Presenter of 5 Presentations
Panel discussion and Q&A (ID 2004)
A New Approach to Managing Alagille Syndrome (ID 2002)
H-O027 - EFFICACY AND SAFETY OF MARALIXIBAT IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (MARCH-PFIC): A RANDOMIZED PLACEBO-CONTROLLED PHASE 3 STUDY (ID 477)
Abstract
Objectives and Study
Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders resulting in disrupted bile composition, cholestasis, and pruritus. We evaluated maralixibat, an ileal bile acid transporter inhibitor, in a Phase 3 placebo-controlled study open to participants with all PFIC types at higher doses than previously studied.
Methods
Participants aged 1-18 years had moderate to severe pruritus and elevated serum bile acid (sBA) levels. Participants were randomized 1:1 to maralixibat 570 µg/kg twice daily or placebo for 26 weeks. Primary and key secondary endpoints were mean change from Baseline in pruritus and sBA, respectively, in participants with non-truncating BSEP deficiency (BSEP cohort). Mean change in pruritus and sBA were also analyzed in All-PFIC cohort (BSEP cohort plus other PFIC types).
Results
93 participants were enrolled (maralixibat=47, placebo=46): 31 in the BSEP cohort, 64 in All-PFIC cohort (31 BSEP, 13 FIC1, 9 MDR3, 7 TJP2, 4 MYO5B) and 29 in exploratory cohort (heterozygosis, variants not found, post-surgical, intermittent sBA). Mean baseline age, sBA, pruritus, and liver biochemistries were balanced between groups. Mean reduction in pruritus (0-4 ItchRO scale) for maralixibat vs placebo was -1.7 vs -0.6 (p=0.0098) in BSEP cohort and -1.8 vs -0.6 (p<0.0001) in All-PFIC cohort. 64% (maralixibat) vs 26% (placebo) of participants achieved clinically meaningful 1-point pruritus reduction (p=0.0023). Mean reduction in sBA for maralixibat vs placebo was -176 vs. 11 µmol/L (p=0.0013) in BSEP cohort and -157.5 vs. 2.9 (p<0.0001) in All-PFIC cohort. In All-PFIC cohort, total and direct bilirubin and weight significantly improved under maralixibat vs placebo. The most common adverse event was diarrhea (57.4% maralixibat vs 19.6% placebo; mostly mild and transient, median duration 5.5 days).
Conclusions
In the largest clinical study in children with PFIC, maralixibat significantly reduced pruritus and sBA and improved bilirubin and growth, with a well-tolerated safety profile.
H-O028 - NATIVE LIVER SURVIVAL IN ODEVIXIBAT SERUM BILE ACID RESPONDERS: DATA FROM THE PEDFIC STUDIES IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (ID 369)
Abstract
Objectives and Study
Patients with progressive familial intrahepatic cholestasis (PFIC) may have continued hepatic damage leading to liver transplantation (LT). The efficacy and safety of odevixibat, an ileal bile acid transporter inhibitor, were assessed in patients with PFIC in the phase 3 PEDFIC 1 and PEDFIC 2 studies. In a pooled analysis of data from these studies, we analysed native liver survival (NLS) in odevixibat-treated patients who met serum bile acid (sBA) treatment response criteria (sBAs reduced ≥70% or levels ≤70 µmol/L at 6 months). NLS was also analysed in partial sBA responders (patients with sBA reductions ≥30% to <70% at 6 months) and nonresponders (patients with sBA reductions <30% at 6 months or who underwent LT or discontinued treatment before 6 months).
Methods
PEDFIC 1 (NCT03566238) was a 24-week, randomised, placebo-controlled study in children with PFIC1 or PFIC2. PEDFIC 2 (NCT03659916) is an ongoing 72‑week extension study in patients of any age with any PFIC type. This pooled analysis spans from patients’ first dose of odevixibat to a cut-off date of 31 January 2022.
Results
Of 98 patients analysed (mean treatment duration, 88 weeks), 35 (36%) were sBA responders, 14 (14%) were partial sBA responders, and 49 (50%) were nonresponders. Mean sBA reductions at 6 months were 87% in responders and 44% in partial responders; there was a mean increase of 27% in nonresponders. All 35 sBA responders and 13 of the 14 partial sBA responders remained transplant free; 8 of the 49 nonresponders underwent LT (Figure). sBA responders had mean improvements at week 24 of treatment vs baseline in alanine aminotransferase and total bilirubin levels.
Conclusions
sBA decreases at 6 months were strongly associated with NLS for up to 3 years in odevixibat-treated patients with PFIC.
H-O029 - MARALIXIBAT IMPROVES CHOLESTATIC PRURITUS AND BILE ACIDS IN CHILDREN WITH FIC1: DATA FROM THE MARCH-PFIC TRIAL (ID 468)
Abstract
Objectives and Study
Familial Intrahepatic Cholestasis type 1 (FIC1) disease is a form of Progressive Familial Intrahepatic Cholestasis (PFIC), a group of autosomal recessive liver disorders of impaired bile acid transport leading to intrahepatic cholestasis, pruritus, and liver failure. Nearly half of FIC1 patients will require a liver transplant, but in many instances, transplant is not curative. Maralixibat (MRX), an ileal bile acid transporter inhibitor, significantly improved pruritus, serum bile acids (sBA), bilirubin, and growth in the All-PFIC cohort from the MARCH-PFIC Phase 3 trial, which used a higher dose of MRX than previously studied. Here we report on results from the FIC1 subgroup.
Methods
Participants from MARCH-PFIC with biallelic disease-causing variations in the ATP8B1 gene received MRX 570 µg/kg BID or placebo for 26 weeks. Key efficacy endpoints included improvements in pruritus, sBA, and bilirubin.
Results
13 FIC1 participants were randomized (n=7 maralixibat; n=6 placebo). Groups were well-balanced with respect to Baseline pruritus score (3.2 vs 3.4 on 0-4 ItchRO[Obs] score) and sBA (206 µmol/L for both). Significant changes from Baseline (CFB) were observed in ItchRO(Obs) response (p=0.0186) and sBA reduction (p=0.0298) in the maralixibat group, whereas no significant CFB were seen in placebo (Table). Three of seven MRX participants achieved sBA response predictive of transplant-free survival vs 0 in placebo. Numerical decreases in total and direct bilirubin (-2.1, -1.7 mg/dL) were observed in maralixibat participants, with increases in placebo. Treatment-emergent adverse events were reported in all participants; no serious events reported in MRX participants. Diarrhea was reported in 4 MRX and 2 placebo, all mild in severity. No participants discontinued treatment.
Conclusions
In participants with FIC1 disease, MRX was well-tolerated and associated with improvements in the efficacy endpoints of pruritus and sBA whereas no significant changes were observed in placebo. Decreased serum bilirubin levels may suggest improvement in liver health.