Reata Pharmaceuticals, a clinical-stage biopharmaceutical company, recently presented results from the LARIAT trial investigating the drug bardoxolone methyl in patients with pulmonary arterial hypertension (PAH). The study entitled “Bardoxolone Methyl Evaluation in Patients with Pulmonary Arterial Hypertension (PAH)” was presented in the 2015 American College of Chest Physicians (CHEST) annual meeting by Ronald Oudiz, M.D., Professor of Medicine, Director of the Pulmonary Hypertension Center and a Faculty Cardiologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Southern California and David Geffen School of Medicine at UCLA.
To view and download slides from the presentation, click here.
Bardoxolone methyl is an investigational, oral antioxidant inflammation modulator (AIM), which, by activating the master transcription factor Nrf2, induces the production of proteins with antioxidant, anti-inflammatory, and cytoprotective properties. It also reduces oxidative stress, promotes energy metabolism and mitochondrial function, and reduces inflammation and inflammatory signaling, namely by reducing mitochondrial reactive oxygen species (ROS) and inhibiting the NF-κB, important activators of the inflammatory response in PAH. Importantly, bardoxolone methyl reduces the production of enzymes important in pulmonary fibrosis and tissue remodeling, an important step in the pathogenesis of PAH.
In the LARIAT trial, patients were under standard PAH therapies at baseline and throughout the study. Treatment with bardoxolone methyl for 16 weeks (2.5 up to 10 mg) resulted in increased patients’ 6-minute walk distance (6MWD, a performance-based function test that measures the exercise capacity of patients during a total of six minutes while walking on a hard, flat surface). PAH patients treated with bardoxolone methyl exhibited a significant increase in 6MWD mean when compared to the results at both baseline (22 m) and placebo-corrected difference of 21.4 m. These alterations in patients’ 6MWD performance was accompanied by improved metabolic performances, including weight loss (in comparison to placebo treated patients, bardoxolone methyl patients exhibited up to 3 kg of weight loss) and decreased expression of creatine kinase, a marker of muscle inflammation.
A group of PAH patients that usually display less favorable responses to PAH therapies, patients with connective tissue disease associated PAH (CTD-PAH), also experienced significant improvements in their 6MWD performance.
Bardoxolone methyl was well tolerated and with no serious drug-related adverse events reported in the LARIAT trial. Notably, contrary to previous observations where patients with advanced kidney disease experienced fluid retention events, no such events were observed in the trial. Additionally, no meaningful changes in blood pressure, heart rate, other measures of fluid status, and echocardiographic parameters were registered.
Currently, Reata Pharmaceuticals is planning an initial phase 3 study in CTD-PAH patients who will undergo a 24-week treatment. The trial’s primary endpoint is to measure patients’ 6MWD. This trial is estimated to begin in 2016 and other trials in another subtypes of PAH are currently being assessed.
Colin Meyer, M.D., Reata’s Chief Medical Officer commented in a press release, “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. Clinically, these effects may acutely translate to increased muscular function, and as we have observed in preclinical models, may reduce pathological cardiovascular remodeling in the long-term. This pharmacology is particularly meaningful to PAH patients with connective tissue disease. These patients have autoimmune disease that causes their PAH, and their inflammatory disease processes often involve more remodeling than other subtypes. This explains why these patients often do not respond well to approved vasodilator therapy relative to idiopathic PAH patients and represent a subset of the PAH population with significant unmet need. 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.”