A Study of Bezafibrate in Mitochondrial Myopathy
Condition: Mitochondrial Diseases
MeSH terms: Mitochondrial Myopathies; Mitochondrial Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to gather preliminary data on whether bezafibrate can improve
      cellular energy production in mitochondrial disease.

      Mitochondrial diseases are rare inherited disorders that arise due to deficient energy
      production within the cells of the body. Consequently, the typical clinical features arise in
      organs with high energy requirements. Mitochondrial disorders exhibit highly variable
      clinical effects, both between individuals and within families. Characteristic symptoms
      include muscle weakness (myopathy), hearing loss, migraine, epilepsy and stroke like episodes
      in addition to diabetes and heart problems. Mitochondrial disorders can therefore impact
      considerably on both quality of life and life expectancy. Despite this, no proven disease
      modifying treatments are available.

      Pre-clinical studies have identified that several existing medications improve mitochondrial
      function. Of these, bezafibrate has the best supportive data and, because it is already
      licensed as a treatment for high blood fats, has a well characterised side effect profile.

      The investigators will therefore conduct a feasibility study of bezafibrate in people with
      mitochondrial myopathy. Ten affected participants will be recruited and will receive a
      titrating course of bezafibrate three times daily for 12 weeks.
    

Detailed description: 
      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.
    

Intervention name(s): Bezafibrate
Intervention type(s): Drug
Intervention description(s): Bezafibrate 200mg-600mg three times daily for 12 weeks.
Other intervention name(s): Bezalip
Intervention MeSH terms: Bezafibrate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other