A Study of Bezafibrate in Mitochondrial Myopathy

Mitochondrial disorders are genetically determined metabolic diseases affecting approximately 1 in 5000 people. Current strategies for treating mitochondrial disorders are limited, and restricted to alleviating symptoms. A recently published Cochrane review did not identify any disease modifying treatments of proven benefit. There is therefore an urgent and currently unmet need for treatments that modify the underlying biochemical deficit and disease trajectory.

Improving deficient oxidative phosphorylation (OXPHOS) pathways through induction of mitochondrial biogenesis is a potential approach to the treatment of mitochondrial disorders. This involves stimulating transcription factors for both nuclear and mitochondrial genomes simultaneously in order to up-regulate respiratory chain (RC) gene expression. This role is fulfilled by peroxisome proliferator activated receptor (PPAR)-γ coactivator-1α (PGC-1α); a pivotal transcriptional co-factor widely considered the master regulator of mitochondrial biogenesis.

PGC-1α interacts with a number of transcription factors. These include α, β/δ and γ isoforms of the peroxisomal proliferator activated receptors (PPARs). This group of ubiquitously expressed nuclear receptors is activated by binding of fatty acids. Subsequently, transcription of genes involved in mitochondrial fatty acid oxidation is induced, thereby enabling cellular metabolic shift from glycolysis. Additionally, PGC-1α co-activates estrogen related receptor alpha (ERRα); nuclear respiratory factors (NRF) 1 and 2 (transcription factors bound to promoter regions of target nuclear genes involved in the respiratory chain); and TFAM (transcription factor A mitochondrial), which modulates mitochondrial DNA transcription and replication.

PGC-1α expression is induced through cold exposure, starvation and exercise. The PPARs, AMP-protein activated kinase (AMPK) and sirtuin 1 (Sirt1) also increase PGC-1α activity and provide a means through which this pathway can be pharmacologically manipulated. Indeed, several compounds have been identified that exert their effect in this way including: bezafibrate and the glitazones (PPAR agonists); metformin and AICAR (AMPK); and resveratrol (Sirt1). Of these, bezafibrate, glitazones and metformin have established relevance in diabetes and hyperlipidaemia. Their mechanism of action also provides a rationale for their use in other metabolic disorders such as obesity and mitochondrial disease.

Indeed,bezafibrate has shown promise as a disease modifying pharmaceutical agent in pre-clinical studies using both cellular and animal models of mitochondrial myopathy.

Cellular models of mitochondrial disease have demonstrated improvements in a variety of measures of mitochondrial function when grown in a bezafibrate enriched medium. This has included a cell line comparable to the specific patient group we propose to review in this feasibility study. Furthermore, a mouse model of mitochondrial myopathy has demonstrated improvement in clinically relevant outcomes including time to disease manifestation and life span.

This phase II, open label, non-randomised feasibility study aims to build on the work obtained in pre-clinical studies and provide proof of principle data in humans affected with the most common form of mitochondrial muscle disease. This study is not designed to provide proof of efficacy. However, should bezafibrate exert a demonstrable molecular effect here, the investigators anticipate the need for larger, randomised trials of bezafibrate in the future. An additional aim of this feasibility study, is therefore obtaining the relevant data to determine how many patients the investigators would need in a larger trial; and what biochemical and clinical measurements the investigators would use to determine drug effect in such a trial.