OC29 Clinical benefits of maralixibat for patients with Alagille syndrome are durable through 7 years of treatment: data from the MERGE study

Maralixibat (MRX), an ileal bile acid transport inhibitor (IBATi), is approved for the treatment of cholestatic pruritus in patients with Alagille Syndrome (ALGS) ≥2 months of age in Europe. Improvements in pruritus, serum bile acids (sBA), and height have been demonstrated from prior clinical trials including ICONIC, which followed participants up to 4 years, as well as IMAGO/IMAGINE and ITCH/IMAGINE-II, which reported outcomes to approximately 1.5 years. Participants from ICONIC, IMAGINE, and IMAGINE-II trials were invited to enroll in MERGE for additional long-term follow-up (LTFU); prior long-term survival outcomes (e.g., liver transplant, death) for this group have been previously reported. Here we report on efficacy in participants with additional LTFU from MERGE, including some participants that have received treatment for 7 years. All participants from ICONIC, IMAGINE and IMAGINE-II were included in the analysis. Impact of MRX was assessed for pruritus [ItchRO(Obs) 0–4 scale, with a ≥1-point reduction considered clinically meaningful], sBA, height and weight z-scores, ALT, total bilirubin (TB) and direct bilirubin (DB). Change from Baseline (CFB) was determined by comparing median (Q1, Q3) values from enrolment in the initial trial (i.e., ICONIC, IMAGO, or ITCH) to data from the visit in MERGE that best aligned with an annual visit. Data were analyzed for 86 participants at Baseline, with follow-up to 1 year for 76 participants, 4 years for 42 participants, and 7 years for 23 participants. Of the 86 participants, 84 had a genetic diagnosis of ALGS via the JAG1 mutation, 2 participants had a genetic diagnosis of ALGS via the NOTCH2 mutation, and 1 participant had an unidentified mutation. Baseline mean (SD) ItchRO(Obs) was 2.65 (0.75) and clinically meaningful reductions over time with CFB of -1.57 (-0.83, -2.14), -2.00 (-1.43, -2.56), and -2.14 (-1.43, -3.00) at 1 year, 4 years and 7 years, respectively. Likewise, Baseline sBA was 254 (207) µmol/L and decreased with CFB of -57 (8, -150) µmol/L, -62 (-32, -152) µmol/L, and -105 (-41, -266) µmol/L at 1 year, 4 years and 7 years. Improvement was observed in height, with Baseline z-score of -1.7 (1.27) and CFB of 0.1 (-0.1, 0.3), 0.3 (0.0, 1.0), and 0.7 (0.0, 1.2) at 1 year, 4 years and 7 years while weight z-scores were largely unchanged. Reductions in TB and DB were observed after treatment with maralixibat. No clinically meaningful changes in ALT or AST were observed with maralixibat treatment. There were no new safety signals. In this unmatched cohort, the benefit of MRX in ALGS patients, including both improvements in clinical outcomes and sBA, persist through 7 years of treatment. No new safety concerns were identified in the long-term.

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