Direct utility of natural history data in analysis of clinical trials: Propensity match-based analysis of Omaveloxolone in Friedreich ataxia using the FA-COMS dataset

David Lynch, Angie Goldsberry, Christian Rummey, Jennifer Farmer, Sylvia Boesch, martin delatycki, Paola Giunti, j chad Hoyle, Caterina Mariotti, Katherine Mathews, Susan Perlman, SH Subramony, George Wilmot, Theresa Zesiwiecz, Lisa Weissfeld, Colin Meyer medRxiv 2022.08.12.22278684; doi: 10.1101/2022.08.12.22278684 

These results suggest a clinically meaningful slowing of FRDA progression with omaveloxolone, and consequently details how propensity-matched analysis contributes to the understanding of the effects of therapeutic agents. This demonstrates the direct value of natural history studies in the evaluation of clinical trials.

Replication dependent and independent mechanisms of GAA repeat instability

Chiara Masnovo, Ayesha F. Lobo, Sergei M. Mirkin; DNA Repair, Volume 118, 2022, 103385, doi:10.1016/j.dnarep.2022.103385. 

Here, we provide a brief historical overview on the discovery of (GAA)n repeat expansions and their association to FRDA, followed by recent advances in the identification of triplex H-DNA formation and replication fork stalling. The main body of this review focuses on the last decade of progress in understanding the mechanism of (GAA)n repeat instability during DNA replication and/or DNA repair. We propose that the discovery of additional mechanisms of (GAA)n repeat instability can be achieved via both comparative approaches to other repeat expansion diseases and genome-wide association studies. Finally, we discuss the advances towards FRDA prevention or amelioration that specifically target (GAA)n repeat expansions.

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

Kevin C. Kemp, Anastasia Georgievskaya, Kelly Hares, Juliana Redondo, Steven Bailey, Claire M. Rice, Neil J. Scolding, Chris Metcalfe & Alastair Wilkins; Nat Commun 13, 4655 (2022). doi:10.1038/s41467-022-31450-w 

 Pharmacological interventions to increase frataxin expression and reverse the deleterious effects of frataxin deficiency are attractive therapeutic approaches in FA. We have shown that a course of G-CSF therapy in participants with FA is safe, is associated with effective HSC mobilisation, and leads to significant elevations in frataxin together with improvements in biochemical deficits associated with FA. Nevertheless, the need for future assessment of G-CSF administration on affected tissues, such as the heart and brain, using a range of dose levels and dosing frequencies is required. The long-term safety of sustained G-CSF administration in people with FA is also unknown. The natural rate of disease progression in FA necessitates prolonged trial periods to sufficiently detect changes in clinical measures. This study provides proof-of-principle evidence to support an efficacy study of G-CSF administration in FA, using repeated courses over a longer period.

 

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

FDA Extends Review of Omaveloxolone in Friedreich Ataxia

August 9, 2022. After Reata Pharmaceuticals submitted an analysis from the MOXIe extension study of the investigational agent as part of the NDA submission, the FDA extended the PDUFA date to February 2023.

Reata continues to hit FDA roadblocks with its Friedreich’s ataxia candidate, noting regulator 'concerns'

Endpoints News. August 8, 2022. 

Reata Pharmaceuticals is facing an FDA wall on its small molecule candidate to treat Friedreich’s ataxia, omaveloxolone. According to the company’s Q2 report, the FDA might still not be sold on the drug. 

 “[The FDA] continues to have concerns regarding the strength of the efficacy evidence. The FDA did not identify any significant clinical safety issues. The FDA stated that the safety review is ongoing, and they are continuing to evaluate the cardiac safety of omaveloxolone in patients with Friedreich’s ataxia. They have not identified any other major safety concerns at this stage of their review,” the Q2 report said. 

 The FDA is expected to make its decision by Nov. 30. Reata stressed it’s still waiting to receive formal minutes from its mid-cycle review meeting with regulators.

Design Therapeutics Highlights Upcoming Milestones and Reports Second Quarter 2022

CARLSBAD, Calif., Aug. 08, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today highlighted anticipated upcoming milestones across its clinical and research-stage pipeline of novel GeneTAC™ small molecules and reported second quarter 2022 financial results.

Initial Data from Single-Ascending Dose Portion of Phase 1 trial for DT-216 Expected in the Fourth Quarter of 2022: DT-216, Design’s lead GeneTAC™ molecule, is designed to treat FA by specifically targeting the GAA repeat expansion mutation, the underlying cause of disease, and restore frataxin (FXN) gene expression. DT-216 is being evaluated in a Phase 1 clinical trial in adult patients with FA. The company plans to report initial data, including safety, tolerability, pharmacokinetics and FXN levels from the single-ascending dose portion of the trial in the fourth quarter of 2022. Design expects to initiate dosing of DT-216 in the multiple-ascending dose portion of the Phase 1 study in the second half of 2022.

Ataxia de friedreich, lucha por la supervivencia

Beatriz Miguel Palacios. Diplomada en Fisioterapia. Hospital Universitario Miguel Servet. Zaragoza, Nuria Bedoya Chocán. Celadora. Hospital Tres Mares. Reinosa, Cantabria., Nuria Sánchez Garrigós. Diplomada en Enfermería. Hospital General de Valdepeñas. Ciudad Real., María Teresa Bartolomé Bueno. FP2 Administrativo. Clínica del Pilar. Zaragoza., Noelia Loren Valles. Técnico en Cuidados Auxiliares de Enfermería. Hospital Miguel Servet. Zaragoza., José Antonio Ortín Clavería. Grado en Fisioterapia. Hospital Universitario Miguel Servet. Zaragoza.; REVISTA SANITARIA DE INVESTIGACIÓN, 5 agosto 2022, ISSN: 2660-7085 

PALABRAS CLAVE: Ataxias hereditarias, fisioterapia, ataxia cerebelosa, marcha, enfermedades cardiovasculares.

Lexeo to start phase I/II clinical trial for patients with FA cardiomyopathy.

5 ago 2022

Importance of an echocardiogram in the evaluation of ataxia

Stokreef S, Lemos M, Quintas S.; BMJ Case Reports CP 2022;15:e248691. doi:10.1136/bcr-2021-248691

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich’s ataxia was confirmed.

Unleashing the potential of AAV gene therapy

Biopharma Dealmakers (Biopharm Deal). 18/7/2022.

Voyager Therapeutics is unlocking the potential of adeno-associated virus gene therapy to treat a range of neurological disorders, broadening the therapeutic window while ensuring efficacy and safety. The company has already secured capsid option and license agreements with Novartis and Pfizer for target-specific use with CNS and cardiac muscle targets. Voyager also has an ongoing collaboration with Neurocrine Biosciences on a preclinical Friedreich’s ataxia (FA) program and two undisclosed discovery programs in which the company’s novel capsids may be deployed.