Outlook Therapeutics’ ONS-5010 for Wet AMD Falls Short of Noninferiority in NORSE EIGHT Trial

ONS-5010 (LYTENAVA), an ophthalmic formulation of bevacizumab for treating wet age-related macular degeneration (AMD), failed to meet the noninferiority endpoint in the NORSE EIGHT clinical trial, according to preliminary topline results announced by Outlook Therapeutics.

About the NORSE EIGHT Trial

NORSE EIGHT is the second of two adequate and well-controlled clinical trials conducted under a special protocol assessment (SPA) agreed upon with the US Food and Drug Administration (FDA) to evaluate ONS-5010 for wet AMD.

This randomized, controlled, parallel-group, masked study included participants with newly diagnosed wet AMD, who were randomized 1:1 to receive:

       • 1.25 mg ONS-5010

       • 0.5 mg intravitreal ranibizumab

Primary Endpoint

The trial’s primary endpoint was the mean change in best-corrected visual acuity (BCVA) from baseline to Week 8. Participants received injections on Day 0, Week 4, and Week 8.

Key Results

The primary endpoint analysis revealed a mean difference of –2.257 BCVA letters between ONS-5010 and ranibizumab (95% CI, –4.044 to –0.470; P = .0863). With the lower bound of the SPA pre-specified noninferiority margin at –3.5, the hypothesis of noninferiority was not met (P > .025).

Additional Findings:

       • In the intent-to-treat (ITT) dataset, BCVA improvement was:

              1. +4.2 letters in the ONS-5010 arm

              2. +6.3 letters in the ranibizumab arm

       • Safety Outcomes: ONS-5010 demonstrated a tolerable safety profile, with ocular adverse event rates comparable to ranibizumab.

Outlook’s Next Steps

Despite the trial results, Outlook Therapeutics remains optimistic about ONS-5010’s potential as a replacement for off-label repackaged bevacizumab in wet AMD treatment.

Key Updates from Outlook:

       • Resubmitting Biologics License Application (BLA): Plans to resubmit in the first quarter of 2025, pending full efficacy and safety results from NORSE EIGHT, expected in January 2025.

       • Manufacturing and Controls (CMC): Remediation of FDA comments in the Complete Response Letter (CRL) is complete, with close alignment achieved through type C and type D meetings.

       • International Launch Plans: Aiming for a 2025 launch in the UK and Germany, where ONS-5010 has already received European Commission and MHRA Marketing Authorization for wet AMD.

Conclusion

While ONS-5010 did not meet its noninferiority endpoint in NORSE EIGHT, its tolerable safety profile and comparable outcomes to ranibizumab provide a foundation for further development. With plans for FDA resubmission and upcoming launches in Europe, Outlook Therapeutics remains committed to advancing ONS-5010 as a viable treatment option for patients with wet AMD.