After a long and bumpy road to approval, Reata Pharmaceuticals Inc. is to roll out the first treatment for Friedreich’s ataxia (FA) in the U.S. for patients aged 16 years and older after the FDA gave its anti-inflammatory Skyclarys (omaveloxolone) the green light.

The company anticipates that patients will have access to the drug, which has also earned a rare pediatric disease priority review voucher, as early as May or June this year.

The news likely came as somewhat a surprise to investors, as shares of the Plano, Texas-based company’s stock (NASDAQ:RETA) unexpectedly plunged the day before the FDA’s decision, following reports that Billy Dunn, director of the FDA’s Office of Neuroscience, was stepping down, prompting SVB Securities analyst Joseph P. Schwartz into proposing a decision had likely already been made. 

FA is a rare, degenerative neuromuscular disorder, which begins in childhood and is usually caused by a mutation in the frataxin gene, resulting in damage to the spinal cord, peripheral nerves and cerebellum, causing unsteady movements and loss of sensation due to nerve injury.

In premarket trading Reata’s shares were up 173% on the news.

Omaveloxolone was awarded fast-track status by the FDA in November 2021 and it also has orphan drug and rare pediatric disease designations for the disease. 

Through its mechanism of action of activating nuclear factor erythroid-2 related factor 2 (Nrf2), orally administered omaveloxolone is designed to induce molecular pathways to resolve inflammation by restoring mitochondrial function, reduce oxidative stress and inhibit pro-inflammatory signaling. 

Reata and the FDA have gone back-and-forth many times on the drug’s development path. Back in August 2020, the FDA was not convinced that the Moxie part 2 of the phase II results (which was the trial used to support the NDA, along with additional supporting data from the part 1 phase II Moxie study and Moxie extension trials), would support approval and asked for more evidence that “lends persuasiveness” to the results.  

Moxie part 2 had gained the agency’s sign-off regarding its primary endpoint: improvement on the modified Friedreich Ataxia Rating Scale (mFARS). Data released in 2019 revealed that patients given omaveloxolone at 150 mg per day turned up a statistically significant, placebo-corrected 2.4-point improvement in mFARS (p=0.014). Given once daily, the treatment proved generally well tolerated. 

The second part of the international, multicenter, double-blind, placebo-controlled, randomized study enrolled 103 patients with FA at 11 study sites in the U.S., Europe and Australia, making it the largest global, interventional study ever conducted in FA. Patients were randomized one to one to 150 mg of omaveloxolone or placebo. The primary analysis population included patients without pes cavus (highly arched foot, often associated with FA; n=82), which can interfere with the patient's ability to perform some components of the mFARS exam. Safety analyses were evaluated in the whole randomized population. 

However, in November 2020, the agency said it had completed an internal review of the baseline-controlled study’s results and concluded that they did not strengthen the part 2 data. It proposed additional exploratory analyses using patients randomized to placebo during the study, even though it believed the potential to strengthen the results was questionable due to the small number of patients available for analysis. 

The company presented the FDA with an updated delayed-start analysis of the Moxie extension data using patient data from the clinical outcome measures in Friedreich’s ataxia study (FA-COMS) as controls, and an analysis of the relevance of Nrf2 to the pathophysiology of the disease.  

After accepting Reata’s NDA in May 2022 along with the additional analysis, the U.S. FDA announced that it would be extending the PDUFA date (originally set as Nov. 30, 2022) by three months to give it time to fully analyze the new data. 

Next steps

Speaking in a conference call following the FDA’s approval, Reata stated that the Moxie extension study would continue, so that the company could obtain more long-term data. 

Meanwhile, the company plans to seek approval in Europe, where omaveloxolone has orphan drug designation, in 2023. However, the EMA wants to see data from patients younger than 16 years old. Speaking in a conference call, the company said it would be working with the EMA on plans to conduct a study in children aged 6 to 16 years (and potentially younger). Meanwhile, it also wants to sit down with the FDA to discuss a potential label expansion in pediatric patients.