BET Inhibitor Reverses Vascular Remodeling in Pulmonary Arterial Hypertension

The use of bromodomain and extra terminal motif (BET)-containing protein inhibitors, particularly those with dual binding affinity for both bromodomains of BRD4, warrants exploration as an effective treatment for patients with pulmonary arterial hypertension (PAH) to promote survival.

In the current study, 3 independent groups evaluated the efficacy of a clinically available BET inhibitor, RVX208, in experimental models of PAH. Results of the analysis were published in the American Journal of Respiratory and Critical Care Medicine.

Acknowledging that there is no current effective therapy to reverse vascular remodeling and inhibit right-sided heart failure in PAH, investigators sought to explore the effectiveness of the BET inhibitor RVX208 in experimental models of PAH. BRD4, which is the most extensively evaluated BET, is involved in a variety of diseases, including cancer, cardiovascular disease, and PAH. BRD4 is upregulated in pulmonary epithelial cells and smooth muscle cells that have been isolated from patients with PAH, mediating expression of FoxM1 and its transcriptional target PLK1 in PAH-smooth muscle cells.

The investigators demonstrated that treatment with RVX208 was associated with normalization of PAH pulmonary vascular smooth muscle cells and epithelial cells, as evidenced by inhibited cell proliferation and inflammation, induced apoptosis, and balanced transforming growth factor-beta/bone morphogenetic protein signaling as shown in a series of in vitro studies. They used 3 rat PAH models (Sugen 5416 hypoxia [SuHx], monocrotaline/aortacaval shunting [MCT/S], and pulmonary artery banding) to evaluate the therapeutic benefits and safety of RVX208.

At a clinically relevant dose, RVX208 improved hemodynamics and reversed pulmonary vascular remodeling in both SuHx and MCT/S rats. Of note, treatment with RVX208 in pulmonary artery banding rats improved cardiac function and increased right ventricular hypertrophy.

The researchers concluded that additional studies are warranted to compare the efficacy of different BET inhibitors in models of PAH. To date, RVX208 is the only BET inhibitor that has been evaluated in phase 3 clinical trials.

Reference

Dai Z, Zhao Y-Y. BET in pulmonary arterial hypertension: exploration of BET inhibitors to reverse vascular remodeling [published online May 21, 2019]. Am J Respir Crit Care Med. doi:10.1164/rccm.201904-0877ED