Mark J. Koury, MD
Dr. Koury indicated no relevant conflicts of interest.
Study Title: A Phase 2a Study to Evaluate the Pharmacokinetics, Safety, Efficacy, Tolerability, and Pharmacodynamics of Sotatercept (ACE-011) for the Correction of Anemia in Subjects With End-Stage Renal Disease on Hemodialysis
ClinicalTrials.Gov Identifier: NCT01146574
Coordinators: Celgene Corporation and Acceleron Pharma, Inc.
Participating Centers: 26 hemodialysis centers in the United States
Accrual Goal: 43 subjects with ongoing recruitment
Study Design: This phase II, randomized, single-dose, double-blind, placebo-controlled study, followed by a multiple-dose, single-blind, placebo-controlled, doseescalation study will evaluate the pharmacokinetics, safety, efficacy, tolerability, and pharmacodynamics of sotatercept in the correction of anemia in subjects with end-stage renal disease on hemodialysis. The study has two parts. In part 1, subjects are randomized to receive either a single 0.1 mg/kg subcutaneous dose of sotatercept or matching placebo in a 3:1 sotatercept-to-placebo ratio. In part 2, subjects will be randomized to one of three dose groups (0.3 mg/kg or 0.5 mg/kg or 0.7 mg/kg) in a 3:1 ratio of sotatercept to placebo. For each dose group, sotatercept will be injected subcutaneous once every 28 days for up to eight treatments. The primary endpoint of the study is characterization of the pharmacokinetics and pharmacodynamics of sotatercept. Notable secondary endpoints include the magnitude and rate of increase in hemoglobin and changes in blood pressure.
Rationale: Sotatercept is a recombinant, chimeric protein consisting of the extracellular domain of human activin receptor type IIa and the Fc domain of human IgG1. It binds activin A and other members of the transforming growth factor-β superfamily of cytokines, thereby inhibiting their functional activity. In a previous clinical study, sotatercept produced dose-dependent increases in hemoglobin, hematocrit, RBCs, and reticulocytes in healthy postmenopausal women. Because sotatercept does not bind the erythropoietin (EPO) receptor and acts more rapidly than EPO, its erythropoiesis-stimulating activity likely involves non-EPO-dependent mechanisms. This clinical trial is one of several examining the erythropoietic effects of sotatercept in chronic anemias including Diamond-Blackfan anemia, transfusion-dependent β-thalassemia, and myelofibrosis.
Comment: Other than androgenic steroids with their significant systemic side effects, medications that stimulate erythropoiesis activate EPO receptors on erythroid progenitor cells. EPO receptors are activated directly by recombinant EPO, EPO-related drugs such as darbepoetin and polyethylene glycol-conjugated EPO, or EPO-mimetic peptides. EPO receptors can be activated indirectly via agents that increase endogenous EPO production through stabilization of the hypoxia-inducible transcription factors HIF-1α and HIF-2α. Drugs that activate EPO receptors have serious potential side effects, specifically aggravation of hypertension and induction of thrombosis. Thus, there exists a need to develop non-EPOdependent mechanisms for treating anemia.
Erythropoietic stimulation via mechanisms that do not involve EPO receptors would have specific advantages in underproduction anemias such as the anemias of myelofibrosis, thalassemias, and marrow failure syndromes that are characterized by endogenous EPO concentrations that are elevated but ineffective. The other ongoing trials of sotatercept may provide information about stimulating erythropoiesis in underproduction anemias with elevated endogenous EPO levels; however, the current trial in renal failure patients on hemodialysis is unique as the markedly reduced capacity of these patients to produce endogenous EPO from their diseased kidneys means that erythropoietic responses to sotatercept (if observed) would be due to EPO-independent mechanisms. Whether the adverse effects of drugs that activate EPO receptors might be averted with sotatercept is of interest because many older patients with anemias also have underlying hypertension and vascular disease. Hypertension, albeit controlled, is common in renal failure patients, and the effect of sotatercept on blood pressure is a relevant secondary endpoint of the study. The anemia of renal failure is often multifactorial with contributions from EPO insufficiency and absolute and functional iron deficiency. Additionally, renal failure patients on hemodialysis have features of anemia of chronic inflammation, a process that is relatively resistant to EPO administration. If sotatercept effectively stimulates erythropoiesis in renal failure patients with the anemia of chronic disease, then less EPO may be required for their care, and sotatercept alone may benefit patients without renal failure who have the anemia of chronic inflammation.
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