Skyclarys (omaveloxolone) / Biogen - LARVOL DELTA

Retraction: RTA408 alleviates retinal ganglion cells damage in mouse glaucoma by inhibiting excessive autophagy. (PubMed, PLoS One) - No abstract available

Journal • Preclinical • Glaucoma • Ophthalmology

RTA-408 overcomes cisplatin-resistant lung cancer by inhibiting WWP1-mediated NCOA4 ubiquitination to induce ferritinophagy and ferroptosis. (PubMed, Free Radic Biol Med) - "We selected A549/DDP cells as a research model and demonstrated through a series of experimental manipulations that RTA-408 inhibited the growth of A549/DDP cells and inhibited the ubiquitinated degradation of nuclear receptor coactivator 4 through down-regulation of WW structural domain-containing E3 ubiquitin-protein ligase 1 (WWP1), which further induced the development of ferritinophagy and ferroptosis. We report for the first time that RTA-408 overcomes cisplatin-resistant lung cancer by targeting WWP1-mediated ferritinophagy and ferroptosis."

Journal • Ataxia • Friedreich ataxia • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • NCOA4 • UBR5

Quebec denies access to rare disease drug despite Health Canada and national approval (Benefits and Pensions Monitor) - "Skyclarys (omaveloxolone), the first and only treatment for Friedreich Ataxia (FA), received Health Canada approval in late 2023 and a public reimbursement recommendation from Canada’s Drug Agency. Yet, as reported by Healthy Debate, Quebec’s Institut national d’excellence en santé et en services sociaux (INESSS) rejected it, citing a lack of long-term data and concerns about cost-effectiveness—even though the drug has also received approval in the US and Europe."

Regulatory • Friedreich ataxia

Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease. (PubMed, J Immunol) - "Transcriptomic and metabolic analyses revealed that RTA-408 reduces glycolysis and mitochondrial respiration in T cells and reprograms their metabolism towards pentose phosphate pathway and glutaminolysis. Our findings highlight the potential of RTA-408 as a modulator of T cell homeostasis, metabolism, and inflammation, supporting its repurposing for inflammatory diseases like IBD."

Journal • Ataxia • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Movement Disorders • Ulcerative Colitis • CD69 • FOXP3 • GZMB • IFNG • IL17A • IL2 • PRF1

Friedreich's ataxia-a rare multisystem disease. (PubMed, Lancet Neurol) - "Despite research advances, the phenotypical heterogeneity of patients with Friedrich's ataxia remains inadequately explained by current knowledge of the underlying genetics. The approval of omaveloxolone by the US Food and Drug Administration and the European Medicines Agency has been a pharmacological milestone; however, further research addressing complex interorgan interactions is crucial for a better understanding of the multisystem nature of Friedreich's ataxia and the development of targeted treatment approaches."

Journal • Review • Ataxia • Cardiomyopathy • Cardiovascular • CNS Disorders • Diabetes • Friedreich ataxia • Metabolic Disorders • Movement Disorders • Musculoskeletal Diseases • FXN

RTA 408 attenuates TBHP-Induced apoptosis in nucleus pulposus cells via Nrf2/ARE and NF-κB signaling pathways: in vitro and in vivo evidence for mitigating rats' intervertebral disc degeneration. (PubMed, Arthritis Res Ther) - "RTA 408 mitigates oxidative stress-induced NPC apoptosis and ECM degradation via dual modulation of Nrf2/ARE activation and NF-κB suppression. Systemic administration of RTA 408 delays IDD progression in vivo, highlighting its therapeutic potential for degenerative spinal disorders. These findings support further clinical exploration of RTA 408 as a novel Nrf2-targeted therapy for IDD."

IO biomarker • Journal • Preclinical • CNS Disorders • Fibrosis • ACAN • ADAMTS5 • ANXA5 • BAX • BCL2 • CASP3 • MMP13 • MMP9 • NFE2L2 • NFKBIA • NQO1

CD5L is a target of transcription factor Nrf2. (PubMed, Biochem Biophys Res Commun) - "Deletion of two of these sequences by CRISPR/Cas9 gene editing led to a profound decrease in CD5L mRNA levels, confirming the critical role of these ARE-like sequences in controlling CD5L expression. Recombinant CD5L (rCD5L) suppressed transforming growth factor β (TGFβ)-directed fibrogenic responses in human lung fibroblasts, suggesting that Nrf2 activators, such as the clinically used omaveloxolone (RTA-408), could protect against pulmonary fibrosis by boosting the levels of CD5L."

Journal • Fibrosis • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CD5 • TGFB1

Characteristics of Adverse Events and Clinical Risks of Omaveloxolone Based on FAERS Data. (PubMed, Cerebellum) - "Although some of these AEs were reported in relatively low frequencies, their clinical severity and elevated signal strengths suggest that omaveloxolone may potentially affect patients' urinary and endocrine systems, warranting particular attention during clinical administration. In conclusion, while omaveloxolone demonstrates multifaceted benefits in improving neurological function in patients with FRDA, its clinical application necessitates comprehensive evaluation of potential risks, and the development of safe and rational therapeutic strategies is crucial for optimizing treatment outcomes."

Adverse events • Journal • Ataxia • Cardiovascular • Diabetes • Fatigue • Friedreich ataxia • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Movement Disorders • Nephrology • Pain

Biogen Initiates Phase 3 Pediatric Study of Omaveloxolone for the Treatment of Friedreich Ataxia (Biogen Press Release) - "Biogen Inc...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...Enrollment has initiated in the United States and we plan to open BRAVE study sites around the world pending final alignment with local regulators and ethics committees."

Trial status • Friedreich ataxia

A Study to Learn More About the Effects and Long-Term Safety of BIIB141 (Omaveloxolone) in Participants With Friedreich's Ataxia Aged 2 to 15 Years Old (clinicaltrials.gov) - P3 | N=255 | Recruiting | Sponsor: Biogen | Not yet recruiting ➔ Recruiting

Enrollment open • Ataxia • Friedreich ataxia • Movement Disorders

Endothelial cell Nrf2 controls neuroinflammation following a systemic insult. (PubMed, iScience) - "We found that peripheral inflammation caused infiltration of macrophages, microglial activation, and inflammatory reactive astrogliosis, all of which could be prevented by RTA-404, an activator of the transcription factor Nrf2 and close structural relative of the recently FDA-approved Nrf2 activator RTA-408 (omaveloxolone). Strikingly, the effects of RTA-404 on brain endothelial activation and downstream neuroinflammatory events were abolished by endothelial cell-specific Nrf2 deletion. This places endothelial cell Nrf2 as a peripherally accessible therapeutic target to reduce the CNS-adverse consequences of systemic inflammation."

Journal • CNS Disorders • Inflammation

A Study to Learn How BIIB141 (Omaveloxolone) is Processed in the Body When Taken as Capsules Compared to Sprinkled on Yogurt in Healthy Adults Aged 18 to 55 (clinicaltrials.gov) - P1 | N=52 | Not yet recruiting | Sponsor: Biogen

New P1 trial

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy. (PubMed, J Am Heart Assoc) - "These data demonstrate that omaveloxolone significantly improved contractile function but not survival in FA hearts because cardiac fibrosis and wall stress persisted even with omaveloxolone treatment. More studies are warranted to determine the cause of premature death in omaveloxolone-treated FXN-cKO female mice."

Journal • Preclinical • Ataxia • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Friedreich ataxia • Genetic Disorders • Heart Failure • Immunology • Movement Disorders • ALDH1A3 • CAMK2D • GDF15 • IL1B • LGALS3 • NQO1 • SIRT1

Effect of the Nrf2/HO-1 pathway on aluminum-induced liver injury. (PubMed, Ecotoxicol Environ Saf) - "In this study, rats were grouped into the control (C), Al exposure (Al), Al exposure + Omaveloxolone (Al+O), and Al exposure + ML385 (Al+M) groups, and their liver function, hepatic Al content, histopathological changes in liver tissue, and hepatocyte apoptosis were assessed...Furthermore, the Nrf2/HO-1 signaling activation mitigated Al-triggered oxidative stress and apoptosis, whereas its inhibition reduced these protective effects. This study indicated that Al exposure could induce s oxidative damage in rat livers and BRL3A cells; activation of the Nrf2/HO-1 pathway serves as a critical compensatory mechanism against Al toxicity, but its protective efficacy is limited."

Journal • Hepatology • Liver Failure

Disruption of KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models. (PubMed, J Clin Invest) - "RTA408's anti-tumor effects may not be exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in MYCN-amplified patients."

Journal • Preclinical • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • FBXW7 • MYCN

Efficacy of Omaveloxolone Treatment for Dysphagia in French Patients With Friedreich's Ataxia (clinicaltrials.gov) - P=N/A | N=40 | Not yet recruiting | Sponsor: Centre Hospitalier Universitaire de Nice

New trial • Ataxia • Friedreich ataxia • Gastrointestinal Disorder • Movement Disorders

MOXIe clinical trial overview of omaveloxolone for patients with Friedreich ataxia (CNSF 2025) - No abstract available

Clinical • Ataxia • CNS Disorders

Calcium-iron crosstalk in epileptogenesis: Unraveling mechanisms and therapeutic opportunities. (PubMed, Neurobiol Dis) - "Clinically, antiepileptic drugs targeting Ca2+ channels (e.g., ethosuximide, zonisamide) and emerging ferroptosis inhibitors (e.g., deferoxamine, RTA 408) underscore the therapeutic potential of modulating these pathways. Future research must prioritize cross-model validation, advanced neuroimaging biomarkers, and multidisciplinary frameworks to translate mechanistic insights into precision therapies. This comprehensive analysis positions Ca2+-Fe2+ crosstalk as a pivotal frontier in epilepsy research, bridging molecular pathophysiology with innovative treatment paradigms."

Journal • Review • CNS Disorders • Epilepsy • Hematological Disorders • Metabolic Disorders • CAV3 • TRPC6

Biogen Disappointed by INESSS Recommendation on SKYCLARYS and its Impact on Quebec Patients with Friedreich Ataxia (Canada Newswire) - "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. A decision to not reimburse SKYCLARYS would leave individuals living with FA in Quebec without public access to the only approved treatment for this rare, progressive, and life-shortening neurodegenerative disease – despite a clear and ongoing medical need."

Reimbursement • Friedreich ataxia

Managing Aminotransferase Elevations in Patients with Friedreich Ataxia Treated with Omaveloxolone: A Review and Expert Opinion on Use Considerations. (PubMed, Neurol Ther) - "We propose patients who pause treatment may have testing repeated after 2 weeks, while those with resolving aminotransferase elevations may reinitiate omaveloxolone with stepwise dose titrations and testing every 2 weeks for ≈ 3 months. 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.Graphical abstract available for this article."

Journal • Review • Ataxia • Friedreich ataxia • Hepatology • Liver Failure • Movement Disorders • Pediatrics

Omaveloxolone Suppresses Cell Growth and Causes Cell Cycle Arrest by Downregulating CDC20 Expression in Glioblastoma Cells Both In Vitro and In Vivo. (PubMed, J Cell Mol Med) - "In a xenograft tumour model, omaveloxolone decreased tumour volume and CDC20 expression. Taken together, these findings suggest that omaveloxolone is a potential drug candidate for GBM treatment by promoting GBM cell death through the downregulation of CDC20 expression."

Journal • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CDC20

Combination therapy with losartan and RTA-408 in a recessive dystrophic epidermolysis bullosa (RDEB) mouse model (SID 2025) - "Our findings indicate that the combination of Losartan and RTA-408 had limited therapeutic benefits compared with single-drug treatment. These results support the continued exploration of multi-drug approaches to mitigate fibrosis and inflammation in RDEB and related disorders."

Combination therapy • Late-breaking abstract • Preclinical • Dermatology • Fibrosis • Immunology • Inflammation • COL7A1 • PTPRC

Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons. (PubMed, Antioxid Redox Signal) - "Omaveloxolone, a nuclear factor erythroid 2-related factor-2 (NRF2) inducer, is the only treatment available...00, 000-000. [Figure: see text]."

Journal • Ataxia • Friedreich ataxia • Inflammation • Movement Disorders • FXN • PRPH

A Study to Find Out How BIIB141 (Omaveloxolone) is Processed in the Body and to Learn More About Its Safety in Participants With Friedreich's Ataxia Aged 2 to 15 Years Old (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: Biogen | N=20 ➔ 35

Enrollment change • Ataxia • Friedreich ataxia • Movement Disorders

Characteristics of RWE used in Regulatory Decision-Making for Marketing Authorization Applications (MAAs) (ISPOR 2025) - " Seven medicines were analyzed: idecabtagene vicleucel (ide-cel), omburtamab, sotorasib, alpelisib, palovarotene, tacrolimus, and omaveloxolone. MAAs containing RWE submitted to the FDA were predominantly for rare diseases medicines and for first-in-class indications. Acceptability of RWE varied based on entire body of evidence. Further investigation into factors influencing RWE acceptability and its integration into MAAs across other regulators such as EMA is warranted."

Hematological Disorders • Rare Diseases