BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Biostatistics Retrophin Inc San Diego California USA

Child Neurology Department Children's Memorial Health Institute Warsaw Poland

Department of Child Neurology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Department of Child Neurology Hospital Universitari Vall d'Hebron Barcelona Spain

Department of Child Neurology Oslo University Hospital Rikshospitalet Oslo Norway

Department of Neurology 1st Faculty of Medicine Charles University and General Faculty Hospital Prague Czech Republic

Department of Neurology Children's National Medical Center Washington District of Columbia USA

Department of Neurology Columbia University College of Physicians and Surgeons New York New York USA

Department of Neurology Hospital Clinic of Barcelona Barcelona Spain

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA

Department of Neurology Sorbonne University AP HP Salpêtrière Hospital Brain and Spine Institute Paris France

Department of Neurology Sorbonne University AP HP Salpêtrière Hospital Paris France

Department of Neurology University of California Irvine Irvine California USA

Department of Neurosurgery and Neurological Sciences Rush University Medical Center Chicago Illinois USA

Department of Neurosurgery CHRU de Montpellier Gui de Chauliac Hospital Montpellier France

Department of Neurosurgery University Hospital of Montpellier Gui de Chauliac Hospital Montpellier France

Department of Pediatrics Division of Child and Adolescent Neurology University of Texas at Houston Medical School Houston Texas USA

Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Departments of Neurology and Human Genetics Emory University School of Medicine Atlanta Georgia USA

Division of Clinical and Metabolic Genetics Department of Pediatrics University of Toronto The Hospital for Sick Children Toronto Ontario Canada

Division of Clinical and Metabolic Genetics The Hospital for Sick Children University of Toronto Toronto Ontario Canada

Edmond J Safra Program in Parkinson's Disease and the Department of Medicine Toronto Western Hospital and the University of Toronto Toronto Ontario Canada

Friedrich Baur Institute at the Department of Neurology University Hospital LMU Munich Munich Germany

German Center for Neurodegenerative Diseases Munich Munich Germany

Movement Disorders Unit Hospital Clinic of Barcelona European Reference Network for Rare Neurological Diseases Barcelona Spain

Munich Cluster for Systems Neurology Munich Munich Germany

Neurology Nicklaus Children's Hospital Miami Florida USA

Rare Disease Institute Division of Genetics and Metabolism Children's National Medical Center Washington District of Columbia USA

Research and Development Retrophin Inc San Diego California USA

See more in PubMed

Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden‐Spatz syndrome. Nat Genet 2001;28(4):345–349. PubMed

Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron accumulation. In: Geschwind DH, Paulson HL, Klein C, eds. Handb Clin Neurol. Amsterdam, The Netherlands: Elsevier BV; 2018:293–305. PubMed PMC

Marshall RD, Collins A, Escolar ML, et al. Diagnostic and clinical experience of patients with pantothenate kinase‐associated neurodegeneration. Orphanet J Rare Dis 2019;14(1):174. PubMed PMC

Hartig MB, Hortnagel K, Garavaglia B, et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol 2006;59(2):248–256. PubMed

Leonardi R, Zhang YM, Rock CO, Jackowski S. Coenzyme a: back in action. Prog Lipid Res 2005;44(2–3):125–153. PubMed

Di Meo I, Carecchio M, Tiranti V. Inborn errors of coenzyme a metabolism and neurodegeneration. J Inherit Metab Dis 2019;42(1):49–56. PubMed

Hortnagel K, Prokisch H, Meitinger T. An isoform of hPANK2, deficient in pantothenate kinase‐associated neurodegeneration, localizes to mitochondria. Hum Mol Genet 2003;12(3):321–327. PubMed

Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. Altered neuronal mitochondrial coenzyme a synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci 2005;25(3):689–698. PubMed PMC

Hogarth P, Kurian MA, Gregory A, et al. Consensus clinical management guideline for pantothenate kinase‐associated neurodegeneration (PKAN). Mol Genet Metab 2017;120(3):278–287. PubMed

Klopstock T, Tricta F, Neumayr L, et al. Safety and efficacy of deferiprone for pantothenate kinase‐associated neurodegeneration: a randomised, double‐blind, controlled trial and an open‐label extension study. Lancet Neurol 2019;18(7):631–642. PubMed

Elbaum D, Beconi MG, Monteagudo E, et al. Fosmetpantotenate (RE‐024), a phosphopantothenate replacement therapy for pantothenate kinase‐associated neurodegeneration: mechanism of action and efficacy in nonclinical models. PLoS One 2018;13(3):e0192028. PubMed PMC

Christou YP, Tanteles GA, Kkolou E, et al. Open‐label fosmetpantotenate, a phosphopantothenate replacement therapy in a single patient with atypical PKAN. Case Rep Neurol Med 2017;2017:3247034. PubMed PMC

Roa P, Stoeter P, Perez‐Then E, Santana M, Marshall RD. A pilot study of a potential phosphopantothenate replacement therapy in 2 patients with pantothenate kinase‐associated neurodegeneration. Int J Rare Dis Orphan Drugs 2017;2(2):1006.

Klopstock T, Escolar ML, Marshall RD, et al. The FOsmetpantotenate replacement therapy (FORT) randomized, double‐blind, placebo‐controlled pivotal trial: study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase‐associated neurodegeneration. Clin Trials 2019;16(4):410–418. PubMed PMC

Marshall RD, Collins A, Escolar ML, et al. A scale to assess activities of daily living in pantothenate kinase‐associated neurodegeneration. Mov Disord Clin Pract 2019;6(2):139–149. PubMed PMC

Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society‐sponsored revision of the unified Parkinson's disease rating scale (MDS‐UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008;23(15):2129–2170. PubMed

Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the Barry‐Albright dystonia scale. Dev Med Child Neurol 1999;41(6):404–411. PubMed

Monbaliu E, Ortibus E, Roelens F, et al. Rating scales for dystonia in cerebral palsy: reliability and validity. Dev Med Child Neurol 2010;52(6):570–575. PubMed

Sharma LK, Subramanian C, Yun M‐K, et al. A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat Commun 2018;9(1):4399. PubMed PMC

Jackowski S. Proposed therapies for pantothenate‐kinase‐associated neurodegeneration. J Exp Neurosci 2019;13:1179069519851118. PubMed PMC

Jeong SY, Hogarth P, Placzek A, et al. 4'‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. EMBO Mol Med 2019;11(12):e10489. PubMed PMC

Hartig MB, Prokisch H, Meitinger T, Klopstock T. Pantothenate kinase‐associated neurodegeneration. Curr Drug Targets EMBO Mol Med 2019;11(12):e10489. PubMed

Meyer E, Kurian MA, Hayflick SJ. Neurodegeneration with brain iron accumulation: genetic diversity and pathophysiological mechanisms. Annu Rev Genomics Hum Genet 2015;16:257–279. PubMed

Venco P, Dusi S, Valletta L, Tiranti V. Alteration of the coenzyme a biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes. Biochem Soc Trans 2014;42(4):1069–1074. PubMed

Hayflick SJ. Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans 2014;42(4):1063–1068. PubMed PMC

Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden‐Spatz syndrome. N Engl J Med 2003;348(1):33–40. PubMed

Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46(2):73–80. PubMed PMC

Zorzi G, Zibordi F, Chiapparini L, et al. Iron‐related MRI images in patients with pantothenate kinase‐associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 2011;26(9):1756–1759. PubMed