Clinical Experience Trial (NORSE ONE)

NORSE ONE, the first registration 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 second 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 relevant primary data (p = 0.0052) and key secondary efficacy endpoints (p = 0.0043), with 41.7% of subjects gaining at least 15 letters of best corrected visual acuity (BCVA). 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).

The safety profile of ONS-5010 in the NORSE clinical program was consistent with that shown in previous studies of bevacizumab in ophthalmic use. Following exposure to bevacizumab-vikg, there was only one subject who reported an adverse event of ocular inflammation in all three completed NORSE clinical studies. In NORSE TWO, there was only a single related ocular adverse event reported in the bevacizumab-vikg study arm (an iritis), which resolved and showed no unanticipated safety signals. When normalizing this single event to the large number of ONS-5010 injections in our clinical trials, it occurred at a 0.05% incidence. 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.

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

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 ocular inflammation.

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, 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. While the FDA acknowledged the NORSE TWO pivotal trial met its safety and efficacy endpoints, the Agency concluded it could not approve the BLA during this review cycle due to several CMC issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence. Outlook Therapeutics is working closely with the FDA to address the Agency’s concerns so that the BLA can be re-submitted for approval. The Company will request a Type A meeting as soon as possible to discuss the CRL and determine potential paths forward for the approval of ONS-5010 for the treatment of wet AMD.

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. 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.