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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. This is a retrospective, longitudinal cohort study of 78 children (<18 years) with FA-HCM diagnosed over four decades, from the UK. Anonymized retrospective demographic and clinical data were collected from baseline evaluation and follow-up. The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

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NeuroVoices: David R. Lynch, MD, PhD, on the First Potentially Approved Friedreich Ataxia Treatment

The professor of neurology at the University of Pennsylvania Perelman School of Medicine discussed the state of care for Friedrich ataxia and omaveloxolone’s potential to become its first approved therapy.

David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine David R. Lynch, MD, PhD

Friedreich ataxia, a rare, inherited, degenerative disease that damages the spinal cord, peripheral nerves, and cerebellum portion of the brain, currently has no FDA-approved therapies available to treat it.1 Although, a therapy with the potential to fill this gap in care has emerged from the pipeline in recent months.

Omaveloxolone (Reata Pharmaceuticals), has shown potential for this patient population after an analysis from the phase 2 MOXIe trial (NCT02255435) revealed a significant difference in modified Friedrich’s Ataxia Rating Scale (mFARS) of –2.18 points (±0.96) between treatment with omaveloxolone and placebo groups.2 Lead author David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, told NeurologyLive that he believes there is good reason to hold out hope in this drug.

Lynch connected with NeurologyLive for a new iteration of NeuroVoices to discuss the findings from the MOXIe trial, why the mechanistic action of omaveloxolone makes it so effective to treat these patients, and whether it has legitimate potential to break through the treatment landscape.

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Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

Cardiac dysfunction pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood in Friedreich's ataxia (FRDA), though are expected to be linked to an energy deficit. The authors modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. These results suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

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Reata Pharmaceuticals Plans NDA Submission for Omaveloxolone in First Quarter of 2022 Following Completion of Pre-NDA Meeting with FDA

Approximately 5,000 Children and Adults in the United States and 22,000 Globally Are Affected with Friedreich’s Ataxia, a Life-Threatening Disease with No Approved Therapies

PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it has completed its pre-New Drug Application (“NDA”) meeting with the United States Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia and reaffirmed its plan to submit an NDA in the first quarter of 2022.

The purpose of the pre-NDA meeting was to discuss the content of Reata’s planned NDA submission. We plan to submit the NDA seeking standard approval for omaveloxolone for the treatment of Friedrich’s ataxia. We are not planning to conduct a second pre-approval clinical study prior to the submission. The FDA indicated that the appropriate approval pathway would be a matter of review after submission of the NDA. In response to our questions about the contents of the filing and because of the seriousness of the indication, the FDA exercised its discretion subject to review to permit us to submit the results of certain nonclinical and clinical studies after approval.

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Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub-second dynamics of resting-state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA-related changes in resting-state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting-state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12-51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median-split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo-parietal junctions (TPJ). FRDA patients with an ASO <11 years presented altered temporal dynamics of those two HMM states compared with FRDA patients with an ASO >11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub-second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub-second network activity and functional brain integration over long timescales.

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