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The Cerebellum
Published in: The Cerebellum 5/2013

01-10-2013 | Original Paper

Triple Therapy with Darbepoetin Alfa, Idebenone, and Riboflavin in Friedreich’s Ataxia: an Open-Label Trial

Authors: Javier Arpa, Irene Sanz-Gallego, Francisco J. Rodríguez-de-Rivera, Francisco J. Domínguez-Melcón, Daniel Prefasi, Javier Oliva-Navarro, Mar Moreno-Yangüela, Samuel I. Pascual-Pascual

Published in: The Cerebellum | Issue 5/2013

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Abstract

Minimal objective evidence exists regarding management of Friedreich’s ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy—darbepoetin alfa, idebenone, and riboflavin—in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m2 in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 μg darbepoetin alfa every 2 or 3 weeks, 10–20 mg/kg/day idebenone, and 10–15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8–56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.
Literature
1.
Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335:1169–75.PubMedCrossRef
2.
Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain. 1998;121:589–600.PubMedCrossRef
3.
Schulz JB, Boesch S, Bürk K, Dürr A, Giunti P, Mariotti C, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5:222–34.PubMedCrossRef
4.
Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and interfamilial clustering of clinical features. Brain. 1981;104:589–620.PubMedCrossRef
5.
Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307:46–9.PubMedCrossRef
6.
Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–7.PubMedCrossRef
7.
Christodoulou K, Deymeer F, Serdaroglu P, Ozdemir C, Poda M, Georgiou DM, et al. Mapping of the second Friedreich’s ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity. Neurogenetics. 2001;3:127–32.PubMedCrossRef
8.
Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet. 1997;16:345–51.PubMedCrossRef
9.
Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997;60:1251–6.PubMed
10.
Cossee M, Campuzano V, Koutnikova H, Fischbeck K, Mandel JL, Koenig M, et al. Frataxin fracas. Nat Genet. 1997;15:337–8.PubMedCrossRef
11.
Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, et al. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998;1:253–7.PubMedCrossRef
12.
Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich’s ataxia patient: implications for diagnosis and carrier studies. Am J Med Genet. 1998;79:396–9.PubMedCrossRef
13.
Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999;45:200–6.PubMedCrossRef
14.
Zuhlke C, Laccone F, Cossee M, Kohlschutter A, Koenig M, Schwinger E. Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. Hum Genet. 1998;103:102–5.PubMedCrossRef
15.
De Castro M, Garcia-Planells J, Monros E, Canizares J, Vazquez-Manrique R, Vilchez JJ, et al. Genotype and phenotype analysis of Friedreich’s ataxia compound heterozygous patients. Hum Genet. 2000;106:86–92.PubMedCrossRef
16.
Pook MA, Al-Mahdawi SA, Thomas NH, Appleton R, Norman A, Mountford R, et al. Identification of three novel frameshift mutations in patients with Friedreich’s ataxia. J Med Genet. 2000;37:E38.PubMedCrossRef
17.
Marmolino D, Acquaviva F. Friedreich’s ataxia: from the (GAA)n repeat mediated silencing to new promising molecules for therapy. Cerebellum. 2009;8:245–59.PubMedCrossRef
18.
Tsou AY, Friedman LS, Wilson RB, Lynch DR. Pharmacotherapy for Friedreich ataxia. CNS Drugs. 2009;23:213–23.PubMedCrossRef
19.
Mancuso M, Orsucci D, Choub A, Siciliano G. Current and emerging treatment options in the management of Friedreich ataxia. Neuropsychiatr Dis Treat. 2010;6:491–9.PubMedCrossRef
20.
Sturm B, Stupphann D, Kaun C, Boesch S, Schranzhofer M, Wojta J, et al. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest. 2005;35:711–7.PubMedCrossRef
21.
Lodi R, Hart PE, Rajagopalan B, Taylor DJ, Crilley JG, Bradley JL, et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol. 2001;49:590–6.PubMedCrossRef
22.
Hart PE, Lodi R, Rajagopalan B, Bradley JL, Crilley JG, Turner C, et al. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol. 2005;62:621–6.PubMedCrossRef
23.
Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur J Neurol. 2008;15:1371–9.PubMedCrossRef
24.
Hausse AO, Aggoun Y, Bonnet D, Sidi D, Munnich A, Rötig A, et al. Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart. 2002;87:346–9.PubMedCrossRef
25.
Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, et al. Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology. 2003;60:1679–81.PubMedCrossRef
26.
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;60:1676–9.PubMedCrossRef
27.
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;6:878–86.PubMedCrossRef
28.
Pineda M, Arpa J, Montero R, Aracil A, Domínguez F, Galván M, et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur J Paediatr Neurol. 2008;12:470–5.PubMedCrossRef
29.
Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch Neurol. 2010;67:941–7.PubMedCrossRef
30.
Lagedrost SJ, Sutton MS, Cohen MS, Satou GM, Kaufman BD, Perlman SL, et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am Heart J. 2011;161:639–45.PubMedCrossRef
31.
González-Cabo P, Vázquez-Manrique RP, García-Gimeno MA, Sanz P, Palau F. Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum Mol Genet. 2005;14:2091–8.PubMedCrossRef
32.
Gonzalez-Cabo P, Ros S, Palau F. Flavin adenine dinucleotide rescues the phenotype of frataxin deficiency. PLoS One. 2010;5:e8872.PubMedCrossRef
33.
Subramony SH. SARA—a new clinical scale for the assessment and rating of ataxia. Nat Clin Pract Neurol. 2007;3:136–7.PubMedCrossRef
34.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–63.PubMedCrossRef
35.
Meier T, Perlman SL, Rummey C, Coppard NJ, Lynch DR. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol. 2012;259:284–91.PubMedCrossRef
36.
37.
Acquaviva F, Castaldo I, Filla A, Giacchetti M, Marmolino D, Monticelli A, et al. Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression. Cerebellum. 2008;7:360–5.PubMedCrossRef
38.
Boesch S, Sturm B, Hering S, Goldenberg H, Poewe W, Scheiber-Mojdehkar B. Friedreich’s ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol. 2007;62:521–4.PubMedCrossRef
39.
Boesch S, Sturm B, Hering S, Scheiber-Mojdehkar B, Steinkellner H, Goldenberg H, et al. Neurological effects of recombinant human erythropoietin in Friedreich’s ataxia: a clinical pilot trial. Mov Disord. 2008;23:1940–4.PubMedCrossRef
40.
Saccà F, Piro R, De Michele G, Acquaviva F, Antenora A, Carlomagno G, et al. Epoetin alfa increases frataxin production in Friedreich’s ataxia without affecting hematocrit. Mov Disord. 2011;26:739–42.PubMedCrossRef
41.
Mariotti C, Fancellu R, Caldarazzo S, Nanetti L, Di Bella D, Plumari M, et al. Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov Disord. 2012;27:446–9.PubMedCrossRef
42.
Sturm B, Helminger M, Steinkellner H, Heidari MM, Goldenberg H, Scheiber-Mojdehkar B. Carbamylated erythropoietin increases frataxin independent from the erythropoietin receptor. Eur J Clin Invest. 2010;40:561–5.PubMedCrossRef
Metadata
Title
Triple Therapy with Darbepoetin Alfa, Idebenone, and Riboflavin in Friedreich’s Ataxia: an Open-Label Trial
Authors
Javier Arpa
Irene Sanz-Gallego
Francisco J. Rodríguez-de-Rivera
Francisco J. Domínguez-Melcón
Daniel Prefasi
Javier Oliva-Navarro
Mar Moreno-Yangüela
Samuel I. Pascual-Pascual
Publication date
01-10-2013
Publisher
Springer US
Published in
The Cerebellum / Issue 5/2013
Print ISSN: 1473-4222
Electronic ISSN: 1473-4230
DOI
https://doi.org/10.1007/s12311-013-0482-y

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