Efficacy and Safety of Toreforant, a Selective Histamine H4 Receptor Antagonist, for the Treatment of Moderate-to-Severe Plaque Psoriasis: Results from a Phase 2 Multicenter, Randomized, Double-blind, Placebo-controlled Trial
August 2018 | Volume 17 | Issue 8 | Original Article | 873 | Copyright © August 2018
Ellen Frankel MD,a Michael Song MD,b Shu Li PhD,b Jingzhi Jiang MS,b Robin L. Thurmond PhD,c Bruce Randazzo MD PhDc,d
aClinical Partners, LLC, Johnston, RI bJanssen Research & Development, LLC, Spring House, PA cJanssen Research & Development, LLC, San Diego, CA dPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Abstract
Background: Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis.
Objective: To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis.
Methods: Biologic-naïve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator’s Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12.
Results: Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported.
Conclusions: Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion.
J Drugs Dermatol. 2018;17(8):873-879.
INTRODUCTION
Orally administered psoriasis therapies that can provide high levels of efficacy, safety, and tolerability remain an unmet need. Toreforant is an orally bioavailable, novel, and selective histamine H4 receptor (H4R) antagonist.1 Antagonism of the H4R has the potential to ameliorate psoriasis via multiple mechanisms. Histamine has been reported to be increased in psoriasis plaques,2 and the H4R is expressed on many cell types that are known to play a pathogenic role in psoriasis, including T cells and plasmacytoid dendritic cells (pDCs).3,4 High levels of H4R expression have been reported on pDCs in the skin and blood of patients with psoriasis, suggesting that activation of the H4R may play a role in the immune-mediated inflammation seen in psoriasis.3 An association between variations in the gene encoding the H4R and severity of psoriasis has also been reported.5 Furthermore, preclinical experimental evidence suggests that the H4R can modulate the interleukin-17 axis, which is known to be critical for the pathogenesis of psoriasis.4,6-8 This was a Phase 2 study to establish proof-of-concept for efficacy of Toreforant and to evaluate the safety of Toreforant in patients with moderate-to-severe plaque psoriasis.
METHODS
Patients
Patients ≥18 years of age diagnosed with moderate-to-severe plaque psoriasis (defined by Investigator’s Global Assessment [IGA] score ≥3, Psoriasis Area and Severity Index [PASI] score ≥12, and involved body surface area [BSA] ≥10%) for at least 6 months before the first dose of study treatment were to be included. Patients with nonplaque psoriasis or drug-induced psoriasis or who had ever received any previous biologic therapy for psoriasis or psoriatic arthritis were to be excluded. Patients had to provide written consent to participate in the study.
