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Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study
Kathleen M Loomes1,2, Robert H Squires3,4, Deirdre Kelly5,6
1Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Insights
Maralixibat improved cholestasis in children with specific genetic liver conditions. Seven patients with nontruncating BSEP deficiency responded, showing reduced bile acids, improved growth, and quality of life, avoiding liver transplants.
Area of Science:
- Hepatology
- Pediatric Gastroenterology
- Rare Disease Research
Background:
- Progressive familial intrahepatic cholestasis (PFIC) causes severe pruritus and impacts children's growth and quality of life (QoL).
- Current treatments often require surgical interventions like liver transplantation, indicating a significant unmet therapeutic need.
Purpose of the Study:
- To assess the long-term efficacy and safety of maralixibat in pediatric patients with familial intrahepatic cholestasis-associated protein 1 (FIC1) or bile salt export pump (BSEP) deficiencies.
- To identify patient subgroups that may benefit from maralixibat treatment.
Main Methods:
- An open-label, Phase 2, international, long-term study (INDIGO) enrolled 33 children (12 months–18 years) with FIC1 or BSEP deficiencies.
- Patients received oral maralixibat (266 μg/kg/day) with optional twice-daily dosing after Week 72, with efficacy assessed up to Week 240.
Main Results:
- Seven of 19 patients with nontruncating BSEP (nt-BSEP) deficiency achieved serum bile acid (sBA) response criteria.
- sBA responders showed significant reductions in sBAs, pruritus, and improvements in height, weight, and QoL, remaining liver transplant-free for over 5 years.
- No patients with FIC1 deficiency or truncating BSEP (t-BSEP) deficiency met sBA responder criteria.
Conclusions:
- Maralixibat efficacy in PFIC is subtype-dependent, with notable benefits observed in patients with nt-BSEP deficiency.
- Maralixibat demonstrated a favorable safety profile and may offer a non-surgical therapeutic option for eligible children with PFIC.
- Sustained improvements in clinical outcomes for responders suggest maralixibat's potential to alter the disease course.
Abstract:
Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiencies, suffer debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open-label, Phase 2, international, long-term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty-three patients, ranging from 12 months to 18 years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)-BSEP, and 19 had ≥ 1 nontruncating mutation (nt)-BSEP. Patients received maralixibat 266 μg/kg orally, once daily, from baseline to Week 72, with twice-daily dosing permitted from Week 72. Long-term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of > 75% from baseline or concentrations <102.0 μmol/L) was achieved in 7 patients with nt-BSEP, 6 during once-daily dosing, and 1 after switching to twice-daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant-free after > 5 years. No patients with FIC1 deficiency or t-BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well-tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt-BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well-tolerated alternative to surgical intervention.
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