Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study.

Autor: Loomes KM; Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Squires RH; Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Kelly D; Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, UK.; University of Birmingham, Birmingham, UK., Rajwal S; Leeds Teaching Hospitals NHS Trust, Leeds, UK., Soufi N; Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, Los Angeles, California, USA.; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Lachaux A; Hepatology and Nutrition Reference Center for Rare Diseases, Children's Hospital of Lyon, HCL, and Claude Bernard Lyon University 1, Lyon, France., Jankowska I; Department of Gastroenterology, Hepatology, Feeding Disorders, and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland., Mack C; Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Setchell KDR; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Karthikeyan P; Leeds Teaching Hospitals NHS Trust, Leeds, UK., Kennedy C; Amplyx Pharmaceuticals, San Diego, California, USA., Dorenbaum A; Department of Pediatrics, Stanford School of Medicine, Palo Alto, California, USA., Desai NK; Takeda Pharmaceuticals, Cambridge, Massachusetts, USA., Garner W; Mirum Pharmaceuticals, Foster City, California, USA., Jaecklin T; Mirum Pharmaceuticals, Basel, Switzerland., Vig P; Mirum Pharmaceuticals, Foster City, California, USA., Miethke A; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Thompson RJ; Institute of Liver Studies, King's College London, London, UK.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2022 Sep; Vol. 6 (9), pp. 2379-2390. Date of Electronic Publication: 2022 May 04.
DOI: 10.1002/hep4.1980
Abstrakt: 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.
(© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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