What is Friedreich’s Ataxia?
FA is a rare genetic disorder caused by mutations in the FXN gene, which provides instructions for making a mitochondrial protein called Frataxin. Deficiency in Frataxin causes iron accumulation in the mitochondria, the energy-production centers of cells, and leads to defective energy production as well as increased oxidative stress, both of which induce cell death pathways. Nerve cells are especially affected because their energy demand is very high. FA leads to the degeneration of the nerve cells in the brain and spinal cord and also damages the peripheral nerves that control muscle movement. This causes a progressive loss of coordination and muscle strength.
One of the therapeutic strategies of delaying or preventing the progression of FA is to improve mitochondrial function.
How does leriglitazone work?
PPAR gamma agonists are a class of molecules that mimic the function of a naturally occurring protein called PPAR gamma. PPAR gamma is a transcription factor (protein) that regulates the biogenesis of other proteins. PGC-1 alpha is a transcriptional co-activator protein that works together with PPAR gamma to regulate the biogenesis of mitochondrial proteins.
Leriglitazone is a best-in-class selective PPAR gamma agonist that induces the PGC-1alpha signaling pathway and restores mitochondrial function and energy production. This results in increased neuronal survival and improved motor function, as shown in studies based on animal models.
Leriglitazone in clinical trials
A Phase 1 clinical trial was conducted in healthy male volunteers to assess the safety, tolerability, and pharmacokinetics (movement through the body) of leriglitazone. The trial also evaluated food effects and brain penetration of leriglitazone, and biomarkers for PPAR gamma engagement.
The results showed that leriglitazone was safe and well-tolerated at concentrations that were well above the levels required for effectiveness. No serious adverse events (side effects) were reported. Leriglitazone showed optimal brain penetration and exerted a broad range of effects that were similar to those previously observed in preclinical studies. There were no relevant food effects. The pharmacokinetic analysis provided a simple and convenient dosing regimen for patients.
A Phase 2 randomized, double-blind, placebo-controlled clinical trial (NCT03917225) called FRAMES, is currently underway to study the effects of leriglitazone on the biochemical, imaging, neurophysiological, and clinical markers of FA in 36 patients. Participants will receive an oral suspension of 15 mg/mL of leriglitazone or placebo, once-a-day for one year. The primary outcome measure of the study is to determine the change from baseline in the cervical spinal cord area using magnetic resonance imaging (MRI) at 48 weeks after treatment with leriglitazone in comparison to placebo treatment. The study also will evaluate the levels of other biomarkers related to FA and the effect of leriglitazone on fatigue, disease severity, and quality of life.
Last updated: Jan. 22, 2020
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