SKYCLARYS 50mg capsules medication leaflet

Skyclarys 50 mg hard capsules

Each hard capsule contains 50 mg omaveloxolone.

For the full list of excipients, see section 6.1.

Hard capsule

Opaque hard capsule with “RTA 408” printed on the light green body in white ink and “50” printed onthe blue cap in white ink. Capsules (size 0) are 21.7 ± 0.3 mm in length, and the outer diameter of thecap is 7.64 ± 0.06 mm.

Skyclarys is indicated for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 yearsand older.

Omaveloxolone should be initiated and supervised by physicians with experience in the treatment ofpatients with Friedreich Ataxia.

The recommended dose is 150 mg omaveloxolone (3 hard capsules of 50 mg each) once daily.

Medicine lost through emesis should not be replaced with an additional dose.

If a dose is missed, the next dose should be taken as usual the following day. A double dose should notbe taken to make up for a missed dose.

Dose modifications for concomitant therapy

The recommended dosages for concomitant use of omaveloxolone with strong or moderatecytochrome P450 (CYP) 3A4 inhibitors or inducers are described in Table 1 (see sections 4.4 and 4.5).

Table 1: Recommended dosage modifications of omaveloxolone with concomitant use of

Concomitant Drug Class Dosage Recommendation

Strong CYP3A4 inhibitor Recommended to avoid concomitant use.

If coadministration cannot be avoided:

* Reduce the dosage of Skyclarys to 50 mgonce daily with close monitoring foradverse reactions.

* If adverse reactions emerge,coadministration with strong CYP3A4inhibitors should be discontinued.

Moderate CYP3A4 inhibitor Recommended to avoid concomitant use.

If coadministration cannot be avoided:

* Reduce the dosage of Skyclarys to 100 mgonce daily with close monitoring foradverse reactions.

* If adverse reactions emerge, further reducethe dosage of Skyclarys to 50 mg oncedaily.

No dose adjustment is required based on age (see section 5.2).

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

The dose should be reduced to 100 mg once daily with close monitoring for adverse reactions inpatients with moderate hepatic impairment (Child-Pugh Class B). Lowering to 50 mg once dailyshould be considered if adverse reactions emerge.

The use of the medicinal product should be avoided in patients with severe hepatic impairment (Child-

Pugh Class C) (see section 5.2).

The effect of moderate and severe renal impairment on the pharmacokinetics of omaveloxolone hasnot been studied (see section 5.2).

The safety and efficacy of Skyclarys in children and adolescents aged less than 16 years have not yetbeen established. No data are available.

This medicinal product is for oral use.

Omaveloxolone should be taken on an empty stomach at least 1 hour before or 2 hours after eating(see sections 4.5 and 5.2).

Skyclarys capsules should be swallowed whole.

For patients who are unable to swallow whole capsules, Skyclarys capsules may be opened, and theentire contents sprinkled onto 2 tablespoons of apple puree. Patients should consume all themedicine/food mixture immediately on an empty stomach at least 1 hour before or 2 hours after eating.

It should not be stored for future use (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Elevation of aminotransferases

Treatment with omaveloxolone in clinical trials with patients with Friedreich’s ataxia has beenassociated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)(see section 4.8). On-treatment aminotransferase elevations of ≥ 3 × the upper limit of normal (ULN)were reported in 29.4% of patients, with maximal values occurring in the majority of patients withinthe first 12 weeks of treatment. Initial increases were followed by a trend toward normalization.

ALT, AST, and bilirubin should be monitored prior to initiation of omaveloxolone, monthly during thefirst 3 months of treatment, and periodically thereafter as clinically indicated. If ALT or AST increasesto > 5 × the ULN, omaveloxolone should be immediately discontinued, and liver function tests shouldbe repeated as soon as possible. If laboratory abnormalities stabilize or resolve, omaveloxolone can bereinitiated. If ALT or AST increases to > 3 × the ULN and bilirubin increases to > 2 × the ULN,omaveloxolone should be immediately discontinued and liver function tests should be repeated.

Testing should be continued as appropriate. When laboratory abnormalities stabilize or resolve,

Skyclarys may be reinitiated with an appropriate frequency of monitoring liver function.

Omaveloxolone is primarily metabolised by CYP3A4 (see section 5.2). Concomitant use of strong ormoderate CYP3A4 inhibitors may significantly increase the systemic exposure of omaveloxolone (seesection 4.5). If concomitant use of strong or moderate CYP3A4 inhibitors is unavoidable, dosereduction of omaveloxolone with monitoring should be considered (see section 4.2).

Concomitant use of omaveloxolone with strong or moderate CYP3A4 inducers may significantlydecrease the exposure of omaveloxolone (see section 4.5), which may reduce the effectiveness ofomaveloxolone. Patients treated with omaveloxolone should be warned to avoid concomitant use of

CYP3A4 inducers while taking omaveloxolone. Alternative medicinal products should be consideredif possible (see sections 4.2 and 4.5).

Lipid abnormalities

Treatment with omaveloxolone has been associated with increases in low-density lipoprotein (LDL)cholesterol and decreases in high-density lipoprotein (HDL) cholesterol. Lipid parameters should beassessed prior to initiation of omaveloxolone and should be monitored periodically during treatment.

Lipid abnormalities should be managed according to standard clinical guidelines.

Elevation of B-type natriuretic peptide (BNP)

Treatment with omaveloxolone has been associated with increases in BNP but without any concurrentincrease in blood pressure or associated events of fluid overload or congestive heart failure. In

Study 1, a total of 13.7% of patients treated with Skyclarys had an increase from baseline in BNP anda BNP above the ULN (100 pg/mL), compared to 3.8% of patients who received placebo. Theincidence of elevation of BNP above 200 pg/mL was 3.9% in patients treated with Skyclarys. Whetherthe elevations in BNP in Study 1 are related to Skyclarys or cardiac disease associated with

Friedreich’s ataxia is unclear.

In a study with a related compound in diabetic patients with chronic kidney disease (CKD), excessheart failure events due to fluid overload were observed among patients with stage IV CKD. Baseline

BNP > 200 pg/mL and prior hospitalization for congestive heart failure were identified as risk factorsfor heart failure among patients who had stage IV CKD but not in patients who had stage 3b CKD.

Cardiomyopathy and diabetes mellitus are common in patients with Friedreich’s ataxia. BNP shouldbe monitored prior to and periodically during treatment. Patients should be advised of the signs andsymptoms of congestive heart failure associated with fluid overload, such as sudden weight gain(≥ 1.4 kg in 1 day or ≥ 2.3 kg in 1 week), peripheral oedema, and shortness of breath. If signs andsymptoms of fluid overload develop, BNP (or NT-proBNP) should be monitored and managedaccording to standard clinical guidance. Treatment with Skyclarys should be interrupted during fluidoverload management. If fluid overload cannot be appropriately managed, treatment with Skyclarysshould be discontinued. Per clinical judgment, more frequent monitoring of patients with a recenthospitalization for fluid overload due to underlying cardiomyopathy, diabetic stage IV CKD, or otheraetiologies is strongly recommended.

Body weight decrease

Treatment with Skyclarys has been associated with mild decreases in body weight. Advise patients tomonitor their weight regularly. Further evaluate the patient if unexplained or clinically significantbody weight decrease occurs.

Skyclarys is associated with a risk of hypersensitivity reactions including urticaria and rash (seesection 4.8).

In the randomized, double-blind, placebo-controlled trial of 51 patients treated with Skyclarys150 mg/day for 48 weeks, the frequency of hypersensitivity events was very common (≥ 1/10). Allevents were non-serious, and all events reported in participants receiving omaveloxolone were mild inseverity. The average time to onset for the omaveloxolone group was 135 days (minimum: 3 days,maximum: 360 days, median: 95 days). Hypersensitivity reactions including urticaria and rash havealso been reported in the post-marketing setting and other clinical trials. In the post-marketing setting,one serious case of drug hypersensitivity has been reported, all events reported in other clinical trialswere mild to moderate in severity. If a hypersensitivity reaction occurs, appropriate measures shouldbe initiated if needed. Patients should be informed of the signs and symptoms of hypersensitivity.

Skyclarys contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free.’

Omaveloxolone is a substrate of CYP3A4. Co-administration of strong or moderate CYP3A4inhibitors or CYP3A4 inducers will affect the pharmacokinetics of omaveloxolone.

Effect of other medicines on pharmacokinetics of omaveloxolone

Strong or moderate CYP3A4 inhibitors

In a clinical study, co-administration of Skyclarys with itraconazole, a strong CYP3A4 inhibitor,increased the area under the curve (AUC0-inf) and maximal plasma concentration (Cmax) byapproximately 4-fold and 3-fold, respectively. In a clinical study with healthy subjects, co-administration of verapamil (120 mg once daily) increased the AUC and Cmax by 1.24-fold and 1.28-fold, respectively. Verapamil is a known moderate CYP3A4 inhibitor and inhibitor of the P-gptransporter. If concomitant use of strong or moderate CYP3A4 inhibitors is unavoidable, dosagereduction of Skyclarys should be considered with monitoring (see sections 4.2 and 4.4). Someexamples of strong and moderate CYP3A4 inhibitors are clarithromycin, itraconazole, ketoconazole,ciprofloxacin, cyclosporine, fluconazole, and fluvoxamine.

As grapefruit and grapefruit juice are inhibitors of CYP3A4, patients should be warned to avoid thesewhile taking Skyclarys (see section 4.4).

Strong or moderate CYP3A4 inducers

In a clinical study, co-administration of omaveloxolone with efavirenz, a moderate CYP3A4 inducer,decreased the area under the curve (AUC0-inf) and maximal plasma concentration (Cmax) byapproximately 49% and 38%, respectively. Due to potential loss of efficacy, patients treated with

Skyclarys should be warned to avoid use of strong or moderate CYP3A4 inducers while taking

Skyclarys and alternatives should be considered if possible. Some examples of strong or moderate

CYP3A4 inducers are carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’swort, and efavirenz.

Effect of omaveloxolone on other medicinal products

The following were evaluated in clinical studies with omaveloxolone 150 mg in healthy subjects:

The AUC of midazolam, a CYP3A4 substrate, was reduced by approximately 45% whenco-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of CYP3A4and can reduce the exposure of CYP3A4 substrates. Concomitant use with Skyclarys may reduce theefficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combinedhormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills (see section 4.6).

CYP2C8 substrates

The AUC of repaglinide, a CYP2C8 substrate, was reduced by approximately 35% whenco-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of CYP2C8and can reduce the exposure of CYP2C8 substrates.

The AUC of rosuvastatin, a BCRP and OATP1B1 substrate, was reduced by approximately 30% whenco-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of BCRP andcan reduce the exposure of BCRP substrates.

There are no data from the use of omaveloxolone in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Skyclarys should not be used during pregnancy or in women of childbearing potential not usingcontraception. Patients should use effective contraception prior to starting treatment with Skyclarys,during treatment, and for 28 days following discontinuation of treatment.

Skyclarys may decrease the efficacy of hormonal contraceptives (see section 4.5). Advise patients toavoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring). Counselfemales using hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonalintrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant useand for 28 days after discontinuation of Skyclarys.

There are no data on the presence of omaveloxolone in human milk. Omaveloxolone is present in themilk of lactating rats and resulted in treatment-related effects in offspring (see section 5.3). A risk tothe newborn infant cannot be excluded. Skyclarys should not be used during breast-feeding.

There are no data on the effects of Skyclarys on human fertility. Animal data did not indicateimpairment of parent male or female fertility (see section 5.3).

Omaveloxolone may have a minor influence on the ability to drive and use machines. Fatigue mayoccur following administration of omaveloxolone (see section 4.8).

The most frequently occurring adverse reactions observed with Skyclarys are ALT increased andheadache (37.3% each); weight decreased (34.0%); nausea (33.3%); AST increased and fatigue(21.6% each); diarrhoea (19.6%); oropharyngeal pain (17.6%); vomiting (15.7%), back pain, musclespasms, and influenza (13.7% each); and decreased appetite (11.8%).

The adverse reactions observed in the randomized, double-blind, placebo-controlled trial in 51 patientstreated with Skyclarys 150 mg/day for 48 weeks (median exposure 0.92 patient years) are listed in

Table 2 by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10),common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1 000 to < 1/100). Within each frequency grouping,adverse reactions are presented in the order of decreasing seriousness. Selected adverse reactions arefurther decribed in following Table 2.

Table 2 Adverse reactions

System Organ Class Preferred Term Frequency Category

Infections and infestations Influenza Very common

Urinary tract infection Common

Immune system disorders Hypersensitivity including Very commonurticaria and rasha

Metabolism and nutrition disorders Decreased appetite Very common

Hypertriglyceridemia Common

Very low density Commonlipoprotein increased

Nervous system disorders Headache Very common

Respiratory, thoracic and mediastinal Oropharyngeal pain Very commondisorders

Gastrointestinal disorders Nausea Very common

Diarrhoea Very common

Vomiting Very common

Abdominal upper pain Common

Abdominal pain Common

Hepatobiliary disorders ALT increased Very common

AST increased Very common

GGT increased Common

Musculoskeletal and connective Back pain Very commontissue disorders Muscle spasms Very common

System Organ Class Preferred Term Frequency Category

Reproductive system and breast Dysmenorrhoea Commondisorders

General disorders and administration Fatigue Very commonsite conditions

Investigations BNP increasedb Common

Weight decreasedc Very commona Cases have been reported in the post-marketing setting with unknown frequency.bBased on laboratory evaluations with values > 200 pg/mL.cBased on weight measured in the clinic with on-treatment weight loss ≥ 5%.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; GGT=gammaglutamyltransferase.

Among patients treated with Skyclarys in the randomized, double-blind, placebo-controlled study,nausea occurred in 33.3% of patients, diarrhoea in 19.6% of patients, vomiting in 15.7% of patients,abdominal upper pain in 9.8% of patients, and abdominal pain in 7.8% of patients. All events wereassessed as either mild or moderate in severity, and 75.8% of the events occurred within the first12 weeks of therapy.

Aminotransferase elevations

Among patients treated with Skyclarys in the randomized, double-blind, placebo-controlled study,adverse reactions of aminotransferase elevations included: ALT increased in 37.3% of patients, ASTincreased in 21.6% of patients, and gamma glutamyltransferase (GGT) increased in 5.9% of patients.

Treatment interruptions due to aminotransferase elevations occurred in 11.8% of all Skyclarys-treatedpatients. One patient (2%) was discontinued for aminotransferase elevation per protocol.

In patients treated with Skyclarys, the incidence of on-treatment elevations of ALT or AST ≥ 3 × the

ULN was 29.4%, with 15.7% experiencing elevations ≥ 5 × the ULN. Elevations of ≥ 3 × the ULNwere generally transient and reversible, with 80% of these patients experiencing maximal levels withinthe first 12 weeks of treatment. None of these patients had ALT or AST levels ≥ 3 × the ULN at thewithdrawal visit. Mean values generally decreased towards baseline with continued treatment or afterinterruption in therapy. No patient had concomitant elevation of total bilirubin > 1.5 × the ULN.

Elevation of BNP

In the randomized, double-blind, placebo-controlled study, increases in laboratory evaluations of BNPwere observed in patients treated with Skyclarys. Mean BNP values were elevated at Week 4, andremained elevated through Week 48, with peak mean elevations at Week 24. Mean BNP valuesremained below the ULN (< 100 pg/mL). A total of 13.7% of patients treated with Skyclarys had anincrease from baseline in BNP and a BNP above the ULN (100 pg/mL), compared to 3.8% of patientswho received placebo; 3.9% of patients had BNP values that exceeded 200 pg/mL while on treatment.

There were no discontinuations due to BNP elevation.

Lipid abnormalities

Among patients treated with Skyclarys in the randomized, double-blind, placebo-controlled study,hypertriglyceridaemia was reported in 3.9% of patients, very low-density lipoprotein increased wasreported in 3.9% of patients, and hypercholesterolaemia was reported in 2.0% of patients. At Week 48in the Skyclarys treatment group, mean LDL increased by approximately 25 mg/dL and mean HDLdecreased by approximately 5 mg/dL. After withdrawal of Skyclarys, mean LDL and HDL levelsreturned to baseline.

Weight decreased

In the randomized, double-blind, placebo-controlled study, weight decrease was reported for 2.0% ofpatients treated with Skyclarys and 1.9% of patients treated with placebo. No serious adverse reactionsor discontinuations due to decreased appetite or weight decrease were reported in either treatmentgroup.

Decrease in body weight was observed after Week 24. The mean weight decrease relative to baselinewas 1.35 kg (SD 3.585 kg) in the Skyclarys group and the mean weight increase relative to baselinewas 1.17 kg (SD 4.108 kg) in the placebo group after 48 weeks of treatment. Among all patients withbaseline BMI < 25 kg/m2 across both treatment groups (Skyclarys, n=37; placebo, n=37), weight lossof at least 5% from baseline was observed in 32.4% of Skyclarys-treated patients versus 2.7% ofplacebo-treated patients.

Based on evaluation of Skyclarys in randomized, placebo-controlled trials, the safety profile of

Skyclarys in paediatric patients aged 16 to less than 18 years (n=24) was consistent with the safetyprofile in adult patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for Skyclarys. For patients who experience overdose, closely monitor andprovide appropriate supportive treatment.

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX25

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 Nrf2pathway is involved in the cellular response to oxidative stress. There is substantial evidence that Nrf2levels 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 theactivity of Nrf2. Binding to Keap1 allows nuclear translocation of Nrf2 and transcription of its targetgenes. In fibroblasts isolated from patients with Friedreich’s ataxia, omaveloxolone was shown torestore Nrf2 protein levels and increase Nrf2 activity. Omaveloxolone was also shown to rescuemitochondrial dysfunction and restore redox balance in these cells, as well as in neurons from mousemodels of Friedreich’s ataxia. Evidence of pharmacodynamic activity was observed inomaveloxolone-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 receivedomaveloxolone 160 mg generally showed the largest increase from baseline for these serum markers.

Effect of omaveloxolone on the QT interval

In a randomized, double-blind, placebo- and active-controlled, 3-way crossover TQTc study in healthysubjects, omaveloxolone and its major metabolites (M17 and M22) alone or combined did not cause aclinically significant QTc prolongation as the upper bound of the 2-sided 90% CI estimate was belowthe regulatory threshold of concern of 10 msec. The mean omaveloxolone Cmax of 319.4 ng/mL in thestudy was 4.5-fold the predicted mean steady-state Cmax (71.5ng/mL) in FA patients and covers theworst-case clinical exposure scenario of a 4.5-fold increase in Cmax, if omaveloxolone is administeredwith food.

The efficacy and safety of Skyclarys were evaluated as a treatment for Friedreich’s ataxia in two partsof 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

Study 1 Part 2 was a randomized, double-blind, placebo-controlled, multicentre study to evaluate thesafety and efficacy of Skyclarys in patients with Friedreich’s ataxia for 48 weeks of treatment. A totalof 103 patients including 24 adolescents were randomized (1:1) to Skyclarys 150 mg/day (N=51) orplacebo (N=52). Patients were excluded from Study 1 if they had BNP levels > 200 pg/mL prior tostudy entry, or a history of clinically significant left-sided heart disease and/or clinically significantcardiac disease, with the exception of mild to moderate cardiomyopathy associated with Friedreich’sataxia. Additionally, patients were excluded from Study 1 if they had a history of clinically significantliver disease (eg, fibrosis, cirrhosis, hepatitis) or clinically relevant deviations in laboratory tests atscreening 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 cavusstatus. Pes cavus population was defined as having a loss of lateral support and was determined if lightfrom a flashlight could be seen under the patient’s arch when barefoot and weight bearing. Theprimary 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 of4 domains to evaluate bulbar function, upper limb coordination, lower limb coordination, and uprightstability. The mFARS has a maximum score of 99, with a lower score on the mFARS signifying lesserphysical impairment. In the FAS, 53.7% were male. The mean age was 23.9 years at study entry, andthe mean age of Friedreich’s ataxia onset was 15.5 years. Baseline mFARS and Friedreich’s ataxia-

Activities of Daily Living (FA-ADL) scores were 39.83 and 10.29 points, respectively. Mean GAA1repeat length was 714.8. At study entry, 92.7% of patients were ambulatory, 37.8% had a history ofcardiomyopathy, and 2.4% had a history of diabetes mellitus.

Treatment with Skyclarys significantly improved mFARS scores, with a least squares mean differenceof -2.41 (standard error 0.955) relative to placebo (p=0.0138) (Table 3). All components of themFARS assessment, including ability to swallow (bulbar), upper limb coordination, lower limbcoordination, and upright stability, favoured Skyclarys over placebo.

Table 3 Study 1 Part 2: mFARS Results (FAS)

Skyclarys (N=40) Placebo (N=42)

Total mFARS

Baselinen 40 42

Mean (SD) 40.95(10.394) 38.78 (11.025)

Week 48n 34 41

Mean (SD) 39.17 (10.019) 39.54 (11.568)

Skyclarys (N=40) Placebo (N=42)

Week 48 Change from baseline

LS Mean (SE) -1.56 (0.689) 0.85 (0.640)

LS Mean Difference (SE) -2.41 (0.955) -p-value vs. placebo 0.0138

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. Themaximum 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 ‑1.94(standard error 0.894) (nominal p=0.0331).

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 GAA1repeat length (Table 4).

Table 4 Study 1 Part 2: Change in mFARS at Week 48 in subgroups (FAS)

Subgroup Least Squares Mean Differencea P-Value(95% CI)

Age< 18 years (n=20) -4.21 (-8.48, 0.06) 0.0532≥ 18 years (n=62) -1.59 (-3.77. 0.58) 0.1486

GAA1 repeat length ≥ 675

Yes (n=39) -4.27 (-6.96, -1.58) 0.0024

No (n=28) -1.95 (-5.20, 1.29) 0.2325

Ambulatory status

Non-ambulatory (n=6) -4.57 (-11.41, 2.27) 0.1864

Ambulatory (n=76) -2.20 (-4.22, -0.18) 0.0336

Abbreviations: CI=confidence interval; FAS=Full Analysis Set; GAA1 repeat length=length of the trinucleotide repeats inthe 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 toplacebo in the primary analysis population (least squares [LS] mean difference in PGIC= -0.43, LSmean difference in CGIC= -0.13). Additionally, treatment of patients with Skyclarys resulted innumerically 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, patientstreated with Skyclarys had lower mFARS scores at 3 years, as compared to a matched natural historygroup. This exploratory analysis should be interpreted cautiously given the limitations of datacollected 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’sataxia (see section 4.2 for information on paediatric use).

Omaveloxolone was absorbed after oral administration in healthy fasted subjects with peak plasmaconcentrations typically observed 7 to 14 hours post dose. Patients with Friedreich's ataxiademonstrated 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 plasmaconcentration vs time curve from time 0 extrapolated to infinity (AUC0-inf) but caused a 4.5-foldincrease in Cmax compared to fasted conditions. It is recommended that Skyclarys be taken withoutfood.

Omaveloxolone Cmax and AUC0-inf were similar when capsule contents were sprinkled on apple pureeor when administered as intact capsules. The median time to achieve Cmax (tmax) of omaveloxolone wasshortened 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 proportionalmanner, 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 moderatemembrane 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 plasmametabolites that accounted for 18.6% and 10.9% of total plasma radioactivity, respectively. The othermetabolites 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 wasrecovered in the faeces within 96 hours after administration.

The average apparent plasma clearance of omaveloxolone is 109 L/hr and the average apparent plasmaterminal half-life is 58 hours (32-94 hours).

Effect of age, sex, and body weight on omaveloxolone pharmacokinetics

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 doseadjustments 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. Theeffect 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), omaveloxoloneclearance was reduced, resulting in higher plasma exposure of omaveloxolone. Subjects with moderatehepatic impairment exhibited up to a 65% increase in AUC and an 83% increase in Cmax compared tosubjects with normal hepatic function. In subjects with severe hepatic impairment, the AUC foromaveloxolone 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 hepaticimpairment (Child-Pugh Class A), there was no change in AUC and only a 29% increase in Cmax. Therecommended 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 safetypharmacology, genotoxicity, and carcinogenic potential.

Based on a panel of in vitro and in vivo mutagenicity tests, omaveloxolone is considered of lowgenotoxic potential. Omaveloxolone was not carcinogenic in a 6-month carcinogenicity study in rasH2mice 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) inpatients with Friedreich’s ataxia.

Preclinical data revealed toxicities related to omaveloxolone. In rats, findings of irreversible kidneyinjury (multifocal renal tubular degeneration/regeneration accompanied by proteinuria) were observedat 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 andmonkeys, respectively. In one male rat from the high dose group at 6 months dosing, the squamousepithelial hyperplasia was associated with a squamous cell carcinoma involving the non-glandular andglandular stomach.

Fertility and early embryonic development

Omaveloxolone, administered at oral doses of 1, 3, and 10 mg/kg/day to male rats for 28 days beforemating and throughout the mating period and to female rats from 14 days before mating, throughoutmating, and until gestation day 7 did not alter male or female fertility. However, pre- andpost-implantation embryonic loss, resorptions, and a decrease in the number of viable embryosoccurred 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 atapproximately 2 times the MHRD based on systemic exposure.

Embryo-foetal development

In an embryo-foetal toxicity study in rats, no maternal toxicity or embryo-foetal abnormalities weredetected in rats at an oral dose corresponding to approximately 6 times the MHRD based on systemicexposure. 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 wereobserved in rats. Embryo-foetal assessment in rabbits demonstrated maternal toxicity that wasassociated with early deliveries and interruptions of pregnancy as well as low foetal body weights at adose level corresponding to exposures lower (0.7-fold) than those at the MHRD; however, in the samestudy, no foetal malformations were observed at approximately 1.4 times the MHRD based onsystemic exposure.

Pre- and post-natal development

In a pre- and post-natal evaluation in rats, administration of omaveloxolone during the period oforganogenesis through lactation at doses of 1, 3, and 10 mg/kg/day was associated with an increasedpercentage of litters with stillborn pups, reduced first generation pup survival, and decreasedmean pup body weights. Decreased reproductive function (reduced mean numbers of corpora lutea andimplantation sites) were observed in F1 females and delayed sexual maturation was observed in F1males at a dose level of approximately 6 times the MHRD based on systemic exposure.  No adversereactions 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 toexcretion of omaveloxolone in milk. Effects were directly linked to exposure to omaveloxolone.

Pregelatinized maize starch

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Silica, colloidal anhydrous

Hypromellose

Titanium dioxide (E171)

Brilliant Blue FCF (E133)

Ferric oxide yellow (E172)

Shellac (E904)

Titanium dioxide (E171)

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

High density polyethylene bottles with child-resistant, foil induction-sealed polypropylene closure.

Pack size of 90 capsules.

Pack size of 270 (3 packs of 90) capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/23/1786/001

EU/1/23/1786/002

Date of first authorisation: 9 February 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.