Outlook Therapeutics has resubmitted its Biologics License Application (BLA) to the US Food and Drug Administration (FDA) for ONS-5010 (LYTENAVA) for the treatment of neovascular age-related macular degeneration (nAMD). Recently, the FDA granted Outlook’s appeal following completion of the Formal Dispute Resolution (FDR) process with the Office of New Drugs (OND).
The appeal reverses the trajectory set by a Complete Response Letter (CRL) issued on December 30, 2025, to Outlook. In the CRL issued at the end of 2025, the FDA noted that the additional mechanistic and natural history data included in the BLA resubmission did not change its prior review conclusion. The prior review mentioned was a CRL issued in August 2025—the second of three. In the CRL, the FDA noted a “lack of substantial evidence of effectiveness” and advised that because LYTENAVA did not meet the primary efficacy endpoint in NORSE EIGHT (NCT06190093), confirmatory evidence of efficacy should be submitted to support the application for LYTENAVA.
Outlook's path to FDA approval
- March 2022—Outlook submits first BLA to the FDA
- May 2022—FDA requests additional information to complete BLA / Outlook voluntarily withdraws BLA
- August 2022—Outlook resubmits first BLA to the FDA
- October 2022—FDA accepts first BLA from Outlook for LYTEVANA
- August 2023—FDA issues first CRL for LYTEVANA
- September 2023—Outlook request Type A meeting with FDA
- November 2023—Outlook completes Type A meeting with FDA
- December 2023—Outlook submits Special Protocol Assessment (SPA) for “required additional adequate and well-controlled study of LYTEVANA
- January 2024—Outlook recieves agreement from FDA to start NORSE EIGHT under SPA and doses first patient
- March 2024—Outlook receives European Union Positive CHMP Opinion for LYTEVANA
- May 2024—Outlook submits UK Marketing Authorization Application (MAA) / receives European Commission Marketing Authorization for LYTENAVA
- July 2024—Outlook receives UK MHRA marketing authorization for LYTEVANA
- September 2024—Outlook completes enrollment in NORSE EIGHT
- January 2025—Outlook releases 12-week efficacy and safety results from NORSE EIGHT
- February 2025—Outlook submits second BLA to FDA
- April 2025—FDA accepts second BLA
- August 2025—FDA issues second CRL to Outlook
- September 2025—Outlook requests second Type A meeting / provides update
- November 2025—Outlook submits third BLA to FDA
- December 2025—FDA issues third CRL to Outlook
- February 2026—Outlook requests third Type A meeting with FDA
- March 2026—Outlook provides update from Type A meeting
- April 2026—FDR request accepted by FDA
- May 2026—Outlook wins appeal following FDR
- June 2026—Outlook submits fourth BLA
However, the OND determined that the results of the NORSE TWO trial (NCT03834753), together with confirmatory evidence from NORSE EIGHT natural history data, and mechanistic and pharmacodynamic data, collectively establish substantial evidence of effectiveness for bevacizumab-vikg in nAMD.
The recent resubmission is classified as a Class 1 resubmission, with a PDUFA date and decision expected within 60 days of FDA’s receipt.
Baruch Kuppermann, MD, PhD, Steinert Endowed Professor, chair of Dept of Ophthalmology and Visual Sciences, and director of Gavin Herbert Eye Institute University of California, Irvine, commented in a press release from Outlook.
“ONS-5010/LYTENAVA has the potential to offer clinicians and patients an important additional option for treating wet AMD. If approved as the first on-label ophthalmic formulation of bevacizumab, ONS-5010 will enable patients to benefit from wider access and provide an attractive alternative for anti-VEGF treatment of wet AMD.”
Bob Jahr, CEO of Outlook Therapeutics, also commented on the company’s journey with LYTENAVA, saying, “Our team worked through an extensive and rigorous review and appeal process, maintaining close collaboration with the FDA. We are encouraged with the Class 1 review designation. We remain committed to bringing ONS-5010/LYTENAVA™ to patients who deserve FDA-approved options for the treatment of nAMD.”
ONS-5010/LYTENAVA is an ophthalmic formulation of bevacizumab: Bevacizumab-vikg in the US and bevacizumab gamma in the EU and UK. It is a recombinant humanized monoclonal antibody (mAb) that selectively binds with high affinity to all isoforms of human VEGF and neutralizes VEGF’s biologic activity through a steric blocking of the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) on the surface of endothelial cells.
If approved, LYTENAVA will be the first and only FDA-approved ophthalmic formulation of bevacizumab supported by “standardized manufacturing, FDA-approved labeling, and robust pharmacovigilance,” according to the company.
LYTENAVA currently holds marketing authorization from the European Commission and the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) for wet AMD, with commercial launches underway in Germany, Austria, and the United Kingdom.
NORSE trials
Results across the first 3 NORSE trials demonstrated a strong benefit-to-risk safety profile, with only 1 ocular inflammation adverse event across all 3 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 participants with wet AMD at 9 trial sites in Australia. It compared bevacizumab-vikg to ranibizumab (Lucentis) as a treatment for wet AMD. Bevacizumab-vikg efficacy and safety data were consistent with data from historical published studies of bevacizumab in ophthalmology.
In the NORSE TWO phase 3 pivotal trial, investigators enrolled 228 patients with wet AMD 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 according to the regimen described in the Lucentis label. The data met both the primary and secondary end points, 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 BLA.
NORSE EIGHT was a randomized, controlled, parallel-group, masked, noninferiority study of approximately 400 patients with newly diagnosed wet AMD. Investigators randomly assigned them 1:1 to receive 1.25 mg ONS-5010 or 0.5 mg ranibizumab intravitreal injections.
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