After announcing its plans to resubmit a new drug application (NDA) for 0.25% reproxalap, Aldeyra Therapeutics, Inc. has enrolled all participants in a phase 3 dry eye chamber clinical trial evaluating the topical ocular candidate for dry eye disease (DED) treatment.
Let’s begin with reproxalap.
Aldeyra’s first-in-class, small-molecule asset is a reactive aldehyde species (RASP) inhibitor currently under clinical development for both DED and allergic conjunctivitis.
Refresher on RASP: This is known to be elevated in ocular and systemic inflammatory disease (such as DED) and cause conjunctival hyperemia, a decrease in tear production, a change in lipid tear composition, and increased ocular inflammation.
Talk about its mechanism of action.
The formulation, when topically administered for DED, has been clinically proven to demonstrate signs of inhibition in symptoms ranging from within minutes to up to 12 weeks post-application
And the clinical data on it so far?
Reproxalap has been clinically investigated in 2,000+ patients across five well-controlled trials so far. Notable findings include:
Phase 2b trial: Primary endpoint was achieved, with the eye drop demonstrating significant improvements in symptoms such as:
- Dryness
- Grittiness
- Stinging
- Burning
- Sign measures such as
- Schirmer’s test
- Tear break-up time
- Osmolarity
- Fluorescein staining
Phase 3 study: Met its primary endpoint and was significantly superior for its two pre-specified endpoints after a single day of dosing:
- Schirmer’s test (p=0.0001)
- ≥10 mm Schirmer test responder proportions (p<0.0001)
Go on …
Plus, the company noted that in four previously completed dry eye chamber clinical trials—when analyzed in aggregate with the trial design and statistical plan discussed with the FDA—ocular discomfort in the dry eye chamber following treatment with reproxalap was statistically lower than that of vehicle (p=0.0003).
Gotcha. Now refresh me on these NDA resubmission plans.
First: The company had originally submitted an NDA to the FDA (which was accepted) in February 2023 and had been given a Prescription Fee Drug User Act (PDUFA) deadline of November 2023.
- The issue: The FDA identified review issues after a late-cycle review meeting with Aldeyra regarding the drug’s clinical data and requested additional data on its chemistry, manufacturing, and controls (CMC) processes.
Then: In November 2023, the FDA sent a company response letter indicating its concerns over the candidate’s adequacy of clinical evidence for its proposed indication.
And most recently: In April 2024, Aldeyra announced it intended to resubmit an NDA for reproxalap (for DED) and initiate a dry eye chamber clinical trial. See here for those details.
- Why this trial is key: Pending positive findings, the data would enable an NDA resubmission and an anticipated 6-month review process to follow.
Alrighty, I’m up to date! Give me the rundown on this phase 3 study.
The randomized, double-masked, vehicle-controlled parallel group trial has enrolled an estimated 132 participants (aged 18-70) with the following criteria:
- History of dry eye-associated ocular discomfort for at least 6 months (prior to study)
- History of eye drop use for DED between 2 weeks to 6 months (prior to study)
Study design: Patients will be randomized into two groups to receive either:
- Reproxalap administered six times a day (6x/day) over two consecutive days
- Vehicle ophthalmic solution administered 6x/day over two consecutive days
And what’s being measured?
The primary outcome measure is ocular discomfort over 100 minutes within the dry eye chamber at Visit 2 and Visit 4, as measured using a 0-100 visual analog scale (VAS) in which 0 indicates no discomfort and 100 is maximum discomfort.
The time frame: Day -14 (prior to the study) to Day 2 of the study.
Note: This outcome measure 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).
So when might data be expected from this study?
Per Clinical Trials, the study is expected to conclude in December 2024 … but data will likely be released in the interim.
And the overarching significance of this NDA resubmission?
If the application is approved, the “draft label could represent the first (DED) label that incorporates clinical data assessed acutely in a dry eye chamber, and potentially the first (DED) label that includes reduction in ocular redness for a chronically administered drug,” Aldeyra stated.