FDA update: Outlook Therapeutics receives CRL for resubmitted ONS-5010 BLA | Ophthalmology Times

Outlook Therapeutics, Inc. reported that the FDA has issued a complete response letter (CRL) concerning the resubmitted biologics license application (BLA) for ONS-5010/LYTENAVA (bevacizumab-vikg).^1,2 The letter noted that the agency cannot approve the application in its current form for the treatment of wet age-related macular degeneration (wet AMD).¹

The FDA stated in the CRL that the additional mechanistic and natural history data included in the BLA resubmission did not change its prior review conclusion, according to Outlook Therapeutics.¹ Although the single adequate and well-controlled study demonstrated efficacy, the FDA again recommended that confirmatory evidence of efficacy be submitted to support the application, without indicating what type of confirmatory evidence would be acceptable.¹

“Our goal has always been to provide [patients with] wet AMD and their physicians with a safe, consistent, FDA-approved alternative to compounded Avastin manufactured in the United States, and that goal has not changed,” said Bob Jahr, chief executive officer of Outlook Therapeutics in a prepared statement.¹

“We are disappointed and disagree with this decision, but we remain fully committed to taking all necessary steps to receive approval in the United States,” Jahr continued. “We continue to believe strongly in the clinical need and commercial potential of the first on-label bevacizumab product for patients in the United States that is specifically formulated, manufactured, and packaged for intravitreal use.”

The BLA resubmission for ONS-5010 was supported by the full data set from the NORSE clinical trial program, including the NORSE TWO adequate and well-controlled pivotal trial, along with confirmatory safety and efficacy data from the other NORSE studies.¹ These included NORSE EIGHT, an adequate and well-controlled noninferiority trial comparing ONS-5010 with ranibizumab in a 12-week study of treatment-naïve patients, with a primary efficacy end point at 8 weeks.¹ The company maintains that the complete NORSE TWO data, together with results from the other NORSE trials, provides sufficient evidence to support approval of the ONS-5010 BLA in the United States.¹

Outlook Therapeutics has received 3 CRLs from the FDA for its ONS-5010/Lytenava application for wet AMD. The timeline of the CRLs is as follows:

• First CRL: Issued in August 2023. This was due to Chemistry, Manufacturing, and Controls (CMC) issues, open observations from manufacturing inspections, and a lack of substantial evidence, according to the company.⁵
• Second CRL: Issued in August 2025. This letter cited a lack of substantial evidence of effectiveness and recommended more confirmatory efficacy data, according to the company.^3,4
• Third CRL: Issued on December 31, 2025, for the subsequent Biologics License Application (BLA) resubmission. The FDA stated that the additional data provided did not alter its previous conclusion that confirmatory evidence of efficacy is needed.¹

The company notes it is evaluating all available pathways toward potential approval in the US and plans to continue pursuing expansion into additional markets in Europe and other regions.¹ LYTENAVA (bevacizumab gamma) has received marketing authorization from the European Commission in the EU and from the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK for the treatment of wet AMD.¹ In June 2025, LYTENAVA became commercially available in Germany and the UK for wet AMD. LYTENAVA is the first and only authorized ophthalmic formulation of bevacizumab approved for the treatment of wet AMD in adults in the European Union and the UK.¹

The Eye Care Network conducted a brief Q&A with David A. Eichenbaum, MD, FASRS, director of research at Retina Vitreous Associates of Florida, in Tampa, for his perspective on what the latest FDA update might mean.

Given the resubmission is considered a complete Class 1 response following a prior CRL, what data or comparability issues might the FDA have identified that might have impacted approval?

David A. Eichenbaum, MD, FASRS: The FDA may must not believe that the compendium of the data is compelling enough to certify the efficacy and safety of ONS-5010.This is probably related to NORSE EIGHT failing its noninferiority end point compared [with] ranibizumab in 2024, or perhaps the resubmission of Chemistry, Manufacturing, and Controls (CMC) data not compelling the FDA to reconsider the reasons for its CRL in 2023.

How does non-approval affect retina specialists’ current use of off-label bevacizumab, and what would it mean for patient management and treatment standardization in wet AMD?

Eichenbaum: Non-approval will not affect current treatment patterns with off-label bevacizumab. Bevacizumab has entrenched prescribing patterns with 20 years of use, a reasonably stable and improved supply chain, and decreasing safety issues over time.

What additional clinical data, end points, or studies might be needed to support a future submission, and how might this influence the strategy for other ophthalmic formulations of bevacizumab?

Eichenbaum: The Outlook [Therapeutics] experience and the circuitous path to this most recent rejection makes it unlikely that ONS-5010 will be approved in the US. Outlook [Therapeutics] would probably need to repeat at least one well-designed trial like NORSE EIGHT but achieve a positive outcome to merit FDA approval. Given Outlook’s experience, it is unlikely that other manufacturers will pursue an ophthalmic formulation of bevacizumab.

References

1. Outlook Therapeutics provides regulatory update on U.S. Food and Drug Administration review of ONS-5010/LYTENAVA (bevacizumab-vikg) for the treatment of wet AMD. News release. December 31, 2025. Accessed December 31, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-provides-regulatory-update-us-food-and-0

2. Outlook Therapeutics announces acceptance of Biologics License Application by U.S. FDA for ONS-5010 as a treatment for wet AMD. News release. November 13, 2025. Accessed November 13, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-announces-acceptance-biologics-license

3. Harp MD. FDA issues complete response letter to Outlook Therapeutics for resubmitted BLA for ONS-5010. Ophthalmology Times. August 28, 2025. Accessed November 13, 2025. https://www.ophthalmologytimes.com/view/fda-issues-complete-response-letter-to-outlook-therapeutics-for-resubmitted-bla-for-ons-5010

4. Outlook Therapeutics requests Type A meeting with FDA following second CRL for ONS-5010. Ophthalmology Times. September 3, 2025. Accessed November 13, 2025. https://www.ophthalmologytimes.com/view/outlook-therapeutics-requests-type-a-meeting-with-fda-following-second-crl-for-ons-5010

5. Hutton D. FDA issues CRL for Outlook Therapeutics’ ONS-5010. Ophthalmology Times. August 30, 2023. Accessed November 13, 2025. https://www.ophthalmologytimes.com/view/fda-issues-crl-for-outlook-therapeutics-ons-5010