Safety and Tolerability of Chenodeoxycholic Acid in Pediatric Patients With Cerebrotendinous Xanthomatosis (RESTORE): An Open-label Phase 3 Study
Biochemical/Metabolic and Therapeutics
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Introduction:
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27A1 gene, leading to sterol 27-hydroxylase deficiency and toxic accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, cataracts, chronic diarrhea, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The RESTORE trial, a Phase 3 randomized withdrawal, crossover study with rescue medication, demonstrated that CDCA is well-tolerated in adults, suppressing abnormal bile acid synthesis and preventing cholestanol and bile alcohol accumulation in plasma. The trial included an open-label component to systematically evaluate CDCA in the pediatric setting. Here, we describe CDCA's safety and tolerability in pediatric patients with CTX.
Methods:
A 24-week, open-label study with 8-week titration and 16-week treatment periods evaluated CDCA dosing in pediatric patients (≥1 month and <16 years). Participants had a confirmed CTX diagnosis, no confounding gastrointestinal (GI) conditions and were not on medications affecting bile acid absorption. Treatment-naive and treatment-experienced participants received CDCA 5, 10, or 15 mg/kg daily (divided TID). Safety endpoints included key laboratory parameters, incidence, and severity of treatment-emergent adverse events (TEAEs) leading to drug discontinuation.
Results:
Five female participants with median age 8.2 years (range: 4-14) were enrolled. The median (Q1-Q3) CDCA exposure was 166 (163-166) days. All participants experienced ≥1 TEAE with infections/infestations being most common (80.0%). No single TEAE occurred in >1 participant. All TEAEs were mild except one moderate gastroenteritis case; the patient remained in the study. All AEs were unrelated to study medication. One patient with Gilbert syndrome was withdrawn from the study due to bilirubin increases possibly unrelated to study medication No serious AEs or clinically relevant trends in laboratory parameters were reported.
Conclusion:
CDCA was generally well tolerated in pediatric patients with CTX. RESTORE is the first systematic evaluation of safety and tolerability in CTX patients.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27A1 gene, leading to sterol 27-hydroxylase deficiency and toxic accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, cataracts, chronic diarrhea, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The RESTORE trial, a Phase 3 randomized withdrawal, crossover study with rescue medication, demonstrated that CDCA is well-tolerated in adults, suppressing abnormal bile acid synthesis and preventing cholestanol and bile alcohol accumulation in plasma. The trial included an open-label component to systematically evaluate CDCA in the pediatric setting. Here, we describe CDCA's safety and tolerability in pediatric patients with CTX.
Methods:
A 24-week, open-label study with 8-week titration and 16-week treatment periods evaluated CDCA dosing in pediatric patients (≥1 month and <16 years). Participants had a confirmed CTX diagnosis, no confounding gastrointestinal (GI) conditions and were not on medications affecting bile acid absorption. Treatment-naive and treatment-experienced participants received CDCA 5, 10, or 15 mg/kg daily (divided TID). Safety endpoints included key laboratory parameters, incidence, and severity of treatment-emergent adverse events (TEAEs) leading to drug discontinuation.
Results:
Five female participants with median age 8.2 years (range: 4-14) were enrolled. The median (Q1-Q3) CDCA exposure was 166 (163-166) days. All participants experienced ≥1 TEAE with infections/infestations being most common (80.0%). No single TEAE occurred in >1 participant. All TEAEs were mild except one moderate gastroenteritis case; the patient remained in the study. All AEs were unrelated to study medication. One patient with Gilbert syndrome was withdrawn from the study due to bilirubin increases possibly unrelated to study medication No serious AEs or clinically relevant trends in laboratory parameters were reported.
Conclusion:
CDCA was generally well tolerated in pediatric patients with CTX. RESTORE is the first systematic evaluation of safety and tolerability in CTX patients.