MOXIe trial

SKYCLARYS was studied in the MOXIe trial, the largest FA study of its kind1,2

Designed in consultation with clinical specialists, patient advocacy groups, and the FDA. The MOXIe trial was an international, double-blind, randomized, placebo-controlled, multicenter, registrational phase 2 trial. A total of 103 patients were randomized in a ratio of 1:1 (the All Randomized Population) to receive SKYCLARYS 150 mg once daily (n=51) or placebo (n=52).

efficacy efficacy
The prespecified primary analysis

The prespecified primary analysis was the change from baseline in the mFARS score compared with placebo at Week 48 in the Full Analysis Population of patients without pes cavus (n=82).2

SKYCLARYS slowed FA disease progression in the pivotal MOXIe trial1

Treatment with SKYCLARYS resulted in less physical impairment relative to placebo at Week 48.
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ADVERSE REACTIONS
  • Adverse reactions reported in 10% or more of patients and greater than placebo were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, musculoskeletal pain, oropharyngeal pain, influenza, vomiting, muscle spasms, back pain, decreased appetite, and rash1
Results from patient subgroups numerically favored SKYCLARYS over placebo1,2:
  • Age (±18 years)
  • Sex
  • GAA repeat length (≥675)
  • Ambulatory status
  • Presence of pes cavus
All 4 components of the mFARS assessment numerically favored SKYCLARYS over placebo.2

Bulbar function

bulbar_function

Lower limb coordination

lower_limb

Upper limb coordination

upper_limb

Upright stability

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In adolescent patients aged 16 to 18 years treated with SKYCLARYS (n=20) a group difference of -4.16 points versus placebo was observed at Week 48.2
The MOXIe trial was not powered to detect a statistically significant difference among subgroups.2

Results of a 3-Year Post Hoc Propensity-Matched Analysis

These exploratory analyses should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.
Lower mFARS scores were observed in patients treated with SKYCLARYS after 3 years relative to a matched set of patients from a natural history study.1

Propensity matching is a method of comparing patients from a clinical trial with an external control by identifying comparable prognostic characteristics. It is informative in cases where a very long follow-up period is required to assess outcomes or when it is difficult to perform randomized controlled trials, such as in certain special patient populations.

chart

An ongoing MOXIe open-label (OLE) assesses long-term safety and tolerability of omaveloxolone in patients with FA who completed MOXIe Part 1 or Part 2 (n=136). A post hoc propensity-matched analysis compared patients in the MOXIe OLE with patients who were not treated with SKYCLARYS who participated in a natural history study, the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS).

Patient characteristics in the propensity-matched analysis:

table

FA-COMS is a large, robust FA natural history study and has enrolled more than 1350 patients who have been followed for up to 15 years.

mFARS

What is mFARS?2,6

The mFARS is a clinically validated neurological assessment that provides a detailed evaluation of a patient’s status and is generally accepted as a clinical trial endpoint due to its correlation with disease progression. mFARS is not required to be used in the clinic in order to treat with SKYCLARYS.

mFARS range is 0-93 points

A higher score is associated with more severe disease.2,6

The mFARS is made up of 4 sections focused on functional abilities6:

Ability to complete many activities of daily living, such as getting dressed and eating

Predictor of time to loss of ambulation; the average score where loss of ambulation occurs is 65

Closely correlated with upright stability in predicting the likely rate of disease progression

Ability to speak clearly

While there is variability in progression, a patient’s mFARS score will worsen (increase) by about 2 points per year on average7

Patients with a younger age of onset may progress faster.

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SKYCLARYS was not evaluated in patients younger than 16 years or older than 40 years of age.

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Review dosing and safety of SKYCLARYS

References:
1. Skyclarys. Prescribing Information. Biogen; 2024. 2. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934 3. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013;126(suppl 1):103-117. doi:10.1111/jnc.12317 4. Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5(4):222-234. doi:10.1038/nrneurol.2009.26 5. Rummey C, Farmer JM, Lynch DR. Predictors of loss of ambulation in Friedreich’s ataxia. eClinicalMedicine. 2020;18:1-9. doi:10.1016/j.eclinm.2019.11.006 6. Rummey C, Corben LA, Delatycki MB, et al. Psychometric properties of the Friedreich Ataxia Rating Scale. Neurol Genet. 2019;5(6):371. doi:10.1212/NXG.0000000000000371 7. Patel M, Isaacs CJ, Seyer L, et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016;3(9):684-694. doi:10.1002/acn3.332 8. Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich’s ataxia: delayed-start analysis of the MOXIe extension. Mov Disord. 2023;38(2):313-320. doi:10.1002/mds.29286 9. Galea CA, Huq A, Lockhart PJ, et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol. 2016;79(3):485-495. doi:10.1002/ana.24595 10. Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 2007;6(3):245-257. 11. Wallace SE, Bird TD. Molecular genetic testing for hereditary ataxia: what every neurologist should know. Neurol Clin Pract. 2018;8(1):27-32. doi:10.1212/CPJ.0000000000000421 12. Data on file. Reata Pharmaceuticals, Inc.; 2022. 13. Lynch DR, Goldsberry A, Rummey C, et al. Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann Clin Transl Neurol. 2024;11(1):4-16. doi:10.1002/acn3.51897 14. Beaulieu-Jones BK, Finlayson SG, Yuan W, et al. Examining the use of real-world evidence in the regulatory process. Clin Pharmacol Ther. 2020;107(4):843-852. doi:10.1002/cpt.1658

INDICATION AND IMPORTANT SAFETY INFORMATION
INDICATION
  • SKYCLARYS is indicated for the treatment of Friedreich ataxia in adults and adolescents aged 16 years and older
IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Elevation of Aminotransferases

  • Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The incidence of elevations of ALT or AST above 5 times and 3 times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with SKYCLARYS. There were no cases of concomitant elevation of transaminases and total bilirubin observed. Maximum increases in ALT and AST occurred within 12 weeks after starting SKYCLARYS. Increases in serum aminotransferases were generally asymptomatic and reversible following discontinuation of SKYCLARYS
  • Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3 months of treatment, and periodically thereafter. If transaminases increase to levels greater than 5 times the ULN, or greater than 3 times the ULN with evidence of liver dysfunction (e.g., elevated bilirubin), immediately discontinue SKYCLARYS and repeat liver function tests as soon as possible. If transaminase levels stabilize or resolve, SKYCLARYS may be reinitiated with an appropriate increased frequency of monitoring of liver function

Elevation of B-Type Natriuretic Peptide

  • Treatment with SKYCLARYS can cause an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. A total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP value above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of elevation of BNP above 200 pg/mL was 4% in patients treated with SKYCLARYS. Cardiomyopathy and cardiac failure are common in patients with Friedreich ataxia. Whether the elevations in BNP are related to SKYCLARYS or cardiac disease associated with Friedreich ataxia is unclear
  • Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function. Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or more of weight gain in a week), peripheral edema, palpitations, and shortness of breath. If signs and symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac function, and manage appropriately. Management of fluid overload and heart failure may require discontinuation of SKYCLARYS

Lipid Abnormalities

  • Treatment with SKYCLARYS can cause changes in cholesterol. In Study 1, 29% of patients treated with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Mean increases were observed within 2 weeks of initiation of SKYCLARYS and returned to baseline within 4 weeks of discontinuing treatment. A total of 16% of patients treated with SKYCLARYS had an increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients who received placebo. The mean increase in LDL-C for all SKYCLARYS-treated patients was 23.5 mg/dL at 48 weeks. A total of 6% of patients treated with SKYCLARYS had decreases in high-density lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The mean decrease in HDL-C for all SKYCLARYS-treated patients was 5.3 mg/dL at 48 weeks
  • Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment. Manage lipid abnormalities according to clinical guidelines

ADVERSE REACTIONS

  • Adverse reactions reported in 10% or more of patients and greater than placebo were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, musculoskeletal pain, oropharyngeal pain, influenza, vomiting, muscle spasms, back pain, decreased appetite, rash

DRUG INTERACTIONS

  • Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be avoided, dosage modifications are recommended
  • Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A inducers
  • Refer to the prescribing information for dosing instructions for concomitant use of CYP3A4 and CYP2C8 substrates and monitor for lack of efficacy of the concomitant treatment
  • Advise patients to avoid concomitant use with combined hormonal contraceptives, implants, and progestin only pills

SPECIFIC POPULATIONS

Pregnancy

  • There are no adequate data on the development risks associated with the use of SKYCLARYS in pregnant women

Lactation

  • There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on milk production and the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SKYCLARYS and any potential adverse effects on the breastfed infant from SKYCLARYS or from the underlying maternal condition

Hepatic Impairment

  • Avoid treatment with SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic impairment
  • Reduced dosage in patients with moderate hepatic impairment with close monitoring for adverse reactions is recommended

Please see full Prescribing Information.

Skyclarys (omaveloxolone) 50mg capsules