Objective: To determine efficacious plasma concentration of leriglitazone from preclinical models of Friedreich´s ataxia (FRDA). To confirm CNS target engagement in a first-in human study.

Background: Peroxisome-proliferator activator receptor gamma (PPARγ)/PPARγ coactivator 1 alpha (PGC1α) pathway is dysregulated in frataxin deficiency and contributes to the disease pathogenesis. Leriglitazone is a novel brain penetrant, small molecule, which selectively acts through the PPARγ and which is in development as a potential treatment for FRDA. Leriglitazone is also in phase 2/3 for the treatment of AMN, and in phase 2 for cALD.

Method: The in vivo knock-in/knock-out (KIKO) mouse model of FRDA was used to assess the effect of leriglitazone on relevant mitochondrial biomarkers. The transgenic YG8sR mice were used to explore the effect of leriglitazone on motor function. Plasma exposure derived from additional PK experiments were used to identify the effective plasma and CSF concentrations in mice. 
A Phase 1, randomized, double-blind, placebo-controlled, single-centre trial was conducted in 33 healthy male volunteers. 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.

Results: In the in vivo preclinical studies, leriglitazone restored levels of mitochondrial markers such as PGC1α, and improved global motor functions.
In the Phase I study, single and multiple doses of leriglitazone appeared to be safe and well tolerated. A decrease in plasma and CSF pro-inflammatory biomarkers (such as Interleukin-8, CXCL10-IP10 or MCP-1) and an increase of adiponectin levels in plasma and CSF were reported at plasma concentrations comparable to the preclinical efficacious exposures. These results are consistent with PPARγ agonism related pharmacology, indicate sufficient CNS target engagement and guide dose selection in clinical studies.

Conclusion: Target plasma concentrations determined in preclinical studies could be safely achieved in a Phase I study. At these plasma concentrations, CNS target engagement was confirmed in healthy volunteers.  This approach has supported the design of the current Phase 2 clinical trial in Friedreich´s Ataxia, and also in other indications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-translational-approach-to-determine-target-concentrations-of-min-102-leriglitazone-to-support-a-phase-ii-study-in-friedreichs-ataxia/