Pharmaceutical compositions comprising human antibodies to pcsk9

Abstract

The present invention relates to Pharmaceutical compositions comprising an antibody specifically binding to human proprotein convertase subtilisin/kexin type 9 (PCSK9), 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 .- 41 . (canceled) 
     
     
         42 . A method for preparing an article of manufacture comprising packaging one or more unit dosage forms of a pharmaceutical composition into a packaging material, wherein the pharmaceutical composition comprises a fixed dose of about 40 to about 500 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 (proprotein convertase subtilisin/kexin type 9), together with a label or package insert 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. 
     
     
         43 . The method of  claim 42 , 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. 
     
     
         44 . The method of  claim 43 , 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-familial hypercholesterolemia (nonFH), heterozygous familial hypercholesterolemia (heFH), and hypercholesterolemia that is uncontrolled by statins. 
     
     
         45 . The method of  claim 42 , wherein the patient further has type 2 diabetes mellitus, cholestatic liver diseases, nephrotic syndrome, hypothyroidism, or obesity. 
     
     
         46 . The method of  claim 45 , wherein the patient has type 2 diabetes mellitus. 
     
     
         47 . The method of  claim 42 , wherein the label or package insert further indicates that a concomitant statin therapy can be administered to the patient. 
     
     
         48 . The method of  claim 42 , 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.   
     
     
         49 . The method of  claim 42 , 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. 
     
     
         50 . The method of  claim 49 , 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. 
     
     
         51 . The method of  claim 42 , wherein each of the unit dosage forms is 75 mg. 
     
     
         52 . The method of  claim 42 , wherein each of the unit dosage forms is 150 mg. 
     
     
         53 . The method of  claim 42 , wherein each of the unit dosage forms is 300 mg. 
     
     
         54 . The method of  claim 42 , wherein each of the unit dosage forms is in a 1 ml injection solution. 
     
     
         55 . The method of  claim 54 , wherein each of the unit dosage forms is 75 mg in a 1 ml injection solution. 
     
     
         56 . The method of  claim 54 , wherein each of the unit dosage forms is 150 mg in a 1 ml injection solution. 
     
     
         57 . The method of  claim 54 , wherein each of the unit dosage forms is 300 mg in a 2 ml injection solution. 
     
     
         58 . The method of  claim 42 , 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. 
     
     
         59 . The method of  claim 42 , 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). 
     
     
         60 . The method of  claim 42 , wherein the label or package insert indicates that the antibody or antigen-binding fragment can be administered to the patient by subcutaneous injection. 
     
     
         61 . The method of  claim 42 , 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.   
     
     
         62 . A method for preparing an article of manufacture comprising packaging a pharmaceutical comprising one or more unit dosage forms of 75 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 (proprotein convertase subtilisin/kexin type 9), together with a label or package insert 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. 
     
     
         63 . A method for preparing an article of manufacture comprising packaging a pharmaceutical comprising one or more unit dosage forms of 150 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 (proprotein convertase subtilisin/kexin type 9), together with a label or package insert 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. 
     
     
         64 . A method for preparing an article of manufacture comprising packaging a pharmaceutical comprising one or more unit dosage forms of 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 (proprotein convertase subtilisin/kexin type 9), together with a label or package insert 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.