FDA to Review Confirmatory Trial Proposal for Omaveloxolone

Reata Pharmaceuticals, along with a group of key opinion leaders and the Friedreich’s Ataxia Research Alliance (FARA), have proposed the launch of a study to confirm the effectiveness of omaveloxolone (RTA 408), the company’s investigational oral therapy for Friedreich’s ataxia (FA).

If accepted by the U.S. Food and Drug Administration (FDA) as a confirmatory trial of the therapy’s benefits, Reata is planning to use data from this study — which may be completed before the end of the year — to submit a new drug application (NDA) in early 2021 requesting the approval of omaveloxolone for FA.

Omaveloxolone is a small molecule activator of Nrf2, a protein known to control the activity of certain genes involved in mitochondrial function and energy production, which are impaired in people with FA.

The proposal came in response to concerns raised by the FDA at a Type C meeting regarding data from the second part of the company’s Phase 2 MOXIe trial (NCT02255435).

MOXIe aimed to investigate the safety, efficacy, and pharmacological properties of omaveloxolone in a group of FA patients.

In the first part of the study, 69 patients received increasing doses of the medication (5 to 300 mg daily) for 12 weeks, to determine the optimal dose of omaveloxolone. This was followed by a second part, in which 103 patients were randomly assigned to receive either 150 mg of omaveloxolone, or a placebo, once a day.

Top-line data after 48 weeks of treatment showed that omaveloxolone led to a 1.93-point improvement in the modified Friedreich’s ataxia rating scale (mFARS) — a measure of FA progression that has been endorsed by the FDA — compared to the placebo. Omaveloxolone was also found to be safe and well-tolerated, with reported adverse events being mild or moderate in severity.

Although the FDA did not express any concerns regarding the reliability of mFARS data, the agency stated that MOXIe findings are insufficient to support the marketing approval of omaveloxolone without additional evidence provided by a confirmatory study.

In preliminary comments for the meeting, the FDA said that Reata would have to conduct a second pivotal trial to obtain new mFARS data similar to the one reported in MOXIe so as to confirm the positive effects of omaveloxolone. Notably, a pivotal study is expected to provide data supporting regulatory approval of a treatment.

In response, the company, along with FARA and a group of key opinion leaders, argued that it would be difficult to carry out another pivotal study in FA, given the disorder’s slow progression, the small number of patients and trial investigators currently available to participate in studies, and limitations imposed by the COVID-19 pandemic.

The three parties also stated that conducting a new pivotal trial at this point would delay the availability of omaveloxolone, a potentially effective therapy to treat people with progressive FA who have no other treatment options.

The FDA recognized the unmet need of FA patients, reiterated its commitment to facilitate the development of omaveloxolone, and showed willingness to accept alternative options to meet regulatory standards.

Instead of a new pivotal clinical trial, Reata, FARA, and key opinion leaders proposed the launch of a crossover study involving patients who received the placebo in the second part of MOXIe and are currently being treated with omaveloxolone in the trial’s open-label extension study.

Because all patients received omaveloxolone and a placebo at different points in time, this means that each participant can be used as their own control. As a main goal, the new study would assess changes in mFARS from the time patients were given a placebo in the original trial until they started receiving omaveloxolone in the extension study, thereby generating independent data from that obtained in the second part of MOXIe.

The FDA acknowledged that a study with this design may be a valuable source of additional information, and has now asked the company to submit a formal proposal with further details.

“If the FDA accepts this approach, we expect to complete the crossover study as early as the fourth quarter of this year,” the company said. “Assuming that the FDA views the crossover study data as sufficiently positive to provide confirmatory evidence, our plan would be to submit an NDA during the first quarter of 2021.”

In turn, if the U.S. agency rejects the proposal or the results are not viewed as confirmatory, Reata stated it will re-consider launching a second pivotal study in FA, as requested by the FDA.

Regardless of the outcome with the FDA, the company stated in its latest financial and business update that it is already planning to submit applications requesting the approval of omaveloxolone outside the U.S.