To see the other types of publications on this topic, follow the link: Omaveloxolone.
Journal articles on the topic 'Omaveloxolone'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Omaveloxolone.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Madsen, Karen L., Astrid E. Buch, Bruce H. Cohen, et al. "Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy." Neurology 94, no. 7 (2020): e687-e698. http://dx.doi.org/10.1212/wnl.0000000000008861.
Full textAbstract:
ObjectiveTo investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.MethodsIn cohorts of 8–13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).ResultsNo differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.ConclusionsOmaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.Clinicaltrials.gov identifierNCT02255422.Classification of evidenceThis study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
2
Kania, Krzysztof, Joanna Kania, Karolina Niekurzak, Maciej Jędrak, Maciej Józefiak, and Piotr Sobkiewicz. "FDA Approves Omaveloxolone based on Successful Moxie Trial Results for Friedreich's Ataxia - Review." Journal of Education, Health and Sport 40, no. 1 (2023): 111–26. http://dx.doi.org/10.12775/jehs.2023.40.01.010.
Full textAbstract:
Introduction: In recent years, the medical community has witnessed a significant breakthrough in the treatment of Friedreich's Ataxia (FRDA), a rare and debilitating genetic disorder affecting the nervous system. This neurological condition, characterized by progressive muscle weakness, impaired coordination, and cardiomyopathy, has long posed challenges for both patients and healthcare professionals alike. However, there is newfound hope with the recent approval of Omaveloxolone by the U.S. Food and Drug Administration (FDA).Aim of the study: This review article aims to present a detailed summary of the FDA's approval of Omaveloxolone as a therapeutic option for Friedreich's Ataxia (FRDA), focusing on the positive results obtained from the MOXIe trial. It covers various aspects of FRDA and explains how Omaveloxolone works as an activator of NRF2, a transcription factor that helps reduce oxidative stress. The MOXIe trial, which examined the safety and effectiveness of Omaveloxolone in FRDA patients, is discussed in detail, including its methodology, primary and secondary goals, and results. Materials and methods: This review was based on available data collected in the PubMed and Google Scholar database, using the key words: FRDA, Friedreich’s Ataxia, Omaveloxolone, RTA 408, NRF2, MOXIe trail.Conclusion: Omaveloxolone has shown significant efficacy in improving neurological function and mFARS scores compared to a placebo in the MOXIe trial. It is well-tolerated with minimal adverse events. Early intervention with Omaveloxolone offers enhanced benefits for managing Friedreich's ataxia progression.
3
Lalitha, A. Nanjundeshwari G. Swetha M. Swetha R. "A Review On Omaveloxolone." International Journal in Pharmaceutical Sciences 1, no. 9 (2023): 447–56. https://doi.org/10.5281/zenodo.8383431.
Full textAbstract:
Omaveloxolone is a semisynthetic triterpenoid used to treat friedreich’s ataxia. It is the second generation oleananetriterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties. It is currently used to test in medical trials for freidreich’s ataxia, a genetic, multi –organ disease involving mitochondrial dysfunction. It is a nuclear factor erythroid 2 related factor 2 (Nrf2) activator. It is reviewed under Food and Drug Administration and it has the potential to first approved treatment for friedreich’s ataxia. Omaveloxolone is not the cure for friedreich’s ataxia, it is the first agent targeting to reach NDA submission. It is the rational and potent therapy that is probably disease modifying in the treatment of friedreich’s ataxia. Omaveloxolone (RTA-408) is an Nrf2 activator, which decreases the susceptibility of cells through oxidative stress and it leads to cell death and tissue degradation. It is good tolerated not having any significant long term adverse effects. Treatment with RTA-408 remarkably improved in the neurological function, it is measured by modified Freidreich’s Ataxia Rating Scale.
4
Kessler, Riley, Sonal Sharma, and David R. Lynch. "Omaveloxolone for the Treatment of Friedreich’s Ataxia." US Neurology 19, no. 2 (2023): 2. http://dx.doi.org/10.17925/usn.2023.19.2.2.
Full textAbstract:
Friedrich’s ataxia (FRDA), a neurodevelopmental and progressive neurodegenerative disease, is the most common inherited form of ataxia. Omaveloxolone was approved by the US Food and Drugs Administration in early 2023, making it the first treatment available to patients with FRDA. This approval was made possible by combining a compelling cellular mechanism and strong clinical evidence provided through the MOXIe study, the multipart clinical trial evaluating the efficacy of omaveloxolone in patients with FRDA. This review discusses the underlying cellular pathology and proposed mechanism of omaveloxolone in FRDA. The MOXIe study is presented in detail, including a discussion of the challenges faced in clinical trials in FRDA, and rare diseases more broadly. Finally, other therapies under investigation are reviewed briefly.
5
KANIA, Krzysztof, Joanna KANIA, Karolina NIEKURZAK, Maciej JĘDRAK, Maciej JÓZEFIAK, and Piotr SOBKIEWICZ. "FDA Approves Omaveloxolone based on Successful Moxie Trial Results for Friedreich's Ataxia - Review." Journal of Education, Health and Sport 40, no. 1 (2023): 11–126. https://doi.org/10.12775/JEHS.2023.40.01.010.
Full textAbstract:
<strong>KANIA, Krzysztof, KANIA, Joanna, NIEKURZAK, Karolina, JĘDRAK, Maciej, JÓZEFIAK, Maciej and SOBKIEWICZ, Piotr. FDA Approves Omaveloxolone based on Successful Moxie Trial Results for Friedreich’s Ataxia - Review.</strong> <strong>Journal of Education, Health and Sport. 2023;</strong><strong>40</strong><strong>(1):</strong><strong>111-</strong><strong>1</strong><strong>26</strong><strong>.</strong><strong> eISSN 2391-8306. DOI </strong><strong>http://dx.doi.org/10.12775/JEHS.2023.40.01.0</strong><strong>10</strong> <strong>https://apcz.umk.pl/JEHS/article/view/449</strong><strong>71</strong> <strong>https://zenodo.org/record/8215177</strong> <strong>The journal has had 40 points in Ministry of Education and Science of Poland parametric evaluation. Annex to the announcement of the Minister of Education and Science of 17.07.2023 No. 32318. Has a Journal's Unique Identifier: 201159. Scientific disciplines assigned: Physical Culture Sciences (Field of Medical sciences and health sciences); Health Sciences (Field of Medical Sciences and Health Sciences).</strong> <strong>Punkty Ministerialne z 2019 - aktualny rok 40 punktów. Załącznik do komunikatu Ministra Edukacji i Nauki z dnia 17.07.2023 Lp. 323</strong><strong>18</strong><strong>. Posiada Unikatowy Identyfikator Czasopisma: 201159.</strong> <strong>Przypisane dyscypliny naukowe: Nauki o kulturze fizycznej (Dziedzina nauk medycznych i nauk o zdrowiu); Nauki o zdrowiu (Dziedzina nauk medycznych i nauk o zdrowiu).</strong> <strong>© The Authors 2023;</strong> <strong>This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland</strong> <strong>Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike.</strong> <strong>(http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited.</strong> <strong>The authors declare that there is no conflict of interests regarding the publication of this paper.</strong> <strong>Received: </strong><strong>09</strong><strong>.0</strong><strong>7</strong><strong>.2023. Revised:</strong><strong>30</strong><strong>.0</strong><strong>7</strong><strong>.2023. Accepted: </strong><strong>31</strong><strong>.0</strong><strong>7</strong><strong>.2023. Published: </strong><strong>08</strong><strong>.0</strong><strong>8</strong><strong>.2023.</strong> <strong>FDA Approves Omaveloxolone based on Successful Moxie Trial Results for Friedreich's Ataxia - Review</strong> Krzysztof Kania Medical University of Warsaw, Poland https://orcid.org/0009-0000-0708-7661 krzysztof.kania.m@gmail.com Joanna Kania Medical University of Lublin, Poland https://orcid.org/0009-0005-6156-6192 1joanna.kania1@gmail.com Karolina Niekurzak Medical University of Lublin, Poland https://orcid.org/0009-0009-5205-2236 karolina.niekurzak71@gmail.com Maciej Jędrak Medical University of Lublin, Poland https://orcid.org/0009-0000-4557-0099 mjedrak2014@gmail.com Maciej Józefiak Wroclaw Medical University, Poland https://orcid.org/0009-0000-3585-5031 jozefiakmaciej19@gmail.com Piotr Sobkiewicz Wroclaw Medical University, Poland https://orcid.org/0009-0007-6610-440X piotr1999.sob@gmail.com <strong>Key words:</strong> FRDA, Friedreich’s Ataxia, Omaveloxolone, RTA 408, NRF2, MOXIe trail. <strong>ABSTRACT</strong> <strong>Introduction: </strong>In recent years, the medical community has witnessed a significant breakthrough in the treatment of Friedreich's Ataxia (FRDA), a rare and debilitating genetic disorder affecting the nervous system. This neurological condition, characterized by progressive muscle weakness, impaired coordination, and cardiomyopathy, has long posed challenges for both patients and healthcare professionals alike. However, there is newfound hope with the recent approval of Omaveloxolone by the U.S. Food and Drug Administration (FDA). <strong>Aim of the study: </strong>This review article aims to present a detailed summary of the FDA's approval of Omaveloxolone as a therapeutic option for Friedreich's Ataxia (FRDA), focusing on the positive results obtained from the MOXIe trial. It covers various aspects of FRDA and explains how Omaveloxolone works as an activator of NRF2, a transcription factor that helps reduce oxidative stress. The MOXIe trial, which examined the safety and effectiveness of Omaveloxolone in FRDA patients, is discussed in detail, including its methodology, primary and secondary goals, and results. <strong>Materials and methods: </strong>This review was based on available data collected in the PubMed and Google Scholar database, using the key words: FRDA, Friedreich’s Ataxia, Omaveloxolone, RTA 408, NRF2, MOXIe trail. <strong>Conclusion: </strong>Omaveloxolone has shown significant efficacy in improving neurological function and mFARS scores compared to a placebo in the MOXIe trial. It is well-tolerated with minimal adverse events. Early intervention with Omaveloxolone offers enhanced benefits for managing Friedreich's ataxia progression. Słowa kluczowe: FRDA, Ataksja Friedreicha, Omaweloksolon, RTA 408, NRF2, szlak MOXIe.
6
Lynch, David R., and Joseph Johnson. "Omaveloxolone: potential new agent for Friedreich ataxia." Neurodegenerative Disease Management 11, no. 2 (2021): 91–98. http://dx.doi.org/10.2217/nmt-2020-0057.
Full textAbstract:
Friedreich ataxia is a slowly progressive neurodegenerative disorder leading to ataxia, dyscoordination, dysarthria and in many individuals vision and hearing loss. It is associated with cardiomyopathy, the leading cause of death in Friedreich ataxia (FRDA), diabetes and scoliosis. There are no approved therapies, but elucidation of the pathophysiology of FRDA suggest that agents that increase the activity of the transcription factor Nrf2 may provide a mechanism for ameliorating disease progression or severity. In this work, we review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.
7
Lynch, David R., Jennifer Farmer, Lauren Hauser, et al. "Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia." Annals of Clinical and Translational Neurology 6, no. 1 (2018): 15–26. http://dx.doi.org/10.1002/acn3.660.
Full text
8
Reisman, Scott A., Sarabjit S. Gahir, Chun-Yue I. Lee, Joel W. Proksch, Mitsumasa Sakamoto, and Keith W. Ward. "Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates." Drug Design, Development and Therapy Volume 13 (April 2019): 1259–70. http://dx.doi.org/10.2147/dddt.s193889.
Full text
9
Urbich, M., R. Lawson, M. Gianinazzi, et al. "CO197 Predicted Clinical Outcomes for Patients Treated With Omaveloxolone for Friedreich Ataxia." Value in Health 27, no. 12 (2024): S51. https://doi.org/10.1016/j.jval.2024.10.273.
Full text
10
Tcheng, Matthew, Veronique Voisin, Marcela Gronda, et al. "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." Blood 144, Supplement 1 (2024): 2778. https://doi.org/10.1182/blood-2024-205308.
Full textAbstract:
Compared to normal hematopoietic cells, AML are uniquely reliant on the mitochondria and its proteome for survival and proliferation. The mitochondrial proteome contains ~1100 unique proteins, of which all but 13 are encoded by nuclear DNA, translated in the cytoplasm and imported into the mitochondria. To measure mitochondrial protein import in AML and normal cells, we developed a novel assay to quantify the mitochondrial import of puromycin labeled proteins. Compared to normal cells, primary AML samples had a 10-fold increase in mitochondrial protein import. Likewise, expression of mitochondrial protein import genes were higher in AML compared to normal. Failure to properly process newly imported proteins into their mature forms leads to protein aggregation resulting in mitochondrial dysfunction. The mitochondrial unfolded protein response (UPRmt) pathway utilizes chaperones and proteases to cleave, fold and degrade newly imported and damaged proteins. Since there are no dedicated UPRmt gene sets in GO, KEGG, and Reactome databases, we curated a 39 gene signature that encompasses the components of UPRmt. UPRmt gene expression was increased in primary AML, compared to normal, and positively correlated with mitochondrial protein import gene expression. We next assessed the dependencies of UPRmt genes in 24 AML cell lines (DepMap database). Across shRNA and CRISPR screens, the mitochondrial AAA+ protease LONP1 was a top dependency. LONP1 is a serine protease that unfolds and degrades damaged or misfolded protein through its ATPase and protease domains, respectively. Compared to normal cells, LONP1 protein was increased &gt;2-fold in 16/30 primary AML samples by immunoblotting. LONP1 was equally expressed across the molecular and cytogenetic AML subgroups in 730 primary AML samples by Reverse Phase Protein Array. LONP1 mRNA expression positively correlated with UPRmt and mitochondrial protein import gene expression. Through its ATPase activity, LONP1 acts in concert with mitochondrial chaperones to fold and solubilize newly imported mitochondrial proteins. We developed a novel confocal-based assay to measure mitochondrial protein aggregation using Proteostat, a dye that fluoresces when bound to aggregated proteins. We visualized the co-localization of Proteostat and the mitochondrial marker TOM20 with confocal microscopy and quantified the co-localization with HALO image analysis. 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. We confirmed the increase in mitochondrial protein aggregation after LONP1 inhibition using immunoblotting of LONP1 substrates in detergent-soluble and -insoluble fractions of mitochondrial lysates. We also demonstrated that the ATPase domain but not the proteolytic domain of LONP1 was necessary for mitochondrial protein solubility. Genetic depletion and chemical inhibition of LONP1 killed AML cell lines and primary AML samples. In primary AML, LONP1 expression positively correlated with sensitivity to LONP1 chemical inhibition or genetic depletion (Omaveloxolone (n= 16, R2=0.64); Bardoxolone methyl (n= 30, R2=0.65); LONP1 shRNA (n=9, R2=0.72)). We also discovered that the ATPase domain but not the proteolytic domain of LONP1 was necessary for AML viability. LONP1 knockdown decreased engraftment of AML lines and primary AML samples with high LONP1 into the marrow of NSG mice. Likewise, systemic treatment with Omaveloxolone and Bardoxolone methyl reduced AML growth in mice xenografted with AML cells and primary samples with high LONP1. Daily treatment of mice with Omaveloxolone and Bardoxolone methyl for 6 days increased mitochondrial protein aggregation in xenografted AML cells but not in normal mouse tissues, despite its cross-reactivity with murine LONP1. 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.
11
Dinkova-Kostova, Albena. "KEAP1/NRF2 as a druggable target." Arhiv za farmaciju 73, no. 2 (2023): 89–108. http://dx.doi.org/10.5937/arhfarm73-43475.
Full textAbstract:
Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by NFE2L2) is an inducible transcription factor that regulates the expression of a large network of genes encoding proteins with cytoprotective functions. NRF2 also has a role in the maintenance of mitochondrial and protein homeostasis, and its activation allows adaptation to numerous types of cellular stress. NRF2 is principally regulated at the protein stability level by three main ubiquitin ligase systems, of which the regulation by Kelch-like ECH-associated protein 1 (KEAP1), a substrate adaptor protein for Cul3/Rbx1-based ubiquitin ligase, is best understood. KEAP1 is a multi-functional protein and, in addition to being a substrate adaptor, it is a sensor for electrophiles and oxidants. Pharmacological inactivation of KEAP1 has protective effects in animal models of human disease, and KEAP1 is now widely recognized as a drug target, particularly for chronic diseases, where oxidative stress and inflammation underlie pathogenesis. Many compounds that target KEAP1 have been developed, including electrophiles that bind covalently to cysteine sensors in KEAP1, non-electrophilic protein-protein interaction inhibitors that bind to the Kelch domain of KEAP1, disrupting its interaction with NRF2, and most recently, heterobifunctional proteolysistargeting chimeras (PROTACs) that promote the proteasomal degradation of KEAP1. The drug development of KEAP1-targeting compounds has led to the entry of two compounds, dimethyl fumarate (BG-12, Tecfidera®) and RTA-408 (omaveloxolone, SKYCLARYS®), in clinical practice. In 2013, dimethyl fumarate was licenced as the first oral first-line therapy for relapsingremitting multiple sclerosis and is also used for the treatment of moderate-to-severe plaque psoriasis. In February 2023, omaveloxolone was approved by the United States Food and Drug Administration as the first and only drug for patients with Friedreich's ataxia.
12
Ghanekar, Shaila D., Wai Wai Miller, Colin J. Meyer, Kelvin J. Fenelon, Alvin Lacdao, and Theresa A. Zesiewicz. "Orphan Drugs In Development For The Treatment Of Friedreich’s Ataxia: Focus On Omaveloxolone." Degenerative Neurological and Neuromuscular Disease Volume 9 (October 2019): 103–7. http://dx.doi.org/10.2147/dnnd.s180027.
Full text
13
Zakuraeva, Karina А., Maria I. Yarmolinskaya, Andrey Yu Vinokurov, and Marina Yu Pogonyalova. "The new method for premature ovarian insufficiency treatment based on the effect of omaveloxolone (RTA 408) on the mitochondrial function of granulosa cells." Journal of obstetrics and women's diseases 73, no. 6 (2025): 53–66. https://doi.org/10.17816/jowd640811.
Full textAbstract:
Background: Premature ovarian insufficiency is a syndrome characterized by secondary hypergonadotropic ovarian insufficiency and a decrease in the ovarian function in women under 40 years of age, thereby leading to impaired reproductive function, metabolic changes, and a decrease in the quality of life. Increased production of reactive oxygen species inhibits the mitochondrial respiration chain and leads to mitochondrial dysfunction and oxidative stress, which are considered as the triggers of premature ovarian insufficiency. To date, there is no universal method of premature ovarian insufficiency prevention, and accepted treatment methods can only compensate for clinical symptoms, but not restore the lost ovarian reserve. Aim: The aim of this study was to develop a new method of premature ovarian insufficiency treatment based on an experimental ovarian granulosa cell model using omaveloxolone (RTA 408). Materials and methods: The cell model of premature ovarian insufficiency used in the study was realized according to the Patent RU 2 815 539 C1, 2023 (by M.I. Yarmolinskaya, K.A. Zakuraeva, A.Yu. Vinokurov, M.Yu. Pogonyalova). Ovarian granulosa cells isolated from three-month Wistar rats were subcultivated five times with subsequent seeding on coverslips. The cells on the coverslips were divided into three groups (three coverslip in each group). In Group 1 (comparison group — premature ovarian insufficiency model without treatment), cells were treated with cyclophosphamide (0.1 mg/ml) during 6 h. In Group 2 (main group — premature ovarian insufficiency model with experimental treatment) cells were pretreated with RTA 408 (2 µl/ml) during 1 h with subsequent addition of cyclophosphamide (0.1 mg/ml) and cultivation during 6 h. And in Group 3 (control group), cells were added no substances. Results: Compared to Groups 2 and 3, the use of omaveloxolone (RTA 408) led to an increase in reduced glutathione level and a decrease in reactive oxygen species production rate, which indicates the antioxidant and anti-inflammatory effects of the drug and may be considered as a perspective strategy of premature ovarian insufficiency treatment. The claimed method expands the number of premature ovarian insufficiency treatment strategies and avoids the use of hormonal medications and surgical procedures, thus reducing the risk of side effects and complications associated with their use.
14
Dong, Yi Na, Elizabeth Mercado-Ayón, Jennifer Coulman, et al. "The Regulation of the Disease-Causing Gene FXN." Cells 13, no. 12 (2024): 1040. http://dx.doi.org/10.3390/cells13121040.
Full textAbstract:
Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease caused in almost all patients by expanded guanine–adenine–adenine (GAA) trinucleotide repeats within intron 1 of the FXN gene. This results in a relative deficiency of frataxin, a small nucleus-encoded mitochondrial protein crucial for iron–sulfur cluster biogenesis. Currently, there is only one medication, omaveloxolone, available for FRDA patients, and it is limited to patients 16 years of age and older. This necessitates the development of new medications. Frataxin restoration is one of the main strategies in potential treatment options as it addresses the root cause of the disease. Comprehending the control of frataxin at the transcriptional, post-transcriptional, and post-translational stages could offer potential therapeutic approaches for addressing the illness. This review aims to provide a general overview of the regulation of frataxin and its implications for a possible therapeutic treatment of FRDA.
15
Jian, Wenting, Huigai Ma, Dingming Wang, et al. "Omaveloxolone attenuates the sepsis-induced cardiomyopathy via activating the nuclear factor erythroid 2-related factor 2." International Immunopharmacology 111 (October 2022): 109067. http://dx.doi.org/10.1016/j.intimp.2022.109067.
Full text
16
Hu, Libin, Yang Cao, Huaijun Chen, et al. "The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice." Oxidative Medicine and Cellular Longevity 2022 (March 11, 2022): 1–18. http://dx.doi.org/10.1155/2022/4564471.
Full textAbstract:
The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO-1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1-like activation and promoted the activation of the M2-like microglial phenotype. Omav inhibited OxyHb-induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.
17
Chang, Kuo-Hsuan, and Chiung-Mei Chen. "The Role of NRF2 in Trinucleotide Repeat Expansion Disorders." Antioxidants 13, no. 6 (2024): 649. http://dx.doi.org/10.3390/antiox13060649.
Full textAbstract:
Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an imbalance of reactive oxygen species that harms cellular components. This review explores the interplay between oxidative stress and the NRF2 pathway in these disorders. NRF2 acts as the master regulator of the cellular antioxidant response, orchestrating the expression of enzymes that combat oxidative stress. Trinucleotide repeat expansion disorders often exhibit impaired NRF2 signaling, resulting in inadequate responses to excessive ROS production. NRF2 activation has been shown to upregulate antioxidative gene expression, effectively alleviating oxidative stress damage. NRF2 activators, such as omaveloxolone, vatiquinone, curcumin, sulforaphane, dimethyl fumarate, and resveratrol, demonstrate neuroprotective effects by reducing oxidative stress in experimental cell and animal models of these diseases. However, translating these findings into successful clinical applications requires further research. In this article, we review the literature supporting the role of NRF2 in the pathogenesis of these diseases and the potential therapeutics of NRF2 activators.
18
Chien, Jia-Ying, Yu-Yau Chou, Jhih-Wei Ciou, Fang-Yun Liu, and Shun-Ping Huang. "The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy." Antioxidants 10, no. 9 (2021): 1466. http://dx.doi.org/10.3390/antiox10091466.
Full textAbstract:
Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most common acute optic neuropathies that affect the over 55-year-old population. NAION causes the loss of visual function, and it has no safe and effective therapy. Bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a semisynthetic triterpenoid with effects against antioxidative stress and inflammation in neurodegeneration and kidney disease that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402 is an FDA-approved compound for the treatment of solid tumors, lymphoid malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also under clinical investigation for Friedreich ataxia (FA). In this study, a rodent anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on retinal ganglion cell (RGC) survival and visual function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the retina and optic nerve. However, these effects were not observed after RTA 408 treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2 and NFκB signaling pathways to protect RGCs from apoptosis and maintain the visual function in an rAION model. These findings indicate that RTA 402 may a potential therapeutic agent for ischemic optic neuropathy.
19
Patel, S. P., F. S. Hodi, D. Gabrilovich, et al. "A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma." Annals of Oncology 28 (December 2017): xi30. http://dx.doi.org/10.1093/annonc/mdx760.
Full text
20
Wu, Yu-Ling, Jui-Chih Chang, Yi-Chun Chao, Hardy Chan, Mingli Hsieh, and Chin-San Liu. "In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3." Antioxidants 11, no. 7 (2022): 1389. http://dx.doi.org/10.3390/antiox11071389.
Full textAbstract:
Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD78) to clarify the resulting pathological mechanism by assaying mitochondrial function, mutant ataxin-3 protein toxicity, and oxidative stress. JM17, 1 μM, comprehensively restored mitochondrial function, decreased mutant protein aggregates, and attenuated intracellular/mitochondrial reactive oxygen species (ROS) levels. Although JM17 induced dose-dependent Nrf2 activation, a low dose of JM17 (less than 5 μM) still had a better antioxidant ability compared to the other Nrf2 activators and specifically increased mitochondrial superoxide dismutase 2 in an Nrf2-dependent manner as shown by knockdown experiments with siRNA. It showed that activation of Nrf2 in response to ROS generated in mitochondria could play an import role in the benefit of JM17. This study presents the diversified regulation of JM17 in a pathological process and helped develop more effective therapeutic strategies for SCA3.
21
Da Conceição, Loiane Mendonça Abrantes, Lucio Mendes Cabral, Gabriel Rodrigues Coutinho Pereira, and Joelma Freire De Mesquita. "An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia." International Journal of Molecular Sciences 25, no. 11 (2024): 5796. http://dx.doi.org/10.3390/ijms25115796.
Full textAbstract:
Friedreich’s Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
22
Boghdeh, Niloufar A., Kenneth H. Risner, Michael D. Barrera, et al. "Application of a Human Blood Brain Barrier Organ-on-a-Chip Model to Evaluate Small Molecule Effectiveness against Venezuelan Equine Encephalitis Virus." Viruses 14, no. 12 (2022): 2799. http://dx.doi.org/10.3390/v14122799.
Full textAbstract:
The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load.
23
Boghdeh, Niloufar A., Brittany McGraw, Michael D. Barrera, et al. "Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses." Viruses 15, no. 3 (2023): 655. http://dx.doi.org/10.3390/v15030655.
Full textAbstract:
New World alphaviruses including Venezuelan Equine Encephalitis Virus (VEEV) and Eastern Equine Encephalitis Virus (EEEV) are mosquito-transmitted viruses that cause disease in humans and equines. There are currently no FDA-approved therapeutics or vaccines to treat or prevent exposure-associated encephalitic disease. The ubiquitin proteasome system (UPS)-associated signaling events are known to play an important role in the establishment of a productive infection for several acutely infectious viruses. The critical engagement of the UPS-associated signaling mechanisms by many viruses as host–pathogen interaction hubs led us to hypothesize that small molecule inhibitors that interfere with these signaling pathways will exert broad-spectrum inhibitory activity against alphaviruses. We queried eight inhibitors of the UPS signaling pathway for antiviral outcomes against VEEV. Three of the tested inhibitors, namely NSC697923 (NSC), bardoxolone methyl (BARM) and omaveloxolone (OMA) demonstrated broad-spectrum antiviral activity against VEEV and EEEV. Dose dependency and time of addition studies suggest that BARM and OMA exhibit intracellular and post-entry viral inhibition. Cumulatively, our studies indicate that inhibitors of the UPS-associated signaling pathways exert broad-spectrum antiviral outcomes in the context of VEEV and EEEV infection, supporting their translational application as therapeutic candidates to treat alphavirus infections.
24
Tcheng, Matthew, Veronique Voisin, Marcela Gronda, et al. "Abstract 3033: Increased mitochondrial protein import necessitates greater reliance on the mitochondrial unfolded protein response (UPRmt) and the protease LONP1 to maintain mitochondrial protein solubility and cell viability in acute myeloid leukemia (AML)." Cancer Research 85, no. 8_Supplement_1 (2025): 3033. https://doi.org/10.1158/1538-7445.am2025-3033.
Full textAbstract:
Abstract Almost all mitochondrial proteins are encoded by nuclear DNA, translated in the cytosol, and imported into the mitochondria. Once inside the mitochondria, these unfolded, aggregation prone precursors are processed and folded into mature forms. Failure to properly process and fold these newly imported proteins results in the formation of toxic aggregates. To counter the mitochondrial stress from newly imported proteins, cells developed the mitochondrial unfolded protein response (UPRmt), a conserved pathway which activates the transcription of mitochondrial proteases and chaperones to fold newly imported precursors and degrade protein aggregates. There are no UPRmt gene sets in the KEGG, Gene Ontology or Reactome databases, so we compiled a 39-gene signature of the known components of the human UPRmt. In primary AML cells, expression of this UPRmt signature was increased compared to normal hematopoietic cells. UPRmt expression was strongly correlated with mitochondrial protein import expression, highlighting the protective role of the UPRmt in countering the stress of increased protein import. Leading edge analysis identified the protease LONP1 as a top driver of the UPRmt signature and analysis of AML cells’ dependency on UPRmt genes (Depmap) also identified LONP1 as a top essential gene. We focused additional studies on LONP1 and its role in protecting AML cells from mitochondrial stress. LONP1 mRNA expression was increased in AML compared to normal hematopoietic cells. LONP1 protein was increased &gt;2-fold in 26/39 primary AML samples, compared to bulk (n=14) and CD34+ (n=3) hematopoietic cells. In AML, LONP1 expression positively correlated with expression of protein import and UPRmt genes as well as decreased overall survival. LONP1 folds newly imported precursors and degrades aggregated mitochondrial proteins. To assess the role of LONP1 in mitochondrial proteostasis, we developed a novel assay to measure mitochondrial protein aggregation. LONP1 genetic depletion and chemical inhibition with Omaveloxolone and bardoxolone methyl increased mitochondrial protein aggregation and cell death in AML lines and primary AML with high LONP1 but not hematopoietic cells or primary AML with low LONP1. In primary AML, sensitivity to LONP1 chemical inhibition or genetic depletion positively correlated with LONP1 expression (Omaveloxolone (n=16, R2=0.64); Bardoxolone methyl (n=30, R2=0.65); LONP1 shRNA (n=9, R2=71)). In summary, AML cells have increased mitochondrial protein import, necessitating a heightened dependence on the UPRmt to maintain mitochondrial proteostasis. Targeting the UPRmt at the level of LONP1 selectively induces mitochondrial protein aggregation and eliminates AML cells while sparing normal hematopoietic cells. Citation Format: Matthew Tcheng, Veronique Voisin, Marcela Gronda, Rose Hurren, Lan Xin Zhang, Yue Feng, Zaynab Mamai, Brady Stock, Yulia Jitkova, Andrea Arruda, Steven M. Kornblau, Mark D. Minden, Aaron D. Schimmer. Increased mitochondrial protein import necessitates greater reliance on the mitochondrial unfolded protein response (UPRmt) and the protease LONP1 to maintain mitochondrial protein solubility and cell viability in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3033.
25
Higa, Yoshiki, Masahiro Hiasa, Hirofumi Tenshin, et al. "The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2." Antioxidants 12, no. 1 (2023): 133. http://dx.doi.org/10.3390/antiox12010133.
Full textAbstract:
Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.
26
Creelan, Ben, Dmitry Gabrilovich, Jhanelle Gray, et al. "Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors." OncoTargets and Therapy Volume 10 (August 2017): 4239–50. http://dx.doi.org/10.2147/ott.s136992.
Full text
27
Jain, Paridhi, Lohit Badgujar, Jelle Spoorendonk, and Katharina Buesch. "Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review." Therapeutic Advances in Rare Disease 3 (January 2022): 263300402211398. http://dx.doi.org/10.1177/26330040221139872.
Full textAbstract:
Objectives: The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease. Methods: Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched. Results: Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( n = 11), followed by recombinant erythropoietin ( n = 6), omaveloxolone ( n = 3), and amantadine hydrochloride ( n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( n = 1), craniocerebral injury ( n = 1), and ventricular tachycardia ( n = 1). Conclusion: Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression. Plain Language Summary A systematic review investigating the effectiveness and safety of treatments for Friedreich ataxia What is Friedreich ataxia? Friedreich ataxia (FA) is a rare genetic condition that causes nervous system damage and movement problems, including muscle weakness and impaired coordination (ataxia). Heart problems, vision problems, spine problems, and diabetes can occur, too. Within 10 to 20 years of the first symptoms, an individual with FA generally requires a wheelchair. Why was this study done? Currently there are no approved treatments for FA. Current treatments focus on relieving symptoms. This study was carried out to obtain a landscape view of all the published evidence about FA treatments. What did the researchers find? • Two scales were most frequently used to assess disease severity: the International Cooperative Ataxia Rating Scale (ICARS) and the FA Rating Scale (modified FARS and FARS-neuro). • Patients on idebenone at 1350 to 2550 mg per day showed improvement in ICARS and FARS scores over 6 months, but scores deteriorated after 12 months in ambulatory patients with FA. • Omaveloxolone at doses of 2.5 to 300 mg per day showed significant improvement in mFARS scores and FA Activity of Daily Living scores at 48 weeks compared with placebo. • Patients treated with vatiquinone showed significant improvements in FARS-neuro scores at 24 months versus natural disease progression. • Other treatments did not show evidence of significant improvement. What does this mean? FA leads to nervous system damage slowly, over an extended period. It is important to keep in mind that many of the studies reviewed here were of fairly short duration, meaning that the effects of a treatment may not have been detectable. Why is this important? This study was undertaken in the hopes that a comprehensive picture of the current treatment landscape for FA will help promote research that will eventually lead to effective treatments to slow down or reverse the damage caused by disease, which are vitally needed.
28
Facharztmagazine, Redaktion. "Zulassung von Omaveloxolon bei Friedreich-Ataxie." DNP – Die Neurologie & Psychiatrie 25, no. 2 (2024): 66. http://dx.doi.org/10.1007/s15202-024-6197-8.
Full text
29
Nitz, Gerhard. "Verordnung von Omaveloxolon bei Friedreich-Ataxie." NeuroTransmitter 35, no. 6 (2024): 41–42. http://dx.doi.org/10.1007/s15016-024-3771-4.
Full text
30
Meißner, Thomas. "Galenus-Kandidat Omaveloxolon: Erstes zugelassenes Medikament bei Friedreich-Ataxie." DNP – Die Neurologie & Psychiatrie 25, no. 4 (2024): 55. http://dx.doi.org/10.1007/s15202-024-6287-7.
Full text
31
Meißner, Thomas. "Galenus-Kandidat Omaveloxolon: erstes zugelassenes Medikament bei Friedreich-Ataxie." NeuroTransmitter 35, no. 7-8 (2024): 49. http://dx.doi.org/10.1007/s15016-024-3814-x.
Full text
32
Cuéllar Rodríguez, Santiago. "Novel Drugs Recently Authorized by EMA and FDA (Q1, 2023)." Anales de la Real Academia Nacional de Farmacia 89, no. 89(01) (2023): 127–34. http://dx.doi.org/10.53519/analesranf.2023.89.01.07.
Full textAbstract:
EMA (EUROPEAN MEDICINES AGENCY): (L) AGENTES ANTINEOPLÁSICOS E INMUNOMODULADORES: Loncastuximab Tesirina (Zynlonta®): linfoma B.FDA (U.S. FOOD & DRUG ADMINISTRATION): (A) TRACTO ALIMENTARIO Y METABOLISMO: Bexagliflozina (Brenzavy®): diabetes mellitus tipo 2. (B) SANGRE Y SISTEMA HEMATOPOYÉTICO: Daprodustat (Jesduvroq®): anemia asociada a insuficiencia renal.(C) SISTEMA CARDIOVASCULAR: Sparsentan (Filspari®): nefropatía por inmunoglobulina A. (L) AGENTES ANTINEOPLÁSICOS E INMUNOMODULADORES: Elacestrant (Orserdu®): cáncer de mama. Pirtobrutinib (Jaypirica®): leucemia de células del manto. (N) SISTEMA NERVIOSO: Lecanemab (Leqembi®): enfermedad de Alzheimer. Trofinetida (Daybue®): síndrome de Rett. Deutetrabenazina (Austedo XR®): corea de Huntington. Omaveloxolona (Skyclarys®): ataxia de Friedreich. Zavegepant (Zavzpret®): migraña.
33
Kropp, Erin M., Sho Matono, Aaron Robida, et al. "Inhibition of Endoplasmic Reticulum Associated Degradation Is Cytotoxic to Relapsed Refractory Multiple Myeloma through Altered Proapoptotic Signaling." Blood 144, Supplement 1 (2024): 3264. https://doi.org/10.1182/blood-2024-203713.
Full textAbstract:
Multiple myeloma (MM), a plasma cell neoplasm, is the second most common hematologic malignancy with a median overall survival of 6.5-10 years. In MM, malignant plasma cells secrete excess immunoglobulins, which are associated with renal failure, low blood counts and bone lesions. Due to their high level of protein synthesis and trafficking, MM cells are highly reliant on endoplasmic reticulum (ER) stress response pathways, including ER associated degradation pathway (ERAD). ERAD is a multiprotein complex that degrades misfolded proteins from the ER as well as regulates secreted and cell membrane associated proteins. Inhibiting ERAD in MM leads to activation of the unfolded protein response (UPR) and induction of apoptosis. Proteasome inhibitors (PIs) disrupt ERAD activity by inhibiting ubiquitin-proteasome degradation of ERAD substrates and are part of the current standard of care for frontline therapy for MM. However, almost all patients eventually develop resistance to PIs resulting in relapsed/refractory disease. While prior studies have shown that targeting alternative proteins in the ERAD pathway is an effective therapeutic strategy to overcome PI resistance, the identification of small molecule inhibitors of ERAD has been limited with traditional screening approaches or chemical modulation that is not specific to the ERAD pathway. To address these limitations, we developed a cell-based screen using an inducible ERAD substrate, null Hong Kong alpha-1 antitrypsin (NHK), to identify inhibitors of ERAD substrate degradation. We screened over 2200 compounds from the FDA repurposing library and identified one inhibitor, omaveloxolone (RTA408), that prevents ERAD-mediated degradation of luminal and membrane substrates. RTA408 was originally described as a E3 ligase inhibitor, which is approved to treat Friedreich's Ataxia. When applied in eleven multiple myeloma cell lines, we observe cytotoxicity with an average half maximal inhibition (IC50) of approximately 270 nanomolar. MM cytotoxicity is additive with lenalidomide or dexamethasone. RTA408 is cytotoxic at nanomolar concentrations in primary malignant plasma cells derived from patients with de novo or PI refractory disease, whereas non-malignant CD3 (T cells) or CD11b (myeloid cells) are spared. We have applied our inhibitors in a xenograft transplant model with MM.1s cells, which have been shown to mimic relapsed refractory disease. Treatment with RTA408 prevents degradation of the endogenous ERAD substrate lambda light chain immunoglobulin and activates the UPR within 30 minutes in MM cells, a faster onset than PIs. In addition, while PI treatment leads to stabilization of c-MYC in MM cells, the activation of the UPR by RTA408 is associated with the degradation of c-MYC, suggesting differential regulation of cytosolic proteins. RTA408 cytotoxicity is mediated by altered cell death receptor signaling leading to caspase 8 activation in the extrinsic apoptotic pathway. Inhibition of cell death receptor complex assembly rescues the cytotoxicity mediated by RTA408, showing that alternative targeting of ERAD can modulate MM cell surface receptor trafficking and activity. These studies identify a novel inhibitor for ERAD substrate degradation, which may represent an alternative therapeutic approach in relapsed refractory MM. 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.
34
Simonetti, Giorgia, Samantha Bruno, Carmine Onofrillo, et al. "Alternative Overexpression of NRF2 or MYC Defines a Subgroup of Poor Prognosis Acute Myeloid Leukemia and Suggests a Novel Therapeutic Strategy By Combined Bromodomain Inhibition and Forced NRF2 Pathway Activation." Blood 132, Supplement 1 (2018): 2639. http://dx.doi.org/10.1182/blood-2018-99-117429.
Full textAbstract:
Abstract Introduction. Inhibition of Bromodomain and extraterminal (BET) proteins was effective against different acute myeloid leukemia (AML) subtypes in preclinical studies (Dawson et al. Nature 2011; Zuber et al. Nature 2011; Dawson et al. Leukemia 2013; Chen et al. Cancer Cell 2014; Gröschel et al. Cell 2014; Zhao et al. Cell Reports 2016). However, the drug had limited clinical activity, suggesting the need of ad hoc combination therapies able to target leukemia stem cells (LSCs) in their microenvironment. Hypoxia is an integral component of the bone marrow microenvironment and plays a crucial role in survival and chemoresistance of LSCs. Aims. The study aims to elucidate the consequences of BETi treatment in AML under hypoxic conditions and identify novel potential combination strategies. Methods. AML cell lines (OCI-AML3: NPM1- and DNMT3A-mutated, Kasumi-1: t(8;21), HL60: MYC-amplified, MOLM-13, NOMO-1: MLL-driven, KG-1: TP53-mutated) were treated with the BET inhibitor (i) GSK1215101A (250/500 nM, 48h) or the NRF2 activator omaveloxolone (NRF2a, 0.2-1 mM, 48h) and with the drug combination (72h) at 1% or 20% O2 concentration. Cell viability, apoptosis and cell cycle were evaluated by trypan blue dye exclusion assay, AnnexinV and PI staining, respectively. Gene expression profiling (HTA2.0, Affymetrix) was carried out on actively translated mRNAs isolated by polysome profiling after 16h of BETi treatment and on 61 primary AML. The TCGA AML dataset was analyzed on the cBioPortal. Gene expression correlation and enrichment analysis were performed by Pearson coefficient and GSEA, respectively. Kaplan-Meier survival curves were compared by Logrank test. Glutathione was quantified by mass spectrometry (Metabolon). Results. BETi induced a dose-dependent reduction of cell viability in AML cells lines under hypoxia (25%-65% decrease at 500 nM) except for HL-60. Under the same conditions, the treatment caused a significant arrest in the G0/G1 phase of the cell cycle in OCI-AML3, Kasumi-1, HL-60 and KG-1 models (p<0.05) and induction of apoptosis in NOMO-1 and Kasumi-1 (40% and 50% AnnexinV+ cells, respectively, p<0.05). BETi reduced the translational rate of Kasumi-1 and OCI-AML3 cells, as determined by a decrease of disome-polysome peaks height. The treatment exacerbated hypoxia-mediated MYC suppression and associated with downregulation of a MYC signature at translational level. Moreover, it induced upregulation of the NRF2 regulator ARNT (p=0.02) and the NRF2 targets CAT, EPHX1, FTH1, GSTM1, MGST1, PRDX1 (p<0.05) under normoxia and/or hypoxia, with reduced KEAP1 mRNA and protein specifically at 1% O2 (p=0.01). These results suggest stabilization of NRF2 protein and activation of the pathway, as strengthened by increased levels of reduced and oxidized glutathione in OCI-AML3 cells (p<0.01). Based on this alternative activation of MYC and NRF2 pathway in AML, we analyzed gene expression and mutation in non-M3 AML from an internal cohort and the TCGA dataset. Upregulation of NRF2 expression and deregulation of MYC (overexpression/driver mutation) occurred in 4% and 9% of cases, respectively (independent of genomic amplification), with mutual exclusivity and an inverse correlation (p=0.03). MYC or NRF2 alterations defined a subgroup of patients with poor overall survival (10 vs. 18.1 months, p=0.04) and progression-free survival (7.2 vs. 17 months, p=0.0006). We then asked whether antioxidant gene expression was a defense response under BETi pressure. However, pharmacological inhibition of NRF2 or glutathione biosynthesis failed to potentiate the anti-leukemic effects of BETi. Conversely, activation of NRF2 pathway, which is effective as single agent on AML cells, potentiates the effects of BETi treatment in non-M3 AML, with reduced cell viability and increased apoptosis. Conclusions. BET protein activity drives alternative NRF2 or MYC overexpression in AML, which defines a subgroup of patients with poor prognosis. NRF2 activation is finely tuned in AML, as both inhibition and activation of the pathway induce cell death. However, NRF2 activation specifically potentiates BETi treatment under hypoxia and normoxia, suggesting a novel combination therapy against AML LSCs. Supported by: EHA Non-Clinical Junior Research Fellowship, ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, Fondazione del Monte BO e RA project. Figure. Figure. Disclosures Cavo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Martinelli:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Roche: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau.
35
"Omaveloxolone." American Journal of Health-System Pharmacy, May 3, 2023. http://dx.doi.org/10.1093/ajhp/zxad072.
Full text
36
Zahir, Hamim, Masako Murai, Lucy Wu, Michelle Valentine, and Scott Hynes. "Clinical Assessment of the Drug–Drug Interaction Potential of Omaveloxolone in Healthy Adult Participants." Journal of Clinical Pharmacology, February 7, 2025. https://doi.org/10.1002/jcph.6189.
Full textAbstract:
AbstractOmaveloxolone is approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years. It is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro. Two drug–drug interaction studies (NCT04008186 and NCT05909644) were performed to evaluate (1) the effect of drug‐metabolizing enzymes (DMEs) and drug transporter (DT) modulators on the pharmacokinetics of omaveloxolone and (2) the effect of omaveloxolone on the pharmacokinetics of DME and DT substrates. Additionally, the safety of coadministering these drugs with omaveloxolone was assessed. Coadministration of the strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0‐∞) by approximately 3‐ and 4‐fold, respectively. Conversely, coadministration with the moderate CYP3A4 inducer efavirenz decreased Cmax and AUC0‐∞ of omaveloxolone by 38.0% and 48.5%, respectively. Omaveloxolone exposure was also increased following coadministration with verapamil, a moderate CYP3A4 and P‐glycoprotein (P‐gp) inhibitor, but it was unaffected by the strong CYP2C8 inhibitor gemfibrozil. Coadministration of omaveloxolone reduced systemic exposure of the substrates of CYP3A4, CYP2C8, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 but had no effect on those of P‐gp and organic cation transporter 1. Omaveloxolone was well tolerated when administered alone and in combination with the DME and DT modulators or substrates. These findings support concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate or strong CYP3A4 inhibitor or inducer, as well as the substrates of certain CYP450 enzymes or transporters.
37
Salinas, Lili, Francisco Figueroa, Claire B. Montgomery, et al. "Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy." Journal of the American Heart Association, June 12, 2025. https://doi.org/10.1161/jaha.124.038505.
Full textAbstract:
Background Friedreich's ataxia (FA) is a genetic disorder caused by a severe decrease in FXN (frataxin) protein expression in mitochondria. The clinical manifestation of this disorder is a cerebellar ataxia; however, the common lethal component in FA is cardiomyopathy. Methods A conditional Fxn flox/null ::MCK‐Cre knockout (FXN‐cKO) mouse model was used to mimic the late‐stage severe cardiomyopathy in FA. Nrf2 (nuclear factor erythroid 2‐related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), were independently tested in this mouse model to determine the effects on cardiac health and lifespan. Results Omaveloxolone significantly improved cardiac contractile function and markers of heart failure in FA such as Nppb , Aldh1a3 , and Gdf15 . Despite improvement in cardiac function, omaveloxolone did not prevent premature death in FXN‐cKO animals and notably accelerated death in FXN‐cKO females. Omaveloxolone decreased oxidative stress and inflammatory marker IL1β (interleukin‐1 beta), and stimulated Nqo1 gene expression above control level. DMF restored elevated HO‐1 ( Hmox ) expression and significantly increased Sirt1 expression. Although both omaveloxolone and DMF restored decreased SERCA2 ( Atp2a) and MCU ( Mcu ) expression and ameliorated elevated phosphorylation of CaMKIIδ at Thr 286 site in FA hearts, DMF did not improve cardiac contractile function and survival. Furthermore, neither omaveloxolone or DMF decreased hypertrophy and fibrosis (Masson trichrome staining and Lgals3 expression) or rescued impaired mitochondrial function and integrative stress response in FXN‐cKO hearts. Conclusions 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.
38
Zahir, Hamim, Masako Murai, Lucy Wu, Michelle Valentine, and Scott M. Hynes. "Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double‐Blind, Placebo‐ and Active‐Controlled, Three‐Way Crossover Study." Clinical and Translational Science 18, no. 2 (2025). https://doi.org/10.1111/cts.70139.
Full textAbstract:
ABSTRACTOmaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose of 150 mg once daily. This double‐blind, randomized, placebo‐ and active‐controlled, three‐way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 mg [open‐label positive control]) administered with an FDA high‐fat meal. Serial pharmacokinetic blood sampling and time‐matched electrocardiogram assessments were performed. The primary endpoint was placebo‐corrected change from baseline in QTcF (ΔΔQTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone Cmax was 319 ng/mL in this study (4.5‐fold the mean steady‐state Cmax [71.5 ng/mL] with the approved dose). The mean QTcF intervals were < 450 ms, and mean changes from baseline were < 10 ms at all timepoints following all doses. The upper limit of the 90% CIs of ΔΔQTcF following omaveloxolone administration was < 10 ms at all timepoints. At the Cmax of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model‐predicted ΔΔQTcF were all < 10 ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst‐case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.
39
Hynes, Scott M., Angie Goldsberry, Patrick D. Henneghan, et al. "Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open‐Label, Single‐Dose, Crossover Study in Healthy Adults." Journal of Clinical Pharmacology, June 4, 2024. http://dx.doi.org/10.1002/jcph.2482.
Full textAbstract:
AbstractOmaveloxolone (SKYCLARYS®) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50‐mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150‐mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (Cmax), AUC0‐t, and AUC0‐∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median tmax, 10 h) compared with sprinkled capsule contents over applesauce (median tmax, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4‐h difference in tmax is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information.
40
Zaoui, Philippe, Melanie Chin, Martin Delatycki, et al. "P0222KIDNEY EFFECTS IN THE MOXIE TRIAL: A STUDY OF OMAVELOXOLONE IN PATIENTS WITH FRIEDRICH'S ATAXIA." Nephrology Dialysis Transplantation 35, Supplement_3 (2020). http://dx.doi.org/10.1093/ndt/gfaa142.p0222.
Full textAbstract:
Abstract Background and Aims Omaveloxolone, an Nrf2 activator, is an investigational drug that targets targets inflammation and mitochondrial dysfunction, metabolic, and bioenergetic pathways. Omaveloxolone is an analog of bardoxolone, methyl which has been shown to improve kidney function in multiple studies of chronic kidney diseases. The MOXIe Part 2 trial investigated omaveloxolone in patients with Friedreich’s ataxia (FA), a rare and serious hereditary disease caused by mitochondrial dysfunction that affects multiple organ systems resulting in ataxia, cardiomyopathy, and reduced lifespan. The study met its primary efficacy endpoint, and omaveloxolone improved neurological function, as assessed by the modified Friedreich’s ataxia rating scale (mFARS). We report the effect of omaveloxolone on kidney function in this patient population. Method The MOXIe trial (NCT02255435) was an international, multi-center, double-blind, placebo-controlled, randomized trial that enrolled 103 patients between 16 and 40 years of age with genetically confirmed FA. Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks. The trial included 24 patients that were younger than 18 years of age. Baseline eGFR for the overall patient population receiving placebo or omaveloxolone was 109.2 ± 21.7 and 113.4 ± 14.7 mL/min/1.73 m2, respectively. Baseline eGFR for the pediatric population receiving placebo or omaveloxolone was 99.1 ± 33.7 and 106.3 ± 15.6 mL/min/1.73 m2, respectively. Serum creatinine was collected at baseline, Weeks 4, 12, 18, 24, 36 and 48 on-treatment and 4-weeks off-treatment at Week 52. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for patients ≥ 18 years of age. For patients &lt;18 years of age, the Bedside Schwartz equation was used to calculate eGFR. Results In placebo patients, mean (SD) eGFR decreased by 4.4 ± 11.0 mL/min/1.73 m2 from baseline whereas patients receiving omaveloxolone had an average increase of +7.0 ± 10.7 mL/min/1.73 m2 from baseline after 48 weeks, resulting in a difference of 11.4 mL/min/1.73 m2 between treatment groups. At Week 52, mean eGFR was -4.2 ± 10.9 mL/min/1.73 m2 relative to baseline in placebo patients and remained +0.9 ± 10.8 mL/min/1.73 m2 above baseline in omaveloxolone patients after 4-weeks off-treatment. In pediatric patients randomized to placebo, at week 48 eGFR decreased by -11.3 ± 14.3 mL/min/1.73 m2 whereas patients receiving omaveloxolone had an average increase of +5.5 ± 14.5 mL/min/1.73 m2 from baseline, resulting in a difference of 16.8 mL/min/1.73 m2 between treatment groups. Conclusion Patients with FA randomized to placebo in the MOXIe trial had eGFR declines over 48 weeks that were similar to rates of decline observed in the most rapidly progressing forms of chronic kidney disease. The rapid kidney function decline in FA reflects the multi-system nature of the disease whereby mitochondrial dysfunction, and associated chronic inflammation, affects not only the central nervous system but also the heart and possibly the kidney. In contrast to placebo, treatment with omaveloxolone improved eGFR in patients with FA and the effects were sustained through one year of treatment. The durability of eGFR improvements are consistent with those observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.
41
Lee, Arnold. "Omaveloxolone: First Approval." Drugs, May 8, 2023. http://dx.doi.org/10.1007/s40265-023-01874-9.
Full text
42
Jiang, Zengxin, Guobin Qi, Wei Lu та ін. "Omaveloxolone inhibits IL-1β-induced chondrocyte apoptosis through the Nrf2/ARE and NF-κB signalling pathways in vitro and attenuates osteoarthritis in vivo". Frontiers in Pharmacology 13 (27 вересня 2022). http://dx.doi.org/10.3389/fphar.2022.952950.
Full textAbstract:
Osteoarthritis (OA) is a common degenerative joint disease. Effective drugs that can halt or decelerate osteoarthritis progression are still lacking. Omaveloxolone is a semisynthetic oleanane triterpenoid exerting antioxidative and anti-inflammatory effects. The present study aims to determine whether omaveloxolone has a therapeutic effect on OA. Chondrocytes were treated with interleukin (IL)-1β to establish an OA cell model in vitro. Indicators of cell viability, oxidative stress, inflammation, cell apoptosis and extracellular matrix (ECM) degradation were investigated. Proteins related to the Nuclear factor erythroid derived-2-related factor 2 (Nrf2)/antioxidant response element (ARE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways were assessed using Western blotting. A destabilized medial meniscus surgery-induced OA rat model was used in vivo. Gait analysis, microcomputed tomography analysis, and histopathological and immunohistochemical analyses were performed to determine the therapeutic effect of omaveloxolone on attenuating osteoarthritis in vivo. The results showed that omaveloxolone exerts antioxidative, anti-inflammatory, antiapoptotic and anti-ECM degradation effects via activation of the Nrf2/ARE signalling pathway and inhibition of the NF-κB signalling pathway in chondrocytes in vitro and attenuates OA progression in vivo, suggesting that omaveloxolone may be a potential therapeutic agent for OA.
43
Pepin, Xavier J. H., Scott M. Hynes, Hamim Zahir, Deborah Walker, Lois Q. Semmens, and Sandra Suarez‐Sharp. "Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling." CPT: Pharmacometrics & Systems Pharmacology, September 2, 2024. http://dx.doi.org/10.1002/psp4.13221.
Full textAbstract:
AbstractOmaveloxolone is a nuclear factor (erythroid‐derived 2)‐like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high‐fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408‐C‐1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high‐fat breakfast on a 150‐mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose‐ranging, food effect, and drug–drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high‐fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first‐pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.
44
Zighan, Madleen, David Arkadir, Liza Douiev, Guy Keller, Chaya Miller, and Ann Saada. "Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects." Frontiers in Molecular Biosciences 9 (August 12, 2022). http://dx.doi.org/10.3389/fmolb.2022.890653.
Full textAbstract:
Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient’s cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.
45
Lee, Kuan‐Ting, Yi‐Chiang Hsu, Ann‐Shung Lieu, Chih‐Lung Lin, and Tai‐Hsin Tsai. "Omaveloxolone Suppresses Cell Growth and Causes Cell Cycle Arrest by Downregulating CDC20 Expression in Glioblastoma Cells Both In Vitro and In Vivo." Journal of Cellular and Molecular Medicine 29, no. 11 (2025). https://doi.org/10.1111/jcmm.70607.
Full textAbstract:
ABSTRACTOmaveloxolone is a synthetic oleanane triterpene with considerable antitumor activity. It induces human glioblastoma (GBM) cell death in vitro and in vivo, but the underlying mechanism remains to be determined. In this study, GBM cell lines (GBM8401 and U‐87 MG cells) were exposed to different concentrations of omaveloxolone (0, 600, 800 and 1000 nM). A cell viability assay was conducted using the PrestoBlue Cell Viability Reagent. Three‐dimensional microscopy revealed changes in cell morphology. Cell cycle, apoptosis and mitochondrial membrane potential were tested using flow cytometry. The expression levels of cell cycle‐related proteins and genes were determined through Western blotting and next‐generation sequencing, respectively. The results indicated that omaveloxolone had significant selective cytotoxicity against human GBM cells and suppressed the migration and invasion of these cancer cells. It also caused cell cycle arrest through the downregulation of cell cycle‐related genes, including cell division cycle 20 homologue (CDC20), as revealed by next‐generation sequencing. 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.
46
Lynch, David R., Angie Goldsberry, Christian Rummey, et al. "Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data." Annals of Clinical and Translational Neurology, September 10, 2023. http://dx.doi.org/10.1002/acn3.51897.
Full textAbstract:
AbstractObjectiveThe natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS.MethodsMOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis.ResultsData from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001).InterpretationThese results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.
47
"Ist Omaveloxolone wirksam bei mitochondrialer Myopathie?" Fortschritte der Neurologie · Psychiatrie 88, no. 10 (2020): 638–39. http://dx.doi.org/10.1055/a-1215-8768.
Full text
48
"A Human AME Study for Omaveloxolone." Case Medical Research, April 30, 2019. http://dx.doi.org/10.31525/ct1-nct03931590.
Full text
49
Boesch, Sylvia, and Elisabetta Indelicato. "Approval of omaveloxolone for Friedreich ataxia." Nature Reviews Neurology, April 3, 2024. http://dx.doi.org/10.1038/s41582-024-00957-9.
Full text
50
Tejera Nevado, Paloma, Tajana Tešan Tomić, Ali Atefyekta, André Fehr, Göran Stenman, and Mattias K. Andersson. "Synthetic oleanane triterpenoids suppress MYB oncogene activity and sensitize T-cell acute lymphoblastic leukemia cells to chemotherapy." Frontiers in Oncology 13 (April 3, 2023). http://dx.doi.org/10.3389/fonc.2023.1126354.
Full textAbstract:
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with poor prognosis. The MYB oncogene encodes a master transcription factor that is activated in the majority of human T-ALLs. In the present study, we have performed a large-scale screening with small-molecule drugs to find clinically useful inhibitors of MYB gene expression in T-ALL. We identified several pharmacological agents that potentially could be used to treat MYB-driven malignancies. In particular, treatment with the synthetic oleanane triterpenoids (OTs) bardoxolone methyl and omaveloxolone decreased MYB gene activity and expression of MYB downstream target genes in T-ALL cells with constitutive MYB gene activation. Notably, treatment with bardoxolone methyl and omaveloxolone led to a dose-dependent reduction in cell viability and induction of apoptosis at low nanomolar concentrations. In contrast, normal bone marrow-derived cells were unaffected at these concentrations. Bardoxolone methyl and omaveloxolone treatment downregulated the expression of DNA repair genes and sensitized T-ALL cells to doxorubicin, a drug that is part of the standard therapy of T-ALL. OT treatment may thus potentiate DNA-damaging chemotherapy through attenuation of DNA repair. Taken together, our results indicate that synthetic OTs may be useful in the treatment of T-ALL and potentially also in other MYB-driven malignancies.