Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

Abstract

Background: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.

Methods: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.

Results: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.

Conclusions: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

FIGURE 1

Pruritus outcomes. (A) Mean change in ItchRO weekly sum score from baseline to week 14/ET in the modified intent-to-treat population overall and in post hoc subgroups of participants with any pruritus at baseline (daily average ItchRO > 0) and those with daily average ItchRO ≥3 at baseline. (B) Mean change in ItchRO weekly sum score from baseline at all assessment time points. Error bars represent 95% CIs. (C) Mean change in 5-D Itch score from baseline to week 14/ET in the modified intent-to-treat population overall and in post hoc subgroups of participants with any pruritus at baseline (daily average ItchRO > 0) and those with daily average ItchRO ≥ 3 at baseline. (D) Mean change in 5-D Itch score from baseline at all assessment time points. Error bars represent 95% CIs. p-values are from paired Wilcoxon signed-rank tests. Abbreviations: 5-D Itch, 5-domain Itch; BL, baseline; ET, early termination; ItchRO, Itch-Reported Outcome; NS, no significance.

FIGURE 2

Serum bile acids over time. Mean change in sBA, and conjugated BA subspecies levels from baseline through to week 6 and week 14/ET in all participants (N = 27), participants with ItchRO score ≥ 3 (n = 8), and participants with sBA levels > 10. (A) sBA (μmol/L); (B) GCA (μmol/L); (C) TCA (μmol/L); (D) GCDCA (μmol/L); (E) TCDCA (μmol/L). Mean values are presented; error bars represent 95% CI; percentages represent change from baseline. Abbreviations: BA, bile acid; CFB, change from baseline; ET, early termination; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; ItchRO, Itch-Reported Outcome; sBA, serum bile acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid.