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

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, Turkiye, 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 mu g/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<middle dot>5 years (IQR 3<middle dot>2 to 8<middle dot>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<middle dot>8 [SD 0<middle dot>5] for odevixibat vs 3<middle dot>0 [0<middle dot>6] for placebo). Mean scratching scores at weeks 21-24 were 1<middle dot>1 (0<middle dot>9) for odevixibat and 2<middle dot>2 (1<middle dot>0) for placebo, representing a least -squares (LS) mean change of -1<middle dot>7 (95% CI -2<middle dot>0 to -1<middle dot>3) for odevixibat and -0<middle dot>8 (-1<middle dot>3 to -0<middle dot>3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0<middle dot>9 [95% CI -1<middle dot>4 to -0<middle dot>3]; p=0<middle dot>0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 mu mol/L [SD 115] with odevixibat vs 246 mu mol/L [121] with placebo) to the average of weeks 20 and 24 (149 mu mol/L [102] vs 271 mu mol/L [167]; LS mean change -90 mu mol/L [95% CI -133 to -48] with odevixibat vs 22 mu mol/L [-35 to 80] with placebo; difference in LS mean change -113 mu mol/L [95% CI -179 to -47]; p=0<middle dot>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.