Targeting Histamine Receptor 4 in Cholinergic Urticaria with Izuforant (LEO 152020): Results from a Phase 2a, Randomised, Double-Blind, Placebo-Controlled, Multicentre, Crossover trial.

BACKGROUND:Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (eg, pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend second-generation H1 antihistamines (sgAHs), ∼90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective, oral H4R antagonist with expected dual anti-pruritic and anti-inflammatory effects. Here we assessed the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. METHODS:This was a phase 2a, randomised, double-blind, placebo-controlled, multi-centre, cross-over trial where CholU patients with an inadequate response to ≥1 standard dose of H1 antihistamine received izuforant 100 mg BID or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in urticaria activity score. Exploratory endpoints included: CholU activity score over 7 days (CholUAS7), urticaria control test, physician's global assessment, patient's global assessment of severity (PGA-S), provocation tests, dermatology life quality index and CholU quality of life (QoL). Pharmacokinetic/pharmacodynamic parameters, serum biomarkers were assessed as well as safety/tolerability. RESULTS:19 patients were randomized and were included in the full analysis set; 18 patients completed treatment (mean age ∼30; CholU duration 8 years). The primary and most prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs placebo (P=0.02), and nonsignificant improvements for other endpoints in QoL and reduced histamine SPT. All AEs occurring with izuforant were considered mild. The most frequently reported (>1 patient) were nausea and upper abdominal pain occurring more frequently with izuforant placebo (3 and 2 patients, respectively) vs placebo (1 patient each). There were no treatment-related SAEs and no patient receiving izuforant discontinued. Treatment with izuforant did not cause down-regulation of its target, H4R. CONCLUSIONS:This was the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements in the primary endpoint and all but one prespecified exploratory endpoint in CholU vs placebo.