Human antibodies to pcsk9 for use in methods of treating particular groups of subjects

Abstract

The present invention relates to methods for treating diseases or conditions in which proprotein convertase subtilisin/kexin type 9 (PCSK9) expression or activity causes an impact by administration of PCSK9-specific antibodies or antigen-binding fragments thereof and preferably by additional administration of an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). The present invention further relates to PCSK9-specific antibodies or antigen-binding fragments thereof for use in the treatment of diseases or conditions in which PCSK9 expression or activity causes an impact. The present invention also relates to articles of manufacture comprising packaging material, PCSK9-specific antibodies or antigen-binding fragments thereof, and a label or packaging insert indicating which groups of patients can be treated with said antibodies or fragments, which groups of patients must not be treated with said antibodies or fragments, and which dosage regimen should be used. The present invention further relates to methods of testing the efficacy of PCSK9-specific antibodies or antigen-binding fragments thereof for the treatment of certain diseases or conditions and for the treatment of specific sub-groups of patients.

1 - 19 . (canceled) 
     
     
         20 . An article of manufacture comprising:
 (a) a packaging material;   (b) one or more unit dosage forms of 75 mg, 150 mg, or 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds proprotein convertase subtilisin/kexin type 9 (PCSK9); and   (c) a label or package insert contained within the packaging material indicating that the antibody or antigen-binding fragment can be administered to a patient having a disease or condition in which PCSK9 expression or activity causes an impact.   
     
     
         21 . The article of manufacture of  claim 20 , wherein the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases. 
     
     
         22 - 29 . (canceled) 
     
     
         30 . The article of manufacture of  claim 21 , wherein the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of elevated total cholesterol levels, elevated non-high-density lipoprotein cholesterol levels, elevated low-density lipoprotein cholesterol (LDL-C) levels, elevated apolipoprotein B100 (ApoB100) levels, primary hypercholesterolemia, familial hypercholesterolemia, non-familiar hypercholesterolemia (nonFH), heterozygous familial hypercholesterolemia (heFH), and hypercholesterolemia that is uncontrolled by statins. 
     
     
         31 . The article of manufacture of  claim 20 , wherein the patient further has type 2 diabetes mellitus, cholestatic liver diseases, nephrotic syndrome, hypothyroidism, or obesity. 
     
     
         32 . The article of manufacture of  claim 31 , wherein the patient has type 2 diabetes mellitus. 
     
     
         33 . The article of manufacture of  claim 20 , wherein the label or package insert further indicates that a concomitant statin therapy can be administered to the patient. 
     
     
         34 . The article of manufacture of  claim 20 , wherein the label or package insert further indicates that the patient falls into one or more of the following groups of subjects:
 (a) subjects having a serum LDL-C level of at least 100 mg/dL;   (b) subjects having a serum high-density lipoprotein cholesterol level of less than 40 mg/dL;   (c) subjects having a serum cholesterol level of at least 200 mg/dL; and   (d) subjects having a serum triacylglycerol level of at least 150 mg/dL, wherein said triacylglycerol level is determined after fasting for at least 8 hours.   
     
     
         35 . The article of manufacture of  claim 20 , wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain complementarity determining region (CDR) sequences set forth in SEQ ID NOs: 76, 78, and 80, and the three light chain CDR sequences set forth in SEQ ID NOs: 84, 86, and 88. 
     
     
         36 . The article of manufacture of  claim 35 , wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively. 
     
     
         37 . The article of manufacture of  claim 20 , wherein each of the unit dosage forms is 75 mg. 
     
     
         38 . The article of manufacture of  claim 20 , wherein each of the unit dosage forms is 150 mg. 
     
     
         39 . The article of manufacture of  claim 20 , wherein each of the unit dosage forms is 300 mg. 
     
     
         40 . The article of manufacture of  claim 20 , wherein each of the unit dosage forms is in a 1 ml injection solution. 
     
     
         41 . The article of manufacture of  claim 40 , wherein each of the unit dosage forms is 75 mg in a 1 ml injection solution. 
     
     
         42 . The article of manufacture of  claim 40 , wherein each of the unit dosage forms is 150 mg in a 1 ml injection solution. 
     
     
         43 . The article of manufacture of  claim 40 , wherein each of the unit dosage forms is 300 mg in a 2 ml injection solution. 
     
     
         44 . The article of manufacture of  claim 20 , wherein each of the unit dosage forms is in a hermetically sealed container selected from the group consisting of a vial, a sachette, a pre-filled syringe, a cartridge for a reusable syringe, a pre-filled autoinjector, and an applicator. 
     
     
         45 . The article of manufacture of  claim 20 , wherein the antibody or antigen-binding fragment thereof binds an epitope comprising one or more of amino acid residues at positions 238, 153, 159 and 343 of hPCSK9 (SEQ ID NO: 755). 
     
     
         46 . The article of manufacture of  claim 20 , wherein the label or package insert indicates that the antibody or antigen-binding fragment can be administered to the patient by subcutaneous injection. 
     
     
         47 . The article of manufacture of  claim 20 , wherein the antibody or antigen-binding fragment thereof achieves one or more of the following when administered to a subject: 
       (a) reduction of LDL-C of at least −60% to at least −75% relative to a predose level with a sustained reduction over at least a 14 day-period upon administering to a subject a dose of 150 mg every two weeks; 
       (b) reduction of LDL-C of at least −50% to −75% relative to a predose level with a sustained reduction over at least a 28 day-period upon administering to a subject a dose of 300 mg every four weeks; 
       (c) increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% relative to a predose level upon administering to a subject a dose of 150 mg every two weeks; and 
       (d) reduction of one or more of: total-cholesterol levels, ApoB levels, non HDL-C levels, and ApoB/ApoA-1 ratio. 
     
     
         48 . An article of manufacture comprising: 
       (a) a packaging material; 
       (b) one or more unit dosage forms of 75 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9; and 
       (c) a label or package insert contained within the packaging material indicating that the antibody or antigen-binding fragment can be administered to a patient having a disease or condition in which PCSK9 expression or activity causes an impact, 
       wherein the antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence and the LCVR amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively. 
     
     
         49 . An article of manufacture comprising: 
       (a) a packaging material; 
       (b) one or more unit dosage forms of 150 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9; and 
       (c) a label or package insert contained within the packaging material indicating that the antibody or antigen-binding fragment can be administered to a patient having a disease or condition in which PCSK9 expression or activity causes an impact, 
       wherein the antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence and the LCVR amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively. 
     
     
         50 . An article of manufacture comprising: 
       (a) a packaging material; 
       (b) one or more unit dosage forms of 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9; and 
       (c) a label or package insert contained within the packaging material indicating that the antibody or antigen-binding fragment can be administered to a patient having a disease or condition in which PCSK9 expression or activity causes an impact, 
       wherein the antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence and the LCVR amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively.