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3603 ACE-536, a Novel GDF-Trap, Increases Hemoglobin, Hematocrit, and Red Blood Cell Levels in Rats and Monkeys

Oral and Poster Abstracts
Poster Session: Hematopoiesis - Cytokines, Signal Transduction, Apoptosis, and Cell Cycle Regulation Poster II
Monday, December 7, 2009, 6:00 PM-8:00 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board III-540

Kenneth Loveday, Ph.D*, Doriana Froim, Ph.D*, Anna Pisania, Ph.D.*, Alissa Fernald*, Mathew Spaits*, R. Scott Pearsall, Ph.D.*, Ravi Kumar, Ph.D.* and Kathryn W. Underwood, Ph.D.*

Acceleron Pharma Inc., Cambridge, MA

Anemia is a common and debilitating complication of several tumor types, especially multiple myeloma and myelodysplastic syndrome, chemotherapy, chronic kidney disease, and many other conditions. The vast majority of therapies approved to treat anemia target the erythropoietin (EPO) pathway; however, recent studies suggest an increased risk of mortality associated with this class of therapy, arising from exposure to high levels of EPO. The TGF-β protein superfamily has been described to play a role in RBC development, but signals through a pathway distinct from EPO. We have developed ACE-536, a novel, GDF-trap derived from the Type II activin receptor fused to the Fc region of IgG1, which binds to and inhibits several ligands in TGF-b protein superfamily.  Here, we report the effects of ACE-536 on hematologic parameters (RBC, hemoglobin, and hematocrit) in Sprague-Dawley rats and cynomolgus monkeys. The study in rats examined the effect of dose on increases in hematology parameters.  Ten male and ten female rats per group received two SC doses (Days 1 and 15) of vehicle, or 6, 20 or 60 mg/kg of ACE-536; hematology parameters were measured on Day 29.  Significant increases (P < 0.05) in RBC count were seen at all three dose levels in both male and female rats, which correlated with increases in hemoglobin and hematocrit.    The maximum hemoglobin concentration occurred at 60 mg/kg in both sexes (combined mean of 18.2 g/dL versus 15.7 g/dL in vehicle control rats).  The corresponding mean hematocrit at 60 mg/kg was 55% versus 47% in vehicle control rats. Two studies were conducted in monkeys to evaluate the time course and the dose response for induction of RBC, hemoglobin, and hematocrit.  In the first study, the time course of erythropoiesis was investigated in 4 male and 4 female cynomolgus monkeys, which received subcutaneous (SC) doses of ACE-536 (10 mg/kg) on Days 1 and 8.  Hematology parameters were evaluated prior to dosing and on Days 3, 8, 15, 29, and 44.  Increases in hematology parameters were noted 48 hours later (Day 3) in both males and females, and maximum increases were seen by Day 29.  The mean increases in hemoglobin were 1.4 g/dL on Day 3 and 2.2 g/dL on Day 29.  In contrast, mean hemoglobin concentration decreased on Day 3 in two vehicle control animals (mean of -0.85 g/dL). In the second study, the hematologic dose response was investigated in 5 male and 5 female cynomolgus monkeys per group, which received SC doses of vehicle, or 0.4, 2, 10 or 30 mg/kg of ACE-536 on Days 1 and 15.  Hematology parameters were evaluated prior to dosing and on Days 13 and 28.  A dose-related increase in hematology parameters was seen in animals treated with ACE-536.  Hemoglobin concentration decreased during the study in vehicle control animals (-1.5 g/dL on Days 13 and 28), most likely due to frequent blood collections for clinical chemistry and pharmacokinetic evaluations.  In contrast, animals treated with ACE-536 had changes in hemoglobin concentration on Day 13 of -0.6, +0.45, +0.57, and +0.52 g/dL at doses of 0.4, 2, 10, and 30 mg/kg, respectively. In conclusion, the administration of ACE-536, a novel, GDF-trap, promotes robust increases in hemoglobin, hematocrit, and RBC levels in animals. This provides evidence that targeting the TGF-β signaling pathway is a viable approach to the treatment of anemia, and that ACE-536 may prove to be an effective alternative to EPO-based therapies.

Disclosures: Loveday: Acceleron Pharma Inc: Employment. Froim: Acceleron Pharma Inc: Employment. Pisania: Acceleron Pharma Inc: Employment. Fernald: Acceleron Pharma Inc: Employment. Spaits: Acceleron Pharma Inc: Employment. Pearsall: Acceleron Pharma: Employment. Kumar: Acceleron Pharma Inc: Employment. Underwood: Acceleron Pharma: Employment.

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