Omaveloxolone

Absorption

Between 50 mg (0.33 times the recommended dosage) and 150 mg, the AUC of omaveloxolone increased in a dose-dependent and dose-proportional manner. However, at the same dose range, the Cmax increased in a less than dose-proportional manner in healthy fasted subjects. The median time to achieve peak plasma concentration was 7 to 14 hours. Compared to fasted conditions, the AUC0-inf and Cmax of omaveloxolone were 350% and 15% higher with a high-fat meal (800 to 1000 calories, with 150, 250, and 500 to 600 calories coming from protein, carbohydrate, and fat, respectively).

Toxicity

Toxicity information regarding omaveloxolone is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as elevation in hepatic transaminases and B-Type natriuretic peptide (BNP), as well as lipid abnormalities. Symptomatic and supportive measures are recommended.
The carcinogenicity of omaveloxolone has not been evaluated. In a bacterial reverse mutation (Ames) assay, omaveloxolone showed negative results, while a chromosomal aberration assay in human peripheral blood lymphocytes showed positive results. Rats given 0, 1, 3, and 10 mg/kg/day of oral omaveloxolone had a higher incidence of pre- and post-implantation loss and resorptions, leading to a decrease in viable embryos at the highest dose. The no-effect dose (3 mg/kg/day) of omaveloxolone for fertility and reproductive function adverse effects was equivalent to an AUC of approximately 2 times the recommended human dose(150 mg/day).

The Uses of Omaveloxolone

Synthetic triterpenoids, such as RTA 408, are antioxidant inflammation modulator (AIM) that can inhibit tumor cell growth and metastasis via oncogenic signaling pathways. RTA 408 is an anticancer, anti-inflammatory, and antioxidant agent that protects human retinal pigment epithelial cells against H2O2-induced cell injury by activating NF-E2-related factor 2.

Indications

Omaveloxolone is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Background

Omaveloxolone (RTA-408) is a semisynthetic oleanane triterpenoid with antioxidant and anti-inflammatory properties. Omaveloxolone acts as an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that mitigates oxidative stress. In patients with Friedreich's ataxia, a genetic disease involving mitochondrial dysfunction, the Nrf2 pathway is impaired, and Nrf2 activity is lower. Therefore, the use of Nrf2 activators such as omaveloxolone represents a therapeutic advantage in this group of patients. In February 2023, omaveloxolone was approved by the FDA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. The use of omaveloxolone for the treatment of conditions involving mitochondrial dysfunction and oxidative stress has also been evaluated.

Biological Activity

omaveloxolone (rta-408) is a novel synthetic triterpenoid that binds to kelch-like ech-associated protein 1 (keap1) and attenuate nuclear factor erythroid 2-related factor 2 (nrf2) degradation [1].keap1 is involved in proteasomal degradation of nrf2, thereby maintaining low basal levels of nrf2. binding to keap1 and blocking its ability to promote nrf2 degradation increase newly synthesized nrf2 accumulated in the nucleus where nrf2 increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes [1].in interferon-γ-stimulated raw 264.7 macrophage cells, low concentrations (≤ 25 nm) of rta-408 activated nrf2 and lowered nitric oxide and pro-inflammatory cytokine levels. at higher concentrations, rta-408 inhibited tumor cell growth, with gi50 of 260 ± 74 nm. meanwhile, rta-408 increased caspase activity in tumor cell lines, but not in normal primary human cells.in mice with radiation-induced dermatitis, topical application of rta-408 (0.01%, 0.1% and 1.0%, q.d.) resulted in dose-dependent improvements in the appearance of skin, with 1.0% rta-408 markedly reducing epidermal and collagen thickening, preventing dermal necrosis, and completely alleviating skin ulcers [2].[1]. probst b l, trevino i, mccauley l, et al. rta 408, a novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity. plos one, 2015, 10(4): e0122942.[2]. reisman s a, lee c y, meyer c j, et al. topical application of the synthetic triterpenoid rta 408 protects mice from radiation-induced dermatitis. radiation research, 2014, 181(5): 512-520.

Pharmacokinetics

The MOXIe study showed that after 4 weeks of administration, the use of omaveloxolone led to robust dose‐dependent changes at 80 ‐300 mg/day.. The effect of omaveloxolone on QTc interval has yet to be defined. The use of omaveloxolone can lead to an elevation in hepatic transaminases (both aspartate transaminase and alanine transaminase) and an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. It can also cause changes in cholesterol.

Metabolism

Omaveloxolone is mainly metabolized by CYP3A, although CYP2C8 and CYP2J2 play also a minor role.