Effect of bezafibrate in adrenomyeloneuropathy

Written on Friday 12 April 2013

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene located in the X chromosome. The pathology is characterized by progressive demyelination associated to very-long-chain fatty acids (VLCFA) accumulation in the body.
Adrenomyeloneuropathy (AMN), the adult form of the disease, is a progressive disease of the spinal cord for which no treatment is available.

It was recently showed that bezafibrate, a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis.

A clinical trial was developed to determine whether bezafibrate reduces VLCFA levels in plasma and lymphocytes of ALD patients.
Ten males with AMN were treated with bezafibrate 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.
Patient follow-up did not reveal adverse events. The clear reduction in plasma triglycerides indicated good patient compliance.
However, there was no reduction in VLCFA in either plasma or lymphocytes from treated patients. Plasma levels of bezafibrate did not exceed 25 µmol per liter.

In conclusion, bezafibrate, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in ALD patients and thus appears to have no therapeutic utility in ALD. It is unclear whether this is due to the low levels of bezafibrate reached in plasma.
Future research work will be  aimed to identify ELOVL1 highly-specific inhibitors acting at much lower concentrations than bezafibrate and well tolerated.

Disease : Adrenomyeloneuropathy (AMN)
Subjects : 10 men with AMN
Type of study : Clinical trial
Laboratory : Dr. Marc Engelen, Department of Neurology, Academic Medical Centre, University of Amsterdam, The Netherlands.

Source: M. Engelen, L. Tran, R. Ofman, J. Brennecke, A.B. Moser, I.M. Dijkstra, R.J. Wanders, B.T. Poll-The, S. Kemp. Bezafibrate for X-linked adrenoleukodystrophy. PLoS One. 2012, 7(7):e41013.

Scientific information provided in collaboration with the INIST-CNRS Institute, Institute for Scientific and Technical Information