Neurokinin-1 receptor antagonist tradipitant improves itch associated with mild atopic dermatitis: Results from EPIONE a randomized clinical trial

Abstract

Importance: Safe oral systemic treatments are needed to treat itch associated with atopic dermatitis (AD). Objective: To examine the efficacy and safety of tradipitant, a neurokinin-1 receptor antagonist, in adults with mild to severe AD. Design, Setting, and Participants: EPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from July 09, 2018 to December 27, 2019 at 74 US centers. Patients were adults 18 years or older with worst itch rated ≥7 on the Worst Itch Numerical Rating Scale (WI-NRS) and ≥ 1% body surface area of AD involvement at screening. Interventions: Patients were randomly assigned (1:1) to twice-daily oral placebo or tradipitant (85 mg) for 8 weeks. Main Outcomes and Measures: The primary endpoint was mean improvement in WI-NRS (baseline to Week 8). Secondary endpoints included disease severity improvement measured by SCORing Atopic Dermatitis (SCORAD) index, the Eczema Area and Severity Index (EASI), and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-ADTM). Results: 341 patients (mean [SD]: age, 41.8 [15.0] years; sex, 243 [64.8%] female) were randomly assigned to placebo (n = 187) or tradipitant (n = 188). EPIONE did not meet its primary endpoint of reduction in pruritus (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 vIGA-AD at baseline, -1.6 (-2.9 to -0.3), P = 0.015). 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 (-0.61 (-1.21 to -0.01), P = 0.0457). Treatment-emergent adverse events (TEAEs) were reported in 63 of 188 (33.5%) tradipitant patients and 43 of 187 (23.0%) placebo patients. TEAEs with > 2% incidence and twice that of placebo included diarrhea (VLY-686 = 5 (2.7%), PBO = 1 (0.5%)), fatigue (VLY-686 = 5 (2.7%), PBO = 0 (0.0%)), and worsening of AD (VLY-686 = 4 (2.1%), PBO = 1 (0.5%)). Conclusions and Relevance: During 8 weeks of treatment, tradipitant was well-tolerated for all study participants, but did not significantly improve worst itch in the overall study population. However, in patients with mild AD at baseline, tradipitant was observed to have a large and rapid antipruritic effect. These data support the role of neurokinin-1 antagonism and substance P signaling in chronic pruritus related to mild AD. If these findings replicate in the on-going phase 3 study, EPIONE2, tradipitant may represent a promising new oral therapy for these mild AD patients.

Involvement of Neuro-Immune Interactions in Pruritus With Special Focus on Receptor Expressions

“…Another NK1R antagonist, tradipitant, was examined in terms of reduction of pruritus associated with AD through inhibition of SP-mediated itch signaling. Tradipitant treatment improved pruritus and sleep in mild AD ( 174 ). Several NK1R antagonists that potentially reduce pruritus activity in dermatological diseases are reviewed by Pojawa-Goła et al ( 146 ) and Reszke et al ( 172 ).…”

Itch in Atopic Dermatitis – What Is New?

“…This may represent an additional or even the preferred pathway by which SP stimulates pruritus in AD. In part, this may explain why a recent clinical trial in AD patients with the specific NK1R-antagonist serlopitant showed numerical but not significant reduction in pruritus (32), while tradipitant, another NK1-receptor antagonist, slightly but significantly reduced itch in these patients (33). In patients with chronic prurigo, serlopitant also significantly reduced pruritus in a phase-2 study; however, it numerically but not significantly reduced pruritus in two phase-3 studies (32).…”