Spaull, R; Hogarth, P; Hayflick, S; Kurian, MA; (2022) Development of a UK phase-2 clinical trial of 4'-phosphopantetheine for pantothenate kinase associated neurodegeneration. Presented at: British Paediatric Neurology Association 2022 Annual Meeting, Dublin, Ireland (Virtual conference).

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Abstract

Background: Pantothenate kinase-associated neurodegeneration (PKAN), a Neurodegeneration with Brain Iron Accumulation (NBIA) disorder, is an inborn error of vitamin B5-coenzyme A (CoA) metabolism caused by biallelic mutations in the PANK2 gene. Children with classic PKAN present at a mean age of 3.4 years, often with gait difficulties and clumsiness; the atypical form presents later in adolescence or early adult life and progresses more slowly. PKAN is characterized by a severe movement disorder, cognitive and neuropsychiatric involvement, and pathological iron accumulation in the basal ganglia; these cause profound disability and risk of premature mortality. There are no proven disease-modifying treatments for PKAN. / Proposed therapy: PKAN is caused by functional loss of the mitochondrially-located PANK2 enzyme which phosphorylates vitamin B5 (pantothenate) in the first step of CoA metabolism. CoA is essential for the tri-carboxylic acid cycle, fatty acid oxidation and synthesis, amino acid metabolism and neurotransmitter synthesis, serving more than 9% of mammalian biochemical reactions. 4’-phosphopantetheine (4’-PPT) is the endogenous precursor to CoA and is found in all cells and many foods. In cultured human cells and the Pank2-knock out mouse model, administration of 4’-PPT corrects disease-specific phenotypes and does not cause toxicity. / Trial design: We will undertake a phase-2 clinical trial of enteral 4’-PPT administered once per day to 24 participants aged 1–25 years. A 6-month placebo-controlled, double-blinded, dose-ranging phase will be followed by an 18-month open-label, single-dose phase. Primary outcome measures are of safety and tolerability with regular blood test and side effect monitoring. The secondary outcome is response to treatment of a blood biomarker measuring the expression of CoASY mRNA, the last enzyme in the CoA synthesis pathway. Exploratory tertiary outcomes include questionnaire and examination-based disease rating scales, activity of daily living scales, measures of dystonia and quality of life, and functional ophthalmological assessments.

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