title: Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis.
abstract: This trial was conducted to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis (AD). Eligible patients were randomly assigned to JNJ-39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-6 Eczema Area and Severity Index (EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment (IGA) and patient-reported outcome (PRO) pruritus assessments (Pruritus Categorical Response Scale [PCRS], Pruritus Numeric Rating Scales [PNRS], Pruritus Interference Numeric Rating Scale [PINRS] and Subject's Global Impressions of Change in Pruritus [SGICP]). Eighty-eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end-point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ-39758979 100 mg (-3.7) and 300 mg (-3.0) versus placebo (-1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ-39758979 300 mg. Safety, including adverse events (AE), was comparable between JNJ-39758979 and placebo with the exception of two patients (both receiving JNJ-39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H4 R-antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ-39758979 appears to be associated with drug-induced agranulocytosis, likely an off-target effect.
authors.affiliation: Research & Development, Janssen Pharmaceutical KK, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Murata
authors.forename: Michael
authors.initials: M
authors.lastname: Song
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hisamichi
authors.forename: Xie L
authors.initials: XL
authors.lastname: Xu
authors.forename: Andrew
authors.initials: A
authors.lastname: Greenspan
authors.forename: Mai
authors.initials: M
authors.lastname: Kato
authors.forename: Chiun-Fang
authors.initials: CF
authors.lastname: Chiou
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.forename: Cynthia
authors.initials: C
authors.lastname: Guzzo
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Mamitaro
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000328:Adult; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D005260:Female; D017442:Histamine Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007564:Japan; D008297:Male; D009503:Neutropenia / Q000139:chemically induced*; D011537:Pruritus / Q000188:drug therapy; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C000590929:4-(3-aminopyrrolidin-1-yl)-6-isopropylpyrimidin-2-ylamine; C418607:HRH4 protein, human; D017442:Histamine Agonists; D011743:Pyrimidines; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
keywords: H4 receptor; Japan; atopic dermatitis; itch