Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study.
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2023-06
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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.Type
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Bowlus, Christopher L, Bertus Eksteen, Angela C Cheung, Douglas Thorburn, Cynthia A Moylan, Paul J Pockros, Lisa M Forman, Alejandro Dorenbaum, et al. (2023). Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study. Hepatology communications, 7(6). p. e0153. 10.1097/hc9.0000000000000153 Retrieved from https://hdl.handle.net/10161/28280.
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Cynthia Ann Moylan
My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from metabolic dysfunction associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD). As part of the MASLD Research Team at Duke, we are investigating the role of environmental contaminants, epigenetics, and genetics on the development of advanced fibrosis and liver cancer from MASLD and other chronic liver diseases. We are also interested in understanding risks for progressive liver disease including developmental programming and in utero exposures and have been investigating these risks through studies of the Newborn Epigenetics Study (NEST). The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratify patients as well as to develop better preventative and therapeutic strategies.
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