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.

Figure 1

Adult Itch Reported Outcome weekly sum score. Patients scored their itch each morning and evening. Data analysis included only the highest score available each day. Missing daily scores were not imputed. The weekly sum score for a given week was only calculated if daily scores were completed for at least 4 of the 7 days that week (compliant week). Missing daily scores for a compliant week were imputed using the average daily score for that week. If for a given week more than three daily scores were missing, then weekly sum scores from the most recent compliant week were used in a last observation carried forward format.

Figure 2

Study design. Dose selection for cohort B was guided by the tolerability of maralixibat in the first 18 patients who completed 4 weeks of treatment in cohort A; the decision was based on the number of patients who lowered their dose or suspended or stopped active treatment owing to gastrointestinal intolerance related to the maralixibat (≥5 patients, cohort B would have received 5 mg maralixibat; <5 patients, cohort B would have received 20 mg maralixibat). Clinic visits were scheduled at baseline (week 0) and weeks 2, 4, 8, and 13. Telephone contact was scheduled at weeks 1, 3, and 17 (follow‐up call).

Figure 3

Patient disposition. Percentages are based on the ITT population.

Figure 4

Adult ItchRO™ weekly sum scores and serum bile acids. (A,B) Change from baseline and (C,D) difference in change for maralixibat versus placebo. (A,C) Adult ItchRO™ weekly sum scores and (B,D) sBA levels are presented at each time point. *P < 0.05 (analysis of covariance model); ***P < 0.0001. In panel B, boxes represent the IQR; the band within each box represents the median; the upper and lower error bars, respectively, represent the maximum and minimum data points excluding outliers; small data points represent outliers (individual data points outside 1.5 × IQR); and the bold, single, large data points represent mean change. All statistical comparisons except those for the primary outcome were considered nominal (not adjusted for multiplicity). Abbreviation: IQR, interquartile range.