A Randomized Double-Masked Phase 2a Trial to Evaluate Activity and Safety of Topical Ocular Reproxalap, a Novel RASP Inhibitor, in Dry Eye Disease
Abstract
Purpose: To determine whether reproxalap, a novel reactive aldehyde species (RASP) inhibitor, is safe and effective for the treatment of the signs and symptoms of dry eye disease (DED).
Methods: In a randomized double-masked parallel-group Phase 2a trial of 3 topical ocular reproxalap formulations (0.1% ophthalmic solution, 0.5% ophthalmic solution, and 0.5% lipid ophthalmic solution), 51 patients with DED were randomly assigned 1:1:1 at a single US site. Eyes were treated bilaterally 4 times daily for 28 days, and standard DED signs and symptoms were assessed at baseline and after 7 and 28 days of dosing. Tear RASP levels were assessed at baseline and at day 28.
Results: The effect of treatment on DED signs and symptoms was similar across the treatment arms, and pooled data from the 28-day treatment period demonstrated significant improvement from baseline in Symptom Assessment in Dry Eye Disease score (P = 0.003), Ocular Discomfort Scale score (P < 0.0001), Ocular Discomfort Score and 4-Symptom Questionnaire overall score (P = 0.0004), Schirmer’s test (P = 0.008), tear osmolarity (P = 0.003), and lissamine green total staining score (P = 0.002). Improvements in DED symptoms were evident within 1 week of therapy, and effect sizes generally approached or exceeded 0.5. No significant changes in safety measures were observed.
Conclusion: The results suggest that the novel RASP inhibitor reproxalap has the potential to mitigate the signs and symptoms of DED, and may represent a new, rapidly and broadly active treatment approach for DED (NCT03162783).
Introduction
Dry eye disease (DED) affects ∼6.8% of the US population, with the prevalence increasing with age.1,2 Impaired vision, lost work productivity, and diminished quality of life are associated with DED.2–9 Despite the availability of 3 approved drugs in the United States, patients with DED experience a higher prevalence of major depression and anxiety10,11 and account for an estimated $3.8 billion per year of health care cost.2,7,8
Reactive aldehyde species (RASP), such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), covalently bind amino and thiol groups on receptors and kinases, and thereby potentiate upstream proinflammatory signaling cascades that involve NF-kB, inflammasomes, scavenger receptor A, and other mediators.12–15 Increased levels of RASP are found in a variety of inflammatory ocular diseases, including Behcet’s disease, Sjögren’s syndrome, noninfectious uveitis, allergic conjunctivitis, and DED.16–27 MDA levels in tears from patients with DED are elevated, and increased MDA levels positively correlate with DED severity.26 Furthermore, in tears and conjunctival biopsies from patients with DED, levels of MDA and HNE are increased compared with those from control participants and correlate with the magnitude of symptoms.27 In addition to proinflammatory signaling, RASP also bind phosphatidylethanolamine,28 a critical component of the tear lipidome, which is critical for moisture retention in ocular surface tissues.29 Thus, RASP represent a potentially important therapeutic target for the treatment of DED.
Reproxalap is a small molecule that rapidly and covalently binds RASP. Reproxalap has been shown to outcompete biological targets for MDA and HNE to inhibit both helper T cell 1 (Th1)- and Th2-mediated inflammation in a number of animal models.30,31 The broad-based anti-inflammatory mechanism of reproxalap may be relevant to a variety of ocular inflammatory conditions, and clinical development of reproxalap has been initiated in patients with noninfectious anterior uveitis, allergic conjunctivitis, and DED. In DED, the activity of reproxalap is potentially 2-fold, the result of modulation of inflammation and prevention of RASP modification of tear lipids, suggesting that reproxalap may represent an important new therapeutic approach for the treatment of DED.
Given the unmet medical need in DED and the multifaceted mechanisms by which RASP are implicated in this condition, a Phase 2a trial was performed to evaluate the activity and safety of 3 topical ocular formulations of the novel RASP inhibitor reproxalap in patients with DED.
Methods
Trial design
Fifty-one patients with DED were enrolled in a Phase 2a single-center randomized double-masked trial (NCT03162783) designed to evaluate the safety, tolerability, and pharmacodynamic activity of topical ocular reproxalap. A vehicle control group was not included in the design as the planned sample size of ∼15 participants per arm did not support formal powering for DED signs or symptoms. Pooling of the 3 active treatment groups was utilized as a method to allow clearer interpretation of drug activity. The trial consisted of a screening and enrollment phase (day 1), a 1-week follow-up (day 8), and a 4-week follow-up (day 29). Participants were randomly assigned in a 1:1:1 ratio to receive either reproxalap 0.5% topical ophthalmic solution, reproxalap 0.1% topical ophthalmic solution, or reproxalap 0.5% topical ophthalmic lipid solution. The lipid solution was similar to the nonlipid formulations except that 5% castor oil was added. Each participant received one drop in each eye 4 times daily (QID) for 29 days. Study participants, investigators, and the sponsor were masked to treatment assignment throughout the trial.
The trial was performed in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. In addition, the trial was performed in accordance with the protocol, the International Conference on Harmonisation Guideline on Good Clinical Practice, and all applicable local regulatory requirements and laws. Each participant provided written consent to participate in the trial before any trial-related procedures, and the trial was carried out with approval from an Institutional Review Board.
Study participant selection
Male and female participants at least 18 years of age with a history of DED in both eyes for at least 6 months were eligible. At screening, participants were required to have a history of use, or desire to use, eye drops for dry eye symptoms within the past 6 months and a score of ≥2 on the Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire (OD4SQ)32 for at least one symptom; a Schirmer’s test score of ≤10 mm and ≥1 mm; a tear film break-up time (TFBUT) of ≤5 s; a corneal fluorescein staining score of ≥2 for at least one region (eg, inferior, superior, or central); a sum corneal fluorescein staining score of ≥4, based on the sum of the inferior, superior, and central regions; and a total lissamine green conjunctival score of ≥2, based on the sum of the temporal and nasal regions. All objective criteria were required in at least 1 eye.
Participants were excluded for any clinically significant slit lamp findings, including active blepharitis, meibomian gland dysfunction, lid margin inflammation, or active ocular allergies that required therapeutic treatment and that may have interfered in the conduct of the trial. Participants also were excluded for ongoing ocular infection or active ocular inflammation; contact lens wear within 7 days of screening visit; or use of eye drops within 2 h of screening visit.
Study assessments
Activity was assessed with TFBUT; fluorescein staining (Ora Calibra® scale for central, superior, inferior, temporal, and nasal regions); Ora Calibra® Ocular Discomfort Scale (ODS)33,34; OD4SQ; Ocular Surface Disease Index (OSDI©)35; and the Symptoms Assessment in Dry Eye Disease (SANDE) questionnaire36 on days 1, 8, and 29. On days 1 and 29, lissamine green staining (Ora Calibra® scale for inferior, superior, central, temporal, and nasal regions); unanesthetized Schirmer’s test; and tear osmolarity were assessed. Adverse events (AEs), visual acuity, and slit lamp biomicroscopy were assessed on days 1, 8, and 29. In addition, undilated fundoscopy examination and intraocular pressure measurements were performed on days 1 and 29. At baseline and after completion of treatment, MDA was measured by ELISA (Cell Biolabs, San Diego, CA) in tears extracted through capillary. Both eyes were pooled per patient. A standard curve was generated, and a 1:60 dilution was established as optimal using 3 μL of tears per patient.
Statistical analysis
Because the trial was exploratory, no formal a priori sample size calculation was employed and no primary or secondary end points were specified. The intention-to-treat (ITT) population included all randomized participants. The safety population included all randomized participants who received study drug.
For assessment of activity, analyses were performed on data from the most severe eye eligible for analysis at baseline, as measured by total corneal fluorescein staining. If total corneal staining was the same in both eyes, then the eye with the worst (higher) ODS score at screening was deemed the most severe eye. If the total corneal staining and ocular discomfort scores were the same for both eyes, then the right eye was selected as the most severe eye.
Pairwise 2-sample t tests were employed to compare the observed treatment means and the changes from baseline at each visit. No imputation was performed for withdrawn participants or missing data. Pooling of the 3 treatment groups was utilized to allow for clearer interpretation of drug activity. Pooled analyses were conducted by including participants from all 3 treatment groups. For pooled average symptomatic change, percentage average improvements for all symptom scales were compared with no change (zero) using a one-way t test, and within-participant standard error bars were plotted as has been previously described.37 Above- and below-median percentage MDA reduction subgroups were compared using 2-way t tests and 1-way t tests versus 0 (no change from baseline).
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