Analysis of long-term treatment effects of odevixibat on clinical outcomes in children with progressive familial intrahepatic cholestasis in odevixibat clinical studies vs external controls from the napped database

Background

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare cholestatic liver diseases characterised by intractable pruritus, elevated serum bile acids (sBAs), and progressive liver damage. NAPPED (NAtural course and Prognosis of PFIC and Effect of biliary Diversion) is a large retrospective database investigating the natural history of PFIC. Odevixibat, an ileal bile acid transporter inhibitor, reduced sBAs and pruritus in patients with PFIC in the phase 3 PEDFIC 1 and PEDFIC 2 studies. We compared clinical outcomes of surgical biliary diversion (SBD), liver transplantation (LT), and death in patients from NAPPED (not treated with odevixibat) with odevixibat-treated patients from the PEDFIC studies.

Methods

The analysis population comprised odevixibat-naive patients from NAPPED and odevixibat-treated patients from PEDFIC 1 and/or PEDFIC 2. Patients with bile salt export pump subtype 3 (BSEP3) mutations were excluded. Eligibility criteria were aligned across cohorts and included genetically proven diagnosis of PFIC1 or PFIC2, sBAs ≥100 µmol/L, alanine aminotransaminase and total bilirubin ≤10× the upper limit of normal, and no prior SBD or LT. Propensity scores, inverse probability of treatment weighting, and matching methods were used to identify and balance baseline covariates, including PFIC1, PFIC2-BSEP1, or PFIC2-BSEP2. The primary endpoint was event-free survival (EFS; time to first event of SBD, LT, or death); secondary endpoints included native liver survival (NLS), SBD-free survival (DFS), and overall survival (OS). Survival outcomes were measured from study day 1; treatment differences were evaluated by weighted log-rank tests and Cox regression.

Results

A cohort of 80 NAPPED patients (controls) was compared with 69 odevixibat-treated patients. Median study duration in the odevixibat cohort was 22.6 months (range: 1.9–39.2 months). Follow-up duration in the NAPPED cohort was truncated accordingly. Odevixibat-treated patients showed significantly higher EFS and DFS than controls (hazard ratio [HR] [95% CI]: 0.20 [0.09−0.45] and 0.13 [0.04−0.39], respectively); numerical improvements in NLS and OS were also observed. Results were consistent when different sensitivity analyses were performed. Additional subgroup analyses indicated that EFS was higher in odevixibat-treated patients with PFIC1 (HR [95% CI]: 0.10 [0.02−0.55]) and PFIC2 (HR [95% CI]: 0.34 [0.12−1.00]) vs controls.

Conclusions

Odevixibat treatment is associated with higher EFS in patients with PFIC without prior SBD upon comparison with matched non-odevixibat-treated patients from the NAPPED registry.