MIN-102 (leriglitazone), a Brain Penetrant PPAR gamma Agonist, Decreases Neuroinflammation and Neurodegeneration and Promotes Re-Myelination in Preclinical Models of X-linked Adrenoleukodystrophy (X-ALD) (759)

Objective: To investigate the preclinical efficacy of a new investigational drug, leriglitazone, in models of neurodegeneration, neuroinflammation and demyelination/remyelination relevant to X-ALD and to other neuroinflammatory conditions. Background: Leriglitazone is a brain penetrant, small molecule, which selectively acts through the peroxisome proliferator-activated receptor gamma and exerts several pleiotropic effects making it an ideal therapeutic approach towards the different pathophysiological alterations of X-linked adrenoleukodystrophy (X-ALD). In the central nervous system X-ALD presents as two main phenotypes: the adult form adrenomyeloneuropathy (AMN) - a progressive spinal cord axonopathy - and the aggressive cerebral inflammatory form (cALD). In this study, we show that leriglitazone can cross intact or altered blood-brain barrier (BBB) and exhibits efficacy in multiple preclinical models relevant for both phenotypes of X-ALD. Design/Methods: Single Abcd1 and double Abcd1/Abcd2 knockouts were used as preclinical models of AMN. The widely used Experimental Autoimmune Encephalomyelitis and the Cuprizone mice models were used to study the potential effects of leriglitazone in neuroinflammation, such as it occurs in cALD, and in enhancing remyelination respectively. Several in vitro models including a BBB transwell system and human cells from X-ALD patients were used to investigate the brain penetration of leriglitazone and its protective effects in macrophages, neurons, microglia, astrocytes and oligodendrocytes. Results: Leriglitazone decreased microglia activation, reversed pro-inflammatory status, prevented early pathological stages that lead to BBB disruption, promoted remyelination by increasing myelination, myelin debris clearance and oligodendrocyte survival. Importantly, leriglitazone influenced progression of neurological disability and reverted motor dysfunction Conclusions: The preclinical data indicate that leriglitazone is a promising therapeutic approach to treat both CNS phenotypes of X-ALD, AMN and cALD, as well as other neuroinflammatory and/or neurodegenerative diseases. Lerigltazone is currently in a phase 2/3 clinical trial in AMN in Europe and US, and in two phase 2 trials, in cALD and Friedreich’s Ataxia respectively, in Europe. Disclosure: Dr. Poli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx and AC Immune. Dr. Poli has received compensation for serving on the Board of Directors of Dimerix. Dr. Vilalta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx therapeutics. Dr. Rodriguez-Pascau has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx Therapeutics S.L.. Dr. Cerrada-Gimenez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employer: Experimentica Ltd.Dr. Berger has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx Therapeutics S.L.. Dr. Berger has received research support from Minoryx Therapeutics S.L.. Dr. Forss-Petter has nothing to disclose. Dr. Weinhofer has nothing to disclose. Dr. Musolino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Minoryx therapeutics S.L.. Dr. Musolino has received research support from Minoryx Therapeutics S.L.. Dr. Martinell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx Therapeutics S.L.. Dr. Pizcueta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Minoryx Therapeutics S.L..