ONS-5010 for Wet AMD Fails to Meet Noninferiority in NORSE EIGHT Trial

ONS-5010, an ophthalmic formulation of bevacizumab for wet age-related macular degeneration (AMD), missed the pre-specified non-inferiority endpoint in preliminary topline results reported from the NORSE EIGHT clinical trial.¹

Announced by Outlook Therapeutics on November 27, 2024, NORSE EIGHT is the second of two adequate and well-controlled clinical trials designed to evaluate ONS-5010 (LYTENAVA) for wet AMD after a special protocol assessment (SPA) confirmed with the US Food and Drug Administration (FDA).

In the announcement, Outlook indicated plans to resubmit the Biologics License Application (BLA) for ONS-5010 in the first quarter of 2025, pending the full month 3 efficacy and safety results from NORSE EIGHT expected in January 2025.

“Outlook Therapeutics remains confident that ONS-5010/ LYTENAVA is an important therapy for the treatment of wet AMD in place of off-label repackaged bevacizumab that has not received regulatory approval for use in ophthalmology,” the company added in the release.

NORSE EIGHT is a randomized, controlled, parallel-group, masked, non-inferiority study of newly diagnosed wet AMD.² Participants are randomized 1:1 to receive 1.25 mg ONS-5010 or 0.5 mg intravitreal ranibizumab with injections on Day 0, Week 4, and Week 8. The primary endpoint was the mean change in best-corrected visual acuity (BCVA) from baseline to Week 8.

Analysis of NORSE EIGHT’s primary endpoint showed the mean difference between ONS-5010 and ranibizumab was –2.257 BCVA letters (95% CI, –4.044 to –0.470; P = .0863), with the lower bound of the SPA pre-specified non-inferiority margin at –3.5.¹ As a result, a hypothesis of noninferiority between ONS-5010 and ranibizumab was not met (P >.025).

In the intent-to-treat (ITT) dataset, results from NORSE EIGHT showed a mean +4.2 letter improvement in BCVA in the ONS-5010 arm and +6.3 letter improvement in the ranibizumab arm. Safety outcomes showed ONS-5010 remained generally tolerable, with comparable ocular adverse event rates to ranibizumab and consistent outcomes with the NORSE clinical trial program.

Outlook announced the completion of the remediation of the Chemistry, Manufacturing, and Controls (CMC) comments received in the FDA’s Complete Response Letter (CRL), with close alignment with the agency for type C and type D meetings.

With plans to resubmit the BLA in the US in 2025, Outlook announced a potential 2025 launch in the UK and Germany, where ONS-5010 has received European Commission and MHRA Marketing Authorization for wet AMD.

References

1. _{Outlook therapeutics® announces preliminary topline results of Norse eight clinical trial. Outlook Therapeutics, Inc. November 27, 2024. Accessed November 27, 2024. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-preliminary-topline-results.}
2. _{Iapoce C. Outlook therapeutics submits ONS-5010 special protocol assessment to FDA. HCP Live. January 2, 2024. Accessed November 27, 2024. https://www.hcplive.com/view/outlook-therapeutics-submits-ons-5010-special-protocol-assessment-fda.}