Clinical Experience Trial (NORSE ONE)

NORSE ONE, the first clinical trial in our clinical program evaluating ONS-5010 to treat wet AMD, is a clinical experience trial. In August 2020 we reported topline results and positive proof-of-concept data for safety and efficacy. In this initial clinical experience trial, we saw the positive trends in efficacy in 3-line visual acuity gains we expected, and ONS-5010 was well-tolerated in this study. Importantly, it showed no ocular adverse events related to inflammation. The results support the established design, inclusion criteria and protocol for NORSE TWO, the pivotal Phase 3 clinical trial evaluating ONS-5010 for treatment of wet AMD. Our initial clinical experience trial was conducted in Australia and compares ONS-5010 with an alternate dosing regimen of ranibizumab (LUCENTIS^®).

Pivotal Phase 3 Trial (NORSE TWO)

NORSE TWO, the first of two registration clinical trials in our clinical program for ONS-5010 to treat wet AMD, is our pivotal trial. We reported positive topline efficacy and safety data in August 2021. In the trial, ONS-5010 achieved highly statistically significant and clinically meaningful primary efficacy data (p = 0.0052) with 41.7% of subjects gaining at least 15 letters of best corrected visual acuity (BCVA), and key secondary efficacy endpoints (p = 0.0035). NORSE TWO enrolled 228 participants at 39 clinical trial sites across the United States. Participants in the trial were treated for 12 months. The primary endpoint for the study was the difference in proportion of patients who gained at least 15 letters in BCVA at 11 months for ONS-5010 dosed monthly, compared to LUCENTIS^®, which was dosed as one of the regimens listed in the LUCENTIS^® label (i.e., patients are treated monthly for the first 3 months followed by less frequent dosing; the PIER regimen).

Safety Trial (NORSE THREE)

Our third clinical trial investigating ONS-5010 for treatment of wet AMD, NORSE THREE, is an open-label safety study that enrolled 197 subjects in the United States and was conducted to ensure that an adequate number of safety exposures to ONS-5010 are available for the BLA regulatory filing. We reported a positive safety profile from this trial in March 2021, with no reports of intraocular inflammation.

The overall safety profile of ONS-5010 in the NORSE clinical program was consistent with that shown in previous studies of bevacizumab in ophthalmic use. There have been no unanticipated safety signals. The most common ocular adverse event was intravitreal injection-related hemorrhage in the tissues on the surface of the eye (conjunctival hemorrhage) that resolved without any sequela. Following exposure to bevacizumab-vikg, there was only one subject who reported an adverse event of intraocular inflammation in all three completed NORSE clinical studies. When normalizing this single event to the large number of ONS-5010 injections in our clinical trials, it occurred at a 0.05% incidence.

NORSE TWO demonstrated safety, and when combined with NORSE ONE and NORSE THREE provides the necessary registration safety database. These ONS-5010 data, when taken as a whole, continue to be consistent with previously published results for bevacizumab in ophthalmology.

Second Registration Trial (NORSE EIGHT)

NORSE EIGHT will be a randomized, controlled, parallel-group, masked, non-inferiority study of approximately 400 treatment naive, wet AMD subjects randomized in a 1:1 ratio to receive 1.25 mg ONS-5010 or 0.5 mg ranibizumab intravitreal injections. Subjects will receive injections at Day 0 (randomization), Week 4, and Week 8 visits. The primary endpoint is mean change in BCVA from baseline to week 8. Outlook Therapeutics expects NORSE EIGHT topline results and resubmission of the ONS-5010 BLA by the end of calendar year 2024. The FDA has acknowledged agreement with the study design through a Special Protocol Assessment (SPA).

Branch Retinal Vein Occlusion

Outlook Therapeutics intends to initiate NORSE FOUR, a registration clinical trial that will evaluate ONS-5010 for use in treating BRVO.

Diabetic Macular Edema

Outlook Therapeutics also intends to commence NORSE FIVE and NORSE SIX, two registration clinical trials to evaluate ONS-5010 in treating DME.

Regulatory Approval Plans

The U.S. Food and Drug Administration (“FDA”), which had accepted Outlook Therapeutics’ Biologics License Application (BLA) for ONS-5010 to treat wet AMD on October 27, 2022, issued a Complete Response Letter (CRL) on the Prescription Drug User Fee Act (PDUFA) goal date of August 29, 2023. Following a Type A meeting with the FDA held in October 2023, the FDA informed Outlook Therapeutics that it can conduct a non-inferiority study evaluating ONS-5010 versus ranibizumab in a 3-month study of treatment naïve patients with a primary efficacy endpoint at 2 months. Subsequently, as discussed with and recommended by the FDA, Outlook Therapeutics submitted the NORSE EIGHT clinical trial protocol and analysis plan that the FDA has reviewed and agreed upon pursuant to the SPA. If the NORSE EIGHT trial is successful, it would satisfy the FDA’s requirement for a second adequate and well-controlled clinical trial to address fully the clinical deficiency identified in the Complete Response Letter (CRL).

Because there is currently no bevacizumab approved for ophthalmic indications in the United States, we submitted ONS-5010 with the FDA as a BLA under the PHSA 351(a) regulatory pathway for new biologics, not as a biosimilar.

Pending approval from the FDA, we expect to submit for regulatory approval of ONS-5010 in multiple markets based on our successful Phase 3 clinical program in wet AMD.