Outlook Therapeutics Resubmits BLA for ONS-5010

Outlook Therapeutics has resubmitted its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for ONS-5010 (bevacizumab-vikg), a recombinant monoclonal antibody designed for the treatment of wet age-related macular degeneration (wet AMD). If approved, the drug will be marketed under the brand name LYTENAVA.

Mechanism of Action of ONS-5010

Bevacizumab-vikg is a recombinant humanized monoclonal antibody (mAb) that binds with high affinity to all isoforms of vascular endothelial growth factor (VEGF). By preventing VEGF from interacting with its receptors—Flt-1 (VEGFR-1) and KDR (VEGFR-2)—on endothelial cells, the drug neutralizes VEGF's biological activity, which is crucial in the pathogenesis of wet AMD.

Company’s Statement on Resubmission

Lawrence Kenyon, Chief Financial Officer and Interim CEO of Outlook Therapeutics, emphasized the significance of the resubmission:

“We remain committed to bringing an ophthalmic bevacizumab to market in the United States and providing retina patients suffering from wet AMD with a much-needed treatment option that has the potential to address the problems associated with unapproved repackaged bevacizumab. Our team has worked diligently to address the FDA’s requests, and we believe this resubmission provides the necessary evidence to support approval of the ONS-5010 BLA in the United States. This resubmission marks a very significant milestone and puts us another step closer to a transformed Outlook Therapeutics.”

FDA’s Initial CRL and the NORSE EIGHT Study

In August 2023, the FDA issued a Complete Response Letter (CRL) for the ONS-5010 BLA. The agency cited several chemistry, manufacturing, and controls (CMC) issues, unresolved observations from pre-approval manufacturing inspections, and a lack of substantial evidence as reasons for non-approval.

To address these concerns, Outlook Therapeutics conducted the NORSE EIGHT trial, a randomized, controlled, parallel-group, masked, non-inferiority study comparing ONS-5010 with ranibizumab in 400 newly diagnosed wet AMD patients. Participants were randomized 1:1 to receive either 1.25 mg of ONS-5010 or 0.5 mg of ranibizumab via intravitreal injection.

Key findings from the NORSE EIGHT trial:

• ONS-5010 demonstrated a mean 4.2-letter improvement in best corrected visual acuity (BCVA) at week 8.

• However, it did not meet the pre-specified non-inferiority endpoint required by the FDA’s special protocol assessment (SPA).

Updated 12-Week Analysis and Clinical Impact

In January 2025, Outlook Therapeutics released additional 12-week safety and efficacy data from NORSE EIGHT, which suggested that ONS-5010 had clinically meaningful anatomic and functional improvements at every measured timepoint.

Comparative BCVA Improvements

• ONS-5010 arm: Mean BCVA improvement ranged from 3.3 to 5.5 letters across weeks 4, 8, and 12.

• Ranibizumab arm: Mean BCVA improvement ranged from 4.5 to 6.5 letters over the same period.

Despite the initial setback in meeting the non-inferiority endpoint, the updated analysis supports ONS-5010’s potential efficacy and safety profile for wet AMD treatment.

Regulatory Outlook and FDA Decision Timeline

The FDA is expected to provide a decision on the resubmitted BLA within six months. If approved, ONS-5010 could provide a standardized ophthalmic bevacizumab formulation, addressing concerns related to off-label repackaging and offering a new treatment alternative for wet AMD patients.