ANALYSIS OF LONG-TERM SAFETY IN MARALIXIBAT-TREATED PARTICIPANTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM MARCH-ON
(2023) NASPGHAN ANNUAL MEETING — Location: San Diego, USA (4.October.2023)
Files
NASPGHAN2023MARCHONSafetyAbstractFINALSUBMITTEDTONASPGHAN1.pdf
Open Access - Adobe PDF
- 121.96 KB
Details
- Authors
Sokal, Etienne 
- et. al.
- Abstract
- 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 discontinuation
- Affiliations
Citations
Ovchinsky, N., Miethke, A., Moukarzel, A., Porta, G., Covarrubias Esquer, J., Sokal, E., & et al. (2023). ANALYSIS OF LONG-TERM SAFETY IN MARALIXIBAT-TREATED PARTICIPANTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM MARCH-ON. NASPGHAN ANNUAL MEETING, San Diego, USA. https://hdl.handle.net/2078.5/101740