Efficacy and Safety of Reproxalap 0.25% Ophthalmic Solution in Dry Eye Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Abstract
Purpose Dry eye disease (DED) is an ocular surface disorder characterized by tear-film instability, inflammation, and symptoms that can impair visual function and quality of life. Reproxalap is a topical reactive aldehyde species (RASP) inhibitor. This systematic review and meta-analysis assessed the efficacy and safety of reproxalap 0.25% ophthalmic solution vs vehicle in adults with DED. Methods MEDLINE/PubMed, Embase, Cochrane CENTRAL/Cochrane Library, and ClinicalTrials.gov were searched through June 20, 2026. The PROSPERO-registered review (CRD420261425460) included randomized trials and public trial-registry results records with extractable 0.25% reproxalap-versus-vehicle data. Outcomes included Schirmer test change and response (at least 10 mm improvement), instillation-site irritation, treatment-emergent adverse events (TEAEs), and discontinuation. Risk of bias and certainty were assessed using RoB 2 and GRADE. Results Six eligible sources involving 2230 randomized participants were included. Reproxalap improved Schirmer test score (mean difference [MD], 2.34 mm; 95% confidence interval [CI], 1.45 to 3.22; P < 0.0001; I2 = 0%) and Schirmer response (risk ratio [RR], 2.04; 95% CI, 1.68 to 2.46; P < 0.0001; I2 = 0%). Instillation-site irritation was more frequent (RR, 27.27; 95% CI, 12.20 to 60.99; P < 0.0001) but was generally mild and transient in published reports. Any TEAE was uncertain (RR, 2.02; 95% CI, 0.92 to 4.44; P = 0.082). Adverse event-related discontinuation was more frequent (RR, 4.88; 95% CI, 2.36 to 10.10), whereas all-cause discontinuation did not differ (RR, 0.99; 95% CI, 0.50 to 1.99). Conclusions Reproxalap 0.25% demonstrated rapid objective tear-production improvements vs vehicle, though routine clinical recommendation must be weighed against frequent, transient instillation-site irritation. No treatment-related serious ocular adverse events were reported. Certainty ranged from low to very low due to reliance on registry-only data, trial program endpoint restructuring, eye-level denominators, and small study numbers.