Overview of LC-FAOD
Long-chain fatty acid oxidation disorders are characterized by a defect in the transformation process of long-chain fatty acids into ATP, or energy. This can lead to low blood sugar, breakdown of the muscles (which can cause severe muscle pain), and hospitalizations leading to early death.
Recently in 2021, a novel drug has been approved by the FDA and Health Canada for the treatment of LC-FAOD, Dojolvi (see article: https://mitofire.com/?p=419).
Here, we’ll explore an off-label drug that is not routinely prescribed in LC-FAOD: bezafibrate.
Mechanism of action of bezafibrate
PPAR (peroxisome proliferator-activated receptors) are receptors comprising the 3 following subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPARβ/δ enhances β-oxidation of fatty acids, which is reduced in LC-FAOD.
Bezafibrate is a relatively broad-spectrum PPAR agonist, meaning that it activates not only PPARβ/δ, but also PPARα and PPARγ. This results in an increase in the β-oxidation of fatty acids. It is limited in its clinical efficacy since as the dose is increased, other unwanted actions occur as we will discuss later.
Clinical studies with bezafibrate in LC-FAOD
Three clinical trials of bezafibrate were conducted, and the results were contradictory.
- The first trial: open-label, 6 month-year duration with a 36-month follow-up (Bonnefront NEJM 2009)
- Results
- Increased levels of fatty acid oxidation levels
- Reduced frequency of rhabdomyolysis
- Reduced creatinine kinase levels
- Improved quality of life
- Results
- 2nd trial: Double-blind, randomized, controlled study (Orngreen Neuro 2014)
- Results
- No benefit over placebo in clinical symptoms or fatty acid oxidation levels during exercise
- Results
- 3rd trial: Open-label clinical trial (Yamada Mol Genet Metab Rep 2018)
- Results
- Improved quality of life
- No other benefits over placebo in other endpoints (acylcarnitine profile, creatinine kinase levels, visual analog scale)
- Results
It should also be noted that in these studies, the dosage of bezafibrate was 600mg/day, which is in the higher ranger compared to the doses used to treat dyslipidemia (400mg/day). And even at these high doses, bezafibrate had minimal impacts on markers of mitochondrial biogenesis.
Here is a comment from Dr. Bastin to the results of the 2nd trial published: https://www.hal.inserm.fr/inserm-02894834v2/document
And a backlash: https://link.springer.com/article/10.1007/s10545-014-9779-3
Given that there is no consensus over the efficiency of bezafibrate and that is has thus not been approved by the FDA, and since it requires relatively high dosages to possibly increase fatty acid oxidation levels, it is not being prescribed routinely.
Side effects/safety profile
Although bezafibrate could be beneficial in short term, there are also concerns about its long-term effects. Bezafibrate was linked to increased serum disease biomarkers of mitochondrial disease, which could mean that bezafibrate could actually exacerbate the mitochondrial disease in the long term. It was shown to increase:
- Fibroblast growth factor 21 (FGF-21)
- Growth and differentiation factor 15 (GDF-15) and amino acids including glutamine and aspartate.
This could be the result of an exacerbation of the mitochondrial disease. However, the study states that it is also possible that these changes were due to the direct effects of bezafibrate on metabolism independent of oxidative phosphorylation.
Furthermore, it was shown to increase plasma creatinine, cause gallstone formation, drug–drug interactions (i.e., gemfibrozil) and myopathy.
Future developments: REN001
REN 001 is another drug being investigated for the treatment of LC-FAOD. It is more specific than bezafibrate for the PPAR delta receptor, thus could be more efficient and could have a better safety profile.
It is currently being investigated in a phase 1b trial with patients with LC-FAOD.
References
https://pubmed.ncbi.nlm.nih.gov/20505667/
https://pubmed.ncbi.nlm.nih.gov/20505667/
https://www.nature.com/articles/s41598-018-19543-3
https://www.medscape.org/viewarticle/920388
