Aldeyra Therapeutics, Inc. released details of its plans to resubmit a new drug application (NDA) for 0.25% reproxalap ophthalmic solution, a potential treatment for dry eye disease (DED).
First, tell me about reproxalap.
The investigational new drug candidate is Aldeyra’s first-in-class, small-molecule modulator of a reactive aldehyde species (RASP).
Note: RASP is known to be elevated in ocular and systemic inflammatory disease as well as cause a decrease in tear production, conjunctival hyperemia, change in lipid tear composition, and increased ocular inflammation.
Also: The candidate is also under clinical development for allergic conjunctivitis (see here for phase 3 topline data, released in June 2023), which including findings that reproxalap demonstrated a statistically significant reduction in ocular itching score across all 11 pre-specified primary endpoint comparisons (P < 0.0001 for each).
How long does it take to work?
Previous study data on reproxalap for DED found that it demonstrated signs of activity ranging from within minutes of administration to up to 12 weeks.
That’s a pretty wide range of time … what other clinical data is available?
In total, the candidate has been investigated in five well-controlled clinical trials.
See here for those details.
Zeroing in on previous Glance coverage, Aldeyra reported positive topline data from a 12-month safety trial that illustrated statistically superior visual acuity (VA) improvements.
Now let’s have some background info.
Here’s a chronological timeline:
- February 2023: The FDA accepted Aldeyra’s original NDA for reproxalap, setting a Prescription Fee Drug User Act (PDUFA) deadline of Nov. 23, 2023.
- October 2023: The agency identified substantive review issues following a late-cycle review meeting with Aldeyra on the drug’s study data (see here for details) from their clinical trials
- FDA requested more data on its chemistry, manufacturing, and controls (CMC) processes.
- November 2023: Days after its PDUFA deadline, the company received a company response letter from the FDA with concerns over the candidate’s adequacy of clinical evidence for its indication
- Per the agency: Reproxalap’s NDA failed to demonstrate efficacy for treating ocular symptoms associated with dry eye
- Also: 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
- Then: Aldeyra submitted a special protocol assessment (SPA) for a dry eye chamber crossover trial on reproxalap.
Gotcha. So what are Aldeyra’s new NDA plans?
Aligning with its SPA submission plans, the company has reported it is planning to initiate a dry eye chamber clinical trial within H1 (the first half of) 2024.
Then—pending positive data from this study—an “NDA resubmission is expected in the second half of 2024,” with an anticipated 6-month review process to follow.
Talk about this planned trial.
Per Aldeyra, the proposed trial will enroll an estimated 100 participants, with each being administered a drug product without the active ingredient (vehicle) both before and during exposure to a dry eye chamber.
“Qualifying patients” will then be randomized to receive either reproxalap or vehicle before and during exposure to an additional dry eye chamber.
And what’s being measured?
The primary endpoint will be ocular discomfort, which is based on previous clinical data that found ocular discomfort in the dry eye chamber after reproxalap treatment was statistically lower than vehicle (p = 0.0003).
What else?
Aldeyra also reported that the trial is expected “to be more than 90% powered to detect a difference between treatment groups.”
Plus, other studies are planned to be conducted in parallel with this study as part of a “comprehensive strategy designed to account for heterogeneity and potential differences in clinical sites and environment.”
These include:
- A clinical trial at a different dry eye chamber
- Traditional 6-week field clinical trial
Lastly .. any input from the company?
Yes! Aldeyra’s President and CEO Todd C. Brady, MD, PhD, noted that, if successful, this dry eye chamber trial “could represent the first pivotal demonstration of rapid improvement in the symptoms of dry eye disease.”