RKER-012, a novel modified ActRIIB ligand trap, attenuated right ventricular cardiomyopathy in a preclinical model of pulmonary arterial hypertension
Authors: Jain P , Materna C , Babbs K , Nurse T , Ishimwe J , Natarajan H , Joshi S , Lerner L , Fisher F , Seehra J , Lachey J 
Published: October 2024

Abstract

Background
The primary cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure. Initially, the RV adapts to heightened pressure through adaptive remodeling, but prolonged pressure overload triggers maladaptive remodeling, culminating in failure. Overactive activin/growth differentiation factor (GDF) signaling has been implicated in cardiomyopathy and heart failure. RKER-012, a research version of KER-012, is an investigational modified activin receptor type IIB (ActRIIB) ligand trap designed to specifically bind and inhibit select TGF-β ligands, including activins A and B and GDFs 8 and 11. RKER-012 previously exhibited a cardioprotective effect in a pulmonary arterial banding (PAB) model of RV dysfunction. To determine the effect of RKER-012 on afterload-induced RV cardiomyopathy caused by increased pulmonary artery pressure, we utilized an angio-obliterative Sugen/hypoxia (SH) rat model of PAH that closely mimics human PAH pathology.

Methods
Male Sprague Dawley rats were subcutaneously (s.c.) injected with one dose of Sugen 5416 and exposed to 10% hypoxia for 3 weeks during which they received either vehicle (SH-Veh; s.c; BIW) or RKER-012 (10 mg/kg; s.c; BIW). Normoxic (Nx) control rats were maintained in room air for 3 weeks with BIW s.c. vehicle treatment. After 3 weeks of treatment, systolic pulmonary arterial pressure (sPAP) and Fulton index (FI) were assessed. Hallmark genes of inflammatory process, endothelial/platelet activation, and fibrosis were evaluated in the RV by qPCR.

Results
Increases in FI (+99.4%;p&lt;0.0001) and sPAP (+250.9%;p&lt;0.0001) were observed in SH-Veh rats vs. Nx rats, consistent with the development of pulmonary and cardiac impairment. In contrast, treatment with RKER-012 reduced FI (-28.0%;p&lt;0.001) and sPAP (-44.5%;p&lt;0.001). In the RV, SH-Veh rats had increased expression of TGF-ß pathway genes involved in inflammation, endothelial/platelet activation, and fibrosis. RKER-012 treatment reduced expression of these genes (Tgf-β1, -44.7%;p=0.003; Fstl3, -43.5%;p=0.0162; Mcp1, -22.5%;p=0.535; Cd68, -60.3%;p=0.0048; Ctgf, -57.1%;p=0.0139; Col1a1, -47.2%, p=0.0255 ;Col3a1, -69.5%;p&lt;0.0001; Lox, -61.4%;p=0.0054; P-selectin, -63.9%;p=0.018) in comparison to SH-Veh treatment.

Conclusion
Consistent with previous findings in a PAB mouse model, RKER-012 treatment protected against increased sPAP and maladaptive cardiac remodeling in a SH rat model of PAH. Additionally, RKER-012 attenuated RV cardiomyopathy by reducing the expression of genes involved in inflammatory and fibrotic processes. These preclinical findings in the RV paralleled the changes in circulating cardiovascular health biomarkers, including reduced NT-proBNP, observed in a Phase 1 trial of KER-012 in healthy volunteers. These findings, along with the safety and tolerability observed in the Phase 1 trial, provided rationale for the ongoing Phase 2 TROPOS trial of KER-012 in patients with PAH (NCT05975905).