Category: anemia


Sotatercept (formerly called ACE-011) is an investigational protein therapeutic that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron is developing sotatercept in collaboration with Celgene Corporation for the treatment of anemia caused by chemotherapy and chronic kidney disease.

Mechanism of Action

Sotatercept, the first in a novel class of anemia therapies, is a soluble fusion protein consisting of the extracellular domain of activin receptor type IIA (ActRIIA) linked to the Fc protein of human IgG1. Sotatercept binds with high affinity to activin A and other proteins in the TGF-β superfamily and inhibits signaling through the ActRIIA receptor.

Sotatercept increases hemoglobin levels and RBCs by a novel mechanism: it is not an erythropoietin (EPO)-based product or EPO-mimetic, does not bind the EPO receptor, but rather targets a pathway that is fundamentally distinct from EPO.  In preclinical studies, administration of sotatercept or a mouse version of the molecule to mice and cynomolgus monkeys was associated with increases in erythropoiesis and total red cell mass.  The precise actions of sotatercept underlying the promotion of erythropoiesis are under investigation.

Sotatercept also affects bone formation.  One of the functions of activin A is to inhibit bone growth.   Activin A signaling through ActRIIA suppresses activity of cells responsible for building bone (osteoblasts) and stimulates cells responsible for breaking down bone (osteoclasts). By blocking signaling through ActRIIA, sotatercept stimulates bone formation. In numerous animal models of diseases involving bone loss, sotatercept significantly increased bone mineral density, improved bone architecture, and increased bone formation rate and bone mechanical strength.  Similar effects were observed in experimental models of cancer-related bone loss (multiple myeloma and breast carcinoma) where treatment with a mouse form of sotatercept resulted in a significant reduction in tumor-induced osteolytic lesions. In the myeloma model, restoration of bone remodeling had a significant indirect effect on tumor burden and increased survival.

Acceleron and Celgene are developing sotatercept in anemia indications where the product’s unique pharmacology could potentially provide an innovative and differentiated alternative to existing anemia therapies.

Disease Overview

Anemia, a deficiency of healthy RBCs, is a debilitating condition that often accompanies chemotherapy or chronic kidney disease.  Patients with anemia typically experience fatigue and weakness, which impairs their quality of life and may limit their ability to receive optimal care.

Treatments for anemia include iron repletion, blood transfusion, and recombinant growth factors called erythropoietin stimulating agents (ESAs).  ESAs are currently the only approved drugs that stimulate the production of RBCs.

Clinical Need

ESAs have been used extensively to treat anemia. Recent studies of ESAs have shown an increased risk of mortality arising from exposure to high levels of recombinant erythropoietin and its derivatives, which may stimulate tumor progression, cause premature mortality, and increase the occurrence of thromboembolic events.  The safety concerns with ESAs have prompted substantial restrictions to their approved uses for the management of patients with cancer and kidney disease.

Sotatercept represents a new approach to anemia treatment.   Clinical trials in patients with CIA and CKD are currently underway to study its potential as a safe, effective treatment for anemia.

Clinical Trials

Acceleron is developing sotatercept together with Celgene Corporation for patients who suffer from anemia.  Sotatercept is currently being studied as a treatment for chemotherapy-induced anemia (CIA) and chronic kidney disease-related (CKD) anemia.

Phase 2/ 3 Study for Chemotherapy-Induced Anemia in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).   For information on this trial, please click here.

Phase 2 Study for Anemia in Patients with End-stage Renal Disease on Dialysis.   For information on this trial, please click here

In Phase 1 clinical studies in healthy volunteers, sotatercept was generally well tolerated, and, consistent with observations in preclinical studies, increased levels of hemoglobin and hematocrit, biomarkers of bone formation, and bone mineral density. The most common clinically significant adverse events observed included increased hemoglobin and increased hematocrit, which were pharmacologic effects of the drug, and also headache, all of which were manageable and reversible.

Abstract

BACKGROUND:

Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney.

METHODS:

Using a rat model of renal ischaemia-reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects.

RESULTS:

ICA treatment resulted in stabilization of HIF-1α and -2α and up-regulation of HIF target genes in a dose-dependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine.

CONCLUSION:

These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO.