Regulatory Decision Summary for Skyclarys

The purpose of this New Drug Submission was to obtain market authorization, pursuant to Section C.08.004 of the Food and Drugs Regulations, for Skyclarys, filed by Biogen Canda Inc.

This submission was filed for omaveloxolone for the treatment of patients with Friedreich’s ataxia. Upon review of the submitted data package, Health Canada authorized Skyclarys for the treatment of Friedreich’s ataxia in patients 16 years of age or older at a dose of omaveloxolone 150 milligrams (mg) taken once daily.

This submission was filed and reviewed under the Priority Review Policy.

Friedreich’s ataxia (FA) is a rare, progressive, serious, genetic, neurodegenerative disease, usually manifesting clinically during the adolescent years or early twenties. Currently, there are no disease-modifying therapies available; thus, a high unmet medical need exists for safe and effective treatments of this condition.

Clinical data generated to support the market authorization of omaveloxolone in the treatment of FA consisted of a single pivotal trial, Study 1402 Part 2, and a longer term open-label trial, Study 1402 Extension. Patients in both trials received the recommended dose of 150 milligrams (mg) once daily. Study 1402 Part 2 was a randomized, double-blind, placebo-controlled trial of 103 patients with FA who were 16-40 years of age at study entry, conducted over 48 weeks, while Study 1402 Extension was an open-label trial for an additional 144 weeks.

The data from the pivotal trial (Study 1402 Part 2, N = 103) demonstrated omaveloxolone’s ability to slow, but not reverse, progression of neurological disease in FA, as measured by the modified Friedreich’s Ataxia Rating Scale (mFARS) score, a validated scale to assess disease progression in FA. It was observed earlier in Phase II development, that patients with advanced pes cavus may have a limited response to omaveloxolone treatment. Thus, the primary, pre-specified efficacy analysis was limited to FA patients without pes cavus (N = 82). At Week 48, patients without pes cavus treated with omaveloxolone demonstrated a statistically significant difference in the mFARS score of 2.4 points (95% Confidence Interval [CI]: −4.31 to −0.5), p = 0.014, favouring omaveloxolone treatment over placebo. This result was supported by a similar 1.9 point (95% CI: -3.71 to -0.16), p = 0.03, difference in mFARS score in favour of omaveloxolone treatment over placebo in the all-randomized population of 103 patients. These results are clinically meaningful, by way of reference, a large natural history registry of FA patients who were not treated with disease-modifying therapy demonstrated an average annual progression of +2.1 points in the mFARS score in propensity-matched patients. Further, the open-label extension trial provided supportive data for an additional 144 weeks.

The primary analysis included 5 adolescent patients (aged 16 or 17 years), who were randomized to omaveloxolone and had mFARS data at baseline and at Week 48, compared to 13 adolescent patients randomized to placebo. A non-statistically significant trend in favour of omaveloxolone treatment was observed in these patients. The inclusion of adolescent patients in the indication for omaveloxolone is supported by identical disease pathophysiology in FA regardless of age, the typical onset of FA disease in the adolescent years, efficacy results consistent with those of the primary efficacy endpoint, and a similar safety profile to that seen in adult FA patients.

The primary safety population included all enrolled patients from Study 1402 Part 2 (N = 103). The most common adverse events (AEs) that occurred with omaveloxolone treatment, compared to placebo, respectively, were increased serum alanine aminotransferase (ALT) (37.3% versus [vs.] 1.9%); headache (37.3% vs. 25.0%); nausea (33.3% vs. 13.5%); fatigue (21.6% vs. 13.5%); abdominal pain (21.6% vs. 5.8%); and increased serum aspartate aminotransferase (AST) (21.6% vs. 1.9%). No serious adverse events were observed in more than a single patient in the safety population, and no patient deaths were recorded.

Increases in serum transaminases, B-type natriuretic protein (BNP), and low-density lipoprotein cholesterol were observed with Skyclarys; these blood levels should be measured prior to initiation of Skyclarys and monitored during ongoing treatment. Dose adjustment or avoidance of omaveloxolone is recommended for patients with advanced hepatic impairment, and with concomitant use of CYP3A4 inhibitors, inducers, or substrates. Appropriate dosing and monitoring recommendations are outlined in the Dosage and Administration and Warnings and Precautions sections of the Skyclarys Product Monograph.

Overall, omaveloxolone treatment attenuated progression of neurologic deterioration in patients with Friedreich’s ataxia who were 16 years of age and older over a period of at least 3 years. However, to date, the effects of omaveloxolone have not been evaluated with respect to the non-neurologic complications of Friedreich’s ataxia.

As noted in the approved Risk Management Plan (RMP), multiple potential safety concerns will be monitored in the post-marketing setting, including drug-induced liver injury, congestive heart failure, use during pregnancy and lactation, and long-term use of omaveloxolone.

A RMP for Skyclarys was submitted by Biogen Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The chemistry and manufacturing information submitted for Skyclarys has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Comparative bioavailability data was reviewed and demonstrated that a high-fat, high-calorie meal had a significant impact on the rate and extent of exposure of omaveloxolone in Skyclarys. Administration of omaveloxolone as capsule contents sprinkled on applesauce did not significantly impact the rate and extent of exposure of omaveloxolone compared with intact capsules. With the exception of the colour of capsule shell, the commercial formulation of Skyclarys is the same as the 50 mg capsule formulation used in the pivotal trial, Study 1402 Part 2, and in the comparative bioavailability studies.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Skyclarys for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about Skyclarys, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.