Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor

Abstract

Background and aims: Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.

Approach and results: We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival.

Conclusions: Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.

Graphical abstract

FIGURE 1

Patient selection for the combined ALGS study population. ITCH: NCT02057692; IMAGINE-II: NCT02117713; IMAGO: NCT01903460; IMAGINE: NCT02047318; and ICONIC: NCT02160782. ^aMaralixibat dose: up to 266 µg/kg/d. ^bThere was 1 common site for the IMAGO/IMAGINE and ICONIC trials; the total number of different sites for the overall study population (N = 76) was 21. ^cMaralixibat dose: 380 µg/kg/d. ^dTwo participants had events before week 48 and also did not have week 48 laboratory samples. Abbreviation: ALGS, Alagille syndrome.

FIGURE 2

Kaplan-Meier estimates of overall 6-year outcomes in children with Alagille syndrome treated with maralixibat. (A) EFS. (B) TFS. The dashed line indicates a 75% survival threshold. The shaded area indicates 95% confidence limits. Abbreviations: EFS, event-free survival; TFS, transplant-free survival.

FIGURE 3

Concordance statistic for prediction of event-free survival in children with Alagille syndrome treated with maralixibat, according to demographics, and clinical and laboratory characteristics. Variables selected for inclusion in the model (ie, those with a concordance statistic ≥0.7) were total bilirubin levels at W48, change in pruritus (as assessed by ItchRO[Obs]) from baseline to W48, sBA (total serum bile acids) levels at W48, and age at enrollment. Abbreviations: ALP, alkaline phosphatase; APRI, AST to platelet ratio index; BL, baseline; ItchRO(Obs), Itch-Reported Outcome (Observer); PedsQL, Pediatric Quality of Life Inventory^TM 4.0 Generic Core Scales; sBA, serum bile acids; W48, week 48.

FIGURE 4

Kaplan-Meier estimates of 6-year EFS in children with Alagille syndrome treated with maralixibat for each predictive variable. (A) Change in pruritus (as measured by ItchRO[Obs]) from baseline to week 48 (>1 point reduction vs. ≤1 point reduction). (B) Total bilirubin levels at week 48 (<6.5 mg/dL vs. ≥6.5 mg/dL). (C) sBA levels at week 48 (<200 µmol/L vs. ≥200 µmol/L). The shaded area indicates 95% confidence limits. Abbreviations: EFS, event-free survival; ItchRO(Obs), Itch-Reported Outcome (Observer); sBA, serum bile acids.