Substantial clinical benefits with odevixibat treatment across progressive familial intrahepatic cholestasis genetic deficiencies: subgroup analysis of serum bile acids, pruritus, and safety using pooled data from the PEDFIC 1 and 2 studies

Background and aims: Odevixibat is an ileal bile acid transporter inhibitor in development to treat cholestatic liver diseases. The phase 3 PEDFIC 1 (P1) and PEDFIC 2 (P2) studies assessed odevixibat in patients with progressive familial intrahepatic cholestasis (PFIC) via serum bile acid (sBA) response and change in pruritus. We describe a pooled analysis of these outcomes in patients with PFIC1 (familial intrahepatic cholestasis 1 [FIC1] deficiency) or PFIC2 (bile salt export pump [BSEP] deficiency). For those with PFIC2, BSEP subtype was also examined (subtype 1: at least 1 p.D482G or p.E297G mutation; subtype 2: at least 1 missense mutation but not p.D482G or p.E297G). Method: This 48-week subgroup analysis included pooled data from P1 (consisting of a 24-week, placebo-controlled treatment period in patients with PFIC1 or PFIC2) and P2 (an ongoing, 72-week, openlabel extension study in patients from P1 or new patients with any type of PFIC, where all patients receive odevixibat). sBA response (ie, ≥70% reduction from baseline or sBAs ≤7 0 μmol/L), change in pruritus based on positive pruritus assessments (PPAs) at the patient level (ie, scratching score ≤1 or a ≥1-point drop from baseline on the PRUCISION instrument), and treatment-emergent adverse events (TEAEs) were assessed.

Results: Of 77 patients who received odevixibat, 20 had PFIC1 (26%) and 51 (66%) had PFIC2. BSEP subtype 1 or 2 were present in 13 (26%) and 36 (71%) patients with PFIC2, respectively (2 additional patients with BSEP subtype 3 were not included in this analysis). During the analysis period, ≥50% of patients met sBA response criteria, regardless of genotype (Figure; panel A). Mean PPAs were above 60% for patients with PFIC2 (including BSEP subtypes 1 and 2); mean PPAs for patients with PFIC1 were 48% (Figure; panel B). Incidence of TEAEs in odevixibat-treated patients with PFIC1 or PFIC2 (80% each) and BSEP subtype 1 and 2 (77% and 86%, respectively) in the pooled population was comparable to that of placebo-treated patients in P1 (85%). Most TEAEs were mild or moderate, self-limiting, and considered by the investigator as not related to study drug.

Conclusion: Patients with PFIC1 or PFIC2 had substantial benefits with odevixibat treatment, including reductions in sBAs and improvement in pruritus symptoms. Long-term treatment with odevixibat was well tolerated, regardless of PFIC classification or BSEP subtype.