A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension

Abstract

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Keywords: outcomes; pulmonary arterial hypertension; sotatercept; survival; treatment.

Figure 1.. Pathogenesis of pulmonary arterial hypertension resulting from an imbalance in TGF-β-activin and bone morphogenetic protein pathways.

(A) The transforming growth factor-β (TGF-β) superfamily pathways are involved in vasculature homeostasis through signaling in the TGF-β-activin and bone morphogenetic protein pathways.(12) The balance of these pathways is critical to cellular differentiation, proliferation, and apoptosis in the pulmonary vasculature. In normal homeostasis, BMPR2 is activated by bone morphogenetic proteins to create downstream antiproliferative signaling that is balanced with activin receptor type IIA downstream pro-proliferative signaling. At the molecular level, a loss of function of the antiproliferative BMP pathway or an imbalance in the pro-proliferative activin pathway can predispose to the development of PAH. Sotatercept is a recombinant activin receptor type IIA fusion protein that acts as a ligand trap to scavage activins and inhibit pro-proliferative activin signally. (B) An imbalance in TGF-β-activin and bone morphogenetic protein pathways may contribute to the pathogenesis of pulmonary arterial hypertension. Molecular changes in the TGF-β-activin and bone morphogenetic protein pathways contribute to the dysregulated proliferation of pulmonary artery endothelial and smooth muscle cells that result in pulmonary vascular remodeling manifested by increasing pulmonary vascular resistance and pulmonary artery pressures. Right ventricular remodeling occurs that eventually results in right ventricular dilation and dysfunction. The continued disease progression leads to right ventricular failure manifested by volume overload and decreasing cardiac output that results in death. BMP, bone morphogenetic protein; bone morphogenetic protein receptor type 2, BMPR2; activin receptor-like kinase, ALK; growth differentiation factor, GDF.

Figure 2.. Summary of the benefits, adverse events, and key unknown questions for the use of sotatercept in the management of pulmonary arterial hypertension.

WHO, World Health Organization; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; CO, cardiac output; RV, right ventricular; ULN, upper limit of normal.

Figure 3.. Putative schema for the hypothetical incorporation and impact of sotarecept on the management of pulmonary arterial hypertension.

Sotatercept has been incorporated into the modern treatment algorithm for PAH using a risk-based, goal-oriented treatment approach aimed at achieving low risk. Given the lack of data for utilization of sotatercept in treatment naïve patients, initiation of sotatercept can be considered for patients not achieving low risk at subsequent follow-up. In the hypothetical example shown, one option for an intermediate-risk patient is the addition of a third agent. The duration of the effect of sotatercept remains unknown. Whether or not sotatercept improves survival remains an area of active investigation.