In this study, researchers are learning more about RTA 408, also known as omaveloxolone, BIIB141, or SKYCLARYS®. The main goal of this study is to learn more about the safety of RTA 408 and how it affects physical effort, movement, coordination, and how participants feel in daily life.

The main questions researchers want to answer in this study are:

• How much physical effort can a participant produce during a cycling test after 12 weeks of treatment?
• How do scores on the modified Friedreich's Ataxia Rating Scale (mFARS) change after 48 weeks?

Researchers will use the modified Friedreich's Ataxia Rating Scale (mFARS) to measure how FA affects the nervous system. The mFARS looks at movement ability, balance, coordination, speech, and how well the arms and legs work.

They will also use a cycling test to measure physical effort, along with questionnaires to learn how participants feel and function in daily life.

Safety will also be tested using physical exams, vital sign checks, echocardiograms (ECHO), electrocardiograms (ECG), and blood and urine tests.

The study will be done in 2 main parts, followed by an optional Extension period:

• In Part 1, participants will be randomly assigned to take different doses of RTA 408 or a placebo by mouth once a day for 12 weeks. A placebo looks like the study drug but contains no real medicine.
• Researchers will compare these doses to decide which one to use in Part 2.
• In Part 2, a different group of participants will take either the chosen dose of RTA 408 (150 mg) or placebo once a day for 48 weeks.
• Participants who complete Part 1 or Part 2 may be able to join an Extension period, where everyone receives RTA 408.
• In the Extension period, participants will continue to receive RTA 408 until the drug becomes commercially available or until they leave the study
• Participants in Part 1 will have up to 9 study visits and 2 phone calls. If they do not move onto the Extension period, they will stay in the study for up to 20 weeks.
• Participants in Part 2 will have up to 10 study visits and 3 phone calls. If they do not move onto the Extension period, they will stay in the study for up to 61 weeks.
• Participants in the Extension period will have 2 visits in the first month, followed by visits every 6 months.

Friedreich's ataxia is an autosomal recessive cerebellar ataxia caused by triplet-repeat expansions. The causative mutation is a trinucleotide (GAA) repeat expansion in the first intron of the frataxin gene, leading to impaired transcription of frataxin. The pathological consequences of frataxin deficiency include a severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation, and an increased sensitivity to oxidative stress.

A hallmark of Friedreich's ataxia is impairment of antioxidative defense mechanisms, which play a major role in disease progression. Studies have demonstrated that nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling is grossly impaired in participants with Friedreich's ataxia. Therefore, the ability of omaveloxolone (RTA 408) to activate Nrf2 and induce antioxidant target genes is hypothesized to be therapeutic in participants with Friedreich's ataxia.

This 2-part study will evaluate the efficacy, safety, and pharmacodynamics of omaveloxolone (RTA 408) in the treatment of participants with Friedreich's ataxia.

Part 1: The first part of this study will be a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of omaveloxolone (RTA 408) at various doses in participants with Friedreich's ataxia.

Part 2: The second part of this study is a randomized, placebo-controlled, double-blind, parallel-group study to evaluate the safety and efficacy of omaveloxolone (RTA 408) 150 mg in participants with Friedreich's ataxia. Participants enrolled in Part 2 will be randomized 1:1 to receive omaveloxolone (RTA 408) 150 mg or placebo.

Extension: The extension will assess long-term safety and tolerability of omaveloxolone (RTA 408) in qualified participants with Friedreich's ataxia following completion of Part 1 or Part 2. Participants will not be unblinded to study treatment in Part 1 or Part 2 upon entering the extension study. Participants will receive open-label omaveloxolone (RTA 408) at 150 mg once daily.

Inclusion Criteria:

1. Have genetically confirmed Friedreich's ataxia
2. Have a modified FARS score ≥20 and ≤80
3. Be male or female and ≥16 years of age and ≤40 years of age
4. Have no changes to exercise regimen within 30 days prior to Study Day 1 and be willing to remain on the same exercise regimen during the 16-week study period
5. Have the ability to complete maximal exercise testing
6. Be able to swallow capsules

Exclusion Criteria:

1. Have uncontrolled diabetes (HbA1c >11.0%)

2. Have B-type natriuretic peptide value >200 pg/mL

3. Have a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease

4. Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus or hepatitis virus (B or C)

5. Have known or suspected active drug or alcohol abuse

6. Have clinically significant abnormalities of clinical hematology or biochemistry, including but not limited to elevations greater than 1.5 times the upper limit of normal of aspartate aminotransferase, or alanine aminotransferase

7. Have any abnormal laboratory test value or serious pre-existing medical condition that, in the opinion of the investigator, would put the patient at risk by study enrollment

8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take any of these drugs during the time of study participation:

   1. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, sildenafil)
   2. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 (e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice)
   3. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin)

9. Have participated in any other interventional clinical study within 30 days prior to Study Day 1

10. Have a cognitive impairment that may preclude ability to comply with study procedures

11. Prior participation in a trial with omaveloxolone (RTA 408)

In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/