Dose-Dependent Cardiac Responses to Intravenous AAVrh.10hFXN Treatment of the MCK Murine Model of Friedreich’s Ataxia

363 Dose-Dependent Cardiac Responses to Intravenous AAVrh.10hFXN Treatment of the MCK Murine Model of Friedreich’s Ataxia; Dolan Sondhi, Alessandria Greco, Nicholas C. Gorman, Bishnu P. De, Isabelle Wilson, Melissa Yost-Bido, Rachel Spokony, Neil R. Hackett, Stephen M. Kaminsky, Richie Khanna, Ronald G. Crystal;(LEXEO Therapeutics, Inc). May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

 At the 33X dose, there was a decrease in ejection fraction, consistent with cardiac toxicity. In summary, there is a substantial survival and cardiac benefit in AAV-mediated expression of frataxin above the normal physiological level achieved at the 10X reference dose in the MCK mouse model of Friedrich’s ataxia, but toxicity at high doses. This provides a rationale for ascending the dose in human clinical studies, but with caution regarding toxicity.

Efficacy and Safety of a Novel FXN Gene Therapy (AVB-202) for the Treatment of Friedreich’s Ataxia

169 Efficacy and Safety of a Novel FXN Gene Therapy (AVB-202) for the Treatment of Friedreich’s Ataxia; Grace K. Pavlath, Jennifer Wheeler, Arden Bond, Jennifer L. Marlowe.(Solid Biosciences); May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

 AVB-202, a novel AAV9 gene therapy product expressing FXN under the control of a CBA promoter, is intended to restore functional levels of frataxin across disease-relevant tissues using a dual route of administration (intravenous and intrathecal) with the goal of preventing progression or reversing cardiac and CNS manifestations of FA.

Larimar Therapeutics Reports Preliminary Top-line Data from Phase 2 Trial’s 25 mg Cohort Showing Increases in Frataxin Levels in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., May 15, 2023 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced preliminary top-line data from the 25 mg cohort of its Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in participants with Friedreich’s ataxia (FA). Participants in the trial’s 25 mg cohort (n=13) were randomized to receive subcutaneous injections of 25 mg CTI-1601 (n=9) or placebo (n=4) daily for 14 days and then every-other-day thereafter until day 28. Data from the cohort indicate CTI-1601 was generally well tolerated and showed increases in frataxin (FXN) levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14.

New Drug Evaluation: Omaveloxolone Oral Capsules

Drug Use Research & Management Program. Oregon State University. Date of Review: June 2023. Brand Name (Manufacturer): Skyclarys™ (Reata Pharmaceuticals, Inc.). 

Recommendation: Maintain omaveloxolone as non-preferred on the Practitioner-Managed Prescription Drug Plan (PMPDP) with clinical prior authorization (PA) criteria to ensure medically appropriate use.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Culley MK, Rao RJ, Mehta M, Zhao J, El Khoury W, Harvey LD, Perk D, Tai YY, Tang Y, Shiva S, Rabinovitch M, Gu M, Bertero T, Chan SY. Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function. Vascul Pharmacol. 2023 May 8:107181. doi: 10.1016/j.vph.2023.107181. Epub ahead of print. PMID: 37164245. 

These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.

AIDE À LA PRISE EN CHARGE DU PATIENT ATTEINT D'UNE MALADIE RARE : l'ataxie de Friedreich

Iris Marolleau. Kinésithér Scient 2023,0653:15-20 - 10/05/2023

L'ataxie de Friedreich est une maladie rare du système nerveux central. C'est une maladie génétique évolutive qui touche le sujet jeune. La rééducation fonctionnelle est primordiale pour améliorer la qualité de vie et l'autonomie de ces patients. Peu d'études et de recommandations existent pour aider les kinésithérapeutes à adopter les bonnes pratiques dans la prise en charge de ces patients. Des fiches d'aide d'évaluation et de rééducation ont été réalisées pour guider le thérapeute.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia

Dr. Carlos Munoz-Zuluaga, Dr. Monica Gertz, Ms. Melissa Yost-Bido, Ms. Alessandria Greco, Mr. Nicholas Gorman, Mr. Alvin Chen, Mr. Vikrum Kooner, Dr. Jonathan B Rosenberg, Dr. Bishnu P De, Dr. Stephen M. Kaminsky, Dr. Alain Bborczuk, Dr. Rodolfo Ricart Arbona, Dr. Heather R Martin, Dr. Sebastien Monette, Dr. Richie Khanna, Dr. Jay A Barth, Dr. Ronald G Crystal, and Dr. Dolan Sondhi. Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. Human Gene Therapy. ahead of print doi:10.1089/hum.2023.020 Online Ahead of Editing: May 11, 2023

 These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA.

Design Therapeutics Provides Pipeline Updates and Reports First Quarter 2023 Financial Results

CARLSBAD, Calif., May 09, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. 

Initial Data from Ongoing Phase 1 MAD Trial of DT-216 for FA Expected in the Third Quarter of 2023: Design is evaluating its lead GeneTAC™ small molecule, DT-216, in an ongoing Phase 1 MAD clinical trial designed to evaluate the safety, tolerability, pharmacokinetic, biodistribution, and pharmacodynamic effects of three weekly doses of DT-216 in adults with FA. FA is a multisystem degenerative disease caused by a GAA nucleotide repeat expansion in the frataxin (FXN) gene that impairs transcription and reduces FXN mRNA. DT-216 is designed to specifically target the GAA repeat expansion mutation and restore FXN gene expression. An unanticipated vendor issue related to the study drug vial stopper caused a short delay in product supply, which has been resolved. Design now anticipates presenting initial results from the MAD trial in the third quarter of 2023. The company plans to initiate a Phase 2 trial in the second half of 2023.

Omaveloxolone: First Approval

Lee A. Omaveloxolone: First Approval. Drugs. 2023 May 8. doi: 10.1007/s40265-023-01874-9. Epub ahead of print. PMID: 37155124. 

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia

Sharadha Dayalan Naidu, Albena T. Dinkova-Kostova, Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia, Trends in Pharmacological Sciences, 2023, doi:10.1016/j.tips.2023.03.005.

Omaveloxolone is the first and only FDA-approved drug for patients with Friedreich’s ataxia. Omaveloxolone has received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the FDA, and Orphan Drug Designation for the treatment of Friedreich’s ataxia from the European Commission. It is currently not approved outside of the USA.