A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis

Abstract

Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium‐dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% confidence interval [CI], –31.8, –21.2) and placebo (–23.4; 95% CI, –30.3, –16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.

Emerging therapies for PBC

“…However, some of these agents have subsequently been proven useful in chronic idiopathic constipation. Maralixibat was shown to reduce bile acid levels and improve pruritus in greater than 50% of patients; however, this did not differ from placebo [86].…”

Editorial: rapid assessment of health‐related quality of life in primary biliary cholangitis—no excuse not to ask

“…Recently, much focus has been directed at therapies to delay progression of PBC, although novel agents targeting symptom burden and quality of life have also recently emerged. Treatment with the ileal bile acid transporter (IBAT) inhibitor linerixibat was associated with improvement in pruritus scores, although this was not seen with the IBAT maralixibat, which may have related to a robust placebo response, trial design or dose used in the latter trial . This emphasises the importance of having simple, valid, disease‐specific instruments to reliably measure symptom extent and response to intervention over time and to identify patients who would benefit most from intervention; tools like PBC‐10 hold great promise.…”

New treatments/targets for primary biliary cholangitis

“…Lopixibat was ineffective in reducing patientreported pruritus scores (despite decreased serum bile acid levels) over a 12-week period. 79 However, GSK2330672 showed efficacy on pruritus in a randomised, double-blind, placebo-controlled, cross-over, phase II study, without evidence of improved biochemical cholestasis over a 14-day period of time. 80 Diarrhoea is the most common adverse effect and might limit the long-term use of IBAT inhibitors.…”