ONS-5010 for Wet AMD Secures Noninferiority in NORSE EIGHT Trial

Julia A. Haller, MD

Credit: Wills Eye Hospital

Complete safety and efficacy analysis of the NORSE EIGHT clinical trial revealed noninferiority of ONS-5010 (LYTENAVA), an ophthalmic formulation of bevacizumab, at 12 weeks to ranibizumab for the treatment of neovascular (wet) age-related macular degeneration (nAMD).¹

Announced by Outlook Therapeutics on January 16, 2025, the full 3-month analysis supports the company’s plan to resubmit the Biologics License Application (BLA) for ONS-5010 in the first quarter of 2025. In November 2024, preliminary topline results from the trial showed that ONS-5010 missed its pre-specific non-inferiority endpoint at Week 8.²

“The 3-month data from NORSE EIGHT provides additional evidence to confirm what retina specialists expected,” Julia A. Haller, MD, ophthalmologist-in-chief at Wills Eye Hospital and Outlook Therapeutics board member, said in a statement.¹ “The clinical trial continues to demonstrate that ONS-5010 injections result in immediate and sustained anatomic efficacy, with steady gains in visual acuity and reliable, consistent safety.”

NORSE EIGHT is the second of dual adequate and well-controlled clinical trials designed to evaluate ONS-5010 for wet AMD after a Special Protocol Assessment (SPA) was confirmed by the US Food and Drug Administration (FDA). Previously, in August 2023, the FDA released a Complete Response Letter (CRL) citing multiple Chemistry Manufacturing and Controls (CMC) issues and a lack of substantial evidence.³

NORSE EIGHT randomized newly diagnosed patients with nAMD in a 1:1 ratio to receive 1.25 mg ONS-5010 or 0.5 mg intravitreal injections at Day 0, Week 4, and Week 8 visits, with a final visit at Week 12. Its primary endpoint was a mean change in best-corrected visual acuity (BCVA) from baseline to Week 8.¹

Initial analysis at Week 8 found that ONS-5010 did not meet the prespecified non-inferiority to ranibizumab endpoint decided in the SPA agreement with the FDA. However, at all time points, Outlook indicated ONS-5010 achieved increasing BCVA improvements with the presence of biologic activity.¹

ONS-5010 achieved mean visual acuity improvements of +5.5 letters, compared with +6.5 letters for ranibizumab, at Week 12 (95% CI, –2.865 to 0.848; P = .0043). Central retinal thickness (CRT) was similar across all time points, including Week 12, for both the ONS-5010 (–123.9 µm) and ranibizumab (–127.3 µm) cohorts.

Safety outcomes showed that ONS-5010 was tolerable with similar adverse event rates to ranibizumab. The full duration of NORSE EIGHT remained consistent with previously reported safety data from the NORSE ONE, NORSE TWO, and NORSE THREE clinical trials, with no cases of retinal vasculitis in either study cohort.

Outlook announced that ONS-5010 has been granted Marketing Authorization in the European Union and the United Kingdom, with plans to launch in the first half of calendar 2025. With statistically significant 12-week results for ONS-5010 in NORSE EIGHT, Outlook confirmed the complete data set and the NORSE TWO pivotal study will support the resubmission of the BLA in the US for nAMD.¹

“Our team continues the necessary work for the planned resubmission of our BLA in the first quarter of calendar 2025,” Lawrence Kenyon, chief financial officer and interim chief executive officer of Outlook Therapeutics, added in a statement.¹ “We remain confident in the potential of ONS-5010/LYTENAVA to provide 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 retinal diseases here in the United States.”

References

1. _{Outlook therapeutics® announces complete twelve week efficacy and safety results of Norse eight clinical trial. Outlook Therapeutics, Inc. January 16, 2025. Accessed January 17, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-complete-twelve-week-efficacy.}
2. _{Iapoce C. Ons-5010 for wet AMD fails to meet noninferiority in Norse eight trial. HCP Live. November 27, 2024. Accessed January 17, 2025. https://www.hcplive.com/view/ons-5010-for-wet-amd-fails-to-meet-noninferiority-in-norse-eight-trial.}
3. _{Iapoce C. Outlook therapeutics submits ONS-5010 special protocol assessment to FDA. HCP Live. January 2, 2024. Accessed January 17, 2025. https://www.hcplive.com/view/outlook-therapeutics-submits-ons-5010-special-protocol-assessment-fda.}