---
title: "Lytenava (bevacizumab-vikg) in Neovascular age-related macular degeneration: drug evaluation"
description: "Drug evaluation on Lytenava (bevacizumab-vikg) in Neovascular age-related macular degeneration, for pharmacy and therapeutics review. Covers Purpose for review, Plain language summary, Research questions, Conclusions, Recommendations, Background, and 5 further headings. 115 evidence topics quoted from 31 sources. Every factual statement is a verbatim quote from the source cited beneath it; the evidence grades, the risk of bias and applicability ratings, and the authorization criteria are the reviewer’s, each traceable to the section that supports it."
canonical: "https://www.evicenter.com/drugs/lytenava--neovascular-age-related-macular-degeneration/monograph/oregon"
published: "2026-10-28T12:03:51-04:00"
modified: "2026-10-28T12:03:51-04:00"
---

# Lytenava (bevacizumab-vikg) in Neovascular age-related macular degeneration: drug evaluation

Every factual statement is a verbatim quote from the source cited beneath it; the evidence grades, the risk of bias and applicability ratings, and the authorization criteria are the reviewer’s, each traceable to the section that supports it.

<a id="oregon-monograph-evaluation-section"></a>

## Evaluation section

<a id="oregon-monograph-topic-evaluation-section-1"></a>

| Field | Value |
| --- | --- |
| Drug | Lytenava (bevacizumab-vikg) |
| Indication reviewed | Neovascular age-related macular degeneration |
| Generic name | Bevacizumab-vikg |
| Brand name (manufacturer) | Lytenava (Outlook Therapeutics) |
| Therapeutic category | Ophthalmic vascular endothelial growth factor (VEGF) inhibitors |
| Dosage form and route | Solution in a single-dose vial, intravitreal injection |
| Orphan designation | Not designated |
| Regulatory status | Approved July 2026 by the Food and Drug Administration, under a biologics license application submitted under section 351(a) of the Public Health Service Act |
| Date of review | October 2026 |
| End date of literature search | September 28, 2026 |
| Review status | Draft for pharmacy and therapeutics committee review |

<a id="oregon-monograph-purpose-for-review"></a>

## 1 Purpose for review

<a id="oregon-monograph-topic-1-1"></a>

### Scope of this review

- To review the evidence for the safety and effectiveness of Lytenava (bevacizumab-vikg) in adults with neovascular (wet) age-related macular degeneration.
- To establish the clinical conditions under which Lytenava is authorized.
- To set out what the evidence shows about Lytenava relative to the comparator used in its trials, ranibizumab, and relative to off-label repackaged bevacizumab.
- The scope is limited to Lytenava and its own trials. Other intravitreal VEGF inhibitors appear only as the comparator arms of those trials.

<a id="oregon-monograph-plain-language-summary"></a>

## 2 Plain language summary

<a id="oregon-monograph-topic-2-1"></a>

### Plain language summary

- Wet age-related macular degeneration (wet AMD) is an eye disease of older adults in which abnormal blood vessels grow at the back of the eye and damage the macula, the part of the retina used for central vision. It is a less common form of late AMD, and it causes faster vision loss. (see 6)
- About 2 out of 100 Medicare beneficiaries have wet AMD, a share that was 2.14% in 2021. Without treatment the disease ends in scarring and blindness. (see 6)
- Before Lytenava, no form of bevacizumab was approved for use in the eye. Eye doctors used bevacizumab made for cancer treatment, repackaged into small syringes by compounding pharmacies, which carries a risk of contamination and of inconsistent strength. (see 6)
- Lytenava is bevacizumab made and approved for injection into the eye. The Food and Drug Administration (FDA) approved it for wet AMD in July 2026. A physician injects 1.25 mg into the eye once a month, about every 28 days, using a separate vial for each eye. (see 7.3, 7.4)
- In the main trial of 228 people, about 4 in 10 people given Lytenava every month gained 3 or more lines on an eye chart after 11 months, against about 2 in 10 people given ranibizumab, another approved eye injection, which was given 5 times in the year against 12 times for Lytenava. (see 8.1)
- In a second trial of 400 people, in which both medicines were given monthly, vision improved by 3.3 letters with Lytenava and 4.5 letters with ranibizumab after 8 weeks. That result did not meet the trial's goal of showing that Lytenava was not worse than ranibizumab. (see 8.2)
- The most common side effect was bleeding on the surface of the eye, in 4 out of 100 people. Any injection into the eye can cause an infection inside the eye, a detached retina, or a rise in eye pressure, so eye pressure is checked before and after each injection. (see 7.3, 10)
- The evidence is of low quality, because the main trial compared Lytenava given 12 times against ranibizumab given 5 times. No trial compared Lytenava with repackaged bevacizumab. The list price is $485 per vial. (see 4, 7.5, 8.1)

<a id="oregon-monograph-research-questions"></a>

## 3 Research questions

<a id="oregon-monograph-topic-3-1"></a>

### Research questions

1. What is the effectiveness of Lytenava (bevacizumab-vikg) in adults with neovascular age-related macular degeneration?
2. What are the harms of Lytenava in adults with neovascular age-related macular degeneration?
3. Are there subgroups, defined by age, baseline visual acuity, prior anti-VEGF treatment, or demographics, in which Lytenava is more effective or associated with fewer harms?
4. Is there evidence that Lytenava differs in effectiveness or safety from off-label repackaged bevacizumab?

<a id="oregon-monograph-conclusions"></a>

## 4 Conclusions

<a id="oregon-monograph-topic-4-1"></a>

### Effectiveness

- There is low-quality evidence from one randomized trial, NORSE TWO, that Lytenava 1.25 mg monthly increased the proportion of participants gaining 15 or more ETDRS letters at month 11 compared with ranibizumab 0.5 mg given monthly for 3 doses and then every 3 months: 41.7% against 23.1%, risk difference 0.1859 (95% CI 0.0442, 0.3086), P = 0.0052. Mean change in BCVA was 11.2 against 5.8 letters. (see 8.1)
- The grade is held at low because the two arms received different numbers of injections, 12 against 5. The trial authors state that both arms showed a similar initial response while dosed monthly and that the ranibizumab dosing regimen is the likely reason the arms separated later. (see 8.1)
- There is low-quality evidence that Lytenava did not meet noninferiority to ranibizumab when both were given every 4 weeks: in NORSE EIGHT the mean BCVA gain at week 8 was 3.3 against 4.5 letters, LS mean difference -2.3 (95% CI -4.0, -0.5), against a prespecified margin of -3.5 letters. The sponsor reports a week 12 difference of -1.009 letters (95% CI -2.865, 0.848), a secondary timepoint. (see 8.2)
- In NORSE ONE, a 61-participant trial including previously treated participants, 2 of 25 (8%) in the Lytenava arm and 5 of 23 (22%) in the ranibizumab arm gained more than 15 letters at month 11. The trial is too small and too sparsely reported to support a conclusion. (see 8.3)
- There is insufficient evidence on quality of life, function, or patient-reported outcomes, which no Lytenava trial reports. (see 8.1, 8.2)

<a id="oregon-monograph-topic-4-2"></a>

### Harms

- There is low-quality evidence that ocular adverse reactions were similar to ranibizumab across five clinical trials: conjunctival hemorrhage 4% against 3%, eye pain 2% against 1%, and vitreous floaters 2% against 1%, in 601 participants given Lytenava and 345 given ranibizumab. (see 10)
- In NORSE TWO, treatment-related adverse events were more frequent with Lytenava, 21 (18.6%) against 9 (7.8%), with 12 injections against 5. Serious adverse events (14 [12.4%] against 16 [13.9%]) and discontinuations due to adverse events (2 [1.8%] against 5 [4.3%]) did not favor ranibizumab. The one study-related serious ocular event was elevated intraocular pressure. (see 8.1)
- Across three trials including 486 participants given Lytenava, one case of ocular inflammation (iritis) was reported, and no case of retinal vasculitis was reported in either arm of NORSE EIGHT. (see 8.1, 8.2)
- There is insufficient evidence on harms beyond 12 months and on arterial thromboembolic events, which the labeling lists as a potential risk of intravitreal VEGF inhibitors. (see 7.3, 8.1)

<a id="oregon-monograph-topic-4-3"></a>

### Subgroups

- There is insufficient evidence for any subgroup in which Lytenava is more effective or safer. The labeling states that no overall differences in efficacy or safety were seen with increasing age in the three completed Phase 3 studies, in which 70% of participants given Lytenava were 65 years or older. (see 8.1)
- NORSE TWO enrolled treatment-naive participants with BCVA of 25 to 67 letters, and 97.3% of the Lytenava arm was White, so the result does not establish effectiveness in previously treated eyes or in other racial groups. (see 8.1)

<a id="oregon-monograph-topic-4-4"></a>

### Comparison with repackaged bevacizumab

- There is insufficient evidence that Lytenava differs from repackaged bevacizumab in effectiveness or safety. No trial compared the two. (see 6, 8.1)
- The NORSE TWO authors compare their result with the monthly bevacizumab arm of the CATT study across trials, 41.7% against 31.3% gaining 15 or more letters, and attribute the difference either to lower potency of repackaged bevacizumab or to worse baseline visual acuity in NORSE TWO (52.1 against 60.2 letters). A cross-trial comparison of this kind does not support a conclusion. (see 8.1)

<a id="oregon-monograph-recommendations"></a>

## 5 Recommendations

<a id="oregon-monograph-topic-5-1"></a>

### Recommendations

- Apply the clinical criteria at 11, which confirm the diagnosis, the prescriber, the absence of a contraindication, the labeled dose, and intraocular pressure monitoring. (see 11)
- Authorize one vial per treated eye per injection, since the labeling states that each vial is for one eye only. (see 7.3)
- Read the NORSE TWO result as evidence of effectiveness against a comparator arm that received fewer injections; NORSE EIGHT, the trial in which both arms were given every 4 weeks, did not meet its noninferiority margin. (see 8.1, 8.2)
- Review the cost of therapy when an average sales price and a permanent HCPCS code are published; the wholesale acquisition cost is $485 per vial. (see 7.5)
- Reassess when NORSE EIGHT is published in full and when NORSE SEVEN, the vial and prefilled syringe study, reports. (see 8.2, 8.5)

<a id="oregon-monograph-background"></a>

## 6 Background

<a id="oregon-monograph-topic-6-1"></a>

### Definition: neovascular (wet) age-related macular degeneration

> “Age-related macular degeneration (AMD) is an eye disease that can blur your central vision.”
> “Wet AMD (also called advanced neovascular AMD), is a less common type of late AMD that usually causes faster vision loss.”
> “It happens when abnormal blood vessels grow in the back of the eye and damage the macula.”

Source: [National Eye Institute](https://www.nei.nih.gov/eye-health-information/eye-conditions-and-diseases/age-related-macular-degeneration)

> “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”
> “VEGF-A strongly inducing vascular proliferation and migration of endothelial cells essential for both physiological and pathological angiogenesis”

Source: [Pugazhendhi et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7866170/)

<a id="oregon-monograph-topic-6-2"></a>

### Risk factors

> “Your risk for AMD increases as you get older. People age 55 and older are more likely to have AMD.”
> “The risk for AMD is also higher for people who: Have a family history of AMD Are Caucasian Smoke”

Source: [National Eye Institute](https://www.nei.nih.gov/eye-health-information/eye-conditions-and-diseases/age-related-macular-degeneration)

<a id="oregon-monograph-topic-6-3"></a>

### Incidence and prevalence

> “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.”
> “The prevalence of nAMD was 862 (/100,000 inhabitants) (95% CI 821–906) in adults aged 44–96 years in 2020.”
> “The incidence of nAMD in women was almost two-fold greater compared to males at the same age.”

Source: [Korva-Gurung et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10262804/)

> “the prevalence of wet AMD remained relatively stable, fluctuating from 2.17% in 2014 to 2.14% in 2021.”

Source: [Singh et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12705084/)

> “Wet macular degeneration accounts for approximately 10% of all AMD cases but is responsible for 90% of legal blindness.”

Source: [BrightFocus Foundation](https://www.brightfocus.org/macular/facts-figures/)

<a id="oregon-monograph-topic-6-4"></a>

### Natural history without treatment

> “Prior to the anti-VEGF era, the clinical manifestation of the natural history of nAMD was the formation of a disciform scar and blindness”
> “AMD leads to blindness when left untreated, due to the development of atrophy and/or disciform scar.”

Source: [Armendariz et al. (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11584703/)

<a id="oregon-monograph-topic-6-5"></a>

### Diagnosis

> “Your doctor may also recommend doing a test called optical coherence tomography (OCT).”

Source: [National Eye Institute](https://www.nei.nih.gov/eye-health-information/eye-conditions-and-diseases/age-related-macular-degeneration)

> “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.”

Source: [Lombardo et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12532941/)

<a id="oregon-monograph-topic-6-6"></a>

### Standard of care before this product: off-label repackaged bevacizumab

> “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.”
> “At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule.”

Source: [CATT Research Group (2011)](https://pmc.ncbi.nlm.nih.gov/articles/PMC3157322/)

> “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.”

Source: [Eyewire+ (2026)](https://eyewire.news/news/fda-approves-outlook-therapeutics-lytenava-as-first-ophthalmic-bevacizumab-for-wet-amd)

> “Because no currently approved ophthalmic formulations of bevacizumab are available, clinicians wishing to treat retinal patients with bevacizumab use unapproved repackaged IV bevacizumab provided by compounding pharmacists, products that have known risks of contamination and inconsistent potency and availability.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

> “Bevacizumab already accounts for the majority of first-line anti-VEGF treatment in wet AMD, underscoring its important role in retina care.”

Source: [Outlook Therapeutics FDA approval announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926086685/tm2621316d1_ex99-1.htm)

<a id="oregon-monograph-topic-6-7"></a>

### Limitations of repackaged bevacizumab

> “During March 6–8, 2013, four patients with age-related macular degeneration received a diagnosis of acute endophthalmitis”
> “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”

Source: [Edison et al. (2015)](https://pmc.ncbi.nlm.nih.gov/articles/PMC4285274/)

> “its use through aliquoting single-use vials has been subjected to scrutiny in terms of quality, consistency, and safety.”
> “There have also been reports of infectious and inflammatory endophthalmitis outbreaks related to the intravitreal use of Avastin in the US, Japan, and South Korea, as well as other countries.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-6-8"></a>

### Treatment burden

> “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”

Source: [Lucenteforte et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12805632/)

> “Approximately half of the patients required caregiver support every visit (37.7%) or occasionally (14.6%)”

Source: [Reitan et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10226541/)

<a id="oregon-monograph-drug-information"></a>

## 7 Drug information

<a id="oregon-monograph-heading-7.1"></a>

### 7.1 Mechanism of action

<a id="oregon-monograph-topic-7.1-1"></a>

#### Drug class and molecular action

> “LYTENAVA is a vascular endothelial growth factor (VEGF) inhibitor”
> “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.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.1-2"></a>

#### Molecule: a full-length monoclonal antibody formulated for intravitreal use

> “ONS-5010 is a full-length, humanized anti-VEGF (Vascular Endothelial Growth Factor) recombinant monoclonal antibody (mAb) that inhibits VEGF and associated angiogenic activity.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

> “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.”

Source: [Outlook Therapeutics FDA approval announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926086685/tm2621316d1_ex99-1.htm)

<a id="oregon-monograph-topic-7.1-3"></a>

#### Pharmacodynamics: central foveal thickness

> “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.”
> “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.”
> “Anatomic data were not used to influence LYTENAVA treatment decisions.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-heading-7.2"></a>

### 7.2 Pharmacokinetics

<a id="oregon-monograph-topic-7.2-1"></a>

#### Pharmacokinetic properties

| Parameter | Result |
| --- | --- |
| Absorption: systemic exposure after intravitreal injection | “Following intravitreal administration of LYTENAVA, the systemic exposure to bevacizumab-vikg is minimal.” |
| Serum concentration after a single 1.25 mg intravitreal dose | “In 14 subjects who received a single 1.25 mg dose of LYTENAVA, the serum bevacizumab-vikg concentration was assessed up to Day 4.”; “ranging from 33 to 270 ng/mL, which was <1% of the Cmax after intravenous infusion of 2 mg/kg bevacizumab-vikg” |
| Distribution | Not reported |
| Metabolism | Not reported |
| Elimination | Not reported |
| Half-life | Not reported |
| Time to maximum serum concentration | “the highest concentrations observed were approximately at Day 4 (the last collection time)” |
| Maximum serum concentration and area under the curve | “due to the limited sample collection, Cmax or AUC could not be adequately characterized” |

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

Abbreviations: AUC = area under the concentration-time curve; Cmax = maximum serum concentration.

<a id="oregon-monograph-topic-7.2-2"></a>

#### Immunogenicity

> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-heading-7.3"></a>

### 7.3 Dosing, administration, and monitoring

<a id="oregon-monograph-topic-7.3-1"></a>

#### Dose, frequency, and administering physician

> “FOR OPHTHALMIC INTRAVITREAL INJECTION. LYTENAVA must only be administered by a qualified physician.”
> “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).”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-2"></a>

#### Dosage form, how supplied, and single-eye use

> “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.”
> “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.”
> “EACH CARTON IS FOR SINGLE-EYE USE ONLY.”
> “The glass vial is for one-time use in one eye only.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-3"></a>

#### Composition, storage, and handling

> “LYTENAVA (bevacizumab-vikg) injection is a sterile, colorless to light brown, opalescent solution for intravitreal use. LYTENAVA does not contain an anti-microbial preservative.”
> “Store LYTENAVA refrigerated at 2oC to 8oC (36oF to 46oF) in the original carton until use to protect from light. DO NOT FREEZE.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-4"></a>

#### Preparation and injection procedure

> “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.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-5"></a>

#### Monitoring after each injection

> “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)].”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-6"></a>

#### Contraindications

> “LYTENAVA is contraindicated in patients with ocular or periocular infections.”
> “LYTENAVA is contraindicated in patients with active intraocular inflammation.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-7"></a>

#### Warnings and precautions

> “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)].”
> “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)].”
> “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).”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.3-8"></a>

#### Use in specific populations

> “The safety and effectiveness of LYTENAVA in pediatric patients have not been established.”
> “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)].”
> “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.”
> “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.”
> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

See the current prescribing information for full details.

<a id="oregon-monograph-heading-7.4"></a>

### 7.4 Regulatory history

<a id="oregon-monograph-topic-7.4-1"></a>

#### Approval and indication

> “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.”
> “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.”
> “Lytenava is indicated for treatment of patients with neovascular (wet) age-related macular degeneration (nAMD).”

Source: [FDA (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/761320Orig1s000ltr.pdf)

> “ISELIN, N.J., July 24, 2026”
> “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)”
> “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.”
> “the Company anticipates that the approval will provide LYTENAVA with 12 years of Reference Product Exclusivity under the BPCIA.”

Source: [Outlook Therapeutics FDA approval announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926086685/tm2621316d1_ex99-1.htm)

<a id="oregon-monograph-topic-7.4-2"></a>

#### First complete response letter, 2023

> “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.”

Source: [Outlook Therapeutics regulatory update (2023)](https://www.sec.gov/Archives/edgar/data/1649989/000110465923096669/tm2325118d1_ex99-1.htm)

<a id="oregon-monograph-topic-7.4-3"></a>

#### NORSE EIGHT, and the 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.”
> “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).”

Source: [Outlook Therapeutics Form 10-Q (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926098415/otlk-20260630x10q.htm)

<a id="oregon-monograph-topic-7.4-4"></a>

#### Final resubmission

> “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.”

Source: [Outlook Therapeutics FDA acceptance announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926074346/tm2618010d1_ex99-1.htm)

<a id="oregon-monograph-topic-7.4-5"></a>

#### Postmarketing commitment, pediatric waiver, and advisory committee

> “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.”
> “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.”
> “Your application for Lytenava was not referred to an FDA advisory committee because this biologic is not the first in its class.”

Source: [FDA (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/761320Orig1s000ltr.pdf)

<a id="oregon-monograph-topic-7.4-6"></a>

#### European Union and United Kingdom

> “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.”

Source: [Outlook Therapeutics Form 10-Q (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926098415/otlk-20260630x10q.htm)

<a id="oregon-monograph-topic-7.4-7"></a>

#### United States launch

> “Outlook Therapeutics is advancing preparations for the U.S. commercial launch of LYTENAVA, planned before the end of calendar 2026.”

Source: [Outlook Therapeutics third quarter fiscal year 2026 results (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926096478/tm2622399d3_ex99-1.htm)

<a id="oregon-monograph-heading-7.5"></a>

### 7.5 Cost of therapy

<a id="oregon-monograph-topic-7.5-1"></a>

#### 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.”

Source: [Outlook Therapeutics Form 8-K (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926108952/tm2625694d1_8k.htm)

<a id="oregon-monograph-topic-7.5-2"></a>

#### Dose and frequency that convert the price to an annual figure

> “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).”
> “EACH CARTON IS FOR SINGLE-EYE USE ONLY.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-7.5-3"></a>

#### Average sales price

No evidence found.

<a id="oregon-monograph-topic-7.5-4"></a>

#### Billing code

> “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.”

Source: [Outlook Therapeutics third quarter fiscal year 2026 results (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926096478/tm2622399d3_ex99-1.htm)

<a id="oregon-monograph-clinical-efficacy-and-safety"></a>

## 8 Clinical efficacy and safety

<a id="oregon-monograph-heading-8.1"></a>

### 8.1 NORSE TWO

<a id="oregon-monograph-topic-8.1-1"></a>

#### Trial design and duration

> “The efficacy of LYTENAVA for the treatment of neovascular (wet) age-related macular degeneration (nAMD) was demonstrated in a randomized, multi-center, masked, active-controlled study (NORSE TWO – NCT03834753).”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

| Field | Quoted record |
| --- | --- |
| Allocation | “Randomized” |
| Intervention Model | “Parallel Assignment” |
| Masking | “Double” |
| Who Masked | “Participant”, “Outcomes Assessor” |
| Phase | “Phase 3” |
| Enrollment | “228” |
| Study Start Date | “2019-06-25” |
| Primary Completion Date | “2021-06-07” |

Source: [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753)

> “Following a screening period of up to 28 days, eligible patients were randomized in a 1:1 ratio to receive either ONS-5010 or ranibizumab in the study eye. Only one eye per patient was designated as the study eye. The injection was performed by an unmasked physician.”
> “All investigators performing the ocular assessments were masked to the study treatment assignment.”
> “Patients in the ranibizumab group underwent sham procedures during visits when they did not receive an active (ranibizumab) injection (Figure 1). The sham procedures were intended to maintain patient masking. The patient was prepped as if they would receive an actual intravitreal injection and the eye was touched by a syringe without a needle.”
> “The last visit of the study differed depending on which treatment group the patient was randomized to, concluding at day 330 for the ranibizumab group and at day 365 for the ONS-5010 group.”
> “Patients who experienced a loss of ≥15 letters (3 lines) compared to their baseline at any visit, were provided with a rescue therapy as determined by the investigator.”
> “Funding: This study was funded by Outlook Therapeutics.”
> “TD and JK are employees of Outlook Therapeutics.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-2"></a>

#### Intervention

> “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).”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

> “Patients randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months.”
> “this is the first study to use an ophthalmic preparation of bevacizumab.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-3"></a>

#### Comparator

> “Patients randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen.”
> “While clinicians often treat nAMD with greater frequency than the ranibizumab arm of the NORSE TWO study, the study was designed to meet a regulatory endpoint of comparison to a previously approved treatment dosing regimen in order to demonstrate the existence of a treatment effect for ONS-5010.”
> “It should be noted that the number of injections in the ONS-5010 group was more than double the number of injections in the ranibizumab group.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-4"></a>

#### Participants

> “All 228 randomized patients were included in the ITT and safety populations (113 patients in the ONS-5010 group and 115 patients in the ranibizumab group), and 163 patients were included in the PP population (85 and 78 patients in the ONS-5010 and ranibizumab groups, respectively).”
> “A total of 228 patients were randomized at 39 study centers across the US. Of those, 198 (86.8%) completed the study. The three most frequently reported reasons for study discontinuation were withdrawal of consent (4.8%), AEs (3.5%), and other reasons (1.8%).”
> “In the ONS-5010 group, nine patients discontinued the treatment and withdrew from the study (five because of AEs, three lost to follow-up, and one withdrew voluntarily); one patient completed treatment but withdrew from the study; and two patients discontinued treatment but completed the study. In the ranibizumab group, 20 patients discontinued the treatment and withdrew from the study (10 due to voluntary withdrawal, five because of AEs, three because of lack of effectiveness, and three for other reasons); one patient discontinued treatment but completed the study.”
> “On the whole, the pandemic resulted in a considerable number of withdrawals from the study either due to TEAEs or due to fear of infection.”
> “Participants who stopped the study because of adverse effects, ineffectiveness, or the need for rescue treatment were considered as nonresponders. Those who left the study for other reasons and missed the BCVA measurement at month 11 were considered missing.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-5"></a>

#### Key inclusion criteria

> “Active primary Subfoveal Choroidal Neovascularization lesions secondary to Age-related macular degeneration (AMD) in the study eye”
> “Best corrected visual acuity of 25-67 letters read (20/50 to 20/320 Snellen equivalent)”
> “Have active leakage on Fluorescein Angiogram involving the fovea”
> “Have edema involving the fovea”
> “Be free of scarring, fibrosis, or atrophy involving the central foveal zone”

Source: [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753)

> “Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-6"></a>

#### Key exclusion criteria

> “Previous subfoveal focal laser photocoagulation in the study eye”
> “Active intraocular inflammation (grade trace or above) in the study eye”
> “Current vitreous haemorrhage in the study eye”
> “Polypoidal choroidal vasculopathy (PCV) in the study eye”
> “Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)”

Source: [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753)

> “Exclusion criteria included: previous use of intravitreal corticosteroids or anti-VEGFs (including Avastin) in the study eye; prior treatment of the study eye with verteporfin, external beam radiation therapy, transpupillary thermotherapy, subfoveal focal laser photocoagulation, vitrectomy or subfoveal surgery; concurrent ocular disease in the study eye that would require treatment during the study duration; history of rhegmatogenous retinal detachment in the study eye; history of idiopathic or autoimmune-associated uveitis, infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye; treatment of the fellow eye with verteporfin within 7 days prior to randomization; and any previous participation in any investigational drug study (other than vitamins and minerals) within one month prior to randomization.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-7"></a>

#### Baseline disease severity and population characteristics

> “Patient ages ranged from 54 to 98 years, with a median age of 79 years.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

| Parameter | Ranibizumab (n = 115) | ONS-5010 (n = 113) |
| --- | --- | --- |
| Male, n (%) | “46 (40.0%)” | “46 (40.7%)” |
| Female, n (%) | “69 (60.0%)” | “67 (59.3%)” |
| Age, mean ± SD | “79.1 ± 8.49” | “78.8 ± 8.30” |
| White, n (%) | “113 (98.3%)” | “110 (97.3%)” |
| Asian, n (%) | “1 (0.9%)” | “1 (0.9%)” |
| Prior anti-VEGF, n (%) | “5 (4.3%)” | “4 (3.5%)” |
| Baseline BCVA, mean ± SD | “51.1 ± 12.96” | “52.1 ± 12.16” |
| Baseline CFT (μm), mean ± SD | “423.7 ± 114.77” | “430.0 ± 150.85” |

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-8"></a>

#### Setting

> “Two hundred twenty-eight eligible patients with neovascular (wet) age-related macular degeneration (nAMD) were enrolled at 39 study centers in the United States.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-9"></a>

#### Endpoints

> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

> “Mean Change in the Best Corrected Visual Acuity”
> “Proportion of Participants Who Gain at Least 10 Letters in the Best Corrected Visual Acuity”
> “Proportion of Participants Who Gain at Least 5 Letters in the Best Corrected Visual Acuity”
> “Proportion of Participants Who Lose Fewer Than 15 Letters in the Best Corrected Visual Acuity”
> “Proportion of Participants With Visual-acuity Snellen Equivalent of 20/200 or Worse”
> “BCVA to be assessed as letters read using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. A positive change represents an improvement in visual acuity.”

Source: [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753)

> “The primary and secondary efficacy analyses were calculated using a Fisher's exact test.”
> “Analysis of the results was based on the intention-to-treat population (ITT), but statistics for the per-protocol population (PP) were also calculated to confirm findings.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-10"></a>

#### Magnitude of benefit and clinical relevance of results

| Field | Ranibizumab 0.5 mg Once Monthly x 3 Months then every 3 Months (N = 115) | LYTENAVA 1.25 mg Once Monthly (N = 113) |
| --- | --- | --- |
| Number of subjects, n/N (%) | “24/104 (23.1)” | “45/108 (41.7)” |
| Risk difference | | “0.1859” |
| 95% CI | | “0.0442, 0.3086” |

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

> “Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of patients gaining ≥ 5 and ≥ 10 letters and patients losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, patients with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

| Parameter, n/N (%) | Ranibizumab (n = 115) | ONS-5010 (n = 113) |
| --- | --- | --- |
| Subjects gaining ≥5 letters from baseline at 11 months | “53/104 (51.0)” | “74/108 (68.5)” |
| Subjects gaining ≥10 letters from baseline at 11 months | “36/104 (34.6)” | “61/108 (56.5)” |
| Subjects losing <15 letters from baseline at 11 months | “86/104 (82.7)” | “101/108 (93.5)” |
| Subjects with a visual acuity Snellen equivalent of 20/200 or worse at 11 months | “25/104 (24.0)” | “14/108 (13.0)” |

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

> “For each of these fixed-sequence secondary endpoints, the difference between study treatment groups was significant (P values range: 0.05 to 0.0016).”
> “The proportion of patients with a Snellen visual acuity equivalent of 20/200 or worse at 11 months (ie, the final secondary efficacy endpoint in the fixed sequence) was lower in the ONS-5010 group (13.0% [14 patients]) with respect to the ranibizumab group (24.0% [25 patients]). However, this difference was not statistically significant (P = 0.0505).”
> “When calculated using the trimmed means fixed approach, the least squares (LS) mean change in BCVA from baseline to 11 months was 19.310 letters in the ONS-5010 group and 14.575 letters in the ranibizumab group (LS mean difference of 4.735 [95% CI = 1.306, 8.163]; P = 0.0035). When calculated using the trimmed means adaptive approach, the LS mean change in BCVA from baseline to 11 months was 13.640 letters in the ONS-5010 group and 5.770 letters in the ranibizumab group. The difference observed between study treatment groups was significant, with an LS mean difference of 7.870 (95% CI = 4.536, 12.599; P = 0.0001).”
> “When the initial (first 3 months) and secondary responses were compared (Figure 2), both treatments displayed a similar initial response when a similar dosing regimen (monthly injections) was used, whereas the bevacizumab group gained more letters in the subsequent months compared to the ranibizumab group. The dosing regimen in the ranibizumab group is the likely reason for differentiation in study arms at later timepoints.”
> “In the CATT study, 31.3% gained ≥15 letters with a mean gain of eight letters.”
> “In the current study, 41.7% gained ≥15 letters with a mean gain of 11.2 letters. It should be noted that the bevacizumab used in the CATT study was commercially acquired and repackaged in glass vials under aseptic conditions.”
> “One reason for this discrepancy could be the lower potency of repackaged bevacizumab, which may affect its overall effectiveness.”
> “While bevacizumab and ranibizumab have shown comparable behavior both in the CATT study and the current study, the greater mean gain of ETDRS letters in the current study is probably due to the worse baseline corrected distance visual acuity in this study (51.1 ± 12.96 and 52.1 ± 12.16 ETDRS for ranibizumab and bevacizumab, respectively) than in the CATT study (60.1 ± 14.3 and 60.2 ± 13.1 ETDRS letters, respectively).”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-11"></a>

#### Safety signals

| Criteria | Ranibizumab (n = 115), n (%) | ONS-5010 (n = 113), n (%) |
| --- | --- | --- |
| At least 1 TEAE | “85 (73.9%)” | “85 (75.2%)” |
| At least 1 TEAE related to study drug/study procedure | “9 (7.8%)” | “21 (18.6%)” |
| At least 1 ocular TEAE | “61 (53.0%)” | “59 (52.2%)” |
| At least 1 serious TEAE | “16 (13.9%)” | “14 (12.4%)” |
| At least 1 TEAE leading to discontinuation | “5 (4.3%)” | “2 (1.8%)” |

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

> “Only one patient in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%).”
> “The frequency of TEAEs considered by the investigators to be related to the study treatment/study procedure was greater in the ONS-5010 group compared with the ranibizumab group (18.6% [21 patients] vs 7.8% [9 patients]). Hypothetically, this may be due to a greater number of injections in the ONS-5010 group (12 injections in the ONS-5010 group versus five injections in the ranibizumab group).”
> “However, the number of SAEs that were considered by the investigators to be related to the procedure or the study treatment was comparable in both groups (two patients vs one patient, respectively).”
> “Notably, across all of the three clinical trials where ONS-5010 was administered, including 486 patients, only one case (<1%) of ocular inflammation AE was reported (iritis).”
> “A total of five patients died, including three in the ONS-5010 group and two in the ranibizumab group. The events that resulted in death were COVID-19 and respiratory failure (both occurring in the same patient of the ONS-5010 group), myocardial infarction and death due to COVID-19 (each occurring in different patients of the ONS-5010 group), and cardiac arrest and cardiac death (each occurring in different patients in the ranibizumab group). These events were not considered by the investigators to be related to the study treatment/study procedure.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-12"></a>

#### Subgroup analyses

> “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)].”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

> “The complementary analyses of the secondary efficacy endpoints using ANCOVA and ANCOVA with multiple imputation consistently showed a greater improvement in BCVA in the ONS-5010 group compared with the ranibizumab group at 11 months (P ≤ 0.0043).”
> “The efficacy analyses conducted using the PP population were generally similar to the analyses conducted using the ITT population, further confirming the efficacy conclusions of the study.”

Source: [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

<a id="oregon-monograph-topic-8.1-13"></a>

#### Risk of bias

| Domain | Rating | Basis |
| --- | --- | --- |
| Selection bias | Unclear | Participants were randomized 1:1 and the arms were similar at baseline in age, sex, race, BCVA, and central foveal thickness, but the method of sequence generation and allocation concealment is not reported. |
| Performance bias | High | Injections were given by an unmasked physician, and the ranibizumab arm received 5 active injections with sham procedures at other visits against 12 active injections, so participant masking for an effort-dependent outcome such as BCVA rests on a needleless sham. |
| Detection bias | Low | All investigators performing the ocular assessments were masked to treatment assignment, and the registry records masking of the outcomes assessor. |
| Attrition bias | High | Discontinuation was unequal, 20 participants withdrawing from the ranibizumab arm against 9 from the Lytenava arm, and the primary analysis counted 108 of 113 and 104 of 115 participants, with withdrawals for adverse effects, ineffectiveness, or rescue counted as nonresponders. |
| Reporting bias | Unclear | All registered endpoints are reported, but the 20/200 or worse endpoint is reported as significant in one passage and as not significant (P = 0.0505) in another, and no quality of life outcome was measured. |
| Other bias | High | The trial was funded by the manufacturer, two authors are its employees, and the authors state that the comparator regimen was chosen to meet a regulatory endpoint. |

<a id="oregon-monograph-topic-8.1-14"></a>

#### Applicability

| Element | Assessment |
| --- | --- |
| Patient | Treatment-naive adults aged 50 years or older with BCVA of 25 to 67 letters (20/50 to 20/320), 97.3% White in the Lytenava arm; eyes previously treated with an anti-VEGF agent, including Avastin, were excluded, so the trial does not show the effect of switching a patient from repackaged bevacizumab. |
| Intervention | Lytenava 1.25 mg monthly for 12 months matches the labeled regimen of 1.25 mg once monthly. |
| Comparator | Ranibizumab given monthly for 3 doses and then every 3 months, which the authors state is less frequent than clinicians usually treat; the product Lytenava would most often replace, repackaged bevacizumab, was not a comparator. |
| Outcomes | Visual acuity gain of 15 or more letters at month 11 is a patient-relevant outcome; quality of life, reading, driving, and other functional outcomes were not measured. |
| Setting | Thirty-nine study centers in the United States, matching a United States plan's care setting. |

<a id="oregon-monograph-topic-8.1-15"></a>

#### Evidence limitations

- The comparator arm received 5 injections against 12 in the Lytenava arm, and the trial authors attribute the separation of the arms after the first 3 months to the ranibizumab dosing regimen (see 8.1).
- This is the only trial in which Lytenava met its primary endpoint, and the FDA cited a lack of substantial evidence of effectiveness in two of its three complete response letters (see 7.4, 8.1).
- Follow-up was 12 months for a chronic disease that requires continued injections (see 8.1).
- Differential discontinuation, 20 participants against 9, and the pandemic-related withdrawals the authors describe add uncertainty to the primary analysis (see 8.1).
- The trial was funded by the manufacturer and two authors are its employees (see 8.1).
- No quality of life or patient-reported outcome was measured (see 8.1).

<a id="oregon-monograph-heading-8.2"></a>

### 8.2 NORSE EIGHT

<a id="oregon-monograph-topic-8.2-1"></a>

#### Trial design and duration

> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

| Field | Quoted record |
| --- | --- |
| Allocation | “N/A” |
| Intervention Model | “Parallel Assignment” |
| Masking | “Triple” |
| Who Masked | “Participant”, “Investigator”, “Outcomes Assessor” |
| Phase | “Phase 3” |
| Enrollment | “400” |
| Study Start Date | “2024-01-24” |
| Primary Completion Date | “2024-11-07” |

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

> “The NORSE EIGHT clinical trial was a randomized, controlled, parallel-group, masked, non-inferiority study of newly diagnosed, wet AMD subjects randomized in a 1:1 ratio to receive 1.25 mg ONS-5010 or 0.5 mg ranibizumab intravitreal injections. Subjects received injections at day 0 (randomization), week 4, and week 8 visits, and returned for a final study visit at week 12.”

Source: [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)

<a id="oregon-monograph-topic-8.2-2"></a>

#### Intervention

| Field | Quoted record |
| --- | --- |
| ONS-5010 bevacizumab dose | “1.25 mg, intravitreal injection” |

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

<a id="oregon-monograph-topic-8.2-3"></a>

#### Comparator

| Field | Quoted record |
| --- | --- |
| Ranibizumab dose | “0.5mg, intravitreal injection” |

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

> “Safety and Effectiveness of ONS-5010 Compared to Lucentis® in Subjects With Neovascular Age-related Macular Degeneration; NORSE EIGHT”

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

<a id="oregon-monograph-topic-8.2-4"></a>

#### Participants

> “400 adult patients with nAMD were randomized (1:1) to LYTENAVA 1.25 mg or ranibizumab 0.5 mg”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-8.2-5"></a>

#### Key inclusion criteria

> “Active primary Subfoveal Choroidal Neovascularization lesions secondary to Age-related macular degeneration (AMD) in the study eye”
> “Best corrected visual acuity of 35-75 letters read (20/32 to 20/200 Snellen equivalent)”
> “Have active leakage on Fluorescein Angiogram involving the fovea”
> “Have edema involving the fovea”
> “Be free of scarring, fibrosis, or atrophy involving the central foveal zone”

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

<a id="oregon-monograph-topic-8.2-6"></a>

#### Key exclusion criteria

> “Current vitreous hemorrhage in the study eye”
> “Polypoidal choroidal vasculopathy (PCV) in the study eye”
> “Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)”

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

<a id="oregon-monograph-topic-8.2-7"></a>

#### Baseline disease severity and population characteristics

> “Mean BCVA at baseline was 58.8 ETDRS letters for the ONS-5010 group and 59.9 letters for the ranibizumab group.”

Source: [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)

<a id="oregon-monograph-topic-8.2-8"></a>

#### Setting

| Field | Quoted record |
| --- | --- |
| Country | “United States” |

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

<a id="oregon-monograph-topic-8.2-9"></a>

#### Endpoints

> “Evaluate the Effectiveness of Intravitreal Injections of ONS-5010 Compared to Ranibizumab in Preventing Vision Loss, as Measured by the Mean Change in Baseline Best Correct Visual Acuity (BCVA) at Week 8”
> “BCVA to be assessed as letters read using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. A positive change represents an improvement in visual acuity.”

Source: [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)

> “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.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

<a id="oregon-monograph-topic-8.2-10"></a>

#### Magnitude of benefit and clinical relevance of results

> “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.”
> “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).”
> “LYTENAVA showed an increase from baseline in BCVA at Week 12 consistent with NORSE TWO.”

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

> “The difference in the means between the ONS-5010 and ranibizumab in the NORSE EIGHT trial was -2.257 BCVA letters with a 95% confidence interval of (-4.044, -0.470) while the lower bound of the pre-specified non-inferiority margin in the SPA was -3.5 at a 95% confidence interval; the hypothesis of noninferiority was not met (p>0.025)”

Source: [Outlook Therapeutics NORSE EIGHT preliminary topline results press release (2024)](https://www.sec.gov/Archives/edgar/data/1649989/000110465924123554/tm2429443d1_ex99-1.htm)

> “The difference in mean BCVA between ONS-5010 and ranibizumab was -1.009 letters (95% confidence interval, -2.865, 0.848), meeting the noninferiority margin at Month 3 (p=0.0043)”
> “ONS-5010 demonstrated mean BCVA improvements of +3.3, +4.2 and +5.5 letters at Months 1, 2, and 3 respectively.”
> “Anatomical response was similar between treatments, with a reduction in central retinal thickness of -123.9 microns for ONS-5010 treated eyes and -127.3 microns for the ranibizumab group.”

Source: [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)

> “In the intent-to-treat (ITT) population, NORSE EIGHT demonstrated a mean 5.5 letter improvement in BCVA in the ONS-5010 arm and 6.5 letter improvement in BCVA in the ranibizumab arm.”

Source: [Outlook Therapeutics NORSE EIGHT complete twelve-week results press release (2025)](https://www.globenewswire.com/news-release/2025/01/16/3010622/0/en/Outlook-Therapeutics-Announces-Complete-Twelve-Week-Efficacy-and-Safety-Results-of-NORSE-EIGHT-Clinical-Trial.html)

<a id="oregon-monograph-topic-8.2-11"></a>

#### Safety signals

> “ONS-5010 was generally well-tolerated with overall ocular adverse event rates comparable to ranibizumab, with no cases of retinal vasculitis reported in either study arm. The most commonly reported adverse event (AE) was conjunctival hemorrhage, which occurred in 5 (2.5%) participants in each group.”

Source: [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)

<a id="oregon-monograph-topic-8.2-12"></a>

#### Subgroup analyses

No evidence found.

<a id="oregon-monograph-topic-8.2-13"></a>

#### Risk of bias

| Domain | Rating | Basis |
| --- | --- | --- |
| Selection bias | Unclear | The labeling and the sponsor describe 1:1 randomization while the registry records allocation as N/A, and baseline characteristics other than BCVA (58.8 and 59.9 letters) are not reported. |
| Performance bias | Low | Both arms received the same schedule of 3 injections every 4 weeks, and the registry records masking of participants, investigators, and outcomes assessors. |
| Detection bias | Low | The registry records masking of the outcomes assessor, and BCVA was measured on ETDRS charts. |
| Attrition bias | Unclear | Participant disposition, discontinuations, and the size of the analysis sets are not reported. |
| Reporting bias | High | The trial is reported only in the labeling and in sponsor announcements, and the week 8 mean gain for Lytenava is 3.3 letters in the labeling and 4.2 letters in the sponsor's month 2 figure. |
| Other bias | High | The trial was conducted by the manufacturer under a special protocol assessment, and its week 12 result, presented as noninferior, is a secondary timepoint. |

<a id="oregon-monograph-topic-8.2-14"></a>

#### Applicability

| Element | Assessment |
| --- | --- |
| Patient | Newly diagnosed adults with BCVA of 35 to 75 letters (20/32 to 20/200), a better-seeing population than NORSE TWO; race and age are not reported. |
| Intervention | Three monthly injections of Lytenava 1.25 mg match the start of the labeled monthly regimen, but treatment beyond week 8 was not studied. |
| Comparator | Ranibizumab 0.5 mg on the same monthly schedule, the equal-dosing comparison that NORSE TWO lacked. |
| Outcomes | Mean BCVA change at week 8 is an early measure for a chronic disease; no outcome beyond week 12 and no quality of life outcome was reported. |
| Setting | United States sites, matching a United States plan's care setting. |

<a id="oregon-monograph-topic-8.2-15"></a>

#### Evidence limitations

- The trial did not meet its prespecified noninferiority margin of -3.5 letters at week 8, the primary endpoint agreed with the FDA under a special protocol assessment (see 7.4, 8.2).
- Follow-up ended at week 12, which shows nothing about maintenance of vision with continued monthly dosing (see 8.2).
- The week 12 result presented as noninferior is a secondary timepoint, analyzed with the parameters of the week 8 endpoint (see 8.2).
- The week 8 figures differ between the labeling and the sponsor's announcements, and no peer-reviewed publication exists (see 8.2).
- Participant disposition, most baseline characteristics, and arm-level adverse event rates other than conjunctival hemorrhage are unreported (see 8.2).

<a id="oregon-monograph-heading-8.3"></a>

### 8.3 NORSE ONE

<a id="oregon-monograph-topic-8.3-1"></a>

#### Trial design and duration

> “A Clinical Effectiveness, Multicenter, Randomized, Double-masked, Controlled Study of the Efficacy and Safety of ONS-5010 in Subjects With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular Degeneration”

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

| Field | Quoted record |
| --- | --- |
| Allocation | “Randomized” |
| Intervention Model | “Parallel Assignment” |
| Masking | “Double” |
| Who Masked | “Participant”, “Outcomes Assessor” |
| Phase | “Phase 3” |
| Enrollment | “61” |
| Study Start Date | “2018-10-01” |
| Primary Completion Date | “2020-07-23” |

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

> “The NORSE 1 clinical trial is a small 30-subject-per-arm clinical experience trial”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-2"></a>

#### Intervention

| Field | Quoted record |
| --- | --- |
| Bevacizumab (ONS-5010) dose | “1.25 mg, intravitreal injection” |

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

<a id="oregon-monograph-topic-8.3-3"></a>

#### Comparator

> “Patients on ONS-5010 were dosed monthly compared to those on ranibizumab, who were dosed using the PIER alternative dosing regimen of three monthly doses followed by quarterly dosing.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-4"></a>

#### Participants

> “NORSE 1 enrolled a total of 61 treatment-naïve and previously treated patients diagnosed with wet AMD at nine sites in Australia.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-5"></a>

#### Key inclusion criteria

> “Active primary or recurrent Subfoveal Choroidal Neovascularization lesions secondary to Age-related macular degeneration (AMD) in the study eye”
> “Best corrected visual acuity of 20/40 to 20/320”
> “Have active leakage on Fluorescein Angiogram involving the fovea”
> “Have edema involving the fovea”
> “Be free of foveal scarring”
> “Be free of foveal atrophy”

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

<a id="oregon-monograph-topic-8.3-6"></a>

#### Key exclusion criteria

> “Previous use of anti-VEGF or bevacizumab within 6 weeks”
> “Polypoidal choroidal vasculopathy (PCV) confirmed by indocyanine green angiography (ICGA)”
> “Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)”

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

<a id="oregon-monograph-topic-8.3-7"></a>

#### Baseline disease severity and population characteristics

No evidence found.

<a id="oregon-monograph-topic-8.3-8"></a>

#### Setting

| Field | Quoted record |
| --- | --- |
| Country | “Australia” |

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

<a id="oregon-monograph-topic-8.3-9"></a>

#### Endpoints

> “Proportion of subjects who gain 15 or more letters in the best corrected visual acuity (BCVA) score”
> “BCVA to be assessed as letters read using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. A positive change represents an improvement in visual acuity.”

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)

<a id="oregon-monograph-topic-8.3-10"></a>

#### Magnitude of benefit and clinical relevance of results

> “Overall, 2 of 25 (8%) patients on the ONS-5010 arm achieved > 15 letters best corrected visual acuity (BCVA) at Month 11 compared to 5 of 23 (22%) patients on the ranibizumab arm.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-11"></a>

#### Safety signals

> “The results from NORSE 1 indicate that the observed safety profile of ONS-5010 in this study is consistent with that of previously reported bevacizumab ophthalmology studies.”
> “There were no statistical differences in safety between LUCENTIS® (ranibizumab) and ONS-5010 in the study and zero cases of ocular inflammation.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-12"></a>

#### Subgroup analyses

> “In the subgroup analysis of treatment-naïve subjects, 2 of 6 (33%) patients on the ONS-5010 arm achieved > 15 letters at Month 11 compared to 4 of 13 (31%) patients in the ranibizumab arm.”
> “Additionally, the subgroup analysis of patients who had a baseline visual acuity of < 67 letters (20/50 or worse) at study entry included 2 of 4 (50%) patients in the ONS-5010 arm and 4 of 9 (44%) patients in the ranibizumab arm achieving > 15 letters at Month 11.”

Source: [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

<a id="oregon-monograph-topic-8.3-13"></a>

#### Risk of bias

The trial is reported only in a sponsor announcement, so a full assessment could not be performed.

| Domain | Rating | Basis |
| --- | --- | --- |
| Selection bias | Unclear | The registry records randomization, but the method, allocation concealment, and baseline characteristics by arm are not reported. |
| Performance bias | Unclear | The registry records masking of participants, but whether sham procedures masked the differing injection schedules is not reported. |
| Detection bias | Low | The registry records masking of the outcomes assessor. |
| Attrition bias | High | The reported results cover 25 and 23 participants of the 61 enrolled, and no reason for the difference is given. |
| Reporting bias | High | Results are available only from a sponsor announcement, with no publication and no confidence intervals or p-values. |
| Other bias | High | The trial was sponsored and reported by the manufacturer. |

<a id="oregon-monograph-topic-8.3-14"></a>

#### Applicability

| Element | Assessment |
| --- | --- |
| Patient | Treatment-naive and previously treated participants with BCVA of 20/40 to 20/320, a broader population than NORSE TWO, enrolled at nine sites in Australia. |
| Intervention | Monthly Lytenava 1.25 mg matches the labeled regimen. |
| Comparator | Ranibizumab on the PIER regimen of three monthly doses followed by quarterly dosing, less frequent than the Lytenava arm. |
| Outcomes | Gain of 15 or more letters at month 11, a patient-relevant outcome; no quality of life outcome. |
| Setting | Australia, so the care setting may differ from a United States plan's. |

<a id="oregon-monograph-topic-8.3-15"></a>

#### Evidence limitations

- With 25 and 23 participants analyzed, the trial cannot detect a difference between arms, and the result numerically favored ranibizumab, 22% against 8% (see 8.3).
- The reported results account for 48 of 61 enrolled participants (see 8.3).
- The trial is unpublished and reported only by the sponsor (see 8.3).

<a id="oregon-monograph-heading-8.4"></a>

### 8.4 NORSE THREE

<a id="oregon-monograph-topic-8.4-1"></a>

#### Trial design and duration

> “A 3-month Study to Assess the Safety of ONS-5010 in Subjects With Visual Impairment Due to Retinal Disorders, NORSE THREE”

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

| Field | Quoted record |
| --- | --- |
| Allocation | “N/A” |
| Intervention Model | “Single Group Assignment” |
| Masking | “None (Open Label)” |
| Phase | “Phase 3” |
| Enrollment | “197” |
| Study Start Date | “2020-10-01” |
| Primary Completion Date | “2021-02-10” |

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

<a id="oregon-monograph-topic-8.4-2"></a>

#### Intervention

> “Subjects enrolled in the study received three monthly intravitreal doses of ONS-5010 / LYTENAVA™.”

Source: [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)

<a id="oregon-monograph-topic-8.4-3"></a>

#### Comparator

| Field | Quoted record |
| --- | --- |
| Intervention Model | “Single Group Assignment” |

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

<a id="oregon-monograph-topic-8.4-4"></a>

#### Participants

> “The open-label study met its goal of ensuring that a sufficient number of individuals have now been treated with ONS-5010 by enrolling 197 treatment-naïve and previously treated subjects with a range of retinal diseases for which an anti-VEGF drug is a therapeutic option, including wet age-related macular degeneration (wet AMD), diabetic macular edema (DME) and branch retinal vein occlusion (BRVO).”

Source: [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)

<a id="oregon-monograph-topic-8.4-5"></a>

#### Key inclusion criteria

> “Active clinical diagnosis and OCT confirmation of one of the following retinal disorders: exudative age-related macular degeneration (AMD), diabetic macular edema (DME), or branch retinal vein occlusion (BRVO) and, in the opinion of the Investigator, requires treatment with an anti-VEGF therapy”

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

<a id="oregon-monograph-topic-8.4-6"></a>

#### Key exclusion criteria

> “Previous use of approved anti-VEGF or Avastin® within 4 weeks preceding randomization”
> “History of inadequate response to previous intravitreal anti-VEGF therapy”
> “Active intraocular inflammation in the study eye”
> “Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)”

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

<a id="oregon-monograph-topic-8.4-7"></a>

#### Baseline disease severity and population characteristics

No evidence found.

<a id="oregon-monograph-topic-8.4-8"></a>

#### Setting

| Field | Quoted record |
| --- | --- |
| Country | “United States” |

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

<a id="oregon-monograph-topic-8.4-9"></a>

#### Endpoints

> “Number of Participants With Adverse Events”

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)

> “The safety endpoints for NORSE THREE were the frequency and incidence of treatment-emergent adverse events and an evaluation of changes in safety parameters.”

Source: [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)

<a id="oregon-monograph-topic-8.4-10"></a>

#### Magnitude of benefit and clinical relevance of results

Not applicable.

<a id="oregon-monograph-topic-8.4-11"></a>

#### Safety signals

> “In the study, 20 out of 197 patients (10%) experienced an adverse event in the study eye that were most commonly associated with the injection procedure and not ONS-5010. There were no serious adverse events associated with treatment. Notably, there were zero cases of ocular inflammation, a concern that has emerged for other anti-VEGF (Vascular Endothelial Growth Factor) therapies to treat retinal conditions.”

Source: [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)

<a id="oregon-monograph-topic-8.4-12"></a>

#### Subgroup analyses

No evidence found.

<a id="oregon-monograph-topic-8.4-13"></a>

#### Risk of bias

| Domain | Rating | Basis |
| --- | --- | --- |
| Selection bias | High | The study is single-arm, with no comparator group. |
| Performance bias | High | The registry records the study as open label. |
| Detection bias | High | Adverse events were assessed by investigators who knew every participant received Lytenava. |
| Attrition bias | Unclear | Participant disposition is not reported. |
| Reporting bias | High | Results are available only from a sponsor announcement, and the event-level adverse event table is unreported. |
| Other bias | High | The study was sponsored and reported by the manufacturer, and the attribution of adverse events to the injection procedure was made by the sponsor. |

<a id="oregon-monograph-topic-8.4-14"></a>

#### Applicability

| Element | Assessment |
| --- | --- |
| Patient | Mixed population with wet AMD, diabetic macular edema, or branch retinal vein occlusion, treatment-naive or previously treated; the share with wet AMD is not reported. |
| Intervention | Three monthly injections of Lytenava 1.25 mg, the start of the labeled regimen. |
| Comparator | None. |
| Outcomes | Adverse event incidence over 3 months only. |
| Setting | United States. |

<a id="oregon-monograph-topic-8.4-15"></a>

#### Evidence limitations

- The study is single-arm and open label, so its adverse event rate of 10% cannot be compared with any control (see 8.4).
- Exposure lasted 3 months, which says nothing about harms of continued monthly dosing (see 8.4).
- The population mixed three retinal diseases, so the rate is not specific to wet AMD (see 8.4).

<a id="oregon-monograph-heading-8.5"></a>

### 8.5 NORSE SEVEN

<a id="oregon-monograph-topic-8.5-1"></a>

#### Trial design and duration

> “A 3-month Study to Compare the Safety of ONS-5010 in Vials Versus PFS in Subjects With Visual Impairment Due to Retinal Disorders, NORSE SEVEN”

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

| Field | Quoted record |
| --- | --- |
| Allocation | “N/A” |
| Intervention Model | “Single Group Assignment” |
| Masking | “None (Open Label)” |
| Phase | “Phase 3” |
| Study Start Date | “2021-11-15” |
| Primary Completion Date | “2027-12” |
| Overall Status | “Active, not recruiting” |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-2"></a>

#### Intervention

| Field | Quoted record |
| --- | --- |
| Bevacizumab (ONS-5010) dose | “1.25 mg, intravitreal injection” |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-3"></a>

#### Comparator

| Field | Quoted record |
| --- | --- |
| Intervention Model | “Single Group Assignment” |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-4"></a>

#### Participants

| Field | Quoted record |
| --- | --- |
| Enrollment | “120” |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-5"></a>

#### Key inclusion criteria

> “Active clinical diagnosis and OCT confirmation of one of the following retinal disorders: exudative age-related macular degeneration (AMD), diabetic macular edema (DME), or branch retinal vein occlusion (BRVO) and, in the opinion of the Investigator, requires treatment with an anti-VEGF therapy”

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-6"></a>

#### Key exclusion criteria

> “Previous use of approved anti-VEGF or Avastin® within 4 weeks preceding randomization”
> “Previous use of Beovu®”
> “History of inadequate response to previous intravitreal anti-VEGF therapy”
> “Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)”

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-7"></a>

#### Baseline disease severity and population characteristics

No evidence found.

<a id="oregon-monograph-topic-8.5-8"></a>

#### Setting

| Field | Quoted record |
| --- | --- |
| Country | “United States” |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-9"></a>

#### Endpoints

> “Frequency and incidence of treatment-emergent adverse events following intravitreal injections of ONS-5010 in vials or PFS”

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

<a id="oregon-monograph-topic-8.5-10"></a>

#### Magnitude of benefit and clinical relevance of results

Not applicable.

<a id="oregon-monograph-topic-8.5-11"></a>

#### Safety signals

No evidence found.

<a id="oregon-monograph-topic-8.5-12"></a>

#### Subgroup analyses

No evidence found.

<a id="oregon-monograph-topic-8.5-13"></a>

#### Risk of bias

The study has reported no results, so only its design can be assessed.

| Domain | Rating | Basis |
| --- | --- | --- |
| Selection bias | High | The study is a single-group design with no control arm. |
| Performance bias | High | The registry records the study as open label. |
| Detection bias | High | Adverse events are assessed without masking. |
| Attrition bias | Unclear | No results are reported. |
| Reporting bias | Unclear | No results are reported. |
| Other bias | Unclear | No results are reported. |

<a id="oregon-monograph-topic-8.5-14"></a>

#### Applicability

| Element | Assessment |
| --- | --- |
| Patient | Mixed population with wet AMD, diabetic macular edema, or branch retinal vein occlusion. |
| Intervention | Lytenava 1.25 mg supplied in vials or in a prefilled syringe; the prefilled syringe is not an approved presentation. |
| Comparator | None. |
| Outcomes | Adverse event incidence only. |
| Setting | United States. |

<a id="oregon-monograph-topic-8.5-15"></a>

#### Evidence limitations

- The study is ongoing, with an estimated primary completion in 2027-12, and has reported no results (see 8.5).
- Its purpose is to compare two presentations of Lytenava, so it will add no comparative effectiveness evidence (see 8.5).

<a id="oregon-monograph-comparative-evidence-table"></a>

## 9 Comparative evidence table

<a id="oregon-monograph-topic-9-1"></a>

### Clinically meaningful endpoints

- Visual acuity gain: the proportion of participants gaining 15 or more ETDRS letters of best corrected visual acuity from baseline, the primary endpoint of NORSE TWO and NORSE ONE. (see 8.1, 8.3)
- Visual acuity change: the mean change from baseline in best corrected visual acuity in ETDRS letters, the primary endpoint of NORSE EIGHT, judged against a noninferiority margin of -3.5 letters, and a secondary endpoint of NORSE TWO. (see 8.1, 8.2)
- Vision loss and blindness: the proportion losing fewer than 15 letters and the proportion with a Snellen equivalent of 20/200 or worse, both secondary endpoints of NORSE TWO; untreated neovascular AMD progresses to disciform scarring and blindness. (see 6, 8.1)
- Treatment burden: repeated intravitreal injections and frequent clinic visits, often with caregiver support; no Lytenava trial reports treatment burden as an endpoint, and the NORSE TWO arms differed in dosing frequency by design. (see 6, 8.1)
- Serious adverse events: at least one serious treatment-emergent adverse event in 14 (12.4%) participants given Lytenava and 16 (13.9%) given ranibizumab in NORSE TWO, with one study-related serious ocular adverse event, elevated intraocular pressure. (see 8.1)
- Withdrawal due to adverse events: treatment-emergent adverse events leading to discontinuation in 2 (1.8%) participants given Lytenava and 5 (4.3%) given ranibizumab in NORSE TWO. (see 8.1)
- Ocular inflammation: NORSE EIGHT reported no case of retinal vasculitis in either arm. (see 8.2)

<a id="oregon-monograph-topic-9-2"></a>

### Primary study endpoints

- NORSE TWO: the proportion of participants who gained 15 or more BCVA letters from baseline to month 11, measured by ETDRS letter score. (see 8.1)
- NORSE EIGHT: the mean change from baseline in BCVA by ETDRS score at week 8, with a noninferiority margin of -3.5 letters. (see 8.2)
- NORSE ONE: the proportion of participants who gained 15 or more letters of BCVA, reported at month 11. (see 8.3)
- NORSE THREE: a safety study; the frequency and incidence of treatment-emergent adverse events and changes in safety parameters. (see 8.4)
- NORSE SEVEN: a safety study; the frequency and incidence of treatment-emergent adverse events after intravitreal injections from vials or prefilled syringes. (see 8.5)

<a id="oregon-monograph-topic-9-3"></a>

### Trials of Lytenava in neovascular age-related macular degeneration

| Reference and study design | Regimens and duration | Patient population | N | Efficacy endpoints | ARR/NNT | Safety outcomes | ARR/NNH |
| --- | --- | --- | --- | --- | --- | --- | --- |
| NORSE TWO; NCT03834753; Phase 3; a randomized, multi-center, masked, active-controlled study; Randomized; Parallel Assignment; Double (Participant, Outcomes Assessor) | 1. LYTENAVA 1.25 mg (N=113) administered once monthly for 1 year; 2. 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); Patients in the ranibizumab group underwent sham procedures during visits when they did not receive an active (ranibizumab) injection | Patient ages ranged from 54 to 98 years, with a median age of 79 years.; Female 67 (59.3%) and 69 (60.0%); White 110 (97.3%) and 113 (98.3%); Baseline BCVA 52.1 ± 12.16 and 51.1 ± 12.96; Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included.; Exclusion: previous use of intravitreal corticosteroids or anti-VEGFs (including Avastin) in the study eye; Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication) | ITT and safety: 1. 113; 2. 115; PP: 1. 85; 2. 78; Analyzed for the primary endpoint: 1. 108; 2. 104; 198 (86.8%) completed the study; Discontinued treatment and withdrew: 1. nine; 2. 20 | Primary: gained ≥ 15 BCVA letters from baseline to Month 11: 1. 45/108 (41.7); 2. 24/104 (23.1); risk difference 0.1859 (95% CI 0.0442, 0.3086); P = 0.0052; Secondary: change in BCVA from baseline to 11 months 1. 11.2 ± 12.19; 2. 5.8 ± 14.80 ETDRS letters; gaining ≥10 letters 1. 61/108 (56.5); 2. 36/104 (34.6); losing <15 letters 1. 101/108 (93.5); 2. 86/104 (82.7); 20/200 or worse 1. 14/108 (13.0); 2. 25/104 (24.0); P = 0.0505 | 18.6%/6 | TEAE leading to discontinuation 1. 2 (1.8%); 2. 5 (4.3%); TEAE related to study drug/study procedure 1. 21 (18.6%); 2. 9 (7.8%); serious TEAE 1. 14 (12.4%); 2. 16 (13.9%); one study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure | 10.8%/10 (related TEAE) |

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf); [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753); [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)

Abbreviations: ARR = absolute risk reduction, or for a harm the absolute risk increase; BCVA = best corrected visual acuity; CI = confidence interval; ETDRS = Early Treatment Diabetic Retinopathy Study; ITT = intent-to-treat; mg = milligram; mmHg = millimeters of mercury; N = number of participants; nAMD = neovascular age-related macular degeneration; NNH = number needed to harm; NNT = number needed to treat; P = probability value; PP = per-protocol; SAE = serious adverse event; TEAE = treatment-emergent adverse event; VEGF = vascular endothelial growth factor

| Reference and study design | Regimens and duration | Patient population | N | Efficacy endpoints | ARR/NNT | Safety outcomes | ARR/NNH |
| --- | --- | --- | --- | --- | --- | --- | --- |
| NORSE EIGHT; NCT06190093; Phase 3; a multicenter, randomized, masked, controlled study; Parallel Assignment; Triple (Participant, Investigator, Outcomes Assessor) | 1. LYTENAVA 1.25 mg; 2. ranibizumab 0.5 mg; administered every 4 weeks for 3 total doses (Day 0, Week 4, and Week 8); final study visit at week 12 | newly diagnosed, wet AMD subjects; Best corrected visual acuity of 35-75 letters read (20/32 to 20/200 Snellen equivalent); Mean BCVA at baseline was 58.8 ETDRS letters for the ONS-5010 group and 59.9 letters for the ranibizumab group.; Exclusion: Polypoidal choroidal vasculopathy (PCV) in the study eye; Uncontrolled glaucoma in the study eye | 400 adult patients with nAMD were randomized (1:1) | Primary: mean change in BCVA at Week 8, NI margin of -3.5 letters: 1. 3.3; 2. 4.5; LS mean difference -2.3 (-4.0, -0.5); did not meet its pre-specified NI margin; Week 12 (secondary timepoint): difference -1.009 letters (95% confidence interval, -2.865, 0.848), p=0.0043; central retinal thickness 1. -123.9 microns; 2. -127.3 microns | NA | conjunctival hemorrhage, which occurred in 5 (2.5%) participants in each group; no cases of retinal vasculitis reported in either study arm | NA |

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf); [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093); [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)

Abbreviations: AMD = age-related macular degeneration; BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; LS = least squares; mg = milligram; NA = not applicable; nAMD = neovascular age-related macular degeneration; NI = non-inferiority; p = probability value; PCV = polypoidal choroidal vasculopathy

| Reference and study design | Regimens and duration | Patient population | N | Efficacy endpoints | ARR/NNT | Safety outcomes | ARR/NNH |
| --- | --- | --- | --- | --- | --- | --- | --- |
| NORSE ONE; NCT03844074; Phase 3; Randomized; Parallel Assignment; Double (Participant, Outcomes Assessor) | 1. ONS-5010 1.25 mg, dosed monthly; 2. ranibizumab 0.5 mg, dosed using the PIER alternative dosing regimen of three monthly doses followed by quarterly dosing; Month 11 | 61 treatment-naïve and previously treated patients diagnosed with wet AMD at nine sites in Australia; Best corrected visual acuity of 20/40 to 20/320; Exclusion: Previous use of anti-VEGF or bevacizumab within 6 weeks | 61 enrolled; reported 1. 25; 2. 23 | Primary: > 15 letters BCVA at Month 11: 1. 2 of 25 (8%); 2. 5 of 23 (22%); treatment-naïve subjects 1. 2 of 6 (33%); 2. 4 of 13 (31%) | NA | no statistical differences in safety; zero cases of ocular inflammation | NA |

Source: [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074); [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)

Abbreviations: AMD = age-related macular degeneration; BCVA = best corrected visual acuity; mg = milligram; NA = not applicable; PIER = the ranibizumab dosing regimen of the PIER study; VEGF = vascular endothelial growth factor

| Reference and study design | Regimens and duration | Patient population | N | Efficacy endpoints | ARR/NNT | Safety outcomes | ARR/NNH |
| --- | --- | --- | --- | --- | --- | --- | --- |
| NORSE THREE; NCT04516278; Phase 3; Single Group Assignment; None (Open Label) | ONS-5010 1.25 mg, intravitreal injection; three monthly intravitreal doses | treatment-naïve and previously treated subjects with a range of retinal diseases, including wet AMD, DME and BRVO; Exclusion: History of inadequate response to previous intravitreal anti-VEGF therapy; Active intraocular inflammation in the study eye | 197 | NA | NA | 20 out of 197 patients (10%) experienced an adverse event in the study eye; There were no serious adverse events associated with treatment.; zero cases of ocular inflammation | NA |

Source: [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278); [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)

Abbreviations: AMD = age-related macular degeneration; BRVO = branch retinal vein occlusion; DME = diabetic macular edema; mg = milligram; NA = not applicable; VEGF = vascular endothelial growth factor

| Reference and study design | Regimens and duration | Patient population | N | Efficacy endpoints | ARR/NNT | Safety outcomes | ARR/NNH |
| --- | --- | --- | --- | --- | --- | --- | --- |
| NORSE SEVEN; NCT05112861; Phase 3; Single Group Assignment; None (Open Label); Active, not recruiting | ONS-5010 1.25 mg, intravitreal injection, in vials or PFS; 3-month study | exudative age-related macular degeneration (AMD), diabetic macular edema (DME), or branch retinal vein occlusion (BRVO); Exclusion: Previous use of Beovu®; History of inadequate response to previous intravitreal anti-VEGF therapy | 120 | NA | NA | NR | NA |

Source: [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)

Abbreviations: AMD = age-related macular degeneration; BRVO = branch retinal vein occlusion; DME = diabetic macular edema; mg = milligram; NA = not applicable; NR = not reported; PFS = prefilled syringe; VEGF = vascular endothelial growth factor

<a id="oregon-monograph-adverse-events"></a>

## 10 Adverse events

<a id="oregon-monograph-topic-10-1"></a>

### Most common ocular adverse reactions across five clinical trials, as listed in the prescribing information

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

Source: [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)

Abbreviations: mg = milligram; N = number of participants in the population

<a id="oregon-monograph-prior-authorization-criteria"></a>

## 11 Prior authorization criteria

<a id="oregon-monograph-heading-11.1"></a>

### 11.1 Goal

<a id="oregon-monograph-topic-11.1-1"></a>

#### Goal

- To set out the clinical conditions under which Lytenava is authorized for neovascular (wet) age-related macular degeneration, in line with the labeling. (see 7.3, 7.4)
- To confine use to the labeled dose and to the population in which the trials observed an effect. (see 7.3, 8.1)

<a id="oregon-monograph-heading-11.2"></a>

### 11.2 Length of authorization

<a id="oregon-monograph-topic-11.2-1"></a>

#### Length of authorization

- Initial authorization covers 12 months, the duration of monthly treatment studied in NORSE TWO. (see 8.1)
- Renewal covers 12 months at a time. (see 8.1)

<a id="oregon-monograph-heading-11.3"></a>

### 11.3 Approval criteria

<a id="oregon-monograph-topic-11.3-1"></a>

#### Approval criteria

| # | Question | If yes | If no |
| --- | --- | --- | --- |
| 1 | What diagnosis is being treated? | Record the diagnosis code. | |
| 2 | Is this a renewal of a previous approval? | Go to renewal criteria. | Go to 3. |
| 3 | Is the request for neovascular (wet) age-related macular degeneration? (see 7.4) | Go to 4. | Does not meet criteria. |
| 4 | Is the patient 18 years of age or older? (see 7.3) | Go to 5. | Does not meet criteria. |
| 5 | Is the product administered by a qualified physician, such as an ophthalmologist or a retina specialist? (see 7.3) | Go to 6. | Does not meet criteria. |
| 6 | Is active choroidal neovascularization documented in the eye to be treated, by fluorescein angiography or optical coherence tomography? (see 6, 8.1) | Go to 7. | Does not meet criteria. |
| 7 | Is the eye to be treated free of ocular or periocular infection and of active intraocular inflammation, with no known hypersensitivity to bevacizumab products? (see 7.3) | Go to 8. | Does not meet criteria. |
| 8 | Is the requested dose 1.25 mg by intravitreal injection once monthly (approximately every 28 days), with one vial per treated eye per injection? (see 7.3) | Go to 9. | Does not meet criteria. |
| 9 | Is the patient receiving no other intravitreal VEGF inhibitor in the same eye? (see 8.1) | Go to 10. | Does not meet criteria. |
| 10 | Is there a documented plan to monitor intraocular pressure before and 30 minutes after each injection? (see 7.3) | Approve for 12 months. | Does not meet criteria. |

<a id="oregon-monograph-topic-11.3-2"></a>

#### Criteria not written

- No criterion sets a visual acuity range, because the two randomized trials enrolled different ranges, 25 to 67 letters and 35 to 75 letters, and the labeling sets none. (see 8.1, 8.2)
- No criterion requires the patient to be treatment-naive. NORSE TWO enrolled treatment-naive participants, but the labeling does not restrict the indication, and NORSE ONE enrolled previously treated participants. (see 8.1, 8.3)
- No criterion requires a trial of another VEGF inhibitor first. Whether to require one is a coverage decision for the plan, and no quote in this document supports a clinical requirement.

<a id="oregon-monograph-heading-11.4"></a>

### 11.4 Renewal criteria

<a id="oregon-monograph-topic-11.4-1"></a>

#### Renewal criteria

| # | Question | If yes | If no |
| --- | --- | --- | --- |
| 1 | Is the request to continue Lytenava for neovascular (wet) age-related macular degeneration? | Go to 2. | Does not meet criteria. |
| 2 | Is there documentation that visual acuity in the treated eye has been maintained, with a loss of fewer than 15 ETDRS letters from baseline, or improved? (see 8.1) | Go to 3. | Does not meet criteria. Refer to the prescriber for review of the treatment plan. |
| 3 | Is intraocular pressure monitoring before and after each injection documented, with no ocular infection or active intraocular inflammation in the treated eye? (see 7.3) | Approve for 12 months. | Does not meet criteria. |

<a id="oregon-monograph-references"></a>

## 12 References

1. [Armendariz et al. (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11584703/)
2. [BrightFocus Foundation](https://www.brightfocus.org/macular/facts-figures/)
3. [CATT Research Group (2011)](https://pmc.ncbi.nlm.nih.gov/articles/PMC3157322/)
4. [ClinicalTrials.gov NCT03834753](https://clinicaltrials.gov/study/NCT03834753)
5. [ClinicalTrials.gov NCT03844074](https://clinicaltrials.gov/study/NCT03844074)
6. [ClinicalTrials.gov NCT04516278](https://clinicaltrials.gov/study/NCT04516278)
7. [ClinicalTrials.gov NCT05112861](https://clinicaltrials.gov/study/NCT05112861)
8. [ClinicalTrials.gov NCT06190093](https://clinicaltrials.gov/study/NCT06190093)
9. [Edison et al. (2015)](https://pmc.ncbi.nlm.nih.gov/articles/PMC4285274/)
10. [Eyewire+ (2026)](https://eyewire.news/news/fda-approves-outlook-therapeutics-lytenava-as-first-ophthalmic-bevacizumab-for-wet-amd)
11. [FDA (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/761320Orig1s000ltr.pdf)
12. [Korva-Gurung et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10262804/)
13. [Lombardo et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12532941/)
14. [Lucenteforte et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12805632/)
15. [Lytenava prescribing information (2026)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761320s000lbl.pdf)
16. [National Eye Institute](https://www.nei.nih.gov/eye-health-information/eye-conditions-and-diseases/age-related-macular-degeneration)
17. [Outlook Therapeutics FDA acceptance announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926074346/tm2618010d1_ex99-1.htm)
18. [Outlook Therapeutics FDA approval announcement (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926086685/tm2621316d1_ex99-1.htm)
19. [Outlook Therapeutics Form 10-Q (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926098415/otlk-20260630x10q.htm)
20. [Outlook Therapeutics Form 8-K (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926108952/tm2625694d1_8k.htm)
21. [Outlook Therapeutics NORSE EIGHT complete twelve-week results press release (2025)](https://www.globenewswire.com/news-release/2025/01/16/3010622/0/en/Outlook-Therapeutics-Announces-Complete-Twelve-Week-Efficacy-and-Safety-Results-of-NORSE-EIGHT-Clinical-Trial.html)
22. [Outlook Therapeutics NORSE EIGHT preliminary topline results press release (2024)](https://www.sec.gov/Archives/edgar/data/1649989/000110465924123554/tm2429443d1_ex99-1.htm)
23. [Outlook Therapeutics NORSE EIGHT presentation press release (2025)](https://www.biospace.com/press-releases/outlook-therapeutics-announces-presentation-of-efficacy-and-safety-results-from-norse-eight-clinical-trial-evaluating-ons-5010-for-the-treatment-of-wet-amd)
24. [Outlook Therapeutics NORSE ONE topline results press release (2020)](https://www.globenewswire.com/news-release/2020/08/26/2084007/0/en/Outlook-Therapeutics-Reports-Topline-Results-and-Positive-Proof-of-Concept-for-ONS-5010-LYTENAVA-bevacizumab-vikg-from-NORSE-1.html)
25. [Outlook Therapeutics NORSE THREE safety results press release (2021)](https://www.globenewswire.com/news-release/2021/03/31/2202384/0/en/Outlook-Therapeutics-Reports-Positive-Safety-Profile-from-NORSE-THREE-Open-Label-Safety-Study-for-ONS-5010-LYTENAVA-bevacizumab-vikg.html)
26. [Outlook Therapeutics regulatory update (2023)](https://www.sec.gov/Archives/edgar/data/1649989/000110465923096669/tm2325118d1_ex99-1.htm)
27. [Outlook Therapeutics third quarter fiscal year 2026 results (2026)](https://www.sec.gov/Archives/edgar/data/1649989/000110465926096478/tm2622399d3_ex99-1.htm)
28. [Pugazhendhi et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7866170/)
29. [Rahhal et al. (2025)](https://pubmed.ncbi.nlm.nih.gov/39535413/)
30. [Reitan et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10226541/)
31. [Singh et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12705084/)

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