The sample size of six to ten patients randomized to omaveloxolone and two to three randomized to placebo for safety controls at each dose level was based upon a traditional dose-escalation design. The small number of patients at each dose was not expected to fully characterize safety, efficacy, or pharmacodynamics, but rather to inform the data safety monitoring board and Reata of the appropriate dose to select for future study. The optimal dose of omaveloxolone associated with robust Nrf2 induction and improvement in markers of mitochondrial function was determined to be 160 mg. At this dose, significant, placebo-corrected improvements were noted in Nrf2 biomarkers.
Clinical activity was assessed under maximal and submaximal conditions. The maximal exercise and 6-minute walk tests were used to determine peak workload and 6-minute walk distance, which reflect exercise capacity during maximal exertion. The submaximal exercise test measured mitochondrial function under submaximal conditions that reflect exertion levels during normal activities of daily living. Heart rate and blood lactate levels increase as mitochondrial function and aerobic capacity are depleted, and these were the two key parameters that were assessed during the submaximal exercise test.
Clinical activity was observed during submaximal but not maximal exercise testing. Omaveloxolone did not improve peak work or 6-minute walk distance versus placebo, which were the primary and secondary endpoints of the trial. However, in the submaximal exercise test, which is a more sensitive assessment of mitochondrial function, a significant lowering of heart rate and blood lactate levels versus placebo was observed. At Week 12, patients treated with 160 mg of omaveloxolone demonstrated a placebo-corrected reduction in heart rate of 12.0 beats per minute (p=0.01) and blood lactate of 1.3 mM (p=0.04) at the end of the test (omaveloxolone, n=10; placebo, n=13). The decrease in heart rate and lactate levels produced by omaveloxolone are indicative of improved mitochondrial function.
The trial was overseen by an independent data safety monitoring board, which identified no safety concerns.
“In patients with mitochondrial disease, an important goal of interventional therapy is lowering perceived effort during every day activities of daily living,” said Professor
Omaveloxolone is an experimental, oral, once-daily activator of Nrf2, a transcription factor that induces molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling. The
Reata is a clinical-stage biopharmaceutical company that develops novel therapeutics for patients with serious or life-threatening diseases by targeting molecular pathways involved in the regulation of cellular metabolism and inflammation. Reata’s two most advanced clinical candidates, bardoxolone methyl and omaveloxolone, target the important transcription factor Nrf2 that promotes the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling.
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Source: Reata Pharmaceuticals, Inc.