Background: MOXIe Part 2 (NCT02255435) was a randomized, double-blind, placebo-controlled trial evaluating omaveloxolone 150 mg once daily for 48 weeks in patients with Friedreich ataxia. Upon study completion, patients could enter an open-label extension. In the MOXIe study, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were reported more frequently with omaveloxolone versus placebo. These elevations were mild to moderate and generally asymptomatic, transient, and reversible following treatment discontinuation. None of the patients who experienced aminotransferase elevations met Hy’s law criteria, defined as concomitant total bilirubin increases >2× the upper limit of normal.
Omaveloxolone is an activator of nuclear erythroid 2 related factor 2 (Nrf2), a transcription factor that regulates the expression of genes involved in redox balance, cellular metabolism, and mitochondrial function. Aminotransferases also play key roles in several metabolic processes and are known to adapt to metabolic demand.
Objectives: We aimed to better understand the relationship between omaveloxolone treatment and aminotransferase levels by assessing the tissue distribution of ALT and AST isoforms in human tissue samples and by measuring the effect of omaveloxolone on aminotransferase gene expression in cultured cells.
Results: ALT and AST influence redox balance and mitochondrial metabolism by contributing to glutathione production and by regulating the NAD+/NADH ratio via the malate-aspartate shuttle. We found that aminotransferases are widely expressed in several human tissues. In addition, expression of the genes encoding ALT and AST was influenced by treatment with omaveloxolone in multiple cell types. The transient rise in serum aminotransferase levels observed with omaveloxolone treatment may occur as a metabolic adaptation driven by the activation of Nrf2. However, the extent to which, or if, this occurs with omaveloxolone is unknown.
Conclusions: The mechanism of action of omaveloxolone alters cellular metabolic pathways that involve aminotransferase activity. These metabolic shifts may have contributed, in part, to the increases in serum aminotransferases observed in MOXIe Part 2.