NASPGHAN 2024: PEDFIC Data Highlight Safety of Odevixibat in Pediatric Patients with PFIC

Data from the PEDFIC program presented at the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) 2024 is providing insight into the safety of odevixibat (Bylvay) for treatment of cholestatic pruritis among patients with progressive familial intrahepatic cholestasis (PFIC), with a particular focus on diarrhea events with the once-daily, non-systemic ileal bile acid transport inhibitor.

“This analysis of the gastrointestinal tolerability profile of odevixibat highlights that diarrhea events during odevixibat treatment were mild or moderate in severity and were generally transient in nature,” wrote investigator.

In 2021, odevixibat made headlines as the first therapy to receive approval from the US Food and Drug Administration for treatment of cholestatic pruritus due to PFIC. In June 2023, the FDA awarded an additional approval to odevixibat for patients the treatment of cholestatic pruritus in patients from 12 months of age with Alagille syndrome. The initial approval of odevixibat in PFIC was based on data from the PEDFIC 1 (NCT03566238) and PEDFIC 2 (NCT03659916) trials.²

PEDFIC 1 was a 24-week, randomized, placebo-controlled study in children with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Per trial protocol, patients were randomized in a 1:1:1 ratio to once-daily oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. The trial enrolled 62 patients and met both of its primary endpoints, with use of odevixibat associated with reduced serum bile acid responses (P = .003) and improved pruritus assessments (P = .004) relative to placebo therapy.³

PEDFIC 2 is a 72-week open-label extension study of enrolled patients from PEDFIC 1 or new patients of any age with any type of PFIC. This study was still ongoing at the time of the analysis performed as part of the NASPGHAN 2024 study, which included pooled data from patients’ first dose of odevixibat to a cutoff date of July 31, 2022.¹

Investigators, who were led by Richard Thompson, MBChB, professor of Molecular Hepatology at King’s College London, pointed out the aim of their analysis was specific to treatment-emergent adverse events in the Medical Dictionary for Regulatory Activities System Organ Class (SOC) of gastrointestinal disorders, with a focus on diarrhea treatment-emergent adverse events. Additional outcomes of interest included analysis of severity, duration, and time to onset, as well as diarrhea treatment-emergent adverse events leading to dose reduction, treatment interruption, or study discontinuation.¹

A total of 119 patients were identified for inclusion in the analysis. This cohort had a median age of 3.6 years, 45% female, and a median exposure to odevixibat was 82 (range, 4 to 201) weeks.¹

The investigators’ analysis revealed 51% of patients experienced a treatment-emergent adverse event within the gastrointestinal disorders SOC, with diarrhea as the most common event, occurring in 24% of patients. Investigators noted all diarrhea treatment-emergent adverse events were mild or moderate in severity and nonserious, and 90% resolved by the data cutoff.¹

The median duration of diarrhea treatment-emergent adverse events was 5 days and drug-related diarrhea occurred in 11%, with a median time to onset of 44 days. Further analysis suggested dose reduction due to diarrhea was required for 3 patients, with symptoms resolving in 2 of these cases. Additionally, 5 patients experienced treatment interruptions due to diarrhea, with a median interruption duration of 4 days, and treatment was discontinued in 2 patients on odevixibat 120 µg/kg due to diarrhea.¹

“In this long-term analysis of data from the PEDFIC studies among odevixibat-treated patients with PFIC, 24% of patients had diarrhea TEAEs, all of which were mild or moderate in severity,” investigators wrote.1

References:

1. Thompson RJ, Artan R, Calvo PL, et al. ONSET AND RESOLUTION OF COMMON GASTROINTESTINAL ADVERSE EVENTS WITH ODEVIXIBAT IN PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: AN EXAMINATION OF DATA FROM THE PEDFIC TRIALS. Presented at NASPGHAN 2024. Hollywood, Florida. November 7 – November 9, 2024.
2. Ipsen. U.S. FDA approves Bylvay® for patients living with cholestatic pruritus due to Alagille syndrome. Ipsen. June 13, 2023. Accessed November 10, 2024. https://www.ipsen.com/press-releases/u-s-fda-approves-bylvay-for-patients-living-with-cholestatic-pruritus-due-to-alagille-syndrome/.
3. Thompson RJ, Arnell H, Artan R, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2022;7(9):830-842. doi:10.1016/S2468-1253(22)00093-0