FDA Issues CRL to Outlook Therapeutics' ONS-5010 for the Treatment of Wet AMD

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Outlook Therapeutics' Biologics License Application (BLA) for ONS-5010, in development for the treatment of wet age-related macular degeneration (AMD).1

Announced by Outlook Therapeutics on August 29, 2025, the CRL cited ONS-5010's failure to achieve the primary efficacy endpoint in the phase 3 NORSE EIGHT trial. This was described as a lack of substantial evidence of effectiveness. The FDA suggested that confirmatory evidence of efficacy be submitted to support the next application. The FDA did, however, reiterate the achievement of NORSE TWO's primary effectiveness endpoint.1

"While we are very disappointed with this outcome, we intend to meet with the FDA to receive additional clarity on their requirements to potentially approve the first on-label bevacizumab product specifically formulated, manufactured, and packaged for intravitreal use in the United States," Bob Jahr, chief executive officer of Outlook Therapeutics, said in a press release.1

ONS-5010 is an ophthalmic formulation of bevacizumab for the treatment of wet AMD. Bevacizumab is a recombinant humanized monoclonal antibody which 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 formulation in the retina.2

Notably, ONS-5010 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.2

ONS-5010 has had a long regulatory road in the US, having received a CRL from the FDA in August of 2023 after their first 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

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.2

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 12.4

ONS-5010 did not, however, meet its primary efficacy 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.4

Outlook Therapeutics has requested a meeting with the FDA to explore further pathways for potential US approval. Additionally, the company has expressed intentions to expand into additional European markets.1

"We remain committed to providing patients with a safe and effective alternative to compound Avastin manufactured in the United States," Jahr said. "It is important to also note that the CRL identified no other outstanding deficiencies in our BLA."1

References

1. Outlook Therapeutics. 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. August 28, 2025. Accessed August 29, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-provides-regulatory-update-us-food-and-drug

2. 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 August 25, 2025. https://ir.oncobiologics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-acceptance-biologics-license-0

3. Campbell P. FDA Issues CRL for Ophthalmic Bevacizumab in Wet AMD. HCPLive. August 30, 2023. Accessed August 25, 2025. https://www.hcplive.com/view/fda-issues-crl-for-ophthalmic-bevacizumab-in-wet-amd

4. Harp M. Outlook Therapeutics completes analysis of 12-week safety and efficacy results of NORSE EIGHT. Ophth Times. January 16, 2025. Accessed August 25, 2025. https://www.ophthalmologytimes.com/view/outlook-therapeutics-completes-analysis-of-12-week-safety-and-efficacy-results-of-norse-eight