Topline results of Reata‘s MOXIe trial show that almost one year of treatment with the investigational oral therapy omaveloxolone (RTA 408) is well-tolerated and leads to significant benefits in neurological function in patients with Friedreich’s ataxia (FA), meeting the Phase 2 trial’s primary goal.
Compared with placebo, daily treatment with omaveloxolone capsules led to a 2.40-point improvement in the modified Friedreich’s ataxia rating scale (mFARS) — a scale to measure FA disease progression endorsed by the FDA — after 48 weeks.
In contrast, mFARS scores rise (worsen) by an average of 1 to 2 points each year in untreated patients in this disease’s natural history.
Reata Pharmaceuticals announced plans, based on these results, to request that omaveloxolone be approved to treat Friedreich’s ataxia in the U.S. and abroad. If regulatory authorities agree, omaveloxolone would become the disease’s first targeted treatment.
“The results of MOXIe represent a truly historic moment for the patients, families, and caregivers that comprise the Friedreich’s ataxia community,” Ronald Bartek, president of the Friedreich’s Ataxia Research Alliance (FARA), which supported the trial, said in a press release. “We look forward to continuing the Reata-FARA partnership as we work in pursuit of approval of the first FA therapy.”
MOXIe was a two-part, randomized and placebo-controlled Phase 2 clinical trial (NCT02255435) to evaluate omaveloxolone’s safety, efficacy, and pharmacodynamics (its effects and mechanism of action) in youth and adults with FA (ages 16-40).
In the trial’s first part, 69 patients (ages 16-37; mean age, 25.6) were given escalating oral doses (between 5 and 300 mg capsules) once a day for 12 weeks to determine the best dose for part two.
Results showed that omaveloxolone’s worked in ways that matched its expected mechanism of action, with improvements in muscular and neurological function best seen at a daily dose of 160 mg.
In its second part, MOXIe enrolled 103 patients at 11 study sites in the U.S., Europe, and Australia, becoming the largest global clinical trial conducted in FA to date. Patients were randomly assigned to either omaveloxolone at 150 mg or placebo capsules once a day.
Treatment with omaveloxolone met its primary endpoint or efficacy goal. At 48 weeks, patients taking omaveloxolone experienced statistically significant relief in muscular and neurological symptoms, corresponding to a 2.4-point reduction in mFARS scores compared to placebo.
mFARS is a physician-assessed neurological rating scale used to measure FA progression, and accepted by FDA to evaluate omaveloxolone’s efficacy. It evaluates speaking and swallowing, upper and lower limb coordination, and standing and walking abilities. Higher mFARS scores represent more severe disease.
Since the study’s start, patients on omaveloxolone experienced a mean reduction of 1.55 points in disease progression measured by mFARS, while those on placebo had a mean score increase of 0.85 points. Benefits reported were “time dependent,” Reata noted, meaning they increased over the course of treatment.
Benefit was seen also for patients with high-arched feet, a foot deformity (pes cavus, Latin for “hollow foot”). When all study patients were analyzed, including those with pes cavus, omaveloxolone benefit could be measured as a 1.93-point mFARS improvement against placebo.
Several other secondary measures of efficacy also were successfully met by omaveloxolone, Reata reported in its release.
Omaveloxolone was found to be generally well-tolerated and safe, with adverse events being mild to moderate. Side effects most commonly associated with its use were headache, nausea, increased levels of liver enzymes (aminotransferases), fatigue, and abdominal pain.
High blood levels of aminotransferases (or transaminases) are normally a sign of liver toxicity. But here, the rise was a consequence of omaveloxolone’s pharmacological workings and were not associated with liver injury, Reata reported. These higher levels are thought to be related to the restoring of mitochondrial function.
Overall rate of serious adverse events was low, with three patients in each group reporting such side effects. Four (8%) omaveloxolone patients and two (4%) placebo patients left the study due to adverse events.
“Patients living with Friedreich’s ataxia experience a devastating and progressive loss of neurological function. … We believe that the MOXIe findings announced today bring us closer to our goal of providing an urgently needed therapy to patients with FA,” said Warren Huff, Reata’s president and CEO.
“On behalf of everyone at Reata, I would like to express my sincere appreciation to all of the patients, families, and investigators who participated in the MOXIe study.”
Omaveloxolone is designed to work by activating Nrf2, a transcription factor that is able to restore mitochondrial function, a fundamental energy-producing pathway within cells that is damaged in people with FA. It also was seen to reduce oxidative stress and block inflammation in preclinical studies.
The potential treatment was initially developed by Reata in collaboration with AbbVie. Recently, Reata reacquired exclusive and worldwide rights to develop, manufacture and commercialize omaveloxolone.