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.