Aldeyra Therapeutics, Inc. is hoping third time’s the charm for its resubmission of (its resubmitted) new drug application (NDA) for topical ocular reproxalap (0.25% reproxalap ophthalmic solution), an investigational candidate for the signs and symptoms of dry eye disease (DED).
This follows the company’s announcement last month of plans to resubmit the NDA in the wake of reporting new positive phase 3 data.
Sounds like quite the regulatory journey up to this point.
It really has been. For some background, check out this timeline of Aldeyra’s initial attempt at an NDA submission for reproxalap (and the FDA’s subsequent rejection).
Then: See here for details on the company’s second submission (in October 2024, with new data) and click here for the federal agency’s most recent rejection (in April 2025).
Before we get any more into this, tell me about reproxalap.
What it is: A small-molecule modulator of reactive aldehyde species (RASP) under clinical development for DED and allergic conjunctivitis (AC).
- Quick RASP refresh: This is a class of molecules elevated in ocular and systemic inflammatory disease and known to cause:
- Decrease in tear production
- Conjunctival hyperemia
- Change in lipid tear composition
- Increased ocular inflammation
To note: Aldeyra’s RASP Modulator Platform targets a family of small protein-binding molecules that, in turn, enable them to simultaneously determine the activity and structure of multiple proteins.
And how does this drop work, exactly?
Aldeyra previously reported reproxalap to be “the first investigational drug with pivotal data supportive of acute and chronic activity in reducing (DED) symptoms,” with signs of activity beginning within minutes of topical administration and lasting up to 12 weeks.
- In addition: The asset has undergone clinical evaluations spanning five clinical studies and nearly 3k patients so far for both its DED and AC indications (with promising safety and efficacy results).
Plus: In August 2024, a phase 3 dry eye chamber trial met its primary endpoint of ocular discomfort—an FDA-accepted DED symptom—from 80 to 100 minutes in the dry eye chamber.
- In reporting this, Aldeyra noted reproxalap to be the first drug “for chronic administration with pivotal data supportive of acute activity in reducing ocular redness.”
And didn’t the company report new phase 3 data recently?
Yes! This was from another phase 3 dry eye chamber trial—a randomized, double-masked, and vehicle-controlled study, to be specific.
Take note: Findings from this study are the only new clinical data included in Aldeyra’s most recent resubmitted NDA—per its agreement with the FDA.
Tell us about those findings.
To start, the study met its prespecified primary outcome (ocular discomfort), in which reproxalap was statistically superior to vehicle from 80 to 100 minutes following chamber entry (details here).
Plus: The eye drop was well tolerated, with no safety signals or treatment-related discontinuations—and resulted in only mild and transient instillation site discomfort that lasted less than 1 minute.
- And importantly: There were no major differences in baseline scores between treatment arms.
Stick with that last finding—why is it key for this new submission?
President and CEO Todd C. Bracy, MD, PhD, noted that this lack of notable baseline differences across treatment arms—coupled with a “highly statistically significant achievement" of that primary endpoint—adequately addressed any prior concerns the FDA raised over the company’s previous NDA resubmission.
As a refresh: Aldeyra had most recently received a Company Response Letter (not for the first time) from the FDA regarding “potential methodological issues” in its prior phase 3 dry eye chamber trial that may have impacted the results.
- Because of that, an additional symptom trial (the aforementioned second dry eye chamber trial) was needed for another NDA resubmission.
Duly noted. So what happens now?
Because this NDA is a resubmission (and not a first-time submission), the FDA has 30 days (instead of the usual 60) to acknowledge acceptance for review. See here for details on this process.
If accepted, a Prescription Drug User Fee Act (PDUFA) will be established, and a submission review could be completed within 6 months.