Stages of Development for MIN-102 Leriglitazone

The drug development process can be thought of as a series of stages, and successful drugs must pass through each stage to become available to patients.

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The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defense. Several research studies in both animal and cell models have shown that the PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is frataxin deficiency, thus contributing to Friedreich ataxia pathogenesis and supporting the PPARγ pathway as a potential therapeutic target. Dr. Massimo Pandolfo and colleagues showed that activation of the PGC-1a pathway with a drug called pioglitazone reversed some of cellular abnormalities observed in the brain and spinal cord of frataxin deficient mice. Dr. David Lynch and colleagues further described that changes in the PGC- 1a pathway are observed in the cerebellum of frataxin deficient mice and likely contributing to a mitochondrial phenotype (deficiency and loss of mitochondria).

Preclinical studies of MIN-102 (leriglitazone) were published that demonstrate rescue of phenotypic features in cellular and animal models of FA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival of the neurons.

Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels.

Leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells.

In the phase 1 clinical study MIN-102 was well tolerated and it was confirmed that the compound crosses the blood brain barrier and engage PPAR gamma within the CNS at an equivalent level as in preclinical studies

December 2020: Minoryx Therapeutics reported initial results of the FRAMES phase II clinical trial of MIN-102 (leriglitazone) in FA patients. This was a randomized, double-blind, placebo-controlled study evaluating the effects of leriglitazone on biochemical, imaging, neurophysiological, and clinical markers in individuals with FA. The study was conducted at 4 sites in Europe (Spain, France, Belgium, and Germany). 39 individuals with Friedreich’s ataxia were enrolled, with 32 completing the study. There was no difference between the treatment group and placebo group in the primary endpoint (change in cervical spinal cord as measured by MRI).

There was some evidence of improvement in the treatment group on some of the secondary endpoints. The treatment group had less accumulation of iron in the dentate nucleus as measured by QSM compared to placebo group and a measure of upper limb function worsened in the placebo group but not the treated group, however this difference was not statistically significant. Treatment with leriglitazone resulted in PPARg engagement, within the target range, in all patients as assessed by the relevant biomarker (adiponectin). Leriglitazone was well tolerated with some anticipated adverse events (side-effects) known to drugs with this mechanism of action, specifically edema and weight gain.

September 2022: Minoryx announced that the EMA had accepted for review the Marketing Authorization Application (MAA) for leriglitazone as a treatment for adult males with x-linked adrenoleukodystrophy. Future studies in FA were delayed due to ongoing development and regulatory activities for leriglitazone in X-ALD.

November 2022: Full publication of all the results from the FRAMES phase II trial became available.

January 2023: Leriglitazone completed a phase II/III clinical study in adult patients with X-ALD (ADVANCE) in the EU and US showing a significant reduction of cerebral lesion progression and a reduction of incidence of progressive cALD and myelopathy symptoms. Results were published in The Lancet Neurology. 

A separate study in pediatric patients with cALD (NEXUS) in EU was 24 weeks of treatment. Evaluable patients in NEXUS were clinically stable and radiologically demonstrated disease arrest or lesion growth stabilization. Finally, a phase III study in adult male patients with progressive cALD (CALYX) recruited in the US.

January 2024: Minoryx Therapeutics and Neuraxpharm Group (Neuraxpharm) announced that the EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended not to grant marketing authorization for leriglitazone as a treatment of X-ALD. Minoryx and Neuraxpharm are seeking a re-examination for conditional approval for patients with cerebral adrenoleukodystrophy (cALD).

News and Press Releases

| Dec 15, 2020

Minoryx’s clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich´s ataxia

Industry News
| Nov 13, 2019

Minoryx Therapeutics receives Orphan Drug Designation from the European Commission for leriglitazone in the treatment of Friedreich’s Ataxia

Industry News
| Oct 17, 2019

Minoryx Therapeutics receives FDA Orphan Drug Designation for leriglitazone in Friedreich’s Ataxia

Industry News
| Oct 8, 2019

Minoryx Therapeutics completes enrollment in FRAMES phase 2 trial with leriglitazone in Friedreich’s Ataxia

Industry News
| Jun 4, 2019

Minoryx Therapeutics announces first patient dosed in the FRAMES phase 2 trial in Friedreich’s Ataxia

Industry News
| Feb 27, 2019

Minoryx Therapeutics receives approval from Spanish Regulatory Agency to initiate phase 2 study in Friedreich’s Ataxia

Industry News