15 February 2020 by Sachindra Joshi

Activin receptor type IIA-Fc (sotatercept) reduces inflammation to alleviate PAH in preclinical models

Introduction: Inflammation and dysregulation of the immune response have been suggested to play important roles in the development of pulmonary arterial hypertension (PAH). ActRIIA-Fc, a selective trap for activins and growth differentiation factors (GDFs), is currently under evaluation in two phase 2 trials in PAH (PULSAR and SPECTRA). We have recently shown that ActRIIA-Fc reverses vascular remodeling in experimental PAH by rebalancing activin-GDF signaling with bone morphogenetic protein signaling. Here, we hypothesized that ActRIIA-Fc also reduces perivascular inflammation in experimental PAH.

Methods: ActRIIA-Fc was evaluated for effects on perivascular inflammation after therapeutic treatment in a Sugen-hypoxia-normoxia rat model of severe angio-obliterative PAH and after preventive treatment in a monocrotaline rat model of PAH exhibiting a pronounced inflammatory component. Flow cytometry and immunohistochemistry were used to quantify inflammatory cells in lungs and perivascular lesions while qRT-PCR was used to measure pulmonary expression of proinflammatory genes.

Results: Consistent with its disease-reversing effects in the Sugen-hypoxia-normoxia model, ActRIIA-Fc significantly increased the numbers of perivascular CD11b+ and CD68+ cells compared to vehicle (by 96% and 150%, respectively) whereas sildenafil did not. ActRIIA-Fc treatment also blunted the increase in expression of Vcam1 and Sele, markers of endothelial injury and known mediators of leukocyte recruitment. In addition, ActRIIA-Fc treatment reduced pulmonary expression of Il6, Ifng, and Ccl2 compared with those in vehicle (p < 0.01). In the monocrotaline model, preventive treatment with ActRIIA-Fc reduced right ventricular hypertrophy and right ventricular systolic pressure by 45% and 49%, respectively, compared to vehicle (p < 0.0001). ActRIIA-Fc treatment also completely normalized the elevated number of pulmonary CD11b+ cells in this model (p < 0.05).

Conclusions: Our results in two preclinical models of PAH indicate that ActRIIA-Fc significantly reduces pulmonary inflammation. This mechanism of action could potentially translate to clinical benefits beyond those of currently available therapies for PAH treatment.

Key Contributors

Sachindra R. Joshi, PhD, Jun Liu MS, R. Scott Pearsall, Ph.D, Patrick Andre, PhD, Gang Li, PhD, Ravindra Kumar, Ph.D Acceleron Pharma, Cambridge MA

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