Bezafibrate for X-linked adrenoleukodystrophy.

Abstract

UNLABELLED:

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate (BF), a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01165060.

• Authors: Marc Engelen, Luc Tran, Rob Ofman, Josephine Brennecke, Ann B Moser, Inge M E Dijkstra, Ronald J A Wanders, Bwee Tien Poll-The, Stephan Kemp
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e41013 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22911730 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypolipidemic Agents
• Bezafibrate

Topics

• Adrenoleukodystrophy (drug therapy, metabolism)
• Bezafibrate (administration & dosage, pharmacology, therapeutic use)
• Humans
• Hypolipidemic Agents (administration & dosage, pharmacology, therapeutic use)
• Male
• Treatment Outcome