Safety and efficacy of (+)-epicatechin in subjects with Friedreich's ataxia: A phase II, open-label, prospective study.
Friedreich ataxia
ataxia
epicatechin
hypertrophy, left ventricular
motor
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
revised:
23
06
2020
received:
15
04
2020
accepted:
13
07
2020
pubmed:
18
7
2020
medline:
25
12
2021
entrez:
18
7
2020
Statut:
ppublish
Résumé
(+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA). This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events. (+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin.
Sections du résumé
BACKGROUND
(+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA).
METHODS
This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy.
RESULTS
Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events.
CONCLUSION
(+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes.
SYNOPSIS
A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin.
Substances chimiques
Antioxidants
0
Catechin
8R1V1STN48
Banques de données
ClinicalTrials.gov
['NCT02660112']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
502-514Informations de copyright
© 2020 SSIEM.
Références
Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423-1427. https://doi.org/10.1126/science.271.5254.1423.
Puccio H, Koenig M. Friedreich ataxia: a paradigm for mitochondrial diseases. Curr Opin Genet Dev. 2002;12(3):272-277. https://doi.org/10.1016/s0959-437x(02)00298-8.
Vaubel RA, Isaya G. Iron-sulfur cluster synthesis, iron homeostasis and oxidative stress in Friedreich ataxia. Mol Cell Neurosci. 2013;55:50-61. https://doi.org/10.1016/j.mcn.2012.08.003.
Bradley JL, Homayoun S, Hart PE, Schapira AH, Cooper JM. Role of oxidative damage in Friedreich's ataxia. Neurochem Res. 2004;29(3):561-567. https://doi.org/10.1023/b:nere.0000014826.00881.c3.
Schulz JB, Dehmer T, Schols L, et al. Oxidative stress in patients with Friedreich ataxia. Neurology. 2000;55(11):1719-1721. https://doi.org/10.1212/wnl.55.11.1719.
Moreno-Ulloa A, Nogueira L, Rodriguez A, et al. Recovery of indicators of mitochondrial biogenesis, oxidative stress, and aging with (−)-epicatechin in senile mice. J Gerontol A Biol Sci Med Sci. 2015;70(11):1370-1378. https://doi.org/10.1093/gerona/glu131.
Fraga CG, Oteiza PI, Galleano M. Plant bioactives and redox signaling: (−)-epicatechin as a paradigm. Mol Aspects Med. 2018;61:31-40. https://doi.org/10.1016/j.mam.2018.01.007.
La Rosa P, Bertini ES, Piemonte F. The NRF2 signaling network defines clinical biomarkers and therapeutic opportunity in Friedreich's ataxia. Int J Mol Sci. 2020;21(3):916. https://doi.org/10.3390/ijms21030916.
Nogueira L, Ramirez-Sanchez I, Perkins GA, et al. (−)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. J Physiol. 2011;589(Pt 18):4615-4631. https://doi.org/10.1113/jphysiol.2011.209924.
Malik V, Rodino-Klapac LR, Mendell JR. Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs. 2012;17(2):261-277. https://doi.org/10.1517/14728214.2012.691965.
Huttemann M, Lee I, Malek MH. Epicatechin maintains endurance training adaptation in mice after 14 days of detraining. FASEB J. 2012;26(4):1413-1422. https://doi.org/10.1096/fj.11-196154.
Shay J, Elbaz HA, Lee I, Zielske SP, Malek MH, Huttemann M. Molecular mechanisms and therapeutic effects of (−)-epicatechin and other polyphenols in cancer, inflammation, diabetes, and neurodegeneration. Oxid Med Cell Longev. 2015;2015:1-13. https://doi.org/10.1155/2015/181260.
Ramirez-Sanchez I, De los Santos S, Gonzalez-Basurto S, et al. (−)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic delta-sarcoglycan null mouse striated muscle. FEBS J. 2014;281(24):5567-5580. https://doi.org/10.1111/febs.13098.
Barnett CF, Moreno-Ulloa A, Shiva S, et al. Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (−)-epicatechin in healthy volunteers. Food Funct. 2015;6(3):824-833. https://doi.org/10.1039/c4fo00596a.
Taub PR, Ramirez-Sanchez I, Ciaraldi TP, et al. Perturbations in skeletal muscle sarcomere structure in patients with heart failure and type 2 diabetes: restorative effects of (−)-epicatechin-rich cocoa. Clin Sci (Lond). 2013;125(8):383-389. https://doi.org/10.1042/CS20130023.
Taub PR, Ramirez-Sanchez I, Ciaraldi TP, et al. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa. Clin Transl Sci. 2012;5(1):43-47. https://doi.org/10.1111/j.1752-8062.2011.00357.x.
Gutierrez-Salmean G, Ciaraldi TP, Nogueira L, et al. Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation. J Nutr Biochem. 2014;25(1):91-94. https://doi.org/10.1016/j.jnutbio.2013.09.007.
Yamazaki KG, Taub PR, Barraza-Hidalgo M, et al. Effects of (−)-epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion. J Am Coll Cardiol. 2010;55(25):2869-2876. https://doi.org/10.1016/j.jacc.2010.01.055.
Shah ZA, Li RC, Ahmad AS, et al. The flavanol (−)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J Cereb Blood Flow Metab. 2010;30(12):1951-1961. https://doi.org/10.1038/jcbfm.2010.53.
Ramirez-Sanchez I, Taub PR, Ciaraldi TP, et al. (−)-Epicatechin rich cocoa mediated modulation of oxidative stress regulators in skeletal muscle of heart failure and type 2 diabetes patients. Int J Cardiol. 2013;168(4):3982-3990. https://doi.org/10.1016/j.ijcard.2013.06.089.
Leonardo CC, Agrawal M, Singh N, Moore JR, Biswal S, Dore S. Oral administration of the flavanol (−)-epicatechin bolsters endogenous protection against focal ischemia through the Nrf2 cytoprotective pathway. Eur J Neurosci. 2013;38(11):3659-3668. https://doi.org/10.1111/ejn.12362.
Nath S, Bachani M, Harshavardhana D, Steiner JP. Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway. J Neurovirol. 2012;18(6):445-455. https://doi.org/10.1007/s13365-012-0122-1.
McDonald C, Henricson E, Oskarsson B, et al. Epicatechin enhances mitochondrial biogenesis, increases dystrophin and utrophin, increases follistatin while decreasing myostatin, and improves skeletal muscle exercise response in adults with Becker muscular dystrophy. Neuromuscul Disord. 2015;25:S314-S315. https://doi.org/10.1016/j.nmd.2015.06.456.
ClinicalTrials.gov (−)-Epicatechin Becker Muscular Dystrophy. 2018.
Israel Ramirez-Sanchez GC, Moreno-Ulloa A, Ciaraldi TP, Henry RR, Villareal F. Evaluation and Comparison of Epicatechin Epimer Effects on Skeletal Muscle Structure, Function, and Regulators of Metabolism. American Diabetes Association 74th Scientific Sessions. San Francisco, CA; Diabetes. 2014;63(Suppl. 1):GPS01.
Moreno-Ulloa A, Najera-Garcia N, Hernandez M, et al. A pilot study on clinical pharmacokinetics and preclinical pharmacodynamics of (+)-epicatechin on cardiometabolic endpoints. Food Funct. 2018;9(1):307-319. https://doi.org/10.1039/c7fo01028a.
Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PC. Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-controlled, crossover trial. Am J Clin Nutr. 2015;101(5):914-921. https://doi.org/10.3945/ajcn.114.098590.
Lynch DR, Farmer JM, Tsou AY, et al. Measuring Friedreich ataxia: complementary features of examination and performance measures. Neurology. 2006;66(11):1711-1716. https://doi.org/10.1212/01.wnl.0000218155.46739.90.
Lynch DR, Farmer JM, Wilson RL, Balcer LJ. Performance measures in Friedreich ataxia: potential utility as clinical outcome tools. Mov Disord. 2005;20(7):777-782. https://doi.org/10.1002/mds.20449.
Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64(7):1261-1262. https://doi.org/10.1212/01.WNL.0000156802.15466.79.
Trouillas P, Takayanagi T, Hallett M, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145(2):205-211. https://doi.org/10.1016/s0022-510x(96)00231-6.
Rezende TJR, Martinez ARM, Faber I, et al. Developmental and neurodegenerative damage in Friedreich's ataxia. Eur J Neurol. 2019;26(3):483-489. https://doi.org/10.1111/ene.13843.
Li XH, Wu F, Zhao F, Huang SL. Fractional anisotropy is a marker in early-stage spinal cord injury. Brain Res. 2017;1672:44-49. https://doi.org/10.1016/j.brainres.2017.07.024.
Patel M, Isaacs CJ, Seyer L, et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016;3(9):684-694. https://doi.org/10.1002/acn3.332.
Rummey C, Corben LA, Delatycki MB, et al. Psychometric properties of the Friedreich Ataxia Rating Scale. Neurol Genet. 2019;5(6):371. https://doi.org/10.1212/NXG.0000000000000371.
Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology. 2003;60(10):1676-1679. https://doi.org/10.1212/01.wnl.0000055872.50364.fc.
Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6(10):878-886. https://doi.org/10.1016/S1474-4422(07)70220-X.
Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch Neurol. 2010;67(8):941-947. https://doi.org/10.1001/archneurol.2010.168.
Zesiewicz T, Salemi JL, Perlman S, et al. Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia. Neurodegener Dis Manag. 2018;8(4):233-242. https://doi.org/10.2217/nmt-2018-0013.
Li L, Voullaire L, Sandi C, et al. Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia. PLoS One. 2013;8(2):e55940. https://doi.org/10.1371/journal.pone.0055940.
Yiu EM, Tai G, Peverill RE, et al. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J Neurol. 2015;262(5):1344-1353. https://doi.org/10.1007/s00415-015-7719-2.
Meier T, Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009;256(Suppl 1):25-30. https://doi.org/10.1007/s00415-009-1005-0.
Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring. Neurology. 2003;60(10):1679-1681. https://doi.org/10.1212/01.wnl.0000068549.52812.0f.
Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hypertrophy in Friedreich's ataxia. Heart. 2002;87(4):346-349. https://doi.org/10.1136/heart.87.4.346.
Ribai P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol. 2007;64(4):558-564. https://doi.org/10.1001/archneur.64.4.558.
Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A. Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Lancet. 1999;354(9177):477-479. https://doi.org/10.1016/S0140-6736(99)01341-0.
Pineda M, Arpa J, Montero R, et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur J Paediatr Neurol. 2008;12(6):470-475. https://doi.org/10.1016/j.ejpn.2007.11.006.
Artuch R, Aracil A, Mas A, et al. Friedreich's ataxia: idebenone treatment in early stage patients. Neuropediatrics. 2002;33(4):190-193. https://doi.org/10.1055/s-2002-34494.
Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009;39(3):283-296. https://doi.org/10.1002/mus.21244.
Gibb CM, Davies PT, Glover V, Steiner TJ, Clifford Rose F, Sandler M. Chocolate is a migraine-provoking agent. Cephalalgia. 1991;11(2):93-95. https://doi.org/10.1046/j.1468-2982.1991.1102093.x.
Katz DL, Doughty K, Ali A. Cocoa and chocolate in human health and disease. Antioxid Redox Signal. 2011;15(10):2779-2811. https://doi.org/10.1089/ars.2010.3697.