Reproxalap 0.25% in dry eye disease: A meta-analysis of randomized controlled trials

Abstract

Background

Dry eye disease (DED) is a common, chronic inflammatory disorder of the ocular surface that can impair vision and reduce quality of life. Reproxalap, a novel reactive aldehyde species (RASP) modulator, has shown potential as a targeted anti-inflammatory therapy.

Objective

To evaluate the efficacy and safety of reproxalap 0.25% in patients with DED, with allergic conjunctivitis included as a secondary exploratory analysis.

Design

Systematic review and meta-analysis.

Data Sources and Methods

PubMed, Embase, and ClinicalTrials.gov were systematically searched to identify randomized controlled trials (RCTs) evaluating reproxalap. Meta-analyses were performed using RevMan 5.4 with a random-effects model.

Results

Twelve RCTs were included, comprising 8 studies in DED (n = 2,283) and 4 studies in allergic conjunctivitis (n = 418). In DED, reproxalap significantly reduced ocular dryness scores (SMD: −0.23, 95% CI: −0.38 to −0.08; I² = 0%), increased Schirmer test mean change from baseline (MD: 2.32 mm, 95% CI: 1.55 to 3.10; I² = 0%), improved Schirmer test responder rates (RR: 2.05, 95% CI: 1.71 to 2.44; I² = 0%), and reduced conjunctival redness (MD: −0.13, 95% CI: −0.25 to −0.02; I² = 36%). Exploratory analyses of allergic conjunctivitis showed favorable effect estimates for ocular itching, tearing, and conjunctival redness. However, heterogeneity was substantial across outcomes (I² = 83–96%), the certainty of evidence was very low according to GRADE, and the findings were not robust in sensitivity analyses.

Conclusion

Reproxalap was associated with consistent improvements across key clinical outcomes in DED. Exploratory allergic conjunctivitis findings should be considered hypothesis-generating rather than clinically conclusive. Interpretation of the overall evidence is limited by exclusive industry sponsorship, evidence of publication bias, and the predominantly subjective nature of the primary endpoints. Further large-scale, independently funded RCTs in DED are warranted to further establish the efficacy and safety of reproxalap.

Registration

PROSPERO CRD420251070669.

Plain language summary

Dry eye disease and allergic conjunctivitis are common conditions that can cause discomfort, redness, itching, and blurred vision, and current treatments are not effective for all patients. Reproxalap is an investigational anti-inflammatory eye drop that targets harmful molecules produced during oxidative stress. We combined evidence from 12 randomized clinical trials involving 2,701 participants to evaluate its effectiveness. In dry eye disease, reproxalap consistently improved symptoms, tear production, and ocular redness, with generally consistent findings across studies. In allergic conjunctivitis, it also reduced itching, tearing, and redness, although these results were highly variable and should be considered exploratory. Because all included trials were sponsored by the manufacturer and publication bias was detected for several outcomes, the findings should be interpreted cautiously. Overall, reproxalap appears promising, particularly for dry eye disease, but larger, independently funded studies with longer follow-up are needed before its role in clinical practice can be established.

Introduction

Inflammatory eye diseases are highly prevalent and contribute significantly to ocular morbidity worldwide.^1–3 Dry eye disease (DED) is a common condition that can impair vision, cause discomfort, and negatively affect daily functioning, sleep, and productivity.^4,5 According to TFOS DEWS II Epidemiology Report, DED affects approximately 5-50% of the general population depending on the geographical location. ⁶ Given the high prevalence and significant functional impairment associated with DED, the development of effective and long-acting treatments is essential.

Corticosteroids are commonly used for acute disease but adverse effects such as ocular hypertension, cataracts and opportunistic infections limit their long term use.^7–9 For chronic cases, Restasis (Cyclosporine 0.05%), Xiidra (lifitegrast 5%), and Cequa (Cyclosporine 0.09%) are used. Despite some clinical efficacy, these medications primarily target only T-cell–mediated adaptive immunity, leaving other inflammatory pathways unmodulated. Moreover, they focus on tear film and corneal improvements without treating underlying damage in adnexal tissues like the lacrimal gland and meibomian glands. ¹⁰

Reactive aldehyde species (RASP) are highly reactive byproducts of lipid peroxidation generated during oxidative stress that can covalently modify proteins and signaling molecules, thereby amplifying inflammatory pathways. ¹¹ Reproxalap, a novel small-molecule RASP inhibitor, selectively neutralizes these reactive species, thereby targeting upstream drivers of inflammation without inducing broad immunosuppression.^11,12 Clinical trials have suggested that reproxalap may improve both signs and symptoms of DED positioning it as a promising investigational therapeutic candidate.^11–13

Despite growing interest, evidence regarding the efficacy of reproxalap remains fragmented, with no comprehensive quantitative synthesis across randomized controlled trials evaluating its effects in DED. Therefore, this meta-analysis aims to evaluate the efficacy of reproxalap 0.25% in improving key clinical outcomes in patients with DED, with allergic conjunctivitis included as a secondary exploratory analysis.

Materials and Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.^14,15 The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD420251070669). Ethical approval was not required.

Information Sources and Search Strategy

A comprehensive literature search was conducted in PubMed, Embase, and ClinicalTrials.gov for articles published from January 2000 to January 2026. Additionally, reference lists of included studies and relevant systematic reviews were manually screened to identify any additional eligible studies. Search terms included combinations of: (“Reproxalap” OR “ADX-102″) AND (“ocular surface disease” OR “dry eye” OR “allergic conjunctivitis”). The detailed search strategy for each database is provided in Supplementary Table S1.

Eligibility Criteria and Study Selection

Studies were included if they met the following criteria: (i) randomized controlled trials (RCTs); (ii) enrolled adult participants aged ≥18 years with dry eye disease (DED) or allergic conjunctivitis; (iii) evaluated reproxalap as the intervention, with only the 0.25% formulation selected when multiple doses were reported; (iv) included a comparator group receiving placebo, vehicle control, or standard treatment; and (v) reported at least one relevant efficacy outcome, including conjunctival redness, ocular itching, Schirmer test scores, or ocular dryness scores. Studies were excluded if they were non-randomized, review articles or meta-analyses, conference abstracts without full data, in vitro or animal studies, or if they lacked a control group.

Mendeley Reference Manager, version 2.122.1 (Elsevier Ltd., Amsterdam, Netherlands) ¹⁶ was utilized to remove duplicates. After removing duplicates, two reviewers (MIB and MR) independently screened the titles and abstracts, and conducted a detailed full-text review of the shortlisted articles. Discrepancies were resolved through consultation with a third reviewer (SA).

Full-text peer-reviewed publications, trial registry postings, and sponsor-posted results were considered eligible if sufficient information was available to extract data for outcomes. When multiple sources reported the same trial, they were treated as duplicate records and the peer-reviewed publication was prioritized, with registry data used only if no full-text publication was available. Each trial contributed to a single indication-specific analysis (dry eye disease or allergic conjunctivitis) based on the enrolled population. No study population was included in more than one pooled analysis.

Data Extraction

Two reviewers (MIB and SG) independently extracted data from each included study using a standardized data extraction form. Where trials included multiple dose arms, only data for reproxalap 0.25% were extracted, as this was evaluated in the majority of included trials. Data from other dose arms were not extracted to avoid unit-of-analysis errors. Where studies reported outcomes at multiple time-points, the pre-specified primary time-point was selected; when no primary time-point was pre-specified, the final available assessment was used. The extracted information comprised patient characteristics (number of participants, age, and sex), study details (design, first author, year of publication, country, sample size, eligibility criteria, and follow-up duration), intervention characteristics (dose and duration of reproxalap), comparator details (placebo or vehicle control), and outcome measures (including changes in conjunctival redness, ocular itching, and Schirmer test scores). Discrepancies between reviewers were resolved through discussion and, when necessary, consultation with a third reviewer (MR).

Risk of Bias Assessment

The methodological quality of included studies was assessed using the Cochrane Risk of Bias 2.0 (RoB 2.0) which examines five key domains: (i) bias related to the randomization process; (ii) bias due to deviations from intended interventions; (iii) bias resulting from missing outcome data; (iv) bias in outcome measurement; and (v) bias in the selection of reported results. Two reviewers independently assessed each study and classified the overall risk of bias as “low,” “high,” or “some concerns.” Discrepancies were resolved through discussion with a third reviewer. Visual summaries were generated using the Robvis visualization tool. ¹⁷

Outcome Measures

Outcomes were assessed according to the specific condition. For dry eye disease (DED), conjunctival redness, Schirmer test outcomes (mean change from baseline and responder rate), and subject-reported ocular dryness were evaluated. For allergic conjunctivitis, subject-reported ocular itching, ocular tearing, and conjunctival redness were assessed. Safety outcomes were additionally extracted where reported. If quantitative synthesis of safety data was not feasible due to inconsistent reporting, a structured qualitative summary was planned.

Because outcome instruments and scales varied across studies, study-specific definitions of each outcome, including measurement instruments, scale ranges, and score directionality, are summarized in Supplementary Table S2. Lower effect estimates indicate improvement in ocular dryness, conjunctival redness, ocular itching, and ocular tearing, whereas higher effect estimates indicate improvement in Schirmer test outcomes.

Data Synthesis and Statistical Analysis

Meta-analyses were performed using Review Manager (RevMan) version 5.4. Continuous outcomes were pooled using standardized mean differences (SMDs) when different measurement scales were used across studies and mean differences (MDs) when identical scales were applied, while dichotomous outcomes were summarized using risk ratios (RRs), each with 95% confidence intervals (CIs). ¹⁸ The DerSimonian and Laird random-effects model was applied due to anticipated clinical and methodological heterogeneity. Heterogeneity was assessed using the I² statistic, with thresholds of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. A two-tailed P-value < 0.05 was considered statistically significant. To evaluate the effect of each study on the pooled estimates and heterogeneity, sensitivity analysis was performed by excluding one study at a time.

Assessment of publication bias was performed using Doi plots and the Luis Furuya-Kanamori (LFK) index, implemented through MetaXL version 5.3. ¹⁹ Values between -1 and +1 indicated no asymmetry, ±1 to ±2 suggested minor asymmetry, and beyond ±2 denoted major asymmetry. The LFK index was selected over traditional methods such as the Egger test due to its enhanced sensitivity and statistical power, particularly in meta-analyses with a limited number of included studies. ²⁰

Certainty of Evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence for each primary outcome, considering factors such as study limitations, inconsistency, indirectness, imprecision, and publication bias.^21,22

Results

Study Selection and Characteristics of Included Studies

A total of 329 records were initially identified through database searches, with an additional 20 records retrieved through citation searching. After removing duplicates and screening titles and abstracts, 12 studies (dry eye disease, n = 8^11,23–29; allergic conjunctivitis, n = 4)^12,30–32 were included. The detailed study selection process is illustrated in the PRISMA flowchart (Figure 1). Collectively, the included RCTs enrolled 2,701 patients (2,283 with DED, 418 with allergic conjunctivitis). The studies were published between 2020 and 2026, with mean participant ages ranging from 40.3 to 63.9 years. Follow-up durations varied across studies. Detailed study characteristics are summarized in Table 1.

Figure 1.

PRISMA Flowchart.

Table 1.

Characteristics of Included Studies.

Study ID (Year, Country)	Study Type	Objective	Inclusion Criteria	Intervention	Control	Total Sample Size	Gender (M/F)	Age*	Follow-up
Dry eye disease (DED)
NCT05424549 (2024, Canada)	RCT (quadruple-masked, single-center)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults aged 18–70 years with ≥6 months of dry eye history, recent topical treatment (2 weeks–6 months), and informed consent	Reproxalap 6×/day for 2 days	Vehicle 6×/day for 2 days	63	22/41	49.05 ± 12.72	19–39 days
Tranquility 2 (2025, USA)	RCT (quadruple-masked, single-center)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap administered 7 times over 2 days	Vehicle administered 7 times over 2 days	361	112/249	63.05 ± 12.59	16–32 days
NCT04971031 (2023, USA)	RCT (double-masked, multicenter)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap administered 7 times over 2 days	Vehicle administered 7 times over 2 days	158	44/114	>18 years	16–32 days
Tranquility (2023, USA)	RCT (double-masked, multicenter)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap (0.25%)	Vehicle over 2 days (pre- and post–dry eye chamber)	327	89/238	>18 years	16–32 days
NCT03916042 (2023, USA)	RCT (double-masked, multicenter)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap QID for 4 weeks, then BID for 8 weeks	Vehicle QID for 4 weeks, then BID for 8 weeks	206	55/151	>18 years	14 weeks
RENEW (2023, USA)	RCT (double-masked, multicenter)	To evaluate the efficacy and safety of 0.25% reproxalap versus vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap (0.25%) QID for 12 weeks	Vehicle QID for 12 weeks; vehicle QID for 4 weeks, then BID for 8 weeks	211	54/157	>18 years	14 weeks
Clark (2021, USA)	RCT (double-masked, multicenter)	To assess the activity of reproxalap compared with vehicle in DED	Adults (≥18 years) with ≥6 months of dry eye history and current or intended eye drop use within 6 months	Reproxalap QID for 12 weeks	Vehicle QID for 12 weeks	200	53/147	32.85 ± 11.42	12 weeks
Radcliffe et al. (2026, USA)	Phase 3 RCT (double-masked, multicenter, vehicle-controlled)	To evaluate the long-term safety of 0.25% reproxalap versus vehicle in DED	Adults ≥18 years with ≥6 months dry eye history, desire/use of eye drops within previous 6 months, OD4SQ symptom score ≥2, Schirmer test 1–10 mm	Reproxalap 0.25% QID for 4 weeks, then BID for 2 weeks or 11 months	Vehicle QID for 4 weeks, then BID for 2 weeks or 11 months	757	225/532	55.7 ± 15.8	6 weeks and 12 months
Allergic Conjunctivitis
INVIGORATE (2023, Canada)	RCT (quadruple-masked, single-center)	To assess the activity of reproxalap under seasonal allergen exposure	Adults (≥18 years) with ≥2 years of moderate-to-severe allergic conjunctivitis, positive ragweed test, chamber-induced itching ≥2.5, and redness ≥2	Reproxalap (0.25%)	Vehicle eye drops	95	42/53	41.2 ± 12.3	2 weeks
Clark et al. (2024, Canada)	RCT (quadruple-masked, single-center)	To evaluate reproxalap (0.25% and 0.5%) in seasonal allergic conjunctivitis using the EEC	Adults (≥18 years) with ≥2 years of ragweed-induced allergic conjunctivitis and positive ragweed skin test	Reproxalap (0.25%)	Vehicle dosed twice	70	28/42	46.91 ± 10.13	212 minutes
ALLEVIATE (2021, USA)	RCT (double-masked, multicenter)	To assess the post-acute activity of reproxalap versus vehicle in seasonal allergic conjunctivitis	Adults (≥18 years) with allergic conjunctivitis, positive seasonal allergen test, and conjunctival challenge itching ≥2.5 and redness ≥2	Reproxalap (0.25% or 0.5%) one drop 10 minutes before allergen challenge	Vehicle one drops 10 minutes before allergen challenge	218	83/135	45.74 ± 14.63	60 minutes
Cavanagh et al. (2022, USA)	Randomized, double-masked, vehicle-controlled Phase 2 trial	To assess reproxalap activity and define clinically relevant thresholds for itching and redness	Adults (≥18 years) with allergic conjunctivitis, positive ragweed skin test, baseline redness and ≥1 symptom ≥1, and challenge-induced itching and redness ≥2	Topical reproxalap ∼4× daily for 28 days	Vehicle eye drops	35	11/24	46.4 ± 13.17	28 days

DED: Dry Eye Disease; QID: four times in a day; BID: twice-daily dosage; EEC: Environmental Exposure Chamber.

*Age reported as mean ± standard deviation (SD) or categorical value.

Quality Assessment

Summary of risk of bias in included studies is illustrated in Figure 2. Several included studies were judged to be at high overall risk of bias, primarily because of concerns regarding selection of the reported results. Outcome summaries and credibility evaluations following the GRADE framework are provided in Table 2.

Figure 2.

Summary of Risk of Bias of Included Studies.

Table 2.

Grading recommendations assessment, development, and evaluation (GRADE) summary of findings (CI: confidence interval; MD: mean difference).

Outcome	No. of participants (studies)	Anticipated absolute effects (95% CI)	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Quality of Evidence (GRADE)
Dry Eye Disease (DED)
Ocular Dryness Score	694 (4 RCTs)	SMD 0.23 lower (0.38 lower to 0.08 lower)	Serious	Not serious	Not serious	Not serious	Strongly detected	⊕⊕◯◯ Low
Schirmer Test Mean Change from Baseline	947 (4 RCTs)	MD 2.32 higher (1.55 higher to 3.10 higher)	Very serious	Not serious	Not serious	Not serious	Undetected	⊕⊕◯◯ Low
Schirmer Test Responder Rate (≥10-mm increase)	973 (2 RCTs)	RR 2.05 (1.71 higher to 2.44 higher)	Very serious	Not serious	Not serious	Not serious	Undetected	⊕⊕◯◯ Low
Conjunctival Redness Score	586 (3 RCTs)	MD 0.13 lower (0.25 lower to 0.02 lower)	Very serious	Not serious	Not serious	Not serious	Strongly detected	⊕◯◯◯ Very low
Allergic Conjunctivitis (AC)
Ocular Itching Score	577 (4 RCTs)	SMD 0.78 lower (1.22 lower to 0.34 lower)	Serious	Serious	Not serious	Not serious	Strongly detected	⊕◯◯◯ Very low
Ocular Tearing Score	264 (3 RCTs)	SMD 1.56 lower (3.11 lower to 0.02 lower)	Not serious	Very serious	Not serious	Serious	Strongly detected	⊕◯◯◯ Very low
Conjunctival Redness Score	359 (3 RCTs)	SMD 1.41 lower (2.44 lower to 0.38 lower)	Not serious	Very serious	Not serious	Serious	Strongly detected	⊕◯◯◯ Very low

Results of Meta-analysis

Dry Eye Disease (DED)

For ocular dryness score (ODS), reproxalap was associated with a lower score compared with control (standardized mean difference [SMD] = −0.23; 95% confidence interval [CI]: −0.38 to −0.08; P = 0.002; I² = 0%) (Figure 3a). For the Schirmer test mean change from baseline, a greater increase was observed in the reproxalap group than in the control group (mean difference [MD] = 2.32 mm; 95% CI: 1.55 to 3.10; P < 0.00001; I² = 0%) (Figure 3b). For the Schirmer test responder rate (≥10-mm increase), the proportion of responders was higher in the reproxalap group than in the control group (risk ratio [RR] = 2.05; 95% CI: 1.71 to 2.44; P < 0.00001; I² = 0%) (Figure 3c). For the conjunctival redness score, lower values were observed in the reproxalap group compared with the control group (MD = −0.13; 95% CI: −0.25 to −0.02; P = 0.02; I² = 36%) (Figure 3d).

Figure 3.

Forest plots comparing reproxalap with control for dry eye disease outcomes: (a) ocular dryness score, (b) Schirmer test mean change from baseline, (c) Schirmer test responder rate (≥10-mm increase), and (d) conjunctival redness score. Negative values favor reproxalap for ocular dryness score and conjunctival redness score; positive values favor reproxalap for Schirmer test mean change; RR >1 favors reproxalap for Schirmer test responder rate.

Secondary Exploratory Analysis: Allergic Conjunctivitis

Reproxalap showed directionally favorable effect estimates for ocular itching, tearing, and conjunctival redness. However, heterogeneity was substantial across outcomes (I² = 83–96%), the certainty of evidence was very low according to GRADE, and the findings were not robust in sensitivity analyses. These results do not provide reliable evidence of treatment efficacy (Supplementary Figure S1).

Safety Outcomes

Safety data were reported inconsistently across studies, precluding formal quantitative synthesis; therefore, a qualitative summary is provided in Supplementary Table S3. The most commonly reported treatment-emergent adverse event was transient instillation-site discomfort or irritation, which was generally mild and self-limited (28–93% with reproxalap vs. 1–9% with vehicle). The wide variation in incidence likely reflects differences in adverse event ascertainment and reporting rather than true differences in risk. Serious adverse events were uncommon and judged unrelated to study treatment. Adverse event–related discontinuations were infrequent in DED trials (1.2–11.1%) and absent in allergic conjunctivitis trials. The longest available follow-up (up to 12 months) ²⁹ showed no treatment-related changes in visual acuity, intraocular pressure, and corneal endothelial cell density, providing preliminary evidence regarding medium-term ocular safety.

Certainty of Evidence (GRADE)

GRADE assessments are summarized in Table 2. Certainty was rated low for three DED outcomes (ocular dryness, Schirmer test mean change, and Schirmer test responder rate) and very low for conjunctival redness in DED, primarily due to risk of bias and publication bias. Across all allergic conjunctivitis outcomes, certainty was rated very low, additionally reflecting serious inconsistency, imprecision, and strongly suspected publication bias.

Sensitivity analysis

For DED outcomes (Supplementary Table S4), pooled estimates for ocular dryness, Schirmer test mean change, and the Schirmer responder rate remained robust and statistically significant throughout the leave-one-out analysis, with no observed heterogeneity (I² = 0%). For conjunctival redness (overall I² = 36%), removal of either NCT04971031 or NCT05424549 increased heterogeneity to 67% and rendered the pooled estimate non-significant.

For allergic conjunctivitis outcomes, pooled estimates were unstable in leave-one-out sensitivity analyses, particularly for ocular tearing, which became non-significant after exclusion of any single study (I² range, 78.0%–98.1%). These findings indicate limited robustness and should be interpreted with caution (Supplementary Table S4).

Publication bias

Publication bias was assessed using Doi plots and the LFK index (Supplementary Figures S2–S7). In DED, major asymmetry was observed for ocular dryness (LFK = 2.66) and conjunctival redness (LFK = −4.22). In contrast, Schirmer test mean change from baseline demonstrated no asymmetry (LFK = 0.64). All allergic conjunctivitis outcomes also showed major asymmetry (LFK range: −3.39 to −3.59).

Discussion

This meta-analysis pooled data from 12 randomized controlled trials (RCTs) involving 2,701 participants to evaluate the efficacy of reproxalap 0.25% for dry eye disease (DED), with a secondary exploratory analysis of allergic conjunctivitis. To our knowledge, this is the first quantitative synthesis to comprehensively evaluate the available randomized evidence on reproxalap in DED. Reproxalap produced statistically significant improvements across all four DED endpoints with no observed heterogeneity, whereas results in allergic conjunctivitis, though consistently directional, were accompanied by substantial heterogeneity (I² = 83–96%). The DED findings were considerably more consistent and clinically interpretable than those for allergic conjunctivitis, with low heterogeneity across primary endpoints. In allergic conjunctivitis, marked heterogeneity, sensitivity to individual-study removal, and very low certainty of evidence limit confidence in the findings, and should be considered exploratory and hypothesis-generating only. Several included trials were judged to be at high overall risk of bias, primarily because of concerns regarding selection of the reported results, and GRADE certainty ranged from low to very low across outcomes, reflecting evidence of publication bias and exclusive industry sponsorship.

Reactive aldehyde species (RASP), including malondialdehyde and 4-hydroxynonenal, arise during lipid peroxidation and covalently modify kinase and receptor residues, activating NF-κB and the NLRP3 inflammasome upstream of cytokine and histamine release.^33,34 Reproxalap sequesters these aldehyde intermediates before they reach their protein targets, placing its point of intervention upstream of the T-cell–mediated cascades targeted by cyclosporine A and lifitegrast.^34,35 In DED, tear RASP levels correlate positively with disease severity, ³³ which provides a mechanistic basis for the Schirmer test improvements observed in this analysis. Although the mean improvement in Schirmer score (2.32 mm) may not be clinically meaningful at the individual level, the responder rate provides a more clinically interpretable measure. The TFOS DEWS II diagnostic framework defines a Schirmer score <10 mm as indicative of aqueous tear deficiency.^6,21 The twofold increase in responders (RR = 2.05) suggests that patients receiving reproxalap were twice as likely as those receiving vehicle to achieve a Schirmer score ≥10 mm, consistent with improved tear production. Reductions in conjunctival redness and ocular dryness scores are consistent with attenuation of vascular NF-κB signaling and modulation of corneal surface nociceptors, respectively. ³⁴ The improvement in ocular dryness score was statistically significant but small (SMD −0.23), and its clinical relevance at the individual patient level is uncertain.

Cyclosporine A and lifitegrast, the approved non-steroidal options for chronic DED, target T-cell–mediated adaptive immunity,^36,37 leaving innate inflammatory inputs, including RASP-driven NF-κB activation—largely unaddressed. ³⁴ Corticosteroids act on these innate pathways but carry well-documented risks of ocular hypertension, cataract formation, and infection that limit long-term use.^38,39 If approved, reproxalap could occupy a pharmacologically distinct position in the treatment landscape. Phase 2a and 2b data suggest early onset of activity within the first week of dosing,^11,33 which is relevant given that real-world discontinuation rates for cyclosporine exceed 60% within three months, partly due to delayed or insufficient benefit. However, no conclusions regarding comparative efficacy or superiority over approved therapies can be drawn from the available evidence. Considering the multifactorial nature of DED,^40,41 reproxalap may have potential utility as an adjunct or as an option for patients refractory to existing therapies.^36,37 Within the broader DED treatment landscape, systematic reviews have evaluated thermal pulsation for meibomian gland dysfunction, ⁴² punctal occlusion for tear retention, ⁴³ topical pharmacologic therapies, ⁴⁴ and emerging approaches such as botulinum toxin A. ⁴⁵ These modalities underscore the multimodal nature of DED management, within which reproxalap’s clinical role remains to be defined. Notably, unlike many existing topical therapies that improve ocular surface signs without consistently relieving symptoms, ⁴⁴ reproxalap demonstrated concurrent improvements in both tear volume and patient-reported dryness.

The consistency of DED findings across trials, using instruments largely harmonized with the TFOS DEWS II framework, ⁴⁰ reinforces their reliability. The I² = 0% across three of four primary endpoints and the stability of estimates through leave-one-out sensitivity analyses indicate that the pooled results are unlikely to reflect individual-study anomalies. The concurrent improvements in both objective (Schirmer test) and subjective (ocular dryness) measures are also noteworthy given the well-established discordance between signs and symptoms in DED,^46,47 and may reflect reproxalap’s broader action across both the lacrimal unit and sensory afferents of the ocular surface. ³⁴ However, most included trials were of short duration, leaving long-term efficacy and safety uncertain. In addition, no head-to-head trials have compared reproxalap with cyclosporine A, lifitegrast, or corticosteroids, precluding conclusions regarding comparative efficacy, tolerability, or optimal patient selection. Furthermore, no cost-effectiveness analyses have been conducted, limiting assessment of reproxalap’s value relative to existing approved therapies.

The allergic conjunctivitis findings should be interpreted cautiously. Although all three outcomes favored reproxalap, substantial heterogeneity (I² = 83–96%), very low certainty of evidence, and sensitivity to individual-study removal limit confidence in these results. The four included trials differed fundamentally in their exposure paradigm. The ALLEVIATE trial ¹² used conjunctival allergen challenge (CAC) with acute, high-dose instillation and outcome assessment at 10–60 minutes; INVIGORATE ³² and the phase 2 chamber trial ³¹ employed a controlled allergen chamber with sustained 3.5-hour exposure and outcomes at 110–210 minutes. The Cavanagh et al. ³⁰ field trial monitored patients under natural seasonal conditions over 28 days, during which pollen counts were often low or negligible. CAC produces rapid, high-intensity symptom escalation; chamber models generate more gradual responses; field trials produce attenuated and variable effects. These are not equivalent pharmacodynamic settings, and pooling their effect sizes introduces heterogeneity that cannot be fully resolved by statistical modeling alone. Sensitivity analysis confirmed this as removing Cavanagh et al. alone reduced I² for conjunctival redness from 94% to 31.7%. Ocular tearing was the most fragile outcome, non-significant on exclusion of any single study, with I² ranging from 78% to 98%, suggesting the evidence here remains insufficiently stable for clinical conclusions. Although the consistent direction of effect is biologically plausible given the role of reactive aldehyde species in mast cell- and histamine-mediated inflammation, the current evidence is insufficient to support definitive clinical conclusions and should be regarded as exploratory and hypothesis-generating pending confirmation in larger, methodologically standardized trials.

As safety outcomes were inconsistently reported, only qualitative synthesis was possible. Available trial data suggest that reproxalap is generally well tolerated in the short term. Transient instillation-site discomfort was the predominant adverse event, with no clinically meaningful ocular safety signals. For context, cyclosporine A 0.05% is associated with ocular burning in up to 17% of patients, with stinging, conjunctival hyperemia, and eye pain each reported in 1–5% of patients,^48,49 while lifitegrast 5% commonly causes instillation-site irritation (15.2%), instillation-site pain (9.8%), and dysgeusia (14.5%), with treatment discontinuation reported in 7% of patients. ⁵⁰ However, these comparisons are indirect, as no head-to-head trials have been conducted. Consequently, definitive conclusions regarding its comparative tolerability cannot yet be drawn.

Publication bias warrants consideration throughout this analysis. The LFK index identified major asymmetry for most outcomes including ocular dryness, conjunctival redness in DED, and all allergic conjunctivitis outcomes. A body of evidence comprising small, industry-funded studies is itself recognized as grounds for suspecting publication bias under the GRADE framework.^21,51 All included trials were conducted by or in close collaboration with a single sponsor (Aldeyra Therapeutics), and no independently funded trials have been published. This is noteworthy given the predominantly subjective, symptom-based endpoints used across the included DED and allergic conjunctivitis trials, which may be more susceptible to reporting bias. The potential influence of pharmaceutical sponsorship on study design and outcome reporting has been recognized in ophthalmic research and should be considered when interpreting these findings. ⁵² This concern is reinforced by the RoB 2 assessment, in which several studies were judged at high overall risk of bias because of concerns regarding selection of reported results. The FDA’s issuance of three consecutive Complete Response Letters for the reproxalap DED NDA (November 2023, April 2025, March 2026), citing inconsistent efficacy results, ⁵³ further underscores the need for additional confirmatory trials before regulatory approval can be achieved.

Future research should prioritize larger, independently funded randomized controlled trials with longer follow-up and active comparators, including cyclosporine A and lifitegrast, to establish the durability of reproxalap’s effects, determine whether benefits extend beyond symptomatic improvement to sustained modulation of ocular surface inflammation, and define its place in the treatment algorithm. Standardized TFOS DEWS II outcome measures should be adopted to improve cross-trial comparability. For allergic conjunctivitis, larger trials using standardized allergen exposure paradigms are needed before definitive clinical conclusions can be drawn. Ongoing trials may help address these evidence gaps.

Strengths and Limitations

This review has several strengths. All included trials were randomized and double-masked, and most were placebo-controlled. This is the largest meta-analysis of reproxalap in dry eye disease (DED) to date, incorporating both objective clinical measures and patient-reported outcomes, with an additional exploratory analysis of allergic conjunctivitis. DED results were notably consistent, with I² = 0% across primary endpoints and stable sensitivity analyses for most outcomes. The application of GRADE provides structured certainty estimates, and the use of the LFK index for bias detection was appropriate given the limited number of studies per outcome.

Several limitations must be acknowledged. The allergic conjunctivitis evidence base is small (four trials, n = 418), and heterogeneity was high and persistent across all three outcomes. All included trials were funded by or conducted in close association with a single sponsor (Aldeyra Therapeutics). Combined with evidence of publication bias across several outcomes and the predominantly subjective primary endpoints, this should temper confidence in the pooled estimates. Subgroup analyses by DED subtype (aqueous-deficient versus evaporative), disease severity, prior treatment history, or patient phenotype were not feasible due to insufficient reporting of individual participant data; meta-regression to explore sources of heterogeneity was similarly precluded by the small number of studies per outcome. Follow-up durations were short across all studies, and no trial evaluated whether benefits are durable beyond several weeks. Most trials were conducted at North American sites, limiting applicability to other populations and climatic conditions. Safety outcomes could not be formally pooled because of insufficient and inconsistently reported data across studies. In addition, no comparative safety data against approved therapies are available, long-term tolerability remains uncertain, and no cost-effectiveness analyses have been conducted.

Conclusion

Reproxalap 0.25% shows consistent, statistically significant improvements across signs and symptoms of dry eye disease. Findings in allergic conjunctivitis are hypothesis-generating only and cannot be reliably assessed from the currently available data due to high heterogeneity and very low certainty of evidence. Interpretation remains limited by the low certainty of the available evidence, exclusive industry sponsorship, evidence of publication bias, the predominantly subjective nature of the primary efficacy endpoints, and the lack of long-term safety data. Further independently funded, long-term randomized controlled trials are needed to better define its clinical role.

ORCID iDs

Muhammad Imaz Bhatti https://orcid.org/0009-0000-9381-0106

Saleha Azeem https://orcid.org/0000-0003-1987-6048

Husam Abu Dawood https://orcid.org/0009-0005-3109-2600

Ethical considerations

As this study is a systematic review and meta-analysis based on previously published data, ethical approval and informed consent were not required.

Consent to participate

As this study is a systematic review and meta-analysis based on previously published data, ethical approval and informed consent were not required.

Data Availability Statement

All data used in this meta-analysis were extracted from previously published studies. The datasets analyzed during the current study are available from the corresponding author upon reasonable request.*