Promising preclinical findings recently published in a peer-reviewed journal opened the door to the launch of a Phase 2 trial testing the therapeutic potential of apabetalone (RVX-208), Resverlogix‘s proprietary therapy, in people with pulmonary arterial hypertension (PAH).
The findings of the study, “Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension,” were published in the American Journal of Respiratory and Critical Care Medicine.
Apabetalone is a selective inhibitor of bromodomain and extra-terminal domain (BET) proteins, a group of proteins that regulate gene activity without altering the DNA sequence (epigenetic proteins), and which are thought to be involved in the progression of PAH.
In previous animal studies, researchers found that inhibiting the activity of the protein BRD4 (a BET protein) — either using small interference RNA (siRNA) or a potent inhibitor of BET proteins called JQ1 — successfully reversed the symptoms of PAH in rats. However, neither siRNA nor JQ1 can be used in the clinic.
Researchers now explored the therapeutic potential of apabetalone, a compound that has been shown to reduce the transcription of BET proteins. Transcription is the process by which DNA is converted into RNA, to then be used in the production of functional proteins.
Two different rat models of PAH were treated with apabetalone, as were as two types of cells — smooth muscle cells and microvascular endothelial cells — isolated from blood vessels from the lungs of patients with the disease.
The investigators first observed that BRD4 was overproduced in cells isolated from patients with idiopathic PAH, compared with cells from healthy control individuals. They also found that BRD4 led to the overproduction of other proteins, specifically FoxM1 and PLK1, that are involved in the DNA damage response.
Remarkably, treatment with apabetalone normalized the levels of BRD4, and reduced the abnormally fast growth, inflammation, and resistance to death in cells isolated from PAH patients, the researchers said.
Moreover, the team showed that treatment with oral apabetalone successfully reversed blood vessels’ remodeling associated with PAH, and improved pulmonary function in both animal models of the disease.
“In conclusion, we describe the unified results of the first multicentre randomized preclinical trial performed in three independent labs that confirmed the therapeutic potential of the clinically available BET inhibitor RVX208 [apabetalone] in various PAH rodent models,” the researchers said.
These results provided the basis for the initiation of a Phase 2 clinical trial to test apabetalone as a potential therapy for PAH patients.
“We are extremely pleased that our collaborative work resulted in this high-profile publication highlighting the potential of apabetalone and BET inhibition in the treatment of PAH and other diseases,” Ewelina Kulikowski, PhD, senior vice president, research & development of Resverlogix, said in a press release.
“Significantly, each independent, yet complementary, study showed treatment efficacy in animal models of this disease. We look forward to advancing this work in a Phase 2 PAH trial later this year,” Kulikowski added.
Resverlogix received funding to support the upcoming Phase 2 trial, which, according to the company, will start later this year, after the completion of an already planned pilot study.