Methods for dosing an activin-actriia antagonist and monitoring of treated patients

Abstract

In certain aspects, the present invention provides methods for dosing a patient with an activin-ActRIIa antagonist and methods for managing patients treated with an activin-ActRIIa antagonist. In certain aspects, the methods involve measuring one or more hematologic parameters in a patient.

1 - 44 . (canceled) 
     
     
         45 . A method for treating anemia in a subject, comprising:
 (i) administering to the subject one or more doses of an activin receptor type Ha (ActRIIa) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 2, 3 or 7, wherein the polypeptide binds to growth differentiation factor 11 (GDF11) and/or activin;   (ii) monitoring in the subject one or more hematologic parameters selected from blood pressure, red blood cell levels, hemoglobin levels, iron stores, transferrin saturation, ferritin level, and hematocrit level;   (iii) determining that the subject has:
 a) blood pressure elevated above baseline or hypertension; 
 b) a red blood cell level greater than the normal range for subjects of similar age and sex; 
 c) a hemoglobin level of greater than the normal range for subjects of similar age and sex; 
 d) iron stores that are lower than the normal range for subjects of similar age and sex; 
 e) a transferrin saturation of less than 20%; 
 f) a ferritin level of less than 100 ng/ml; or 
 g) a hematocrit level greater than the normal range for subjects of similar age and sex; and 
   (iv) as a result, reducing the number of doses and/or delaying administration of a further dose to the subject.   
     
     
         46 . The method of  claim 45 , wherein step (iv) comprises reducing the number of doses administered to the subject. 
     
     
         47 . The method of  claim 45 , wherein step (iv) comprises delaying administration of a further dose of the ActRIIa polypeptide to the subject. 
     
     
         48 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a blood pressure elevated above baseline or is determined to be hypertensive. 
     
     
         49 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a red blood cell level greater than the normal range for subjects of similar age and sex. 
     
     
         50 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a hemoglobin level of greater than the normal range for subjects of similar age and sex. 
     
     
         51 . The method of  claim 45 , wherein the subject is determined in step (iii) to have iron stores that are lower than the normal range for subjects of similar age and sex. 
     
     
         52 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a transferrin saturation of less than 20%. 
     
     
         53 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a ferritin level of less than 100 ng/ml. 
     
     
         54 . The method of  claim 45 , wherein the subject is determined in step (iii) to have a hematocrit level greater than the normal range for subjects of similar age and sex. 
     
     
         55 . The method of  claim 45 , wherein if the subject is determined in step (iii) to have a blood pressure elevated above baseline or is determined to be hypertensive, the method further comprises administering a blood pressure lowering agent to the subject until the subject's blood pressure is not elevated above baseline or until the subject is not hypertensive. 
     
     
         56 . The method of  claim 45 , wherein the anemia is a result of a myelodysplastic syndrome. 
     
     
         57 . The method of  claim 45 , wherein the anemia is a result of a hemoglobinopathy. 
     
     
         58 . The method of  claim 45 , wherein the anemia is a result of a thalassemia. 
     
     
         59 . The method of  claim 45 , wherein the anemia is a result of sickle cell disease. 
     
     
         60 . The method of  claim 45 , wherein the anemia is a result of chronic renal disease or chronic renal failure. 
     
     
         61 . The method of  claim 45 , wherein the anemia is a result of acute renal disease or acute renal failure. 
     
     
         62 . The method of  claim 45 , wherein the ActRIIa polypeptide comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         63 . The method of  claim 45 , wherein the ActRIIa polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         64 . The method of  claim 45 , wherein the ActRIIa polypeptide is a fusion protein comprising an immunoglobulin Fc domain. 
     
     
         65 . The method of  claim 45 , wherein the ActRIIa polypeptide comprises one or more amino acid modifications selected from the group consisting of: a glycosylated amino acid, a polyethylene glycolated (PEGylated) amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety. 
     
     
         66 . The method of  claim 45 , wherein the ActRIIa polypeptide comprises the amino acid sequence of SEQ ID NO: 7. 
     
     
         67 . The method of  claim 45 , wherein the ActRIIa polypeptide binds to activin. 
     
     
         68 . The method of  claim 45 , wherein the ActRIIa polypeptide binds to activin A, activin B, and/or GDF11. 
     
     
         69 . The method of  claim 45 , wherein the ActRIIa polypeptide inhibits signaling by activin and/or GDF11. 
     
     
         70 . The method of  claim 69 , wherein the ActRIIa polypeptide inhibits signaling by activin A. 
     
     
         71 . The method of  claim 69 , wherein the ActRIIa polypeptide inhibits signaling by activin B.