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.