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Trial 1 was a 24-week, randomized, double-blind, placebo-controlled study comparing two dosage levels of odevixibat (40 mcg/kg and 120 mcg/kg) administered once daily. Sixty-two patients were randomized to receive one of the following treatments: odevixibat 40 mcg/kg/day (n=23), odevixibat 120 mcg/kg/day (n=19), or placebo (n=20).
In Trial 1, adverse reactions occurring at an incidence of ≥2% in odevixibat treatment groups and higher than in the placebo group included:
Diarrhea (placebo: 10%; 40 mcg/kg/day: 39%; 120 mcg/kg/day: 21%)
Increased transaminases (ALT, AST) (placebo: 5%; 40 mcg/kg/day: 13%; 120 mcg/kg/day: 21%)
Vomiting (40 mcg/kg/day: 17%; 120 mcg/kg/day: 16%)
Abdominal pain (40 mcg/kg/day: 13%; 120 mcg/kg/day: 16%)
Increased blood bilirubin (placebo: 10%; 40 mcg/kg/day: 13%; 120 mcg/kg/day: 11%)
Fat-soluble vitamin deficiency (A, D, E) (placebo: 5%; 120 mcg/kg/day: 16%)
Splenomegaly (120 mcg/kg/day: 11%)
Cholelithiasis (120 mcg/kg/day: 5%)
Dehydration (120 mcg/kg/day: 5%)
Fracture (40 mcg/kg/day: 4%)
Trial 2 was a 72-week, open-label, single-arm study in patients with PFIC Type 1, 2, and 3. Odevixibat was administered at a dose of 120 mcg/kg once daily. Treatment-emergent adverse reactions were similar to those observed in Trial 1. Adverse reactions observed in Trial 2 but not described in Trial 1 included increased INR (16%), epistaxis (9%), coagulopathy (3%), iron-deficiency anemia (3%), prolonged prothrombin time (2%), as well as variceal bleeding, stomal bleeding, hematochezia, and rectal bleeding (each <1%). The most common reason for treatment discontinuation of odevixibat was abnormal liver function tests (elevated ALT, AST, direct and total bilirubin).
Among the 33 patients who discontinued odevixibat in Trial 2, five underwent or were referred for liver transplantation, and one patient underwent surgical biliary diversion (SBD). A total of 19 patients in Trial 2 received surgical intervention, including one patient who underwent SBD followed by liver transplantation, 15 patients who underwent liver transplantation alone, and three patients who underwent SBD alone.
Trial 3 was a 24-week, randomized, double-blind, placebo-controlled study evaluating a single dosage level of odevixibat (120 mcg/kg) administered once daily. Fifty-two patients were randomized to receive either odevixibat 120 mcg/kg/day (n=35) or placebo (n=17).
In Trial 3, adverse reactions occurring at an incidence of ≥5% in ALGS patients and higher than in the placebo group included:
Diarrhea (placebo: 6%; odevixibat: 29%)
Abdominal pain (placebo: 6%; odevixibat: 14%)
Hematoma (odevixibat: 9%)
Weight loss (odevixibat: 6%)
No patients discontinued study treatment due to adverse reactions.
Trial 4 was a 72-week, open-label extension study in 49 pediatric patients with ALGS aged 1 to 15 years. Odevixibat was administered at a dose of 120 mcg/kg once daily. Treatment-emergent adverse reactions were similar to those observed in Trial 3. The most common reason for treatment discontinuation of odevixibat was gastrointestinal disorders, including diarrhea and abdominal pain.
Odevixibat treatment carries a potential risk of drug-induced liver injury (DILI).
Elevations or worsening of liver function tests during treatment were observed in PFIC and ALGS trials. Among the six patients who experienced DILI, two underwent liver transplantation.
The following adverse reactions have been identified during post-approval use of odevixibat. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: Gastrointestinal bleeding, gingival bleeding, liver transplantation
Investigations: Increased gamma-glutamyl transferase, decreased hemoglobin
Nervous system disorders: Extra-axial hemorrhage (subdural hemorrhage)
Respiratory, thoracic and mediastinal disorders: Epistaxis
FDA，2025.03
