Journal article
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
Genetics in medicine, Vol.27(7), 101449
07/2025
DOI: 10.1016/j.gim.2025.101449
PMID: 40297984
Abstract
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.
Patients (≥16 years) received CDCA 750 mg/day for two 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for two 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.
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 mild/moderate in severity and not considered treatment-related.
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.
Details
- Title: Subtitle
- 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
- Creators
- Yaz Y Kisanuki - The Ohio State University Wexner Medical CenterPaulo R. Nobrega - Universidade Federal do CearáRyan Himes - Children's Hospital of New OrleansSuman Jayadev - University of WashingtonJohn A. Bernat - University of IowaVikram Prakash - Orlando HealthJames B. Gibson - Dell Children's Medical Center of Central TexasAustin Larson - Children's Hospital ColoradoPaulo Sgobbi - Universidade Federal de São PauloAndrea E. DeBarber - Oregon Health & Science UniversityEdward Murphy - Travere Therapeutics, San Diego, CABrian Fedor - Travere Therapeutics, San Diego, CACheryl Wong Po Foo - Travere Therapeutics, San Diego, CARana Dutta - Mirum Pharmaceuticals, Inc., Foster City, CAMichael Imperiale - Mirum Pharmaceuticals, Inc., Foster City, CAWill Garner - Mirum Pharmaceuticals, Inc., Foster City, CAJoanne Quan - Mirum Pharmaceuticals, Inc., Foster City, CAPamela Vig - Mirum Pharmaceuticals, Inc., Foster City, CAP. Barton Duell - Oregon Health & Science UniversitySarah Perez - Tulane UniversityRitesh A. Ramdhani - Donald & Barbara Zucker School of Medicine at Hofstra/NorthwellJonas Alex Saute - Hospital de Clínicas de Porto AlegreSarah J. FeddersenMyrl D. HolidaAlpa SidhuTheresa M. CzechAlina V. DumitrescuJohanna Henriques NehmAna Luísa DubielaTamires Silva AlvesMariana Horn SchererPaula de Castro PereiraBruno Rutkoski DorrFrancini PetrolliFranciele Santos MacielGladis Reyes-PimentelSandra K. KostykJaysingh SinghChristine MartinezWladimir Bocca Vieira de Rezende PintoPaulo de Lima SerranoRicardo Evangelista Marrocos de AragãoPedro Braga-NetoManoel Alves Sobreira NetoRESTORE Study Group Collaborators
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.27(7), 101449
- DOI
- 10.1016/j.gim.2025.101449
- PMID
- 40297984
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- Elsevier Inc; NEW YORK
- Grant note
- Travere TherapeuticsMirum PharmaceuticalsMirum Pharmaceuticals, Inc
The RESTORE trial was funded by Travere Therapeutics and Mirum Pharmaceuticals. Chenodiol tablets are owned by Mirum Pharmaceuticals, Inc. This analysis was funded by Mirum Pharmaceuticals, Inc. Mai Nguyen and Kai Liu designed and oversaw assay development, validation, and RESTORE sample analyses for cholestanol and 23S-pentol, in collaboration with Andrea DeBarber. Medical writing and editorial support for the development of this manuscript were provided by Roy Garcia, PhD and Eliza Prangley, PhD, of Precision AQ in Bethesda, Maryland, and funded by Mirum Pharmaceuticals, Inc.
- Language
- English
- Electronic publication date
- 04/25/2025
- Date published
- 07/2025
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics; Neurology (Pediatrics); Ophthalmology and Visual Sciences
- Record Identifier
- 9984815917202771
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