Characterizing Population Pharmacokinetics of Vatiquinone in Healthy Volunteers and Patients with Friedreich’s Ataxia

Hu, Y.; Gao, L.; Lee, L.; Cherry, J.J.; Kong, R. Characterizing Population Pharmacokinetics of Vatiquinone in Healthy Volunteers and Patients with Friedreich’s Ataxia. Pharmaceuticals 2025, 18, 1339. doi:10.3390/ph18091339 

A two-compartment model effectively described the pharmacokinetic profiles of vatiquinone after oral administration. Covariates significantly impacted exposures, including body weight, meals, disease status, comedications and body mass index.

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing

Hannes Erdmann, Annalisa Schaub, Morghan C Lucas, Veronika Scholz, Anna Benet-Pages, Kerstin Becker, Christine Dineiger, Veronika Mayer, Inga van Buren, Eva Breithausen, Karl Akbari, Isabell Cordts, Mayra Sauer, Christine Schneider, Rosanna Krakowsky, Franziska Schnabel, Konstanze Dunker, Lena Fabritius, Johannes Gerb, Denis Grabova, Ken Möhwald, Marius Näher, Karoline Steinmetz, Franziska Thiessen, Alexander Jäck, Christiane Schneider-Gold, Simone Zittel, Christina Petersen, Isolde Schreyer, Larissa Mämecke, Sibylle Wilfling, Gilbert Wunderlich, David Brenner, Yorck Hellenbroich, Kirsten Muhle, Tessa Huchtemann, Inga Claus, Thomas Klopstock, Michael Strupp, Johannes Levin, Günter Höglinger, Doreen Huppert, Sandra Becker-Bense, Filipp Filippopulos, Fabian Kilpert, Elsa Leitão, Sabine Kaya, Christel Depienne, Florian Schöberl, Teresa Neuhann, Elke Holinski-Feder, Andreas Zwergal, Angela Abicht, Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing, Brain, 2025;, awaf318, doi:10.1093/brain/awaf318 

We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8% (1:125)

Design Therapeutics Faces Regulatory Hurdle While Maintaining Financial Stability

01.09.25 09:19, Börse Global (en). 

Clinical Program Pivot Following FDA Decision A significant development emerged from regulatory discussions with the U.S. Food and Drug Administration. The agency imposed a clinical hold on Design Therapeutics' planned expansion of its key RESTORE-FA study within the United States. This critical trial evaluates the promising drug candidate DT-216P2 as a treatment for Friedreich's ataxia, a progressive neurological disorder. While initial pharmacokinetic data had shown encouraging results, the FDA's decision has substantially delayed the program's advancement and raised questions about the regulatory path forward. Despite this setback in the U.S. market, the company continues to progress with the study outside American borders. 

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model. Jarmon G. Lees, Haoxiang Zhang, Lebei Jiao, Anne M Kong, Ren Jie Phang, Li Li, Nan Su, Anthony S. Mukhtar, Alice Pébay, Mirella Dottori, Louise Corben, Martin Delatycki, Roger Peverill, Stephen Wilcox, Jarny Choi, Jeffrey M. Pullin, Davis McCarthy, Jill S. Napierala, Marek Napierala, Shiang Y. Lim bioRxiv 2025.08.20.671405; doi:10.1101/2025.08.20.671405 

This preclinical human model provides valuable insight into the pathogenesis of FRDA and provides a platform for developing early-stage therapeutic interventions.

In vivo gene therapy: A strategy for mutations, degenerations, and tumors

Tao Wang, Mingyang Yu, Ping Liu, Zhiqiang Song, Cheng Li, Jianmin Yang, Na Liu, In vivo gene therapy: A strategy for mutations, degenerations, and tumors, Genes & Diseases, 2025, 101808, ISSN 2352-3042, doi:10.1016/j.gendis.2025.101808. 

 The current review summarizes the development of DNA nucleases and delivery vectors for in vivo gene therapy, emphasizing recent progress.

Spatial perspective taking is impaired in spinocerebellar ataxias and Friedreich ataxia

Karamazovova, S., Laczó, M., Matuskova, V. et al. Spatial perspective taking is impaired in spinocerebellar ataxias and Friedreich ataxia. Sci Rep 15, 31126 (2025). doi:10.1038/s41598-025-16302-z 

This study aimed to investigate perspective taking in patients with SCA and Friedreich ataxia (FRDA) using two tests. The Perspective-Taking/Spatial Orientation Test (PTSOT) was administered to 30 SCA patients, 30 FRDA patients, and 34 healthy controls (HC). In addition, SCA and HC completed the Directional-approach Task and a comprehensive neuropsychological assessment. SCA patients performed significantly worse than HC on both perspective taking tests. FRDA patients performed better than SCA and differed from HC only in a subset of PTSOT measures. Perspective taking performance in SCA was associated with global cognition and multiple cognitive domains but not with cerebellar motor impairment.

Alpha–lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia

Talaverón-Rey, M., Reche-López, D., Povea-Cabello, S. et al. Alpha–lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia. Orphanet J Rare Dis 20, 453 (2025).doi:10.1186/s13023-025-03990-z 

 Treatment with ALA was able to correct partially the pathological alterations in mutant fibroblasts. The optimal ALA concentration was dependent on the number of expanded GAA triplet repeats in the FXN gene. The positive effect of ALA was also confirmed in induced neurons derived from FRDA mutant fibroblasts. Our results also suggest that the positive effect of ALA was mediated by Peroxisome Proliferator-Activated Receptor Gamma activation. 

Conclusions: Our results suggest that ALA treatment can increase the expression levels of frataxin and reverse the mutant phenotype in cellular models of FRDA.

 

PTC Therapeutics Receives Complete Response Letter for Vatiquinone NDA

WARREN, N.J., Aug. 19, 2025 /PRNewswire/ -- PTC Therapeutics, Inc., announced today that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) related to the New Drug Application (NDA) for vatiquinone for the treatment of children and adults living with Friedreich's ataxia.

"We are of course disappointed by the FDA's decision to not approve vatiquinone," said Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics. "We believe the data collected to date demonstrate that vatiquinone could provide a safe and effective therapy for both children and adults living with Friedreich's ataxia. We plan to meet with the FDA to discuss potential steps to address the issues raised in the CRL.

" The FDA stated in the CRL that substantial evidence of efficacy was not demonstrated for vatiquinone and that an additional adequate and well-controlled study would be needed to support NDA resubmission.

Propensity-matched analysis comparing omaveloxolone treatment to Friedreich ataxia natural history data: a plain language summary

Lynch, D. R., Goldsberry, A., Rummey, C., Farmer, J., Boesch, S., Delatycki, M. B., … Meyer, C. (2025). Propensity-matched analysis comparing omaveloxolone treatment to Friedreich ataxia natural history data: a plain language summary. Future Neurology, 20(1). doi:10.1080/14796708.2025.2524313 

Friedreich ataxia (FA) is an inherited disorder that gets worse over time and affects movement, coordination, and speech. Omaveloxolone (Skyclarys®) capsules are a medicine that has been approved to treat FA in people aged 16 years and older. The approval is based on findings from the MOXIe clinical trial program. This program had 3 parts (Part 1, Part 2, and the MOXIe Open Label Extension). The MOXIe Part 2 study showed that omaveloxolone slowed the worsening of the disease in people with FA compared with those who received an inactive drug–or placebo–over 48 weeks (or 11 months). The study also showed that omaveloxolone causes side effects that were considered manageable, allowing most patients to continue using it.

Sensory nerve action potential reappearance after omaveloxolone treatment in patients with Friedreich ataxia

Sensory nerve action potential reappearance after omaveloxolone treatment in patients with Friedreich ataxia. Melita Rotar, Lea Leonardis; Clinical Neurophysiology Volume 178, October 2025, 2110974. doi:10.1016/j.clinph.2025.2110974 (Letter to the Editor).