Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial.

INTRODUCTION: This clinical trial assessed the activity of reproxalap, a novel reactive aldehyde species modulator, and estimated clinically relevant thresholds for changes in ocular itching and redness in an allergic conjunctivitis field trial. METHODS: This was a randomized, double-masked, vehicle-controlled phase 2 trial. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days in an environmental setting with approximately four doses per day of either 0.25% reproxalap, 0.5% reproxalap, or vehicle. Patients recorded ocular itching, redness, tearing, and eyelid swelling scores (each with a 0-4 scale, except for a 0-3 scale for swelling), and completed the Allergic Conjunctivitis Quality of Life Questionnaire at the beginning and end of the trial. RESULTS: Mixed model of repeated measures analysis demonstrated statistically lower itching and tearing scores (pooled P = 0.026 and P < 0.001, respectively) and numerically lower redness and eyelid swelling scores than vehicle on days when pollen exceeded the 95th percentile value. Using three anchor-based and three distribution-based approaches, the meaningful within-patient change and the between-group meaningful difference for patient-reported ocular itching and redness was estimated to be approximately 0.5. The most common treatment-emergent adverse event associated with reproxalap was transient irritation upon instillation. CONCLUSION: In a field clinical trial, reproxalap was well tolerated and superior to vehicle in reducing ocular itching on high-pollen days. The clinical meaningfulness threshold estimates of 0.5 units are among the first such calculations generated for the standard ocular itching and redness scores, providing important context for the clinical interpretation of clinical trials in allergic conjunctivitis.

While allergic conjunctivitis affects millions of patients worldwide, treatments with new mechanisms have not been introduced in decades. Reproxalap, a medicine being investigated as a treatment for allergic conjunctivitis, works by regulating reactive aldehyde species­molecules that are increased in a variety of inflammatory diseases. This clinical trial assessed the activity of reproxalap and estimated what amount of change in ocular itching and redness should be considered clinically important. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days and were given one of three possible eye drops at approximately four doses per day: 0.25% reproxalap; 0.5% reproxalap; or vehicle, which was composed of the same ingredients but does not contain reproxalap. Patients recorded ocular itching, redness, tearing, and eyelid swelling (all scales ranged from 0 [none] to 4 [severe] except for eyelid swelling, which ranged from 0 to 3), and completed a quality-of-life questionnaire on allergic conjunctivitis at the beginning and end of the trial. The results indicated that reproxalap was significantly better than vehicle in reducing itching and tearing scores and was better than vehicle in reducing redness and eyelid swelling scores on days when pollen counts were high. The trial also suggested that a reduction in ocular itching and redness scores of approximately 0.5 or more (scale 0­4) is likely to be clinically important. Overall, reproxalap was well tolerated and no safety concerns were noted. The most common side effect was transient ocular discomfort after eye drop administration.

A Post-Acute Ocular Tolerability Comparison of Topical Reproxalap 0.25% and Lifitegrast 5% in Patients with Dry Eye Disease.

PURPOSE: To assess the subjective eye drop experience of patients with dry eye disease (DED) over approximately 1 hour after a single dose of two formulations of reproxalap versus lifitegrast. METHODS: Two formulations of topical ocular reproxalap 0.25% were evaluated versus lifitegrast ophthalmic solution 5% in patients with DED in a single-center, double-masked, active-comparator, single-dose crossover clinical trial. Nineteen patients had test article topically administered to both eyes. Treatments were administered 2 to 4 days apart. Comfort assessments, including ocular discomfort, blurry vision, and dysgeusia assessments; ocular descriptive assessments; quality of life assessments; and overall experience questions were completed after each treatment over one hour, beginning at 90 seconds. RESULTS: Both reproxalap formulations scored better in ocular discomfort score (ODS), blurry vision, and dysgeusia assessments than lifitegrast at each timepoint and cumulatively over all time points after instillation. There were lower rates of negative responses for both reproxalap formulations compared to lifitegrast across ocular discomfort, blurry vision, and dysgeusia assessments, and the durations of negative responses were shorter with reproxalap than with lifitegrast. The reproxalap groups experienced fewer quality of life impacts. No significant safety findings were observed following reproxalap or lifitegrast administration. CONCLUSION: The reproxalap eye drop experience over 1 hour after instillation was superior to that of lifitegrast. There were no statistically significant differences between reproxalap groups for ODS, blurry vision, or dysgeusia. The improved performance of reproxalap with regard to the most commonly reported side effects of lifitegrast (ie, ocular discomfort, blurry vision, and dysgeusia) may result in greater patient adherence and lower discontinuation rates.

Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial.

PURPOSE: To assess the post-acute activity and clinical utility of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, versus vehicle in patients with seasonal allergic conjunctivitis. DESIGN: Parallel-group, double-masked, randomized Phase 3 trial. METHODS: Two topical ocular reproxalap concentrations (0.25% and 0.5%) were evaluated versus vehicle in patients with allergic conjunctivitis randomized 1:1:1 and treated with test article 10 minutes prior to conjunctival seasonal allergen challenge. The primary endpoint was area under the post-acute ocular itching score (range = 0-4) curve from 10 to 60 minutes after challenge. The key secondary endpoint was the proportion of subjects with ≥2 points improvement from their peak ocular itching score at baseline. RESULTS: A total of 318 patients were randomized at 11 US sites. Both concentrations of reproxalap (0.25% and 0.5%) achieved the primary endpoint (P < .0001 and P = .003, respectively) and the key secondary endpoint (P = .0005 and P = .02, respectively). Time to complete resolution of ocular itching was statistically faster for both reproxalap concentrations than for vehicle (P < .0001 and P = .001, respectively). No safety or tolerability concerns were noted. The most common adverse event was mild and transient instillation site irritation. CONCLUSION: Reproxalap was effective at reducing ocular itching in patients with allergic conjunctivitis. Reproxalap activity was clinically relevant, as assessed by responder-based and distributional analyses. ALLEVIATE represents one of the first allergic conjunctivitis Phase 3 trials of a novel mechanism of action in decades, and is unique among conjunctival allergen challenge trials in assessing clinical relevance with standard and validated techniques.