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Drug Profile

Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations

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Pages 251-258 | Received 13 Sep 2023, Accepted 23 Jan 2024, Published online: 30 Jan 2024

References

  • Bidichandani SI, Delatycki MB. Friedreich Ataxia. In: Adam M, Mirzaa G, Pagon R, Wallace S, Bean L, Gripp K Amemiya A, editors. GeneReviews® [internet]. Seattle (WA): University of Washington, Seattle; 1998 Dec 18 [updated 2017 Jun 1]. p. 1993–2023.
  • Campuzano V, Montermini L, Moltò MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–1427. doi: 10.1126/science.271.5254.1423
  • Lynch DR, Schadt K, Kichula E, et al. Friedreich ataxia: multidisciplinary clinical care. J Multidiscip Healthc. 2021;14:1645–1658. doi: 10.2147/JMDH.S292945
  • Chutake YK, Lam C, Costello WN, et al. Epigenetic promoter silencing in Friedreich ataxia is dependent on repeat length. Ann Neurol. 2014;76(4):522–528. doi: 10.1002/ana.24249
  • Burnett R, Melander C, Puckett JW, et al. DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich’s ataxia. Proc Natl Acad Sci U S A. 2006;103(31):11497–11502. doi: 10.1073/pnas.0604939103
  • Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997;6(11):1771–1780. doi: 10.1093/hmg/6.11.1771
  • Pandolfo M. Frataxin deficiency and mitochondrial dysfunction. Mitochondrion. 2002;2(1–2):87–93. doi: 10.1016/S1567-7249(02)00039-9
  • Marmolino D, Manto M, Acquaviva F, et al. PGC-1alpha down-regulation affects the antioxidant response in Friedreich’s ataxia. PLoS One. 2010;5(4):e10025. doi: 10.1371/journal.pone.0010025
  • Babady NE, Carelle N, Wells RD, et al. Advancements in the pathophysiology of Friedreich’s ataxia and new prospects for treatments. Mol Genet Metab. 2007;92(1–2):23–35. doi: 10.1016/j.ymgme.2007.05.009
  • Strawser CJ, Schadt KA, Lynch DR. Therapeutic approaches for the treatment of Friedreich’s ataxia. Expert Rev Neurother. 2014;14(8):949–957. doi: 10.1586/14737175.2014.939173
  • Strawser C, Schadt K, Hauser L, et al. Pharmacological therapeutics in friedreich ataxia: the present state. Expert Rev Neurother. 2017;17(9):895–907. doi: 10.1080/14737175.2017.1356721
  • Kearney M, Orrell RW, Fahey M, et al. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev. 2012 Apr 18;4:CD007791.
  • Soragni E, Miao W, Iudicello M, et al. Epigenetic therapy for Friedreich ataxia. Ann Neurol. 2014;76(4):489–508. doi: 10.1002/ana.24260
  • Vyas PM, Tomamichel WJ, Pride PM, et al. A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich’s ataxia mouse model. Hum Mol Genet. 2012;21(6):1230–1247. doi: 10.1093/hmg/ddr554
  • Piguet F, de Montigny C, Vaucamps N, et al. Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of friedreich ataxia. Mol Ther. 2018;26(8):1940–1952. doi: 10.1016/j.ymthe.2018.05.006
  • Igoillo-Esteve M, Oliveira AF, Cosentino C, et al. Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight. 2020 Jan 30;5(2):e134221. doi: 10.1172/jci.insight.134221
  • Lynch DR, Hauser L, McCormick A, et al. Randomized, double-blind, placebo-controlled study of interferon-γ 1b in friedreich ataxia. Ann Clin Transl Neurol. 2019;6(3):546–553. doi: 10.1002/acn3.731
  • Pandolfo M, Arpa J, Delatycki MB, et al. Deferiprone in friedreich ataxia: a 6-month randomized controlled trial. Ann Neurol. 2014;76(4):509–21. doi: 10.1002/ana.24248
  • Zesiewicz T, Salemi JL, Perlman S, et al. Double-blind, randomized and controlled trial of EPI-743 in Friedreich’s ataxia. Neurodegener Dis Manag. 2018;8(4):233–242. doi: 10.2217/nmt-2018-0013
  • Pandolfo M, Reetz K, Darling A, et al. Efficacy and safety of Leriglitazone in patients with Friedreich ataxia: a phase 2 double-blind, randomized controlled trial (Frames). Neurol Genet. 2022;8(6):e200034. doi: 10.1212/NXG.0000000000200034
  • Lynch DR, Mathews KD, Perlman S, et al. Double blind trial of a deuterated form of linoleic acid (RT001) in friedreich ataxia. J Neurol. 2023;270(3):1615–1623. doi: 10.1007/s00415-022-11501-4
  • Lynch DR, Perlman SL, Meier T. Meier T.A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol. 2010;67(8):941–947. doi: 10.1001/archneurol.2010.168
  • Lynch DR, Farmer J, Hauser L, et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018;6(1):15–26. doi: 10.1002/acn3.660
  • Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212–225. doi: 10.1002/ana.25934
  • Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich’s ataxia: delayed-start analysis of the MOXIe extension. Mov Disord. 2023;38(2):313–320. doi: 10.1002/mds.29286
  • Lynch DR, Goldsberry A, Rummey C, et al. Direct utility of natural history data in analysis of clinical trials: propensity match-based analysis of omaveloxolone in friedreich ataxia using the FA-COMS dataset. Annals Of Clin Transl Neurol. 2024;11(1):4–16.
  • Subramony SH, Lynch DL. A milestone in the treatment of ataxias: approval of omaveloxolone for Friedreich Ataxia. Cerebellum. 2023 May 23. doi: 10.1007/s12311-023-01568-8
  • Profeta V, McIntyre K, Wells M, et al. Omaveloxolone: an activator of Nrf2 for the treatment of friedreich ataxia. Expert Opin Investig Drugs. 2023;32(1):5–16. doi: 10.1080/13543784.2023.2173063
  • Clay A, Hearle P, Schadt K, et al. New developments in pharmacotherapy for friedreich ataxia. Expert Opin Pharmacother. 2019;20(15):1855–1867. doi: 10.1080/14656566.2019.1639671
  • Petrillo S, D’Amico J, La Rosa P, et al. Targeting NRF2 for the treatment of Friedreich’s ataxia: a comparison among drugs. Int J Mol Sci. 2019;20(20):5211. doi: 10.3390/ijms20205211
  • Paupe V, Dassa EP, Goncalves S, et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in friedreich ataxia. PLoS One. 2009;4(1):e4253. doi: 10.1371/journal.pone.0004253
  • Wilson RB, Lynch DR, Fischbeck KH. Normal serum iron and ferritin concentrations in patients with Friedreich’s ataxia. Ann Neurol. 1998 Jul;44(1):132–134. doi: 10.1002/ana.410440121
  • Wilson RB, Lynch DR, Farmer JM, et al. Increased serum transferrin receptor concentrations in Friedreich ataxia. Ann Neurol. 2000;47(5):659–661. doi: 10.1002/1531-8249(200005)47:5<659:AID-ANA17>3.0.CO;2-T
  • Abeti R, Baccaro A, Esteras N, et al. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich’s ataxia models. Front Cell Neurosci. 2018;12:188.
  • Loan JJM, Al-Shahi Salman R, McColl BW, et al. Activation of Nrf2 to optimise immune responses to intracerebral haemorrhage. Biomolecules. 2022;12(10):1438. doi: 10.3390/biom12101438
  • Jiang Z, Qi G, Lu W, et al. Omaveloxolone inhibits IL-1β-induced chondrocyte apoptosis through the Nrf2/ARE and NF-κB signalling pathways in vitro and attenuates osteoarthritis in vivo. Front Pharmacol. 2022;13:952950. doi: 10.3389/fphar.2022.952950
  • Jian W, Ma H, Wang D, et al. Omaveloxolone attenuates the sepsis-induced cardiomyopathy via activating the nuclear factor erythroid 2-related factor 2. Int Immunopharmacol. 2022;111:109067. doi: 10.1016/j.intimp.2022.109067
  • Hu L, Cao Y, Chen H, et al. The novel Nrf2 activator omaveloxolone regulates microglia phenotype and ameliorates secondary brain injury after intracerebral hemorrhage in mice. Oxid Med Cell Longev. 2022;2022:1–18. doi: 10.1155/2022/4564471
  • Cohen-Nowak AJ, Cohen AJ, Correia ED, et al. Omaveloxolone attenuates squamous cell carcinoma growth and disease severity in an epidermolysis bullosa mouse model. Exp Dermatol. 2022;31(7):1083–1088. doi: 10.1111/exd.14564
  • Sun J, Li JY, Zhang LQ, et al. Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Oxid Med Cell Longev. 2021;2021:1–17. doi: 10.1155/2021/9577874
  • Luginbuhl AJ, Hobelmann K, Rodin J, et al. Synthetic triterpenoid RTA-408: limits radiation damage to normal tissue. Laryngoscope. 2022;132(6):1196–1204. doi: 10.1002/lary.29930
  • Tsai TH, Lin SH, Wu CH, et al. Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage-induced delayed cerebral vasospasm and secondary brain injury. PLoS One. 2020;15(10):e0240122. doi: 10.1371/journal.pone.0240122
  • Reisman SA, Ferguson DA, Lee CI, et al. Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis. J Biochem Mol Toxicol. 2020;34(9):e22526. doi: 10.1002/jbt.22526
  • Zhang JH, Yang X, Chen YP, et al. Nrf2 activator RTA-408 protects against ozone-induced acute asthma exacerbation by suppressing ROS and γδT17 cells. Inflammation. 2019;42(5):1843–1856. doi: 10.1007/s10753-019-01046-6
  • Shekh-Ahmad T, Eckel R, Dayalan Naidu S, et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018;141(5):1390–1403. doi: 10.1093/brain/awy071
  • Rabbani PS, Ellison T, Waqas B, et al. Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds. Diabet Res Clin Pract. 2018;139:11–23. doi: 10.1016/j.diabres.2018.02.021
  • Han P, Qin Z, Tang J, et al. RTA-408 protects kidney from ischemia-reperfusion injury in mice via activating Nrf2 and downstream GSH biosynthesis gene. Oxid Med Cell Longev. 2017;2017:7612182. doi: 10.1155/2017/7612182
  • Liu X, Ward K, Xavier C, et al. The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation. Redox Biol. 2016;8:98–109. doi: 10.1016/j.redox.2015.12.005
  • Goldman DC, Alexeev V, Lash E, et al. The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice. Radiat Res. 2015;183(3):338–344. doi: 10.1667/RR13900.1
  • Reisman SA, Lee CY, Meyer CJ, et al. Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis. Radiat Res. 2014;181(5):512–520. doi: 10.1667/RR13578.1
  • Reisman SA, Lee CY, Meyer CJ, et al. Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin. Arch Dermatol Res. 2014;306(5):447–454. doi: 10.1007/s00403-013-1433-7
  • Reisman SA, Goldsberry AR, Lee CY, et al. Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers. BMC Dermatol. 2015;15(1):10. doi: 10.1186/s12895-015-0029-7
  • Chien JY, Chou YY, Ciou JW, et al. The effects of two Nrf2 activators, bardoxolone methyl and omaveloxolone, on retinal ganglion cell survival during ischemic optic neuropathy. Antioxidants (Basel). 2021;10(9):1466. doi: 10.3390/antiox10091466
  • Zighan M, Arkadir D, Douiev L, et al. Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects. Front Mol Biosci. 2022;9:890653. doi: 10.3389/fmolb.2022.890653
  • Jasoliya M, Sacca F, Sahdeo S, et al. Dimethyl fumarate dosing in humans increases frataxin expression: a potential therapy for Friedreich’s ataxia. PLoS One. 2019 Jun 3;14(6):e0217776. doi: 10.1371/journal.pone.0217776
  • Reisman SA, Gahir SS, Lee CI, et al. Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates. Drug Des Devel Ther. 2019;13:1259–1270.
  • Creelan BC, Gabrilovich DI, Gray JE, 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. Onco Targets Ther. 2017 Aug 29;10:4239–4250. doi: 10.2147/OTT.S136992
  • Regner SR, Lagedrost SJ, Plappert T, et al. Analysis of echocardiograms in a large heterogeneous cohort of patients with friedreich ataxia. Am J Cardiol. 2012;109(3):401–405. doi: 10.1016/j.amjcard.2011.09.025
  • Pousset F, Legrand L, Monin ML, et al. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 2015;72(11):1334–1341. doi: 10.1001/jamaneurol.2015.1855
  • Myers L, Farmer JM, Wilson RB, et al. Antioxidant use in Friedreich ataxia. J Neurol Sci. 2008;267(1–2):174–176. doi: 10.1016/j.jns.2007.10.008
  • Lynch DR, Farmer JM, Tsou AY, et al. Measuring friedreich ataxia: complementary features of examination and performance measures. Neurology. 2006;66(11):1711–1716. doi: 10.1212/01.wnl.0000218155.46739.90
  • Rummey C, Corben LA, Delatycki MB, et al. Psychometric properties of the friedreich ataxia rating scale. Neurol Genet. 2019;5(6):371. doi: 10.1212/NXG.0000000000000371
  • Friedman LS, Farmer JM, Perlman S, et al. Measuring the rate of progression in friedreich ataxia: implications for clinical trial design. Mov Disord. 2010;25(4):426–432. doi: 10.1002/mds.22912
  • Patel M, Isaacs CJ, Seyer L, et al. Progression of friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016;3(9):684–694. doi: 10.1002/acn3.332
  • Regner SR, Wilcox NS, Friedman LS, et al. Friedreich ataxia clinical outcome measures: natural history evaluation in 410 participants. J Child Neurol. 2012;27(9):1152–1158. doi: 10.1177/0883073812448462
  • Worth AJ, Basu SS, Deutsch EC, et al. Stable isotopes and LC-MS for monitoring metabolic disturbances in Friedreich’s ataxia platelets. Bioanalysis. 2015;7(15):1843–1855. doi: 10.4155/bio.15.118
  • Delatycki MB, Holian A, Corben L, et al. Surgery for equinovarus deformity in Friedreich’s ataxia improves mobility and independence. Clin Orthop Relat Res. 2005;430:138–141. doi: 10.1097/01.blo.0000150339.74041.0e
  • Anzovino A, Chiang S, Brown BE, et al. Molecular alterations in a mouse cardiac model of friedreich ataxia: an impaired Nrf2 response mediated via upregulation of Keap1 and activation of the Gsk3β axis. Am J Pathol. 2017;187(12):2858–2875. doi: 10.1016/j.ajpath.2017.08.021
  • Mejia E, Lynch A, Hearle P, et al. Ectopic burden via holter monitors in friedreich ataxia. Pediatr Neurol. 2021;117:29–33. doi: 10.1016/j.pediatrneurol.2021.01.004
  • Chang P, Zhang X, Zhang J, et al. BNP protects against diabetic cardiomyopathy by promoting Opa1-mediated mitochondrial fusion via activating the PKG-STAT3 pathway. Redox Biol. 2023;62:102702. doi: 10.1016/j.redox.2023.102702
  • Sarzani R, Allevi M, Di Pentima C, et al. Role of cardiac natriuretic peptides in heart structure and function. Int J Mol Sci. 2022;23(22):14415. doi: 10.3390/ijms232214415
  • Fravel MA, Ernst M. Drug interactions with antihypertensives. Curr Hypertens Rep. 2021;23(3):14. doi:10.1007/s11906-021-01131-y
  • Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4):310–322. doi: 10.2174/138920008784220664
  • https://go.drugbank.com/drugs/DB12513
  • Madsen KL, Buch AE, Cohen BH, et al. Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial. Neurology. 2020;94(7):e687–e698. doi: 10.1212/WNL.0000000000008861
  • Brackhan M, Arribas-Blazquez M, Lastres-Becker I. Aging, NRF2, and TAU: a perfect match for neurodegeneration? Antioxidants (Basel). 2023 Aug 4;12(8):1564. doi: 10.3390/antiox12081564

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