The FDA has sent Aldeyra Therapeutics, Inc. a company response letter regarding its new drug application (NDA) for 0.25% reproxalap ophthalmic solution, a potential treatment for dry eye disease (DED).
This follows the agency’s late-cycle meeting with the company last month, which identified major issues over the drug’s study data (see here for details) from their clinical trials.
Refresh me on reproxalap.
The investigational new drug candidate is Aldeyra’s first-in-class, small-molecule modulator of a reactive aldehyde species (RASP).
RASP is known to be elevated in ocular and systemic inflammatory disease as well as causing a decrease in tear production, conjunctival hyperemia, change in lipid tear composition, and increased ocular inflammation.
To note, the FDA accepted a new drug application (NDA) for reproxalap earlier this year for DED, with a Prescription Drug User Fee Act (PDUFA) date of November 23, 2023 (which has officially come and gone).
Further, the candidate is also under clinical development (with positive phase 3 trial data released in June 2023) for allergic conjunctivitis.
How quickly can it work?
Per previous study data evaluating an indication for the treatment of DED, reproxalap has illustrated signs of activity ranging from within minutes of administration to up to 12 weeks.
More clinical details, please.
The reproxalap NDA submission for the indication of treating DED was based on data from its performance in five well-controlled clinical trials. See here for the details.
In February 2023, Aldeyra reported positive topline data from a 12-month safety trial that illustrated statistically superior visual acuity (VA) improvements.
Switching to reproxalap’s potential indication for allergic conjunctivitis—in June 2023—topline data from a phase 3 trial found that reproxalap-treated patients demonstrated a statistically significant reduction in ocular itching score across all 11 pre-specified primary endpoint comparisons (P < 0.0001 for each).
Similarly, for the secondary endpoint, reproxalap patients exhibited a statistically significant reduction from baseline versus vehicle (P = 0.004).
Gotcha. Talk more about what happened last month.
The FDA expressed concerns regarding the adequacy of clinical evidence for reproxalap’s indication for DED and requested more data on reproxalap’s chemistry, manufacturing, and controls (CMC) processes.
See our coverage here.
Now this company response letter.
Per the letter (according to Aldeyra), the FDA stated that Aldeyra’s NDA failed to demonstrate efficacy for treating ocular symptoms associated with dry eye, and that “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted.
Why the need for an additional trial?
The FDA’s DED guidance recommends an investigational candidate demonstrate efficacy through two symptom trials and two sign trials.
Let’s take note: Aldeyra has already conducted three trials (previously mentioned above) of this kind:
- Two for ocular redness
- One for DED symptoms
So what’s next?
Aligned with this guidance, Aldeyra recently submitted a special protocol assessment (SPA) for a DED chamber crossover trial on reproxalap, which could potentially allow for the company to resubmit its NDA.
And the new timeline?
Per the company, the FDA has 45 days to review the SPA with feedback expected by December 2023.
If accepted, the proposed trial (reported cost estimated at less than $2 million) could release topline data within the first half of 2024.
Significance?
According to Aldeyra CEO and President Todd C. Brady, MD, PhD, if the SPA and trial results are a success—along with the approval of a resubmitted NDA—”the drug label may be the first label in dry eye disease to contain acute reduction in ocular redness, as well as a combination of chronic and acute symptomatic benefit.”This could potentially highlight “the rapid activity of reproxalap on both signs and symptoms of dry eye disease”, he stated.