The third time was not the charm for Aldeyra Therapeutics’ new drug application (NDA) resubmission to the FDA for reproxalap to treat the signs and symptoms of dry eye disease (DED).
The federal agency sent the company its third complete response letter (CRL) in a rejection of this latest attempt to secure regulatory approval.
Oh dear. Shall we start with a look at reproxalap?
Sure thing.
But after reporting on this eye drop-formulated, small-molecule modulator of reactive aldehyde species (RASP)—also currently under clinical development for allergic conjunctivitis (AC)—over the last 3+ years, it might be easier for us to direct you to our prior rundowns.
- See here for more details on what a RASP is.
- Click here to read how Aldeyra’s RASP Modulator Platform is utilized in reproxalap’s mechanism of action (MOA).
- And check out how the drop works.
What makes it unique from other dry eye drops?
The company has referred to reproxalap as the first investigational drug with pivotal clinical data “supportive of acute and chronic activity” in reducing DED symptoms
In fact, signs of activity have been shown to begin within minutes of topical administration and last up to 12 weeks.
Do we have clinical data to back that up?
Indeed we do: Safety and efficacy findings from five clinical studies conducted on over 3,000 patients plus additional results from (more than one) phase 3 dry eye chamber trial
See here for the August 2024 positive reporting from one of those dry eye chamber studies, and see here for results from a second dry eye chamber trial.Take note: That second trial’s data was requested by the FDA and was the only new clinical data in Aldeyra’s most recent NDA resubmission for reproxalap.
Speaking of those … talk about these multiple NDA submissions.
Check out this timeline of reproxalap’s initial NDA submission in late 2022 (which the FDA accepted for review in February 2023) and Aldeyra’s receipt of the first CRL (in November 2023).
Fast forward to October 2024: Aldeyra resubmitted its NDA—with new positive phase 3 data—and the FDA accepted the submission in November 2024.
But then, in April 2025: The federal agency rejected this NDA (see here for details on why).
One month after this—and in light of updated positive phase 3 data—the company announced plans in May 2025 to (once again) resubmit its NDA.
This resubmission was announced in June 2025, and the FDA accepted the (now third) NDA package to review in July 2025.
And that brings us up to date?
It does.
So what’s the FDA’s latest reasoning?
In announcing this third CRL, Aldeyra quoted three specific snippets from the letter:
- The first: That the agency noted a “lack of substantial evidence consisting of adequate and well-controlled investigations … that the drug product (reproxalap) will have the effect it purports or is represented to have under conditions of use prescribed, recommended, or suggested in its proposed labeling.”
- The second: That Aldeyra’s "application has failed to demonstrate efficacy in adequate and well controlled studies in the treatment of signs and symptoms of (DED).”
- And the third: That the “totality of evidence from the completed clinical trials does not support the effectiveness of the product.”
Were there any issues taken with the drug’s safety or manufacturing?
No, thankfully. As with the review of reproxalp’s previous two NDA submissions, the FDA identified “no safety or manufacturing concerns," according to Aldeyra.
The company also noted that, during the NDA review period, label drafts were provided by the FDA twice—once in December 2025 and again earlier this month.
- For context: Label drafts are proposed versions of an investigational drug’s prescribing information, patient labeling, and container labels submitted by sponsors (such as Aldeyra) for regulatory review to ensure the drug’s safety, efficacy, and compliance.
And in this case: Aldeyra stated it “does not believe that label negotiations were completed.”
How interesting ... so did the FDA recommend next steps?
The agency advised that “the reasons for failure in certain trials” (presumably included in reproxalap’s NDA package) should “be explored,” and that Aldeyra should identify the “populations or certain conditions in which reproxalap may be effective.”
- Editor’s note: Let’s keep in mind that, as we mentioned, the eye drop is also under clinical development for allergic conjunctivitis.
Importantly: “The FDA did not recommend conducting additional trials or request submission of additional confirmatory evidence,” according to the company.
But what does that mean for Aldeyra?
It doesn’t appear the company is calling it quits on its quest for regulatory approval and eventual market access.
In fact, while Aldeyra shared that it has no plans to pursue additional clinical trials on the investigational eye drop, it does intend to "expeditiously request a Type A meeting” with the FDA to “understand the actions needed for NDA approval”—likely within the next 30 days.
- See here for a refresher on Type A meetings.
Does that mean … a fourth NDA submission?
It’s entirely possible.
But let’s also not forget that AbbVie, Inc. holds some cards, as the company has an exclusive option to collaborate with Aldeyra on a U.S. commercialization of reproxalap.
Only time will tell what will happen …. so stay tuned.