(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/192111 Al 17 December 2015 (17.12.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/18 (2006.01) A61P 17/02 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 39/395 (2006.01) C07K 19/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/035706 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 12 June 2015 (12.06.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/012,109 13 June 2014 (13.06.2014) US kind of regional protection available): ARIPO (BW, GH, 62/045,808 4 September 2014 (04.09.2014) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: ACCELERON PHARMA, INC. [US/US]; TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 128 Sidney Street, Cambridge, MA 02139 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventor: ATTIE, Kenneth, M.; 228 Marlboroug Street, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Boston, MA 021 16 (US). GW, KM, ML, MR, NE, SN, TD, TG). (74) Agents: VARMA, Anita et al; Ropes & Gray LLP, Prudential Tower, 800 Boylston Street, Boston, MA 02199 Published: (US). — with international search report (Art. 21(3)) - © (54) Title: METHODS AND COMPOSITIONS FOR TREATING ULCERS (57) Abstract: The present disclosure provides compositions and methods for treating or preventing ulcers in subjects having low ¾ red blood cell levels and/or hemoglobin levels (e.g, anemia). In some embodiments, the compositions of the disclosure may be used S to treat or prevent ulcers associated with anemia. METHODS AND COMPOSITIONS FOR TREATING ULCERS RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Serial Nos., 62/012,109, filed June 13, 2014, and 62/045,808, filed September 4, 2014. The disclosures of each of the foregoing applications are hereby incorporated in their entirety. BACKGROUND OF THE INVENTION The mature red blood cell, or erythrocyte, is responsible for oxygen transport in the circulatory systems of vertebrates. Red blood cells contain high concentrations of hemoglobin, a protein that binds to oxygen in the lungs at relatively high partial pressure of oxygen (p0 2) and delivers oxygen to areas of the body with a relatively low p0 2. Mature red blood cells are produced from pluripotent hematopoietic stem cells in a process termed erythropoiesis. Postnatal erythropoiesis occurs primarily in the bone marrow and in the red pulp of the spleen. The coordinated action of various signaling pathways controls the balance of cell proliferation, differentiation, survival, and death. Under normal conditions, red blood cells are produced at a rate that maintains a constant red cell mass in the body, and production may increase or decrease in response to various stimuli, including increased or decreased oxygen tension or tissue demand. The process of erythropoiesis begins with the formation of lineage committed precursor cells and proceeds through a series of distinct precursor cell types. The final stages of erythropoiesis occur as reticulocytes are released into the bloodstream and lose their mitochondria and ribosomes while assuming the morphology of mature red blood cell. An elevated level of reticulocytes, or an elevated reticulocyte:erythrocyte ratio, in the blood is indicative of increased red blood cell production rates. In general, anemia is a condition that develops when a subject's blood lacks enough healthy red blood cells or less than the normal quantity of hemoglobin. Anemia may also be diagnosed when there is decreased oxygen-binding capacity of red blood cells, which may result from a deformity in one or more hemoglobin subunits. As human cells depend on oxygen for survival, anemia can result in a wide range of clinical complications including, e.g., tissue damage. For example, it has been reported that ulcers are the one of most common cutaneous manifestation of chronic anemia disorders, particularly in hemolytic anemias such as sickle-cell disease and thalassemia. See, e.g., Keast et al. (2004) Ostomy Wound Manage., 50(10): 64-70; Trent et al. (2004) Adv Skin Wound Care, 17(8): 410-416; J.R. Eckman (1996) Hematol Oncol Clin North Am., 10(6): 1333-1344; and Rassi et al. (2008) Pediatric Annals 37(5): 322-328. The underlying mechanism for ulcer formation in anemic patients has not been completely defined. However, it is believed that multiple complications of anemia contribute to ulcer development including, for example, ischemia, decreased nitric oxide bioavailability, vascular obstruction, thrombosis, and hypoxia. Id. Ulcer healing in anemic patients is typically a slow process, and such patients are also at a high risk of recurrent ulceration. See, e.g., Keast et al. (2004) Ostomy Wound Manage., 50(10): 64-70; Trent et al. (2004) Adv Skin Wound Care, 17(8): 410-416; J.R. Eckman (1996) Hematol Oncol Clin North Am., 10(6): 1333-1344; and Rassi et al. (2008) Pediatric Annals 37(5): 322-328. Furthermore, most therapies have had limited success in the treatment of ulcers occurring in anemic patients. Thus, it is an object of the present disclosure to provide alternative methods for treating or preventing ulcers associated with anemia. SUMMARY OF THE INVENTION In part, the present disclosure demonstrates that ActRII antagonists can be used to alter various blood parameters (e.g., red blood cell levels, hemoglobin levels, iron levels, bilirubin levels, nitrogen levels, etc.) in patients that have anemia as well as treat complications associated with anemia including, for example, ulcers. In particular, the disclosure demonstrates that administration of a GDF Trap polypeptide, which is soluble form of an ActRIIB polypeptide having an acidic amino acid at position 79 with respect to instant SEQ ID NO:l, increases red blood cell levels and/or hemoglobin levels in patients having various types of hemolytic anemia, particularly the hemoglobinopathic anemias, thalassemia and sickle-cell disease. Surprisingly, in addition to directly affecting various red blood cell parameters, the disclosed ActRII antagonist ameliorates other complications associated with anemia. For example, treatment with a GDF Trap protein was shown to increase hemoglobin levels and promote wound healing of a cutaneous (skin) ulcer in a human patient having thalassemia. In some instances, amelioration of these associated complications is of equal or greater importance to patient health and quality of life as the treatment of the underlying anemia. Therefore, in certain embodiments, the disclosure provides methods of using one or more ActRII antagonists to increase red blood cell levels and/or hemoglobin levels in patients in need thereof and to treat or prevent one or more complications associated with low red blood cell levels and/or hemoglobin levels in these patients. In particular, the disclosure provides methods for treating or preventing an ulcer, particularly a cutaneous ulcer, in a subject in need thereof that has low levels of red blood cells and/or hemoglobin or is otherwise classified as a subject having an anemia [e.g., hereditary spherocytosis, hereditary elliptocytosis, hereditary stomacytosis, glucose6- phosphate dehydrogenase deficiency, sickle-cell disease, thalassemia (both alpha and beta), and paroxysmal nocturnal hemoglobinuria] by administering one or more ActRII antagonists. In some embodiments, the disclosure provides methods for treating an ulcer, particularly a cutaneous ulcer, in a subject in need thereof that has low levels of red blood cells and/or hemoglobin or is otherwise classified as a subject having an anemia [e.g., hereditary spherocytosis, hereditary elliptocytosis, hereditary stomacytosis, glucose6-phosphate dehydrogenase deficiency, sickle-cell disease, thalassemia (both alpha and beta), and paroxysmal nocturnal hemoglobinuria] by administering one or more ActRII antagonists. In some embodiments, the disclosure provides methods for preventing an ulcer, particularly a cutaneous ulcer, in a subject in need thereof that has low levels of red blood cells and/or hemoglobin or is otherwise classified as a subject having an anemia [e.g., hereditary spherocytosis, hereditary elliptocytosis, hereditary stomacytosis, glucose6-phosphate dehydrogenase deficiency, sickle-cell disease, thalassemia (both alpha and beta), and paroxysmal nocturnal hemoglobinuria] by administering one or more ActRII antagonists. In some embodiments, the methods of the disclosure relate to treating or preventing an ulcer, particularly a cutaneous ulcer, in a subject that has a hemolytic anemia by administering one or more ActRII antagonists. In some embodiments, the methods of the disclosure relate to treating an ulcer, particularly a cutaneous ulcer, in a subject that has a hemolytic anemia by administering one or more ActRII antagonists. In some embodiments, the methods of the disclosure relate to preventing an ulcer, particularly a cutaneous ulcer, in a subject that has a hemolytic anemia by administering one or more ActRII antagonists. In particular, the methods of the disclosure relate, in part, to methods of treating or preventing an ulcer, particularly a cutaneous ulcer, in a subject that has a hemoglobinopathy anemia by administering one or more ActRII antagonists.