Regulatory News: Chenodiol for the Treatment of Cerebrotendinous Xanthomatosis: FDA Approval Summary

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27A1 gene which encodes the mitochondrial enzyme sterol 27-hydroxylase. This enzyme deficiency leads to abnormalities in bile acid synthesis, including deficient production of the primary bile acid chenodeoxycholic acid (CDCA) and loss of feedback inhibition on the enzyme 7α-hydroxylase, resulting in increased production of abnormal bile acids and bile alcohols, and accumulation of cholestanol, a toxic cholesterol metabolite, in various organs and tissues. Clinical manifestations of CTX include chronic diarrhea, juvenile-onset bilateral cataracts, tendon xanthomas, and progressive neurological dysfunction (pyramidal and cerebellar signs, seizures, dementia, and psychiatric disturbances).

Chenodiol is an orally administered exogenous CDCA that replaces the deficient bile acid in CTX. Chenodiol has been approved in the United States since 1983 for the treatment of radiolucent gallstones in adults and has been used off-label for the treatment of CTX for over 40 years. Although chenodiol is considered standard of care for the treatment of CTX worldwide, there have been no prospective, randomized, controlled trials to confirm the treatment benefit.

The FDA requires substantial evidence of effectiveness for drug approval, with benefits outweighing risks. Substantial evidence of effectiveness for chenodiol in patients with CTX was established using data from one adequate and well-controlled trial with confirmatory evidence. The recommended dosing regimen of 250 mg three times per day for adults was evaluated in a single trial in 14 patients aged 16 years and older with CTX. Chenodiol treatment resulted in lower levels of cholestanol compared to when treatment was withdrawn, which the review team considered clinically meaningful based on available literature supporting the role of cholestanol reduction and normalization in stabilizing or improving clinical symptoms for CTX patients. The confirmatory evidence providing strong mechanistic support includes the well-established etiology of the disease and the mechanism of action of chenodiol in replacing the deficient bile acid and restoring normal bile acid synthesis homeostasis. Since chenodiol treatment has been associated with hepatotoxicity, product labeling recommends monitoring liver transaminase and bilirubin levels and considering interrupting treatment if levels are significantly elevated. With all factors and limitations considered, the benefits of chenodiol were determined to outweigh the risks for adult patients with CTX.

The author declares no conflicts of interest.