Chemical formula: C₃₃H₄₄F₂N₂O₃ Molecular mass: 554.332 g/mol PubChem compound: 71811910
The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown. Omaveloxolone has been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. There is substantial evidence that Nrf2 levels and activity are suppressed in cells from patients with Friedreich’s ataxia.
Omaveloxolone binds to Kelch-like ECH-associated protein 1 (Keap1), a protein that regulates the activity of Nrf2. Binding to Keap1 allows nuclear translocation of Nrf2 and transcription of its target genes. In fibroblasts isolated from patients with Friedreich’s ataxia, omaveloxolone was shown to restore Nrf2 protein levels and increase Nrf2 activity. Omaveloxolone was also shown to rescue mitochondrial dysfunction and restore redox balance in these cells, as well as in neurons from mouse models of Friedreich’s ataxia. Evidence of pharmacodynamic activity was observed in omaveloxolone-treated patients, with dose-dependent changes in the products of Nrf2 target genes, serum ferritin and GGT, across the dose range of 20 mg to 300 mg. Patients who received omaveloxolone 160 mg generally showed the largest increase from baseline for these serum markers.
Omaveloxolone was absorbed after oral administration in healthy fasted subjects with peak plasma concentrations typically observed 7 to 14 hours post dose. Patients with Friedreich’s ataxia demonstrated a 2.3-fold faster absorption of omaveloxolone than fasted healthy subjects.
Co-administration of a high-fat meal resulted in a small increase (1.15-fold) in area under the plasma concentration vs time curve from time 0 extrapolated to infinity (AUC0-inf) but caused a 4.5-fold increase in Cmax compared to fasted conditions. It is recommended that omaveloxolone be taken without food.
Omaveloxolone Cmax and AUC0-inf were similar when capsule contents were sprinkled on apple puree or when administered as intact capsules. The median time to achieve Cmax (tmax) of omaveloxolone was shortened from approximately 10 hours to 6 hours when sprinkled on apple puree.
The absolute or relative bioavailability of omaveloxolone has not been determined.
The total plasma omaveloxolone exposure (AUC) increased in a dose-dependent and dose proportional manner, but Cmax increased in a less than dose proportional manner in healthy fasted subjects.
Omaveloxolone is 97% bound to protein in human plasma. Omaveloxolone shows low to moderate membrane permeability. The average apparent volume of distribution is 7361 L (105 L/kg).
Following a single oral dose of [14C]-omaveloxolone administered to healthy male subjects, omaveloxolone was found to be eliminated by metabolism via CYP3A4 to a series of 30 metabolites, of which 7 metabolites were quantified and identified. Metabolites M22 and M17 were major plasma metabolites that accounted for 18.6% and 10.9% of total plasma radioactivity, respectively. The other metabolites were minor, each accounting for less than 10% of total plasma radioactivity exposure. None of the metabolites has meaningful pharmacological activity.
Following a single oral dose of radio-labeled omaveloxolone administered to healthy male subjects, approximately 92.5% of the dosed radioactivity was recovered within a 528-hour collection period: 92.4% via the faeces and 0.1% via the urine. The majority (90.7%) of the administered dose was recovered in the faeces within 96 hours after administration.
The average apparent plasma clearance of omaveloxolone is 109 L/hr and the average apparent plasma terminal half-life is 58 hours (32-94 hours).
Population pharmacokinetic analyses indicate that there is no clinically meaningful effect of age (16-71 years), sex, or body weight on the pharmacokinetics of omaveloxolone and no dose adjustments based on these factors are necessary.
Population pharmacokinetic analysis confirmed that estimated glomerular filtration rate values ≥63 mL/min/1.73 m² did not have a significant effect on the pharmacokinetics of omaveloxolone. The effect of moderate or severe renal impairment on the pharmacokinetics of omaveloxolone is unknown.
In subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher plasma exposure of omaveloxolone. Subjects with moderate hepatic impairment exhibited up to a 65% increase in AUC and an 83% increase in Cmax compared to subjects with normal hepatic function. In subjects with severe hepatic impairment, the AUC for omaveloxolone was increased by 117% as compared to subjects with normal hepatic function. However, the data in subjects with severe hepatic impairment are limited. In subjects with mild hepatic impairment (Child-Pugh Class A), there was no change in AUC and only a 29% increase in Cmax. The recommended dosage for patients with hepatic impairment is described in section 4.2.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, and carcinogenic potential.
Based on a panel of in vitro and in vivo mutagenicity tests, omaveloxolone is considered of low genotoxic potential. Omaveloxolone was not carcinogenic in a 6-month carcinogenicity study in rasH2 mice up to doses corresponding to approximately 14.6 and 54.5 times in males and females, respectively, the maximum human recommended dose (MHRD) and systemic exposure (AUC) in patients with Friedreich’s ataxia.
Preclinical data revealed toxicities related to omaveloxolone. In rats, findings of irreversible kidney injury (multifocal renal tubular degeneration/regeneration accompanied by proteinuria) were observed at clinically relevant dose levels in rats after 28 days of daily oral exposure up to 6 months. Furthermore, reversible observations of hyperplasia of the GI tract (forestomach, oesophagus, larynx) was observed in rats and monkeys already after 28 days of dosing, up to 6 or 9 months in rats and monkeys, respectively. In one male rat from the high dose group at 6 months dosing, the squamous epithelial hyperplasia was associated with a squamous cell carcinoma involving the non-glandular and glandular stomach.
Omaveloxolone, administered at oral doses of 1, 3, and 10 mg/kg/day to male rats for 28 days before mating and throughout the mating period and to female rats from 14 days before mating, throughout mating, and until gestation day 7 did not alter male or female fertility. However, pre- and post-implantation embryonic loss, resorptions, and a decrease in the number of viable embryos occurred at the dose corresponding to approximately 6 times the maximum human recommended dose (MHRD) based on systemic exposure. No effects on pre- and post-implantation loss occurred at approximately 2 times the MHRD based on systemic exposure.
In an embryo-foetal toxicity study in rats, no maternal toxicity or embryo-foetal abnormalities were detected in rats at an oral dose corresponding to approximately 6 times the MHRD based on systemic exposure. However, at doses achieving exposure levels 19 times the MHRD, post-implantation loss, resorptions as well as decreases in number of viable fetuses, litter size, and foetal body weight were observed in rats. Embryo-foetal assessment in rabbits demonstrated maternal toxicity that was associated with early deliveries and interruptions of pregnancy as well as low foetal body weights at a dose level corresponding to exposures lower (0.7-fold) than those at the MHRD; however, in the same study, no foetal malformations were observed at approximately 1.4 times the MHRD based on systemic exposure.
In a pre- and post-natal evaluation in rats, administration of omaveloxolone during the period of organogenesis through lactation at doses of 1, 3, and 10 mg/kg/day was associated with an increased percentage of litters with stillborn pups, reduced first generation pup survival, and decreased mean pup body weights. Decreased reproductive function (reduced mean numbers of corpora lutea and implantation sites) were observed in F1 females and delayed sexual maturation was observed in F1 males at a dose level of approximately 6 times the MHRD based on systemic exposure. No adverse reactions were observed at a dose of approximately 2 times the MHRD based on systemic exposure. Dose-dependent increases in omaveloxolone plasma concentrations were observed in pups, due to excretion of omaveloxolone in milk. Effects were directly linked to exposure to omaveloxolone.
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