Efficacy, safety, and tolerability of chenodeoxycholic acid (CDCA) in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized withdrawal, double-blind, placebo-controlled, crossover phase-3 study

Purpose: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in CYP27A1, resulting in sterol 27-hydroxylase deficiency and accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, diarrhea, cataracts, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The effects of CDCA withdrawal on CTX biomarkers and safety in adult patients were evaluated. Methods: Patients (≥16 years) received CDCA 750-mg/day for 2 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for 2 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods. Results: CDCA withdrawal resulted in a 20-fold increase in 23S-pentol and increases in cholestanol (2.8-fold), 7αC4 (50-fold), and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most of them mild/moderate in severity and not considered treatment related. Conclusion: CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.