Just one month after the FDA rejected its new drug application (NDA) for 0.25% reproxalap ophthalmic solution (reproxalap), Aldeyra Therapeutics, Inc. announced positive phase 3 data on the investigational dry eye disease (DED) treatment.
First things first: a reproxalap refresh.
Its claim to fame: Reproxalap is Aldeyra’s flagship investigational candidate, under clinical development for DED and allergic conjunctivitis.
What it is: A small-molecule modulator of the molecule class reactive aldehyde species (RASP)—known for their elevation in ocular and systemic inflammatory disease.
- See here for details on the ocular impact of RASPs.
And in connection to Aldeyra: These are instrumental in its RASP Modulator Platform, designed to target a family of small protein-binding molecules that, in turn, enable them to simultaneously determine the activity and structure of multiple proteins.
So how does this candidate work, exactly?
Reproxalap is formulated as an eye drop topically applied to the eye.
As for a timeframe on its efficacy: The company previously reported DED clinical data that found it began to demonstrate signs of activity beginning within minutes of administration and extending up to 12 weeks.
And the conclusion Aldeyra has drawn based on clinical investigations (of nearly 3K patients) thus far:
- “Reproxalap is the first investigational drug with pivotal data supportive of acute and chronic activity in reducing symptoms, and the first investigational drug for chronic administration with pivotal data supportive of acute activity in reducing exacerbation of ocular redness.”
Speaking of clinical data … talk about the latest reporting.
That would be on a phase 3 dry eye chamber trial.
Keep in mind: The company previously reported favorable data from another phase 3 dry eye chamber study back in August 2024.
What we know about this study:
- Design: A randomized, double-masked, vehicle-controlled dry eye chamber trial
- Participants: 116 DED patients
- Setup: Randomized into two groups to receive either reproxalap or a vehicle solution before and during exposure to an additional dry eye chamber
- Reproxalap group (n = 58)
- Vehicle group (n = 58)
- The primary outcome measure: Ocular discomfort (based on a symptom score of 0 to 100)
And these new findings?
Starting with the study’s prespecified primary outcome: Reproxalap was found to be statistically superior to vehicle from 80 to 100 minutes following chamber entry.
- LS mean difference [95% confidence interval] ‑6.5 (‑10.5, ‑2.5), P=0.002
Additionally: Reproxalap was observed to be well tolerated, with no safety signals or treatment-related discontinuations—which, the company noted, was similar to its recently completed DED field trial.
- And across treatment arms, investigators noted “no notable differences in baseline scores.”
Any adverse events?
The most common adverse event reported: mild and transient instillation site discomfort (which was consistent with prior clinical research on reproxalap).
So what’s significant about this data?
Zeroing in on that note about no major difference in baseline scores between treatment arms, Aldeyra stated that this could potentially address (and resolve) issues raised by the FDA in its company response letter (CRL) sent to the company last month.
To note: This CRL was issued by the federal agency in response to Aldeyra’s second attempt to submit a new drug application (NDA) for reproxalap’s DED indication.
- For some background on this situation, check out our abbreviated timeline.
And what did these issues include?
Two main concerns over reproxalap’s NDA:
- The NDA failed to demonstrate its efficacy in “adequate and well controlled studies” for treating “ocular symptoms associated with dry eyes.”
- At least one additional “adequate and well controlled study” still needs to be conducted to demonstrate reproxalap’s positive effect in treating dry eye ocular symptoms.
And an additional issue noted: The FDA’s questioning of clinical trial data submitted with this latest NDA, with the CRL stating that a misinterpretation of the results may have been due to methodological issues such as a difference in baseline scores across treatment arms.
That last note is major, isn’t it?
It really is. As President and CEO Todd C. Brady, MD, PhD, shared, the company is looking forward to a Type A meeting with the FDA to discuss next steps.
Remember: Type A meetings are typically reserved for discussions between a company and the FDA on an otherwise stalled product development program to determine whether to proceed with NDA submission or to address important safety issues.
So what’s the plan?
Pending a positive outcome from this meeting, Aldeyra hopes to resubmit its reproxalap NDA mid-2025 (followed by a 6-month review period).
Here’s hoping the third time is the charm!