Evaluation of the pharmacokinetic parameters of leriglitazone in plasma and urine after single and multiple oral administration in healthy male volunteers. Evaluation of pro-inflammatory biomarkers in plasma and CSF after oral administration of leriglitazone in healthy male volunteers.

Adrenoleukodystrophy (X-ALD) is a rare and inherited neurodegenerative disorder. The disease is due to mutations in the gene of ALDP, which result in the accumulation of VLCFA, particularly in the brain, nerves and adrenal glands. The build-up of VLCFA leads to inflammation and myelin degeneration, causing a wide range of neurological symptoms that usually worsen over time.

Leriglitazone is a differentiated peroxisome proliferator-activated receptor γ (PPARγ) agonist with a superior profile for central nervous system (CNS) related diseases with excellent in-vivo efficacy. Treatment with leriglitazone has the potential to reduce cerebral inflammation and slow disease progression.

A Phase 1, randomized, double-blind, placebo-controlled, single-center clinical trial was conducted in healthy male volunteers where single doses of 30 mg, 90 mg, and 270 mg and multiple doses of 135 mg/day and 270 mg/day were administered over 8 days. Plasma, urine and CSF samples were collected to evaluate PK parameters and biomarker levels.

A total of 33 subjects were included in the study. Single and multiple doses of leriglitazone appeared to be safe and well tolerated. A decrease in plasma pro-inflammatory biomarkers (such as Interleukin-8, CXCL10-IP10 or MCP-1) and an increase of adiponectin levels in plasma and CSF were reported. These results are consistent with PPARγ agonism related pharmacology and indicate sufficient CNS target engagement.

Tolerability and pharmacodynamic results warrant the evaluation of leriglitazone as treatment for X-ALD.   Leriglitazone is currently in clinical phase 2/3 for the treatment of AMN, in phase 2 for cALD and in phase 2 for Friedreich´s Ataxia.