The FDA issued Outlook Therapeutics, Inc. a complete response letter (CRL) stating it will not approve the Biologics License Application (BLA) for ONS-5010 (bevacizumab-vikg), an investigational biologic for ophthalmic use, for the treatment of wet age-related macular degeneration (AMD).
Refresh me on the company.
Based in Iselin, New Jersey, Outlook Therapeutics is a biopharmaceutical company focused entirely on the development of a potential first FDA-approved bevacizumab ophthalmic formulation targeting indications for the treatment of the following retinal diseases:
- Wet AMD
- Diabetic macular edema (DME)
- Branch retinal vein occlusion (BRVO)
And this drug?
ONS-5010, also referred to as Lytenava, is intended to be delivered as an intravitreal injection.
Bevacizumab-vikg, the formulation’s active ingredient, is a recombinant humanized monoclonal antibody (mAb) that selectively binds with a high affinity all isoforms (similar proteins with different genes) of human vascular endothelial growth factor (VEGF).
How does it work?
The mAB neutralizes the biologic activity of the VEGF by blocking its binding to receptors, located on the endothelial cell surface.
After injection, this binding of bevacizumab-vikg to VEGF prevents VEGF from interacting with its receptors, resulting in:
- Reduced endothelial cell proliferation
- Vascular leakage
- New blood vessel formation in the retina
How has it performed in clinical trials?
The formulation was studied in three trials:
- NORSE ONE (NCT03844074)
- Registration trial
- Compared to ranibizumab.
- Positive proof-of-concept data for safety and efficacy:
- Positive trends in efficacy in 3-line visual acuity (VA) gains
- Well-tolerated with no ocular adverse events related to inflammation.
- NORSE TWO (NCT03834753)
- Registration trial
- Compared to ranibizumab
- Positive topline efficacy and safety data
- Achieved statistically significant and clinically relevant primary data (p = 0.0052)
- 41.7% gained at least 15 letters of best-corrected visual acuity (BCVA)
- NORSE THREE (NCT04516278)
- Open-label safety study
- Reported positive safety profile; no ocular inflammation
Gotcha. So why the rejection?
According to Outlook, while the FDA acknowledged that while the NORSE TWO pivotal trial met its safety and efficacy endpoints, “the agency concluded it could not approve the BLA during this review cycle.”
The following reasons were listed as to why:
- Several chemistry, manufacturing, and controls (CMC) issues
- Open observations from pre-approval manufacturing inspections
- Lack of substantial evidence
How has the company responded?
According to Outlook President and CEO Russell Trenary, they will request a formal meeting with the agency to better understand the issues with the company’s BLA and how to resolve them, as well as potential next steps for a resolution.
What else to know?
To note, this isn’t the first time the FDA rejected Outlook’s BLA for ONS-5010.
The company originally submitted a BLA in March 2022 before voluntarily withdrawing it in May 2022 to provide additional info the agency requested.
The company then resubmitted the BLA in August 2022 and was accepted in October 2022.
The intended Prescription Drug User Fee Act (PDUFA) date had been set for August 29, 2023.