Reata Pharmaceuticals has presented the first results of its LARIAT Phase 2 study, a trial assessing the efficacy and safety of experimental therapy bardoxolone methyl in the treatment of pulmonary arterial hypertension (PAH). The report, titled “Initial Data Report from ‘LARIAT’: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy,” was presented at the annual meeting of the American College of Chest Physicians (CHEST 2015) in Montreal, Canada, and showed findings that the company called “very encouraging.”
The presentation slides can be seen here: http://reatapharma.wpengine.com/wp-content/uploads/2015/10/LARIAT_CHEST_Final.pdf.
Ronald Oudiz, MD, Professor of Medicine, David Geffen School of Medicine at UCLA, Director of the Pulmonary Hypertension Center and a Faculty Cardiologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, presented the data.
Bardoxolone methyl is an antioxidant inflammation modulator (AIM) drug that targets important inflammatory pathways involved in regulating the immune response and oxidative damage. In previous pre-clinical studies, it has been found to inhibit NF-κB, a protein essential to the regulation of the immune response to infection. The faulty regulation of this protein, such as in PAH where it has been found to be increased, has been linked to pathogenesis processes such as inflammation and autoimmune responses. Moreover, this compound has been shown to activate Nrf2, a protein involved in the regulation of antioxidant proteins with protective effects against inflammation and oxidative damage. In this way, the drug has the potential to suppress reactive oxygen species (ROS) production that is also involved in inflammatory processes in PAH, reduce fibrosis, and attenuate the effects of mitochondrial damage found in PAH patients by increasing cellular respiration and energy production.
The LARIAT study aims to assess the tolerability, safety and efficacy of Bardoxolone methyl relative to a placebo control group in patients with PAH on stable background therapy. The researchers intend to determine recommended dose range, and efficacy of the compound was determined through exercise capacity using the variable 6-minute walk distance (6MWD). Patients were randomized in groups, receiving once a day placebo or bardoxolone methyl at doses of 2.5, 5 or 10 mg for 16 weeks of treatment.
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Analysis of efficacy revealed that the compound increased 6MWD throughout the dose range. Patients treated with the drug showed a significantly increase of 6MWD: 22 meters compared to baseline treatment and 21.4 meters of placebo-corrected difference. Bardoxolone methyl was able to achieve a result that other therapies struggle to reach. In patients with 6MWD baseline values greater than 450 meters, other therapies have failed to achieve significant changes, but in the Bardoxolone methyl trial the changes in patients with 6MWD values higher or lower than 450 meters were similar. Researchers attribute these improvements in exercise capacity to weight loss, as patients in the treatment groups lost 3 kilograms and experienced a reduction in muscle inflammation, measured by decreased values of creatine kinase.
In patients with a connective tissue disease co-morbidity, the therapeutic effect was higher, which usually is not observed in such patients. The patients showed an increase in 6MWD of 30 meters when compared to baseline and a placebo-corrected increase of 44 meters. No serious adverse effects were reported and more discontinuations of treatment were observed in the placebo group. Patients with kidney disease did not experience fluid retention events in the LARIAT study. Dose of medication did not change the tolerability or safety profiles. These results reveal a potential for increased muscular function, and are specifically important to the sub-set of patients with connective tissue disease, a group with unmet therapeutic needs.
“The initial data from LARIAT are very encouraging and indicate that bardoxolone methyl’s novel mechanism of action may provide a new approach to PAH therapy,” said Colin Meyer, MD, Reata’s Chief Medical Officer. “On the basis of these data and recent interactions with the FDA, we are excited to announce that we are planning to initiate a phase 3 study of bardoxolone methyl in patients with CTD-PAH in 2016.”