Reply to Piquereau and Perros and to Pullamsetti and de Jesus Perez

From the Authors:

In a recent issue of the Journal, we reported results from the first multicenter, preclinical study to show the therapeutic benefits of the BET (bromodomain and extraterminal motif) inhibitor RVX208 in multiple animal models of pulmonary arterial hypertension (PAH) (1). In their letter to the editor, Piquereau and Perros raised concerns about the potential cardiotoxic effects of BET inhibitors in patients with PAH based on published data demonstrating structural and functional alterations of the heart in healthy rodents treated with the pan-BET inhibitor I-BET-151 (2). A contrast must be drawn between highly potent, nonselective BET inhibitors such as I-BET-151, which are under development for oncology indications, and RVX208, which is a BD2-selective BET inhibitor with lower potency that has an excellent cardiovascular (CV) safety profile to date. A series of phase 2 studies evaluating RVX208 in a total of 789 patients with CV disease recently demonstrated a >40% reduction in major CV events (3). RVX208 is currently being evaluated in a phase 3 clinical trial involving 2,425 patients with high-risk type 2 diabetes and coronary artery disease (ClinicalTrials.gov identifier: NCT02586155). This study is being monitored by an independent data and safety monitoring board, which recommended that the study should continue as per protocol. To date, the total exposure in patients with high-risk CV disease is approaching 2,000 subjects, with no heart failure signal identified. To ensure the safety of the drug in the context of right ventricular dysfunction, we conducted experiments in a rat model of increased ventricular afterload induced by pulmonary artery banding. Treatment with RVX208 was not accompanied by deleterious effects, and, on the contrary, promoted the ventricular response to increased afterload (1). Combined, these results affirm a favorable safety profile of RVX208 for use in patients with PAH and PAH-associated right ventricular dysfunction and support the establishment of a clinical trial. Finally, as pointed out by Pullamsetti and de Jesus Perez, a comprehensive understanding of how domain- and isoform-selective BET inhibition can regulate specific transcriptional and biological responses will further refine its applications in the clinical arena.