Chenodiol, First Treatment for Cerebrotendinous Xanthomatosis, Receives FDA Approval

Key Takeaways

Chenodiol is the first FDA-approved treatment for cerebrotendinous xanthomatosis, a rare lipid storage disease caused by a CYP27A1 gene mutation.
CTX leads to impaired cholesterol breakdown, causing atypical cholesterol metabolite deposits in organs and tissues, resulting in damage.
Chenodiol replaces deficient bile acids, reducing abnormal cholesterol deposits and addressing CTX-related clinical abnormalities.
The FDA highlights its dedication to supporting drug development for rare diseases, offering a new treatment option for CTX patients.

This marks the first FDA-approved treatment for this rare lipid storage disease.

Updated Friday, February 21, 2025, at 2:14 PM.

The FDA has approved chenodiol tablets (Ctexli; Mirum Pharmaceuticals) for the treatment of cerebrotendinous xanthomatosis (CTX). With this approval, chenodiol has become the first FDA-approved drug to treat this very rare lipid storage disease.¹

Image credit: Olivier Le Moal | stock.adobe.com

CTX is a rare genetic metabolic disorder that is caused by a mutation in a gene called CYP27A1, which results in a deficiency of the enzyme that is important in the body's ability to break down fats. As a result of reduced bile acid production in the liver, patients with CTX are unable to break down cholesterol in a normal way, resulting in the removal of atypical cholesterol metabolites in various places within the body, such as the brain, liver, skin, and tendons. This leads to damage to those organs and tissues. If not treated, patients with CTX can experience symptoms—chronic diarrhea, juvenile bilateral cataracts, tendon xanthomas, and neurologic deterioration—that disrupt their quality of life and can progress over time.¹

Chenodiol helps replace deficient levels of 1 of the bile acids, reducing the abnormal deposits of cholesterol metabolites thought to be responsible for CTX-related clinical abnormalities. The recommended dosage is 250 mg taken orally 3 times per day.¹

The approval is based on data from the phase 3 RESTORE (NCT04270682) trial.^1,2 RESTORE enrolled patients 16 years of age and older (adult cohort, median age: 41.5 years)³ with CTX to test the effects of chenodiol in a randomized, double-blind crossover segment, and patients aged at least 1 month and younger than 16 (pediatric cohort) in an open-label dose titration portion.²

In the adult cohort, patients received either 250 mg of chenodiol 3 times per day for 2 open-label periods lasting 8 weeks of the study, or blinded chenodiol or placebo for 2 double-blind periods lasting 4 weeks. Patients eligible for enrollment had a clinical diagnosis of CTX with biochemical confirmation, were not known to have another malabsorption or confounded inflammatory gastrointestinal condition, and could not be taking cholic acid and/or medications that impact bile acid absorption.^2,3

RESTORE’s primary end point was change in the urinary bile alcohol 5β-cholestane-3α,7α,12α,23S,25-pentol (23S-pentol) biomarker from baseline to the end of each double-blind treatment period. Secondary efficacy end points included the following: changes in plasma cholestanol and 7a-hydroxy-4-cholesten-3-one (7αC4) at the end of each double-blind period; and number of patients who required rescue chenodiol during the double-blind periods. In addition, safety parameters, including treatment-emergent adverse events (TEAEs), were also assessed.^2,3

These findings included data on the 14 adult participants with CTX with biochemical confirmation. The data show that chenodiol withdrawal after the open-label treatment period resulted in a statistically significant 20-fold increase (95% CI: 10.3, 43.5 P < .0001) in urine 23S-pentol (ng/mL), a 2.8-fold increase (95% CI: 1.5, 5.2; P = .0083) in plasma cholestanol (μg/mL), and a 50-fold increase (95% CI: 25.0, 66.7; P < .0001) in plasma 7αC4 (ng/mL). Additionally, approximately 61.5% of patients on placebo (95% CI: 31.6, 86.1; P = .0006) required blinded rescue medication during the double-blind withdrawal periods. This proportion was considered statistically significant, according to the investigators.³

About the Trial

Trial Name: Study to Evaluate Patients With Cerebrotendinous Xanthomatosis (RESTORE)

ClinicalTrials.gov ID: NCT04270682

Sponsor: Mirum Pharmaceuticals, Inc.

Completion Date: October 4, 2023

The most reported TEAEs while on chenodiol were diarrhea (n = 5) and headache (n = 3). Most of these occurrences were either mild to moderate in severity and were not considered to be related to treatment.³

"The FDA is dedicated to supporting new drug development for rare diseases, including very rare metabolic diseases like CTX," Janet Maynard, MD, MHS, director of the Office of Rare Diseases, Pediatrics, Urologic, and Reproductive Medicine in the FDA Center for Drug Evaluation and Research, said in a news release. "CTX is a progressive multisystemic disorder that significantly impacts patients and previously lacked approved treatments. Today's approval provides a safe and effective treatment option for CTX."¹

REFERENCES

1. PR Newswire. FDA approves first treatment for cerebrotendinous xanthomatosis, a rare lipid storage disease. News release. February 21, 2025. Accessed February 21, 2025. https://www.prnewswire.com/news-releases/fda-approves-first-treatment-for-cerebrotendinous-xanthomatosis-a-rare-lipid-storage-disease-302382475.html

2. Study to Evaluate Patients With Cerebrotendinous Xanthomatosis (RESTORE). ClinicalTrials.gov identifier: NCT04270682. Updated October 28, 2024. Accessed February 21, 2025. https://clinicaltrials.gov/study/NCT04270682

3. DeBarber A, Kisanuki Y, Nobrega P, et al. P142: Efficacy, safety and tolerability of chenodeoxycholic acid in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized, placebo-controlled phase 3 study. GIM Open. 2024;2(Supplement 1):101039. doi:10.1016/j.gimo.2024.101039