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Comparative Study
. 2024 Jun 1;79(6):1279-1292.
doi: 10.1097/HEP.0000000000000727. Epub 2023 Dec 25.

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Bettina E Hansen  1   2   3 , Shannon M Vandriel  4 , Pamela Vig  5 , Will Garner  5 , Douglas B Mogul  5 , Kathleen M Loomes  6 , David A Piccoli  6 , Elizabeth B Rand  6 , Irena Jankowska  7 , Piotr Czubkowski  7 , Dorota Gliwicz-Miedzińska  7 , Emmanuel M Gonzales  8 , Emmanuel Jacquemin  8 , Jérôme Bouligand  9 , Lorenzo D'Antiga  10 , Emanuele Nicastro  10 , Henrik Arnell  11 , Björn Fischler  12 , Étienne Sokal  13 , Tanguy Demaret  13 , Susan Siew  14 , Michael Stormon  14 , Saul J Karpen  15 , Rene Romero  15 , Noelle H Ebel  16 , Jeffrey A Feinstein  17 , Amin J Roberts  18 , Helen M Evans  18 , Shikha S Sundaram  19 , Alexander Chaidez  19 , Winita Hardikar  20 , Sahana Shankar  21 , Ryan T Fischer  22 , Florence Lacaille  23 , Dominique Debray  24 , Henry C Lin  25 , M Kyle Jensen  26 , Catalina Jaramillo  26 , Palaniswamy Karthikeyan  27 , Giuseppe Indolfi  28 , Henkjan J Verkade  29 , Catherine Larson-Nath  30 , Ruben E Quiros-Tejeira  31 , Pamela L Valentino  32 , Maria Rogalidou  33 , Antal Dezsőfi  34 , James E Squires  35 , Kathleen Schwarz  36 , Pier Luigi Calvo  37 , Jesus Quintero Bernabeu  38   39 , Andréanne N Zizzo  40 , Gabriella Nebbia  41 , Pinar Bulut  42 , Ermelinda Santos-Silva  43 , Rima Fawaz  44 , Silvia Nastasio  45 , Wikrom Karnsakul  46 , María Legarda Tamara  47 , Cristina Molera Busoms  48 , Deirdre A Kelly  49 , Thomas Damgaard Sandahl  50 , Carolina Jimenez-Rivera  51 , Jesus M Banales  52 , Quais Mujawar  53 , Li-Ting Li  54 , Huiyu She  54 , Jian-She Wang  54 , Kyung Mo Kim  55 , Seak Hee Oh  55 , Maria Camila Sanchez  56 , Maria Lorena Cavalieri  56 , Way Seah Lee  57 , Christina Hajinicolaou  58 , Chatmanee Lertudomphonwanit  59 , Orith Waisbourd-Zinman  60 , Cigdem Arikan  61 , Seema Alam  62 , Elisa Carvalho  63 , Melina Melere  64 , John Eshun  65 , Zerrin Önal  66 , Dev M Desai  67 , Sabina Wiecek  68 , Raquel Borges Pinto  69 , Victorien M Wolters  70 , Jennifer Garcia  71 , Marisa Beretta  72 , Nanda Kerkar  73 , Jernej Brecelj  74 , Nathalie Rock  75 , Eberhard Lurz  76 , Niviann Blondet  32 , Uzma Shah  77 , Richard J Thompson  78 , Binita M Kamath  4 ; Global ALagille Alliance (GALA) Study Group
Affiliations
Comparative Study

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Bettina E Hansen et al. Hepatology. .

Abstract

Background and aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.

Approach and results: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.

Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

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Conflict of interest statement

Bettina E. Hansen consults and received grants from Calliditas, CymaBay, and Intercept. She consults for Albireo, Enyo, Eiger, Ipsen, and Mirum. Shannon M. Vandriel consults and received grants from Mirum. She consults for Albireo. Pamela Vig is employed by and owns stock in Mirum. Will Garner is employed by and owns stock in Mirum. Douglas B. Mogul is employed by and owns stock in Mirum. Kathleen M. Loomes consults and received grants from Albireo and Mirum. She consults for Travere. Dorota Gliwicz-Miedzińska received grants from ExCEEd Orphan. Emmanuel M. Gonzales consults, advises, is on the speakers’ bureau, and received grants from Albireo and Mirum. He consults and is on the speakers’ bureau for CTRS. He consults for Vivet. Emmanuel Jacquemin consults for CTRS and Vivet. Lorenzo D’Antiga consults and advises Albireo and Mirum. He consults for Advanz, Spark, and Tome. He advises Alexion, AstraZeneca, Genespire, Selecta, and Vivet. Emanuele Nicastro consults for Albireo and Mirum. Henrik Arnell advises Mirum. He is employed by Albireo and Baxter. Étienne Sokal consults, advises, owns stock, holds intellectual property rights, and has other interests with Cellaion. He consults for Ipsen and Mirum. Saul J. Karpen consults for Albireo, HemoShear, Intercept, and Mirum. Rene Romero consults for Albireo and Mirum. He received grants from Gilead. Noelle H. Ebel consults and is on the speakers’ bureau for Ipsen and Mirum. Shikha S. Sundaram advises Albireo and Mirum. Ryan T. Fischer advises and is on the speakers’ bureau for Albireo, Ipsen, and Mirum. Henry C. Lin advises Albireo and Mirum. M. Kyle Jensen consults, advises, and received grants from Albireo. He consults for GLG and Guidepoint Global. Palaniswamy Karthikeyan consults for Cepton Strategies. He advises Albireo. Giuseppe Indolfi advises Albireo and Mirum. Henkjan J. Verkade consults and advises Albireo and Mirum. Pamela L. Valentino is on the speakers’ bureau for Mirum. Antal Dezsőfi advises Mirum. Kathleen Schwarz consults and advises Sarepta. She consults for Mirum and Up to Date. She advises and received grants from Albireo and Gilead. She is employed by NASPGHAN. Pier Luigi Calvo advises Albireo, Ipsen, Mirum, and Nestlé. Andréanne N. Zizzo advises Mirum. Gabriella Nebbia consults and advises Albireo. Rima Fawaz consults for Albireo, the Hepatic Adjudication Committee, and Mirum. Wikrom Karnsakul received grants from Albireo, Gilead, Mirum, and Travere. Cristina Molera Busoms advises Alexion, Mirum, and Orphalan. Deirdre A. Kelly consults, advises, received grants, and is employed by Albireo and Mirum. She consults, advises, and received grants from Intercept. She consults and advises AstraZeneca. She consults for Alnylam, Freeline, GlaxoSmithKline, Orphalan, and Takeda. She received grants from AbbVie and Gilead. Jesus M. Banales consults, advises, and received grants from Albireo and CymaBay. He consults and advises Ikan Biotech and OWL-Rubio Metabolomics. He is on the speakers’ bureau and received grants from Incyte. He is on the speakers’ bureau for AstraZeneca and Intercept. He received grants from Roche. Quais Mujawar advises Medison and Mirum. He owns stock in Bausch Health and Sun Pharma. Orith Waisbourd-Zinman consults for Neopharm Israel. Sabina Wiecek is employed by the Department of Pediatrics, Medical University of Silesia. Raquel Borges Pinto is employed by Hospital Criança Conceição. Nanda Kerkar advises Albireo, Alexion, Ipsen, and Mirum. She received royalties from Elsevier. Jernej Brecelj is on the speakers’ bureau for Swixx Biopharma. Eberhard Lurz consults, advises, and is on the speakers’ bureau for Ipsen, Mirum, Nutricia, and Takeda. Richard J. Thompson consults and owns stock in Generation Bio and Rectify Pharma. He consults for Albireo, Alnylam, and Mirum. Binita M. Kamath consults and received grants from Albireo and Mirum. She consults for Astellas. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Selection of the GALA control group. *A minimum amount of follow-up time was considered to avoid immortal time bias (ie, an early observed effect due to survivor treatment selection bias). Abbreviation: GALA, Global ALagille Alliance.
FIGURE 2
FIGURE 2
Kaplan-Meier estimates of EFS in the maralixibat and GALA control cohorts. The number at risk is the original number of participants (at time 0) minus those who had an event or were censored (eg, lost to follow-up) before the start of the given period. Shaded areas represent 95% CIs. *Cox regression models for the primary analysis: primary prespecified (adjusted), where the effect of maralixibat versus GALA log-likelihood test was adjusted for age, sex, bilirubin, and alanine aminotransferase (according to the statistical analysis plan), and primary unadjusted. Abbreviations: EFS, event-free survival; GALA, Global ALagille Alliance.
FIGURE 3
FIGURE 3
Primary, sensitivity, and subgroup analyses of EFS. Sensitivity and subgroup analyses for the primary comparison included SAP-specified analyses (Cox regression model adjusted for age, sex, total bilirubin, and ALT); Unadjusted [univariate Cox proportional hazards model that only contains treatment as a covariate (EFS)]; Adjusted 1 (Cox regression model adjusted for age, total bilirubin, and GGT); Adjusted 2 (Cox regression model adjusted for age, total bilirubin, GGT, ALT, and region); Adjusted 3 (Cox regression model adjusted for age, total bilirubin, GGT, ALT, sex, and year of birth); and Adjusted 4 (Cox regression model adjusted for age, total bilirubin, GGT, and sBA). Random visit 1 and random visit 2 represent a visit randomly selected uniformly among all eligible visits. Random visit, Method 2 first selected a year at random among all eligible visits and then randomly selected a visit within that year. This was done to account for participants who would have “clusters” of visits due to hospitalization that could skew the selection of a random visit toward that cluster. Landmark time points [x] removed events occurring within either group within the first [x] months of the selected index time. Abbreviations: ALT, alanine aminotransferase; ATT, average treatment effect in the treated; EFS, event-free survival; GGT, gamma-glutamyl transferase; IPTW, inverse probability of treatment weights; SAP, statistical analysis plan; sBA, serum bile acid.
FIGURE 4
FIGURE 4
Kaplan-Meier estimates of EFS in the maralixibat and GALA control cohorts with landmark time points for events occurring in the first (A) 3 months, (B) 6 months, and (C) 12 months. The number at risk is the original number of participants (at time 0) minus those who had an event or were censored (eg, lost to follow-up) before the start of the given period. Participants who had events within the first 3, 6, or 12 months were excluded from the analysis (thus, there are no events within these respective periods). This was done to avoid immortal time bias. Shaded areas represent 95% CIs. Abbreviations: aHR, adjusted hazard ratio; EFS, event-free survival; GALA, Global ALagille Alliance.
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References

    1. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: The epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67:148–156. - PMC - PubMed
    1. Kamath BM, Spino C, McLain R, Magee JC, Fredericks EM, Setchell KD, et al. . Unraveling the relationship between itching, scratch scales, and biomarkers in children with Alagille syndrome. Hepatol Commun. 2020;4:1012–1018. - PMC - PubMed
    1. Kamath BM, Stein P, Houwen RHJ, Verkade HJ. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40:1812–1822. - PMC - PubMed
    1. Bergasa NV. Pruritus of cholestasis In: Carstens E, Akiyama T, eds. Itch: Mechanisms and Treatment. CRC Press/Taylor & Francis; 2014:61–88.
    1. Emerick KM, Elias MS, Melin-Aldana H, Strautnieks S, Thompson RJ, Bull LN, et al. . Bile composition in Alagille syndrome and PFIC patients having partial external biliary diversion. BMC Gastroenterol. 2008;8:47. - PMC - PubMed

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