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

September 30, 2021. 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.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Li Li, Devon M. Conradson, Vinita Bharat, Min Joo Kim, Chung-Han Hsieh, Paras S. Minhas, Amanda M. Papakyrikos, Aarooran Sivakumaran Durairaj, Anthony Ludlam, Katrin I. Andreasson, Linda Partridge, Michael A. Cianfrocco & Xinnan Wang; Nature Metabolism. 2021 Sep;3(9):1242-1258. DOI: 10.1038/s42255-021-00443-2. PMID: 34504353. 

 Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

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

César Vásquez-Trincado, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeová, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert, Human Molecular Genetics, 2021;, ddab216, doi:10.1093/hmg/ddab216

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.

Microvascular Breakdown Due to Retinal Neurodegeneration in Ataxias

Christopher A. Turski MD, Gabrielle N. Turski MD, Jennifer Faber MD, Stefan J. Teipel MD, Frank G. Holz MD, Thomas Klockgether MD, Robert P. Finger MD; Mov Disord. (2021), doi:10.1002/mds.28791

These findings demonstrate a distinct pattern of concurrent changes in vessel density of the retinal superficial vascular complex, encompassing the superficial vascular plexus, RPC network and cdONH, and retinal GCL volume, providing new insights into the ongoing degeneration in ataxias. Our findings may have relevance for design of novel therapeutic approaches for ataxias and possibly other neurodegenerative diseases.

The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC

Naeije G, Coquelet N, Wens V, et al. . Human Brain Mapping. 2021 Sep. DOI: 10.1002/hbm.25621. PMID: 34523778. ; 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.

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis

Peng L, Wang S, Chen Z, Peng Y, Wang C, Long Z, Peng H, Shi Y, Hou X, Lei L, Wan L, Liu M, Zou G, Shen L, Xia K, Qiu R, Tang B, Ashizawa T, Klockgether T, Jiang H.; Mov Disord. 2021 Sep 14. doi: 10.1002/mds.28783. Epub ahead of print. PMID: 34519102. 

 bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age

Plasma idebenone monitoring in Friedreich's ataxia patients during a long-term follow-up

Paredes-Fuentes AJ, Cesar S, Montero R, Latre C, Genovès J, Martorell L, Cuadras D, Colom H, Pineda M, Del Mar O'Callaghan M, Sarquella-Brugada G, Darling A, Artuch R.; Biomed Pharmacother. 2021 Sep 7;143:112143. doi: 10.1016/j.biopha.2021.112143. Epub ahead of print. PMID: 34507114. 

The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.

A translational approach to determine target concentrations of MIN-102 (leriglitazone) to support a Phase II study in Friedreich’s ataxia

S. Poli, L. Rodríguez-Pascau, J. Ros, P. González-Cabo, E. Britti, D. Lynch, G. Pina, S. Pascual, M. Cerrada-Gimenez, D. Eckland, E. Traver, J. Wetering-de-Rooij, M. Martinell, U. Meya, P. Pizcueta.; Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/a-translational-approach-to-determine-target-concentrations-of-min-102-leriglitazone-to-support-a-phase-ii-study-in-friedreichs-ataxia/. Accessed September 7, 2021. 

Target plasma concentrations determined in preclinical studies could be safely achieved in a Phase I study. At these plasma concentrations, CNS target engagement was confirmed in healthy volunteers. This approach has supported the design of the current Phase 2 clinical trial in Friedreich´s Ataxia, and also in other indications.

Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation

Chiang S, Braidy N, Maleki S, Lal S, Richardson DR, Huang ML.; Redox Biol. 2021 Jun 10;46:102038. doi: 10.1016/j.redox.2021.102038. Epub ahead of print. PMID: 34416478; PMCID: PMC8379503. 

This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.

Retrotope eyes $100m raise for neurodegenerative disease platform

https://www.clinicaltrialsarena.com   27 Aug 2021 California-based Retrotope aims to expand its investor pool as it prepares to potentially go public in the coming years. 

Currently, Retrotope has ongoing trials for RT001 in three of the four most common orphan neurodegenerative diseases— amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and Friedreich’s ataxia (FA). The ALS and PSP trials are Phase II, while the FA trial is a Phase II/III potentially IND-enabling study, company president Anil Kumar said.

Determine Range of Tissue Frataxin Concentrations and Other Potential Biomarkers

ClinicalTrials.gov Identifier: NCT05028764, First Posted : August 31, 2021; Sponsor: Larimar Therapeutics, Inc. 

Brief Summary: To examine range of tissue frataxin (FXN) concentrations, specific ribonucleic acids, other proteins and specialized lipids in the buccal cells, blood, and skin cells of normal healthy volunteers without Friedreich's ataxia (FRDA).