Skyclarys (omaveloxolone) for Friedreich’s ataxia
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What is Skyclarys for Friedreich’s ataxia?
Skyclarys (omaveloxolone) is an oral treatment that is expected to slow or prevent the progression of Friedreich’s ataxia (FA) in adults and certain adolescents with the inherited disorder. It was approved in February 2023 in the U.S., making it the first and only approved therapy for FA.
Originally developed by Reata Pharmaceuticals in collaboration with AbbVie, the worldwide rights to commercialize Skyclarys were reacquired by Reata in 2019.
Skyclarys became available to U.S. patients in June 2023.
Therapy Snapshot
| Brand Name: | Skyclarys |
| Chemical Name: | omaveloxolone |
| Usage: | FA treatment for patients ages 16 and older |
| Administration: | Oral capsules |
How does Skyclarys work?
FA is caused by genetic mutations that lead to low levels of frataxin, a protein that’s necessary for the functioning of mitochondria, which serve as the energy production centers of cells.
In FA, mitochondrial dysfunction and impairments in cellular energy production drive chronic inflammation and vulnerability to oxidative stress, a type of cell damage. Oxidative stress is marked by an imbalance between the production of toxic reactive oxygen species and the antioxidant defenses needed to clear them. As a consequence, patients experience progressive neurodegeneration and a loss of muscle strength and coordination.
Skyclarys is designed to activate nuclear factor erythroid 2-related factor 2 (NrF2), a type of protein called a transcription factor whose signaling is impaired in FA patients. NrF2 works to activate genes that promote mitochondrial function, boost antioxidant responses, and prevent inflammation.
In doing so, the therapy is expected to slow or prevent disease progression in people with FA.
Who can use Skyclarys?
The U.S. Food and Drug Administration approved Skyclarys in February 2023 for people with FA who are 16 or older. Skyclarys now is under review for a similar indication by the European Medicines Agency.
Who should not use Skyclarys?
There are no contraindications for Skyclarys’ use. However, the therapy’s FDA label warns that it is not recommended for patients being treated with moderate or strong CYP3A inhibitors, which include certain antifungal medications, antibiotics, and antiretroviral therapies. Reducing Skyclarys’ dosage and monitoring patients is an alternative when using both types of treatments is unavoidable. In addition, moderate or strong CYP3A4 inducers, such as the herbal therapy St. John’s wort, should be avoided while on Skyclarys.
How is Skyclarys administered?
Skyclarys comes in the form of opaque hard capsules, each containing 50 mg of the medication. Capsules are light green with a blue cap and are imprinted with “RTA 408” in white ink on the body and “50” in white ink on the cap.
The recommended dosage is 150 mg (three capsules) taken orally once per day. For patients with moderate liver impairments, the recommended dose is 100 mg (two capsules), which can be further reduced to 50 mg if adverse reactions occur.
The treatment should be taken on an empty stomach at least one hour before eating. Capsules should be swallowed whole and not opened, crushed, or chewed. Patients should avoid grapefruit and grapefruit juice while using Skyclarys.
Skyclarys in clinical trials
The approval of Skyclarys was supported by data from the two-part MOXIe clinical trial (NCT02255435) , which enrolled FA patients at sites in Australia and the U.S., as well as study centers in Europe.
MOXIe trial
After the completion of Phase 1 trials that established the therapy’s safety in healthy volunteers, the Reata-sponsored Phase 2 MOXIe trial was launched to evaluate the safety, efficacy, and pharmacodynamics, or effects on the body, of oral Skyclarys in FA patients. The trial tested the treatment against a placebo in 172 participants, ages 16-40.
In its first part, 69 patients were given escalating doses (5-300 mg) of Skyclarys or a placebo, once daily for 12 weeks, or about three months. The results showed that Skyclarys led to increases in Nrf2, which were associated with improvements in mitochondrial function. Mitochondria are the so-called powerhouses of cells. Neurological function also was improved, as assessed by the modified Friedreich’s Ataxia Rating Scale (mFARS), a standard evaluation of FA progression. The maximum therapeutic effect was observed at the 160 mg dose.
The study’s second part evaluated the safety and efficacy of 150 mg Skyclarys in 103 FA patients, who were randomly assigned to receive the treatment or a placebo for 48 weeks.
Skyclarys led to a significant 2.4-point improvement in mFARS scores relative to the placebo group, meeting the trial’s main goal. While patients on Skyclarys saw an average 1.55-point decrease (an improvement), those in the placebo group saw an average 0.85-point increase in scores, indicating disease progression. Overall, the results reflected a reduction in disease severity with Skyclarys.
Other clinical measures, including participant and clinician impressions of changes, and the ability of patients to perform activities of daily living, also generally favored Skyclarys.
Participants who completed the main trial were eligible to enter its open-label extension phase, in which all received 150 Skyclarys daily. Results after nearly three years of treatment indicated that gains made in the main trial were maintained, with those who had been taking Skyclarys since the study’s start seeing lower mFARS scores compared with those originally on a placebo.
mFARS scores also were significantly lower among Skyclarys-treated patients compared with the natural history of the disease. The rate of disease progression over the three years was 55% slower among Skyclarys-treated MOXIe participants compared with matched FA patients from a natural history study of the disease (NCT03090789).
Common side effects of Skyclarys
The most common side effects associated with Skyclarys include:
- elevated liver enzymes
- headache
- nausea
- abdominal pain
- fatigue
- diarrhea
- musculoskeletal pain.
Elevated liver enzymes
Skyclarys can cause an elevation in certain liver enzymes. In clinical testing, this occured in the first 12 weeks after starting treatment, and was generally asymptomatic and reversible.
Liver enzyme levels should be monitored when starting treatment, every month for the first three months of using Skyclarys, and periodically thereafter. If evidence of liver dysfunction is observed, Skyclarys should be stopped. Treatment can be restarted after stabilization with increased monitoring.
Increased levels of heart function marker
Some patients using Skyclarys in clinical testing have experienced increases in B-type natriuretic peptide (BNP), a marker of heart function. While it isn’t clear whether these elevations were related to Skyclarys itself or cardiac disease associated with FA, BNP elevations can nevertheless indicate cardiac failure.
BNP levels should be checked before starting treatment, and patients should be monitored for signs and symptoms of heart failure, including fluid retention (sudden weight gain), swelling, palpitations, and shortness of breath. Should patients experience BNP elevations or signs of heart failure during treatment, heart function should be promptly evaluated.
High cholesterol
Skyclarys can lead to changes in blood cholesterol levels, which in a clinical trial emerged in the first two weeks of treatment and returned to normal thereafter. Cholesterol levels should be measured before a patient begins using Skyclarys and periodically during treatment.
Potential issues for pregnancy, breastfeeding, and contraception
In animal studies, use of Skyclarys during pregnancy and lactation has been associated with signs of developmental toxicity, growth impairments, death, and neurobehavioral changes in offspring.
There is insufficient data about the use of Skyclarys in pregnant or lactating FA patients. Patients who are pregnant or wish to become pregnant should discuss the matter with their healthcare team.
Skyclarys may decrease the effectiveness of hormonal contraceptives. Women using contraception at the same time as Skyclarys should discuss alternative non-hormonal contraceptive methods with their doctor.
Friedreich’s Ataxia News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Skyclarys
Skyclarys was approved by the U.S. Food and Drug Administration (FDA) in February 2023 for adults and adolescents, ages 16 and older, with Friedreich’s ataxia. The FDA’s approval made Skyclarys the first and only therapy for the disease in the U.S.
Friedreich’s ataxia (FA) is characterized by dysfunction of mitochondria, which are the energy production centers in cells, chronic inflammation, and oxidative stress, a type of cell damage marked by overproduction of toxic reactive oxygen species that outweighs the body’s antioxidant defenses. Skyclarys is intended to activate NrF2, which stands for nuclear factor erythroid 2-related factor 2, a type of protein called a transcription factor whose signaling is impaired in people with FA. NrF2 activates genes that promote mitochondrial function, boost antioxidant responses, and prevent inflammation.
There is no direct evidence reported of an interaction between alcohol and Skyclarys. Patients are, however, advised to talk to their healthcare providers about the use of alcohol or other substances while taking Skyclarys.
In the Phase 2 MOXIe trial (NCT02255435), whose results supported the approval of Skyclarys by the U.S. Food and Drug Administration, improvements in the function of mitochondria (the so-called powerhouses of cells) and in neurological function were most evident about three months (12 weeks) after starting Skyclarys treatment. Benefits were seen as early as four weeks into therapy. There is, however, no standard timeline for Skyclarys’ benefits, as each person may respond differently to the medication.
The most common side effects of Skyclarys are elevated levels of liver enzymes, headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain; such pain may affect bones, joints, ligaments, tendons, or muscles. The therapy’s prescribing information includes warnings about the risk of increased liver enzymes, high levels of B-type natriuretic peptide (BNP), which is a marker of heart function, and changes in the blood levels of cholesterol, all of which have happened in clinical testing. Measurements of each of these levels are recommended before and periodically after starting treatment.
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