD Are Caucasian Smoke” (opens the source at this quote in a new tab)

“Pooled data from the Rotterdam, Beaver Dam Eye, and Blue Mountains studies report a positive correlation with a 2–4-fold likelihood of developing any type of AMD in smokers when compared to non-smokers” (opens the source at this quote in a new tab)

“Numerous studies have reported that Caucasians are more likely to develop AMD than blacks, including the Baltimore Eye Study, which reported a four-fold higher risk in whites than in blacks” (opens the source at this quote in a new tab)

Anatomic basis: the retinal pigment epithelium, Bruch's membrane, and drusen

“Damage to the retinal pigment epithelium (RPE) is considered to be a hallmark of AMD.” (opens the source at this quote in a new tab)
“Age‐related structural abnormalities within Bruch's membrane have also been associated with AMD.” (opens the source at this quote in a new tab)
“The AMD spectrum spans early‐stage AMD, during which drusen, pigment epithelial detachment (PED) and vitelliform lesions are observed, to late stage AMD, with choroidal neovascularization (CNV, neovascular AMD) or geographic atrophy (GA).” (opens the source at this quote in a new tab)

Global incidence trend, 2006 to 2020

“The incidence of nAMD was 71 (95% CI 55–90) and 102 (95% CI 88–118) per 100,000 person years in 2006 and 2020, respectively.” (opens the source at this quote in a new tab)

Incidence by age group

“In the age group of 75–84 years, the incidence increased 1.2-fold from 300 in 2006 to 366 in 2020.” (opens the source at this quote in a new tab)
“The increase in the age group of 85–96 years was 2.4-fold from 200 in 2006 to 471 in 2020.” (opens the source at this quote in a new tab)

Incidence by sex

“The incidence of nAMD in women was almost two-fold greater compared to males at the same age.” (opens the source at this quote in a new tab)

Global prevalence and projected growth

“the number of people suffering from AMD is expected to increase from 196 million in 2020 to 288 million in 2040” (opens the source at this quote in a new tab)

Prevalence in a population-based cohort

“The prevalence of nAMD was 862 (/100,000 inhabitants) (95% CI 821–906) in adults aged 44–96 years in 2020.” (opens the source at this quote in a new tab)
“In the oldest 75–84 and 85–96 age categories the nAMD prevalence was 2865/100,000 (3%, 95% CI 2665–3079) and 2620/100,000 (3%, 95% CI 2323–2956), respectively.” (opens the source at this quote in a new tab)

United States prevalence among Medicare beneficiaries

“the prevalence of wet AMD remained relatively stable, fluctuating from 2.17% in 2014 to 2.14% in 2021.” (opens the source at this quote in a new tab)

Prevalence by race and ethnicity

“the prevalence of wet AMD showed a progressive decrease across White, Native American, Asian, Hispanic, and Black populations” (opens the source at this quote in a new tab)

United States burden estimates

“Nearly 20 million U.S. adults are living with some form of age-related macular degeneration.” (opens the source at this quote in a new tab)
“Wet macular degeneration accounts for approximately 10% of all AMD cases but is responsible for 90% of legal blindness.” (opens the source at this quote in a new tab)

Untreated disease course

“Prior to the anti-VEGF era, the clinical manifestation of the natural history of nAMD was the formation of a disciform scar and blindness” (opens the source at this quote in a new tab)
“AMD leads to blindness when left untreated, due to the development of atrophy and/or disciform scar.” (opens the source at this quote in a new tab)

Magnitude of untreated vision loss

“ranibizumab not only prevented loss of vision in nAMD treatment-naïve patients (the natural history for these patients), but also, and for the first time ever in this disease, that their vision could recover, as shown by the 7.2 letters gained on average in the ranibizumab 0.5 mg dose group (the dose subsequently marketed) versus an average loss of 10.4 letters by the sham group.” (opens the source at this quote in a new tab)

Scarring despite treatment

“Scar tissue was detected in approximately half of the patients after two years of intensive treatment” (opens the source at this quote in a new tab)

Contribution to overall disease burden

“While less common than dry AMD, wet or nvAMD accounts for almost 90% of blindness associated with AMD.” (opens the source at this quote in a new tab)

Mortality attributable to neovascular AMD

No evidence found.

Choroidal neovascularization

“Neovascular AMD, wherein abnormal vessels break through Bruch's membrane (Figure 2) is one of the leading causes of blindness in the West” (opens the source at this quote in a new tab)

Role of vascular endothelial growth factor

“VEGF-A strongly inducing vascular proliferation and migration of endothelial cells essential for both physiological and pathological angiogenesis” (opens the source at this quote in a new tab)

Progression from early disease to neovascular disease

“The AMD spectrum spans early‐stage AMD, during which drusen, pigment epithelial detachment (PED) and vitelliform lesions are observed, to late stage AMD, with choroidal neovascularization (CNV, neovascular AMD) or geographic atrophy (GA).” (opens the source at this quote in a new tab)

Fibrotic end stage

“Disciform degeneration was defined as "fibrous tissue proliferation beneath the pigment epithelium or retina" by Green in 1977” (opens the source at this quote in a new tab)

Amsler grid self-monitoring

“The Amsler grid consists of horizontal and vertical lines intersecting at a central fixation point.” (opens the source at this quote in a new tab)
“the patient assesses whether the lines are parallel or show distortion (metamorphopsia).” (opens the source at this quote in a new tab)

Optical coherence tomography

“Your doctor may also recommend doing a test called optical coherence tomography (OCT).” (opens the source at this quote in a new tab)

Optical coherence tomography angiography

“Optical coherence tomography angiography (OCTA) is a non-invasive imaging technique that allows visualization of retinal and choroidal blood vessels by detecting motion contrast caused by blood flow.” (opens the source at this quote in a new tab)
“Unlike traditional dye-based angiographic methods, such as fluorescein angiography (FA) or indocyanine green angiography (ICGA), OCTA does not require intravenous contrast agents and can capture volumetric data within seconds.” (opens the source at this quote in a new tab)

Home optical coherence tomography as an adjunct to office-based diagnosis

“Home-based optical coherence tomography (OCT) has emerged as a potential tool to bridge this surveillance gap by enabling frequent, patient-administered imaging between office visits” (opens the source at this quote in a new tab)

Visual symptoms: central vision blur and distortion

“Age-related macular degeneration (AMD) is an eye disease that can blur your central vision.” (opens the source at this quote in a new tab)

“waviness, blurring, or gaps, which may indicate macular pathology.” (opens the source at this quote in a new tab)

Vascular signs: leaking, abnormal blood vessels

“It happens when abnormal blood vessels grow in the back of the eye and damage the macula.” (opens the source at this quote in a new tab)

Functional impact: activities requiring central vision

“AMD doesn't cause complete blindness, but losing your central vision can make it harder to see faces, read, drive, or do close-up work like cooking or fixing things around the house.” (opens the source at this quote in a new tab)

Falls and fall-related injury

“They are twice as common among older people with AMD” (opens the source at this quote in a new tab)

“35% of the participants reporting that they had incurred injuries during a fall” (opens the source at this quote in a new tab)

Concern about falling

“high CF (FES-I ≥ 23) was identified in just under half of the participants (48%) at baseline, and the proportion increased significantly to 65% at follow-up” (opens the source at this quote in a new tab)

Anxiety and depression

“Clinically significant severity of depression symptoms was found in 4.2% of patients, mild manifestations of depression were found in 8.3%” (opens the source at this quote in a new tab)
“79.2% demonstrated moderate reactive anxiety; 12.5% of the subjects had a low level of reactive anxiety. 81.7 % of the respondents were subject to moderate and high personal anxiety.” (opens the source at this quote in a new tab)

Progressive fibrotic scarring

“large disciform scars are rarely encountered in the clinic. However long-term studies show that smaller and less severe fibrotic scars are not uncommon and develop over time despite optimal treatment.” (opens the source at this quote in a new tab)

Treatment-day time burden

“The majority of patients reported to spend 1–3 hours (43.1%), followed by 4–6 hours (30.8%)” (opens the source at this quote in a new tab)

Emotional burden of injection visits

“Patients reported that they were nervous or struggled to sleep prior to treatment” (opens the source at this quote in a new tab)
“33.1% of patients reported to be stressed and 15.4% struggled to sleep” (opens the source at this quote in a new tab)
“The majority of patients reported the treatment as uncomfortable (54.6%) or as somewhat painful (26.2%)” (opens the source at this quote in a new tab)

Caregiver involvement in treatment visits

“Approximately half of the patients required caregiver support every visit (37.7%) or occasionally (14.6%)” (opens the source at this quote in a new tab)

Falls-related concern and quality of life

“Concern about falling is another common issue for older people, with far-reaching implications including activity restriction, reduced quality of life” (opens the source at this quote in a new tab)

Annual per-patient cost

“We estimated an annual all-cause cost for patients with nAMD of $24,520 per patient” (opens the source at this quote in a new tab)
“newly diagnosed patients incurred slightly lower costs ($18,943)” (opens the source at this quote in a new tab)

Outpatient and injection-related resource use

“Mean (SD) annual nAMD-related outpatient burden was 6.6 (4.8) visits overall” (opens the source at this quote in a new tab)
“Overall mean (SD) annual anti-VEGF–related outpatient visit burden was 3.9 (4.2) visits” (opens the source at this quote in a new tab)

Cost by disease activity status

“The nAMD-related outpatient visit costs were roughly 4 and roughly 7 times higher, respectively, for the active CNV group ($8,658 [SD = $11,612]) compared with the inactive CNV ($2,406 [SD = $5,510]) and inactive scar ($1,198 [SD = $3,035]) groups (P < 0.0001).” (opens the source at this quote in a new tab)

National cost estimates

“Estimates of the global cost of visual impairment due to AMD are $343 billion, including $255 billion in direct healthcare costs.” (opens the source at this quote in a new tab)

Lost work productivity and wages

“Mean wages lost due to impaired work productivity ranged from $1,395 to $55,180.” (opens the source at this quote in a new tab)
“Mean wages lost due to unemployment ranged from $22,314 USD to $58,886 USD a year.” (opens the source at this quote in a new tab)

Unemployment associated with AMD-related vision loss

“The mean unemployment rate attributed to AMD ranged from 5.50% to 77.00%.” (opens the source at this quote in a new tab)

Caregiver work absence and added household expense

“22% requiring a caregiver to take time off from work for transportation.” (opens the source at this quote in a new tab)
“The financial burden of AMD is further exacerbated by additional expenses such as transportation costs, costs for caregivers, and healthcare costs.” (opens the source at this quote in a new tab)

Caregiver time burden per treatment visit

“Approximately half of the patients required caregiver support every visit (37.7%) or occasionally (14.6%)” (opens the source at this quote in a new tab)

Ranibizumab mechanism of action

“Ranibizumab binds to the receptor binding site of active forms of VEGF-A” (opens the source at this quote in a new tab)

Ranibizumab indication and dosing for wet AMD

“LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (AMD)” (opens the source at this quote in a new tab)
“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)

Aflibercept mechanism of action

“Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.” (opens the source at this quote in a new tab)

Aflibercept indication and dosing for wet AMD

“Neovascular (Wet) Age-Related Macular Degeneration (AMD)” (opens the source at this quote in a new tab)
“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)

Faricimab mechanism of action

“Faricimab is a humanized bispecific antibody that acts through inhibition of two pathways by binding to VEGF-A and Ang-2.” (opens the source at this quote in a new tab)

Faricimab indication and extended dosing intervals

“VABYSMO is a vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) inhibitor indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (nAMD)” (opens the source at this quote in a new tab)

“At week 48, after 4 initial monthly doses in the VABYSMO arm, 45% of patients received the Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the remaining 22% of patients received dosing every 8 weeks.” (opens the source at this quote in a new tab)

Ranibizumab biosimilars

“ranibizumab-nuna (Byooviz; Biogen/Samsung Bioepis), was approved in September 2021 for wet AMD, RVO, and myopic CNV.” (opens the source at this quote in a new tab)
“ranizumab-eqrn (Cimerli; Coherus Biosciences), was FDA approved in both 0.3 mg and 0.5 mg doses in October 2022 for DME, diabetic retinopathy (DR), wet AMD, RVO, and myopic CNV.” (opens the source at this quote in a new tab)
“first FDA-designated interchangeable biosimilar, meaning it can be substituted for reference ranibizumab at the pharmacy level” (opens the source at this quote in a new tab)

Anticipated cost savings from biosimilars

“biosimilars are estimated to cost patients around 30% to 40% less than the original biologic.” (opens the source at this quote in a new tab)

Agents included in current comparative evidence

“aflibercept 2 mg, aflibercept 8 mg, bevacizumab 1.25 mg (off‐label or on‐label), brolucizumab 6 mg, faricimab 6 mg, ranibizumab 0.5 mg, and the corresponding biosimilars.” (opens the source at this quote in a new tab)

Origin of off-label use

“ophthalmologists began treating neovascular AMD with off-label use of bevacizumab (Avastin, Genentech), since the drug had a target specificity similar to that of ranibizumab and was available at low cost.” (opens the source at this quote in a new tab)

Comparative efficacy versus ranibizumab (CATT trial)

“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)
“At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule.” (opens the source at this quote in a new tab)

Repackaging and contamination risk

“During March 6–8, 2013, four patients with age-related macular degeneration received a diagnosis of acute endophthalmitis” (opens the source at this quote in a new tab)
“Investigation of pharmacy A revealed multiple areas in which practices did not conform to United States Pharmacopeial Convention Chapter 797 standards for compounding sterile preparations or to recommended best practices for repackaging bevacizumab; these deficiencies might have contributed to bevacizumab contamination” (opens the source at this quote in a new tab)

Clinical decision-making around bevacizumab non-response

“For wet AMD patients who have a suboptimal response to Avastin (bevacizumab, Genentech) treatment, 88.4 percent of the physicians say they'll switch to Eylea (aflibercept, Regeneron). A smaller percentage, 11.1, say they'll switch to Lucentis.” (opens the source at this quote in a new tab)

Historical role of verteporfin photodynamic therapy

“In 2000 photodynamic therapy with verteporfin (PDT-V) was approved by the United States' Food and Drug Administration for the treatment of subfoveal CNV due to AMD.” (opens the source at this quote in a new tab)
“PDT-V alone has been shown in a large number of cases to require retreatments every 3 months.” (opens the source at this quote in a new tab)

National Eye Institute description of photodynamic therapy

“Photodynamic therapy (PDT) is a much less common treatment for wet AMD that doctors sometimes use along with anti-VEGF injections.” (opens the source at this quote in a new tab)
“a light-sensitive medicine called verteporfin that "turns on" when hit by a specific type of laser (sometimes called a cold laser)” (opens the source at this quote in a new tab)

Frequent injections and monitoring visits

“requires repeated and frequent intravitreal injections of the drug, which are necessary to maintain the therapeutic effect, frequent clinical visits to monitor efficacy and safety, and a significant financial burden associated with high drug costs” (opens the source at this quote in a new tab)

Treatment burden on patients and caregivers

“Approximately half of the patients required caregiver support every visit (37.7%) or occasionally (14.6%)” (opens the source at this quote in a new tab)

Contamination risk specific to repackaged bevacizumab

“Investigation of pharmacy A revealed multiple areas in which practices did not conform to United States Pharmacopeial Convention Chapter 797 standards for compounding sterile preparations or to recommended best practices for repackaging bevacizumab; these deficiencies might have contributed to bevacizumab contamination” (opens the source at this quote in a new tab)

Persistent fibrotic scarring despite treatment

“long-term studies show that smaller and less severe fibrotic scars are not uncommon and develop over time despite optimal treatment.” (opens the source at this quote in a new tab)

Response heterogeneity across agents and patients

“Patients with the minor allele of rs2285714 respond worse to antiangiogenic therapy.” (opens the source at this quote in a new tab)

First FDA-approved ophthalmic bevacizumab formulation

“rigorous clinical evidence, validated manufacturing, approved labeling, comprehensive quality systems, and ongoing FDA regulatory oversight” (opens the source at this quote in a new tab)
“Rather than relying on repackaged formulations originally intended for intravenous use, physicians now have access to a purpose-built ophthalmic formulation of bevacizumab designed specifically for intravitreal administration that delivers the manufacturing consistency, product quality, and regulatory oversight patients deserve.” (opens the source at this quote in a new tab)

Relationship to compounded/repackaged bevacizumab

“Bevacizumab has long been used off-label as an anti-VEGF therapy for retinal diseases because of its comparatively low cost, despite lacking an FDA-approved ophthalmic formulation.” (opens the source at this quote in a new tab)

Manufacturer statement on positioning

“It's really been the retina community that has been supporting us and steadfast in sustaining us through this journey because they've been requesting and wanting an FDA-approved [formulation of bevacizumab],” (opens the source at this quote in a new tab)
“this is a bevacizumab that has been specifically designed for ophthalmology use, which I think is really important.” (opens the source at this quote in a new tab)

Commercial launch plans and care setting

“Outlook Therapeutics expects to make LYTENAVA™ available to eligible patients in the United States before year-end” (opens the source at this quote in a new tab)

Market context into which Lytenava enters

“The U.S. anti-VEGF retina market is estimated at approximately $8.5 billion annually, with millions of intravitreal injections administered every year.” (opens the source at this quote in a new tab)

FDA-licensed indication

“Lytenava is indicated for treatment of patients with neovascular (wet) age-related macular degeneration (nAMD).” (opens the source at this quote in a new tab)

Genetic modifiers of anti-VEGF response

“Patients with the minor allele of rs2285714 respond worse to antiangiogenic therapy.” (opens the source at this quote in a new tab)
“For both rs800292 and rs6677604, carriage of the A allele was protective and decreased the nAMD risk.” (opens the source at this quote in a new tab)

Knowledge-guided individualization

“Unraveling the association between AMD genetics and response to therapy could pave the way for personalized AMD treatment, with genetic variants serving as predictors of its outcome, treatment regimen, and dosage mode.” (opens the source at this quote in a new tab)

Lesion and dosing-driven heterogeneity across agents

“aflibercept 2 mg, aflibercept 8 mg, bevacizumab 1.25 mg (off‐label or on‐label), brolucizumab 6 mg, faricimab 6 mg, ranibizumab 0.5 mg, and the corresponding biosimilars.” (opens the source at this quote in a new tab)
“One main underlying factor influencing visual outcomes is the average number of injections over time,” (opens the source at this quote in a new tab)

Sex-related heterogeneity in incidence and burden

“The incidence of nAMD in women was almost two-fold greater compared to males at the same age.” (opens the source at this quote in a new tab)

Treat-and-extend regimens

“requires repeated and frequent intravitreal injections of the drug, which are necessary to maintain the therapeutic effect, frequent clinical visits to monitor efficacy and safety, and a significant financial burden associated with high drug costs” (opens the source at this quote in a new tab)
“monthly, monthly for the first three months followed by PRN, every eight weeks, quarterly cross‐over from monthly to PRN, and treat‐and‐extend protocols” (opens the source at this quote in a new tab)

Home optical coherence tomography as a safety net between visits

“Home-based optical coherence tomography (OCT) has emerged as a potential tool to bridge this surveillance gap by enabling frequent, patient-administered imaging between office visits” (opens the source at this quote in a new tab)
“Persistent or recurring fluid was identified in 121 (65%) intervals, on average 32 days prior to the next office visit.” (opens the source at this quote in a new tab)
“Home OCT monitoring provides adjunctive information to support early detection of fluid and may facilitate timely clinical evaluation.” (opens the source at this quote in a new tab)

Amsler grid self-monitoring between visits

“Its portability and ease of use enable patients to participate actively in the management of their ocular health, allowing earlier detection of disease progression and more timely medical intervention.” (opens the source at this quote in a new tab)

Extended-interval dosing to reduce visit burden

“At week 48, after 4 initial monthly doses in the VABYSMO arm, 45% of patients received the Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the remaining 22% of patients received dosing every 8 weeks.” (opens the source at this quote in a new tab)

Postmarketing commitment on reference standard qualification

“We remind you of your postmarketing commitment: 5036-1 Implement a two-tiered reference standard system by qualifying a working reference standard. Submit the qualification report(s) and requalification protocol for the working reference standard in a Prior Approval Supplement to the BLA.” (opens the source at this quote in a new tab)
“The timetable you submitted on July 17, 2026, states that you will conduct this study according to the following schedule: Final Report Submission: 7/2027” (opens the source at this quote in a new tab)

Pediatric study waiver

“We are waiving the pediatric study requirement for this application because necessary studies are impossible or highly impracticable as the conditions rarely or never occur in pediatrics.” (opens the source at this quote in a new tab)

No advisory committee referral

“Your application for Lytenava was not referred to an FDA advisory committee because this biologic is not the first in its class.” (opens the source at this quote in a new tab)

Adverse experience and distribution reporting

“You must submit adverse experience reports under the adverse experience reporting requirements at 21 CFR 600.80.” (opens the source at this quote in a new tab)
“You must submit distribution reports under the distribution reporting requirements at 21 CFR 600.81.” (opens the source at this quote in a new tab)

Biological product deviation reporting

“You must submit reports of biological product deviations under 21 CFR 600.14. You should promptly identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution.” (opens the source at this quote in a new tab)

Manufacturing change control

“Any changes in the manufacturing, testing, packaging, or labeling of Lytenava, or in the manufacturing facilities, will require the submission of information to your BLA for our review and written approval, consistent with 21 CFR 601.12.” (opens the source at this quote in a new tab)

Vision stabilization and improvement with anti-VEGF therapy

“Anti-VEGF treatment improves vision in about one third (1 out of 3) people who take it.” (opens the source at this quote in a new tab)
“For a vast majority (9 out of 10), it at least stabilizes vision.” (opens the source at this quote in a new tab)

Contrast with untreated natural history

“ranibizumab not only prevented loss of vision in nAMD treatment-naïve patients (the natural history for these patients), but also, and for the first time ever in this disease, that their vision could recover, as shown by the 7.2 letters gained on average in the ranibizumab 0.5 mg dose group (the dose subsequently marketed) versus an average loss of 10.4 letters by the sham group.” (opens the source at this quote in a new tab)

Persistence of fibrotic scarring as a limit on outcomes

“long-term studies show that smaller and less severe fibrotic scars are not uncommon and develop over time despite optimal treatment.” (opens the source at this quote in a new tab)