It looks as though the second time was not the charm for Outlook Therapeutics, Inc., as the FDA has issued a company response letter (CRL) to the company for its Biologics License Application (BLA) resubmission of bevacizumab-vikg (ONS-5010), intended to treat wet age-related macular degeneration (AMD).
This letter follows nearly 5 months after the federal agency accepted Outlook’s BLA resubmission.
First: Let’s talk bevacizumab.
As the active ingredient in Outlook’s investigational candidate, bevacizumab is a recombinant humanized monoclonal antibody (mAb).
- Its mechanism of action (MOA): The mAb acts as an antiangiogenic agent by targeting and binding to vascular endothelial growth factor (VEGF) to prevent tumors from forming, growing, and spreading.
- Notably, the mAB was first commercialized in the United States as Avastin (by Roche/Genentech) in 2004 for the treatment of metastatic colorectal cancer.
And in the context of wet AMD?
See here for details on how it neutralizes the VEGF’s biologic activity via an intravitreal (IVT) injection administered on a monthly basis.
- Importantly: Outlook has already received regulatory approval for the candidate under the name LYTENAVA (bevacizumab gamma) in the European Union (EU) and the United Kingdom.
Now to this BLA in the U.S.
As we noted, the FDA’s recent CRL is the second sent to Outlook in regards to its BLA for ONS-5010.
The first letter was sent in August 2023.
- See here for our previous coverage on the timeline of this ongoing situation, including details on the issues the FDA identified with that previous BLA submission (hint: it involved a lack of substantial evidence).
So what did this second submission include?
Essentially, more clinical data (from an “adequate and well-controlled clinical trial”) on ONS-5010, as well as additional chemistry, manufacturing, and controls (CMC) information.
- Check out the details from the NORSE EIGHT study (NCT06190093), which—though it reported positive findings—did not see ONS-5010 meet its primary endpoint.
And the FDA’s new reasoning for rejection?
Echoing its previous issues with Outlook’s initial BLA, the agency reportedly identified just one major deficiency with the resubmission: “a lack of substantial evidence of effectiveness.”
Specifically: Since ONS-5010 failed to meet its primary endpoint in the NORSE EIGHT trial, the FDA recommended that “confirmatory evidence of efficacy” should be submitted to support its BLA.
So more clinical data? Does that mean a new trial needs to be initiated?
Not quite, thankfully. In advising on this, the FDA also “reiterated” that the efficacy data needed could actually come from one of the clinical studies ONS-5010 has already undergone.
That study: NORSE TWO, which—take note—met its primary endpoint for … effectiveness.
So why wasn’t this data included in the April 2025 BLA resubmission?
Good question. We asked the company the very same.
As of the time of publication, we have not yet heard back.
Give me a quick look at this study.
A highlights version: As a registrational trial, NORSE TWO (NCT03834753) compared ONS-0510 (1.25 mg) to 0.5 mg ranibizumab (both IVT-administered) among wet AMD patients.
The positive topline efficacy and safety findings:
- Statistically significant and clinically relevant primary data (p = 0.0052)
- 41.7% of patients gained at least 15 letters of best-corrected visual acuity (BCVA)
Nice! So does that mean the BLA can be resubmitted (again)?
It certainly looks that way.
According to Outlook CEO Bob Jahr, the company plans to meet with the FDA to “receive additional clarity” on the agency’s BLA requirements to support U.S. regulatory approval for ONS-5010.
- The potential: Jahr noted that ONS-5010 (which would assume the LYTENAVA brand name) could become the first on-label bevacizumab product “specifically formulated, manufactured, and packaged for (IVT) use in the United States.”
… and beyond the United States?
With regulatory approval already secured in the EU and UK, Outlook also intends to continue efforts to expand into additional markets across Europe.
As always, stay tuned for updates on this!
*Disclaimer: The information provided in this article does not and is not intended to constitute legal advice; instead, all information, content, materials available herein are for general information purposes only.