FDA Issues Complete Response Letter for ONS-5010 for Wet AMD

Announced by Outlook Therapeutics on December 31, 2025, the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to ONS-5010 for the treatment of wet age-related macular degeneration (AMD).1

In the CRL, the FDA determined that the additional mechanistic and natural history data provided in the resubmission failed to alter the previous review conclusion, which stated that confirmatory evidence of efficacy must be submitted to support the application. According to the release, the FDA has not yet indicated what type of confirmatory evidence would be acceptable.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," Bob Jahr, chief executive officer of Outlook Therapeutics, said in a statement. "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."1

ONS-5010 is an ophthalmic formulation of bevacizumab for the treatment of wet AMD. Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to all isoforms of human vascular endothelial growth factor (VEGF) with high affinity, neutralizing VEGF’s biologic activity through a steric blocking of its binding to its receptors on endothelial cells. This reduces endothelial cell proliferation, vascular leakage, and new blood vessel formation in the retina.2

ONS-5010 has previously received regulatory approval in the European Union and the United Kingdom in 2024 for the first authorized use of an ophthalmic formulation of bevacizumab for the treatment of wet AMD.3

ONS-5010 has had a long regulatory road in the US, having received a Complete Response Letter from the FDA in August of 2023 after their first Biologics License Application (BLA). At the time, despite the pivotal NORSE TWO trial achieving its safety and efficacy endpoints, the FDA concluded it was unable to approve the BLA on account of several Chemistry Manufacturing and Controls (CMC) issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.3,4

On April 8, 2025, Outlook Therapeutics announced the FDA’s acceptance of a new BLA, which allows ONS-5010 – under the brand name LYTENAVA – 12 years of regulatory exclusivity after regulatory approval. This resubmission was based on the NORSE EIGHT trial results, as well as the additional CMC data requested by the FDA.3

On August 28, 2025, however, the FDA issued another CRL, citing a lack of substantial evidence of effectiveness. Outlook Therapeutics conducted a Type A meeting, after which a third BLA was submitted on November 3, 2025. The submission contains the same data from NORSE TWO and NORSE EIGHT, as well as a response to the CRL crafted from the official minutes of the Type A meeting.5

NORSE EIGHT was a randomized, controlled, parallel group, masked, non-inferiority study investigating the difference in best-corrected visual acuity (BCVA) and retinal thickness between ONS-5010 and ranibizumab. After analysis, investigators announced on January 16, 2025, that ONS-5010 demonstrated noninferiority to ranibizumab at week 12.6

ONS-5010 did not, however, meet its primary non-inferiority endpoint by week 8, as suggested in the special protocol assessment with the FDA. Investigators did note the consistent BCVA improvement across all time points, the generally good tolerability, and the safety and efficacy results compared to NORSE ONE, NORSE TWO, and NORSE THREE.6

According to the press release, Outlook Therapeutics continues to explore all available pathways for approval while expanding into additional markets in Europe, where it has already received several regulatory approvals.1

"Our goal has always been to provide wet AMD patients and their physicians with a safe, consistent, FDA-approved alternative to compounded Avastin manufactured in the United States, and that goal has not changed," Jahr said.1

References

1. Outlook Therapeutics. Outlook Therapeutics Provides Regulatory Update on US Food and Drug Administration Review of ONS-5010/LYTENAVA (bevacizumab-vikg) for the Treatment of Wet AMD. 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. Outlook Therapeutics Announces Acceptance of Biologics License Application by US FDA for ONS-5010 as a Treatment for Wet AMD. November 13, 2025. Accessed December 24, 2025. https://ir.oncobiologics.com/news-releases/news-release-details/outlook-therapeutics-announces-acceptance-biologics-license

3. Outlook Therapeutics. Outlook Therapeutics Announces Acceptance of Biologics License Application by U.S. FDA for ONS-5010 as a Treatment for Wet AMD. April 8, 2025. Accessed December 24, 2025. https://ir.oncobiologics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-acceptance-biologics-license-0

4. Campbell P. FDA Issues CRL for Ophthalmic Bevacizumab in Wet AMD. HCPLive. August 30, 2023. Accessed December 24, 2025. https://www.hcplive.com/view/fda-issues-crl-for-ophthalmic-bevacizumab-in-wet-amd

5. Outlook Therapeutics. Outlook Therapeutics Re-Submits Biologics License Application for ONS-5010. November 3, 2025. Accessed December 24, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-re-submits-biologics-license-application

6. Harp M. Outlook Therapeutics completes analysis of 12-week safety and efficacy results of NORSE EIGHT. Ophth Times. January 16, 2025. Accessed December 24, 2025. https://www.ophthalmologytimes.com/view/outlook-therapeutics-completes-analysis-of-12-week-safety-and-efficacy-results-of-norse-eight