EP547 (MRGPRX4 inverse agonist) for cholestatic pruritus due to primary biliary cholangitis or primary sclerosing cholangitis: Results from the phase 2 randomized, placebo-controlled PACIFIC study.

INTRODUCTION AND OBJECTIVES: MRGPRX4, a chemosensory Mas-related G protein-coupled receptor activated by bile acids, has been implicated in the pathogenesis of cholestatic pruritus, a frequent and burdensome symptom in patients with primary biliary or sclerosing cholangitis (PBC/PSC). The phase 2 PACIFIC study investigated EP547, a MRGPRX4 inverse agonist, in patients with moderate-to-severe cholestatic pruritus. PATIENTS AND METHODS: Patients with PBC or PSC and a mean daily Worst Itch Numerical Rating Scale (WI-NRS) ≥4 were randomized 1:1 to once-daily oral 100 mg EP547 or placebo during a 6-week double-blind, placebo-controlled (DBPC) period. All patients then received EP547 in a 6-week open-label extension period. The primary endpoint was the change from baseline (CFB) in WI-NRS at Week 6. Secondary endpoints included the 5-D Itch Scale, the Patient Global Impression of Severity, the Patient Global Impression of Change, and safety and tolerability. RESULTS: Sixty-one patients (PBC, n=44; PSC, n=17; median [range] age, 54.0 [21-77] years; female, 78.7%) received EP547 (n=31) or placebo (n=30). No substantial improvement was observed with EP547 versus placebo in WI-NRS scores at Week 6 (least squares mean [SE] CFB, -1.8 [0.4] vs -2.2 [0.4]). No secondary efficacy endpoints were met. EP547 was generally well tolerated, with no grade ≥3 treatment-emergent adverse events (TEAEs) reported in the DBPC period and no dose interruptions or treatment discontinuations due to TEAEs throughout the study. CONCLUSIONS: Results from the PACIFIC study suggest that mechanisms other than MRGPRX4 activation are responsible for pruritus in patients with PBC or PSC.