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A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial§

Authors

  • David R. Lynch MD, PhD,

    Corresponding author
    1. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3. Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    • Children's Hospital of Philadelphia, Division of Neurology, Abramson Research Center, Room 502, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA
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    • David R. Lynch, Steven M. Willi, and Robert B Wilson contributed equally to the present work.

  • Steven M. Willi MD,

    1. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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    • David R. Lynch, Steven M. Willi, and Robert B Wilson contributed equally to the present work.

  • Robert B. Wilson MD, PhD,

    1. Department of Pathology and Lab Medicine, University of Pennsylvania, Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • M. Grazia Cotticelli PhD,

    1. Department of Pathology and Lab Medicine, University of Pennsylvania, Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Karlla W. Brigatti MS,

    1. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3. Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Eric C. Deutsch BS,

    1. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3. Department of Pharmacology, University of Pennsylvania, Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Olena Kucheruk MPH,

    1. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • William Shrader PhD,

    1. Edison Pharmaceuticals, Mountain View, California, USA
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  • Patrice Rioux MD, PhD,

    1. Edison Pharmaceuticals, Mountain View, California, USA
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  • Guy Miller MD, PhD,

    1. Edison Pharmaceuticals, Mountain View, California, USA
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  • Amale Hawi PhD,

    1. Penwest Pharmaceuticals, Patterson, New York, USA
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  • Thomas Sciascia MD

    1. Penwest Pharmaceuticals, Patterson, New York, USA
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  • Funding agencies: The in vitro work in the present study was funded by the Friedreich Ataxia Research Alliance (to R.B.W.) and Penwest Pharmaceutical. The clinical trial was sponsored by Penwest Pharmaceuticals.

  • Relevant conflicts of interest/financial disclosures: David R. Lynch and Steven M. Willi received grant support from Penwest Pharmaceutical to perform the present trial. David R. Lynch has also received support for clinical trials from Edison Pharmaceutical and Santhera Pharmaceutical and is an unpaid consultant to Apopharma and Lundbeck. Thomas Sciascia and Amale Hawi were employed by Penwest at the time of the study. Guy Miller and William Shrader hold stock in Edison Pharmaceuticals, the owner of EPI-A0001. Guy Miller is an employee and receives 100% of his compensation from Edison Pharmaceuticals. William Shrader is a compensated consultant for Edison Pharmaceuticals. Patrice Rioux was previously employed by Edison Pharmaceuticals.

  • §

    Clinicaltrials.gov identifier: NCT01035671.

  • Full financial disclosures and author roles may be found in the online version of this article.

Abstract

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit. © 2012 Movement Disorder Society

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