Summary Basis of Decision for Skyclarys

Clinical Pharmacology

In non-clinical studies, omaveloxolone has been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro. The Nrf2 pathway is involved in the cellular response to oxidative stress, and may play a role in restoring mitochondrial function.

Following oral administration of a single 150 mg dose of omaveloxolone in healthy, fasted adults, the peak plasma concentration was reached in 7 to 14 hours and the total plasma exposure (as measured by the area under the concentration-time curve) of the drug increased in a dose-dependent manner. Omaveloxolone is 97% bound to plasma proteins and is widely distributed. It is primarily metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP2C8 and CYP2J2. Following a single oral dose of radiolabelled omaveloxolone administered to healthy male subjects, over 92.4% of the drug was recovered in the feces, whereas the renal route of elimination was insignificant (0.1%). The apparent plasma terminal half-life of omaveloxolone is about 64 hours.

Studies in healthy adults show that there are no clinically meaningful differences in the pharmacokinetics of omaveloxolone with respect to age, gender, or race/ethnic origin. Omaveloxolone and its major metabolites, alone or combined, did not cause a clinically significant corrected QT (QTc) interval prolongation in healthy subjects.

The concomitant use of omaveloxolone with strong CYP3A4 inhibitors should be avoided because they increase omaveloxolone exposure by 3- to 4-fold. Patients should be monitored for adverse reactions and the dose of omaveloxolone should be adjusted, if necessary, when the drug is used with moderate inhibitors of CYP3A4. The concomitant use with strong or moderate CYP3A4 inducers should be avoided to prevent loss of omaveloxolone efficacy. Omaveloxolone can reduce the efficacy of CYP3A4 substrates such as oral hormonal contraceptives; accordingly, concomitant use should be avoided and/or a back-up method of contraception should be employed. Omaveloxolone can reduce the systemic exposure and potentially, the efficacy of CYP2C8 substrates such as some antidiabetic agents (e.g., repaglinide). If concomitant use cannot be avoided, the efficacy of these drugs should be monitored and their doses adjusted accordingly.

Omaveloxolone is a weak inducer of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1), and can potentially affect the efficacy of substrates of BCRP and OATP1B1 (e.g., some statins). Doses of such drugs should be adjusted, if necessary.

The submitted data on drug-drug interactions included modelling studies, which were determined to be inadequate to predict the outcomes of some interactions. However, drug-drug interactions have also been evaluated in subjects in clinical studies. The results and associated dosing recommendations are presented in the Product Monograph for Skyclarys.

Data suggest that no dose adjustment of omaveloxolone is necessary in patients with mild hepatic impairment. Patients with moderate hepatic impairment should be given 100 mg of omaveloxolone daily, which can be lowered to 50 mg if adverse reactions occur. The use of omaveloxolone should be avoided in patients with severe hepatic impairment.

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

Clinical Efficacy

The clinical development program of Skyclarys included Study 1402 Part 2, a pivotal, double-blind, randomized, placebo-controlled clinical study in 103 patients with Friedreich’s ataxia, and Study 1402 Extension, an open-label extension study in 149 patients with Friedreich’s ataxia.

In Study 1402 Part 2, 51 patients were randomized to receive 150 mg of Skyclarys orally once daily and 52 patients were randomized to receive placebo, over 48 weeks. Randomization was stratified by pes cavus status, i.e., patients with pes cavus or patients without pes cavus. Enrolled patients were 16 to 40 years of age, had genetically confirmed Friedreich’s ataxia, and a baseline modified Friedreich’s Ataxia Rating Scale (mFARS) score between 20 and 80. Twenty-four adolescent patients (16 or 17 years of age) were enrolled in Study 1402 Part 2 (9 patients in the Skyclarys group and 15 patients in the placebo group). Treatment with omaveloxolone is not expected to affect the patient’s foot structure, the concern was that a severe pes cavus (foot deformity, determined by the flashlight test), may impact a patient’s ability to perform the mFARS in Study 1402 Part 2, which might potentially reduce the sensitivity of the mFARS to detect a treatment effect. Thus, the primary prespecified efficacy analysis was limited to the population of 82 patients with Friedreich’s ataxia without pes cavus.

The primary efficacy endpoint of the study was the change in the mFARS score from baseline to Week 48. The mFARS score and the corresponding assessments provide a tangible, quantifiable, and meaningful measure of a patient’s disease progression in Friedreich’s ataxia. The primary efficacy analysis was powered to detect a 2-point change in the mFARS score.

The primary prespecified efficacy analysis showed that patients treated with Skyclarys experienced a mean decrease from baseline in mFARS score of -1.56 points (95% confidence interval [CI]: -2.93 to -0.18) at Week 48. In contrast, in patients who were randomized to placebo, a mean increase in mFARS score of +0.85 points (95% CI: -0.43 to 2.13) was observed, resulting in a between-treatment group difference of -2.41 points (95% CI: -4.31 to -0.5; p = 0.014) in favour of Skyclarys. Further, in the all-randomized population of 103 patients with Friedreich’s ataxia, regardless of pes cavus status, treatment with Skyclarys resulted in an improvement of -1.94 points in mFARS score (95% CI: -3.71 to -0.16; p = 0.03), relative to placebo, at Week 48. These results are clinically meaningful; by way of comparison, a large natural history registry of patients with Friedreich’s ataxia 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.

The results for the prespecified Friedreich’s ataxia population (without pes cavus) and the all-randomized population (regardless of pes cavus status) were supported by consistent trends in mFARS scores in favour of Skyclarys in a variety of patient subgroups (defined by patient age, gender, and baseline mFARS status), as well as by the results of the secondary endpoints that evaluated neurologic function and activities of daily life. The inclusion of adolescent patients with Friedreich’s ataxia in the indication for Skyclarys is supported by identical disease pathophysiology regardless of age, the typical onset of the 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 patients with Friedreich’s ataxia.

Study 1402 Extension, the open-label extension study, although not statistically powered to evaluate efficacy, provided supportive data that demonstrated sustained efficacy of Skyclarys in patients with Friedreich’s ataxia 16 years of age and older over a period of up to an additional 144 weeks of treatment. In total, 11 adolescent patients were enrolled in the open-label extension study.

Overall, Skyclarys demonstrated statistically significant and clinically relevant reductions in mFARS scores after 48 weeks of treatment, limiting the progression of neurologic impairment and the deterioration of activities of daily living in patients with Friedreich’s ataxia.

Indication

The New Drug Submission for Skyclarys was filed by the sponsor with the following proposed indication:

Skyclarys (omaveloxolone) is indicated for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older.

Health Canada approved the following indication:

Skyclarys (omaveloxolone) is indicated for the treatment of Friedreich’s ataxia in patients 16 years of age and older.

For more information, refer to the Product Monograph for Skyclarys, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Skyclarys in patients with Friedreich’s ataxia was primarily evaluated in Study 1402 Part 2, whereas supportive data were provided from the open-label, long-term extension trial, Study 1402 Extension (see Clinical Efficacy section).

The primary safety population consisted of the 103 randomized patients with Friedreich’s ataxia in Study 1402 Part 2 and included patients who received at least one 150 mg dose of Skyclarys. In the Skyclarys group, 86.3% of patients completed the study to Week 48, compared to 96.2% in the placebo group. Of the patients who discontinued treatment prior to Week 48, 4 (7.8%) patients in the Skyclarys group and 2 (3.8%) patients in the placebo group discontinued treatment due to the occurrence of an adverse event.

The most common adverse events that occurred with Skyclarys treatment, compared to placebo, 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%). These adverse events generally occurred in the first 12 weeks of treatment.

No serious adverse events were reported in more than one patient exposed to Skyclarys. One Skyclarys-treated patient discontinued treatment due to increased serum transaminase values, but no serious adverse events related to hepatic dysfunction were reported. No patient deaths occurred during the study.

Elevations of serum transaminases were noted in the Skyclarys-treated patients. In 31.4% of patients in the Skyclarys group, ALT or AST values exceeded the prespecified threshold of greater than 3 times the upper limit of normal. In 15.7% of these patients, ALT or AST values were greater than 5 times the upper limit of normal, and in 2 (3.9%) patients, ALT or AST values were greater than 10 times the upper limit of normal. Mean increases in ALT and AST levels were maximal at Week 2 of Skyclarys treatment and trended back toward baseline values over time while therapy was continued for 48 weeks. In patients who required study drug withdrawal, AST and ALT levels declined to baseline values within 4 weeks of drug discontinuation. No noteworthy increases of bilirubin were observed with any of these transaminase elevations and there were no cases meeting Hy’s law criteria.

Fourteen percent of patients treated with Skyclarys had an increase in B-type natriuretic peptide above the upper limit of normal of 100 pg/mL, compared to 4% of patients who received placebo. The incidence of elevation of B-type natriuretic peptide above 200 pg/mL was 4% in patients treated with Skyclarys. It is unclear whether the increases in natriuretic peptides were related to underlying cardiomyopathy seen in patients with Friedreich’s ataxia or represented a potential adverse drug reaction. Further, changes in lipoproteins were noted with Skyclarys treatment at Week 48, with a mean increase in low-density lipoprotein (LDL) cholesterol of 23.5 mg/dL and a mean decrease of 5.3 mg/dL in high-density lipoprotein (HDL) cholesterol.

The primary safety analysis included 24 adolescent patients who were 16 or 17 years of age at study entry (9 patients in the Skyclarys group and 15 patients in the placebo group). In these patients, there were no adverse events of interest that occurred more frequently with Skyclarys treatment than those reported in adults.

The open-label, long-term extension study, Study 1402 Extension, included 149 patients and provided data for up to an additional 144 weeks of treatment in support of the long-term safety of Skyclarys in patients with Friedreich’s ataxia. No new safety signals were identified.

Overall, the safety profile of Skyclarys was considered acceptable and consistent with the known pharmacodynamic effects of the Nrf2 activator drug class.

Appropriate warnings and precautions are in place in the approved Product Monograph for Skyclarys to address the identified safety concerns.

For more information, refer to the Product Monograph for Skyclarys, approved by Health Canada and available through the Drug Product Database.

Omaveloxolone was shown to increase the expression of genes regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and to improve mitochondrial function in numerous in vitro studies. The effects of omaveloxolone were attenuated in cells in which the gene coding for Nrf2 was deleted. These in vitro results suggest that omaveloxolone works via the activation of the Nrf2 pathway.

The safety pharmacology program did not reveal adverse effects of omaveloxolone on the cardiovascular, pulmonary, or central nervous systems.

Omaveloxolone is primarily metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP2C8 and CYP2J2. Two major metabolites, M22 and M17, have been identified in human plasma. These metabolites were significantly less potent than omaveloxolone in in vitro assays. Qualitatively, the metabolism of omaveloxolone in monkeys, rats, and mice (CD-1 and rasH2) was similar to that of humans.

Repeated administration of omaveloxolone to rats and monkeys resulted in toxicity. The administration of omaveloxolone to rats for up to 26 weeks at dose levels of 0.3 mg/kg or greater resulted in irreversible kidney injury, characterized by tubular degeneration/regeneration and an increased incidence of basophilic tubules, and was correlated with proteinuria in males. In monkeys, findings were limited to non-adverse tubular degeneration/regeneration at 100 mg/kg after 39 weeks of treatment. In rats, partially reversible liver findings consisted of increased liver weight, hepatocellular hypertrophy, individual hepatocyte necrosis, and bile duct hyperplasia and hypertrophy, with associated changes in biochemical parameters (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, bilirubin). In monkeys, increases in liver weight were not associated with adverse liver findings at doses up to 100 mg/kg for up to 9 months; however, adverse prolongations in activated partial thromboplastin time (suggesting delayed coagulation) were noted in females receiving 100 mg/kg. In addition, hyperplasia of the gastrointestinal tract (forestomach, esophagus, and larynx) was noted after 28 days and 6 months of dosing in rats. Similar changes occurred in monkeys after 28 days and 9 months of dosing. The observations were fully reversible in monkeys and only partially reversible in rats after a 28-day recovery period. In rats, the no-observed-adverse-effect level (NOAEL) was exceeded after 26 weeks of administration and based on plasma exposure at the lowest dose administered (0.3 mg/kg), and the safety margin was lower than the maximum recommended human dose. In monkeys, the NOAEL after 39 weeks of administration was determined to be 30 mg/kg, and based on plasma exposure, the safety margin was 1.7 times the maximum recommended human dose.

With regard to genotoxicity, the mammalian chromosome aberration assay indicated that omaveloxolone was mutagenic, both with and without metabolic activation. The results of the bacterial reverse mutation assay, however, were negative, both with and without metabolic activation. Additionally, two in vivo studies (comet assay on rat liver cells and rat bone marrow micronucleus test) were also negative. Using a weight of evidence approach, it is therefore concluded that the genotoxic potential of omaveloxolone is low.

In a 26-week carcinogenicity study in rasH2 mice, omaveloxolone did not show any clear carcinogenic potential. A 2-year carcinogenicity study in rats is ongoing, and the sponsor has committed to submitting the data once available.

The administration of omaveloxolone to rats did not have an impact on male or female fertility. However, increases in pre- and post-implantation losses and the number of early and late resorptions, and decreases in the number of implantation sites and number of viable embryos, were noted at a dose of 10 mg/kg. The NOAEL for embryonic development was thus set at 3 mg/kg, providing a safety margin of 2 times the maximum recommended human dose. In rabbits, poor pregnancy outcomes were noted at a dose of 10 mg/kg or greater, and gravid uterine weights were slightly lower at a dose of 30 mg/kg, correlating with lower fetal body weights. The maternal NOAEL was set at 3 mg/kg, providing a safety margin of 0.3 times the maximum recommended human dose, while the developmental NOAEL was set at 10 mg/kg, providing a margin of 0.7 times the maximum recommended human dose. Omaveloxolone concentrations were measurable in plasma from culled pups, and in milk samples collected from lactating female rats. Additional findings in rats included an increase in the number of stillbirths, increased postnatal mortality, lower pup body weights, delayed sexual maturation in male pups, and impaired reproductive parameters. The NOAEL for reproduction and fertility was thus established at 3 mg/kg. In line with results obtained in this study, the Product Monograph for Skyclarys states that Skyclarys should not be used during pregnancy. Furthermore, in patients who are breastfeeding, an informed decision needs to be made to either discontinue using the product or avoid breastfeeding.

For more information, refer to the Product Monograph for Skyclarys, approved by Health Canada and available through the Drug Product Database.

The quality (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. Proper pharmaceutical development studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review.

Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC). The proposed in-use period of 30 days is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Skyclarys is of human or animal origin.