Introduction

Omaveloxolone is an oral, small molecule activator of Nrf2 that targets inflammatory, metabolic and oxidative stress pathways and has been approved for use in Friedreich ataxia, a severe genetic disease marked by progressive muscle incoordination and weakness. Omaveloxolone therapy is associated with transient, mild-to-moderate serum aminotransferase levels during therapy but has not been linked to instances of clinically apparent liver injury with jaundice.

Background

Omaveloxolone (oh ma vel ox” oh lone) is an orally available, small molecule activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that stimulates gene pathways involved in antioxidative and antiinflammatory responses, and is used to treat Friedreich ataxia, a severe genetic disease marked by progressive incoordination, muscle loss, and weakness. Friedreich ataxia is caused by a defect in the frataxin gene due to repeated and excessive expansion of GAA codons which results in iron-sulfur clusters within mitochondria leading to oxidative stress, inflammation, and cellular damage. The Nrf2 pathway is reduced in patients with Friedreich ataxia resulting in excessive oxidative stress and mitochondrial injury in muscle. Omaveloxolone is a semi-synthetic triterpenoid that activates the Nrf2 pathway and was shown to stimulate Nrf2 in cell culture and in animal models of Friedreich ataxia and other conditions marked by oxidative stress. In a prospective, placebo-controlled trial, omaveloxolone improved symptoms and was associated with a lack of progression in muscle weakness. Omaveloxolone was approved in the United States for use in adults and adolescents 16 years of age or older with Friedreich ataxia in 2023. Omaveloxolone is available in capsules of 50 mg under the brand name Skyclarys. The recommended dose is 150 mg (3 capsules) once daily. A lower dose can be used in response to adverse events and as initial therapy in patients with preexisting moderate hepatic impairment. Side effects can include headache, nausea, abdominal pain, diarrhea, fatigue, and musculoskeletal pain. Laboratory abnormalities include a high rate of ALT and AST elevation and hyperlipidemia. Severe adverse events are uncommon but can include marked cholesterol elevations and fluid overload. Monitoring of serum aminotransferase and cholesterol levels during therapy is recommended.

Hepatotoxicity

In the prelicensure clinical trials in 82 patients with Friedreich ataxia, serum aminotransferase elevations occurred in 37% of treated compared to 2% of placebo recipients and were above 5 times ULN in 16% vs 0%. The ALT and AST elevations, however, were not accompanied by symptoms or bilirubin elevations and appeared to be due to induction of the serum enzymes (ALT, AST, and GGT) rather than liver injury. Aminotransferase elevations often improved during continued therapy. Nevertheless, monitoring of serum aminotransferase and bilirubin levels is recommended at least during the first 3 months of therapy. In the prelicensure clinical studies and subsequently after approval of omaveloxolone, there have been no reports of clinically apparent liver injury with jaundice linked to its use. However, Friedreich ataxia is a rare disease and clinical experience with use of omaveloxolone has been limited.

Likelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury).

Mechanism of Injury

The causes of serum enzyme elevations during omaveloxolone therapy are believed to be due to enzyme induction. The frequency of the elevations is dose related and was observed in experimental animals in preclinical studies with no histologic evidence of damage to the liver. Omaveloxolone is metabolized in the liver largely by cytochrome 3A4, and it is susceptible to drug-drug interactions with moderate or strong inducers or inhibitors of CYP 3A4 concurrent use of which should be avoided.

Outcome and Management

Monitoring of laboratory tests including ALT, AST, GGT, and bilirubin levels is recommended before, every month for 3 months, and then periodically thereafter. Elevations above 5 times the ULN should lead to temporary discontinuation, and any elevations in aminotransferase levels accompanied by jaundice or symptoms of liver disease to prompt discontinuation. Omaveloxolone should not be used in patients with severe hepatic disfunction (Child Pugh C) and started at a lower dose in those with moderate dysfunction (Child Pugh B).

Drug Class: Genetic Disorder Agents