How did Outlook's description of NORSE EIGHT change?

Outlook Therapeutics Form 8-K, filed November 27, 2024

ONS-5010 did not meet the pre-specified non-inferiority endpoint at week 8 set forth in the special protocol assessment (SPA) with the U.S. Food and Drug Administration (FDA).

Outlook Therapeutics Form 8-K, filed November 27, 2024

today announced preliminary topline results of NORSE EIGHT, the second of two adequate and well controlled clinical trials evaluating ONS-5010 in wet AMD patients.

Outlook Therapeutics Form 8-K, filed May 15, 2025

following Type A meetings with the FDA in Q4 CY2023 to address the ONS-5010 Complete Response Letter (CRL), the FDA informed Outlook Therapeutics that, in order to meet the FDA’s requirement for a second adequate and well-controlled clinical trial of ONS-5010, it could conduct a non-inferiority study evaluating ONS-5010 versus ranibizumab in a 12 week study of treatment naïve patients with a primary efficacy endpoint at 8 weeks (NORSE EIGHT).

Outlook Therapeutics Form 10-K, filed December 19, 2025

The NORSE TWO primary endpoint difference in proportion of subjects gaining at least 15 letters in Best Corrected Visual Acuity, or BCVA, score was met and was both highly statistically significant and clinically relevant. For a discussion of NORSE TWO, please see “Our Product Candidate Portfolio— ONS-5010/LYTENAVA — Bevacizumab for Ophthalmic Use—Clinical Development Status —NORSE TWO”. In the intent to treat, or ITT, primary dataset, the percentage of patients who gained at least 15 letters who were treated with ONS-5010/LYTENAVA, was 41.7%, and the percentage of patients who gained at least 15 letters who were treated with ranibizumab was 23.1% (p = 0.0052).

Outlook Therapeutics Form 10-K, filed December 19, 2025

As agreed to with the FDA in the SPA, NORSE EIGHT was a randomized, controlled, parallel-group, masked, non-inferiority study of approximately 400 newly diagnosed, wet AMD subjects randomized in a 1:1 ratio to receive 1.25 mg ONS-5010/LYTENAVA or 0.5 mg ranibizumab intravitreal injections. Subjects received injections at Day 0 (randomization), Week 4, and Week 8 visits, with a final follow-up visit at Week 12. The primary endpoint was the mean change in best corrected visual acuity (BCVA) from baseline to week 8.

Outlook Therapeutics Form 10-K, filed December 19, 2025

In December 2023, we submitted a Special Protocol Assessment, or SPA, to the FDA for this study (NORSE EIGHT) seeking confirmation that, if successful, it would address the FDA’s requirement for a second adequate and well-controlled clinical trial to support our planned resubmission of the ONS-5010/LYTENAVA BLA. In January 2024, we received confirmation that the FDA had reviewed and agreed upon the NORSE EIGHT trial protocol pursuant to the SPA.

Outlook Therapeutics Form 10-K, filed December 19, 2025

At week 12, the difference in the mean between ONS-5010/LYTENAVA and ranibizumab was -1.009 BCVA letters with a 95% confidence interval of (-2.865, 0.848) in the NORSE EIGHT trial. Applying the statistical parameters from the week 8 primary endpoint with the lower bound of the non-inferiority margin at -3.5 with a 95% confidence interval, the noninferiority margin was met at week 12, indicating that the two study arms are not different at this timepoint.

Outlook Therapeutics Form 8-K, filed January 2, 2026

The ONS-5010 BLA resubmission was based on the complete data set from the NORSE clinical trial program, which included the successful NORSE TWO adequate and well controlled pivotal clinical trial as well as confirmatory safety and efficacy data from all other NORSE trials, including NORSE EIGHT, an adequate and well controlled non-inferiority study evaluating ONS-5010 versus ranibizumab in a 12-week study of treatment naïve patients with a primary efficacy endpoint at 8 weeks.

Outlook Therapeutics Form 8-K, filed February 11, 2026

At FDA’s request, Outlook Therapeutics also conducted NORSE EIGHT, a second adequate and well-controlled Phase 3 study. While NORSE EIGHT did not meet its primary endpoint at 8 weeks, the study demonstrated a positive trajectory consistent with NORSE TWO through 12 weeks of treatment and provided important functional and mechanistic/pharmacodynamic evidence of efficacy. Specifically, NORSE EIGHT showed consistent gains in best-corrected visual acuity across all measured timepoints, low variability, and results aligned with the established anti-VEGF mechanism of action.

Outlook Therapeutics Form 8-K, filed March 5, 2026

NORSE EIGHT, along with other information submitted to the BLA, demonstrated confirmatory evidence of efficacy and safety of ONS-5010 supporting the successful NORSE TWO trial, including functional and pharmacodynamic evidence consistent with the anti-VEGF mechanism of action.

Outlook Therapeutics Form 8-K, filed May 26, 2026

In its formal response, OND determined that the results of the NORSE TWO trial, together with confirmatory evidence including NORSE EIGHT, natural history, and mechanistic and pharmacodynamic data, establish substantial evidence of effectiveness for LYTENAVA™ for the treatment of nAMD. The response directs the Division and OSM to work with Outlook Therapeutics to reach an agreement on final labeling. As indicated in the formal decision, it is anticipated that this will be a Class 1 resubmission with a PDUFA date and decision expected within 60 days of FDA’s receipt of the resubmission.