Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial.

Autor:	Ovchinsky N; Pediatric Gastroenterology and Hepatology, Hassenfeld Children's Hospital, NYU Langone, New York, NY, USA., Aumar M; Univ Lille, CHU Lille, Pediatric Gastroenterology, Hepatology, and Nutrition, Inserm U1286 Infinite, CHU Lille Pôle Enfant, Lille, France., Baker A; Paediatric Liver Centre, King's College Hospital, London, UK. Electronic address: alastair.baker@nhs.net., Baumann U; Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany., Bufler P; Department of Pediatric Gastroenterology, Nephrology, and Metabolic Diseases, Charité Universitätsmedizin Berlin, Berlin, Germany., Cananzi M; Pediatric Gastroenterology, Digestive Endoscopy, Hepatology, and Care of the Child With Liver Transplantation, Department of Children's and Women's Health, University Hospital of Padova, Padova, Italy., Czubkowski P; Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland., Durmaz Ö; Istanbul University, Istanbul Faculty of Medicine, Istanbul, Türkiye., Fischer R; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA., Indolfi G; Meyer Children's Hospital IRCCS, Florence, Italy., Karnsakul WW; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Lacaille F; Pediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France., Lee WS; Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Maggiore G; Hepatology, Gastroenterology, Nutrition, Digestive Endoscopy, and Liver Transplantation Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy., Rosenthal P; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Francisco, San Francisco, CA, USA., Ruiz M; Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France., Sokal E; Université Catholique de Louvain, Cliniques St Luc, Service de Gastroentérologie et Hépatologie Pédiatrique, Brussels, Belgium., Sturm E; Pediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany., van der Woerd W; Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands., Verkade HJ; Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Groningen, Beatrix Children's Hospital and University Medical Center Groningen, Groningen, Netherlands., Wehrman A; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA., Clemson C; Ipsen, Cambridge, MA, USA., Yu Q; Ipsen, Cambridge, MA, USA., Ni Q; Ipsen, Cambridge, MA, USA., Ruvido J; Ipsen, Cambridge, MA, USA., Manganaro S; Ipsen, Cambridge, MA, USA., Mattsson JP; Ipsen, Cambridge, MA, USA.
Jazyk:	angličtina
Zdroj:	The lancet. Gastroenterology & hepatology [Lancet Gastroenterol Hepatol] 2024 Jul; Vol. 9 (7), pp. 632-645. Date of Electronic Publication: 2024 Apr 23.
DOI:	10.1016/S2468-1253(24)00074-8
Abstrakt:	Background: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. Methods: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Findings: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Interpretation: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Funding: Albireo Pharma, an Ipsen company. Competing Interests: Declaration of interests NO has received research support to their institution from Albireo Pharma (an Ipsen company) and Mirum, and consulting fees from Albireo Pharma (an Ipsen company). UB has received grants or contracts and consulting fees from Mirum, Albireo Pharma (an Ipsen company), and Alexion. PB has received an unrestricted research grant from Albireo Pharma (an Ipsen company) and payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum; and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. MC has received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. RF has received payments or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum, and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company). GI has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company), Mirum, and Kedrion Pharma. PR has received research support to their institution from Albireo Pharma (an Ipsen company); grants or contracts from AbbVie, Arrowhead, Gilead, Merck, Mirum, Takeda, and Travere; consulting fees from Albireo Pharma (an Ipsen company), Ambys, Audentes, BioMarin, Dicerna, Encoded, Gilead, MedinCell, Mirum, RNAV8, Takeda, and Travere; and payment or honoraria for speakers bureaus from Mirum. MR has received consulting fees from Albireo Pharma (an Ipsen company), Grifols, Mirum, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum and Takeda; and support for attending meetings or travel, or both, from Mirum and Albireo Pharma (an Ipsen company). ESt has received unrestricted grants from Albireo Pharma (an Ipsen company) and Mirum; consulting fees from Albireo Pharma (an Ipsen company) and Mirum; and payment or honoraria to their institution for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum. WvdW has received consulting fees from Mirum. HJV has received grants or contracts to their institution from Albireo Pharma (an Ipsen company), Mirum, and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition; and consulting fees paid to their institution from Albireo Pharma (an Ipsen company) and Mirum. AW has received research support from Albireo Pharma (an Ipsen company), and has participated on a data safety monitoring or advisory board for Mirum. QY was previously employed at Albireo Pharma (an Ipsen company). CC, JPM, and SM were previously employed at Albireo Pharma (an Ipsen company) and received salary and stock options. JPM also held patents with and received support for attending meetings or travel, or both, from Albireo Pharma (an Ipsen company). QN and JR are current employees of Ipsen and receive salary or stock options (or both). MA, PC, ÖD, WSL, AB, WWK, FL, GM, and ESo declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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