General Information

Skyclarys (omaveloxolone) activates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

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

Skyclarys is supplied as capsules for oral administration. Obtain ALT, AST, bilirubin, BNP, and lipid parameters prior to initiating and during treatment.

 The recommended dosage of Skyclarys is 150 mg (3 capsules) taken orally once daily. Administer Skyclarys on an empty stomach at least one hour before eating. Capsules should be swallowed whole. Do not open, crush, or chew. If a dose of Skyclarys is missed, take the next dose at its scheduled time the following day. A double dose should not be taken to make up for a missed dose.

Mechanism of Action

The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown. Omaveloxolone have 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.

Side Effects

Side effects associated with the use of Skyclarys may include, but are not limited to, the following:

• elevated liver enzymes (AST/ALT)
• headache
• nausea
• abdominal pain
• fatigue
• diarrhea
• musculoskeletal pain

Clinical Trial Results

The FDA approval of Skyclarys was based on the MOXIe Part 2 trial and a post hoc Propensity-Matched Analysis of the open-label MOXIe Extension trial.

MOXIe Part 2 was a randomized, double-blind, placebo-controlled study. Patients with genetically confirmed Friedreich’s ataxia and baseline modified Friedreich’s Ataxia Rating Scale (“mFARS”) scores between 20 and 80 were randomized 1:1 to receive placebo or 150 mg of Skyclarys daily. The primary endpoint was change from baseline in mFARS score compared to placebo at Week 48 in the Full Analysis Population of patients without severe pes cavus (n=82). The mFARS is a clinical assessment tool to assess patient function and is used in clinical trials to assess the efficacy of investigational products for use in Friedreich’s ataxia. Treatment with Skyclarys resulted in statistically significant lower mFARS scores (less impairment) relative to placebo at Week 48. The placebo-corrected difference between the two groups was -2.41 points. 

In a post hoc Propensity-Matched Analysis, mFARS progression of patients treated with 150 mg of Skyclarys daily in the open-label MOXIe Extension trial was compared to the progression of propensity score-matched untreated patients in the largest natural history study of Friedreich’s ataxia, Clinical Outcome Measures in Friedreich’s ataxia (“FA-COMS”). All patients enrolled in the MOXIe Extension study with at least one post-baseline assessment (n=136) were matched one to one with patients from the FA-COMS study (n=136). Lower (improved) mFARS scores were observed in patients treated with Skyclarys after 3 years relative to the matched set of untreated patients from the FA-COMS natural history study.