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Mitochondrial Dysfunction in Friedreich Ataxia
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Rosella Abeti, Annalisa Baccaro, Paola Giunti
In human fibroblasts from patients a marked sensitivity was found to pro-oxidant agents (Paupe et al., 2009; Shan et al., 2013), which was due to the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) failure to translocate from cytosol to nucleus (Paupe et al., 2009). Recently, we demonstrated that Omaveloxolone (Omav) (which specifically triggers the Nrf2 pathway) had a beneficial effect on oxidative stress and mitochondrial dysfunction in FRDA models (Creelan et al., 2017; Abeti et al., 2018a). The turnover of Nrf2 is regulated through ubiquitination where Omav operates; pre-treating the cells with this compound the oxidative stress was reduced and the cell survival was promoted (Abeti et al., 2016, 2018a). Importantly, Nrf2 is also involved in mitochondrial biogenesis; indeed, Hayashi and colleagues found a reduced mtDNA copy number in knockout Nrf2 mice (Hayashi et al., 2017).
Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia
Published in Expert Opinion on Investigational Drugs, 2023
Victoria Profeta, Kellie McIntyre, McKenzie Wells, Courtney Park, David R Lynch
Drug interactions of omaveloxolone with other specific medications have been empirically tested in one study. The Phase I study population consisted of healthy volunteers in a parallel assignment intervention model [97]. In part I, single doses of the following medications were administered to the subjects while taking 150 mg of omav: Midazolam, Repaglinide, Metformin, Rosuvastatin, and Digoxin. Part two tested subjects taking 150 mg of omav on day 1 through 13 and 600 mg of gemfibrozil twice a day on day 10 through 18. Part 3 studied participants taking omav on day 1 through 13 and itraconazole day 10 through 18. Part 4 studied subjects taking omav on day 1 through 13 and verapamil on day 10 through 18 [97]. There are currently no results published in this study, but they may be important to the practical use of omaveloxolone in FRDA.
Designing phase II clinical trials in Friedreich ataxia
Published in Expert Opinion on Emerging Drugs, 2021
Omaveloxolone is a small molecule that prevents ubiquitination of Nrf2, a regulator of expression of antioxidant proteins, thus increasing Nrf2 levels [30]. In vitro, Omaveloxolone increases mitochondrial function and normalizes certain biomarkers of FRDA in LBCLs [31–33]. A phase II, double-blind, randomized, placebo-controlled, dose-ranging trial for Omaveloxolone was conducted in two parts. Part 1 assessed safety and tolerability and analyzed peak workload in an exercise test in 52 FRDA patients compared to 17 patients on placebo [34]. Omaveloxolone was taken orally for 12 weeks at a dose range from 2.5 to 300 mg per day. Results from part 1 of this study showed that Omaveloxolone was well tolerated with generally mild adverse events and determined that the optimal dose after 4 weeks of treatment was between 80 and 300 mg. In part 2 of this study, 51 patients received 150 mg per day Omaveloxolone and 52 patients received placebo for 48 weeks [35]. This study met its primary endpoint; a significant decrease in mFARS (modified FARS) score in the treatment group, but not placebo group. The two-part design of this study offered the chance to select the optimal dose and outcome measure while gaining insight into early, unpowered efficacy that likely contributed to the success of the overall phase II trial [36]. Presently, Omaveloxolone is pending FDA approval based on data from the phase IIb trial.
Emerging therapies in Friedreich’s Ataxia
Published in Expert Review of Neurotherapeutics, 2020
Theresa A. Zesiewicz, Joshua Hancock, Shaila D. Ghanekar, Sheng-Han Kuo, Carlos A. Dohse, Joshua Vega
Omaveloxolone (Omav) is an Nrf2 activator that acts to prevent Nrf2 ubiquitination, allowing Nrf2 to target antioxidative genes [Figure 1] and reduce the expression of the inflammatory cytokines TNF-alpha and IL-6. The pharmacokinetics, safety, and tolerability of Omav were evaluated in a phase 2 dose-finding study in 69 patients over 12 weeks called ‘MOXIe’ [40,41]. The inclusion criteria included a genetically confirmed diagnosis of FRDA and a modified Friedreich’s Ataxia Rating Scale (mFARS) score of 10 and 80. The ‘mFARS’ is an abbreviated form of the FARS, or the Friedreich’s Ataxia Rating Scale, and is comprised of four sections: bulbar (speaking and swallowing), upper limb coordination, lower limb coordination, and upright stability, including standing and walking. The primary outcome measure in the study was cardiopulmonary exercise testing of ‘peak work-load’ on a stationary bike; secondary outcomes included the mFARS scores at 4 and 12 weeks, as well as the 9-hole peg test, and timed 25-foot walk test. The study was a dose-ranging study (2.5–300 mg/day), and participants were randomized by a 3:1 ratio of Omav treatment and placebo. While Omav did not significantly change the primary outcome measure at the study endpoint, it led to an improvement in mFARS scores in a dose-dependent manner [41]: patients who were treated with Omav on a dose of 160 mg experienced a mean improvement of 3.8 points in mFARS compared to baseline (p < 0.001) and a 2.3 points improvement in mFARS compared to those patients taking placebo (p = 0.06) [41].