Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data.

INTRODUCTION: Friedreich ataxia (FRDA) is a rare autosomal recessive disease, marked by loss of coordination as well as impaired neurological, endocrine, orthopedic, and cardiac function. There are many symptomatic medications for FRDA, and many clinical trials have been performed, but only one FDA-approved medication exists. AREAS COVERED: The relative absence of the frataxin protein (FXN) in FRDA causes mitochondrial dysfunction, resulting in clinical manifestations. Currently, the only approved treatment for FRDA is an Nrf2 activator called omaveloxolone (Skyclarys). Patients with FRDA also rely on various symptomatic medications for treatment. Because there is only one approved medication for FRDA, clinical trials continue to advance in FRDA. Although some trials have not met their endpoints, many current and upcoming clinical trials provide exciting possibilities for the treatment of FRDA. EXPERT OPINION: The approval of omaveloxolone provides a major advance in FRDA therapeutics. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring, disease-modifying therapy in the future.

Expression and processing of mature human frataxin after gene therapy in mice.

Friedreich's ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN. However, unlike endogenous hFXN, endogenous mFXN is further processed into N-terminally truncated, extra-mitochondrial mFXN forms of unknown function. This study assessed mature exogenous hFXN expression levels in the heart and liver of C57Bl/6 mice 7-10 months after intravenous administration of a recombinant adeno-associated virus encoding hFXN (AAVrh.10hFXN) and examined the potential for hFXN truncation in mice. AAVrh.10hFXN induced dose-dependent expression of hFXN in the heart and liver. Interestingly, hFXN was processed into truncated forms, but found at lower levels than mature hFXN. However, the truncations were at different positions than mFXN. AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia.

OBJECTIVE: Current treatments for Friedreich's ataxia, a neurodegenerative disorder characterized by decreased intramitochondrial frataxin, do not address low frataxin concentrations. Nomlabofusp (previously CTI-1601) is a frataxin replacement therapy with a unique mechanism of action that directly addresses this underlying frataxin deficiency. Phase 1 studies assessed the safety, pharmacokinetic, and pharmacodynamic profiles of subcutaneously administered nomlabofusp in adults with Friedreich's ataxia. METHODS: Patients were enrolled in two Phase 1, double-blind, placebo-controlled studies. The single ascending-dose (SAD) study (NCT04176991) evaluated single doses of nomlabofusp (25, 50, 75, or 100 mg) or placebo. The multiple ascending-dose (MAD) study (NCT04519567) evaluated nomlabofusp (25 mg daily for 4 days then every third day, 50 mg daily for 7 days then every 2 days, or 100 mg daily) or placebo for 13 days. RESULTS: Patients aged 19-69 years were enrolled (SAD, N = 28; MAD, N = 27). Nomlabofusp was generally well tolerated through 13 days. Most adverse events were mild and resolved quickly. No serious adverse events or deaths were reported. Peak nomlabofusp plasma concentrations occurred 15 min after subcutaneous administration. Nomlabofusp plasma exposures increased with increasing doses and daily administration and decreased with reduced dosing frequency. Increased frataxin concentrations were observed in buccal cells, skin, and platelets with higher and more frequent nomlabofusp administration. INTERPRETATION: Results from this study support a favorable safety profile for nomlabofusp. Subcutaneous nomlabofusp injections were quickly absorbed; higher doses and daily administration resulted in increased tissue frataxin concentrations. Future studies will evaluate longer-term safety and possible efficacy of nomlabofusp.

Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations.

INTRODUCTION: Omavaloxolone, an NRF2 activator, recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval. AREAS COVERED: The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA. EXPERT OPINION: Omaveloxolone provides a significant advance in the treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.

Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia.

Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disease (NDD) characterized primarily by progressive sensory and spinocerebellar ataxia associated with hypertrophic cardiomyopathy. FA is due to an intronic GAA repeat expansion within the frataxin gene (FXN) leading to reduced levels of frataxin (FXN) which causes mitochondrial dysfunction, production of reactive oxygen species (ROS), and altered iron metabolism. To date there is no resolutive cure for FA; however, the FDA has recently approved omaveloxolone - a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) - as the first treatment for FA. We discuss herein the urgency to find a resolutive cure for NDDs that will most probably be achieved via combinatorial therapy targeting multiple disease pathways, and how omavaloxolone serves as an example for future treatments.

A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia.

The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia.

OBJECTIVE: Decreased expression of the mitochondrial protein frataxin is the cause of the neurodegenerative disorder Friedreich's ataxia. In patients with cardiac disorders, the death rate of this disease is very high, up to 66%. In order to combat Friedreich ataxia, which is a potentially toxic disorder, de novo drug discovery and design have been created utilizing the approach of compound engineering with halogens. This study aimed to investigate the potential for effective treatment of Friedreich ataxia. MATERIALS AND METHODS: The screening of twenty different agonist compounds was carried out in order to find the most promising agonist compound that may be used for molecular docking prediction against the Frataxin Protein. The compound with the lowest binding energies is then optimized by halogens. The final candidate's drug-like properties are identified through Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling. Lipinski's rule of five was checked. Molecular dynamic stimulations were evaluated. RESULTS: The most potent agonist compound was identified out of twenty different compounds utilizing a docking approach against the Frataxin Protein. The compound with the lowest binding energies was next subjected to optimization by halogens. The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol  has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations. CONCLUSIONS: The selected agonist is one of the most potent compounds in increasing Frataxin protein expression. Furthermore, optimization with halogens can be a productive approach to improve the candidate's drug efficacy. The development of effective medications for the treatment of Friedreich ataxia would be aided by the results of these computational investigations.

Manejo anestésico de una tormenta tiroidea en un paciente afecto de ataxia de Friederich. A propósito de un caso / Anaesthetic management of thyroid storm in a patient with Friederich's ataxia. A case report

Paciente de 26 años afecto de ataxia de Friederich con una miocardiopatía hipertrófica no obstructiva sometido a una tiroidectomía total por una tirotoxicosis secundaria a amiodarona persistente (a pesar de elevadas dosis de antitiroideos y corticoides), que intraoperatoriamente presentó un episodio sugestivo de tormenta tiroidea.La tormenta tiroidea es una urgencia endocrinológica que asocia una elevada morbimortalidad. Para mejorar la supervivencia es de vital importancia un diagnóstico temprano y un tratamiento precoz que incluya: un tratamiento sintomático, el tratamiento de las manifestaciones cardiovasculares, neurológicas y/o hepáticas y de la tirotoxicosis, así como suprimir o evitar estímulos desencadenantes y practicar un tratamiento definitivo.(AU)

A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing a total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm.Thyroid storm is an endocrine emergency that is associated with high morbimortality. Early diagnosis and treatment, which is of vital importance to improve survival. Treatment includes: symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment.(AU)

Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model.

In the absence of YFH1, the yeast ortholog of the human FXN gene, budding yeast Saccharomyces cerevisiae experience similar problems to those of cells with Friedreich's ataxia (FRDA). The comparable phenotypic traits consist of impaired respiration, problems in iron homeostasis, decreased oxidative stress tolerance, and diminished iron-sulfur cluster synthesis, rendering yeast of potential use in FRDA modeling and drug trials. Deferiprone, an iron chelator, is one of the long-term studied potential drugs for FRDA, whereas metformin is a biguanide prescribed to treat type 2 diabetes. In the present study, the effects of deferiprone and metformin treatment on the yeast FRDA model are explored via RNA-sequencing analyses. The comparative inquiry of transcriptome data reveals new promising roles for metformin in FRDA treatment since deferiprone and metformin treatments produce overlapping transcriptional and phenotypic responses in YFH1Δ cells. The results revealed that both deferiprone and metformin treatment does not rescue aerobic respiration in YFH1Δ cells, but they alleviate the FRDA phenotype probably by triggering the retrograde mitochondria-to-nucleus signaling.

Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases.

Neurodegenerative diseases are a major global health burden particularly with the increasing ageing population. Hereditary predisposition and environmental risk factors contribute to the heterogeneity of existing pathological phenotypes. Traditional clinical interventions focused on the use of small drugs have often led to failures due to the difficulties in crossing the blood-brain barrier and reaching the brain. In this regard, nanosystems can specifically deliver drugs and improve their bioavailability, overcoming some of the major challenges in neurodegenerative disease treatment. This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among the latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most widespread type of ataxia; it represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects.

Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia.

INTRODUCTION: Friedreich ataxia (FRDA) is a rare autosomal recessive degenerative disorder characterized by ataxia, dysarthria, diabetes, cardiomyopathy, scoliosis, and occasionally vision loss in late-stage disease. The discovery of the abnormal gene in FRDA and its product frataxin has provided insight into the pathophysiology and mechanisms of treatment. AREAS COVERED: Although the neurologic phenotype of FRDA is well defined, there are currently no established pharmacological treatments. Omaveloxolone, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is currently under review by the Food and Drug Administration (FDA) and has the potential to be the first approved treatment for FRDA. In the present report, we have reviewed the basic and clinical literature on Nrf2 deficiency in FRDA, and evidence for the benefit of omaveloxolone. EXPERT OPINION: The present perspective suggests that omaveloxolone is a rational and efficacious therapy that is possibly disease modifying in treatment of FRDA.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension.

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.

OBJECTIVES: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. METHODS: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2. RESULTS: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study. INTERPRETATIONS: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia.

Friedreich's ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cell (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G-CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

Metabolomics analysis reveals dysregulation in one carbon metabolism in Friedreich Ataxia.

Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with one­carbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.