Outlook Therapeutics reported new 12-week safety and efficacy results from the NORSE EIGHT clinical trial evaluating ONS-5010 / LYTENAVA (bevacizumab-vikg) for the treatment of wet age-related macular degeneration (AMD).
Let’s start with ONS-5010.
An investigational ophthalmic formulation of bevacizumab, ONS-5010 is intended to be administered as an intravitreal (IVT) injection to treat the following retinal diseases:
- Wet AMD
- Diabetic macular edema (DME)
- Branch retinal vein occlusion (BRVO)
About bevacizumab-vikg: The active ingredient in ONS-5010 is a recombinant humanized monoclonal antibody (mAb) that:
- Selectively binds with a high affinity to all isoforms of human vascular endothelial growth factor (VEGF)
- Note: Isoforms are functionally similar proteins with different encoded genes.
- Neutralizes VEGF’s biologic activity by blocking it from binding from its receptors on the endothelial cell surface
And what does this do, exactly?
When used in ONS-5010 post-injection, this neutralization results in:
- Reduced endothelial cell proliferation
- Vascular leakage
- New blood vessel formation in the retina
Gotcha. Now talk about this clinical study.
The NORSE EIGHT trial was designed as a randomized, controlled, parallel-group, masked, noninferiority study (NCT06190093).
The setup:
- Participants: 400 (approximately; aged 50+) newly diagnosed with wet AMD
- The doses: 1:1 randomization to receive IV-administered injections of:
- 1.25 mg ONS-5010
- 0.5 mg ranibizumab (Lucentis; Genentech)
- The administration times: Day 1, Week 4, and Week 8
- The outcome measure: Effectiveness of IVT injections of ONS-5010 versus ranibizumab to prevent vision loss (baseline to Week 8)
- Measured via mean change in baseline best-corrected visual acuity (BCVA) at Week 8
And the findings?
Overall: The company reported ONS-5010 demonstrated noninferiority to ranibizumab at Week 12.
Difference in the mean between ONS-5010 and ranibizumab:
- -1.009 BCVA letters with a 95% confidence interval of (-2.865, 0.848)
In the intent-to-treat (ITT) population, the mean change in BCVA at Week 12 was:
- ONS-0510: +5.5 letters
- Ranibizumab: +6.5 letters
Note: The noninferiority margin was met at Week 12 (p = 0.0043), which indicated “that the two study arms are not different at this timepoint," Outlook stated.
Go on …
Notably, all three study timepoints demonstrated similar outcomes in both study arms for change in central retinal thickness.
Stick with visual improvements for a moment.
You got it. And let’s also remember that a special protocol assessment (SPA) was in place for this study.
While the company previously reported the study failed to meet its prespecified noninferiority endpoint at Week 8 (as set by the SPA), BCVA data across all study timepoints demonstrated an improvement in both vision and the presence of biologic activity.
ONS-5010’s mean VA improvements:
- At Week 4: +3.3 letters
- At Week 8: +4.2 letters
- At Week 12: +5.5 letters
How about its safety data?
The candidate was “generally well-tolerated” with overall ocular adverse events deemed to be comparable to that of ranibizumab.
As for safety: Results demonstrated across the study’s entire duration were consistent with those reported in previous NORSE trials (we’ll get to those in a moment)—including no cases of retinal vasculitis reported in either study arm.
Nice! And speaking of comparing to previous trials …
That would be three prior NORSE studies:
- NORSE ONE (NCT03844074)
- NORSE TWO (NCT03834753)
- NORSE THREE (NCT04516278)
See here for details on the results from each.
So … what does all this data mean for OSN-05010?
Outlook Interim CEO Lawrence Kenyon stated that these “statistically significant” 12-week results—combined with the entire NORSE EIGHT data set—confirm the previously-reported success of the pivotal phase 3 NORSE TWO study on the candidate.
And because of this, the data will “support the resubmission of our [Biologics License Application] in the United States,” concluded Kenyon, who is also the company’s chief financial officer.
Resubmission, you say?
Indeed. As you may remember, the company previously attempted (and failed) to submit a BLA for ONS-0510 in 2023.
- See here for details on that, including the company response letter the FDA issued to Outlook.
And the company’s hope for the updated BLA?
“We remain confident in the potential of ONS-5010 … to provide an important therapy for the treatment of wet AMD in place of off-label repackaged bevacizumab that has not received regulatory approval for use in retinal diseases here in the United States,” Kenyon stated.
Lastly, what’s the timeframe for this submission?
Q1 2025.