†Evaluation of Chenodeoxycholic Acid Treatment in Adult Patients with Cerebrotendinous Xanthomatosis: A Randomized, Placebo-Controlled Phase 3 Study

Study Funding

Mirum Pharmaceuticals, Inc.

Background/Synopsis

Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder of bile acid synthesis caused by biallelic pathogenic variants in the CYP27A1 gene, encoding the sterol 27-hydroxylase enzyme, which leads to abnormal bile acid synthesis and toxic accumulation of cholestanol, bile alcohols and other metabolites. Chenodeoxycholic acid (CDCA) treatment is considered the standard-of-care for CTX.

Objective/Purpose

We evaluated the efficacy and safety of CDCA on biomarkers of CTX in the first Phase 3, randomized withdrawal, double-blind (DB), placebo (PBO)-controlled, two-period x two-treatment cross-over study with rescue medication (RESTORE).

Methods

A 24-week randomized withdrawal, DB, crossover study with a 30-day safety follow-up was conducted in adult patients (≥16 years of age) with CTX who received 250 mg CDCA TID for two 8-week open label (OL) periods of the study and either blinded CDCA or PBO for two 4-week DB periods. Eligible participants had a clinical diagnosis of CTX with biochemical confirmation, no known malabsorption or GI conditions, and not on cholic acid and/or medication impacting bile acid absorption. The primary endpoint was change in the urinary bile alcohol biomarker 5β-cholestane-3α,7α,12α,23S,25-pentol (23S-pentol) from Baseline (BL) to the end of each DB treatment period. Key secondary efficacy endpoints included: percent changes in plasma cholestanol and 7α-hydroxy-4-cholesten-3-one (7αC4) at end of each DB period and proportion of patients requiring rescue medication (CDCA) during the DB periods. Safety parameters were also assessed.

Results

The analysis included 14 participants with a median (min, max) age at enrollment of 41.5 (16, 55) years, the majority were white males, and all had a clinical diagnosis of CTX with biochemical confirmation. CDCA withdrawal after the OL treatment period resulted in a statistically significant 20-fold increase (95% CI: 10.3, 43.5 p<0.0001) in urine 23S-pentol (ng/mL), a 2.8-fold increase (95% CI: 1.5, 5.2; p=0.0083) in plasma cholestanol (µg/mL), and a 50-fold increase (95% CI: 25.0, 66.7; p<0.0001) in plasma 7αC4 (ng/mL; placebo relative to CDCA). A significant proportion of participants on PBO (61.5% [95% CI: 31.6, 86.1]; p=0.0006) required blinded rescue medication during the DB withdrawal periods. Most commonly reported TEAEs on CDCA were diarrhea (n=5) and headache (n=3) with the majority mild to moderate in severity and not considered treatment related.

Conclusions

Withdrawal of CDCA treatment led to significant increases in CTX biomarkers. CDCA treatment is well-tolerated and can effectively suppress abnormal bile acid synthesis in CTX, preventing accumulation of cholestanol and bile alcohols. This underscores the potential for CDCA to help CTX patients avoid disease progression.