Bezafibrate for X-linked adrenoleukodystrophy.
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.


BACKGROUND
ClinicalTrials.gov NCT01165060.
Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Marc
M
Engelen
Luc
L
Tran
Rob
R
Ofman
Josephine
J
Brennecke
Ann B
AB
Moser
Inge M E
IM
Dijkstra
Ronald J A
RJ
Wanders
Bwee Tien
BT
Poll-The
Stephan
S
Kemp
D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000378:metabolism; D001629:Bezafibrate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D016896:Treatment Outcome
D000960:Hypolipidemic Agents; D001629:Bezafibrate