A Study to Learn About the Effects and Safety of RTA 408 (Omaveloxolone) in People Aged 16 to 40 With Friedreich's Ataxia

A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia (MOXIe)

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.

Study Overview

• Status: Completed
• Conditions: Friedreich Ataxia
• Intervention / Treatment: Drug: Placebo; Drug: Omaveloxolone Capsules, 2.5 mg; Drug: Omaveloxolone Capsules, 5 mg; Drug: Omaveloxolone Capsules, 10 mg; Drug: Omaveloxolone Capsules, 20 mg; Drug: Omaveloxolone Capsules, 40 mg; Drug: Omaveloxolone Capsules, 80 mg; Drug: Omaveloxolone Capsules, 160 mg; Drug: Omaveloxolone Capsules, 300 mg; Drug: Omaveloxolone Capsules, 150 mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Murdoch Childrens Research Institute
• Austria
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck
• Italy
  • Milan, Italy, 20133
    • Neurological Institute Carlo Besta
• United Kingdom
  • London, United Kingdom, WC1E 6BT
    • University College of London
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Neurology
    • Tampa, Florida, United States, 33612
      • USF Ataxia Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University Hospital - Neurology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Stead Family Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Ohio State University - Neurology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Omaveloxolone 2.5 and 5 mg; Participants received omaveloxolone 2.5 mg, oral capsule, QD for 2 weeks, followed by 5 mg Omaveloxolone, oral capsule, QD for 10 weeks.	Drug: Omaveloxolone Capsules, 2.5 mg; Other Names: RTA 408 Capsules 2.5 mg; Drug: Omaveloxolone Capsules, 5 mg; Other Names: RTA 408 capsules, 5 mg
Experimental: Part 1: Omaveloxolone 10 mg; Participants received omaveloxolone 10 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 10 mg; Other Names: RTA 408 capsules, 10 mg
Experimental: Part 1: Omaveloxolone 20 mg; Participants received omaveloxolone 20 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 20 mg; Other Names: RTA 408 capsules, 20 mg
Experimental: Part 1: Omaveloxolone 40 mg; Participants received omaveloxolone 40 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 40 mg; Other Names: RTA 408 capsules, 40 mg
Experimental: Part 1: Omaveloxolone 80 mg; Participants received omaveloxolone 80 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 80 mg; Other Names: RTA 408 capsules, 80 mg
Experimental: Part 1: Omaveloxolone 160 mg; Participants received omaveloxolone 160 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 160 mg; Other Names: RTA 408 capsules, 160 mg
Experimental: Part 1: Omaveloxolone 300 mg; Participants received omaveloxolone 300 mg, oral capsule, QD for 12 weeks.	Drug: Omaveloxolone Capsules, 300 mg; Other Names: RTA 408 capsules, 300 mg
Placebo Comparator: Part 1: Placebo; Participants received placebo, oral capsule, QD for 12 weeks.	Drug: Placebo
Experimental: Part 2: Omaveloxolone 150 mg; Participants received omaveloxolone 150 mg, oral capsule, QD for 48 weeks.	Drug: Omaveloxolone Capsules, 150 mg; Other Names: RTA 408 capsules, 150 mg
Placebo Comparator: Part 2: Placebo; Participants received placebo, oral capsule, QD for 48 weeks.	Drug: Placebo
Experimental: OLE: Placebo/ Omaveloxolone; All eligible participants who had received either omaveloxone or placebo in Part 1 and eligible participants who received placebo in Part 2 received omaveloxone, 150 mg, oral capsule, QD, until the drug was available through commercial channels or alternate post-trial access mechanisms, or until participant withdrawal, whichever was sooner (up to approximately 370 weeks).	Drug: Omaveloxolone Capsules, 150 mg; Other Names: RTA 408 capsules, 150 mg
Experimental: OLE: Omaveloxolone/ Omaveloxolone; All eligible participants who had received omaveloxone in Part 2 continued to receive omaveloxolone, 150 mg, oral capsule, QD until the drug was available through commercial channels or alternate post-trial access mechanisms, or until participant withdrawal, whichever was sooner (up to approximately 370 weeks).	Drug: Omaveloxolone Capsules, 150 mg; Other Names: RTA 408 capsules, 150 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Change From Baseline in Peak Work During Maximal Exercise Testing at Week 12	Cycle ergometry using a recumbent stationary bicycle was used to conduct maximal exercise testing and workload was increased incrementally. Peak work is defined as the workload at which participants reach maximal volition (defined as an inability to continue to exercise due to exhaustion). A positive change from baseline suggests an improvement.	Baseline, Week 12
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug whether or not it is considered to be study drug related. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as any AEs, regardless of relationship to study drug, that had an onset or worsened in severity on or after the first dose of study drug.	From first dose of study drug up to end of Part 1 of the study (up to Week 16)
Part 2: Change From Baseline in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48	The Friedreich Ataxia Rating Scale (FARS) is a neurological-exam-based rating scale with five sections: Bulbar (section A), Upper Limb Coordination (section B), Lower Limb Coordination (section C), Peripheral Nervous System (section D), and Upright Stability (section E). mFARS is the sum of sections A (score 0 to 11), B (score 0 to 36), C (score 0 to 16), and E (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function.	Baseline, Week 48
Part 2: Number of Participants With TEAEs and TESAEs	An AE was any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug whether or not it is considered to be study drug related. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as any AEs, regardless of relationship to study drug, that had an onset or worsened in severity on or after the first dose of study drug.	From first dose of study drug up to end of Part 2 of the study (up to Week 52)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Change From Baseline in the mFARS at Week 12	The FARS is a neurological-exam-based rating scale with five sections: Bulbar (section A), Upper Limb Coordination (section B), Lower Limb Coordination (section C), Peripheral Nervous System (section D), and Upright Stability (section E). mFARS is the sum of sections A (score 0 to 11), B (score 0 to 36), C (score 0 to 16), and E (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function.	Baseline, Week 12
Part 2: Number of Participants With Patient Global Impression of Change (PGI-C)	The PGI-C is a 7-point scale that requires participants to assess how much their illness has improved or worsened relative to their baseline state at the beginning of the trial. Participants self-rated their perceived change by completing the following statement: "Since I began trial treatment, my overall status is:" 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse and 7=Very much worse. Lower score indicates better improvement. The categories with at least one participant having a PGI-C score are reported.	Week 48
Part 2: Number of Participants With Clinical Global Impression of Change (CGI-C)	The CGIC scale is a 7 point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of an intervention. The CGIC was assessed by completing the following statement "Compared to the participant's condition at the start of the trial, this participant's overall status is", where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Lower score indicates better improvement. The categories with at least one participant having a CGIC score are reported.	Week 48
Part 2: Change From Baseline in Performance on a 9-Hole Peg Test (9-HPT) at Week 48	The 9-HPT is a brief, standardized, quantitative test of upper extremity (arm and hand) function. Both the dominant and nondominant hands were tested twice (2 consecutive trials of the dominant hand, followed immediately by 2 consecutive trials of the nondominant hand). The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. The times recorded for the two trials for each hand are averaged, and the reciprocal average value for each hand was used in analyses. Longer test times reflect more impairment on the participant's upper extremity function, thus a negative change from baseline suggests an improvement.	Baseline, Week 48
Part 2: Change From Baseline in Performance on a 25-Foot Timed Walk Test (T25-FWT) at Week 48	The T25-FWT is a quantitative mobility and leg function performance test based on time (in seconds) to complete a 25-foot walk. Participants were instructed to attempt two T25-FWT trials at each visit. Both walk times were averaged, and the reciprocal average value was used in analyses. Longer test times reflect more impairment on the participant's ability to walk, thus a negative change from baseline suggests an improvement.	Baseline, Week 48
Part 2: Total Number of Falls	A fall was defined as "the participant unintentionally coming to rest on the ground or at a lower level." The total number of falls before and after study drug administration has been reported.	Up to Week 48
Part 2: Change From Baseline in Peak Work During Maximal Exercise Testing at Week 48	Cycle ergometry using a recumbent stationary bicycle was used to conduct maximal exercise testing and workload was increased incrementally. Peak work is defined as the workload at which participants reach maximal volition (defined as an inability to continue to exercise due to exhaustion). A positive change from baseline suggests an improvement.	Baseline, Week 48
Part 2: Change From Baseline in the Activities of Daily Living (ADL) Score at Week 48	The ADL scale examines the ability of participants to complete everyday tasks (e.g., holding a fork, dressing). The ADL is a 9-question assessment, with the total score being the sum of 9 questions. The ADL survey assesses 9 concepts: (1) speech; (2) swallowing; (3) cutting food and handling utensils; (4) dressing; (5) personal hygiene; (6) falling; (7) walking; (8) quality of sitting position; and (9) bladder function. Each of these is rated on a 5-point scale where 0= normal and 4= severe disability/inability to carry out activity independently, for a total possible score of 0 to 36, with higher scores representing greater disability/dependency. A negative change from baseline indicates improvement.	Baseline, Week 48

Collaborators and Investigators

• Sponsor: Biogen
• Collaborators: AbbVie; Friedreich's Ataxia Research Alliance

Publications and helpful links

General Publications

• Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb;89(2):212-225. doi: 10.1002/ana.25934. Epub 2020 Nov 5.
• Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018 Nov 10;6(1):15-26. doi: 10.1002/acn3.660. eCollection 2019 Jan.
• Perlman S, Zhang S, Setyawan J, Yang H, Jiang A, Hua Q, Boudreau J, Khan S, Bajaj A, Lynch DR, Lawson R. The clinical burden of Friedreich ataxia in the United States: A retrospective claims database analysis. J Neurol Sci. 2025 Aug 15;475:123594. doi: 10.1016/j.jns.2025.123594. Epub 2025 Jun 25.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2015
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): December 19, 2025

Study Registration Dates

• First Submitted: September 30, 2014
• First Submitted That Met QC Criteria: September 30, 2014
• First Posted (Estimated): October 2, 2014

Study Record Updates

• Last Update Posted (Actual): September 3, 2026
• Last Update Submitted That Met QC Criteria: August 13, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Oxidative Stress; RTA 408; RTA 408 Capsules; Mitochondrial dysfunction; omaveloxolone
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolic Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Spinal Cord Diseases; Cerebellar Diseases; Spinocerebellar Degenerations; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Mitochondrial Diseases; Friedreich Ataxia; Substandard Drugs; Pharmaceutical Preparations; omaveloxolone; ORF 50 transactivator
• Other Study ID Numbers: RTA 408-C-1402; 2024-517436-22 (Other Identifier: EU CTIS Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No