<p>Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates</p>

Abstract

Background Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich’s ataxia. Methods The present study evaluated the pharmacokinetics (PK) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich’s ataxia patients. Pharmacodynamic (PD) evaluations in monkeys consisted of Nrf2 target gene mRNA expression in peripheral blood mononuclear cells (PBMCs), liver, lung, and brain. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich’s ataxia patient PK profile. Results Oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measureable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes in PBMCs and tissues was also observed. Clinically, oral administration of omaveloxolone to Friedreich’s ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. Conclusion Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich’s ataxia patients after oral administration.

Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia

“…When a similar assay was performed with N. fowleri , we noted a more uniform behavior with most compounds reaching a maximum inhibition of about 75% at 24 h. One exception is bardoxolone methyl, which inhibited about 85% of growth at 24 h and 97% at 48 h. Although bardoxolone methyl is not CNS penetrant, this result opens the path for exploring similar compounds with better pharmacokinetics such as omaveloxolone (Reisman et al, 2019). In our study, 2x EC 50 concentration of amphotericin B did not induce growth inhibition at 24 h but showed maximum growth inhibition at 48 h. Previous studies have explored the killing kinetic of posaconazole over N. fowleri where they observed ~20% inhibition after 8 h of treatment with 50 μM.…”

Current and Emerging Clinical Treatment in Mitochondrial Disease

“…Omaveloxolone is an oleanolic triterpenoid that prevents nuclear factor erythroid 2-related factor 2 (Nrf2) degradation, inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pro-inflammatory pathway [ 43 ]. This inhibition has been shown to improve oxidative phosphorylation and mitochondrial biogenesis in patients with mitochondrial myopathy ( n = 53) [ 43 ].…”

“…Omaveloxolone is an oleanolic triterpenoid that prevents nuclear factor erythroid 2-related factor 2 (Nrf2) degradation, inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pro-inflammatory pathway [ 43 ]. This inhibition has been shown to improve oxidative phosphorylation and mitochondrial biogenesis in patients with mitochondrial myopathy ( n = 53) [ 43 ]. A phase 2 double-blind, dose-ranging, placebo-controlled RCT of omaveloxolone in 53 patients with mitochondrial myopathy failed to meet its primary outcome (peak workload assessed via an incremental cycling exercise test) [ 44 ].…”

KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease

“…The other is RTA-408 (omaveloxolone, figure 5 b ) for the treatment of Friedreich's ataxia, mitochondrial myopathy, ocular inflammation, ocular pain, corneal endothelial cell loss, cataract surgery, melanoma and radiation dermatitis in breast cancer patients [ 23 ]. Recently, Reata Pharmaceuticals reported the evaluation of the pharmacokinetics and tissue distribution of orally administered RTA-408 to cynomolgus monkeys after single and multiple oral doses, and the initial results from a clinical trial in Friedreich's ataxia patients [ 126 ]. Dose-dependent plasma levels of RTA-408 and induction of NRF2 target genes were detected in peripheral blood mononuclear cells, liver, lung, and brain of the animals.…”