Despite clinicians’ widespread use of unapproved repackaged intravenous (IV) bevacizumab from compounding pharmacies to treat ophthalmic diseases such as wet AMD, DME and BRVO, no other manufacturer has previously sought approval from the FDA for use of bevacizumab in these diseases.

Outlook Therapeutics is developing ONS-5010 / LYTENAVA™ as an investigational ophthalmic formulation of bevacizumab for a new BLA filing under the PHSA 351(a) regulatory pathway.

If approved, ONS-5010 will be the first and only FDA-approved, on-label bevacizumab approved initially for the treatment of wet-AMD and potentially for other ophthalmic indications (DME and BRVO).

The U.S. Food and Drug Administration had accepted Outlook Therapeutics’ Biologics License Application (BLA) for ONS-5010 to treat wet AMD on October 27, 2022, and 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. The Company’s clinical registration program design for ONS-5010 was reviewed and agreed upon by the FDA in an end-of-Phase 2 (EOP2) meeting in April 2018.

NORSE ONE is a clinical experience trial that evaluated ONS-5010 vs an alternate dosing regimen of ranibizumab (LUCENTIS^®); it demonstrated proof-of-concept for using ONS-5010 as a treatment for wet AMD and validated the clinical trial protocol for NORSE TWO.

NORSE TWO, the second of two registration clinical trials, is our pivotal trial. We reported strongly positive efficacy and safety topline 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 BCVA. It was designed as a superiority trial comparing ONS-5010 dosed monthly with 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).

NORSE THREE is an open-label safety study that 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.

Outlook Therapeutics re-submitted a BLA with the U.S. FDA for ONS-5010 to treat wet AMD on August 30, 2022. This followed a voluntary withdrawal of the initial BLA submission in May 2022, in order to provide supplemental information the FDA requested.

The Company also intends to initiate registration studies for ONS-5010 for approvals in diabetic macular edema (DME) and branch retinal vein occlusion (BRVO).

Outlook Therapeutics expects to establish responsible pricing for ONS-5010, if approved. If approved for marketing, ONS-5010 has the potential to help lower the aggregate costs of treating retinal diseases for the overall healthcare system.