Administration of a Novel GDF Trap Prevents Anemia Induced by Renal Insufficiency and Augments Recovery From Blood Loss.
Authors: Cadena Samuel M. , Mitchell Dianne , Ucran Jeff , Liharska Katia , Sako Dianne , Monnell Travis , Kumar Ravindra , Underwood Kathryn W. , Pearsall R. Scott 
Published: October 2019

Abstract
Abstract 4037
Poster Board III-973
This study investigated the effect of inhibiting GDF signalling via administration of a soluble form of a modified activin type II receptor (ACE-536) in anemia models.
Anemia is a debilitating complication associated with several chronic diseases, including chronic kidney disease (CKD), and results in fatigue, shortness of breath, decreased quality of life and increased risk of mortality. Recombinant human EPO (rhEPO) is the most commonly prescribed therapy for CKD induced anemia. However, approximately one-third of patients treated with rhEPO are hyporesponsive, requiring high doses to obtain minimal increases in hemoglobin, and 5-10% of CKD-anemia patients are fully non-responsive to treatment. Moreover, there is increasing evidence to suggest that hyporesponsive patients have significantly increased risk for adverse drug reactions to rhEPO, including cardiovascular events. Therefore, novel, non-EPO based therapies to correct anemia may provide an alternative to EPO-based therapies to treat anemia. Various members of the TGF-β superfamily have been implicated in erythropoiesis. We have developed ACE-536, a soluble GDF-trap derived from the Type II activin receptor fused to the Fc region of IgG1, which binds to and inhibits several ligands in the TGF-β superfamily. Elsewhere, we report that administration of ACE-536 leads to rapid increases in red blood cells (RBC) in normal mice. Here, we report on the effects of ACE-536 in two disease models of anemia.
To study the effects in a model of anemia related to renal insufficiency, nephrectomized (CKD) or sham-operated (SHAM) C57BL/6 mice were randomized to receive ACE-536 at 10 mg/kg or an equal volume of vehicle control (TBS; tris-buffered saline) for 4 weeks. Compared to baseline values, the SHAM-TBS group maintained the same red blood cell mass by the end of the four-week treatment period, whereas the CKD-TBS mice showed a significant decline (-6%; P<0.001). In contrast, SHAM and CKD mice receiving ACE-536 displayed a 24% and 19% increase in total red blood cells (P<0.001), respectively. Hemoglobin and hematocrit measurements also increased accordingly with treatment. The SHAM-TBS group exhibited no change in either parameter over the four-week treatment period, while the CKD-TBS group showed a significant decline in both hemoglobin and hematocrit (P<0.05 and P<0.001, respectively). Finally, SHAM and CKD mice receiving ACE-536 showed a significant increase in hemoglobin (P<0.001 and P<0.01, respectively) and hematocrit (P<0.001 and P<0.05, respectively) compared to their respective baseline values.
We next investigated the effect of ACE-536 in recovery from blood loss to determine its role in a more acute model of anemia. Blood loss in Sprague-Dawley rats was achieved by removing 20% of total blood volume which, at 24 hours, resulted in a 14% decrease in total red blood cells and hemoglobin. At this point rats were randomized to receive ACE-536 at 10 mg/kg or an equal volume of TBS. Two days post randomization, hematological parameters returned to baseline levels in the ACE-536 treated rats; however, these same parameters remained significantly lower in the TBS treated group until day 6. Therefore, targeting the TGF-β signaling pathway with ACE-536, a novel, GDF-trap, is a viable therapeutic approach for the prevention and treatment of anemia induced by CKD and blood loss, and represents a potential alternative to EPO-based therapy.

Disclosures:
Cadena: Acceleron Pharma: Employment. Mitchell:Acceleron Pharma: Employment. Ucran:Acceleron Pharma: Employment. Liharska:Acceleron Pharma: Employment. Sako:Acceleron Pharma: Employment. Monnell:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment. Underwood:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment.