Objective: To assess the safety, tolerability, and pharmacokinetics of single oral doses of RE-024 in healthy adult volunteers.

Background: PKAN is a rare, autosomal recessive, progressive, neurodegenerative disease manifesting primarily as parkinsonism and dystonia, and is grouped as an NBIA disorder (Neurodegeneration with Brain Iron Accumulation). Onset is usually in childhood, eventually leading to severe functional impairment and often early mortality. PKAN is typically associated with a distinctive “eye-of-the-tiger” finding on T2 MRI, which aids diagnosis. The PanK2 enzyme phosphorylates pantothenic acid (PA) to form phosphopantothenic acid (PPA) and is the rate limiting step of Coenzyme A synthesis. In PKAN, PanK2 gene mutations render the PanK2 enzyme dysfunctional. RE-024 is a phosphopantothenic acid (PPA) precursor designed to deliver PPA to cells, aiming to restore the product of the dysfunctional PanK2 enzyme.

Methods: This was a randomized, placebo-controlled Phase 1 study in N=40 healthy adult volunteers were administered a single ascending oral dose of 75, 225, 450, 900, or 1800 mg of RE-024. A blinded Safety Review Committee assessed safety and tolerability findings between cohorts. Blood was collected at defined intervals over 48 hours to measure RE-024 levels.

Results: There were no serious adverse events (SAEs) or dropouts, and all treatment-emergent AEs (TEAEs) were of mild intensity. Rates of subjects reporting TEAEs were similar in the RE-024 (11/30 subjects; 36.7%) vs placebo (3/10 subjects; 30%) groups. AEs were judged not related (1), unlikely related (8), or possibly related (12), and the majority of possibly related TEAEs (8/12) were related to product taste. The remaining TEAEs judged possibly related included dry throat (placebo), throat irritation (900 mg dose), diarrhea (75 mg dose) and hiccups (225 mg dose). RE-024 was rapidly absorbed. Increases in mean Cmax and mean AUC were greater than dose proportional between 75 and 450 mg doses, and less than dose proportional between 450 and 1800 mg.

Conclusions: RE-024 given in single oral doses up to 1800 mg was safe and well tolerated, with no dose-related safety signals. RE-024 was rapidly absorbed, with exposures consistent with increasing dose levels. Overall, results support further clinical development of RE-024 for the treatment of patients with PKAN.

ACMG.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-healthy-volunteer-phase-1-study-of-re-024-a-potential-phosphopantothenate-replacement-therapy-for-patients-with-pantothenate-kinase-associated-neurodegeneration-pkan/