Methods for dosing an actriib antagonist and monitoring of treated patients

Abstract

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

1 . A method for managing a patient that has been treated with, or is a candidate to be treated with, an ActRIIb antagonist, the method comprising monitoring in the patient one or more hematologic parameters that correlate with increased red blood cell levels. 
     
     
         2 . The method of  claim 1 , wherein the hematologic parameters are one or more of the following: red blood cell levels, blood pressure, or iron stores. 
     
     
         3 . The method of  claim 1 , the method further comprising administering to the patient the ActRIIb antagonist in an amount that is appropriate to the observed level of said hematologic parameter in the patient. 
     
     
         4 . The method of  claim 1 , wherein, if the patient has blood pressure elevated above baseline or is hypertensive, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         5 . The method of  claim 1 , wherein, if the patient has blood pressure elevated above baseline or is hypertensive, the patient is treated with a blood pressure lowering agent prior to administration of the ActRIIb antagonist. 
     
     
         6 . The method of  claim 1 , wherein if the patient has uncontrolled hypertension, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         7 . The method of  claim 1 , wherein if the patient has a red blood cell level greater than the normal range for patients of similar age and sex, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         8 . The method of  claim 1 , wherein if the patient has a hemoglobin level of greater than 15 g/dL, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         9 . The method of  claim 1 , wherein if the patient has a hemoglobin level greater than 10, 11 or 12 g/dL, dosing with the activin-ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         10 . The method of  claim 1 , wherein if the patient has iron stores that are lower than the normal range for patients of similar age and sex, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         11 . The method of  claim 1 , wherein if the patient has a transferrin saturation of less than 20%, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         12 . The method of  claim 1 , wherein if the patient has a ferritin level of less than 100 ng/ml, dosing with the ActRIIb antagonist is reduced, delayed or terminated. 
     
     
         13 . The method of  claim 1 , wherein if the patient has iron stores that are lower than the normal range for patients of similar age and sex, the patient is treated with an iron supplement prior to dosing with the ActRIIb antagonist. 
     
     
         14 . The method of  claim 1 , wherein if the patient has a transferrin saturation of less than 20%, the patient is treated with an iron supplement prior to dosing with the activin-ActRIIb antagonist. 
     
     
         15 . The method of  claim 1 , wherein if the patient has a ferritin level of less than 100 ng/ml, the patient is treated with an iron supplement prior to dosing with the ActRIIb antagonist. 
     
     
         16 . The method of  claim 1 , wherein monitoring red blood cell levels comprises monitoring one or more of the following: hemoglobin levels and hematocrit levels. 
     
     
         17 . The method of  claim 1 , wherein monitoring blood pressure comprises monitoring one or more of the following: systolic blood pressure, diastolic blood pressure or mean arterial blood pressure. 
     
     
         18 . The method of  claim 1 , wherein monitoring iron stores comprises monitoring one or more of the following: transferrin saturation, ferritin levels or total iron binding capacity. 
     
     
         19 . A method for dosing a patient with an ActRIIb antagonist, the method comprising dosing the patient in amounts and at intervals selected so as to reduce the risk of causing a rise in hemoglobin levels greater than 1 g/dL in two weeks. 
     
     
         20 . The method of  claim 1 , wherein the patient is suffering from anemia. 
     
     
         21 . The method of  claim 1 , wherein the patient is in need of bone growth, increased bone density or increased bone strength. 
     
     
         22 . The method of  claim 1 , wherein the patient is suffering from a bone-related disorder. 
     
     
         23 . The method of  claim 1 , wherein the patient has cancer. 
     
     
         24 . The method of  claim 23 , wherein the patient has breast cancer. 
     
     
         25 . The method of  claim 1 , wherein the patient is suffering from a disorder associated with muscle loss or insufficient muscle growth. 
     
     
         26 . The method of  claim 1 , wherein the ActRIIb antagonist is an antibody that binds to a target protein selected from the group consisting of: an activin and ActRIIB. 
     
     
         27 . The method of  claim 1 , wherein the ActRIIb antagonist is inhibin or a conservative variant of inhibin. 
     
     
         28 . The method of  claim 1 , wherein the ActRIIb antagonist is a protein comprising a follistatin domain that binds to and antagonizes activin. 
     
     
         29 . The method of  claim 1 , wherein the ActRIIb antagonist is a protein selected from the group consisting of: follistatin, follastatin-related gene (FLRG) and a conservative variant of the forgoing. 
     
     
         30 . The method of  claim 1 , wherein the ActRIIb antagonist is an ActRIIb polypeptide selected from the group consisting of:
 a) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1;   b) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 2;   c) a polypeptide comprising at least 50 consecutive amino acids selected from SEQ ID NO: 1; and   d) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 3.   
     
     
         31 . The method of  claim 30  wherein the polypeptide has one or more of the following characteristics:
 i) binds to an ActRIIb ligand with a K D  of at least 10 −7  M; and   ii) inhibits ActRIIb signaling in a cell.   
     
     
         32 . The method of  claim 30  wherein said polypeptide is a fusion protein including, in addition to an ActRIIb polypeptide domain, one or more polypeptide portions that enhance one or more of in vivo stability, in vivo half life, uptake/administration, tissue localization or distribution, formation of protein complexes, and/or purification. 
     
     
         33 . The method of  claim 30  wherein said fusion protein includes a polypeptide portion selected from the group consisting of: an immunoglobulin Fc domain and a serum albumin. 
     
     
         34 . The method of  claim 30  wherein said polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent. 
     
     
         35 . The method of  claim 30  wherein the ActRIIb antagonist is an ActRIIb-Fc fusion protein comprising an amino acid sequence selected from the group consisting of:
 a) an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3,   b) the amino acid sequence of SEQ ID NO: 3,   c) the amino acid sequence of SEQ ID NO: 2,   d) the amino acid sequence of SEQ ID NO: 8, and   e) the amino acid sequence of SEQ ID NO: 9.   
     
     
         36 . A method for administering an ActRIIb-Fc fusion protein to a patient, the method comprising administering the ActRIIb-Fc fusion protein no more frequently than once per 10 days. 
     
     
         37 . The method of  claim 35  wherein the activin antagonist is administered to the patient no more frequently than once per 30 days. 
     
     
         38 . The method of  claim 35  wherein the activin antagonist is administered to the patient no more frequently than once per 60 days. 
     
     
         39 . A method for administering an ActRIIb-Fc fusion protein to a patient in need thereof, the method comprising administering the ActRIIb-Fc fusion protein to a patient having a hemoglobin level of less than 10 g/dL. 
     
     
         40 . The method of  claim 39 , wherein the patient has a hemoglobin level of less than 11 g/dL. 
     
     
         41 . The method of  claim 39 , wherein the patient has a hemoglobin level of less than 12 g/dL. 
     
     
         42 . The method of  claim 39 , wherein the patient is in need of muscle growth or increased muscle strength. 
     
     
         43 . The method of  claim 39 , wherein the patient is suffering from a muscle related disorder. 
     
     
         44 . The method of  claim 39 , wherein the patient has a bone disorder. 
     
     
         45 . The method  claim 39 , wherein the patient is need of bone growth or increased bone strength.