Reata Pharmaceuticals, Inc., a biopharmaceutical company based in Irving, Texas, recently announced positive data from the Phase 2 clinical trial LARIAT assessing the company’s candidate product bardoxolone methyl for pulmonary arterial hypertension (PAH). The results were recently presented by Dr. Ronald Oudiz, 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, at the 2015 American College of Chest Physicians (CHEST) annual meeting in Montreal, Canada. The presentation was entitled “Initial Data Report from ‘LARIAT’: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy.”
PAH is a life-threatening condition characterized by the increase of blood pressure in the pulmonary arteries that supply blood to the lungs that can lead to difficulties in breathing and right-sided heart failure. It is estimated that PAH affects 15,000 to 20,000 individuals in the United States with 60% to 80% of the patients dying within five years after being diagnosed. The second most common subtype of PAH is connective tissue disease-associated PAH, where PAH pathology is linked to autoimmune conditions like scleroderma.
Bardoxolone methyl is an oral, once daily, antioxidant inflammation modulator (AIM) which has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for PAH treatment. This experimental drug targets a pathway linked to a protein called Nrf2, which regulates the expression of genes that can increase anti‐inflammatory mediators and the cellular antioxidant content. The drug is also thought to reduce the production of enzymes linked to fibrosis and tissue remodeling.
The randomized, dose ranging, Phase 2 clinical trial LARIAT (A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Pulmonary Hypertension; NCT02036970) evaluated the efficacy, safety and tolerability of bardoxolone methyl in 24 PAH patients under stable background therapy.
Researchers showed that treatment with bardoxolone methyl (doses of 2.5, 5 or 10 mg) for 16 weeks increased the patient’s exercise capacity (assessed by the 6-minute walk distance [6MWD] test). Furthermore, patients also experienced an improvement in metabolic parameters such as a mean weight loss of 3 kg in comparison to patients in the placebo group, and a reduction in creatine kinase levels, a marker of muscle inflammation. In particular, patients with connective tissue disease-associated PAH, in whom PAH therapies are usually less effective, also experienced an improvement in the 6MWD test in comparison to the placebo group.
In terms of safety, bardoxolone methyl was found to be well-tolerated by the patients, with no report of serious adverse events associated with the treatment.
“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,” said Reata’s Chief Medical Officer Dr. Colin Meyer in a press release provided to Scleroderma News.
“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,” he said.
“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 [connective tissue disease]-PAH in 2016,” concluded Dr. Meyer.
Reata is planning to perform additional studies in other subtypes of PAH.