Skyclarys (omaveloxolone) / Biogen - LARVOL DELTA

Attenuation of cerebral ischemia-reperfusion induced neurotoxicity by telmisartan, ertugliflozin, and omaveloxolone through Nrf2/HO-1 pathway modulation: In vivo and in silico insights. (PubMed, Toxicol Rep) - "In silico analysis revealed strong binding through highly negative docking scores of telmisartan and ertugliflozin to Nrf2 negative regulators Keap1 and GSK-3β, supported by stable molecular dynamics simulations, suggesting direct inhibition. In conclusion, omaveloxolone, telmisartan, and ertugliflozin alleviate ischemia-reperfusion induced neurotoxicity via potential Nrf2-mediated antioxidant and anti-inflammatory mechanisms, highlighting their potential preventive role in conditions predisposing to stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Diabetes • Hypertension • Metabolic Disorders • Oncology • Reperfusion Injury • Vascular Neurology • HMOX1 • IL6 • KEAP1 • MMP9 • TNFA

RTA-408 Enhances Radiosensitivity and Inhibited Tumor Progression via JNK Pathway in Glioblastoma. (PubMed, Kaohsiung J Med Sci) - "RTA-408 exerts antitumour and radiosensitizing effects via activation of the JNK pathway and inhibits GBM progression. These findings highlight its potential as a novel therapeutic strategy for the treatment of GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CCND1

Computational modeling of ATM signaling: a predictive framework for drug repurposing in ataxia-telangiectasia. (PubMed, NPJ Syst Biol Appl) - "We evaluated the effects of spermidine, omaveloxolone, and HDAC4 inhibition, revealing mechanisms by which these compounds modulate dysfunctional signaling...Our results highlight the synergistic potential of combining autophagy activation and epigenetic modulation to partially restore homeostasis in ATM-deficient cells. This work introduces a generalizable modeling framework for simulating disease-specific signaling dysfunction and identifying therapeutic interventions, illustrating the value of computational systems biology in rare disease drug repurposing."

Journal • Ataxia • CNS Disorders • Genetic Disorders • Immunology • Movement Disorders • Primary Immunodeficiency • Rare Diseases • ATM • HDAC4

Friedreich Ataxia. (PubMed, Pediatr Neurol) - "In this review, we summarize the clinical features, routine management, pathophysiology, and emerging therapies for this devastating disease. The recent approval of omaveloxolone makes recognition of Friedreich ataxia and its treatment essential for all pediatric neurologists."

Journal • Ataxia • CNS Disorders • Friedreich ataxia • Gene Therapies • Movement Disorders • Pediatrics

Omaveloxolone as a Disease-Modifying Therapy in Leigh Syndrome: Insights from Patient-Derived Neurons and an N-of-One Clinical Trial (Neuroscience 2025) - "Additionally, in a preliminary clinical observation involving one patient, administration of Oma led to the upregulation of NRF2 target genes, OxPhos-related transcripts, and PGC1α expression in peripheral blood. These cellular and transcriptomic changes suggest that Oma may help restore mitochondrial function and provide therapeutic benefit by modifying disease progression in LS."

Clinical • CNS Disorders • Psychiatry

Cheminformatics-based drug repurposing using random forest classifier and GAN model (ALS-MND 2025) - "The RF classifier achieved 91.2% accuracy. All 10 GAN-generated compounds were predicted as ALS-targeting by the classifier. Tanimoto similarity values between generated and real ALS drugs ranged from 0.212 and 0.214, with multiple matches to omaveloxolone, an FDA-approved drug for Friedreich's ataxia."

Ataxia • Friedreich ataxia • Movement Disorders

Local Activation of Nrf2 Inhibits Arteriovenous Fistula Stenosis in Mice (KIDNEY WEEK 2025) - "However, a single higher dose of either bardoxolone (1 μg/kg) or omaveloxolone (2 μg/kg) was enough to improve patency. Bardoxolone methyl reduced the volume of the stenotic lesion from 0.4 mm 3 to 0.2 mm 3 (Fig 1). Conclusion Our results suggest that local Nrf2 activation at the time of AVF creation potentially improves maturation rates by inhibiting stenosis."

Preclinical • Cardiovascular

Inhibition of Endoplasmic Reticulum Associated Degradation Is Cytotoxic to Relapsed Refractory Multiple Myeloma through Altered Proapoptotic Signaling (ASH 2024) - "MM cytotoxicity is additive with lenalidomide or dexamethasone. RTA408 is efficacious in primary malignant plasma cells from patients with PI resistance and represents an alternative mechanism to target ER protein degradation with unique effects on proapoptotic signaling and degradation of cytosolic proteins. Further studies are planned for ERAD target protein identification, evaluate ERAD substrate regulation of proapoptotic signaling, and test the application of this inhibitor with combinatorial MM therapeutic approaches."

Ataxia • Friedreich ataxia • Hematological Malignancies • Movement Disorders • Multiple Myeloma • Oncology • Plasmacytoma • Targeted Protein Degradation • CASP8 • ITGAM • MYC

The Mitochondrial Unfolded Protein Response (UPRmt) Is Upregulated in Acute Myeloid Leukemia (AML) and Inhibiting the UPRmt Protease, LONP1, Leads to Mitochondrial Protein Aggregation and Cell Death Selectively in AML (ASH 2024) - "Genetic depletion and chemical inhibition (Omaveloxolone and Bardoxolone methyl) of LONP1 increased mitochondrial protein aggregation in AML cell lines and primary AML samples with high LONP1 but not normal cells or AML samples with low LONP1 and low mitochondrial protein import. In summary, a subset of AML patients have increased mitochondrial protein import and upregulate UPRmt as a protective response. Targeting UPRmt and the processing of newly imported mitochondrial proteins at the level of LONP1 leads to increased mitochondrial protein aggregation and cell death in AML while sparing normal hematopoietic cells in vitro and in vivo."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • LONP1

KEAP1 C151 active site catalysis drives electrophilic signaling to upregulate cytoprotective enzyme expression. (PubMed, Redox Biol) - "NRF2 activators in clinical use and trials (omaveloxolone, bardoxolone methyl, and sulforaphane) readily compete with monobromobimane for C151. Overall, this work suggests enzymatic catalysis is the primary reason that C151 acts as a sensor cysteine for therapeutic, electrophilic NRF2 activators, highly favoring reaction with C151 over other cellular cysteines. The kinetic targeting of electrophiles such as sulforaphane and omaveloxolone to the C151 active site provides an explanation for how electrophilic compounds can be selective pharmacological agents."

Journal • Inflammation • KEAP1

Early experience on omaveloxolone in adult patients with Friedreich's ataxia: a real-world observational study. (PubMed, J Neurol) - "Omaveloxolone seems to be safe and well-tolerated in adult FRDA patients in the real-life setting. No significant worsening of symptoms was observed with no signs of progression, as well as the improvement of inflammatory biomarkers after 24 weeks of treatment, but no predictive factors for the disease response have been identified. However, the short duration, and the small sample size limit the generalizability of the results. Further studies with longer observation are needed to clearly define the efficacy of omaveloxolone in FRDA."

Journal • Observational data • Real-world evidence • Ataxia • Cardiovascular • CNS Disorders • Congestive Heart Failure • Friedreich ataxia • Heart Failure • Movement Disorders • Musculoskeletal Diseases • Renal Disease • FXN • IL6

LEQEMBI global in-market sales of approximately $121 million represents year-over-year growth of 82%; U.S. in-market sales of approximately $69 million shows continued steady growth; ex-U.S. in-market sales of approximately $52 million reflects continued demand growth, offset by a partial drawdown of the previously disclosed Q2 inventory build in China (Biogen Press Release) - "SKYCLARYS global revenue of approximately $133 million represents 30% year-over-year growth; U.S. revenue of approximately $75 million impacted by a Medicare true up...ZURZUVAE revenue of approximately $55 million showed strong continued growth; now approved in the European Union"

Commercial • Alzheimer's Disease • Depression • Friedreich ataxia • Pain • Parkinson's Disease

A Study to Learn if Taking BIIB141 (Omaveloxolone) Affects How Omeprazole is Processed in the Body and About BIIB141's Safety in Healthy Adults Aged 18 to 55 (clinicaltrials.gov) - P1 | N=22 | Completed | Sponsor: Biogen | Recruiting ➔ Completed

Trial completion

Synthesis and Biological Profile of Omaveloxolone: The Cornerstone for Friedreich Ataxia Treatment. (PubMed, Int J Mol Sci) - "Through these mechanisms, OMA contributes to tissue protection and inflammation reduction in patients with FA. The review also highlights future perspective, focusing on the challenges associated with OMA reprofiling through innovative drug delivery approaches and its potential repurposing for diseases beyond FA."

Journal • Review • Ataxia • Friedreich ataxia • Inflammation • Metabolic Disorders • Movement Disorders

Bidirectional regulation of KEAP1 BTB domain-based sensor activity. (PubMed, Redox Biol) - "Co-crystal structural analyses and functional studies using potent NRF2-inducing CDDO-derivatives, synthetic electrophilic compounds structurally related to clinically approved molecules such as Omaveloxolone, revealed that the key sensor residue, Cys151, resides in a structurally elaborate environment within the BTB domain...In contrast, a Cys151-targeting NRF2 inhibitor induces an opposite rearrangement of the BTB homodimer. This study elucidates the molecular mechanism by which the BTB domain finely regulates KEAP1-CUL3 ubiquitin ligase activity."

Journal • Targeted Protein Degradation • KEAP1

The Impact of Friedreich Ataxia Progression on Mobility (MDS Congress 2025) - "Omaveloxolone slowed disease progression in the MOXIe Part 2 (MOXIe2) trial vs placebo as demonstrated by significant improvement in mFARS scores and a nominally significant improvement (p=0.04) in ADL after 48 weeks... FA is a progressive disease that causes increasing challenges with mobility, as demonstrated for different 10-point mFARS ranges. In both trial and registry data, worsening of ADL scores for mobility-related questions correlated strongly with increases in mFARS scores."

Ataxia • CNS Disorders • Movement Disorders

Pleozymes, A Multifunctional Nanozyme for Targeting Metabolic Deficits in Friedreich's Ataxia (MDS Congress 2025) - "We tested a synthetic nano-enzyme Pleozyme for its protective effects in human FRDA-iPSC-derived cells with and without FRDA approved SKYCLARYS® (Omaveloxolone)... These findings demonstrate Pleozyme's ability to improve mitochondrial bioenergetics, reduce oxidative stress, and restore cardiomyocyte function in FRDA models. The study provides strong preclinical evidence supporting further in vivo evaluation and potential clinical translation of Pleozyme as a novel therapy for FRDA and related mitochondrial dysfunction."

Ataxia • CNS Disorders • Movement Disorders • Vascular Neurology • FXN • KEAP1

Design and Outcome Measures of BRAVE, a Phase 3 Study of Omaveloxolone in Pediatric Patients With Friedreich Ataxia (MDS Congress 2025) - P2 | "Results from this study will inform the efficacy and safety of omaveloxolone in patients with FA aged 2 to <16 years, with the goal of providing expanded approval in this pediatric population with unmet need."

Clinical • P3 data • Ataxia • CNS Disorders • Movement Disorders

Long-Term Efficacy and Safety of Omaveloxolone in Patients With Friedreich Ataxia: 4-Year Data From the Ongoing MOXIe Open-Label Extension (MDS Congress 2025) - P2 | "Findings from the MOXIe OLE, the longest study of a disease-modifying therapy in patients with FA, showed slow disease progression with ≈4 years of omav treatment (+1.1 versus ≈2.0 mFARS points/year observed in natural history studies), with no significant disease progression in bulbar function and upper limb coordination, underscoring omav's potential to alter the course of FA."

Clinical • Late-breaking abstract • Ataxia • CNS Disorders • Movement Disorders

Nrf2/ARE pathway agonist omaveloxolone attenuates adverse cardiac remodeling in pressure-induced cardiac dysfunction. (PubMed, J Cardiovasc Pharmacol) - No abstract available

Journal

Oxidative Stress and Antioxidant Therapies in Friedreich's Ataxia. (PubMed, Cells) - "Among the antioxidant treatments tested in FRDA patients, only omaveloxolone and, to a lesser extent, idebenone (particularly for cardiac hypertrophy) have shown some efficacy. Therefore, these drugs may be useful in treating FRDA and are likely candidates for future clinical trials. Future studies investigating oxidative stress and antioxidant therapies in FRDA should adopt a prospective, multicenter, long-term, double-blind design."

Journal • Review • Ataxia • Friedreich ataxia • Metabolic Disorders • Movement Disorders

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 | Completed | Sponsor: Biogen | Recruiting ➔ Completed

Trial completion

A Study to Learn if Taking BIIB141 (Omaveloxolone) Affects How Omeprazole is Processed in the Body and About BIIB141's Safety in Healthy Adults Aged 18 to 55 (clinicaltrials.gov) - P1 | N=22 | Recruiting | Sponsor: Biogen | Not yet recruiting ➔ Recruiting

Enrollment open

Leriglitazone improves iron homeostasis and ferroptotic markers in frataxin-deficient dorsal root ganglia neurons. (PubMed, Biomed Pharmacother) - "In summary, our findings in this neuronal model suggest that targeting the PPARγ pathway with leriglitazone may be a promising therapeutic strategy for FA by improving mitochondrial function, bioenergetic cell alterations, and iron homeostasis. Likewise, a combination therapy with omaveloxolone may be an alternative for FA patients."

Journal • Ataxia • Cardiomyopathy • Cardiovascular • CNS Disorders • Friedreich ataxia • Hypertrophic Cardiomyopathy • Movement Disorders

Omaveloxolone promotes macrophage M2 polarization by activating the NRF2-Keap1 pathway and improves myocardial remodeling induced by pressure overload. (PubMed, J Cardiovasc Pharmacol) - "Omav activates the Nrf2-Keap1 pathway, affects STAT3 phosphorylation, ultimately alleviates M1 macrophage polarization, promotes M2 macrophage polarization, and improves myocardial remodeling. Omav may be a potential therapeutic agent for pathological myocardial remodeling."

Journal • Inflammation