Biogen Launches Phase 3 Pediatric Trial Of Omaveloxolone For Friedreich Ataxia

Biogen Inc.June 23, 2025. It has begun dosing in the global Phase 3 BRAVE trial to test omaveloxolone (SKYCLARYS®) in children aged 2 to 16 with Friedreich ataxia (FA), a rare neurological illness. About 255 participants will be included in the randomized, double-blind experiment, which will have a 52-week treatment duration and an open-label extension. SKYCLARYS is now the only approved therapy for FA in people aged 16 and up, and it is available in more than 40 countries.

The primary endpoint of the BRAVE research is the Upright Stability Score, which is part of the modified FA rating scale and is used to assess progression in children. Global enrollment is still ongoing.

The clinical burden of Friedreich ataxia in the United States: A retrospective claims database analysis

The clinical burden of Friedreich ataxia in the United States: A retrospective claims database analysis, Perlman, Susan et al.. Journal of the Neurological Sciences, Volume 0, Issue 0, 123594. doi:10.1016/j.jns.2025.123594

 After matching, the study included 652 patients with FRDA and 3260 matched controls (mean age 33.2 years; 51.4 % females). During the follow-up period (median 26.2 months for cases and 28.3 months for controls), the incremental clinical burden in FRDA cases vs. matched controls was high: patients with FRDA had significantly higher odds of loss of ambulation (odds ratio: 158.0 [95 % confidence interval (CI): 112.4–222.3]), cardiomyopathy (59.2 [41.6–84.1]), scoliosis (49.0 [35.4–67.9]), falls (7.4 [5.9–9.2]), diabetes (2.5 [2.0–3.2]), head injury (2.4 [1.9–3.0]), and fracture (3.3 [2.6–4.2]) compared to controls (all p < 0.001). Patients with FRDA also experienced a higher risk of mortality than controls (hazard ratio: 3.9 [95 % CI: 2.4–6.4]).

Stable Isotope Labeling in Bacteria Enables Characterization and Quantification of Frataxin Protein in a Friedreich’s Ataxia Zebrafish Model

Stable Isotope Labeling in Bacteria Enables Characterization and Quantification of Frataxin Protein in a Friedreich’s Ataxia Zebrafish Model, Teerapat Rojsajjakul, Wonwook Do, Robert B. Wilson, and Ian A. Blair Analytical Chemistry Article ASAP DOI: 10.1021/acs.analchem.4c07095

We developed an alternative strategy involving the use of a stable isotope-labeled internal standard coupled with analysis by high-sensitivity ultrahigh-performance liquid chromatography-multiple reaction monitoring-mass spectrometry (UHPLC-MRM/MS). UHPLC-MRM/MS with a SILIB internal standard was the only way to validate zebrafish heterozygous for a knockout mutation in zFXN as a model for FRDA, illustrating its utility for the characterization and quantification of very low abundance tissue proteins.

Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia

De Toni F, Ragaglia V, Schecter D, Miller AS, Gonzalez E, Wagner EJ, Xu X, Payne RM, Mess JN, Baile MG, Clements-Egan A, Shankar G. Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia. AAPS J. 2025 Jun 25;27(5):112. doi: 10.1208/s12248-025-01093-y. PMID: 40562976. 

We demonstrate that subcutaneous administration of nomlabofusp distributes in a dose-dependent manner to several organs including the dorsal root ganglion, heart, and skeletal muscle, which are known to be predominantly affected in Friedreich's ataxia, as well as to other tissues, including skin. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. In the knockout mice, we show that the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and that treatment with nomlabofusp halts the progression of cardiac dysfunction and significantly increased survival. Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increases human frataxin in Friedreich's ataxia-relevant tissues and provide evidence of pharmacologic effects.

Larimar Therapeutics Announces FDA Recommendations on Safety Database, and Other Details of Nomlabofusp BLA Submission for Friedreich’s Ataxia Program

BALA CYNWYD, Pa., June 23, 2025 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced FDA safety database recommendations and refined timeline for Biologics License Application (BLA) submission to allow for the inclusion of the recommended safety data from adults and children with Friedreich’s Ataxia (FA). This comes following written responses from the U.S. Food and Drug Administration (FDA) based on discussions under the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program.

Biogen Disappointed by INESSS Recommendation on SKYCLARYS™ and its Impact on Quebec Patients with Friedreich Ataxia

TORONTO, June 5, 2025 /CNW/ - Biogen Canada Inc. is disappointed by INESSS's recommendation against listing SKYCLARYS™ (omaveloxolone), despite its therapeutic potential for individuals living with Friedreich ataxia (FA) — a community in urgent need of treatment options.

Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies

Fogel, B.L., Klopstock, T., Lynch, D.R., Maltecca, F., Verma, M., Minassian, B.A., Platt, F.M., Gonçalves, D.F., Puccio, H., Roos, A. and Synofzik, M. (2025), Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies. Ann Neurol. doi:10.1002/ana.27271 

 Autosomal recessive cerebellar ataxias (ARCAs) represent over 200 clinically heterogeneous genetic conditions involving degeneration of the cerebellum and associated tracts with resultant impairment of balance and coordination. Advancements in genomic testing have enabled rapid identification of the majority of known recessive disorders, shifting research focus to the development of targeted mechanistic treatments addressing underlying physiological pathways. Molecular classification allows recognition of cellular, biochemical, and genetic targets for high-effect precision therapy development. ARCAs represent a significant global health burden, requiring establishment of a robust pathway for novel therapeutic discovery through modification of mechanisms of disease pathogenesis and subsequent clinical trial development.

Health-related quality of life and productivity burden for non-professional caregivers of adults with rare diseases: a real-world study

Johnson, B., Gibson, G., Baskerville, D. et al. Health-related quality of life and productivity burden for non-professional caregivers of adults with rare diseases: a real-world study. Orphanet J Rare Dis 20, 282 (2025). doi:10.1186/s13023-025-03796-z 

The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.

Biogen Initiates Phase 3 Pediatric Study Of Omaveloxolone For The Treatment Of Friedreich Ataxia

CAMBRIDGE, Mass., June 18, 2025 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) announced the initiation of dosing in the BRAVE study, a global Phase 3 clinical trial. The BRAVE study will evaluate the efficacy and safety of omaveloxolone in children with Friedreich ataxia (FA) between the ages of 2 to < 16 . Both non-ambulatory and ambulatory participants may qualify for the study. Participants will be randomized 2:1 to receive omaveloxolone or placebo once a day for 52 weeks before having the opportunity to move into the open-label extension (OLE). Currently, omaveloxolone is commercialized under the brand name SKYCLARYS® in over 40 countries, including in the U.S. and the European Union, and is the only approved product for FA in adults and adolescents aged 16 years and older.

Friedreich's ataxia—a rare multisystem disease

Friedreich's ataxia—a rare multisystem disease, Reetz, KathrinCosta, Ana Sofia et al., The Lancet Neurology, Volume 24, Issue 7, 614 - 624 

Friedreich's ataxia is a rare autosomal recessive neurodegenerative disease. Most patients have a homozygous GAA repeat expansion in the FXN gene, resulting in a deficiency of the mitochondrial protein frataxin. Disease onset occurs typically in adolescence but can vary widely, ranging from early childhood to late adulthood. Friedreich's ataxia is increasingly recognised as a multisystem disorder, affecting not only the nervous system, but also the heart and musculoskeletal system, and metabolism. Common extraneural manifestations include cardiomyopathy, which is the most common cause of mortality, and also scoliosis and diabetes.

Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons

Yang W, Thompson B, Miellet S, Maddock M, Napierala M, Dottori M, Kwa F. Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons. Antioxid Redox Signal. 2025 May 23. doi: 10.1089/ars.2024.0756. Epub ahead of print. PMID: 40406806. 

We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant in vitro FRDA model. Conclusion: SF offers a multipronged approach to alleviating the different cellular events underlying FRDA.

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy Lili Salinas BA , Francisco Figueroa BS , Claire B. Montgomery BS , Phung N. Thai PhD , Nipavan Chiamvimonvat MD , Gino Cortopassi PhD , and Elena N. Dedkova DVM, The Journal of the American Heart Association (JAHA): Cardiovascular and Cerebrovascular Disease doi:10.1161/JAHA.124.038505 

 In conclusion, we determined that omaveloxolone was much more effective in recovering cardiac contractile dysfunction in FXN‐cKO mice as compared with DMF. However, neither of the drugs improved structural derangements, fibrosis, hypertrophy, or improved survival rates. These data suggest that omaveloxolone, but not DMF, could improve cardiac contractile performance and potentially enhance the quality of life in FA patients with a late‐stage cardiomyopathy. Importantly, we noticed that cardiac function was impaired significantly more in FXN‐cKO males versus females; however, omaveloxolone‐treated FXN‐cKO females started dying sooner as compared with vehicle‐treated animals. This observation is highly important and suggests that women living with FA may experience negative side effects of Skyclarys and therefore, may require dose adjustment. It is possible that omaveloxolone overstimulating Nrf2 signaling in FXN‐cKO female mice led to a shift in redox potential into a too reduced state

Cerebellar transcranial direct current stimulation in Friedreich ataxia: anatomy matters

Roderick P.P.W.M. Maas, Dennis J.L.G. Schutter, Cerebellar transcranial direct current stimulation in Friedreich ataxia: anatomy matters, Clinical Neurophysiology, 2025, 2110784, ISSN 1388-2457, doi:10.1016/j.clinph.2025.2110784. 

In this issue of Clinical Neurophysiology, Naeije and colleague demonstrate, for the first time, an association between improvements in motor and non-motor symptoms following cerebellar tDCS and ataxia patients’ anatomical characteristics. patients with larger anterior and posterior lobe GM volumes were more likely to experience favorable effects on motor and non-motor symptoms, respectively, as compared to individuals with smaller volumes. Skin-cerebellum distance was not found to be correlated with tDCS-induced clinical changes. both in FA and in ataxia types with more marked cerebellar atrophy, the preliminary work by Naeije and colleagues marks an important first step towards developing individually tailored cerebellar tDCS interventions for patients with ataxia.

Design Therapeutics Announces Start of Friedreich Ataxia Patient Dosing Ex-U.S. in its RESTORE-FA Phase 1/2 Multiple-Ascending Dose Trial of DT-216P2

CARLSBAD, Calif., June 04, 2025 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. today announced that the first Friedreich ataxia (FA) patient has been dosed via intravenous (IV) infusion in its RESTORE-FA (Reactivating Expression Suppressed Through Overcoming Repeat Expansion for FA) open-label Phase 1/2 multiple-ascending dose (MAD) clinical trial of DT-216P2. 

The RESTORE-FA trial is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of IV and subcutaneous administration of DT-216P2 in patients with FA. DT-216P2 has been administered in one patient to date with no adverse events reported, including no injection site thrombophlebitis. The trial is currently open for enrollment in Australia. Design anticipates reporting data from the MAD trial, including levels of frataxin (FXN) expression based on 12 weeks of dosing, in 2026.

Managing Aminotransferase Elevations in Patients with Friedreich Ataxia Treated with Omaveloxolone: A Review and Expert Opinion on Use Considerations

Authors: Susan Perlman, Mathieu Anheim, Sylvia Boesch, James H. Lewis, David R. Lynch. Published in: Neurology and Therapy. doi:10.1007/s40120-025-00752-8

Use considerations herein may inform decisions on monitoring and managing ALT and AST elevations, which potentially help to encourage the treatment adherence needed to achieve the slowing of FA progression seen in MOXIe.

EMA approved orphan medicines since the implementation of the orphan legislation

Hahl, E., Kurko, T., Koskinen, H. et al. EMA approved orphan medicines since the implementation of the orphan legislation. Orphanet J Rare Dis 20, 266 (2025).doi:10.1186/s13023-025-03756-7

The number of orphan medicines in EU has increased significantly since the introduction of the orphan legislation, i.e., from 2000 to 2022. The selection of orphan medicines tends to focus on medicines used for treating cancer and inborn errors of metabolism or immune system disorders. The coverage of orphan medicines is still minor compared to number of orphan diseases and it seems that the orphan medicines market is focused on rare conditions with highest prevalence. The development of orphan medicines for paediatric use has not been proportionate to the prevalence of rare diseases in children. Orphan medicines with marketing authorisation often target diseases or disease groups that already have available treatments, while several rare diseases remain without available treatment.