Acceleron Pharma Inc. (NASDAQ:XLRN), a biopharmaceutical company dedicated to the discovery, development, and commercialization of TGF-beta superfamily therapeutics to treat serious and rare diseases, today announced that research published in the journal Science Translational Medicine describes how a murine version of the investigational agent sotatercept acts to restore balance in key signaling pathways whose disruption drives the disease pathology of pulmonary arterial hypertension (PAH).
The research may provide a mechanistic rationale for the positive topline results reported earlier this year from the PULSAR Phase 2 clinical trial of sotatercept in patients with PAH.
The article reports that in experimental human cell-based tissue and animal models of pulmonary hypertension and PAH, sotatercept exhibited consistent effects across multiple components of disease, including suppressed proliferation of pulmonary arterial smooth muscle and microvascular endothelial cells, reduced pulmonary pressures, lessened right ventricular hypertrophy, improved right ventricular function, and attenuated vascular remodeling. The anti-remodeling effects were not seen with a PAH standard-of-care therapy included in the study as a comparator. The researchers concluded that sotatercept exerted its beneficial effects on these pathologic hallmarks by selectively binding the TGF-beta superfamily ligands activin A, activin B, and growth differentiation factor (GDF) 8 and GDF11. Signaling of these ligands, which may induce cellular proliferation, has been found to be upregulated in PAH—which in turn may impair signaling of bone morphogenetic protein receptor type 2 (BMPR-II), which is thought to be protective.
“Dysregulated BMP and TGF-beta signaling has long been implicated in the pathology of PAH,” said Paul B. Yu, M.D., Ph.D., Associate Physician, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Associate Professor of Medicine, Harvard Medical School, and the study’s principal investigator. “Here we demonstrate that the murine version of sotatercept rebalances this signaling to improve hemodynamics and attenuate vascular remodeling, at the same time revealing how large a role activin A, activin B, GDF8, and GDF11 play as drivers of pulmonary vascular disease. Targeting these ligands with sotatercept to restore balanced signaling could represent a promising therapeutic approach.”
“The publication of Paul Yu’s elegant research highlights the importance of TGF-beta superfamily biology to the underlying pathology of pulmonary vascular disease and provides biological support for sotatercept’s activity in PAH,” said Jay T. Backstrom, M.D., M.P.H., Executive Vice President and Head of Research and Development at Acceleron. “Based on our recent clinical trial results establishing proof-of-concept, we have great enthusiasm for sotatercept’s potential as a novel therapy for patients with PAH. This research brings added confidence in and clarity to the underlying biology behind sotatercept’s hypothesized mechanism of action as we shape our clinical development plans in the pulmonary space.”