The FDA has agreed to grant Outlook Therapeutics Special Protocol Assessment (SPA) for its NORSE EIGHT clinical trial protocol that will evaluate the use of its investigational ophthalmic formulation of bevacizumab for wet age-related macular degeneration (AMD).
First things first: explain an SPA.
According to the FDA, a SPA is a process where companies develop a specific investigational candidate and then request a meeting with the agency to come to an agreement on the design / size specifications of certain clinical trials.
The purpose: to “determine if they adequately address scientific and regulatory requirements for a study that could support market approval.”
It’s important to note, however, that an SPA agreement doesn’t necessarily guarantee the FDA will accept the filing of a new drug application (NDA) or biologics license application (BLA), or that the respective trial results will support regulatory approval. That’s important to remember (I’ll explain later).
Now tell me about this formulation.
ONS-5010 (Lytenava; bevacizumab-vikg) is currently under development as an intravitreal injection to be administered for the potential treatment of wet AMD and other retinal diseases:
- Diabetic macular edema (DME)
- Branch retinal vein occlusion (BRVO)
More specifically, though, bevacizumab-vikg—the formulation’s active ingredient—is a recombinant humanized monoclonal antibody (mAb) that selectively binds with a high affinity to all isoforms (functionally similar proteins with different encoded genes) of human vascular endothelial growth factor (VEGF).
And its mechanism of action?
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 receptor-receptor interaction, resulting in:
- Reduced endothelial cell proliferation
- Vascular leakage
- New blood vessel formation in the retina
Give me some clinical data.
Before we get to the NORSE EIGHT trial, let’s discuss the three prior clinical trials this formulation has already undergone.
- 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
Now … didn’t the FDA already reject this candidate?
Technically speaking, yes. Back in August 2023, the agency declined to approve Outlook’s Biologics License Application (BLA) for ONS-5010, listing three reasons as to why in a company response letter (CRL). Click here for that coverage.
Prior to that, the company had submitted the original BLA for the candidate in March 2022 before voluntarily withdrawing it in May 2022 to provide additional info the agency requested (and later submitting the BLA in August 2022, which was later accepted in October 2022).
Gotcha. Now talk about this NORSE EIGHT trial.
The trial is designed as a randomized, controlled, parallel-group, masked, non-inferiority study that has set a target enrollment of an estimated 400 newly-diagnosed wet AMD patients.
Participants will be randomized 1:1 to receive either of the following, administered via intravitreal injections:
- 1.25 mg ONS-5010
- 0.5 mg ranibizumab
Injections will be administered at Day 1, Week 4, and Week 8 visits.
What’s being measured?
Per Outlook, the primary endpoint, measured from baseline to Week 8, will be the mean change in best-corrected visual acuity (BCVA).
So what’s the intended endgame for this?
Pending the trial’s success, it would meet the FDA’s requirement as the second clinical trial to “address fully the clinical deficiency outlined in the [CRL],” according to the company.
And when can we expect a data readout?
Topline results—as well as a potential resubmission of ONS-5010’s BLA—are anticipated by the end of 2024.
Any other updates to know about?
Just a few…
Outlook also revealed it has entered into a definitive securities purchase agreement with both institutional and accredited investors to secure up to $172 million in gross proceeds.
Why is that important?
“We believe that the funds we expect to receive in this financing will position Outlook Therapeutics to support the ONS-5010 development pathway through potential FDA approval and launch,” stated Russell Trenary, president and CEO.