Reply to Chen et al.: BET Signaling: A Novel Therapeutic Target for Pulmonary Hypertension?

From the Authors:

We thank Chen and colleagues for their interest in the BET (bromodomain and extraterminal motif) inhibitor as a promising therapeutic target for pulmonary arterial hypertension (PAH). As mentioned by Chen and colleagues, bringing a new compound into clinical practice stands on a solid scientific foundation not only with regard to potential drug efficacy but also with regard to anticipated side effects.

In the past two decades, we have witnessed the development of more than 10 drugs either enhancing pathways involved in vasodilation (nitric oxide–cyclic guanosine monophosphate and prostacyclin) or antagonizing vasoconstriction (endothelin) in addition to other pleiotropic effects. Because these processes are not unique for the pulmonary circulation, the use of these drugs may also be accompanied by increased systemic vasodilation, which at a certain level can be expected to reduce coronary to right ventricular (RV) perfusion gradient, increase neurohormonal activation, and diminish left ventricular end-diastolic pressures, ultimately promoting coronary and systemic hypoperfusion, increased right-to-left shunting (in case of intracardiac shunt), and further RV dysfunction through an enhanced septal shift in a setting of ventricular interdependence and pericardial constraints (1). Fortunately, except for the combination of sildenafil and riociguat (2), most studies confirmed that the limited effect of these vasodilators on systemic blood pressure was presumably offset by the pulmonary vasodilation resulting in increased cardiac output. Similarly, the detrimental effects of more recent therapeutic targets on the RV may easily be overlooked when the compound under investigation markedly improves the PAH pulmonary vasculature. Therefore, recent recommendations suggest that any new drug developed for PAH should be tested in preclinical models for its specific effects also on the pressure-overloaded RV (1, 3).

In humans, RV function is most commonly assessed using right heart catheterization, echocardiography, and cardiac magnetic resonance, whereas circulating biomarkers can serve as a noninvasive surrogate marker (4). In our recently published multicenter preclinical validation of BET inhibition for PAH (5), we documented that RVX208, a clinically available BET inhibitor, mitigates proproliferative, prosurvival, and proinflammatory pathways in cultured PAH vascular cells, leading to significant pulmonary histological and hemodynamic improvements in diverse rat models with experimentally induced PAH. Not surprisingly, BET inhibition was associated with significant hemodynamic improvements, confirming previous results documenting the beneficial effects of BRD4 inhibition on RV function (6) and coronary perfusion (7). More importantly, and as previously recommended (1, 3), we specifically studied the effects of RVX208 treatment in RV pressure load induced by pulmonary artery banding. Interestingly, RVX208 was associated with an increase in RV stroke volume, work, and power, suggesting some improvements in RV function independent of the afterload, confirming the safety of the drug during RV compromise in rats.

Although inhibition of BET impacts diverse cellular functions and interferes with proproliferative, prosurvival, procalcific, and proinflammatory pathways, to name a few, none of those were anticipated to result in changes in systemic blood pressure. Importantly, in the most recent cardiovascular outcomes study in 2,425 subjects over 2 years, apabetalone was not associated with any changes in blood pressure (8).

Therefore, the published data support the establishment of a clinical trial with RVX208 in patients with PAH specifically addressing the safety of BET inhibition in this specific study population. Based on extensive preclinical and human data, RVX-208 is not expected to negatively influence RV function or systemic hemodynamics in human PAH.