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

Clark, David L.; Cavanagh, Bill; Shields, Alan L.; Karpecki, Paul; Sheppard, John D.; Brady, Todd C.

doi:10.1016/j.ajo.2021.04.023

Cited by 15 publications

(20 citation statements)

References 22 publications

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“…Compounding the problem of variability in allergen exposure, many patients monitor pollen counts to avoid exposure during high-pollen days. The variability of pollen exposure in field trials suggests that conjunctival challenge trials and real-world allergen chamber exposures may be more efficient designs for the assessment of drug activity in allergic conjunctivitis [ 9 , 10 ]. Nonetheless, consistent with prior clinical results, the activity of reproxalap over vehicle across all four symptom scores, which were statistically significant for pooled itching ( P = 0.026) and tearing ( P < 0.001) scores, during high-pollen days (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In both controlled and environmental settings, the typical method for assessment of activity in patients with allergic conjunctivitis includes measurement of ocular itching and redness on a 0 (none) to 4 (severe) scale [ 9 – 11 ]. Although the clinically important difference in ocular itching score between treatment groups has traditionally been set at 1 unit [ 12 ], evidence justifying 1 unit as a meaningful difference is lacking.…”

Section: Introductionmentioning

confidence: 99%

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

Cavanagh¹,

Gomes

Starr

et al. 2022

Ophthalmol Ther

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cavanagh¹,

Gomes

Starr

et al. 2022

Ophthalmol Ther

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“…Reproxalap is a novel, topically administered reactive aldehyde species (RASP) inhibitor that has demonstrated clinical activity in noninfectious anterior uveitis, 4 dry eye disease, 5,6 and allergic conjunctivitis. 7 RASP potentiates inflammation via covalent protein signaling by increasing the activity of a variety of inflammatory mediators, including nuclear factor kappa B and inflammasomes. [8][9][10] Posthistaminic factors, including cellular infiltrate, cytokines, and other RASP-mediated inflammatory mediators, perpetuate the signs and symptoms of allergic conjunctivitis after allergen-induced histamine levels have declined.…”

Section: Introductionmentioning

confidence: 99%

Reproxalap Improves Signs and Symptoms of Allergic Conjunctivitis in an Allergen Chamber: A Real-World Model of Allergen Exposure

Clark¹,

Karpecki²,

Salapatek³

et al. 2022

OPTH

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Purpose: To assess the prophylactic and treatment activity of reproxalap, a novel reactive aldehyde species inhibitor, in a real-world model of allergen exposure. Methods: In a randomized, double-masked, vehicle-controlled, crossover Phase 2 trial, 70 adult patients with ≥2 years of moderate to severe allergic conjunctivitis history, a positive skin test to ragweed pollen, and allergen chamber-induced ocular itching and redness scores of ≥2.5 and ≥2 (both scales range from 0 to 4), respectively, were randomized 1:1:1 to one of three sequences: 0.25% reproxalap, 0.5% reproxalap, and placebo; 0.5% reproxalap, placebo, and 0.25% reproxalap; or placebo, 0.25% reproxalap, and 0.5% reproxalap. Symptoms and conjunctival redness were assessed over 3.5 hours in an allergen chamber of aerosolized ragweed pollen (3500 grains/m 3 ). Test article was administered bilaterally just before chamber entry and at 90 minutes after chamber entry. Results: Reproxalap was safe and well tolerated; 66 of 70 enrolled patients completed all visits. Relative to vehicle, both concentrations of reproxalap demonstrated statistically significant and clinically relevant improvements in ocular itching, tearing, and redness over the duration of exposure in the chamber (P < 0.001 for all assessments). Prophylactic and treatment activity of drug were demonstrated. Conclusion:In an allergen chamber, reproxalap, a novel reactive aldehyde species inhibitor, was statistically superior to vehicle across the typical symptoms and signs of allergic conjunctivitis. These data are among the first rigorous clinical results demonstrating drug improvement in allergic conjunctivitis in an allergen chamber, a real-world model of allergen exposure.

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“…One novel therapeutic approach is the recent development of aldehyde-trapping drugs. The novel reactive aldehyde species (RASP) inhibitor ADX-102, also known as Reproxalap, was recently reported to be safe and effective for the treatment of dry eye disease (DED) [40,41] as well as ocular inflammatory conditions such as noninfectious anterior uveitis and allergic conjunctivitis [15]. Such clinical trials reported that ADX-102 is safe and effective for human use.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Trapping by ADX-102 Is Protective against Cigarette Smoke and Alcohol Mediated Lung Cell Injury

et al. 2022

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Most individuals diagnosed with alcohol use disorders smoke cigarettes. Large concentrations of malondialdehyde and acetaldehyde are found in lungs co-exposed to cigarette smoke and alcohol. Aldehydes directly injure lungs and form aldehyde protein adducts, impacting epithelial functions. Recently, 2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol (ADX-102) was developed as an aldehyde-trapping drug. We hypothesized that aldehyde-trapping compounds are protective against lung injury derived from cigarette smoke and alcohol co-exposure. To test this hypothesis, we pretreated mouse ciliated tracheal epithelial cells with 0–100 µM of ADX-102 followed by co-exposure to 5% cigarette smoke extract and 50 mM of ethanol. Pretreatment with ADX-102 dose-dependently protected against smoke and alcohol induced cilia-slowing, decreases in bronchial epithelial cell wound repair, decreases in epithelial monolayer resistance, and the formation of MAA adducts. ADX-102 concentrations up to 100 µM showed no cellular toxicity. As protein kinase C (PKC) activation is a known mechanism for slowing cilia and wound repair, we examined the effects of ADX-102 on smoke and alcohol induced PKC epsilon activity. ADX-102 prevented early (3 h) activation and late (24 h) autodownregulation of PKC epsilon in response to smoke and alcohol. These data suggest that reactive aldehydes generated from cigarette smoke and alcohol metabolism may be potential targets for therapeutic intervention to reduce lung injury.

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

Cited by 15 publications

References 22 publications

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

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

Reproxalap Improves Signs and Symptoms of Allergic Conjunctivitis in an Allergen Chamber: A Real-World Model of Allergen Exposure

Aldehyde Trapping by ADX-102 Is Protective against Cigarette Smoke and Alcohol Mediated Lung Cell Injury

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