Neurokinin‐1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial

Abstract

Atopic dermatitis (AD) is a relapsing and remitting disease characterized by intense pruritus that can lead to scratching and eczematous lesions that vary in extent and severity.1 Over 60% of AD cases are mild, characterized by slight erythema, induration and lichenification.2, 3 Chronic pruritus, pruritus lasting more than 6 weeks, has been reported by 91% of AD patients.4, 5 The pathophysiology of AD is driven by a combination of skin barrier dysfunction, neuroinflammation and immune system dysregulation.6, 7 Elevated substance P (SP) is found in both serum and lesional skin of patients with AD.5, 8, 9 SP, a neuropeptide released from the activation of sensory neurons, preferentially binds to the neurokinin-1 (NK-1) receptor and is a known itch mediator.5 Tradipitant (VLY-686), a novel NK-1 receptor antagonist, has the potential to reduce itch related to AD through inhibition of SP-mediated itch signalling. We examined the efficacy and safety of tradipitant, in reduction of chronic pruritus in adults with mild to severe AD. EPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted at 74 US centres. Altogether 375 patients [mean (SD): age, 41.8 (15.0) years; sex, 243 (64.8%) female] were randomly assigned to tradipitant (n = 188) or placebo (n = 187). Although there was a numerical benefit in the tradipitant group over placebo, EPIONE did not meet its primary endpoint of reduction in pruritus [Least Squares (LS) Mean difference (95% CI), −0.2 (−0.8 to 0.4), P = 0.567]. However, robust antipruritic effect was observed in patients with mild lesion severity [rated 1 or 2 by the validated Investigator Global Assessment for Atopic Dermatitis at baseline −1.6 (−2.9 to −0.3), P = 0.015; Figs 1 and 2a]. This result was confirmed by daily diary [−2.09 (−3.31 to −0.87), P = 0.001] and observed after one full day of treatment [Fig. 2b, −0.61 (−1.21 to −0.01), P = 0.0457]. Improvement in nighttime sleep was also observed in mild AD [−1.46 (−2.60 to −0.32) P = 0.013]. The most frequent treatment-emergent adverse events (TEAEs) were mild to moderate. There were no common TEAEs identified in the treatment arm, defined by >5% incidence. Tradipitant treatment resulted in a clinically meaningful reduction in patient-reported worst itch and sleep disturbance in the mild AD study population. Statistically significant improvement was seen after one day of treatment for itch and two days for sleep. It is possible that the immediate and robust improvements observed in the mild AD subgroup were seen not only because of different levels of cutaneous inflammation between AD severities but also because of distinct AD endotypes including different clinical manifestations, molecular levels and genetic associations.10 The concept of different endotypes in AD underlines the need for targeted therapeutics in different AD disease types.11 Itch related to nerve hypersensitivity causes increased scratching which worsens eczema and induces excoriations. Suppression of itch in mild AD can thus prevent worsening of atopic dermatitis. In our study, we saw no significant Eczema Area and Severity Index or SCORing Atopic Dermatitis (SCORAD) index improvement in early weeks; however, we did not expect improvement of acute lesions but rather of excoriations in the long term. Improvement in excoriations of mild patients was largest at Week 2 (P = 0.0374). We observed numerical improvement across all time-points studied in terms of lesion severity (excoriations). Tradipitant may represent a new oral systemic option for mild AD patients based on the well-tolerated safety profile and immediate robust improvement in itch and sleep. Future studies are needed to confirm these efficacy results and refine treatment recommendations for AD patients who despite having mild lesions, experience significant pruritus. SEW is a former employee of Vanda and a stockholder. CX is an employee of Vanda and a stockholder. ARK is an employee of Vanda and a stockholder. JLB is an employee of Vanda and a stockholder. MAM is an employee of Vanda and a stockholder. JW is an employee of Vanda and a stockholder. SPS is an employee of Vanda and a stockholder. BP is an employee of Vanda and a stockholder. SS is an investigator for Dermasence, Galderma, Kiniksa Pharmaceuticals, Menlo Therapeutics, Trevi Therapeutics, Novartis, Sanofi, and Vanda Pharmaceuticals Inc.; and is a consultant and/or member of the advisory board for Almirall, Bayer, Beiersdorf, Bellus Health, Bionorica, Cara Therapeutics, Celgene, Clexio Biosciences, DS Biopharma, Galderma, Menlo Therapeutics, Novartis, Perrigo, and Trevi Therapeutics. CP is an employee of Vanda and a stockholder. GB is an employee of Vanda and a stockholder. MHP is Chief Executive Officer of Vanda. Vanda Pharmaceuticals Inc. The sponsor designed the study. All authors, including those representing the sponsor, contributed to data interpretation and writing of the report. All authors had final responsibility for the decision to submit for publication. Vanda shares data related to this trial in peer-reviewed journals, medical conferences and Clinicaltrials.gov. Individual patient data are not publically available.

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