Reata Pharmaceuticals Inc.'s surprise victory in the pivotal, second part of the phase II study called Moxie with Nrf2 activator omaveloxolone in patients with Friedreich's ataxia (FA) energized Wall Street and sharpened appetites for data due shortly with another candidate in the class, bardoxolone methyl, in the works for Alport syndrome (AS).
Shares of the Irvine, Texas-based firm (NASDAQ:RETA) rocketed by almost 57%, or $57.33, to close Tuesday at $157.92 after FA results were disclosed from the experiment called Moxie, which met its primary endpoint of change in the modified Friedreich's Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks. 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, and Reata plans to talk with regulators in the U.S. and elsewhere about submitting omaveloxolone for approval.
Chief Medical Officer Colin Meyer said the FDA has "commented in writing that mFARS could serve as a basis for approval, either accelerated or full approval, and that determination will be made on the basis of the data which, in our view, [are] quite strong. Based upon us showing activity in patients with pes cavus [highly arched foot, often associated with FA], we think it's likely that those patients would be on the label," he added during a conference call with investors. Moxie is the first study to demonstrate a significant improvement in neurological function in patients with FA.
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 1-to-1 to 150 mg of omaveloxolone or placebo. The primary analysis population included patients without pes cavus (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.
A physician-assessed neurological rating scale used to measure FA disease progression, mFARS includes four sections that measure the patient's performance of activities such as speaking and swallowing, upper limb coordination, lower limb coordination, and standing and walking. Patients treated with omaveloxolone experienced a mean improvement in mFARS of -1.55 points from baseline, while those on placebo experienced a mean worsening in mFARS of +0.85 points from baseline. The placebo-corrected improvements in mFARS turned out to be time-dependent, increasing over the course of treatment with the largest improvement observed after 48 weeks.
Omaveloxolone treatment also improved the mFARS scores of patients with pes cavus. When subjects with the condition are included in the analysis of the mFARS scores at week 48, the drug produced a mean statistically significant, placebo-corrected 1.93-point improvement in mFARS (n=103; p=0.034). Omaveloxolone treatment also improved several secondary endpoints, and was well-tolerated. Four (8%) omaveloxolone patients and two (4%) placebo patients discontinued due to an adverse event (AE), and AEs were generally mild to moderate in intensity, and the most common AEs (>20%) observed more frequently compared to placebo were headache, nausea, increased aminotransferases, fatigue and abdominal pain. In Moxie, the aminotransferase increases were associated with improvements (reductions) in total bilirubin and were not associated with liver injury. Overall, the rate of serious AEs was low, with three patients in each group reporting SAEs while on drug. Two more omaveloxolone-treated patients reported SAEs about two weeks after receiving their final dose.
Analyst: 'Real pro move'
SVB Leerink analyst Joseph Schwartz noted that "prior to the top-line results, investors had cited two uncertainties for Moxie," including a post hoc analysis that identified pes cavus patients, and their "negative drag on the results," along with Reata's decision to continue to enroll pes cavus into the second part of the trial. "With today's outcome uplifting the overhang that existed, we now turn to [the study called Cardinal], a trial that has also implemented findings from post hoc analyses." Backers of the company "may feel more confident on the expected Cardinal readout" with bardoxolone in AS, he wrote in a report.
Last week, Reata agreed to pay former partner Abbvie Inc., of North Chicago, $330 million plus royalties to reacquire ex-U.S. development, manufacturing and commercialization rights for both Nrf2 activators as well as other next-generation candidates in the class. Rights to certain Asian markets for bardoxolone remain licensed to Kyowa Hakka Kirin Co. Ltd., of Tokyo. "The recent financial engineering executed by management looks like a real pro move," Schwartz said, maximizing the impact of the latest news to shareholders. "Detailed data disclosure is due at future medical meetings and publications will be interesting, but we are convinced by the robust improvements seen on multiple concordant measures, so we are increasing our probability of success to 90%," and raising the price target to $230 with an outperform rating. (See BioWorld, Oct. 11, 2019.)
FA is a genetic, progressive, neurodegenerative movement disorder, with a typical age of onset between 10 and 15 years, according to the National Organization for Rare Disorders. First symptoms may include unsteady posture, frequent falling, and progressive difficulty in walking due to impaired ability to coordinate voluntary movements. Affected people often develop slurred speech and scoliosis, along with foot deformities. The disease is also often associated with cardiomyopathy. AS is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the ears and eyes. It occurs in three types, with X-linked the most common.