- What is Leriglitazone
Leriglitazone (MIN-102) is a novel, orally bioavailable and selective PPAR gamma agonist with a potential best-in-class profile indicated for CNS diseases. It is one of the several metabolites of pioglitazone and has a demonstrated brain penetration and safety profile in humans, allowing PPAR gamma engagement in the CNS above the level that can be safely achieved with pioglitazone and other glitazones. It showed robust preclinical proof-of-concept in animal models of multiple diseases by modulating pathways leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, demyelination and axonal degeneration.
1Best-in-class, selective PPAR gamma agonist Central role in CNS. Metabolite of pioglitazone 2In humans, demonstrated CNS exposure and engagement required for efficacy 3Orally bioavailable. Specifically formulated as suspension to achieve high and controlled exposure in patients 4MoA validated in animal models of multiple CNS diseases 5CMC ready for industrial development 6Granted patents in European jurisdictions and US covering multiple CNS indications until 2035
Leriglitazone has successfully completed a phase 1 clinical trial showing good safety, tolerability and CNS engagement of PPAR gamma at equivalent levels than those required for efficacy in preclinical models. A pivotal phase 2/3 trial in AMN (ADVANCE) and a phase 2 in FRDA (FRAMES) are currently ongoing, and recruitment in a phase 2 study in cerebral Adrenoleukodystrophy (cALD) has started. In addition, the development in other orphan CNS diseases is in preparation.
Mechanism of Action in X-ALD
In X-ALD, mutations in the ABCD1 gene located on the X-chromosome cause defective function of the ABCD1 transporter, normally responsible for bringing VLCFAs (very long-chain fatty acids) into the peroxisome. The defective function of the transporter leads to an accumulation of very long-chain fatty acids (VLCFA) in several tissues and a pathogenic cascade of events that contribute to membrane destabilization of the myelin sheath, mitochondrial dysfunction, oxidative stress, neuroinflammation and compromised blood brain barrier (BBB) integrity.
Leriglitazone (MIN-102), by activating PPAR gamma, modulates the expression of genes involved in mitochondrial biogenesis (PGC-1a) and therefore restores the lost energy balance, decreases oxidative stress and restores mitochondrial function caused by accumulation of VLCFAs. Leriglitazone also increases expression of genes involved in oligodendrocytes differentiation (olig2, neuroD1) promoting remyelination by oligodendrocyte survival and differentiation and modulates neurotrophin levels resulting in improved neuronal survival. Leriglitazone also interacts with the inflammatory pathway active in X-ALD by decreasing NF-kB levels, reducing macrophage/microglia activation and consequently neuro-inflammation. It also reduces monocyte adhesion to the endothelial cells of the blood brain barrier, a mechanism with a prominent role in the initiation of the cALD phenotype.
Mechanism of Action in FRDA
FRDA is caused by gene mutations which result in deficient expression of the mitochondrial protein frataxin (FXN) and subsequent changes in mitochondrial function. In particular mitochondrial iron metabolism is affected causing iron accumulation, mitochondrial dysfunction and oxidative damage. Frataxin is highly expressed in cardiomyocytes and in dorsal spinal column neurons. The maintenance of mitochondrial homeostasis is crucial during the progression of the disease.
Through the activation of the PPAR gamma/PGC-1 alpha pathway, leriglitazone restores mitochondrial function and energy production. This results in increased neuronal survival and decreased neurite degeneration, and improvement of motor function in animal models of the diseases.