Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Reata Ireland Limited, Block A, Georges Quay Plaza, Georges Quay, Dublin 2, D02 E440 Ireland
The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown. Omaveloxolone has 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. There is substantial evidence that Nrf2 levels and activity are suppressed in cells from patients with Friedreich’s ataxia.
Omaveloxolone binds to Kelch-like ECH-associated protein 1 (Keap1), a protein that regulates the activity of Nrf2. Binding to Keap1 allows nuclear translocation of Nrf2 and transcription of its target genes. In fibroblasts isolated from patients with Friedreich’s ataxia, omaveloxolone was shown to restore Nrf2 protein levels and increase Nrf2 activity. Omaveloxolone was also shown to rescue mitochondrial dysfunction and restore redox balance in these cells, as well as in neurons from mouse models of Friedreich’s ataxia. Evidence of pharmacodynamic activity was observed in omaveloxolone-treated patients, with dose-dependent changes in the products of Nrf2 target genes, serum ferritin and GGT, across the dose range of 20 mg to 300 mg. Patients who received omaveloxolone 160 mg generally showed the largest increase from baseline for these serum markers.
The efficacy and safety of Skyclarys were evaluated as a treatment for Friedreich’s ataxia in two parts of a randomized, double-blind, placebo-controlled, study (Study 1 [NCT02255435; EudraCT 2015-002762-23]) and in an ongoing, open-label extension to Study 1.
Study 1 Part 2 was a randomized, double-blind, placebo-controlled, multicentre study to evaluate the safety and efficacy of Skyclarys in patients with Friedreich’s ataxia for 48 weeks of treatment. A total of 103 patients including 24 adolescents were randomized (1:1) to Skyclarys 150 mg/day (N=51) or placebo (N=52). Patients were excluded from Study 1 if they had BNP levels >200 pg/mL prior to study entry, or a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, with the exception of mild to moderate cardiomyopathy associated with Friedreich’s ataxia. Additionally, patients were excluded from Study 1 if they had a history of clinically significant liver disease (eg, fibrosis, cirrhosis, hepatitis) or clinically relevant deviations in laboratory tests at screening including ALT and/or AST > 1.5-fold ULN, bilirubin >1.2-fold ULN, alkaline phosphatase >2-fold ULN, or albumin < lower limit of normal (LLN). Randomization was stratified by pes cavus status. Pes cavus population 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 primary efficacy endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score compared to placebo at Week 48 for patients without pes cavus (ie, the full analysis set [FAS]; 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. In the FAS, 53.7% were male. The mean age was 23.9 years at study entry, and the mean age of Friedreich’s ataxia onset was 15.5 years. Baseline mFARS and Friedreich’s ataxiaActivities of Daily Living (FA-ADL) scores were 39.83 and 10.29 points, respectively. Mean GAA1 repeat length was 714.8. At study entry, 92.7% of patients were ambulatory, 37.8% had a history of cardiomyopathy, and 2.4% had a history of diabetes mellitus.
Treatment with Skyclarys significantly improved mFARS scores, with a least squares mean difference of -2.40 (standard error 0.956) relative to placebo (p=0.0141) (Table 3). All components of the mFARS assessment, including ability to swallow (bulbar), upper limb coordination, lower limb coordination, and upright stability, favoured Skyclarys over placebo.
Table 3. Study 1 Part 2: mFARS Results (FAS):
| Skyclarys (N=40) | Placebo (N=42) | |
|---|---|---|
| Total mFARS | ||
| Baseline | ||
| n | 40 | 42 |
| Mean (SD) | 40.94 (10.393) | 38.77 (11.026) |
| Week 48 | ||
| n | 34 | 41 |
| Mean (SD) | 39.17 (10.019) | 39.54 (11.568) |
| Week 48 Change from baseline | ||
| LS Mean (SE) | -1.55 (0.689) | 0.85 (0.640) |
| LS Mean Difference (SE) | -2.40 (0.956) | - |
| p-value vs. placebo | 0.0141 | |
Abbreviations: FAS=Full Analysis Set; LS=least squares; mFARS=modified Friedreich’s ataxia rating scale.
Note: mFARS scores can range from 0 to 99 points. Within each section of the mFARS, the minimum score is 0. The maximum score for each section is as follows: 11 points for Bulbar Function, 36 points for Upper Limb Coordination, 16 points for Lower Limb Coordination, and 36 points for Upright Stability.
In the All Randomized Population (N=103), which included all patients regardless of pes cavus status, Skyclarys improved mFARS scores relative to placebo, with a least squares mean difference of ‑1.93 (standard error 0.895) (nominal p=0.0342).
In exploratory subgroup analyses, point estimates for changes in mFARS consistently favoured Skyclarys relative to placebo across subgroups based on baseline age, ambulatory status, and GAA1 repeat length (Table 4).
Table 4. Study 1 Part 2: Change in mFARS at Week 48 in subgroups (FAS):
| Subgroup | Least Squares Mean Differencea (95% CI) | P-Value |
|---|---|---|
| Age | ||
| <18 years (n=20) | -4.16 (-8.43, 0.12) | 0.0565 |
| ≥18 years (n=62) | -1.60 (-3.78. 0.58) | 0.1485 |
| GAA1 repeat length ≥675 | ||
| Yes (n=39) | -4.27 (-6.96, -1.57) | 0.0025 |
| No (n=28) | -1.94 (-5.19, 1.31) | 0.2355 |
| Ambulatory status | ||
| Non-ambulatory (n=6) | -4.57 (-11.42, 2.27) | 0.1867 |
| Ambulatory (n=76) | -2.19 (-4.22, -0.17) | 0.0344 |
Abbreviations: CI=confidence interval; FAS=Full Analysis Set; GAA1 repeat length=length of the trinucleotide repeats in the GAA1 allele composed of 1 guanine and 2 adenines; mFARS=modified Friedreich’s ataxia rating scale.
a Least squares mean difference is Skyclarys ₋ placebo.
Although Study 1 was not powered to detect a difference in the key secondary endpoints, Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC), PGIC and CGIC scores at Week 48 were numerically improved in patients treated with Skyclarys relative to placebo in the primary analysis population (least squares [LS] mean difference in PGIC = -0.43, LS mean difference in CGIC = -0.13). Additionally, treatment of patients with Skyclarys resulted in numerically improved FA-ADL scores relative to placebo, with an LS mean difference of -1.30 points (standard error=0.629).
In a post hoc,propensity-matched analysis of long term open-label treatment with Skyclarys, patients treated with Skyclarys had lower mFARS scores at 3 years, as compared to a matched natural history group. This exploratory analysis should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.
The European Medicines Agency has deferred the obligation to submit the results of studies with Skyclarys in the paediatric population aged 2 years to less than 16 years in treatment of Friedreich’s ataxia (see section 4.2 for information on paediatric use).
Omaveloxolone was absorbed after oral administration in healthy fasted subjects with peak plasma concentrations typically observed 7 to 14 hours post dose. Patients with Friedreich’s ataxia demonstrated a 2.3-fold faster absorption of omaveloxolone than fasted healthy subjects.
Co-administration of a high-fat meal resulted in a small increase (1.15-fold) in area under the plasma concentration vs time curve from time 0 extrapolated to infinity (AUC0-inf) but caused a 4.5-fold increase in Cmax compared to fasted conditions. It is recommended that Skyclarys be taken without food.
Omaveloxolone Cmax and AUC0-inf were similar when capsule contents were sprinkled on apple puree or when administered as intact capsules. The median time to achieve Cmax (tmax) of omaveloxolone was shortened from approximately 10 hours to 6 hours when sprinkled on apple puree (see section 4.2).
The absolute or relative bioavailability of omaveloxolone has not been determined.
The total plasma omaveloxolone exposure (AUC) increased in a dose-dependent and dose proportional manner, but Cmax increased in a less than dose proportional manner in healthy fasted subjects.
Omaveloxolone is 97% bound to protein in human plasma. Omaveloxolone shows low to moderate membrane permeability. The average apparent volume of distribution is 7361 L (105 L/kg).
Following a single oral dose of [14C]-omaveloxolone administered to healthy male subjects, omaveloxolone was found to be eliminated by metabolism via CYP3A4 to a series of 30 metabolites, of which 7 metabolites were quantified and identified. Metabolites M22 and M17 were major plasma metabolites that accounted for 18.6% and 10.9% of total plasma radioactivity, respectively. The other metabolites were minor, each accounting for less than 10% of total plasma radioactivity exposure. None of the metabolites has meaningful pharmacological activity.
Following a single oral dose of radio-labeled omaveloxolone administered to healthy male subjects, approximately 92.5% of the dosed radioactivity was recovered within a 528-hour collection period: 92.4% via the faeces and 0.1% via the urine. The majority (90.7%) of the administered dose was recovered in the faeces within 96 hours after administration.
The average apparent plasma clearance of omaveloxolone is 109 L/hr and the average apparent plasma terminal half-life is 58 hours (32-94 hours).
Population pharmacokinetic analyses indicate that there is no clinically meaningful effect of age (16-71 years), sex, or body weight on the pharmacokinetics of omaveloxolone and no dose adjustments based on these factors are necessary.
Population pharmacokinetic analysis confirmed that estimated glomerular filtration rate values ≥63 mL/min/1.73 m² did not have a significant effect on the pharmacokinetics of omaveloxolone. The effect of moderate or severe renal impairment on the pharmacokinetics of omaveloxolone is unknown.
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. Subjects with moderate hepatic impairment exhibited up to a 65% increase in AUC and an 83% increase in Cmax compared to subjects with normal hepatic function. In subjects with severe hepatic impairment, the AUC for omaveloxolone was increased by 117% as compared to subjects with normal hepatic function. However, the data in subjects with severe hepatic impairment are limited. In subjects with mild hepatic impairment (Child-Pugh Class A), there was no change in AUC and only a 29% increase in Cmax. The recommended dosage for patients with hepatic impairment is described in section 4.2.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, and carcinogenic potential.
Based on a panel of in vitro and in vivo mutagenicity tests, omaveloxolone is considered of low genotoxic potential. Omaveloxolone was not carcinogenic in a 6-month carcinogenicity study in rasH2 mice up to doses corresponding to approximately 14.6 and 54.5 times in males and females, respectively, the maximum human recommended dose (MHRD) and systemic exposure (AUC) in patients with Friedreich’s ataxia.
Preclinical data revealed toxicities related to omaveloxolone. In rats, findings of irreversible kidney injury (multifocal renal tubular degeneration/regeneration accompanied by proteinuria) were observed at clinically relevant dose levels in rats after 28 days of daily oral exposure up to 6 months. Furthermore, reversible observations of hyperplasia of the GI tract (forestomach, oesophagus, larynx) was observed in rats and monkeys already after 28 days of dosing, up to 6 or 9 months in rats and monkeys, respectively. In one male rat from the high dose group at 6 months dosing, the squamous epithelial hyperplasia was associated with a squamous cell carcinoma involving the non-glandular and glandular stomach.
Omaveloxolone, administered at oral doses of 1, 3, and 10 mg/kg/day to male rats for 28 days before mating and throughout the mating period and to female rats from 14 days before mating, throughout mating, and until gestation day 7 did not alter male or female fertility. However, pre- and post-implantation embryonic loss, resorptions, and a decrease in the number of viable embryos occurred at the dose corresponding to approximately 6 times the maximum human recommended dose (MHRD) based on systemic exposure. No effects on pre- and post-implantation loss occurred at approximately 2 times the MHRD based on systemic exposure.
In an embryo-foetal toxicity study in rats, no maternal toxicity or embryo-foetal abnormalities were detected in rats at an oral dose corresponding to approximately 6 times the MHRD based on systemic exposure. However, at doses achieving exposure levels 19 times the MHRD, post-implantation loss, resorptions as well as decreases in number of viable fetuses, litter size, and foetal body weight were observed in rats. Embryo-foetal assessment in rabbits demonstrated maternal toxicity that was associated with early deliveries and interruptions of pregnancy as well as low foetal body weights at a dose level corresponding to exposures lower (0.7-fold) than those at the MHRD; however, in the same study, no foetal malformations were observed at approximately 1.4 times the MHRD based on systemic exposure.
In a pre- and post-natal evaluation in rats, administration of omaveloxolone during the period of organogenesis through lactation at doses of 1, 3, and 10 mg/kg/day was associated with an increased percentage of litters with stillborn pups, reduced first generation pup survival, and decreased mean pup body weights. Decreased reproductive function (reduced mean numbers of corpora lutea and implantation sites) were observed in F1 females and delayed sexual maturation was observed in F1 males at a dose level of approximately 6 times the MHRD based on systemic exposure. No adverse reactions were observed at a dose of approximately 2 times the MHRD based on systemic exposure. Dose-dependent increases in omaveloxolone plasma concentrations were observed in pups, due to excretion of omaveloxolone in milk. Effects were directly linked to exposure to omaveloxolone.
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