ANALYSIS OF SAFETY IN MARALIXIBAT-TREATED PARTICIPANTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM THE MARCH TRIAL

Background: Maralixibat (MRX) is a novel, minimally absorbed, orally-administered inhibitor of the ileal bile acid transporter (IBAT) that interrupts the enterohepatic circulation of bile acids to improve cholestatic pruritus. MARCH, a 26-week randomized Phase 3 study, is the largest and most genetically inclusive clinical trial of Progressive Familial Intrahepatic Cholestasis (PFIC) to date, and achieved primary and key secondary endpoints of reduction in cholestatic pruritus, serum bile acids (sBA), improved bilirubin, and growth. Here, we provide a detailed analysis of safety data observed in the study. Methods: Treatment-emergent adverse events (TEAEs) and laboratory data from MARCH were analyzed. Results: 93 PFIC patients were randomized to MRX 570 µg/kg twice daily (n=47) or placebo (PBO; n=46). Median (min, max) treatment exposure was 183 (10, 203) days. TEAEs included diarrhea (57.4% vs 19.6%), and abdominal pain (25.5% vs 13%) for MRX vs PBO, respectively. Diarrhea was mostly grade 1, transient, with a median duration of 5.5 days; there were no severe or serious events. One patient with mild diarrhea discontinued therapy. Abdominal pain was also mostly mild and transient and, in nearly all instances, was concurrent with diarrhea. There were no clinically meaningful changes observed in either group from baseline in transaminase levels. Transaminase AEs were observed in 17% and 6.5% of MRX and PBO patients, respectively. Among the 8 MRX patients with transaminase elevations, 6 had resolution of the elevation without drug interruption; 2 patients had ongoing stable elevation even after drug interruption (n=1) or dose reduction (n=1) and both ultimately resumed prior maximum dose. No patients discontinued MRX due to transaminase elevation. Bilirubin increase was less common in MRX vs PBO (14.9% vs 19.6%). FSV deficiency, which was reported as an AE, was also less common in MRX vs PBO (27.7% vs 34.8%). Fractures were seen in 6.4% of MRX and in 0% of PBO; none were considered related as all had clear alternative causes for fracture, including pre-existing vitamin D deficiency which was stable or improved on MRX. Serious AEs were reported in 10.6% of MRX and 6.5% of PBO patients; none were deemed related (except 1 event of mild bilirubin increase in MRX); all resolved without any dose modifications. Conclusions: The MARCH study is the largest PFIC study conducted across PFIC types. MRX was well tolerated, with GI effects being the most frequent event but generally mild and self-limiting. FSV deficiency and bilirubin increase were more frequently seen in the PBO grou