IRVING, Texas—Positive developments for rare diseases are often frustratingly few and far between, as industry engagement and low patient numbers for trials make advancements difficult. But for one such disease, Friedreich’s ataxia (FA), there’s cause for optimism: encouraging trial data that could lead to the first FDA-approved treatment.
The data in question come from Reata Pharmaceuticals Inc.’s registrational Part 2 portion of its Phase 2 MOXIe trial of omaveloxolone (omav) in patients with FA. The study is an international, multicenter, double-blind, placebo-controlled, randomized trial that enrolled 103 FA patients at 11 sites in the United States, Europe and Australia, making it the largest global, interventional FA study ever. Omaveloxolone is an experimental, oral, once-daily activator of Nrf2, a transcription factor that plays a role in the restoration of mitochondrial function, reduction of oxidative stress and inhibition of pro-inflammatory signaling. The compound has received orphan drug designation from both the FDA and the European Commission for the treatment of Friedreich’s ataxia.
Patients received 150 mg of either omaveloxolone or placebo, and the primary analysis population included patients without pes cavus, a musculoskeletal foot deformity that occurs in more than half of FA patients and can inhibit a patient’s ability to perform certain components of the modified Friedreich’s Ataxia Rating Scale (mFARS) exam. mFARS is a physician-assessed neurological rating scale for measuring disease progression, and includes four sections: speaking and swallowing, upper limb coordination, lower limb coordination, and standing and walking. The FDA has deemed mFARS an acceptable primary endpoint to assess omaveloxolone’s efficacy in FA patients.
Roughly 5,000 individuals in the United States suffer from FA, with global estimates at 22,000.
“Until now, Friedreich’s ataxia has proven intractable to treatment. A number of interventional studies have been conducted in FA, and none have demonstrated a significant therapeutic effect on the progression of this disease. As a consequence, there are no FDA-approved therapies for patients with FA,” Warren Huff, president and CEO of Reata, said in a conference call regarding the MOXIe data. “Friedreich’s ataxia is a disease of mitochondrial dysfunction. The underlying cause of FA is a mutation in the gene for frataxin, a mitochondrial protein that helps assemble the iron-sulfur clusters that are necessary for the production of cellular energy in the form of ATP. In FA, mitochondrial respiration is suppressed, and energy production is dramatically reduced. This affects the function and viability of nerve cells … these impairments manifest clinically as a worsening in neurologic function that correlates with reduced whole-body respiration.”
“Friedreich’s ataxia researchers have established that Nrf2, the target of omav, is suppressed, and Nrf2 signaling is impaired in FA patients,” he added. “This contributes to mitochondrial dysfunction and reduced cellular energy production.”
Omaveloxolone treatment led to a statistically significant, placebo-corrected 2.40 point improvement in mFARS relative to placebo after 48 weeks of treatment. (An improvement consists of a decrease in a patient’s mFARS rating.) Patients in the omav arm saw a mean mFARS improvement of -1.55 points from baseline, while patients in the placebo arm saw a mean mFARS worsening of +0.85 points from baseline. The observed improvements were time-dependent, increasing over the course of the treatment timeframe and showing the largest improvement after 48 weeks of treatment.
Patients with pes cavus also saw improved mFARS scores. Factoring these patients into the analysis at 48 weeks, the mean improvement was 1.93 points.
To put this improvement in perspective, Dr. Colin Meyer, chief medical officer and executive vice president of product development at Reata, noted in a conference call that “Patients treated with omav for 48 weeks regained an amount of function that is typically lost in the course of one year.”
“The results of MOXIe represent a truly historic moment for the patients, families, and caregivers that comprise the Friedreich’s ataxia community,” said Ronald Bartek, president of the Friedreich’s Ataxia Research Alliance (FARA). “Based on the results reported today for omaveloxolone, we are hopeful that our community will finally have its first approved therapy that can slow this relentlessly progressive disease. We are extremely proud of, and grateful for, the FA community including all those who have participated in this clinical trial and in the natural history study important in designing the trial. We are also grateful to the clinical teams who conducted the trial and to our Reata colleagues. We look forward to continuing the Reata-FARA partnership as we work in pursuit of approval of the first FA therapy.”
Omaveloxolone was generally well tolerated, with only four omaveloxolone patients (8 percent) and two placebo patients (4 percent) discontinuing due to an adverse event (AE). Adverse events were generally mild to moderate in intensity. Among the most common AEs was an increase in aminotransferases, which Reata notes is related to the restoration of mitochondrial function, adding that “In MOXIe, the aminotransferase increases were associated with improvements (reductions) in total bilirubin and were not associated with liver injury.”
Huff remarked in the company’s conference call regarding the MOXIe results that Reata intends to meet with the appropriate regulatory bodies, including the FDA, to discuss how to move forward. The company is also exploring the idea of an early-access program in the U.S., he added.
And Reata isn’t putting all its eggs in the FA basket, either.
“We believe that the results are also important because they provide proof of concept that improvements in mitochondrial function from omav treatment may provide a therapeutic benefit in a number of other neurodegenerative diseases,” Huff commented in the call. “The processes of neuroinflammation and impaired energy production that Nrf2 activation can resolve occur in other regions of the brain, causing other rare and debilitating neurodegenerative diseases. We’ve studied omav and related molecules and have observed promising preclinical results in models of Huntington’s disease, ALS, Parkinson’s disease, Alzheimer’s disease and epilepsy. We plan to develop omav clinically for one or more of these diseases.”