Japan's Ministry of Health, Labour and Welfare (MHLW) has granted regulatory approval for Bylvay (odevixibat) to treat pruritus associated with progressive familial intrahepatic cholestasis (PFIC), marking a significant milestone for patients with this rare genetic liver disorder. The approval makes Bylvay the first once-daily ileal bile acid transport inhibitor available in Japan for PFIC treatment, offering a non-surgical therapeutic option for infants, young children, and adults.
PFIC represents a group of rare genetic disorders characterized by bile acid accumulation in the liver, leading to progressive liver damage and potentially liver failure. The condition affects an estimated 100 children and infants in Japan and severely impacts quality of life through debilitating symptoms including severe itching (pruritus), skin mutilation, sleep disruption, irritability, and impaired cognitive and social development.
Clinical Evidence Supporting Approval
The Japanese approval was based on data from a Phase III, open-label study conducted in Japan that evaluated the efficacy and safety of odevixibat in pediatric patients with PFIC types 1 and 2. The study confirmed improvements in serum bile acid levels and pruritus consistent with results from the global Phase III PEDFIC trial.
The PEDFIC trial, described as the largest global Phase III trial ever conducted in PFIC, provided compelling evidence for odevixibat's efficacy. In this randomized, double-blind, placebo-controlled 24-week study involving 62 patients, odevixibat demonstrated significant improvements across key endpoints.
The trial met its first primary endpoint for pruritus reduction, with 55% of patients receiving odevixibat achieving a reduction in pruritus symptoms compared to 30% of patients on placebo. The second primary endpoint focused on serum bile acid (sBA) response, defined as patients showing either a 70% or greater reduction from baseline or levels of 70 μmol/L or less at Week 24. Significantly more patients achieved an sBA response with odevixibat, with 33% showing reduced sBA levels compared to no patients on placebo at Week 24.
Safety Profile and Mechanism of Action
Odevixibat demonstrated a favorable safety profile in clinical trials, with no drug-related serious adverse events reported and a low incidence of gastrointestinal events, including diarrhea and frequent bowel movements. The treatment was generally well-tolerated across the study population.
Bylvay functions as a potent, once-daily ileal bile acid transport inhibitor (IBATi) that acts locally in the small intestine with minimal systemic absorption. The mechanism involves reducing reabsorption of bile acid back to the liver, thereby addressing the underlying pathophysiology of PFIC.
Clinical Impact and Expert Perspectives
"Children with PFIC often endure relentless itching that affects their daily quality of life. This includes regular, nightly sleep disturbance, which can have a negative impact on the whole family," said Sandra Silvestri, MD, PhD, Executive Vice President, Chief Medical Officer at Ipsen. "The approval of Bylvay as a once-daily oral therapy represents a welcomed new option in how we approach this disease and offers new hope for patients and families in Japan living with the devastating impact of PFIC."
Dr. Hiroki Kondou, Associate Professor in the Department of Pediatrics at Kindai University Nara Hospital, emphasized the clinical significance: "Early diagnosis and intervention are critical in PFIC to manage symptoms and preserve liver function. This approval of Bylvay provides patients and caregivers with a new treatment option that has the potential to reduce itching, and thereby improve sleep quality, while potentially supporting the preservation of liver."
Disease Characteristics and Patient Population
PFIC encompasses several subtypes, with PFIC1 and PFIC2 typically manifesting in infancy or early childhood, while PFIC3 can present from infancy through adolescence. The condition affects males and females equally, occurring at a rate ranging from 1 per 50,000 to 1 per 100,000 births. While some presentations can occur in adulthood, PFIC typically manifests and is most aggressive in infants and young children.
The disease significantly impacts patients' daily lives through severe itching that can result in skin mutilation, sleep loss, irritability, poor attention, and impaired school function, highlighting the critical need for effective therapeutic interventions.
Regulatory and Development History
The Phase III clinical development plan for Bylvay in Japan was initially managed by Jadeite Medicines Inc, which received Orphan Drug Designation for odevixibat in PFIC from Japan's Ministry of Health, Labour and Welfare in May 2023. As part of a strategic collaboration, the new drug application was subsequently transferred to Ipsen's Tokyo headquarters, with Ipsen assuming responsibility for commercialization in Japan.
Bylvay has previously received approvals in other major markets, including the European Union in June 2021 as the first drug treatment option for all PFIC types in patients aged 6 months or older, and in the United States for patients 3 months of age and older with cholestatic pruritus due to PFIC. The drug has received orphan exclusivity for PFIC treatment in both the EU and US markets.
