After nearly one year of its use, omaveloxolone (RTA 408) significantly improved neurological function across several clinical measures in people with Friedreich’s ataxia (FA), and was generally safe and well tolerated, according to results from the MOXIe Phase 2 trial.
These findings were published in the Annals of Neurology in the study, “Safety and Efficacy of Omaveloxolone in Friedreich’s Ataxia (MOXIe Study).”
Omaveloxolone (RTA-408), developed by Reata Pharmaceuticals, is an investigational oral therapy designed to activate Nrf2, a protein that regulates gene activity to restore energy production in cells — which is impaired in people with FA.
MOXIe isa two-part, randomized and placebo-controlled Phase 2 clinical trial (NCT02255435), evaluating the safety and efficacy of omaveloxolone in adolescents and adults with FA, ages 16-40.
The first part was a dose-escalation phase, where 69 patients were given increasing oral daily doses of omaveloxolone (between 2.5 and 300 mg), or a placebo, for 12 weeks to determine the best dose for part two.
During this phase, treated patients showed dose-dependent improvements in select measures, including cardiopulmonary exercise testing and neurological function, as assessed by the modified Friedreich’s Ataxia Rating Scale (mFARS), an FDA-endorsed scale to measure disease progression.
In the second part, MOXIe enrolled 103 patients at 11 study sites in the U.S., Europe, and Australia. These people were randomly assigned to either omaveloxolone at 150 mg or placebo capsules once a day for 48 weeks.
A total of 94 (91%) patients completed the 48 weeks of treatment, including 44 of 51 patients (86%) randomized to omaveloxolone, and 50 of 52 participants (96%) randomized to placebo.
The primary efficacy analysis was limited to patients without the foot deformity pes cavus, and included 40 omaveloxolone-treated patients and 42 given a placebo. Safety analyses included all patients.
At 48 weeks compared with baseline (study start) measures, treated patients experienced a mean decrease in mFARS of 1.55 points while those on place had a mean increase in mFARS of 0.85, representing a difference between treatment groups of 2.40 points. Of note, increases in mFARS scores represent worsening neurological function.
Omaveloxolone improved each component within the mFARS assessment, including bulbar (face, head, and neck), upper limb, and lower limb coordination, though the greatest effects were seen in upright stability — which consistently worsened over time among those receiving a placebo.
A secondary analysis on the global Part 2 population — which included patients with pes cavus — confirmed the primary analysis, showing a difference between omaveloxolone and placebo groups of 1.93 mFARS points.
Improvements in mFARS with omaveloxolone’s use were seen regardless of sex and age, although the greatest gains in those less than 18 years of age. In this patient subgroup, mFARS scores increased (worsened) by 2.52 points in those given a placebo, while scores dropped by 1.63 points in those on omaveloxolone — representing an improvement of 4.16 points.
Researchers then examined these data through a different statistical approach, to reduce the likelihood that the original analysis methodology may have yielded inaccurate results. This analysis showed an even greater benefit from omaveloxolone’s use, with treated patients experiencing differences of 2.83 points in their mFARS scores compared with those on placebo.
Gains in other clinical measures were also seen with 48 weeks of treatment against placebo, including the patient-reported measure Patient Global Impression of Change (PGIC) and the clinician’s assessment Clinical Global Impression of Change (CGIC), but these differences were not statistically significant.
But treatment significantly improved Activities of Daily Living (FA-ADL) scores, a measure of daily self-care activities, compared with placebo, with scores favoring omaveloxolone in all nine FA-ADL sections.
Omaveloxolone’s use also led to increased ferritin levels (a measure of overall iron) and lowered total bilirubin (a marker for poor liver function) compared with placebo, which was “consistent with restoration of biochemical abnormalities.”
Adverse events were reported in all patients in both groups. The most common, and more frequent with omaveloxolone than placebo, included headache, nausea, fatigue, diarrhea, and abdominal pain. Increased ALT and AST levels (suggesting abnormal liver function) were reported, but these increases were reversed.
Most adverse events in those given omaveloxolone were limited to the first 12 weeks, with fewer events reported between weeks 12 and 48.
Serious adverse events were experienced by three omaveloxolone patients and two placebo patients, and by two additional omaveloxolone patients two weeks after receiving the final dose. Four patients on omaveloxolone and two on a placebo stopped treatment due to side effects. No serious adverse events occurred in pediatric patients resulting in discontinued treatment.
“In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well-tolerated,” the researchers wrote. “It represents a potential therapeutic agent in [Friedreich’s ataxia].”
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