Reata Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company based in Irving, Texas, recently announced that it will present encouraging data on bardoxolone methyl for pulmonary arterial hypertension (PAH) at the upcoming 2015 American College of Chest Physicians (CHEST) annual meeting in Montreal, Canada.
PAH is a life-threatening condition characterized by the increase of blood pressure in the pulmonary arteries that supply blood to the lungs. The disease can lead to difficulties in breathing, right-sided heart failure and eventually death. It is estimated that PAH affects 15,000 to 20,000 individuals in the United States, predominantly middle‐aged women, and leads to a high mortality rate where 60 to 80% of the patients succumb to the disease within five years after diagnosis. The current available therapies only offer symptomatic improvement, mainly by attenuating vasoconstriction. There is therefore an urgent need for new, effective PAH therapies.
Bardoxolone methyl is an oral, once daily, antioxidant inflammation modulator (AIM) that has been granted orphan drug designation by the US Food and Drug Administration 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. Preclinical data results indicate that the activation of the Nrf2 pathway may also control multiple genes that stimulate cellular energy production within the mitochondria (cellular organelles where the energy for the body is produced) and facilitates mitochondrial efficiency and homeostasis. Bardoxolone methyl is thought to directly target inflammation and the mitochondrial dysfunction observed in PAH patients, having the potential to interfere with aspects of the PAH pathology that are not significantly mitigated by the current available therapies.
The second most common subtype of PAH is connective tissue disease‐associated PAH, where PAH pathology is linked to autoimmune conditions like lupus and scleroderma. Interestingly, bardoxolone methyl and analogs of the compound have been shown to be efficient in preclinical models of both lupus and scleroderma.
The efficacy, safety and tolerability of bardoxolone methyl has now been assessed in a randomized, dose ranging, Phase 2 clinical trial called LARIAT (A Dose‐Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Pulmonary Hypertension; NCT02036970) in patients with PAH who are under stable background therapy. The efficacy of the drug was determined through exercise capacity by the 6-minute walk distance (6MWD) test, in order to establish whether bardoxolone methyl could complement the already approved PAH therapies.
The data to be presented at the upcoming CHEST meeting is based on the analysis of the initial three patient cohorts (24 patients in total) who have received either a placebo or bardoxolone methyl for a period of 16 weeks. All patients enrolled were stable on at least one approved PAH therapy. The 6MWD test was performed at baseline and at every 4 weeks.
“We are excited to present top‐line data from our Phase 2 LARIAT study. Bardoxolone methyl has the potential to be a first‐in‐class treatment for PAH that impacts aspects of the disease that are unaddressed by current therapies, including inflammation and mitochondrial dysfunction. Clinically, these manifest as markedly reduced exercise capacity and fatigue, despite optimal treatment with available therapies. In preclinical models, we have demonstrated that bardoxolone methyl directly improves mitochondrial function and energy production in the skeletal muscle while not affecting systemic hemodynamics,” said Reata’s Chief Medical Officer Dr. Colin Meyer in a press release. “This profile is unique and should complement available therapies, all of which have primary vasodilatory effects. On the basis of the emerging preclinical and clinical data, we are further expanding our development program and plan to study bardoxolone methyl in other forms of pulmonary hypertension, including pulmonary hypertension caused by interstitial lung disease.”
Findings from the study will be presented on October 27, 2015 in the Palais des Congrès de Montréal Convention Center (Room 513ef), within the session Late‐Breaking Abstracts (8:45 to 10:00 am), by Dr. Ronald Oudiz, Professor of Medicine, David Geffen School of Medicine at UCLA. The presentation is entitled “Initial Data Report from ‘LARIAT’: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy.”