04 February 2019

The BRD4 Inhibitor Apabetalone (RVX-208) Improves experimental PAH in Sugen/hypoxia rat model

Rationale:

Pulmonary arterial hypertension (PAH) is a proliferative remodeling disease characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis. The upregulation of Bromodomain-containing 4 (BRD4) in lungs, distal pulmonary arteries and PASMC of patients compared to control as well as in rat Sugen/Hypoxia model may lead to this phenotype of the disease. Apabetalone is a first-in-class orally active inhibitor of Bromodomain and extraterminal domain (BET) transcriptional regulators, including BRD4. Therefore, we hypothesized that inhibition of BET with Apabetalone reverses PAH.

Methods and Results:

In vitro, human PAH-PASMC treated with Apabetalone (10 to 50uM) showed less proliferation than vehicle-treated cells (n=4, p<0.05, Ki-67 immunostaining). This decrease in proliferation was associated with greater amount of apoptosis (n=4-5, p<0.01, Annexin V staining). In vivo, using unbiased methodologies (randomization, blinding approaches), we showed that Apabetalone administered orally alone or with standard of care (Macitentan and Tadalafil) in Sugen/Hypoxia PAH rats significantly decreased mean pulmonary artery and right ventricle systolic pressures and improved cardiac output and stroke volume (all p<0.05, n=5-10, right heart catheterization). Ex vivo experiments showed that Apabetalone significantly decreased vascular remodeling, decreased proliferation and increased apoptosis in PAH-PASMC compared to vehicle (all p<0.05, n=6-10, Elastica Van Gieson, Ki-67 and TUNEL staining). Mechanistically, Apabetalone effects are associated with FOXM1 downregulation (a transcription factor implicated in PAH development) (p<0.05 n=4-10) leading to a decrease in Plk1, IL6 and Mcp1 expression (qRT-PCR). These findings were all duplicated independently by the Netherland PAH consortium.

Conclusion:

Overall, we demonstrated that Apabetalone alone and in combination with SOC resulted in a significant improvement of hemodynamic and RV function in experimental PAH. Given that Apabetalone is in a phase 3 clinical trial cardiovascular disease, our study supports the development of an early proof of concept clinical trial in PAH patients

 

Key Contributors

Eve Tremblay 1, Alice Bourgeois 1, Sandra Martineau 1, Marie-Claude Lampron1, Ravi Jahagirdar 2, Ewelina Kulikowski 2, Olivier Boucherat 1, Steeve Provencher 1, Sébastien Bonnet 1: 1 Pulmonary hypertension research group CRIUCPQ, Québec, Qc, Canada 2 Resverlogix Corp, Calgary, AB, Canada


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