Outlook Therapeutics has received a third complete response letter (CRL) from the FDA regarding its biologics license application (BLA) resubmission for ONS-5010/Lytenava (bevacizumab-vikg) for the treatment of wet age-related macular degeneration (AMD).

In the CRL, the FDA indicated that the additional mechanistic and natural history data included in the resubmission did not change the agency’s prior conclusion. While the FDA acknowledged that one adequate and well-controlled clinical study demonstrated efficacy, it again recommended that confirmatory evidence of efficacy be submitted to support approval. The agency did not specify what type of confirmatory evidence would be acceptable.

In August 2023, the FDA issued its first CRL to Outlook for ONS-5010, citing at the time "several CMC issues, open observations from preapproval manufacturing inspections, and a lack of substantial evidence." In August 2025, the FDA issued another CRL to the company for its BLA resubmission. In that CRL, the FDA said it could not approve the application in its present form, citing a lack of substantial evidence of effectiveness. The FDA advised 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 CRL was issued despite NORSE TWO meeting its primary endpoint for effectiveness.

“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,” said Bob Jahr, Chief Executive Officer of Outlook Therapeutics. “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. 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 based on the complete data set from the NORSE clinical trial program. This included the NORSE TWO pivotal phase 3 trial, which the company described as an adequate and well-controlled study demonstrating efficacy, as well as confirmatory safety and efficacy data from additional NORSE trials. Among these was NORSE EIGHT, an adequate and well-controlled noninferiority study comparing ONS-5010 with ranibizumab in treatment-naïve wet AMD patients, with a primary efficacy endpoint at 8 weeks.

Outlook said it continues to believe that the totality of data from NORSE TWO, combined with results from the other NORSE studies, provides sufficient evidence to support approval of the ONS-5010 BLA in the United States.

The company is now exploring all available regulatory pathways for potential US approval, while continuing to advance its commercial expansion strategy outside the US. As previously announced, Lytenava (bevacizumab gamma) has received Marketing Authorization from the European Commission in the European Union and from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom for the treatment of wet AMD.

In June 2025, Lytenava became commercially available in Germany and the UK. Outlook said it plans to expand its commercial presence in additional European countries and continues to explore potential collaborations with commercial and distribution partners both within and beyond Europe. Lytenava is the first and only authorized ophthalmic formulation of bevacizumab for the treatment of wet AMD in adults in the EU and UK.