SKYCLARYS Capsule Ref.[90506] Active ingredients: Omaveloxolone

Potential to Prolong the QT Interval

The effect of omaveloxolone on the QTc interval has not been adequately characterized.

Absorption

The median (range) time to achieve peak plasma concentration was 7 to 14 (1 to 24) hours. The total plasma omaveloxolone exposure based on area under the concentration-time curve (AUC) increased in a dose-dependent and dose proportional manner over a dose range of 50 mg (0.33 times the recommended dosage) to 150 mg, but maximum omaveloxolone plasma concentration (C_max) increased in a less than dose proportional manner over the dose range in healthy fasted subjects.

Effect of Food

Omaveloxolone C_max and AUC_0-inf increased by approximately 350% and 15%, respectively, with a high-fat meal (800-1000 calories, approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared to fasted conditions [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution of omaveloxolone is 7361 L (105 L/kg for a 70 kg person). Protein binding of omaveloxolone is 97%.

Elimination

The mean (range) terminal half-life of omaveloxolone is 57 hours (32 to 90 hours). The mean apparent plasma clearance of omaveloxolone is 109 L/hr.

Metabolism

Omaveloxolone is primarily metabolized by CYP3A with minor metabolism by CYP2C8 and CYP2J2.

Excretion

Following administration of a single oral dose of radiolabeled omaveloxolone 150 mg to healthy subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours after administration) and 0.1% in urine.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of omaveloxolone based on age (16 to 71 years of age), sex, race, or body weight (41 to 128 kg). The effect of renal impairment on the pharmacokinetics of omaveloxolone is unknown.

Patients with Hepatic Impairment

There were no clinically significant differences in the pharmacokinetics of omaveloxolone in subjects with mild hepatic impairment (Child-Pugh Class A). In subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher plasma exposure of omaveloxolone. The omaveloxolone AUC increased up to 1.65-fold and C_max increased up to 1.83-fold in subjects with moderate hepatic impairment. The omaveloxolone AUC increased up to 2.17-fold in subjects with severe hepatic impairment; however, this change was variable [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Strong CYP3A Inhibitors: Omaveloxolone C_max increased 3-fold and AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor) [see Drug Interactions (7.1)].

Moderate CYP3A Inhibitors: Omaveloxolone C_max and AUC increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and P-gp inhibitor) [see Drug Interactions (7.1)].

Strong and Moderate CYP3A Inducers: The effect of concomitant use with moderate and strong CYP3A4 inducers is unknown; however, a significant reduction in omaveloxolone exposure is likely following concomitant use based on its metabolic pathway.

Certain CYP450 Enzymes or Transporter Substrates: Omaveloxolone decreased the AUC of midazolam (CYP3A4 substrate) by approximately 45%, AUC of repaglinide (CYP2C8 substrate) by approximately 35%, and AUC of rosuvastatin (BCRP and OATP1B1 substrate) by approximately 30% [see Drug Interactions (7.2)]. There were no clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) or metformin [(organic cation transporter (OCT)1 substrate] when co-administered with omaveloxolone.

Other Drugs: No clinically significant differences in the pharmacokinetics of omaveloxolone are expected following concomitant use with weak CYP3A4 inhibitors or strong CYP2C8 inhibitors.

In Vitro Studies

CYP Enzymes: Omaveloxolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Omaveloxolone is not an inducer of CYP1A2 and CYP2B6.

Drug Transporters: Omaveloxolone is not an inhibitor of BCRP, BSEP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K. Omaveloxolone inhibited the renal transporter OAT1.

Carcinogenesis

Carcinogenicity studies have not been conducted with omaveloxolone.

Mutagenesis

Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vitro (rat micronucleus and comet) assays.

Impairment of Fertility

Oral administration of omaveloxolone (0, 1, 3, and 10 mg/kg/day) to male and females rats prior to and during mating and continuing in females to gestation day 7 produced an increase in pre-and post-implantation loss and resorptions, resulting in a decrease in viable embryos at the highest dose tested. The no-effect dose (3 mg/kg/day) for adverse effects on fertility and reproductive function was associated with plasma exposures (AUC) approximately 2 times that in humans at the recommended human dose of 150 mg/day.

The efficacy of SKYCLARYS was evaluated in a 48-week, randomized, double-blind, placebo-controlled study in patients 16 to 40 years of age with Friedreich’s Ataxia (Study 1; NCT02255435).

A total of 103 patients were randomized (1:1) to receive SKYCLARYS 150 mg once daily (n=51) or placebo (n=52).

Enrolled patients had to have a stable modified Friedreich’s Ataxia Rating Scale (mFARS) score between 20 and 80, be able to complete maximal exercise testing, and have a left ventricular ejection fraction of at least 40%. In Study 1, 53% of enrolled patients were male, 97% were White, and the mean age was 24 years at study entry. Patients with or without pes cavus were included in Study 1. Pes cavus was defined as having a loss of lateral support and was determined if light from a flashlight could be seen under the patient’s arch when barefoot and weight bearing.

The prespecified primary analysis was the change from baseline in the mFARS score compared to placebo at Week 48 in the Full Analysis Population of patients without pes cavus (n=82). The mFARS is a clinical assessment tool to assess patient function, which consists of 4 domains to evaluate bulbar function, upper limb coordination, lower limb coordination, and upright stability. The mFARS has a maximum score of 99, with a lower score on the mFARS signifying lesser physical impairment.

Treatment with SKYCLARYS resulted in statistically significant lower mFARS scores (less impairment) relative to placebo (see Table 4) at Week 48.

Table 4. Primary Analysis in Full Analysis Population: mFARS Least Squares (LS) Mean Change from Baseline at Week 48:

SD = Standard Deviation; LS = Least Squares; CI = Confidence Interval

The All Randomized Population (N=103), which included all patients regardless of pes cavus status, demonstrated similar results to the Full Analysis Population of lower mFARS scores in patients treated with SKYCLARYS compared to placebo, with a nominally significant least squares mean difference between treatment groups of ‑1.94 (95% CI: -3.71, -0.16, p=0.0331).

In a post hoc, propensity-matched analysis, lower mFARS scores were observed in patients treated with SKYCLARYS after 3 years relative to a matched set of untreated patients from a natural history study. These exploratory analyses should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.