Session Information
Date: Thursday, June 23, 2016
Session Title: Clinical trials and therapy in movement disorders
Session Time: 12:00pm-1:30pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To confirm the mechanism of action of RE-024, and evaluate its activity in human cellular models and brain penetration in animal models.
Background: Pantothenate kinase-associated neurodegeneration (PKAN) is caused by mutations in the PANK2 gene which encodes pantothenate kinase (PanK). Phosphorylation of pantothenic acid (PA, vitamin B5) by PanK is the rate limiting step in Coenzyme A (CoA) formation, a key factor in several cellular processes. RE-024 is being developed by Retrophin, Inc. as a disease modifying phosphopantothenate (PPA) replacement therapy to improve clinical manifestations in PKAN patients.
Methods: Pharmacokinetic and microdialysis studies were conducted in mice, rats and monkeys following established procedures. RE-024, PA and PPA were quantified in multiple matrices using LC MS/MS. The effect of RE-024 on in vitro CoA levels was determined in shRNA PanK2 silenced human neuroblastoma cells. Blood brain barrier (BBB) permeability of RE-024, PA and PPA was assessed in vitro, and in vivo in microdialysis studies. RE-024 mechanism of action in liver and brain was confirmed using isotopically labelled RE-024.
Results: RE-024 increased CoA levels and tubulin acetylation in shRNA PanK2 silenced human neuroblastoma cells. RE-024-derived PPA was incorporated into liver and brain CoA. RE-024 was permeable to the BBB, however, after an oral dose, it was only quantifiable in brain dialysate in monkeys, not in rats or mice. This difference was attributed to the rapid metabolism of RE 024 in rat and mouse blood, with insufficient circulation time to distribute to brain. The rate of metabolism of RE-024 in monkey blood is similar to human, and is sufficiently slow to allow distribution to the brain. In monkey dialysate, RE-024 concentrations were ∼30% of the blood concentration.
Conclusions: In vitro, RE-024 increases CoA levels and tubulin acetylation. In vivo, it delivers intact PPA intracellularly that is incorporated into CoA in the liver and brain. In species with rapid blood metabolism, such as mice and rats, it will not reach brain tissue. In the monkey (slower metabolic rate) it reaches the brain. The similar in vitro rate of metabolism in monkey and human suggest that RE-024 will reach the human brain. Species differences in metabolic rates indicate that mouse and rat models are not suitable for evaluation of efficacy of RE 024.
ACMG, March 2016.
To cite this abstract in AMA style:
M. Beconi, E. Monteagudo, A. Di Marco, S. Malancona, D. Elbaum, S. Harper. RE-024: Mechanism of action and efficacy in non-clinical models [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/re-024-mechanism-of-action-and-efficacy-in-non-clinical-models/. Accessed June 14, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/re-024-mechanism-of-action-and-efficacy-in-non-clinical-models/