Outlook Therapeutics, Inc. announced that the FDA has issued a complete response letter (CRL) following the company’s resubmission of a new drug application (NDA) for ONS-5010 (bevacizumab-vikg).
This marks the company’s third attempt to seek commercial approval of its wet age-related macular degeneration (AMD) therapeutic.
Let’s start with a general look at CRLs.
The FDA will issue a CRL when it determines that it cannot approve a submitted NDA in its current form due to specific deficiencies—ranging from minor (such as labeling issues) to major (a request for new clinical trials)—identified in the application.
And as for the letter Outlook Therapeutics received: The FDA determined that, despite including new data in the submitted package, Outlook Therapeutics’ latest attempt to seek regulatory approval for bevacizumab has, once again, come up short.
Before we get into those deficiencies, talk about this candidate.
A brief rundown on the therapeutic:
- As a monthly intravitreal (IVT) injection, ONS-5010 is formulated with the recombinant humanized monoclonal antibody (mAB) bevacizumab.
- See how this mAB works to neutralize the biologic activity of vascular endothelial growth factor (VEGF) and treat wet AMD.
And its supporting clinical data?
ONS-5010 has undergone clinical evaluation in four studies:
- NORSE ONE registrational trial
- NORSE TWO registrational trial
- NORSE THREE open-label trial
- NORSE EIGHT randomized non-inferiority trial
Take note: Those initial three studies were included in Outlook’s initial BLA submission, while the NORSE EIGHT study was added to the company’s second BLA submission following the FDA’s request for more data.
What do we know about the findings from these trials?
Click here for details on those first three NORSE trials.
And see here for the positive 12-week results Outlook Therapeutics reported on the NORSE EIGHT study in May 2025, in which ONS-5010 demonstrated noninferiority to ranibizumab.
- Important to note, however: This study failed to meet its primary endpoint.
And regarding those two prior BLA rejections?
The two CRLs FDA sent Outlook Therapeutics were issued at the following timepoints:
- First CRL: Sent in August 2023 following an initial submission in 2022
- Second CRL: Sent in September 2025 after the agency’s April 2025 submission acceptance
For both BLAs: The federal agency requested more clinical data (hence the inclusion of NORSE EIGHT’s findings).
Now to this latest CRL.
Despite the company’s third BLA including “additional mechanistic and natural history data information,” from “one adequate and well-controlled study” that demonstrated efficacy, the FDA essentially said that it still didn’t address the issue identified in its second CRL from just a few months ago.
That issue: Included a “lack of substantial evidence of effectiveness,” largely due to the fact that—as we mentioned—the NORSE EIGHT trial (whose data was added to the second BLA package, keep in mind) hadn’t met its primary goal.
Couldn’t the company have included efficacy data from the other NORSE trials?
They definitely could have, especially considering that those studies all met their primary endpoints—and the NORSE TWO trial actually met its goal for effectiveness, specifically.
- See here for a look at that.
In fact, the FDA also previously noted this as an option for the company in its second CRL.
So … was NORSE TWO’s efficacy data included in this third submission?
Great question—we actually asked Outlook Therapeutics this (but regarding its second submission).
In the case of this third BLA: The company shared that its third BLA submission was based on the “complete data set from the NORSE clinical trial program” encompassing the:
- “Successful NORSE TWO adequate and well-controlled pivotal trial”
- Confirmatory safety and efficacy data from all other NORSE trials, including NORSE EIGHT”
So … though it’s not entirely clear, it’s possible that NORSE TWO’s efficacy data was included in the third BLA package.
Gotcha. Now expand on the type of data needed for this BLA to be approved.
According to Outlook Therapeutics, the federal agency “again recommended that confirmatory evidence of efficacy be submitted to support [what will be] the [fourth BLA] application.”
But the company also noted that “the FDA has not indicated what type of confirmatory evidence would be acceptable.”
Interesting … so where does that leave the company?
Outlook Therapeutics noted that it “continues to believe” that NORSE TWO’s complete clinical data set—combined with the data from the other NORSE clinical trials— “provides the required evidence to support approval of the ONS-5010 BLA” in the U.S.
Further: While CEO Bob Jahr expressed the company’s disappointment and disagreement with the agency’s latest decision, he added that “we remain fully committed to taking all necessary steps” to receive approval from the FDA.
And what’s next?
Outlook Therapeutics is reportedly exploring “all available pathways for potential approval” in the United States, while continuing to pursue expansion into other commercial markets across the globe.
Take note: ONS-5010 has already received regulatory approval in the European Union and marketing authorization in the United Kingdom under the brand name LYTENAVA (bevacizumab gamma).
Translation … is another BLA submission in store?
From the sounds of it, yes. Though there’s no exact timeframe for a fourth attempt at regulatory approval.
As for ONS-5010’s significance: Its regulatory approval would mark the prescription drug as the first on-label bevacizumab product specifically formulated for IVT retinal use in the U.S.—where Roche’s Avastin is currently used as an off-label/compounded treatment for wet AMD.