Aldeyra Therapeutics, Inc. announced that the FDA has issued a complete response letter (CRL) following the company’s resubmission of a new drug application (NDA) for its flagship investigational candidate: reproxalap 0.25% ophthalmic solution (reproxalap).
Let’s just get straight to the point: What does this CRL mean?
In general: A CRL is sent when the FDA concludes it cannot approve an NDA in its current form due to specific deficiencies in the application—ranging from minor (such as labeling issues) to major (a request for new clinical trials).
- In this case: The FDA determined that Aldeyra’s second attempt at FDA approval for repreoxalap as a treatment for dry eye disease (DED) has, once again, failed (over major deficiencies).
Got it. Now give me some background on this situation.
As we previously reported in November 2024 (following the FDA’s acceptance of Aldeyra’s second NDA submission for reproxalap), a timeline works best for breaking this down.
- February 2023: The FDA accepted Aldeyra’s original NDA for reproxalap, setting a Prescription Fee Drug User Act (PDUFA) deadline for November 2023.
- October 2023: The FDA identified substantive review issues following a late-cycle review meeting with Aldeyra on the drug’s clinical study data from their clinical trials, and additional data on its chemistry, manufacturing, and controls (CMC) processes was requested
- November 2023: The company was issued a CRL that detailed concerns over the clinical evidence for reproxalap’s DED indication
- The FDA’s reasoning: NDA failed to demonstrate efficacy for treating ocular symptoms associated with dry eye.
- The request: At least one additional adequate and well-controlled study is needed to demonstrate a positive effect on the treatment of ocular symptoms of dry eye.
- In response: Aldeyra submitted a special protocol assessment (SPA) for a dry eye chamber crossover trial on reproxalap
I’m up to date. So what is the FDA’s reasoning in this latest CRL?
To start: Aldeyra emphasized the agency identified no manufacturing or safety issues with reproxalap.
However: The FDA reportedly highlighted two main issues.
- 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.
What else?
The company further shared that the CRL called out concerns over the clinical trial data that was submitted with this latest NDA that “may have affected interpretation of the results.”
- This misinterpretation may have been due to methodological issues such as a difference in baseline scores across treatment arms.
A regulatory refresh: Per the FDA’s draft guidance for DED-based NDAs, DED efficacy of an investigational candidate can be demonstrated through two symptom and two sign clinical trials.
I want to hear about these clinical trials, but first: give me a rundown on reproxalap.
What it is: A small-molecule modulator of reactive aldehyde species (RASP) formulated as an ophthalmic solution and administered via eye drops.
- Quick RASP refresh: This is a class of molecules known to be elevated in ocular and systemic inflammatory disease and is also known to cause:
- Tear production decrease
- Conjunctival hyperemia
- Lipid tear composition change
- Ocular inflammation increase
And in the context of Aldeyra’s candidate?
Reproxalap is one of the company’s RASP modulator investigational candidates.
How they’re utilized: Via Aldeyra’s RASP Modulator Platform, designed to target a family of small protein-binding molecules—thus enabling it to “influence the activity and structure of multiple proteins simultaneously.”
- Notably: This differs from traditional therapeutics that typically only target specific proteins.
In other words: Aldeyra’s approach for treating immune-mediated diseases like DED and allergic conjunctivitis (its other investigational indication) involves “modulating” the immune system with pharmaceuticals (such as reproxalap) to reduce RASP levels and, in turn, prevent RASP-linked inflammation and toxicity.
And how does this translate to reproxalap’s mechanism of action?
Previous clinical data on the DED candidate found it to demonstrate signs of activity starting just minutes after topical administration and lasting up to 12 weeks.
As the company previously reported: Reproxalap is “the first investigational drug with pivotal data supportive of acute and chronic activity in reducing (DED) symptoms.”
Gotcha. So about that trial data; what’s the latest?
Aside from the five clinical studies reproxalap has undergone (for both DED and allergic conjunctivitis), its most recent data comes from that phase 3 dry eye chamber crossovers study.
- Remember: This study was conducted in response to the FDA’s request in that initial CRL for more clinical data.
The data thus far: Aldeyra reported positive findings in August 2024, with reproxalap being well-tolerated, and the trial met its primary outcome of ocular discomfort from 80 to 100 minutes in the dry eye chamber.
And what’s next for the company and its candidate?
Aldeyra expects to meet with the FDA within the next month to discuss this latest CRL as well as its ongoing DED-indicated reproxalap clinical trials.
And speaking of trials: The company also reported plans to release new data from an ongoing DED field trial and chamber clinical trial in Q2 2025.
Are there plans for a third reproxalap NDA submission then?
Indeed there are. Pending positive data from the aforementioned DED trials (and its meetings with the FDA), Aldeyra intends to resubmit its NDA in mid-2025.