PTC Therapeutics Announces Initiation of Global Phase 3 Clinical Trial to Evaluate Vatiquinone in Friedreich Ataxia

SOUTH PLAINFIELD, N.J., Nov. 30, 2020 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced the initiation of the registration-directed Phase 3 MOVE-FA study evaluating vatiquinone (PTC743) in children and young adults with Friedreich ataxia (FA) The Phase 3 MOVE-FA trial is an 18-month parallel arm, placebo-controlled study evaluating vatiquinone versus placebo in approximately 110 children and young adults with FA. The primary endpoint is the change from baseline in the modified Friedreich ataxia rating scale (mFARS), with key secondary endpoints assessing ambulation and activities of daily living. This endpoint strategy was developed in consultation with both the FDA and European Medicines Agency. The study will include sites in the U.S., E.U., Australia and Latin America.

FDA sends Reata back to the drawing board

Evaluate Vantage, Madeleine Armstrong, November 25, 2020

The need for another pivotal trial of omaveloxolone in Friedreich's ataxia looks increasingly likely. This result for omaveloxolone was not entirely unexpected; Reata said during its second-quarter results that the FDA had asked for a second pivotal trial to support the Moxie study. Part two of Moxie was declared a success, but only after Reata switched endpoints to increase its chances after the first part failed (Reata looks to outsmart Abbvie again, October 15, 2019).

Overview of Friedreich's ataxia models: Comparison of frataxin protein levels and phenotype

27 November 2020. The Jackson Laboratory .

Watch this presentation from Dr. Cat Lutz, Senior Director of Mouse Repository & In Vivo Pharmacology at The Jackson Laboratory, titled: Overview of Friedreich's ataxia models: Comparison of frataxin protein levels and phenotype. This talk was presented at the SelectScience® Virtual Neuroscience Summit.

https://www.selectscience.net/SelectScience-TV/Videos/overview-of-friedreichs-ataxia-models-comparison-of-frataxin-protein-levels-and-phenotype/?videoID=5178

Central Nervous System Therapeutic Targets in Friedreich Ataxia

Dr. Ian Harding, Dr. David R Lynch, Dr. Arnulf Koeppen, and Dr. Massimo Pandolfo; Human Gene Therapy 0 0:ja; doi:10.1089/hum.2020.264

In general, the proprioceptive system appears to be affected early, while later in the disease the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress towards novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In the present work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different timepoints. As most major targets of long-term therapy are in the CNS, the present review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations here include physiological, pathological and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.

New drug confirmed as a potential therapeutic agent for a rare disease, Friedreich's Ataxia

http://biotech-spain.com , 25/11/2020, Fuente: IRB Lleida. Institut de Recerca Biomèdica.

It is the leriglitazone that improves the loss of frataxin, the cause of the disease .

A recent study has confirmed the benefits of the drug leriglitazone in treating Friedrich's Ataxia, a rare disease that affects 2-4 people in 100,000 and for which there is currently no effective cure. Research has confirmed that this drug improves the deficiencies of frataxin loss in cellular and animal models of Friedreich's Ataxia. This disease is caused by a deficiency in frataxin levels, which leads to mitochondrial dysfunction with neurological and cardiac involvement. The research has been published in the journal Neurobiology of Disease.

The research has been carried out in collaboration between the company Minoryx Therapeutics, the Oxidative stress biochemistry Stress Group of the University of Lleida (UdL) and the Institute of Biomedical Research of Lleida (IRBLleida), the Department of Physiology of the Faculty of Medicine and Dentistry of the University of Valencia - INCLIVA, the Centre for Biomedical Research Network on Rare Diseases (CIBERER) and the Department of Paediatrics and Neurology of The Children's Hospital of Philadelphia.

Confirman un nuevo fármaco como potencial agente terapéutico para tratar la ataxia de Friedreich

Universitat de València, GABINETE DE PRENSA, 25 noviembre de 2020.

La investigación ha confirmado los beneficios del fármaco leriglitazona para tratar la ataxia de Friedrich, una enfermedad rara que afecta a 2-4 personas de cada 100.000 y para la cual, actualmente, no hay una cura efectiva. La investigación es una colaboración entre el grupo de investigación que lidera Federico Pallardó, la empresa Minoryx Therapeutics, y el INCLIVA, perteneciente al Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), el Grupo de Investigación Bioquímica del Estrés Oxidativo, de la Universidad de Lleida (UdL) y el Instituto de Investigación Biomédica de Lleida (IRBLleida), y el Departamento de Pediatría y Neurología del The Children's Hospital of Philadelphia.

Reata Provides Update on Omaveloxolone Program for Patients with Friedreich’s Ataxia

November 24, 2020 17:00 ET | Source: Reata Pharmaceuticals, Inc. PLANO, Texas, Nov. 24, 2020 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that the U.S. Food and Drug Administration (“FDA”) completed its internal review of the Baseline-Controlled Study results of omaveloxolone for the treatment of patients with Friedreich’s ataxia (“FA”) and concluded that the results do not strengthen the results of Part 2 of the MOXIe study. The FDA proposed some additional exploratory analyses using patients randomized to placebo during the MOXIe Part 2 study, but stated that the potential for these analyses to strengthen the study results was questionable due to the small number of patients available for analysis. The FDA stated that they remain interested in reviewing the results of the additional exploratory analyses as those may inform the future development program. The Company plans to submit to the FDA the analyses that they proposed and to request a meeting with the FDA to discuss the development program. In addition, based on the FDA’s conclusion, the Company is considering the next steps for the development program, including whether to conduct a second pivotal study in patients with FA. “Omaveloxolone improved motor function as measured by the modified Friedreich’s Ataxia Rating Scale in both Part 2 of the MOXIe study and the Baseline-Controlled study. We are grateful to the families, physicians, investigators, and advocates who have supported this program to date,” said Warren Huff, Reata’s Chairman and Chief Executive Officer. “Though we are disappointed in the FDA’s feedback on this program, we will carefully consider the potential paths forward for making omaveloxolone available to patients with FA.”

Hand dexterity and pyramidal dysfunction in Friedreich Ataxia, a finger tapping study

Gilles Naeije MD, PhD Antonin Rovai PhD Massimo Pandolfo MD Xavier De Tiège MD, PhD.; Mov Disord Clin Pract. Accepted Author Manuscript. doi:10.1002/mdc3.13126

This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA. FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher SARA scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, while the four other patients with constant FT rate had normal CMCT.

Progression Characteristics in Friedreich's Ataxia: A 4-Year Observational Study

Reetz, Kathrin and Dogan, Imis and Hilgers, Ralf-Dieter and Giunti, Paola and Mariotti, Caterina and Nanetti, Lorenzo and Durr, Alexandra and Ewenczyk, Claire and Boesch, Sylvia and Nachbauer, Wolfgang and Klopstock, Thomas and Stendel, Claudia and Javier Rodríguez de Rivera Garrido, Francisco and Schöls, Ludger and Hayer, Stefanie and Klockgether, Thomas and Giordano, Ilaria and Didszun, Claire and Rai, Myriam and Pandolfo, Massimo and Schulz, Jörg B. and Group, EFACTS Study. "Preprints with The Lancetare are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed". doi:10.2139/ssrn.3723615

Background: The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich’s ataxia (FRDA) in a prospective multinational registry study. We aimed to assess progression and metric characteristics of clinical rating scales based on longitudinal 4-year data.

Antiferroptotic Activity of Phenothiazine Analogues: A Novel Therapeutic Strategy for Oxidative Stress Related Disease

Jun Liu, Indrajit Bandyopadhyay, Lei Zheng, Omar M. Khdour, and Sidney M. Hecht; ACS Med. Chem. Lett. 2020, 11, 11, 2165–2173,  September 15, 2020, doi:10.1021/acsmedchemlett.0c00293.

Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b–5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.

Analysis of Postural Control in Sitting by Pressure Mapping in Patients with Multiple Sclerosis, Spinal Cord Injury and Friedreich’s Ataxia: A Case Series Study

Reguera-García, M.M.; Leirós-Rodríguez, R.; Álvarez-Barrio, L.; Alonso-Cortés Fradejas, B.; Sensors 2020, 20, 6488.

The tests applied were: pressure mapping, seated Lateral Reach Test, seated Functional Reach Test, Berg Balance Scale, Posture and Postural Ability Scale, Function in Sitting Test, and Trunk Control Test. The participants with Friedreich’s ataxia showed a tendency to present a higher mean pressure on the seat of subject’s wheelchair compared to other groups. In parallel, users with spinal cord injury showed a tendency to present the highest values of maximum pressure and area of contact. People with different neurological pathologies and similar results in functional tests have very different results in the pressure mapping. Although it is not possible to establish a strong statistical correlation, the relationships between the pressure mapping variables and the functional tests seem to be numerous, especially in the multiple sclerosis group.

Left ventricular unloading with transaortic Impella 2.5 implantation in a pediatric patient supported by ECLS.

Sandoval Boburg, R., Mustafi, M., Magunia, H., Kling, S., Schlensak, C. and Popov, A.‐F., Artificial Organs. Accepted Author Manuscript. (2020) doi:10.1111/aor.13862 

We report the case of a 12-year old female patient with Friedreich´s Ataxia and diabetes mellitus. Due to a progressive multi-organ failure a veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was implanted through the axillary vessels. However, due to a lack of ejection and severe dilatation of the left ventricle, an Impella 2.5 was implanted. Due to the small diameter of the femoral arteries, we performed a trans-aortic implantation through a median sternotomy via a dacron tube graft. We report on the procedure and peri-operative outcome.

Minoryx’s preclinical data for leriglitazone in Friedreich’s Ataxia published in Neurobiology of Disease Journal

Mataró, Barcelona, Spain and Gosselies, Belgium, November 16, 2020 – Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders with high unmet need, today announces the publication in ‘Neurobiology of disease’ of preclinical data on its lead compound, leriglitazone, showing potential therapeutic action and protection against neurodegeneration, in particular against Friedreich’s Ataxia (FRDA).

The preclinical data, published on November 7, 2020, supports the on-going clinical development in treating FRDA. The results show that the company’s lead compound, leriglitazone, improves impairments that are derived from frataxin loss – the genetic deficiency that causes FRDA.

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

La Rosa, P.; Petrillo, S.; Fiorenza, M.T.; Bertini, E.S.; Piemonte, F.; Biomolecules 2020, 10, 1551. doi:10.3390/biom10111551 

This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

Cardiomyopathy as the first manifestation of Friedreich's ataxia

Rafael Tuzino Leite Neves Maffei; Giulio de los Santos Fortuna; Luca Campolino Rosso; Pedro Dragone Pires; Ivan Rondelli Autops Case Rep, vol.10, n3, e2020204, 2020; doi:10.4322/acr.2020.204 

 We present the case of a female patient diagnosed in childhood with Friedreich Ataxia (FA). At the age of 6, she developed left congestive heart failure with cardiomyopathy, as evident on echocardiogram. Neurologic signs only appeared at age 7, including marked loss of muscle mass, gait instability, muscle clonus, and Babinski's signal. At age 27, she had a stroke and was hospitalized; a few days later, she had a cardiorespiratory arrest with asystole, leading to death. The autopsy disclosed severe cardiomyopathy and significant myocardial replacement with fibrosis; therefore, the cause of death was assumed to be heart failure. Compared to the literature, our case has some unique features, such as cardiac disease as the presenting manifestation instead of gait instability, which is the major initial sign in most FA cases. Since our patient was submitted to an autopsy, it was an opportunity to retrieve important data to confirm the diagnosis and to evaluate the pathophysiology of this entity, such as myocardium fibrosis and cerebellar degeneration. In summary, our case demonstrates that cardiac disease can be the first manifestation of FA, with eventual diagnostic and prognostic implications. In addition, the autopsy provided findings of severe cardiomyopathy associated with FA.

Epigenetic Regulation of the Clinical Signs of Friedreich’s Disease

E. P. Nuzhny, N. Yu. Abramycheva, N. S. Nikolaeva, M. V. Ershova, S. A. Klyushnikov, S. N. Illarioshkin & E. Yu. Fedotova; Neurosci Behav Physi (2020). doi:10.1007/s11055-020-00998-9 

Studies of genetic-epigenetic interactions identified correlations between the extent of methylation of a series of CpG sites in the UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded alleles of the FXN gene in patients with FD. We also found a link between methylation and the presence of the extraneural signs of FD: cardiomyopathy was more likely to be present when the CpG site of the promoter region was hypermethylated, while impairments to carbohydrate metabolism were more common in hypomethylation of CpG sites in the DOWN-GAA area. Conclusions. The data obtained here provide evidence that epigenetic modifications of the FXN gene make a significant contribution to forming the clinical picture of FD.

The Nrf2 induction prevents ferroptosis in Friedreich’s Ataxia

Piergiorgio La Rosa, Sara Petrillo, Riccardo Turchi, Francesco Berardinelli, Tommaso Schirinzi, Gessica Vasco, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Enrico S. Bertini, Katia Aquilano, Fiorella Piemonte, Redox Biology, 2020, 101791, doi:10.1016/j.redox.2020.101791.

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.

PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Laura Rodríguez-Pascau, Elena Britti, Pablo Calap-Quintana, Yi Na Dong, Cristina Vergara, Fabien Delaspre, Marta Medina, Jordi Tamarit, Federico V. Pallardó, Pilar Gonzalez-Cabo, Joaquim Ros, David R. Lynch, Marc Martinell, Pilar Pizcueta, Neurobiology of Disease, 2020, 105162, doi:10.1016/j.nbd.2020.105162. 

Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.

Electrocardiogram in Friedreich's ataxia: A short‐term surrogate endpoint for treatment efficacy

Sandra Mastroianno MD Michele Germano MD Angela Maggio MD Raimondo Massaro MD Domenico Rosario Potenza MD Aldo Russo MD Massimo Carella PhD Giuseppe Di Stolfo MD, PhD; Ann Noninvasive Electrocardiol. 2020; 00:e12813. doi:10.1111/anec.12813 

We describe the case of a 21‐year‐old patient affected by Friedreich's ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.

Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial Dynamics and Metabolism

Agrò, M.; Díaz-Nido, J. , Int. J. Mol. Sci. 2020, 21, 8251. doi:10.3390/ijms21218251 (registering DOI)

Alternative forms of frataxin have been described, with different cellular localization and tissue distribution, including a cerebellum-specific cytosolic isoform called FXN II. Here, we explored the functional roles of FXN II in comparison to the mitochondrial FXN I isoform, highlighting the existence of potential cross-talk between cellular compartments. To achieve this, we transduced two human cell lines of patient and healthy subjects with lentiviral vectors overexpressing the mitochondrial or the cytosolic FXN isoforms and studied their effect on the mitochondrial network and metabolism. We confirmed the cytosolic localization of FXN isoform II in our in vitro models. Interestingly, both cytosolic and mitochondrial isoforms have an effect on mitochondrial dynamics, affecting different parameters. Accordingly, increases of mitochondrial respiration were detected after transduction with FXN I or FXN II in both cellular models. Together, these results point to the existence of a potential cross-talk mechanism between the cytosol and mitochondria, mediated by FXN isoforms. A more thorough knowledge of the mechanisms of action behind the extra-mitochondrial FXN II isoform could prove useful in unraveling FRDA physiopathology.