ANALYSIS OF LONG-TERM SAFETY IN MARALIXIBAT-TREATED PARTICIPANTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM MARCH-ON

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 reduce toxic bile acids and improve cholestatic pruritus. In MARCH, a 26-week, randomized, placebo-controlled, Phase 3 study (N=93) for patients with progressive familial intrahepatic cholestasis (PFIC), MRX was well tolerated with mild/self-limiting diarrhea and abdominal pain being the most commonly reported gastrointestinal adverse events (AEs) and were more common in the treatment group vs placebo (PBO). Bilirubin increase and fat soluble vitamin (FSV) deficiency events were more frequent in the PBO group, and ALT laboratory assessments were not different between groups. MARCH-ON is an ongoing, open-label, long-term extension study for participants who completed MARCH. In this interim safety analysis up to 106 weeks, we describe the evidence of safety with longer follow-up, and inclusion of the MARCH PBO participants into MARCH-ON, adding to the overall safety analysis. Methods: Treatment-emergent AEs (TEAEs) and laboratory data from MARCH-ON were analyzed longitudinally for all participants who opted to enroll (N=85) as of June 23, 2022. Safety was assessed for participants who received PBO in MARCH and initiated MRX in MARCH-ON (PBO-MRX group: n=38) and for participants who received MRX in MARCH and continued beyond 26 weeks of treatment into MARCH-ON (MRX-MRX group; n=47). Data are reported below for events of interest using pooled FDA Medical Query (FMQ) terms (gastrointestinal events, transaminases increased, bilirubin increased, and FSV deficiency). Results: In MARCH-ON, mean (SD) exposure in all MRX-treated participants was 340 (205) days [MRX-MRX: 386 (205) days; PBO-MRX: 284 (193) days]. There were 82 (96.5%) participants with a TEAE, with the most common affected system being gastrointestinal (n=63; 74.1%). Overall, 7 (8.2%) had a severe AE, none of which were considered related to MRX; 14 (16.5%) had a serious AE with 1 (1.2%) considered related to MRX (increased blood bilirubin). There was 1 (1.2%) death due to respiratory infection and not related to MRX. Three participants (3.5%) had 4 AEs (diarrhea; bilirubin and ALT increase; and cirrhosis) leading to discontinuation. The proportion of participants with AEs of interest from the PBO-MRX group in MARCH-ON were lower than those observed from the MRX-treated participants from MARCH for diarrhea (13 [34.2%] vs 27 [57.4%]), abdominal pain (8 [21.1%] vs 12 [25.5%]), hyperbilirubinemia (1 [2.6%] vs 7 [14.9%]), transaminases increased (5 [13.2%] vs 8 [17.0%]), and FSV deficiency (10 [26.3%] vs 13 [27.7%]). Participants who previously received MRX in MARCH and did not report an event were less likely to report an event in MARCH-ON. New initial onsets of the following terms were reported: diarrhea (n=3), increased bilirubin (n=3), transaminases increased (n=1), and FSV deficiency (n=4). Conclusions: In this safety analysis of long-term treatment with MRX out to 106 weeks from MARCH-ON, no new safety signals were observed. The frequency of events was slightly lower than previously reported and decreased over time in participants with extended follow-up. MRX was well-tolerated overall, as evidenced by a low rate of discontinuatio

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

EFFICACY AND SAFETY OF MARALIXIBAT IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (MARCH-PFIC): A RANDOMIZED PLACEBO-CONTROLLED PHASE 3 STUDY

EFFICACY AND SAFETY OF MARALIXIBAT IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (MARCH-PFIC): A RANDOMIZED PLACEBO-CONTROLLED PHASE 3 STUD

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Background: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. Methods: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. Findings: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. Interpretation: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC