1Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
2Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
4Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
5Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, UK.
6University of Birmingham, Birmingham, UK.
7Leeds Teaching Hospitals NHS Trust, Leeds, UK.
8Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, Los Angeles, California, USA.
9Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
10Hepatology and Nutrition Reference Center for Rare Diseases, Children's Hospital of Lyon, HCL, and Claude Bernard Lyon University 1, Lyon, France.
11Department of Gastroenterology, Hepatology, Feeding Disorders, and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.
12Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
13Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
15Amplyx Pharmaceuticals, San Diego, California, USA.
16Department of Pediatrics, Stanford School of Medicine, Palo Alto, California, USA.
17Takeda Pharmaceuticals, Cambridge, Massachusetts, USA.
18Mirum Pharmaceuticals, Foster City, California, USA.
19Mirum Pharmaceuticals, Basel, Switzerland.
20Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
21Institute of Liver Studies, King's College London, London, UK.
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.