Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia.

Abstract:

Objective:Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435). Methods:Sixty-nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5-300 mg/day. Results:Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day. Interpretation:Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.

journal_name

Ann Clin Transl Neurol

authors

Lynch DR,Farmer J,Hauser L,Blair IA,Wang QQ,Mesaros C,Snyder N,Boesch S,Chin M,Delatycki MB,Giunti P,Goldsberry A,Hoyle C,McBride MG,Nachbauer W,O'Grady M,Perlman S,Subramony SH,Wilmot GR,Zesiewicz T,Meyer C

doi

10.1002/acn3.660

subject

Has Abstract

pub_date

2018-11-10 00:00:00

pages

15-26

issue

1

issn

2328-9503

pii

ACN3660

journal_volume

6

pub_type

杂志文章,随机对照试验
  • Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy.

    abstract:OBJECTIVE:Trinucleotide GGC repeat expansion in the 5'UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51021

    authors: Fang P,Yu Y,Yao S,Chen S,Zhu M,Chen Y,Zou K,Wang L,Wang H,Xin L,Hong T,Hong D

    更新日期:2020-04-01 00:00:00

  • Rescue levodopa-carbidopa intestinal gel (LCIG) therapy in Parkinson's disease patients with suboptimal response to deep brain stimulation.

    abstract:OBJECTIVE:To evaluate the effectiveness of levodopa-carbidopa intestinal gel (LCIG) as an add-on rescue therapy following deep brain stimulation (DBS) for treatment of motor fluctuations. BACKGROUND:Both DBS and LCIG are FDA-approved therapies for treatment of motor fluctuations in advanced PD. Few studies have examin...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.50889

    authors: Elkouzi A,Ramirez-Zamora A,Zeilman P,Barabas M,Eisinger RS,Malaty IA,Okun MS,Almeida L

    更新日期:2019-10-01 00:00:00

  • Treatment of natalizumab-associated PML with filgrastim.

    abstract:Objective:There is no consensus on the treatment of progressive multifocal leukoencephalopathy (PML) occurring in multiple sclerosis (MS) patients treated with natalizumab (Nz). We report novel immune activating treatment with filgrastim of Nz-associated PML in MS patients treated at Rush University Medical Center. Me...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.776

    authors: Stefoski D,Balabanov R,Waheed R,Ko M,Koralnik IJ,Sierra Morales F

    更新日期:2019-04-08 00:00:00

  • Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience.

    abstract:OBJECTIVE:To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center. METHODS:We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used T...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51002

    authors: Beecroft SJ,Yau KS,Allcock RJN,Mina K,Gooding R,Faiz F,Atkinson VJ,Wise C,Sivadorai P,Trajanoski D,Kresoje N,Ong R,Duff RM,Cabrera-Serrano M,Nowak KJ,Pachter N,Ravenscroft G,Lamont PJ,Davis MR,Laing NG

    更新日期:2020-03-01 00:00:00

  • A single-center SCN8A-related epilepsy cohort: clinical, genetic, and physiologic characterization.

    abstract:OBJECTIVE:Pathogenic variants in SCN8A, encoding the voltage-gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single-tertiary care center, with biophysical data on identified Nav1.6 variants and ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.50839

    authors: Zaman T,Abou Tayoun A,Goldberg EM

    更新日期:2019-08-01 00:00:00

  • An image-based model of brain volume biomarker changes in Huntington's disease.

    abstract:Objective:Determining the sequence in which Huntington's disease biomarkers become abnormal can provide important insights into the disease progression and a quantitative tool for patient stratification. Here, we construct and present a uniquely fine-grained model of temporal progression of Huntington's disease from pr...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.558

    authors: Wijeratne PA,Young AL,Oxtoby NP,Marinescu RV,Firth NC,Johnson EB,Mohan A,Sampaio C,Scahill RI,Tabrizi SJ,Alexander DC

    更新日期:2018-04-02 00:00:00

  • Using urine to diagnose large-scale mtDNA deletions in adult patients.

    abstract:OBJECTIVE:The aim of this study was to evaluate if urinary sediment cells offered a robust alternative to muscle biopsy for the diagnosis of single mtDNA deletions. METHODS:Eleven adult patients with progressive external ophthalmoplegia and a known single mtDNA deletion were investigated. Urinary sediment cells were u...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51119

    authors: Varhaug KN,Nido GS,de Coo I,Isohanni P,Suomalainen A,Tzoulis C,Knappskog P,Bindoff LA

    更新日期:2020-08-01 00:00:00

  • Expression of IL-33 and its epigenetic regulation in Multiple Sclerosis.

    abstract::We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. Based on our previous studies we proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.47

    authors: Zhang F,Tossberg JT,Spurlock CF,Yao SY,Aune TM,Sriram S

    更新日期:2014-05-01 00:00:00

  • Plasma urate concentrations and possible REM sleep behavior disorder.

    abstract:OBJECTIVE:To examine how urate concentrations are related to the risk of having possible REM sleep behavior disorder (pRBD) in a community-based cohort. METHODS:The study included 12,923 Chinese adults of the Kailuan Study, free of Parkinson disease (PD) and dementia. Plasma urate concentrations were measured in 2006,...

    journal_title:Annals of clinical and translational neurology

    pub_type: 临床试验,杂志文章

    doi:10.1002/acn3.50929

    authors: Shen Y,Li J,Schwarzschild M,Pavlova M,He S,Ascherio A,Wu S,Cui L,Gao X

    更新日期:2019-12-01 00:00:00

  • White matter predicts functional connectivity in premanifest Huntington's disease.

    abstract:OBJECTIVES:The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and functi...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.384

    authors: McColgan P,Gregory S,Razi A,Seunarine KK,Gargouri F,Durr A,Roos RA,Leavitt BR,Scahill RI,Clark CA,Tabrizi SJ,Rees G,Track On‐HD Investigators.,Coleman A,Decolongon J,Fan M,Petkau T,Jauffret C,Justo D,Lehericy S,Ni

    更新日期:2017-01-16 00:00:00

  • Biomarkers for REM sleep behavior disorder in idiopathic and narcoleptic patients.

    abstract::To search for discriminating biomarkers, 30 patients with idiopathic rapid-eye-movements sleep behavior disorder (iRBD) were compared with 17 patients with RBD within narcolepsy type 1. Both groups underwent extensive examinations, including skin biopsy searching for phosphorylated α-synuclein deposits and whole-night...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.50833

    authors: Antelmi E,Pizza F,Donadio V,Filardi M,Sosero YL,Incensi A,Vandi S,Moresco M,Ferri R,Marelli S,Ferini-Strambi L,Liguori R,Plazzi G

    更新日期:2019-09-01 00:00:00

  • Isradipine plasma pharmacokinetics and exposure-response in early Parkinson's disease.

    abstract:OBJECTIVES:Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of israd...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51300

    authors: Venuto CS,Yang L,Javidnia M,Oakes D,James Surmeier D,Simuni T

    更新日期:2021-01-18 00:00:00

  • Obesity and the risk of Multiple Sclerosis. The role of Leptin.

    abstract:OBJECTIVE:To investigate the effects of leptin on different T-cell populations, in order to gain more insight into the link between leptin and obesity. METHODS:Three hundred and nine RRMS patients and 322 controls participated in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or earl...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51291

    authors: Marrodan M,Farez MF,Balbuena Aguirre ME,Correale J

    更新日期:2020-12-28 00:00:00

  • Plasma neuronal exosomal levels of Alzheimer's disease biomarkers in normal aging.

    abstract::Plasma neuronal exosomal levels of pathogenic Alzheimer's disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.309

    authors: Abner EL,Jicha GA,Shaw LM,Trojanowski JQ,Goetzl EJ

    更新日期:2016-04-13 00:00:00

  • Screening of conventional anticonvulsants in a genetic mouse model of epilepsy.

    abstract:OBJECTIVE:Epilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.413

    authors: Hawkins NA,Anderson LL,Gertler TS,Laux L,George AL Jr,Kearney JA

    更新日期:2017-04-26 00:00:00

  • A plasma diagnostic model of human T-cell leukemia virus-1 associated myelopathy.

    abstract:OBJECTIVE:Human T-cell leukemia virus-1 (HTLV-1) associated myelopathy/tropic spastic paraparesis (HAM/TSP) is induced by chronic inflammation in spinal cord due to HTLV-1 infection. Cerebrospinal fluid (CSF) neopterin or proviral load are clinically measured as disease grading biomarkers, however, they are not exactly...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.169

    authors: Ishihara M,Araya N,Sato T,Saichi N,Fujii R,Yamano Y,Ueda K

    更新日期:2015-03-01 00:00:00

  • Altered cortical thickness following prenatal sodium valproate exposure.

    abstract::Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.74

    authors: Wood AG,Chen J,Barton S,Nadebaum C,Anderson VA,Catroppa C,Reutens DC,O'Brien TJ,Vajda F

    更新日期:2014-07-01 00:00:00

  • Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5.

    abstract:OBJECTIVES:To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan. METHODS:Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51019

    authors: Chou CT,Soong BW,Lin KP,Tsai YS,Jih KY,Liao YC,Lee YC

    更新日期:2020-04-01 00:00:00

  • Dissociated multimodal hubs and seizures in temporal lobe epilepsy.

    abstract:OBJECTIVE:Brain connectivity at rest is altered in temporal lobe epilepsy (TLE), particularly in "hub" areas such as the posterior default mode network (DMN). Although both functional and anatomical connectivity are disturbed in TLE, the relationships between measures as well as to seizure frequency remain unclear. We ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.173

    authors: Douw L,DeSalvo MN,Tanaka N,Cole AJ,Liu H,Reinsberger C,Stufflebeam SM

    更新日期:2015-04-01 00:00:00

  • Serum neurofilament levels and patient-reported outcomes in multiple sclerosis.

    abstract:OBJECTIVE:Serum neurofilament light (sNfL) is a promising new biomarker in multiple sclerosis (MS). We explored the relationship between sNfL and health outcomes and resource use in MS patients. METHODS:MS patients with serum samples and health-outcome measurements collected longitudinally between 2011 and 2016 were a...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51305

    authors: Galetta K,Deshpande C,Healy BC,Glanz B,Ziehn M,Saxena S,Paul A,Saleh F,Collins M,Gaitan-Walsh P,Castro-Mendoza P,Weiner HL,Chitnis T

    更新日期:2021-01-25 00:00:00

  • Behavioral profile of unruptured intracranial aneurysms: a systematic review.

    abstract:OBJECTIVES:To systematically review the literature on the neuropsychological, psychosocial, and functional profiles of patients with unruptured intracranial aneurysms. METHODS:This review was limited to peer-reviewed research articles that reported cognitive, psychosocial, and/or functional profiles of patients with u...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.41

    authors: Bonares MJ,de Oliveira Manoel AL,Macdonald RL,Schweizer TA

    更新日期:2014-03-01 00:00:00

  • Impact of stroke mechanism in acute basilar occlusion with reperfusion therapy.

    abstract:Objective:We aimed to evaluate the impact of underlying mechanism of basilar artery (BA) occlusion on the outcomes after endovascular therapy (EVT) for reperfusion and the outcome factors associated with each mechanism, and to identify radiologic parameters enabling to distinguish the underlying mechanism. Methods:Fro...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.536

    authors: Lee WJ,Jung KH,Ryu YJ,Kim JM,Lee ST,Chu K,Kim M,Lee SK,Sohn CH,Roh JK

    更新日期:2018-01-30 00:00:00

  • Divergent neural responses to narrative speech in disorders of consciousness.

    abstract:Objective:Clinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ intersubject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls. Methods...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.470

    authors: Iotzov I,Fidali BC,Petroni A,Conte MM,Schiff ND,Parra LC

    更新日期:2017-09-27 00:00:00

  • Infectious risk stratification in multiple sclerosis patients receiving immunotherapy.

    abstract::The increasing number of potent treatments for multiple sclerosis warrants screening for infections. To investigate the prevalence of infections in two independent German patient cohorts with multiple sclerosis/neuromyelitis optica spectrum disorders (NMOSD), we performed a retrospective chart review study of multiple...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.491

    authors: Graf J,Leussink VI,Dehmel T,Ringelstein M,Goebels N,Adams O,MacKenzie CR,Warnke C,Feldt T,Lammerskitten A,Klotz L,Meuth S,Wiendl H,Hartung HP,Aktas O,Albrecht P

    更新日期:2017-11-24 00:00:00

  • Longitudinal advanced MRI case report of white matter radiation necrosis.

    abstract::Radiation necrosis mostly occurs in and near the radiation field. We used magnetic resonance imaging to study radiation-induced necrosis of atypical onset, severity, and extent following stereotactic radiosurgery for a symptomatic arteriovenous malformation. Susceptibility-sensitive imaging, T1-relaxation, myelin wate...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.704

    authors: Wiggermann V,Lapointe E,Litvin L,Graf C,Hernández-Torres E,McKenzie M,Vavasour IM,Laule C,MacMillan EL,Li DKB,Kolind SH,Rauscher A,Traboulsee AL

    更新日期:2018-12-10 00:00:00

  • Accuracy of FGF-21 and GDF-15 for the diagnosis of mitochondrial disorders: A meta-analysis.

    abstract:OBJECTIVE:Given their diverse phenotypes, mitochondrial diseases (MDs) are often difficult to diagnose. Fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) represent promising biomarkers for MD diagnosis. Herein we conducted a meta-analysis to compare their diagnostic accuracy for MDs. M...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.51104

    authors: Lin Y,Ji K,Ma X,Liu S,Li W,Zhao Y,Yan C

    更新日期:2020-07-01 00:00:00

  • RNAseq analysis for the diagnosis of muscular dystrophy.

    abstract::The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in clinical genetic diagnostics, including the application of whole-exome sequencing and next-generation sequencing-based ge...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.267

    authors: Gonorazky H,Liang M,Cummings B,Lek M,Micallef J,Hawkins C,Basran R,Cohn R,Wilson MD,MacArthur D,Marshall CR,Ray PN,Dowling JJ

    更新日期:2015-12-08 00:00:00

  • Metabotropic glutamate receptor 5: a target for migraine therapy.

    abstract:INTRODUCTION:Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine-specific target, ...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.302

    authors: Waung MW,Akerman S,Wakefield M,Keywood C,Goadsby PJ

    更新日期:2016-07-01 00:00:00

  • Improved diagnosis of Parkinson's disease from a detailed olfactory phenotype.

    abstract:OBJECTIVE:To assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease. METHODS:We analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological s...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.447

    authors: Gerkin RC,Adler CH,Hentz JG,Shill HA,Driver-Dunckley E,Mehta SH,Sabbagh MN,Caviness JN,Dugger BN,Serrano G,Belden C,Smith BH,Sue L,Davis KJ,Zamrini E,Beach TG

    更新日期:2017-09-08 00:00:00

  • Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain.

    abstract:OBJECTIVE:The mechanism of action of anti-B cell therapy in multiple sclerosis (MS) is not fully understood. Here, we compared the effect of anti-CD20 therapy on microglial activation in two distinct focal rat models of MS. METHODS:The effect of anti-CD20 therapy on lesion formation and extralesional microglial activa...

    journal_title:Annals of clinical and translational neurology

    pub_type: 杂志文章

    doi:10.1002/acn3.94

    authors: Anthony DC,Dickens AM,Seneca N,Couch Y,Campbell S,Checa B,Kersemans V,Warren EA,Tredwell M,Sibson NR,Gouverneur V,Leppert D

    更新日期:2014-09-01 00:00:00