Multiple‐dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA‐IgG1), a novel erythropoietic agent, in healthy postmenopausal women

Abstract

Ligands of the transforming growth factor-beta superfamily and activin-receptor signaling play an important role in erythropoiesis. Sotatercept, an activin receptor type IIA (ActRIIA) ligand trap, is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1. Sotatercept, originally developed to increase bone mineral density, was noted to have robust effects on erythropoiesis. Here, we evaluated the safety, pharmacokinetic properties, and pharmacodynamic effects of sotatercept in 31 healthy postmenopausal women. Sotatercept was administered at dose level 0.1, 0.3, or 1 mg/kg every 28 days subcutaneously for up to four doses. Sotatercept was generally safe and well tolerated, and elicited clinically significant, dose-dependent increases in hemoglobin, hematocrit, and red blood cell counts that persisted for up to 4 months. The effect of sotatercept on hemoglobin was dose-limiting. Sotatercept also increased bone mineral density and biomarkers of bone formation. The sotatercept serum exposure-dose relationship was linear, with a mean terminal half-life of approximately 23 days. ActRIIA ligands are important regulators of erythrocyte production in healthy individuals. Clinical studies are ongoing to explore the potential of sotatercept to treat anemia and diseases of ineffective erythropoiesis as well as an agent to increase bone mineral density.

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

“…Surprisingly, competition for ACVR2A/B led to a selective reduction in activin pathway signaling in bone with no apparent alteration in BMP signaling. The high bone mass phenotype we observed in Bmpr2-cKO mice is consistent with previous reports detailing the negative effect of activin on bone formation and matrix mineralization (Alves et al, 2013;Bialek et al, 2013;Eijken et al, 2007;Fajardo et al, 2010;Ikenoue et al, 1999;Koncarevic et al, 2010;Lotinun et al, 2010;Pearsall et al, 2008;Perrien et al, 2007;Ruckle et al, 2009;Sherman et al, 2013).…”

“…BMPs therefore can utilize ACVR2A/B and also the BMP-specific type 2 receptor, BMPR2, allowing for potential competition for ACVR2A/B by BMPs and activin based on the availability of BMPR2. We examined this hypothesis in the context of the mouse skeleton, taking advantage of the fact that postnatal bone formation and mineralization is under tight reciprocal regulation by BMPs and activins (Alves et al, 2013;Eijken et al, 2007;Fajardo et al, 2010;Ikenoue et al, 1999;Koncarevic et al, 2010;Li et al, 2013;Lotinun et al, 2010;Matsumoto et al, 2012;Mishina et al, 2004;Nicks et al, 2009;Pearsall et al, 2008;Perrien et al, 2007;Ruckle et al, 2009;Sakai et al, 2000;Sherman et al, 2013;Simic et al, 2006;Zhang et al, 2009;Zhao et al, 2002). Surprisingly, engineering specific deletion of BMPR2 in bone-forming cells (Bmpr2-cKO mice) selectively reduces activin pathway activation but has no apparent effect on BMP signaling.…”

RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1

“…[17][18][19] This molecule antagonizes signaling downstream of ActRIIA through sequestering distinct members within the transforming growth factor-b (TGF-b) family, including bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and Activin molecules, from binding to the endogenous receptor. Injection of RAP-011 (the murine form of ACE-011) into murine models of anemia can restore red blood cell parameters.…”

“…17,20 Furthermore, a study using sotatercept in healthy volunteers demonstrated that it can increase hemoglobin levels. 18 Currently, sotatercept is being evaluated for efficacy in anemia associated with diseases such as b-thalassemia, myelodyspastic syndrome and renal disease. Also, there is an ongoing clinical trial to test the efficacy of sotatercept in the treatment of DBA.…”

New renal anemia drugs: is there really anything new on the horizon?

“…Last, but not least, new potential drug could be sotatercept (ACE-011). This activin receptor type IIA (ActRIIA) ligand trap is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1 that binds several members of the transforming growth factor (TGF)-b superfamily [18]. Sotatercept, originally developed to increase bone mineral density, was noted with serendipity to have robust effects on erythropoiesis.…”