The new peroxisome proliferator-activated receptor gamma (PPARgamma) agonist leriglitazone (hydroxypioglizatone; Minoryx Therapeutics), has a better profile for treating neurodegenerative diseases, such as X-linked adrenoleukodystrophy (X-ALD), than similar drugs, including pioglitazone (Actos; Takeda).

Reported in the June 2, 2021, edition of Science Translational Medicine (STM), the findings of this international study, which included preclinical and healthy volunteer studies, support using leriglitazone in X-ALD and possibly in other neuroinflammatory and neurodegenerative conditions.

"Leriglitazone development began in 2014," said study leader, Pilar Pizcueta, the director of biology at leriglitazone's developer, Minoryx Therapeutics of Barcelona, Spain.

"This is the second study showing leriglitazone's potential in central nervous system (CNS) disorders, with the first having covered its use in Friedreich's ataxia," said Pizcueta.

"Additionally, recent clinical data have shown clinical benefits with leriglitazone in both Friedrich's ataxia and X-ALD, while pioglitazone failed in CNS clinical trials," he told BioWorld Science.

X-ALD is a rare potentially fatal inherited peroxisomal disorder, which presents as two main phenotypes: adrenomyeloneuropathy (AMN) and cerebral ALD (cALD).

The disease is due to ABCD1 gene mutations resulting in loss of function of encoded ALDP protein, an ATP-binding transporter in the peroxisomal membrane, which transports very long chain fatty acids (VLCFAs) into peroxisomes for degradation.

ALDP deficiency results in VLCFA accumulation in plasma and tissues, resulting in impairment particularly in the brain, nervous system, and adrenal glands.

To date, no effective pharmacological treatments are available for X-ALD, although PPARgamma agonists have shown promise in this regard.

PPARgamma agonists

Acting via genetic activation or repression of multiple pathways, PPARgamma agonists have shown neuroprotective and restorative effects in preclinical models of neurodegenerative diseases, including Parkinsonism and Alzheimer's disease.

Notably, PPARgamma agonists, whose activity can be monitored via adiponectin levels, modulate key genes that counteract oxidative stress, stimulate mitochondrial biogenesis, and decrease inflammation through repressing the nuclear factor kappaB (NF-kappaB) pathway.

However, PPARgamma agonists have been unsuccessfully tested in clinical trials in neurodegenerative diseases, possibly due to insufficient CNS target exposure.

Leriglitazone hydrochloride is being developed for treating neurodegenerative diseases, due to its good BBB penetration, bioavailability and safety profile.

In the new study, leriglitazone was found to decrease oxidative stress, increase the ATP concentration, and have neuroprotective effects in primary rodent neurons and astrocytes after VLCFA-induced toxicity simulating X-ALD.

"At the highest doses in rodent neurons, leriglitazone reduced oxidative stress and reactive oxygen species (ROS) production by 60% and 45%, respectively, and increased ATP concentration to values similar to vehicle, resulting in a 71% increase in neuroprotection, as evaluated using immunofluorescence," said Pizcueta.

Leriglitazone's efficacy in treating X-ALD was further validated in mouse AMN models and in autoimmune encephalomyelitis (EAE) surrogate mouse models of the neuroinflammatory component of cALD, which reproduce cALD features, including microglial activation, brain demyelination and axonal degeneration.

"Leriglitazone was shown to be effective in X-ALD-related in vivo Abcd1 knockout (KO) models, in which it elicited significant dose-dependant improvements in motor dysfunction, as assessed using rotarod and balance beam testing," said Pizcueta.

"In the EAE neuroinflammatory model, leriglitazone significantly reduced disease progression and improved the clinical score in a dose-dependent manner, compared to untreated vehicle group controls, validating leriglitazone's strong antinflammatory effect."

In spinal cord tissues from these models, leriglitazone improved motor function and restored markers of oxidative stress, mitochondrial function and inflammation, while decreasing neurological disability in the EAE mice.

"Leriglitazone reduced microglia activation in spinal cord tissues, which is important, as reduced axonal degeneration could translate into clinical benefits in AMN, in which the pathological hallmark is axonopathy," noted Pizcueta.

To better understand leriglitazone's mode of action in possibly preventing early stages of cALD, the researchers used an in vitro BBB model, in which adhesion of human X-ALD monocytes to brain endothelial cells was shown to be decreased after leriglitazone, suggesting it may prevent progression to pathologically disrupted BBB.

Importantly, leriglitazone-treated X-ALD monocyte-derived patient macrophages were found to be less inclined toward an inflammatory phenotype.

This is a significant finding, because "human ABCD1 deficiency leads to an impaired plasticity of X-ALD macrophages and incomplete establishment of anti-inflammatory responses," said Pizcueta.

"In that regard, leriglitazone reversed the proinflammatory status in monocyte-derived macrophages from patients with AMN by significantly decreasing [tumor necrosis factor-alpha] TNF-alpha expression in inflammatory activated cells."

Importantly, leriglitazone treatment increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thereby promoting remyelination.

"Development of cALD is characterized by rapid progression of demyelinating lesions in the brain that may result from abnormalities in the capacity of oligodendrocytes to correctly differentiate and remyelinate, while microglia play a key role in myelin debris phagocytosis, which is necessary for remyelination," noted Pizcueta.

"Leriglitazone treatment increased the capacity of microglia to phagocytose myelin debris under inflammatory and noninflammatory conditions and protected oligodendrocyte precursor cells and oligodendrocytes," he added.

"These findings suggest a role for leriglitazone in preventing demyelination and/or promoting remyelination, further supporting its effect in modulating severe axonopathy by preserving myelinated axons after demyelination."

Finally, a phase I study in healthy volunteers confirmed these inflammatory biomarker changes and target engagement in plasma and CSF, as confirmed by increased adiponectin, at preclinically effective doses.

Collectively, these study findings support the use of leriglitazone in X-ALD and in other neuroinflammatory and neurodegenerative conditions.

"We recently completed a phase II/III study in AMN and are now engaging with regulatory agencies to discuss a potential approval pathway, based on such data," said Pizcueta.

"Additionally we have an ongoing phase II study in pediatric cALD patients and we recently completed a phase II in Friedreich's ataxia, for which we are now preparing a phase III trial," he said.

"We believe that leriglitazone could become the first approved therapy for AMN and a complementary therapy for cALD. In future, we will be continuing its development in X-ALD, while expanding its role in other neurodegenerative and neuroinflammatory diseases."