FDA issues complete response letter to Outlook Therapeutics for resubmitted BLA for ONS-5010

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) to Outlook Therapeutics’ biologics license application (BLA) resubmission for ONS-5010 (bevacizumab-vikg) for the treatment of wet age-related macular degeneration (AMD).

The recent CRL included only 1 deficiency, for a lack of substantial evidence of effectiveness.¹ According to Outlook, the FDA advised in the CRL that, because ONS-5010 did not meet the primary efficacy endpoint in NORSE EIGHT, it is recommended that confirmatory evidence of efficacy be submitted to support the application for ONS-5010. The pre-specified non-inferiority endpoint at week 8 was set forth in the special protocol assessment (SPA) with the FDA at the end of 2023.

The company previously resubmitted the BLA in February 2025, and the FDA accepted the resubmission in April 2025.² The BLA resubmission was based on the efficacy and safety demonstrated in the NORSE EIGHT clinical trial, as well as additional CMC information requested by the FDA. During a Type A meeting with the FDA, the organization informed Outlook it could conduct a noninferiority study evaluating ONS-5010 vs ranibizumab in a 12-week study of treatment-naive patients with a primary efficacy end point at 8 weeks (NORSE EIGHT).

Outlook was previously issued a CRL from the FDA in August 2023.³ For the 2023 submission, it was noted that the FDA “could not approve the BLA during the review cycle due to several CMC issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.”

After the CRL in 2023, Outlook Therapeutics stock underwent a 1-for-20 reverse stock split as “part of the Company’s plan to regain compliance with the minimum bid price ($4 per share) requirement for continued listing on the Nasdaq Capital Market.”

Bob Jahr, CEO of Outlook Therapeutics, commented on the CRL in a press release from the company.

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

The company plans to request a meeting with the FDA to explore pathways for potential approval in the US. Additionally, the company stated its intention to continue its efforts to expand into additional markets in Europe.

In March 2024, the European Medicines Agency (EMA) issued a positive Committee for Medicinal Products for Human Use (CHMP) opinion on ONS-5010. In June 2025, LYTENAVA (bevacizumab gamma) became commercially available in Germany and the UK for the treatment of wet AMD.⁴

NORSE Trials

Results across the first 3 NORSE trials demonstrated a strong benefit-to-risk safety profile, with only one ocular inflammation adverse event across all three registration trials. The most common adverse reaction (≥ 5%) reported in patients receiving bevacizumab-vikg was conjunctival hemorrhage associated with the needle injection procedure (5%).

NORSE ONE was a clinical experience trial involving 61 wet AMD participants at nine trial sites in Australia, and compared bevacizumab-vikg to ranibizumab (LUCENTIS) as a treatment for wet AMD. Bevacizumab-vikg efficacy and safety data were consistent with historical published studies of bevacizumab in ophthalmology.

In the NORSE TWO Phase 3 pivotal trial, investigators enrolled a total of 228 wet AMD patients at 39 sites in the US. It was designed as a superiority study comparing the safety and efficacy of bevacizumab-vikg ophthalmic bevacizumab dosed monthly against ranibizumab, dosed according to the regimen described in the Lucentis label. The data met both the primary and secondary endpoints with high statistical significance and clinical relevance.

NORSE THREE was an open-label safety study of bevacizumab-vikg in 197 patients conducted in the US to provide the necessary number of retina patients dosed with bevacizumab-vikg 5010 to complete the safety requirements for submitting a biologics license application.

NORSE EIGHT was a randomized, controlled, parallel-group, masked, non-inferiority study of approximately 400 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.

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

2. Harp MD. FDA accepts biologics license application from Outlook Therapeutics for ONS-5010 for the treatment of wet AMD. Published April 9, 2025. Accessed August 28, 2025. https://www.ophthalmologytimes.com/view/fda-accepts-biologics-license-application-from-outlook-therapeutics-for-ons-5010-for-the-treatment-of-wet-amd

3. Hutton D. FDA issues CRL for Outlook Therapeutics’ ONS-5010. Published August 30, 2025. Accessed August 28, 2025. https://www.ophthalmologytimes.com/view/fda-issues-crl-for-outlook-therapeutics-ons-5010

4. Harp MD. Outlook Therapeutics stock undergoes 1-for-20 reverse stock split. Published March 14, 2024. Accessed August 28, 2025. https://www.ophthalmologytimes.com/view/outlook-therapeutics-stock-undergoes-1-for-20-reverse-stock-split