Omaveloxolone (RTA 408), an investigation medicine by Reata Pharmaceuticals, improves neurological function in people with Friedreich’s ataxia, according to results from part one of the MOXIe trial presented today at IARC 2017.
David Lynch, a pediatric neurologist at Children’s Hospital of Philadelphia and a principal investigator for the Phase 2 clinical study, delivered these results in Friday’s presentation, “Safety, Efficacy, and Pharmacodynamics of Omaveloxolone in Friedreich’s Ataxia Patients (MOXIe Trial): Part 1 Results.” IARC 2017 is taking place in Pisa, Italy, through Saturday.
Friedreich’s ataxia (FA) is the most common inherited recessive ataxia, caused by a mutation in the frataxin gene that leads to reduced expression of the frataxin protein. Frataxin is found in mitochondria — the energy-producing organelles of a cell — and at lower-than-normal levels leaves cells unable to produce sufficient energy while increasing their sensitivity to oxidative stress. Oxidative stress is marked by an imbalance in the response of antioxidant cells to damaging molecules, called reactive oxygen species or ROS.
One treatment approach for FA aims to re-establish the cell’s antioxidant mechanisms. Previous studies show that the nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor for inducing expression of antioxidant enzymes that might restore equilibrium — homeostasis — in cells.
Nrf2 levels are strongly impaired in FA patients.
“Nrf2 is suppressed in FA and contributes to oxidative stress, mitochondrial dysfunction, and reduced ATP [energy] production,” Lynch said in his presentation.
Omaveloxolone is an Nrf2 activator being tested in the MOXIe clinical (NCT02255435) in Friedreich’s ataxia patients.
The study is divided in two parts, evaluating the efficacy, safety, and pharmacodynamics of omaveloxolone as an FA therapy. In part one, enrolled patients were randomly assigned to a placebo (control) group or to dose-escalation omaveloxolone groups to determine the treatment’s optimal dose. Part two was designed to confirm the drug’s efficacy and safety.
At IARC 2017, Lynch presented the results from the first part of the trial.
A total of 69 FA patients (average age upon study entry, 25.6 years; average age at diagnosis, 15.3 years) were randomized 3:1 to receive either omaveloxolone or placebo. Omaveloxolone was administered at dose levels of 5, 10, 20, 40, 80, 160, and 300 mg. Treatment was given once a day for a total of 12 weeks to patients in the therapy groups.
Multiple clinical assessments of muscular and neurological functions were performed in part one, allowing Lynch to report that “omaveloxolone induces Nrf2 and restores mitochondrial function.”
Optimal changes in pharmacodynamic parameters and drug efficacy were found in those given omaveloxolone at the 80 and 160 mg doses. According to Lynch, the top dose of 300 mg lacked additional benefit when compared to lower doses.
The 160 mg dose led to improvements of 3.8 points in the modified Friedreich’s Ataxia Rating Scale (mFARS) score when compared to baseline, and of 2.3 points relative to patients receiving a placebo.
mFARS “provides a way to measure disease progression over time,” Lynch said in an interview with Friedreich’s Ataxia News. “The average FA patient progresses about two points per year, depending on where they are in the disease and the severity of the disease, so one point of progression is about the amount of time that a person would typically progress in one to two years.”
Lynch considered the 3.8 point improvement seen with the 160 mg dose significant, saying “that much improvement, is quite an improvement.”
People in more advanced disease stages often develop a gait abnormality, called pes cavus, characterized by toes pointing down and high arched feet. Part one trial results showed that omaveloxolone at 160 mg led to greater benefits in patients without this musculoskeletal foot deformity — their mFARS score improved by 6.0 points compared to baseline and by 4.4 points relative placebo controls, when patients with pes cavus were removed from the analysis.
According to Lynch, at this point, the “meaning of the relatively greater improvement in people without pes cavus is unclear.”
Concerning safety, omaveloxolone was well-tolerated and had a “very acceptable adverse event profile,” Lynch said. The only reported adverse events were generally mild in severity.
Of note, “there were more upper respiratory infections in people treated with omaveloxolone. Why? We don’t know,” the researcher said, adding “apart from this, there were really almost no major adverse events attributed to the drug.”
Overall, results to date show that omaveloxolone at its optimal, 160 mg dose leads to improvements in neurological function as denoted by the mFARS score. They support a further investigation of omaveloxolone, set to take place in part two of the MOXIe trial.
The study is actively recruiting FA patients with mFARS scores between 20 and 80 at sites across the U.S., and in Austria, Australia, and the U.K. More information is available on its clinical trials.gov page.