Reata Pharmaceuticals Initiates Rolling Submission of New Drug Application with U.S. FDA for Omaveloxolone for the Treatment of Patients with Friedreich’s Ataxia

January 31, 2022. PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA), (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, today announced that the company has initiated a rolling submission of a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia. The rolling submission allows Reata to submit portions of the regulatory application to the FDA for review on an ongoing basis. The company reiterates that it expects to complete the submission of the NDA by the end of the first quarter of 2022. 

Plans to Complete Submission by the End of the First Quarter of 2022 If Approved, Omaveloxolone Would Become the First Therapy Indicated for the Treatment of Patients with Friedreich’s Ataxia

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Rodríguez LR, Lapeña-Luzón T, Benetó N, et al.; Antioxidants (Basel, Switzerland). 2022 Jan;11(1). DOI: 10.3390/antiox11010165. PMID: 35052668.

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Comparing pipelines across ten rare neurological diseases

Pharmaceutical Technology. January 27, 2022. 

 While much progress has been made in some rare neurological diseases, others are only beginning to see interest from developers.

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Marta Medina-Carbonero, Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Elisa Cabiscol, Joaquim Ros & Jordi Tamarit. Cell. Mol. Life Sci. 79, 74 (2022). doi:10.1007/s00018-021-04100-5 

 We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.

Hsa-miR223-3p circulating level is upregulated in Friedreich’s ataxia and inversely associated with HCLS1 associated protein X-1, HAX-1

Andrea Quatrana, Elena Morini, Francesca Tiano, Chiara Vancheri, Luca Panarello, Silvia Romano, Christian Marcotulli, Carlo Casali, Caterina Mariotti, Alessia Mongelli, Mario Fichera, Alessandra Rufini, Ivano Condò, Giuseppe Novelli, Roberto Testi, Francesca Amati, Florence Malisan; Human Molecular Genetics, 2022;, ddac005, doi:10.1093/hmg/ddac005 

This study describes for the first time the association between hsa-miR223-3p and HAX-1 expression in FRDA, thus supporting a potential role of this microRNA as non-invasive epigenetic biomarker for FRDA.

Enfermedad cardiaca en la ataxia de Friedreich. Revisión diagnóstica y terapéutica

Sánchez Ortiz, M; Ibarra Reyes; López Pérez; Revista Ocronos. Vol. V. Nº 1–Enero 2022. Pág. Inicial: Vol. V; nº1: 91 

Presentamos el caso de un varón de 27 años, con antecedentes de FRDA desde hace 11 años, válvula aorta bicúspide, hipertrofia ventricular izquierda y fumador. Su tratamiento farmacológico es citicolina de dispensación hospitalaria para la ataxia de Friedreich. Ingresado por deterioro de su clase funcional y palpitaciones de 15 días de evolución.

The attitude of patients with progressive ataxias towards clinical trials

Gilbert Thomas-Black, Andrada Dumitrascu, Hector Garcia-Moreno, Julie Vallortigara, Julie Greenfield, Barry Hunt, Susan Walther, Mackenzie Wells, David R. Lynch, Hugh Montgomery & Paola Giunti. Orphanet J Rare Dis 17, 1 (2022). doi:10.1186/s13023-021-02091-x 

Knowledge of motivations for and barriers to trial participation as well as the acceptability of investigations, time commitments and routes of drug administration should inform better, more patient focused trial design. This in turn may improve recruitment and retention of participants to future trials.

Friedreich’s Ataxia Misdiagnosed as Lumbar Disc Prolapse: Case Report

Naglaa Hussein, Matthew Bartels, Mohammad Dwary; Int J Phys Med Rehabil, Vol.9 Iss.5 No:1000614

Chronic low back pain not responding to the usual treatment, particularly associated with balance and gait disturbance, could be, although rarely, a presenting feature of Friedreich’s ataxia and full clinical and electrophysiological examination should be conducted to prove or disprove such diagnosis.

TQS-168: ALS and exploratory development ongoing in Friedreich’s Ataxia and other indications

Tranquis Therapeutics, Inc., 01/10/2022; 

Our initial therapeutic candidates have been designed to cross the blood brain barrier and modulate microglia in the brain to treat a range of immune-mediated and mitochondrial diseases, starting with amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, and other indications (e.g. Frontotemporal Dementia (FTD), Huntington’s Disease, Friedreich’s Ataxia, Muscular Dystrophy, Parkinson’s, and Alzheimer’s disease). 

Because our platform targets such fundamental cell energy modulators, like PGC1α, present in all mammalian cells, it appears to have clinical utility across a broad range of immune-mediated and mitochondrial diseases—beyond the CNS. 

TQS-168 ALS and exploratory development ongoing in Frontotemporal Dementia, Huntington’s Disease, Muscular Dystrophy, Friedreich’s Ataxia and other indications

Magnetic resonance imaging evaluation of spinal cord lesions: what can we find? - Part 1. Neoplastic, vascular, metabolic, and traumatic injuries

Pereira RG, Ribeiro BNF, Pereira TRGC, Bahia PRV, Marchiori E.; Radiologia Brasileira. 2021 Nov-Dec;54(6):406-411. DOI: 10.1590/0100-3984.2020.0127. PMID: 34866701; PMCID: PMC8630944. 

Friedreich ataxia: On MRI, the spinal cord may show a reduction in its anteroposterior diameter, together with changes in signal intensity in its posterior and lateral columns.

Transcriptional Analysis of Nuclear-Encoded Mitochondrial Genes in Eight Neurodegenerative Disorders: The Analysis of Seven Diseases in Reference to Friedreich's Ataxia

Elsadany M, Elghaish RA, Khalil AS, Ahmed AS, Mansour RH, Badr E, Elserafy M.; Front Genet. 2021 Dec 20;12:749792. doi: 10.3389/fgene.2021.749792. PMID: 34987545; PMCID: PMC8721009. 

In this study, we analyzed the transcriptional changes of nuclear-encoded mitochondrial (NEM) genes in eight NDDs to specifically address the association of these genes with the diseases. Previous studies show strong links between defects in NEM genes and neurodegeneration, yet connecting specific genes with NDDs is not well studied. Friedreich's ataxia (FRDA) is an NDD that cannot be treated effectively; therefore, we focused first on FRDA and compared the outcome with seven other NDDs, including Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, multiple sclerosis, and Parkinson's disease.

The dynamin-related protein 1 is decreased and the mitochondrial network is altered in Friedreich’s ataxia cardiomyopathy

Bojjibabu Chidipi, Mariana Burgos Angulo, Syed Islamuddin Shah, Michelle Rieser, Ganim Ullah, Thomas V. McDonald, Sami F. Noujaim; The International Journal of Biochemistry & Cell Biology, Volume 143, 2022, 106137, doi:10.1016/j.biocel.2021.106137. 

 We found a significantly higher mitochondrial footprint, decreased mitochondrial fission protein dynamin-related protein, and mitochondrial fission rate over fusion with more giant mitochondrial clusters in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy, compared to an unaffected individual. We also found significantly depolarized mitochondrial membrane potential and higher reactive oxygen species levels in Friedreich ataxia human induced pluripotent stem cell cardiomyocytes. Our results show that frataxin's depletion may dampen the mitochondrial fission machinery by reducing dynamin-related protein1. The loss of mitochondrial fission might lead to elevated reactive oxygen species and depolarized mitochondrial membrane potential, which may cause oxidative damage in Friedreich ataxia hypertrophic cardiomyopathy. Further investigations are needed to identify the mechanism of downregulating dynamin-related protein1 due to the frataxin deficiency in Friedreich ataxia hypertrophic cardiomyopathy.