Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia

被引:19
作者
Pandolfo, Massimo [1 ,2 ]
Reetz, Kathrin [3 ,4 ]
Darling, Alejandra [5 ]
de Rivera, Francisco Javier Rodriguez [6 ]
Henry, Pierre-Gilles [7 ]
Joers, James [7 ]
Lenglet, Christophe [7 ]
Adanyeguh, Isaac [7 ]
Deelchand, Dinesh [7 ]
Mochel, Fanny [8 ,9 ]
Pousset, Francoise [10 ,11 ,12 ]
Pascual, Silvia [13 ]
Van den Eede, Delphine [14 ]
Martin-Ugarte, Itziar [13 ]
Vila-Brau, Anna [13 ]
Mantilla, Adriana [13 ]
Pascual, Maria [13 ]
Martinell, Marc [13 ]
Meya, Uwe [13 ]
Durr, Alexandra [15 ]
机构
[1] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada
[2] Univ Libre Bruxelles, Brussels, Belgium
[3] Rhein Westfal TH Aachen, Dept Neurol, Aachen, Germany
[4] Forschungszentrum Julich, JARA BRAIN Inst Mol Neurosci & Neuroimaging, Julich, Germany
[5] Hosp St Joan de Deu, Barcelona, Spain
[6] La Paz Univ Hosp, Madrid, Spain
[7] Univ Minnesota, Ctr Magnet Resonance Res, Dept Radiol, Minneapolis, MN USA
[8] Sorbonne Univ, Inst Cerveau ICM, Paris, France
[9] Grp Hosp Pitie Salpetriere, AP HP, Dept Genet, Paris, France
[10] Sorbonne Univ, Pitie Salpetriere Univ Hosp, AP HP, Dept Cardiol, Paris, France
[11] Hop La Pitie Salpetriere, Inst Cardiometab & Nutr ICAN, Paris, France
[12] URC Lariboisiere Univ Hosp, Allies Cardiovasc Trials Initiat & Organized Netw, Paris, France
[13] Minoryx Therapeut SL, Barcelona, Spain
[14] Minoryx Therapeut BE, Charleroi, Belgium
[15] Sorbonne Univ, Paris Brain Inst, CNRS, INSERM,AP HP, Paris, France
关键词
FAT DISTRIBUTION; MITOCHONDRIAL BIOGENESIS; INSULIN SENSITIVITY; THIAZOLIDINEDIONE; FRATAXIN; PIOGLITAZONE; PROGRESSION; MECHANISMS; DISEASE; IRON;
D O I
10.1212/NXG.0000000000200034
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background and Objectives Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor. agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study. Methods In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset >= 25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myoinositol (tNAA/mIns) ratio. Results Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, -0.39 [0.55] mm(2); placebo, 0.08 [0.72] mm(2); p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%). Discussion The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA. Trial Registration Information ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1. Classification of Evidence This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.
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页数:13
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