A cholesterol-lowering medication, bezafibrate, taken daily for 12 weeks did not induce the formation of new mitochondria in people with mitochondrial myopathy carrying a mutation in the MTTL1 gene, a small observational study reports.
Its use also altered certain metabolic pathways, changes that could raise safety concerns with longer-term use, its researchers cautioned.
The study “Metabolic effects of bezafibrate in mitochondrial disease” was published in the journal EMBO Molecular Medicine.
Several different ways of treating mitochondrial disorders are being developed. One involves inducing the formation of new mitochondria, a process called biogenesis. Several compounds have shown promise in mitochondrial biogenesis, and among these bezafibrate has the most extensive preclinical evidence.
Bezafibrate works to lower the levels of lipids, such as cholesterol and triglycerides. Approved since 1978 (and sold under brand names that include Bezalip, Cedur, Eulitop, and Befizal), bezafibrate is available in Canada and the European Union, but not in the U.S.
Despite the extensive work on animal models and human cell lines, “there are no comparable human studies” for bezafibrate, the study noted.
Researchers in the U.K. conducted a small Phase 2 open-label and observational study to evaluate the effects of bezafibrate in patients with mitochondrial disease.
Their study (NCT02398201) enrolled six unrelated adults (four women, age range 44 to 57) with mitochondrial myopathy (muscle disease) due to a mutation (m.3243A>G) in the MTTL1 gene of skeletal muscle cells.
Participants received 600 mg to 1,200 mg bezafibrate daily for 12 weeks. In the first six weeks, they were given 200 mg three times daily, followed by a dose of 400 mg three times daily for the remaining six weeks.
Its primary goal was to evaluate the safety of inducing mitochondrial biogenesis with bezafibrate. Additional (secondary) aims included preliminary evidence of effectiveness, to support a subsequent randomized controlled trial.
All six people completed the study.
Results showed that treatment caused no changes in body mass index (BMI), a measure of body fat.
No clinically significant adverse events were reported, with the exception of one case of acute abdominal pain due to constipation that was resolved during the night. This is a common side effect of bezafibrate treatment and mitochondrial disease. Liver function was not affected.
Researchers detected an impairment in the filtration capacity of the kidneys of three patients, but this was reversible.
They also saw a reduction in the number of complex IV-deficient muscle fibers — commonly used to diagnose myopathies — after treatment, as well as improved cardiac function.
But these positive findings were accompanied by increases in blood levels of two markers of mitochondrial dysfunction — called fibroblast growth factor 21 (FGF-21) and growth and differentiation factor 15 (GDF-15) — and by a deregulation in the metabolism of certain fats (fatty acids) and amino acids (the building blocks of proteins).
The treatment apparently resulted in no increase in the levels of mitochondria, as shown by no changes in the number of copies of mitochondrial DNA.
Researchers also saw no change after treatment in participants’s exercise capacity, measured using an accelerometer worn at the wrist.
“Although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae,” they wrote, adding that “at present, there is no compelling evidence to use bezafibrate as a treatment for mitochondrial disease due to the m.3243A>G mutation.”
The team also suggested that “bezafibrate should be used with caution to treat dyslipidaemia [abnormal fat levels in the blood] in patients with mitochondrial disorders.”
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