EP3634469A1 - Methods for treating hyperlipidemia in diabetic patients by administering a pcsk9 inhibitor - Google Patents

Methods for treating hyperlipidemia in diabetic patients by administering a pcsk9 inhibitor

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Publication number
EP3634469A1
EP3634469A1 EP18737034.1A EP18737034A EP3634469A1 EP 3634469 A1 EP3634469 A1 EP 3634469A1 EP 18737034 A EP18737034 A EP 18737034A EP 3634469 A1 EP3634469 A1 EP 3634469A1
Authority
EP
European Patent Office
Prior art keywords
patient
antibody
antigen
binding fragment
insulin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18737034.1A
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German (de)
English (en)
French (fr)
Inventor
Maja BUJAS-BOBANOVIC
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Biotechnology SAS
Original Assignee
Sanofi Biotechnology SAS
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Filing date
Publication date
Application filed by Sanofi Biotechnology SAS filed Critical Sanofi Biotechnology SAS
Priority claimed from PCT/IB2018/054182 external-priority patent/WO2018225041A1/en
Publication of EP3634469A1 publication Critical patent/EP3634469A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21062—Subtilisin (3.4.21.62)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the field of therapeutic treatments of diseases and disorders which are associated with elevated levels of lipids and lipoproteins. More specifically, the invention relates to the use of PCSK9 inhibitors to treat diabetic patients with hyperlipidemia, including hypercholesterolemia.
  • Hyperlipidemia is a general term that encompasses diseases and disorders characterized by or associated with elevated levels of lipids and/or lipoproteins in the blood. Hyperlipidemias include hypercholesterolemia, hypertriglyceridemia, combined
  • hyperlipidemia and elevated lipoprotein a (Lp(a)).
  • Lp(a) lipoprotein a
  • a particular prevalent form of hyperlipidemia in many populations is hypercholesterolemia.
  • Hypercholesterolemia particularly an increase in low-density lipoprotein (LDL) cholesterol (LDL-C) levels, constitutes a major risk for the development of atherosclerosis and coronary heart disease (CHD) (Sharrett et al., 2001 , Circulation 104:1 108-1 1 13).
  • LDL low-density lipoprotein
  • CHD coronary heart disease
  • LDL-C levels reduces the risk of CHD with a strong direct relationship between LDL-C levels and CHD events; for each 1 mmol/L ( ⁇ 40 mg/dL) reduction in LDL-C, cardiovascular disease (CVD) mortality and morbidity is lowered by 22%.
  • CVD cardiovascular disease
  • Greater reductions in LDL-C produce greater reduction in CHD events, and comparative data of intensive versus standard statin treatment suggest that the lower the LDL-C level, the greater the benefit in patients at very high cardiovascular (CV) risk.
  • CVD cardiovascular disease
  • T1 type 1
  • T2 type 2 diabetes mellitus
  • ASCVD atherosclerotic CVD
  • lowering LDL-C using statins leads to significant reductions in CV events in DM patients, with further CV risk reduction associated with additional LDL-C-lowering using concomitant ezetimibe.
  • many patients with DM continue to have persistent lipid abnormalities and are therefore exposed to a residual risk of CV events.
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • anti-PCSK9 antibodies have undergone extensive clinical investigation, the efficacy and safety of alirocumab in the diabetic population are not fully understood.
  • treatment regimens for anti-PCSK9 antibodies that provide optimal efficacy and safety for the treatment of hypercholesterolemia in diabetic patients receiving insulin therapy who are at high CV risk.
  • the instant disclosure provides methods for treating hypercholesterolemia in a patient with diabetes mellitus (DM) receiving insulin therapy.
  • the methods comprise administering one or more doses of an antibody or an antigen-binding fragment thereof which specifically binds human PCSK9 to a patient with
  • the patient has a high cardiovascular risk.
  • the patient receives a concomitant antidiabetic therapy in addition to insulin therapy.
  • the methods comprise a method for treating
  • T1 DM type 1 diabetes mellitus
  • PCSK9 subtilisin/kexin type 9
  • 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In other embodiments, 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In other embodiments, 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair comprising SEQ ID NOs: 1/6.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof competes for binding with an antibody or antigen-binding fragment thereof that comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof binds to an epitope on PCSK9 that overlaps with the epitope of an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91 , and 92.
  • the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:85, and an LCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:89.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab and LY3015014. In certain embodiments, the antibody or antigen-binding fragment thereof is alirocumab.
  • the method disclosed herein further comprises (c) administering to the patient one or more following doses of 75 mg of the antibody or antigen-binding fragment thereof about every two weeks if, e.g., after 8 weeks, the LDL-C level in the patient is lower than the threshold level, or administering one or more following doses of 150 mg of the antibody or antigen-binding fragment thereof about every two weeks if, e.g., after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level.
  • the threshold level is 70 mg/dL.
  • the method disclosed herein further comprises (c) administering to the patient one or more following doses of 300 mg of the antibody or antigen-binding fragment thereof about every four weeks if, e.g., after 8 weeks, the LDL-C level in the patient is lower than the threshold level, or administering one or more following doses of 150 mg of the antibody or antigen-binding fragment thereof about every two weeks if, e.g., after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level.
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • the statin therapy is a maximally tolerated dose statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.ln certain embodiments, the patient is intolerant to a statin.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin,
  • the patient further receives a further concomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional anti-diabetic therapy is selected from the group consisting of a glucagon like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha- glucosidase inhibitor, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator-activated receptor (PPAR-)(alpha, gamma or alpha/gamma) agonist or modulator, amylin, an amylin analogue, a G-protein coupled receptor 1 19
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient, e.g., by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, e.g., by at least 25%, 30%, 35%, or 40%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient (e.g., by at least about 6.0%, about 6.5%, about 7.0% or about 7.5% after 12 or 24 weeks of treatment).
  • ApoC3 apolipoprotein C3
  • the antibody or antigen-binding fragment thereof reduces the number of lipoprotein particles in the patient (e.g. , by at least about 20%, about 30%, about 40% or about 50%% after 12 or 24 weeks of treatment). In other embodiments, the antibody or antigen-binding fragment thereof reduces the size of lipoprotein particles in the patient (e.g., by at least about 1.5%, about 2%, about 2.5%, or about 3% after 12 or 24 weeks of treatment).
  • the antibody or antigen-binding fragment thereof (a) does not affect the hemoglobin A1 c (HbA1 c) level of the patient; and/or (b) does not affect the fasting plasma glucose (FPG) level of the patient.
  • the methods comprise a method for treating hypercholesterolemia in a patient with type 1 diabetes mellitus (T1 DM), the method comprising:
  • PCSK9 subtilisin/kexin type 9
  • the methods comprise a method for treating hypercholesterolemia in a patient with type 1 diabetes mellitus (T1 DM), the method comprising:
  • subtilisin/kexin type 9 PCSK9; and (c) administering to the patient one or more following doses of 300 mg of the antibody or antigen-binding fragment thereof about every four weeks if, after 8 weeks, the LDL-C level in the patient is higher than a threshold level, or administering one or more following doses of 150 mg of the antibody or antigen-binding fragment thereof about every two weeks if, after 8 weeks, the LDL-C level in the patient is lower than or equal to the threshold level,
  • the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6, and wherein the patient receives a concomitant insulin therapy.
  • the threshold level is 15 mg/dL. In another embodiment, the threshold level is 25 mg/dL.
  • the methods comprise a method for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM) , the method comprising:
  • PCSK9 subtilisin/kexin type 9
  • 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In other embodiments, 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In other embodiments, 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair comprising SEQ ID NOs: 1/6.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof competes for binding with an antibody or antigen-binding fragment thereof that comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof binds to an epitope on PCSK9 that overlaps with the epitope of an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid 5 sequence of SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof comprises the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) and a light chain variable region (LCVR) comprising the amino acid sequences set forth in SEQ ID NOs: 85 and 89, respectively.
  • the antibody or antigenic) binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91 , and 92.
  • the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:85, and an LCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the 15 amino acid sequence set forth in SEQ ID NO:89.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab and LY3015014. In certain embodiments, the antibody or antigen-binding fragment thereof is alirocumab.
  • the method disclosed herein further comprises (c)
  • the threshold level is 70 mg/dL.
  • the method disclosed herein further comprises (c) administering to the patient one or more following doses of 300 mg of the antibody or antigen-binding fragment thereof about every four weeks if, e.g., after 8 weeks, the LDL-C
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • the statin therapy is a maximally tolerated dose statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the patient is intolerant to a statin.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin,
  • the patient further receives a concomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional anti-diabetic therapy is selected from the group consisting of a glucagon like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator- activated receptor (PPAR-)(alpha, gamma or alpha/
  • GLP-1 glucose-dependent insulinotropic
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient, e.g., by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, e.g., by at least 20%, 25%, 30%, or 35%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient (e.g., by at least about 6.0%, about 6.5%, about 7.0% or about 7.5% after 12 or 24 weeks of treatment).
  • ApoC3 apolipoprotein C3
  • the antibody or antigen-binding fragment thereof reduces the number of lipoprotein particles in the patient (e.g. , by at least about 20%, about 30%, about 40% or about 50%% after 12 or 24 weeks of treatment). In other embodiments, the antibody or antigen-binding fragment thereof reduces the size of lipoprotein particles in the patient (e.g., by at least about 1.5%, about 2%, about 2.5%, or about 3% after 12 or 24 weeks of treatment).
  • the antibody or antigen-binding fragment thereof (a) does not affect the hemoglobin A1 c (HbA1 c) level of the patient; and/or (b) does not affect the fasting plasma glucose (FPG) level of the patient.
  • HbA1 c hemoglobin A1 c
  • FPG fasting plasma glucose
  • the methods comprise a method for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM), the method comprising:
  • the methods comprise a method for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM), the method comprising:
  • PCSK9 subtilisin/kexin type 9
  • the threshold level is 15 mg/dL. In another embodiment, the threshold level is 25 mg/dL.
  • the methods comprise a method for treating hypercholesterolemia in a patient with T2DM and atherosclerotic cardiovascular disease (ASCVD), the method comprising:
  • PCSK9 subtilisin/kexin type 9
  • the ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease.
  • CHD comprises acute myocardial infarction, silent myocardial infarction, and unstable angina.
  • the 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In certain embodiments, the 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks. In certain embodiments, the 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair comprising SEQ ID NOs: 1/6.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope on PCSK9 that overlaps with the epitope of an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof comprises the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) and a light chain variable region (LCVR) comprising the amino acid sequences set forth in SEQ ID NOs: 85 and 89, respectively.
  • the antibody or antigen- binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91 , and 92.
  • the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:85, and an LCVR having an amino acid sequence at least 90%, 95%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:89.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab, and LY3015014. In certain embodiments, the antibody or antigen-binding fragment thereof is alirocumab.
  • the method further comprises:
  • the method further comprises:
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • the statin therapy is a maximally tolerated dose statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the patient is intolerant to a statin.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin.
  • the patient receives a concomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional anti-diabetic therapy is selected from the group consisting of an a glucagon like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator-activated receptor (PPAR-)(alpha, gamma or alpha/gamma) agonist or modulator, amylin, an amylin analogue, a G-protein coupled receptor 1 19
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient, e.g., by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, e.g., by at least 20%, 25%, 30%, 35%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the number and/or size of lipoprotein particles in the patient. In certain embodiments, the antibody or antigen-binding fragment thereof:
  • the methods comprise a method for treating hypercholesterolemia in a patient with T2DM and ASCVD, the method comprising:
  • the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6, and wherein the patient receives a concomitant insulin therapy.
  • Figure 1 is a diagram illustrating the overall design of the main phase of the study described in Example 2 herein.
  • the study includes a screening period, a double-blinded treatment period, and a safety observation period.
  • Figure 2 is a graph showing the LS means (+/-SE) of percent change of calculated LDL-C levels from baseline in the ITT population of patients with Type 1 Diabetes as per IVRS.
  • Least-squares (LS) means and standard errors (SE) were taken from mixed-effect model with repeated measures (MMRM) analysis.
  • the model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, and the interactions treatment group-by-time point, strata-by-time point, treatment group-by-strata and treatment group-by-strata-by-time point, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline-by-time point interaction.
  • MMRM model was run on all patients in the ITT population (i.e. Type 1 and Type 2 Diabetes patients).
  • Figure 3 is a graph showing the LS means (+/-SE) of percent change of calculated LDL-C levels from baseline in the ITT population of patients with Type 2 Diabetes as per IVRS.
  • Least-squares (LS) means and standard errors (SE) were taken from mixed-effect model with repeated measures (MMRM) analysis.
  • the model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, and the interactions treatment group-by-time point, strata-by-time point, treatment group-by-strata and treatment group-by-strata-by-time point, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline-by-time point interaction.
  • MMRM model was run on all patients in the ITT population (i.e. Type 1 and Type 2 Diabetes patients).
  • Figure 4 is a graph showing the percentage changes from baseline to Week 24 in non-HDL-C, LDL-C, ApoB, and LDL-PN in the ITT population with Type 2 Diabetes and ASCVD.
  • Figure 5 is a graph showing the percentages of individuals achieving non-HDL-C ⁇ 100 mg/dL, LDL-C ⁇ 70 mg/dL, and ApoB ⁇ 80 mg/dL at Week 24 in the ITT population with Type 2 Diabetes and ASCVD.
  • compositions for treating diabetic patients with hypercholesterolemia on insulin therapy result in a reduction of lipoprotein levels (e.g., LDL-C and/or Lp(a)) in the serum of such patients.
  • lipoprotein levels e.g., LDL-C and/or Lp(a)
  • the present disclosure also provides a PCSK9 inhibitor (e.g., an antibody or antigen-binding fragment thereof that specifically binds PCSK9 (e.g., human PCSK9) or a composition comprising the PCSK9 inhibitor for use in treating a diabetic patients with hypercholesterolemia on insulin therapy.
  • a PCSK9 inhibitor e.g., an antibody or antigen-binding fragment thereof that specifically binds PCSK9 (e.g., human PCSK9) or a composition comprising the PCSK9 inhibitor for use in treating a diabetic patients with hypercholesterolemia on insulin therapy.
  • the PCSK9 inhibitor or composition is useful in reducing the levels of lipoprotein (e.g., LDL-C and/or Lp(a)) in the serum of such patients.
  • lipoprotein means a biomolecular particle containing both protein and lipid.
  • lipoproteins include, e.g., low density lipoprotein (LDL), very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and lipoprotein (a) (Lp(a)).
  • Diabetes mellitus is a group of metabolic diseases in which a person has high blood sugar levels, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.
  • the most common types of diabetes are: (1 ) type 1 diabetes, where the body fails to produce insulin; (2) type 2 diabetes, where the body fails to use insulin properly, combined with an increase in insulin deficiency over time; and (3) gestational diabetes, where women develop diabetes due to their pregnancy. All forms of diabetes increase the risk of long-term complications, which typically develop after many years.
  • macrovascular disease arising from atherosclerosis of larger blood vessels
  • microvascular disease arising from damage of small blood vessels.
  • macrovascular disease conditions are ischemic heart disease, myocardial infarction, stroke and peripheral vascular disease.
  • microvascular diseases are diabetic retinopathy, diabetic nephropathy, as well as diabetic neuropathy.
  • the patient to be treated has type 1 diabetes mellitus (T1 DM) or type 2 diabetes mellitus (T2DM) and is receiving insulin therapy.
  • T1 DM type 1 diabetes mellitus
  • T2DM type 2 diabetes mellitus
  • the patient has been diagnosed with T1 DM or T2DM for at least one year.
  • the patient was diagnosed with T1 DM prior to the age of 30 years.
  • the T1 DM patient has a C-peptide level lower than 0.2 pmol/mL.
  • the patient has a glycosylated hemoglobin (HbA1 c) level lower than 10%.
  • HbA1 c glycosylated hemoglobin
  • the patient to be treated has
  • LMT lipid modifying therapy
  • Hypercholesterolemia is considered not to be adequately controlled by an LMT if serum LDL-C concentrations in patient are not reduced to a recognized, medically-acceptable level, e.g., less than 70 mg/dL, (taking into account the patient's relative risk of coronary heart disease) after at least 4 weeks on the LMT.
  • the LMT is a maximally tolerated statin therapy.
  • maximum tolerated statin therapy means the highest dose of statin that can be administered to a patient without causing unacceptable adverse side effects in that patient.
  • the methods disclosed herein include treating a patient with T1 DM or T2DM who has hypercholesterolemia that is not adequately controlled by a daily dose of a statin selected from the group consisting of atorvastatin (including atorvastatin + ezetimibe), rosuvastatin, cerivastatin, pitavastatin, fluvastatin, lovastatin, simvastatin (including simvastatin + ezetimibe), pravastatin, and combinations thereof.
  • a patient does not receive a concomitant statin therapy if the patient is intolerant to this therapy.
  • Statin intolerant patients may have, for example, skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping, that begin or increase during statin therapy and stopped when statin therapy is discontinued.
  • the present methods and compositions are useful for treating patients who have hypercholesterolemia and diabetes and are receiving insulin therapy.
  • the patient to be treated may also exhibit one or more of additional selection criteria. For example, a patient may be selected for treatment if the patient has a calculated LDL-C level greater than or equal to 70 mg/dL, 100 mg/dL, or 130 mg/dL.
  • the patient may be treated with an maximally tolerated dose of statin, optionally in combination with at least one other lipid modifying therapy (LMT) for at least 4 weeks, or wherein the patient has been treated with optimal dose of at least one non-statin LMT for at least 4 weeks if the patient is statin intolerant.
  • LMT lipid modifying therapy
  • statin can be defined, for example, as the dose prescribed based on regional practice or local guidelines or is the dose that is maximally tolerated due to adverse effects on higher doses as specified in the local prescribing information for pediatric patients.
  • Statin intolerance can be defined, for example, as inability to tolerate at least 2 statins: one statin at the lowest daily starting dose, and another statin at any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping, that began or increased during statin therapy and stopped when statin therapy was discontinued.
  • Patients not receiving a daily regimen of a statin e.g. , 1 to 3 times weekly are also considered as not able to tolerate a daily dose.
  • a patient may be selected for treatment if the patient has a high cardiovascular (CV) risk.
  • CVD includes without limitation coronary heart disease (CHD) and CHD risk equivalents.
  • CHD includes without limitation acute myocardial infarction (Ml), silent Ml, unstable angina, coronary revascularization procedure (e.g. , percutaneuous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)), and clinically significant CHD (e.g., diagnosed by invasive or noninvasive testing, such as coronary angiography, stress test using treadmill, stress echocardiography, or nuclear imaging).
  • CHD risk equivalents include without limitation peripheral arterial disease (e.g., as described in the inclusion criteria of Example 2) and previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, of atherothrombotic origin.
  • CV risk factors include without limitation hypertension, current cigarette smoking, age ⁇ 45 years for men and ⁇ 55 years for women, history of micro/macroalbuminuria, history of diabetic retinopathy, family history of premature CHD (in father or brother before 55 years of age; in mother or sister before 65 years of age), low HDL-C (male ⁇ 40 mg/dL [1 .0 mmol/L] and female ⁇ 50 mg/dL [1 .3 mmol/L]), and documented chronic kidney disease (CKD) (e.g., as defined in the inclusion criteria of Example 2).
  • CKD documented chronic kidney disease
  • the high CV risk patient has atherosclerotic cardiovascular disease (ASCVD).
  • ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease.
  • CHD comprises acute myocardial infarction, silent myocardial infarction, and unstable angina.
  • the CHD is defined as acute myocardial infarction, silent myocardial infarction, or unstable angina.
  • insulin therapy comprising insulin or its derivatives.
  • Insulins on the market differ in the origin of the insulin (e.g., bovine, porcine, human insulin) and also in their composition, whereby the profile of action (onset of action and duration of action) can be influenced.
  • the profile of action onset of action and duration of action
  • insulin products it is possible to obtain a wide variety of profiles of action and to set blood sugar levels which are as close as possible to physiological.
  • Exemplary insulin therapies may include naturally- occurring insulin, such as human insulin, as well as modified insulins with an extended duration of action, such as insulin glargine (Gly(A21)-Arg(B31)-Arg(B32) human insulin, e.g., Lantus ® ).
  • Insulin glargine is injected as an acidic, clear solution and, on account of its solution properties in the physiological pH range of the subcutaneous tissue, is precipitated as a stable hexamer associate.
  • Insulin glargine is injected once daily and is notable over other long-activity insulins for its flat serum profile and the associated reduction in the risk of nocturnal hypoglycemias (Schubert-Zsilavecz et al., 2:125-130 (2001)).
  • Insulin glargine may be administered at concentrations higher than 100U/mL, e.g. 270 - 330U/mL of insulin glargine or 300U/mL of insulin glargine (as disclosed in EP 2387989),
  • Other exemplary insulin therapies include: insulin glulisine (e.g. Apidra ® ), insulin detemir (e.g. Levemir ® ), insulin lispro (e.g. Humalog ® , Liprolog ® ), insulin degludec (e.g. DegludecPlus ® , IdegLira (NN9068)), insulin aspart and aspart formulations (e.g.
  • basal insulin and analogues e.g. LY2605541 , LY2963016, NN1436), PEGylated insulin lispro (e.g. LY- 275585), long-acting insulins (e.g. NN1436, Insumera (PE0139), AB-101 , AB-102, Sensulin LLC), intermediate-acting insulins (e.g. Humulin ® N, Novolin ® N), fast-acting and short-acting insulins (e.g.
  • Humulin ® R Novolin ® R, Linjeta ® (VIAject ® ), PH20 insulin, NN1218, HinsBet ® ), premixed insulins, SuliXen , NN1045, insulin plus Symlin , PE-0139, ACP-002 hydrogel insulin, and oral, inhalable, transdermal and buccal or sublingual insulins (e.g.
  • Exubera ® Nasulin ® , Afrezza ® , insulin tregopil, TPM-02 insulin, Capsulin ® , Oral-lyn ® , Cobalamin ® oral insulin, ORMD-0801 , Oshadi oral insulin, NN1953, NN1954, NN1956, VIAtab ® ).
  • Also suitable are those insulin derivatives which are bonded to albumin or another protein by a bifunctional linker.
  • the methods comprise administering to a patient a therapeutic composition comprising a PCSK9 inhibitor.
  • a PCSK9 inhibitor is any agent which binds to or interacts with human PCSK9 and inhibits the normal biological function of
  • PCSK9 in vitro or in vivo.
  • categories of PCSK9 inhibitors include small molecule PCSK9 antagonists, nucleic acid-based inhibitors of PCSK9 expression or activity (e.g., siRNA or antisense), peptide-based molecules that specifically interact with PCSK9 (e.g., peptibodies), receptor molecules that specifically interact with PCSK9, proteins comprising a ligand-binding portion of an LDL receptor, PCSK9-binding scaffold molecules (e.g.
  • PCSK9 inhibitors that can be used in the context of the present methods are anti-PCSK9 antibodies or antigen-binding fragments of antibodies that specifically bind human PCSK9.
  • human proprotein convertase subtilisin/kexin type 9 or "human PCSK9” or “hPCSK9”, as used herein, refers to PCSK9 having the nucleic acid sequence shown in SEQ ID NO:197 and the amino acid sequence of SEQ ID NO:198, or a biologically active fragment thereof.
  • antibody is intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g. , IgM).
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, C H 1 , C H 2 and C H 3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
  • the light chain constant region comprises one domain (C L 1 ).
  • V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino- terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the anti-PCSK9 antibody may be identical to the human germline sequences, or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side- by-side analysis of two or more CDRs.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody, “antigen- binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g. , from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g. , phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained
  • FR3-CDR3-FR4 peptide FR3-CDR3-FR4 peptide.
  • Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen- binding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • shark variable IgNAR domains are also encompassed within the expression "antigen- binding fragment," as used herein.
  • An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the V H and V L domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain V H -V H , V H -V L or V L -V L dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V L domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigen-binding fragment of an antibody include: (i) V H -C H 1 ; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H - C H 1 -C H 2; (v) VH-CH1 -CH2-C h 3; (vi) VH-C h 2-C h 3; (vii) V H -C L ; (viii) V L -C H 1 ; (ix) V L -C H 2; (x) V L - C H 3; (xi) V L -C H 1 -C H 2; (xii) V L -C h 1 -CH2-C h 3; (xiii) V L -C H 2-C H 3
  • variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 (e.g. , 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or V L domain (e.g., by disulfide bond(s)).
  • antigen-binding fragments may be monospecific or multispecific (e.g., bispecific).
  • a multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present methods using routine techniques available in the art.
  • the constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity.
  • the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • human antibody is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g. , a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • Human antibodies can exist in two forms that are associated with hinge
  • an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond.
  • the dimers are not linked via inter- chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody).
  • the frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody.
  • a single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human lgG1 hinge.
  • the instant methods encompass antibodies having one or more mutations in the hinge, C H 2 or C H 3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
  • an "isolated antibody,” as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody” for purposes of the present methods.
  • An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the term "specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions.
  • Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
  • an antibody that "specifically binds" PCSK9 includes antibodies that bind PCSK9 or portion thereof with a K D of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay.
  • An isolated antibody that specifically binds human PCSK9 has cross-reactivity to other antigens, such as PCSK9 molecules from other (non
  • the anti-PCSK9 antibodies useful for the present methods may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases.
  • the methods include the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations").
  • Germline mutations A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof.
  • all of the framework and/or CDR residues within the V H and/or V L domains are mutated back to the residues found in the original germline sequence from which the antibody was derived.
  • only certain residues are mutated back to the original germline sequence, e.g. , only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1 , CDR2 or CDR3.
  • one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e.
  • the antibodies may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence.
  • antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.
  • the use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present methods.
  • the methods include the use of anti-PCSK9 antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions.
  • the present methods include the use of anti- PCSK9 antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g. , 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein.
  • surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcoreTM system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).
  • K D is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.
  • epitope refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope.
  • a single antigen may have more than one epitope.
  • different antibodies may bind to different areas on an antigen and may have different biological effects.
  • Epitopes may be either conformational or linear.
  • a conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain.
  • a linear epitope is one produced by adjacent amino acid residues in a polypeptide chain.
  • an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.
  • the anti-PCSK9 antibody used in the methods is an antibody with pH-dependent binding characteristics.
  • pH-dependent binding means that the antibody or antigen-binding fragment thereof exhibits "reduced binding to PCSK9 at acidic pH as compared to neutral pH" (for purposes of the present disclosure, both expressions may be used interchangeably).
  • antibody with pH-dependent binding characteristics includes antibodies and antigen-binding fragments thereof that bind PCSK9 with higher affinity at neutral pH than at acidic pH.
  • the antibodies and antigen-binding fragments bind PCSK9 with at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more times higher affinity at neutral pH than at acidic pH.
  • the anti-PCSK9 antibodies with pH-dependent binding characteristics may possess one or more amino acid variations relative to the parental anti- PCSK9 antibody.
  • an anti-PCSK9 antibody with pH-dependent binding characteristics may contain one or more histidine substitutions or insertions, e.g., in one or more CDRs of a parental anti-PCSK9 antibody.
  • methods are provided comprising administering an anti-PCSK9 antibody which comprises CDR amino acid sequences (e.g., heavy and light chain CDRs) which are identical to the CDR amino acid sequences of a parental anti-PCSK9 antibody, except for the substitution of one or more amino acids of one or more CDRs of the parental antibody with a histidine residue.
  • the anti-PCSK9 antibodies with pH-dependent binding may possess, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more histidine substitutions, either within a single CDR of a parental antibody or distributed throughout multiple (e.g., 2, 3, 4, 5, or 6) CDRs of a parental anti- PCSK9 antibody.
  • the present methods include the use of anti-PCSK9 antibodies with pH-dependent binding comprising one or more histidine substitutions in HCDR1 , one or more histidine substitutions in HCDR2, one or more histidine substitutions in HCDR3, one or more histidine substitutions in LCDR1 , one or more histidine substitutions in LCDR2, and/or one or more histidine substitutions in LCDR3, of a parental anti-PCSK9 antibody.
  • the expression “acidic pH” means a pH of 6.0 or less (e.g., less than about 6.0, less than about 5.5, less than about 5.0, etc.).
  • the expression “acidic pH” includes pH values of about 6.0, 5.95, 5.90, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1 , 5.05, 5.0, or less.
  • the expression “neutral pH” means a pH of about 7.0 to about 7.4.
  • the expression “neutral pH” includes pH values of about 7.0, 7.05, 7.1 , 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.
  • Non-limiting examples of anti-PCSK9 antibodies that can be used in the context of the present methods include, e.g., alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab, LY3015014, or antigen-binding portions of any of the foregoing antibodies.
  • Methods for generating human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present methods to make human antibodies that specifically bind to human PCSK9.
  • VELOCIMMUNETM technology see, for example, US 6,596,541 , Regeneron Pharmaceuticals or any other known method for generating monoclonal antibodies
  • high affinity chimeric antibodies to PCSK9 are initially isolated having a human variable region and a mouse constant region.
  • the VELOCIMMUNE® technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation.
  • the DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions.
  • the DNA is then expressed in a cell capable of expressing the fully human antibody.
  • lymphatic cells such as B-cells
  • the lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest.
  • DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain.
  • Such an antibody protein may be produced in a cell, such as a CHO cell.
  • DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.
  • high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region.
  • the antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc, using standard procedures known to those skilled in the art.
  • the mouse constant regions are replaced with a desired human constant region to generate the fully human antibody, for example wild- type or modified lgG1 or lgG4. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
  • the antibodies that can be used possess high affinities, as described above, when measured by binding to antigen either immobilized on solid phase or in solution phase.
  • the mouse constant regions are replaced with desired human constant regions to generate the fully human antibodies. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
  • human antibodies or antigen-binding fragments of antibodies that specifically bind PCSK9 which can be used in the context of the methods include any antibody or antigen-binding fragment which comprises the three heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 and 1 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
  • HCVR heavy chain variable region
  • human antibodies or antigen-binding fragments of antibodies that specifically bind PCSK9 which can be used in the context of the methods include any antibody or antigen-binding fragment which comprises the three heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs 37, 45, 53, 61 , 69, 77, 85, 93, 101 , 109, 1 17, 125, 133, 141 , 149, 157, 165, 173, 181 , and 189, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
  • HCVR heavy chain variable region
  • the antibody or antigen-binding fragment may comprise the three light chain CDRs (LCVR1 , LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs 6 and 15, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
  • LCVR1 light chain CDRs
  • LCVR2 light chain variable region
  • the antibody or antigen-binding fragment may comprise the three light chain CDRs (LCVR1 , LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs 41 , 49, 57, 65, 73, 81 , 89, 97, 105, 1 13, 121 , 129, 137, 145, 153, 161 , 169, 177, 185, and 193, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
  • LCVR light chain variable region
  • sequence identity between two amino acids sequences is determined over the entire length of the reference amino acid sequence, i.e. the amino acid sequence identified with a SEQ ID NO, using the best sequence alignment and/or over the region of the best sequence alignment between the two amino acid sequences, wherein the best sequence alignment can be obtained with art known tools, e.g. Align, using standard settings, preferably EMBOSS::needle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.
  • the antibody or antigen-binding protein comprises the six CDRs (HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) selected from the group consisting of SEQ ID NOs:1/6 and 1 1/15.
  • the antibody or antigen-binding protein comprises the six CDRs (HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) selected from the group consisting of SEQ ID NOs:37/41 , 45/49, 53/57, 61/65, 69/73, 77/81 , 85/89, 93/97, 101/105, 109/1 13, 1 17/121 , 125/129, 133/137, 141 /145, 149/153, 157/161 , 165/169, 173/177, 181/185, and 189/193.
  • HCVR/LCVR heavy and light chain variable region amino acid sequence pairs
  • the anti-PCSK9 antibody, or antigen-binding protein, that can be used in the methods has HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 amino acid sequences selected from SEQ ID NOs: 2/3/4/7/8/10 (mAb316P [also referred to as "REGN727,” or “alirocumab”]) and 12/13/14/16/17/18 (mAb300N) (See US Patent App. Publ No. 2010/0166768) and 12/13/14/16/17/18, wherein SEQ ID NO:16 comprises a substitution of histidine for leucine at amino acid residue 30 (L30H).
  • the antibody or antigen-binding protein comprises
  • the antibody or antigen-binding protein comprises an HCVR amino acid sequence of SEQ ID NO: 1 and an LCVR amino acid sequence of SEQ ID NO: 6. In certain exemplary embodiments, the antibody or antigen-binding protein comprises an HCVR amino acid sequence of SEQ ID NO: 1 1 and an LCVR amino acid sequence of SEQ ID NO: 15.
  • the antibody or antigen-binding protein comprises an HCVR amino acid sequence of SEQ ID NO: 1 1 and an LCVR amino acid sequence of SEQ ID NO: 15 comprising a substitution of histidine for leucine at amino acid residue 30 (L30H).
  • the present methods include administering a PCSK9 inhibitor to a patient, wherein the PCSK9 inhibitor is contained within a pharmaceutical composition.
  • the pharmaceutical compositions are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's
  • compositions include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax
  • Example pharmaceutical formulations comprising anti-PCSK9 antibodies that can be used in the context of the present methods include any of the formulations as set forth in US 8,795,669 (describing, inter alia, exemplary formulations comprising alirocumab), or in [00108] Various delivery systems are known and can be used to administer the
  • composition e.g., encapsulation in liposomes, microparticles,
  • microcapsules capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432).
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • a pharmaceutical composition can be delivered subcutaneously or intravenously with a standard needle and syringe.
  • a pen delivery device readily has applications in delivering a pharmaceutical composition.
  • Such a pen delivery device can be reusable or disposable.
  • a reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused.
  • a disposable pen delivery device there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
  • Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition. Examples include, but are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and Co., Indianapolis, IN),
  • NOVOPENTM I, II and III Novo Nordisk, Copenhagen, Denmark
  • NOVOPEN JUNIORTM Novo Nordisk, Copenhagen, Denmark
  • BDTM pen Becton Dickinson, Franklin Lakes, NJ
  • OPTIPENTM OPTIPEN PROTM
  • OPTIPEN STARLETTM OPTICLIKTM
  • SURECLICKTM SOLOSTARTM pen
  • FLEXPENTM Novo Nordisk
  • KWIKPENTM Eli Lilly
  • the pharmaceutical composition can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201).
  • polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida.
  • a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of
  • the injectable preparations may include dosage forms for intravenous,
  • injectable preparations may be prepared by known methods.
  • the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil
  • oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • the amount of PCSK9 inhibitor (e.g., anti-PCSK9 antibody) administered to a patient is, generally, a therapeutically effective amount.
  • therapeutically effective amount means a dose of PCSK9 inhibitor that results in a detectable reduction (at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more from baseline) in one or more parameters selected from the group consisting of LDL-C, ApoB, ApoB100, non-HDL-C, total cholesterol, VLDL-C, triglycerides, ApoC3, TRL particles, Lp(a) and remnant cholesterol).
  • a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1 .0 mg, about 1 .5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420
  • a therapeutically effective amount of an anti-PCSK9 antibody is 30 mg, 40 mg or 75 mg (e.g., in the case of alirocumab for patients with body weight less than 50 kg, and/or younger than or equal to 17 years old), 50 mg, 75 mg or 150 mg (e.g., in the case of alirocumab for patients with body weight greater than or equal to 50 kg, and/or younger than or equal to 17 years old), or 140 mg or 420 mg (e.g., in the case of evolocumab).
  • Other dosing amounts of PCSK9 inhibitors will be apparent to persons of ordinary skill in the art.
  • the amount of anti-PCSK9 antibody contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e. , mg/kg).
  • the anti-PCSK9 antibody may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of body weight.
  • multiple doses of a PCSK9 inhibitor may be administered to a subject over a defined time course (e.g., on top of a daily therapeutic statin regimen or other background LMT).
  • the methods according to this aspect comprise sequentially administering to a subject multiple doses of a PCSK9 inhibitor.
  • “sequentially administering” means that each dose of PCSK9 inhibitor is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
  • the present methods includes sequentially administering to the patient a single initial dose of a PCSK9 inhibitor, followed by one or more secondary doses of the PCSK9 inhibitor, and optionally followed by one or more tertiary doses of the PCSK9 inhibitor.
  • the terms "initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the individual doses of a pharmaceutical composition comprising a PCSK9 inhibitor.
  • the "initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses may all contain the same amount of the PCSK9 inhibitor, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of PCSK9 inhibitor contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment.
  • two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").
  • each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , 1 1 ⁇ 2, 2, 21 ⁇ 2, 3, 31 ⁇ 2, 4, 41 ⁇ 2, 5, 51 ⁇ 2, 6, 61 ⁇ 2, 7, 71 ⁇ 2, 8, 81 ⁇ 2, 9, 91 ⁇ 2, 10, 101 ⁇ 2, 1 1 , 1 1 1 ⁇ 2, 12, 121 ⁇ 2, 13, 131 ⁇ 2, 14, 141 ⁇ 2, 15, 151 ⁇ 2, 16, 161 ⁇ 2, 17, 171 ⁇ 2, 18, 181 ⁇ 2, 19, 191 ⁇ 2, 20, 201 ⁇ 2, 21 , 21 1 ⁇ 2, 22, 221 ⁇ 2, 23, 231 ⁇ 2, 24, 241 ⁇ 2, 25, 251 ⁇ 2, 26, 261 ⁇ 2, or more) weeks after the immediately preceding dose.
  • the phrase "the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antigen-binding molecule which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
  • the methods according to this aspect may comprise administering to a patient any number of secondary and/or tertiary doses of a PCSK9 inhibitor.
  • a single secondary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
  • only a single tertiary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
  • each secondary dose may be administered at the same frequency as the other secondary doses.
  • each secondary dose may be administered to the patient 1 to 2, 4, 6, 8 or more weeks after the immediately preceding dose.
  • each tertiary dose may be administered at the same frequency as the other tertiary doses.
  • each tertiary dose may be administered to the patient 1 to 2, 4, 6, 8 or more weeks after the immediately preceding dose.
  • the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
  • the present methods include administration regimens comprising an up-titration option (also referred to herein as "dose modification").
  • an "up-titration option” means that, after receiving a particular number of doses of a PCSK9 inhibitor, if a patient has not achieved a specified reduction in one or more defined therapeutic parameters, the dose of the PCSK9 inhibitor is thereafter increased.
  • a therapeutic regimen comprising administration of 75 mg doses of an anti-PCSK9 antibody to a patient at a frequency of once every two weeks, if after 8 weeks (i.e., 5 doses administered at Week 0, Week 2 and Week 4, Week 6 and Week 8), the patient has not achieved a serum LDL-C concentration of less than 70 mg/dL, then the dose of anti-PCSK9 antibody is increased to e.g., 150 mg administered once every two weeks thereafter (e.g. , starting at Week 10 or Week 12, or later).
  • the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 75 mg at a frequency of once every two weeks.
  • the about 75 mg dose is maintained if the patient's LDL-C measured after one or more, two or more, three or more, four or more, or five or more doses is ⁇ 70 mg/dL.
  • the about 75 mg dose is discontinued if the patient's LDL-C measured after one or more, two or more, three or more, four or more, or five or more doses remains >70 mg/dL, and the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is subsequently administered to the patient at a dose of about 150 mg at a frequency of once every two weeks.
  • the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 300 mg at a frequency of once every four weeks. In certain embodiments, the about 300 mg dose is maintained if the patient's LDL-C measured after one or more, two or more, three or more, four or more, or five or more doses is ⁇ 70 mg/dL.
  • the about 300 mg dose is discontinued if the patient's LDL-C measured after one or more, two or more, three or more, four or more, or five or more doses remains >70 mg/dL, and the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is subsequently administered to the patient at a dose of about 150 mg at a frequency of once every two weeks.
  • the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 150 mg at a frequency of once every two weeks.
  • the about 150 mg dose is discontinued if the patient's LDL-C measured after at least one dose or at least two, three, four, or five consecutive doses is ⁇ 10, 15, 20, or 25 mg/dL, and the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is subsequently administered to the patient at a dose of about 75 mg at a frequency of once every two weeks.
  • the about 150 mg dose is administered to the patient as a constant dose.
  • the about 150 mg dose is administered to the patient after a dose adjustment as disclosed herein (e.g., from about 75 mg every two week, or from about 300 mg every four weeks).
  • the methods may comprise administering a PCSK9 inhibitor to a patient in combination with ("on top of) the patient's previously prescribed lipid modifying therapy (LMT).
  • LMTs include, but are not limited to statins, fibrates, niacin (e.g., nicotinic acid and its derivatives), bile acid sequestrants, ezetimibe, lomitapide, phytosterols, orlistat, etc.
  • a PCSK9 inhibitor may be administered to a patient in combination with a stable daily therapeutic statin regimen.
  • Exemplary daily therapeutic statin regimens that a PCSK9 inhibitor may be administered in combination with in the context of the present methods include, e.g.
  • statin therapy is a maximally tolerated statin therapy for the patient.
  • an agent which inhibits cholesterol uptake and or bile acid re-absorption e.g. , ezetimibe
  • an agent which increase lipoprotein catabolism such as niacin
  • activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22- hydroxycholesterol.
  • methods comprising administering a PCSK9 inhibitor (e.g. , an anti-PCSK9 antibody such as alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab or LY3015014) to a patient in combination with an inhibitor of angiopoietin-like protein 3 (e.g., an anti-ANGPTL3 antibody such as
  • an inhibitor of angiopoietin-like protein 4 e.g. , an anti-ANGPTL4 antibody such as the anti-ANGPTL4 antibody referred to in US Patent No. 9,120,851 as ⁇ 1 ⁇ 268 ⁇ " or "H4H284P"
  • an inhibitor of angiopoietin-like protein 8 e.g., an anti-ANGPTL8 antibody.
  • methods comprising administering a PCSK9 inhibitor (e.g., an anti-PCSK9 antibody such as alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab or LY3015014) to a patient in combination with an a further anti-diabetic therapy in addition to insulin therapy.
  • a PCSK9 inhibitor e.g., an anti-PCSK9 antibody such as alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab or LY301501
  • exemplary additional antidiabetic therapies include without limitation:
  • GLP-1 glucagon like peptide 1
  • GLP-1 GLP-1 analogues
  • GLP-1 receptor agonists for example: GLP-1 (7-37), GLP-1 (7-36)amide, lixisenatide (e.g. Lyxumia ® ), exenatide (e.g. exendin-4, rExendin-4, Byetta ® , Bydureon ® , exenatide NexP), exenatide-LAR, liraglutide (e.g.
  • Victoza ® semaglutide, taspoglutide, albiglutide, dulaglutide, albugon, oxyntomodulin, geniproside, ACP-003, CJC-1 131 , CJC-1 134-PC, GSK-2374697, PB-1023, TTP-054, langlenatide (HM-1 1260C), CM-3, GLP-1 Eligen, AB-201 , ORMD-0901 , NN9924, NN9926, NN9927, Nodexen, Viador-GLP-1 , CVX-096, ZYOG-1 , ZYD-1 , ZP-3022, CAM-2036, DA-3091 , DA-15864, ARI-2651 , ARI-2255, exenatide-XTEN (VRS-859), exenatide-XTEN + Glucagon-XTEN (VRS-859 + AMX-808) and polymer-bound GLP-1 and GLP-1 analogues;
  • BHM098 dual GLP-1/glucagon receptor agonists
  • dual GLP-1/glucagon receptor agonists e.g. BHM-034, OAP-189 (PF-05212389, TKS-1225), TT-401/402, ZP2929, LAPS-HMOXM25, MOD-6030;
  • gastrointestinal peptides such as peptide YY 3-36 (PYY3-36) or analogues thereof and pancreatic polypeptide (PP) or analogues thereof;
  • glucagon receptor agonists or antagonists glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, ghrelin antagonists or inverse agonists, xenin and analogues thereof;
  • GIP glucose-dependent insulinotropic polypeptide
  • dipeptidyl peptidase-IV (DPP-4) inhibitors for example: alogliptin (e.g. Nesina ® , Kazano ® ), linagliptin (e.g. Ondero ® , Trajenta ® , Tradjenta ® , Trayenta ® ), saxagliptin (e.g. Onglyza ® ' Komboglyze XR ® ), sitagliptin (e.g.
  • alogliptin e.g. Nesina ® , Kazano ®
  • linagliptin e.g. Ondero ® , Trajenta ® , Tradjenta ® , Trayenta ®
  • saxagliptin e.g. Onglyza ® ' Komboglyze XR ®
  • sitagliptin e.g.
  • sodium-dependent glucose transporter 2 (SGLT-2) inhibitors for example: canagliflozin, dapagliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, empagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, ertugliflozin, EGT-0001442, LIK-066, SBM-TFC-039, and KGA- 3235 (DSP-3235);
  • SGLT-1 inhibitors e.g. LX-2761 , KGA-3235
  • SGLT-1 inhibitors in combination with anti-obesity drugs such as ileal bile acid transfer (IBAT) inhibitors (e.g. GSK-1614235 + GSK-2330672);
  • (k) biguanides e.g. metformin, buformin, phenformin
  • thiazolidinediones e.g. pioglitazone, rosiglitazone), glitazone analogues (e.g. lobeglitazone);
  • PPAR- peroxisome proliferator-activated receptors
  • agonists or modulators e.g. saroglitazar (e.g. Lipaglyn ® ), GFT-505), or PPAR gamma partial agonists (e.g. lnt-131);
  • sulfonylureas e.g. tolbutamide, glibenclamide, glimepiride, Amaryl ® , glipizide
  • meglitinides e.g. nateglinide, repaglinide, mitiglinide
  • alpha-glucosidase inhibitors e.g. acarbose, miglitol, voglibose
  • amylin and amylin analogues e.g. pramlintide, Symlin ® ;
  • GPR1 19 G-protein coupled receptor 1 19 agonists (e.g. GSK-1292263, PSN-821 , MBX-
  • GPR40 agonists e.g. TUG-424, P-1736, P-1 1 187, JTT-851 , GW9508, CNX-01 1 -67, AM-
  • G-protein-coupled bile acid receptor 1 G-protein-coupled bile acid receptor 1 agonists (e.g. INT-777, XL-475, SB756050);
  • diabetes immunotherapeutics for example: oral C-C chemokine receptor type 2 (CCR-2) antagonists (e.g. CCX-140, JNJ-41443532 ), interleukin 1 beta (IL-1 B) antagonists (e.g. AC- 201), or oral monoclonal antibodies (MoA) (e.g. methalozamide, WP808, PAZ-320, P-1736, PF-05175157, PF-04937319);
  • CCR-2 C-C chemokine receptor type 2
  • IL-1 B interleukin 1 beta
  • MoA oral monoclonal antibodies
  • anti-inflammatory agents for the treatment of the metabolic syndrome and diabetes, for example: nuclear factor kappa B inhibitors (e.g. Triolex ® );
  • AMPK adenosine monophosphate-activated protein kinase stimulants
  • PXL-008 Imeglimin
  • Debio-0930 MT-63-78
  • R-118 adenosine monophosphate-activated protein kinase stimulants
  • inhibitors of 1 1 -beta-hydroxysteroid dehydrogenase 1 (1 1 -beta-HSD-1) e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585
  • activators of glucokinase e.g. PF-04991532, TTP-399 (GK1 -399), GKM-001 (ADV- 1002401 ), ARRY-403 (AMG-151), TAK-329, TMG-123, ZYGK1;
  • DGAT diacylglycerol O-acyltransferase
  • LCQ-908 pradigastat
  • protein tyrosine phosphatase 1 e.g. trodusquemine
  • inhibitors of glucose-6- phosphatase inhibitors of fructose-1 ,6-bisphosphatase
  • glycogen phosphorylase inhibitors of glycogen phosphorylase
  • inhibitors of phosphoenol pyruvate carboxykinase inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase
  • simvastatin e.g. Zocor ® , Inegy ® , Simcor ®
  • atorvastatin e.g. Sortis ® , Caduet ®
  • rosuvastatin e.g. Crestor ®
  • pravastatin e.g
  • Antara ® Lipofen ® , Lipanthyl ®
  • gemfibrozil e.g. Lopid ® , Gevilon ®
  • etofibrate simfibrate, ronifibrate, clinofibrate, clofibride
  • nicotinic acid and derivatives thereof e.g. niacin, including slow release formulations of niacin
  • nicotinic acid receptor 1 agonists e.g. GSK-256073
  • PPAR-delta agonists acetyl- CoA-acetyltransferase (ACAT) inhibitors (e.g. avasimibe), cholesterol absorption inhibitors (e.g.
  • ezetimibe Ezetrol ® , Zetia ® , Liptruzet ® , Vytorin ® , S-556971
  • bile acid-binding substances e.g. cholestyramine, colesevelam
  • IBAT ileal bile acid transport
  • MTP microsomal triglyceride transfer protein
  • AEGR-733 lomitapide
  • SLx-4090 granotapide
  • modulators of proprotein convertase subtilisin/kexin type 9 PCSK9
  • alirocumab (REGN727/SAR236553), AMG-145, LGT- 209, PF-04950615, MPSK3169A, LY3015014, ALD-306, ALN-PCS, BMS-962476, SPC5001 , ISIS-394814, 1 B20, LGT-210, 1 D05, BMS-PCSK9Rx-2, SX-PCK9, RG7652), LDL receptor up-regulators, for example liver selective thyroid hormone receptor beta agonists (e.g.
  • eprotirome (KB-21 15), MB0781 1 , sobetirome (QRX-431), VIA-3196, ZYT1), HDL- raising compounds such as: cholesteryl ester transfer protein (CETP) inhibitors (e.g. anacetrapib (MK0859), dalcetrapib, evacetrapib, JTT-302, DRL-17822, TA-8995, R-1658, LY-2484595, DS-1442), or dual CETP/PCSK9 inhibitors (e.g. K-312), ATP-binding cassette (ABC1 ) regulators, lipid metabolism modulators (e.g.
  • CETP cholesteryl ester transfer protein
  • BMS-823778, TAP-301 , DRL-21994, DRL-21995), phospholipase A2 (PLA2) inhibitors e.g. darapladib, Tyrisa ® , varespladib, rilapladib
  • ApoA-l enhancers e.g. RVX-208, CER-001 , MDCO-216, CSL-1 12
  • cholesterol synthesis inhibitors e.g. ETC-1002
  • lipid metabolism modulators e.g. BMS-823778, TAP- 301 , DRL-21994, DRL-21995
  • omega-3 fatty acids and derivatives thereof e.g.
  • icosapent ethyl (AMR101 ), Epanova ® , AKR-063, NKPL-66, PRC-4016, CAT-2003); (cc) bromocriptine (e.g. Cycloset , Parlodel ), phentermine and phentermine formulations or combinations (e.g. Adipex-P, lonamin, Qsymia ® ), benzphetamine (e.g. Didrex ® ), diethylpropion (e.g. Tenuate ® ), phendimetrazin (e.g. Adipost ® , Bontril ® ), bupropion and combinations (e.g.
  • bromocriptine e.g. Cycloset , Parlodel
  • phentermine and phentermine formulations or combinations e.g. Adipex-P, lonamin, Qsymia ®
  • benzphetamine
  • naltrexone e.g. Naltrexin ® , naltrexone + bupropion
  • CBD1 cannabinoid receptor 1
  • MCH-1 melanin-concentrating hormone
  • Cametor ® Cametor ®
  • orlistat e.g. Xenical ® , Calobalin ®
  • angiogenesis inhibitors e.g. ALS-L1023
  • betahistidin and histamine H3 antagonists e.g. HPP-404
  • AgRP agouti related protein
  • serotonin re-uptake inhibitors such as fluoxetine (e.g. Fluctine ® ), duloxetine (e.g. Cymbalta ® ), dual or triple monoamine uptake inhibitors (dopamine, norepinephrine and serotonin reuptake) such as sertraline (e.g.
  • FGFR4 fibroblast growth factor receptor 4
  • Adipotide ® prohibitin targeting peptide-1
  • telmisartan e.g. Kinzal ® , Micardis ®
  • candesartan e.g. Atacand ® , Blopress ®
  • valsartan e.g. Diovan ® , Co-Diovan ®
  • losartan e.g. Cosaar ®
  • eprosartan e.g. Teveten ®
  • irbesartan e.g. Aprovel ® , CoAprovel ®
  • olmesartan e.g.
  • Votum ® tasosartan, azilsartan (e.g. Edarbi ® ), dual angiotensin receptor blockers (dual ARBs), angiotensin converting enzyme (ACE) inhibitors, ACE-2 activators, renin inhibitors, prorenin inhibitors, endothelin converting enzyme (ECE) inhibitors, endothelin receptor (ET1/ETA) blockers, endothelin antagonists, diuretics, aldosterone antagonists, aldosterone synthase inhibitors, alpha-blockers, antagonists of the alpha-2 adrenergic receptor, beta-blockers, mixed alpha-/beta-blockers, calcium antagonists, calcium channel blockers (CCBs), nasal formulations of the calcium channel blocker diltiazem (e.g.
  • CP-404 dual mineralocorticoid/CCBs, centrally acting antihypertensives, inhibitors of neutral endopeptidase, aminopeptidase-A inhibitors, vasopeptide inhibitors, dual vasopeptide inhibitors such as neprilysin-ACE inhibitors or neprilysin-ECE inhibitors, dual-acting AT receptor-neprilysin inhibitors, dual AT1 /ETA antagonists, advanced glycation end-product (AGE) breakers, recombinant renalase, blood pressure vaccines such as anti-RAAS (renin-angiotensin-aldosteron-system) vaccines, AT1 - or AT2-vaccines, drugs based on hypertension pharmacogenomics such as modulators of genetic polymorphisms with antihypertensive response, thrombocyte aggregation inhibitors, and others; and
  • the additional anti-diabetic therapy is a GLP-1 therapy (e.g. , lixisenatide).
  • the GLP-1 therapy is formulated with methionine (e.g., L-methionine or D-methionine).
  • methionine e.g., L-methionine or D-methionine.
  • polysorbate e.g. , polysorbate 20, polysorbate 80
  • poloxamer e.g. , poloxamer 188
  • benzalkonium chloride histidine, lysine, and/or EDTA are absent or substantially absent from the formulation of the GLP-1 therapy.
  • the formulation of the GLP-1 therapy is free or substantially free of surfactants, such as polyols (e.g. , polypropylene glycols, polyethylene glycols, poloxamers, Pluronics, Tetronics), partial and fatty acid esters and ethers of polyhydric alcohols such as those of glycerol and sorbitol (e.g., Span.RTM., Tween.RTM., Myrj.RTM., Brij.RTM., Cremophor.RTM).
  • the formulation of the GLP-1 therapy can comprise a suitable preservative (e.g.
  • glycerol dextrose, lactose, sorbitol, mannitol, glucose, NaCI, calcium or magnesium compounds such as CaCI 2 .
  • concentrations of glycerol, dextrose, lactose, sorbitol, mannitol, and glucose are customarily in the range of 100-250 mM, NaCI in a concentration of up to 150 mM.
  • the insulin therapy that the patient receives is combined with the additional anti-diabetic therapy (e.g., any of the foregoing anti-diabetic therapies which are not insulin therapies).
  • the anti-diabetic therapy comprises a combination of an insulin therapy (e.g. , insulin glargine) and a GLP-1 therapy (e.g. , lixisenatide).
  • an insulin therapy e.g. , insulin glargine
  • a GLP-1 therapy e.g. , lixisenatide
  • These therapies can be provided either separately or in a single pharmaceutical composition.
  • insulin glargine and lixisenatide can be formulated in a single pharmaceutical composition (e.g., Soliqua ® 100/33) for daily injection.
  • additional therapeutically active component(s) may be administered just prior to, concurrent with, or shortly after the administration of a PCSK9 inhibitor; (for purposes of the present disclosure, such administration regimens are considered the administration of a PCSK9 inhibitor "in combination with” an additional therapeutically active component).
  • the present methods include pharmaceutical compositions and methods of use thereof in which a PCSK9 inhibitor is co-formulated with one or more of the additional therapeutically active component(s) as described elsewhere herein.
  • the present methods of treatment including treating a patient with
  • PCSK9 inhibitor such as an antibody or antigen- binding fragment thereof that specifically binds PCKS9
  • the PCSK9 inhibitor can be administered as an add-on to the patient's pre-existing insulin therapy and/or LMT (if applicable), such as an add-on to the patient's pre-existing daily therapeutic insulin and/or statin regimen.
  • the methods include add-on therapeutic regimens wherein the PCSK9 inhibitor is administered as add-on therapy to the same stable multiple daily insulin regimen and/or daily therapeutic statin regimen (i.e. , same dosing amount of statin) that the patient was on prior to receiving the PCSK9 inhibitor.
  • the PCSK9 inhibitor is administered as add-on therapy to a therapeutic insulin and/or statin regimen comprising an insulin and/or a statin in an amount that is more than or less than the dose of insulin and/or stain the patient was on prior to receiving the PCSK9 inhibitor.
  • the daily dose of insulin and/or statin administered or prescribed to the patient may (a) stay the same, (b) increase, or (c) decrease (e.g., up- titrate or down-titrate) in comparison to the daily statin dose the patient was taking before starting the PCSK9 inhibitor therapeutic regimen, depending on the therapeutic needs of the patient.
  • the methods result in the reduction in serum levels of one or more lipid component selected from the group consisting of LDL-C, ApoB, ApoB100, non-HDL-C, total cholesterol, VLDL-C, triglycerides, Lp(a), HDL-C, LDL particle number, LDL particle size, ApoC3, ApoA-1 , triglyceride-rich lipoprotein cholesterol (TRL-C), and remnant cholesterol.
  • one or more lipid component selected from the group consisting of LDL-C, ApoB, ApoB100, non-HDL-C, total cholesterol, VLDL-C, triglycerides, Lp(a), HDL-C, LDL particle number, LDL particle size, ApoC3, ApoA-1 , triglyceride-rich lipoprotein cholesterol (TRL-C), and remnant cholesterol.
  • administering will result in a mean percent reduction from baseline in serum low density lipoprotein cholesterol (LDL-C) of at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or greater; a mean percent reduction from baseline in ApoB of at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or greater; a mean percent reduction from baseline in ApoB100 of at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or greater; a mean percent reduction from baseline in non-HDL-C of at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or greater; a mean percent reduction from baseline in total cholesterol of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, or greater; a mean percent reduction from baseline in VLDL-C of at least about 5%, 10%, 15%, 20%, 25%, 30%, or greater; a mean percent reduction from baseline in VLDL-C of at least about 5%, 10%,
  • the present methods include treating a patient with hypercholesterolemia and T1 DM that is receiving insulin therapy, the methods comprising administering multiple doses of an anti-PCSK9 antibody or antigen binding fragment thereof to the patient at a dosing amount of about 75 to 150 mg per dose, and a dosing frequency of about once every two weeks or every four weeks, or a dosing regimen in accordance with an up- titration dosing regimen as disclosed herein.
  • the patient may exhibit a reduction in LDL-C level from baseline of at least 35%, 50%, or 60%.
  • following one or more weeks of treatment with the anti-PCSK9 antibody the patient exhibits a reduction in LDL-C level from baseline of about 35%, 50%, or 60%, or more.
  • the present methods also include treating a patient with hypercholesterolemia and T2DM that is receiving insulin therapy, the methods comprising administering multiple doses of an anti-PCSK9 antibody or antigen binding fragment thereof to the patient at a dosing amount of about 75 to 150 mg per dose, and a dosing frequency of about once every two weeks or every four weeks, or a dosing regimen in accordance with an up- titration dosing regimen as disclosed herein.
  • the patient may exhibit a reduction in LDL-C level from baseline of at least 40%, 48%, or 54%.
  • following one or more weeks of treatment with the anti-PCSK9 antibody the patient exhibits a reduction in LDL-C level from baseline of about 40%, 48%, or 54%, or more.
  • the present methods do not alter the patient's diabetic parameters.
  • the method does not affect (e.g. , does not change by greater than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%) the hemoglobin A1 c (HbA1 c) level of the patient.
  • the method does not affect (e.g. , does not change by greater than 2%, 4%, 6%, 8%, 10%, 12%, 15%, 18%, or 20%) the fasting plasma glucose (FPG) level of the patient.
  • FPG fasting plasma glucose
  • the present invention relates to uses of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (PCSK9), for treating hypercholesterolemia in a patient with type 1 diabetes mellitus (T1 DM).
  • PCSK9 human proprotein convertase subtilisin/kexin type 9
  • the present invention relates to methods for treating hypercholesterolemia in a patient with type 1 diabetes mellitus (T1 DM).
  • said use and/or method comprises the steps:
  • the 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab and LY3015014.
  • the antibody or antigen-binding fragment thereof is alirocumab.
  • said use and/or method comprises further the steps:
  • said use and/or method comprises further the step:
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT concomitant lipid-modifying therapy
  • the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • statin therapy is a maximally tolerated statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin.
  • the patient receives a concomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional concomitant antidiabetic therapy is selected from the group consisting of a glucagon like peptide 1 (GLP-1 ) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose- dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha-glucosidase inhibitor, a sodium- dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator-activated receptor (PPAR-)(alpha, gamma or alpha/gamma) agonist or modulator, amylin, an amylin an
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient by at least 30%, 35%, 40%, or 45%.
  • the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient by at least 25%, 30%, 35%, or 40%.
  • the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient.
  • the antibody or antigen-binding fragment thereof reduces the number and/or size of lipoprotein particles in the patient.
  • the present inventions relate to uses and/or methods for treating hypercholesterolemia in a patient with type 1 diabetes mellitus (T1 DM), the method comprising the steps:
  • the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6, and wherein the patient receives a concomitant insulin therapy.
  • the present inventions relate to uses and/or methods for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM), the method comprising the steps:
  • the 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab, and LY3015014.
  • the antibody or antigen-binding fragment thereof is alirocumab.
  • one embodiment of said use and/or method further comprises the step:
  • one embodiment of said use and/or method further comprises the step:
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT concomitant lipid-modifying therapy
  • the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • statin therapy is a maximally tolerated dose statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the patient is intolerant to a statin.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin.
  • the patient receives aconcomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional anti-diabetic therapy is selected from the group consisting of an a glucagon like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator- activated receptor (PPAR-)(alpha, gamma or alpha/gamma) agonist or modulator, amylin, an amylin analogue
  • GLP-1 glucose-dependent insulinotropic polypeptide
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient by at least 30%, 35%, 40%, or 45%.
  • the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient by at least 20%, 25%, 30%, or 35%.
  • the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient.
  • the antibody or antigen-binding fragment thereof reduces the number and/or size of lipoprotein particles in the patient.
  • the present inventions relate to uses and/or methods for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM), the method comprising the steps:
  • the present invention relates to uses of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (PCSK9), for treating hypercholesterolemia in a patient with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD).
  • PCSK9 human proprotein convertase subtilisin/kexin type 9
  • the present invention relates to methods for treating hypercholesterolemia in a patient with T2DM and ASCVD.
  • said use and/or method comprises the steps:
  • ASCVD coronary heart disease
  • ischemic stroke ischemic stroke
  • peripheral arterial disease ischemic stroke
  • the CHD comprises acute myocardial infarction, silent myocardial infarction, and unstable angina.
  • the 75 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 150 mg of the antibody or antigen binding fragment is administered to the patient every two weeks.
  • the 300 mg of the antibody or antigen binding fragment is administered to the patient every four weeks.
  • the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4, and the three light chain CDRs set forth in SEQ ID NOs: 7, 8, and 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 6.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab, and LY3015014. [00208]ln one embodiment of said use and/or method the antibody or antigen-binding fragment thereof is alirocumab.
  • said use and/or method further comprises the step:
  • said use and/or method further comprises the step:
  • the threshold level is 70 mg/dL.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the patient further receives a concomitant lipid-modifying therapy (LMT).
  • LMT concomitant lipid-modifying therapy
  • the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, niacin, an omega-3 fatty acid, and a bile acid sequestrant.
  • the LMT is a statin therapy.
  • statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cerivastatin.
  • statin therapy is a maximally tolerated dose statin therapy.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the patient is intolerant to a statin.
  • the insulin therapy is selected from the group consisting of human insulin, Insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, and basal insulin.
  • the patient receives a concomitant anti-diabetic therapy in addition to insulin therapy.
  • the additional anti-diabetic therapy is selected from the group consisting of an a glucagon like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a ghrelin antagonist or inverse agonist, xenin, a xenin analogue, a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, an SGLT-1 inhibitor, a peroxisome proliferator- activated receptor
  • GLP-1 glucose-dependent insulinotropic polypeptide
  • the antibody or antigen-binding fragment thereof reduces the LDL-C level of the patient by at least 30%, 35%, 40%, or 45%.
  • the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient by at least 20%, 25%, 30%, or 35%.
  • the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient.
  • the antibody or antigen-binding fragment thereof reduces the number and/or size of lipoprotein particles in the patient.
  • the present invention relates to uses and/or methods for treating hypercholesterolemia in a patient with T2DM and ASCVD, the method comprising: (a) selecting a high cardiovascular risk patient receiving insulin therapy that has
  • the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 6, and wherein the patient receives a concomitant insulin therapy.
  • mAb316P Human anti-PCSK9 antibodies were generated as described in US Patent No. 8,062,640.
  • the exemplary PCSK9 inhibitor used in the following Example is the human anti-PCSK9 antibody designated "mAb316P," also known as "REGN727,” or "alirocumab.”
  • mAb316P has the following amino acid sequence characteristics: a heavy chain comprising SEQ ID NO:5 and a light chain comprising SEQ ID NO:9; a heavy chain variable region (HCVR) comprising SEQ ID NO:1 and a light chain variable domain (LCVR) comprising SEQ ID NO:6; a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO:2, a HCDR2 comprising SEQ ID NO:3, a HCDR3 comprising SEQ ID NO:4, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO:7, a LCDR2 comprising SEQ ID NO:8 and a LCDR3 comprising SEQ ID NO:10.
  • Example 2 A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients with Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular Risk Not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy
  • CVD cardiovascular disease
  • the primary objectives of the study were: (a) to evaluate the efficacy of alirocumab in comparison with placebo in the reduction of calculated low-density lipoprotein cholesterol (LDL-C) after 24 weeks of treatment in high cardiovascular risk patients with diabetes treated with insulin and with hypercholesterolemia not adequately controlled on maximally tolerated LDL-C lowering therapy; and (b) to evaluate the safety and tolerability of alirocumab in patients with diabetes treated with insulin.
  • LDL-C low-density lipoprotein cholesterol
  • the secondary objectives of the study was to evaluate the efficacy of alirocumab in comparison to placebo on other lipid parameters at Weeks 12 and 24 (e.g., measured LDL- C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo B), total cholesterol (TC), lipoprotein a (Lp(a)), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) levels, triglyceride rich lipoproteins (TGRL), apolipoprotein A-1 (Apo A-1 ), apolipoprotein C3 (ApoC3), and LDL particle number and size.
  • LDL- C measured LDL- C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo B), total cholesterol (TC), lipoprotein a (Lp(a)), high-density lipoprotein cholesterol (HDL-C),
  • Statin dose and dose regimen as well as dose and dose regimen of other lipid modifying treatment(s) (if applicable) was stable throughout the entire study duration including for 4 weeks prior to the screening period, during the screening period, and from screening to randomization. Patients were on a stable diet for glucose and lipid management throughout the entire study duration from screening to the Week 24 visit. Patients were receiving treatment for diabetes in accordance with local/regional standards of care.
  • Alirocumab was administered subcutaneously with a starting dose of 75 mg Q2W for 12 weeks with a blinded up-titration to alirocumab 150 mg Q2W at Week 12 if the LDL-C at the Week 8 visit was >70 mg/dL (1.81 mmol/L). Patients who have an LDL-C ⁇ 70 mg/dL (1 .81 mmol/L) at the Week 8 visit continued with alirocumab 75 mg Q2W until the end of the treatment period.
  • Ad verse events that had occurred within 70 days of the last dose of investigational medicinal product (IMP) were documented. Patients with a serious adverse event (SAE) or an adverse event of special interest (AESI) were followed until resolution, stabilization, or death.
  • SAE serious adverse event
  • AESI adverse event of special interest
  • the study enrolled a total of 517 patients, including 76 patients with T1 DM and 441 patients with T2DM.
  • statin that was tolerated by the patient for at least 4 weeks prior to the screening visit (Week -3) with or without other LMT.
  • the maximum dose/regimen of statin that was tolerated by the patient was the highest registered dose/regimen tolerated by the patient based on the Investigator's judgment or concerns.
  • Some examples of acceptable reasons for a patient taking a lower statin dose included, but were not limited to, adverse effects on higher doses, advanced age, low body mass index (BMI), regional practices, local prescribing information, or concomitant medications. Patients may have been on an alternate day dose of statin as long as the dose is consistently taken (e.g. , dose every Monday, Wednesday, Friday, etc). Concomitant treatment with more than 1 statin was not permitted.
  • statin intolerance Patients who had documented statin intolerance, as judged by the Investigator, and who were no longer on statin therapy as a result were also eligible for the study. The reason(s) for not being on a maximum dose/regimen of statin (including statin intolerance) were documented in the case report form.
  • HbA1 c Patients with an elevated HbA1 c (up to 10%) were eligible provided that there was no plan to target a lower HbA1 c during the study, based on the judgment of the Investigator.
  • History of CHD included at least one of the following:
  • coronary revascularization procedure e.g. , percutaneuous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)
  • PCI percutaneuous coronary intervention
  • CABG coronary artery bypass graft surgery
  • CHD diagnosed by invasive or noninvasive testing such as coronary angiography, stress test using treadmill, stress echocardiography, or nuclear imaging.
  • CHD risk equivalents included at least one of the following:
  • Cardiovascular risk factors included at least one of the following:
  • thyroid replacement therapy could be included if the dosage of thyroxin had been stable for at least 3 months prior to screening and the patient's sensitive thyroid stimulating hormone (s-TSH) levels were within ⁇ 10% of the normal range of the laboratory at the screening visit;
  • patient was the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol;
  • Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).
  • Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.
  • Class III Marked limitation of physical activity. Comfortable at rest, but less than (Moderate) ordinary activity causes fatigue, palpitation, or dyspnea.
  • Step alirocumab drug product was supplied at a concentration of 75 mg/mL and 150 mg/mL in an aqueous buffer, pH 6.0, containing sucrose, histidine, and polysorbate 20, both as 1 mL volume, in an auto-injector (also known as prefilled pen).
  • Sterile placebo for alirocumab was prepared in the same formulation as alirocumab without the addition of protein as 1 mL volume in a prefilled pen, for the patients to perform injection training, as well as for those in the placebo treatment arm.
  • the patient or another designated person
  • the initial dose was 75 mg administered subcutaneously once Q2W.
  • the dose was increased in a blinded fashion to 150 mg Q2W at Week 12 for patients randomized to alirocumab if the Week 8 LDL-C value is ⁇ 70 mg/dL (1 .81 mmol/L).
  • the patients randomized to placebo were administered their injection subcutaneously Q2W throughout the duration of the 24-week treatment period.
  • a prefilled pen training guide (auto-injector training guide) was provided to the sites and instructions for use (auto-injector for use) were provided to the patient.
  • Each administration of IMP consisted of 1 ml_ subcutaneous injection in the abdomen, thigh, or outer area of upper arm (i.e., deltoid region). If another concomitant drug was being injected at the same site planned for the IMP injection, then the patient was advised to use an alternate location for administration of the IMP.
  • the IMP could be administered by self-injection or by another designated person (such as a spouse, relative, etc). In case a designated person was due to inject alirocumab to a patient during the study, it was ensured that this person had been adequately trained prior to administering the injection.
  • a designated person was due to inject alirocumab to a patient during the study, it was ensured that this person had been adequately trained prior to administering the injection.
  • anyone that planned to administer the IMP was trained by the study staff.
  • the used prefilled pen was discarded in a sharps container which was provided to patients. It was recommended that the subcutaneous IMP injections be rotated within an anatomical area (e.g., right thigh, then left thigh or right abdomen, then left abdomen). Patients also had the option to inject in a different anatomical area (e.g. , thigh then abdomen or the outer area of upper arm, etc) during the study.
  • anatomical area e.g., right thigh, then left thigh or right abdomen, then left abdomen.
  • the first IMP injection was done at the site by the patient or another designated person (such as spouse, relative, etc) under direct site staff supervision. Patients were monitored at the investigational site for at least 30 minutes after this first injection in this study. If the designated person changed during the course of the study, the new designated person was trained with placebo.
  • IMP subcutaneous injections were then performed outside of the clinic, Q2W up to the last injection. If the injection was scheduled to take place on the same date as the site visit, then the IMP was administered after the blood sampling had been completed. In exceptional cases, if a patient preferred to have the injection performed at the study site and provisions were able to be made to accommodate the administration of injections at the site, it was also allowed. [00267]IMP should be administered subcutaneously Q2W, ideally at approximately the same time of the day. However, it was acceptable to have a window period of ⁇ 3 days. The time of the day was based upon the patient's preference.
  • bile acid-binding sequestrants such as cholestyramine, colestipol, colesevelam
  • fibrates such as Fenofibrate
  • omega-3 fatty acids >1000 mg daily
  • AII fibrates were allowed at entry if the patient had tolerated the medication and remained on a stable dose. If the patient required the introduction of a fibrate during the course of the study (i.e. , as rescue treatment in response to a TG alert), only fenofibrate was allowed to be added. Background LMT and insulin were provided by the Sponsor. Patients obtained these medications in compliance with local regulations.
  • Code breaking could be performed at any time by using the proper module of the interactive voice response system (IVRS)/interactive web response system (IWRS), depending on which system was used for the site, and/or by calling any other phone number provided by the Sponsor for that purpose.
  • IVRS interactive voice response system
  • IWRS interactive web response system
  • forms e.g., AE, SAE
  • code-breaking material was also kept at the entity responsible for the "24 hour alert system”; but this system should be used in very exceptional cases only (i.e. , unavailability of IVR/IWR system or inability to contact Investigator and/or site staff).
  • the randomized list of treatment kit numbers was generated centrally by the sponsor.
  • the IMP alirocumab 75 or 150 mg kits, or placebo kit
  • the IMP was packaged in accordance with this list.
  • the Trial Supply Operations Manager provided the randomized list of treatment kit numbers, and the Study Biostatistician provided the randomization scheme to the centralized treatment allocation system provider. Then, this centralized treatment allocation system provider generated the patient randomization list according to which it allocated the treatments to the patients.
  • diabetes type i.e., Type 1 versus Type 2.
  • the treatment kit numbers were allocated using the centralized treatment allocation system on randomization visit (Day 1 , Week 0), and then at Week 12 as re-supply visits, and at unscheduled visits if needed.
  • the treatment kit allocated at Week 12 was based on their Week 8 LDL-C level following the up-titration rules. Regular transfer of data was planned between the central laboratory and the centralized treatment allocation system provider in order to proceed in a blinded manner for study sites and sponsor.
  • a randomized patient was defined as a patient who was registered and assigned with a treatment kit number from the centralized treatment allocation system, as documented from its log file. A patient could not be randomized more than once in the study. If a treatment was used without contacting the centralized treatment allocation system, then the patient was considered as not randomized and withdrawn from the study.
  • each double-blind treatment kit either alirocumab or placebo for alirocumab, was prepared to contain 6 prefilled pens in a child resistant package.
  • all double-blind treatment kit boxes for injection had the same look and feel and therefore will be labeled with a double-blind label.
  • a training kit containing 1 placebo for alirocumab prefilled pen was prepared for the purpose of instructing patients on injection administration which was to be performed prior to randomization at screening visit (Week-3, Visit 1). If deemed necessary, a second injection training with placebo for alirocumab was performed using an additional training kit prior to randomization. Injection training with placebo was performed and documented in the CRF, including if the designated person who administered IMP to the patient changed during the course of the study. [00294]Packaging was in accordance with the administration schedule. The content of the labeling was in accordance with the local regulatory specifications and requirements.
  • the IMP was stored in a refrigerator between +2°C and +8°C (36°F to 46° F) at the site.
  • the temperature of the site refrigerator was checked daily and recorded on a log sheet.
  • the IMP that was stored at the investigational site was kept in an appropriate locked room, under the responsibility of the Investigator or designee or other authorized person in accordance with the storage conditions indicated on the label.
  • Baseline characteristics included standard demography (e.g., age, race, weight, height, etc.), disease characteristics including medical history, and medication history for each patient.
  • the primary efficacy endpoint was the percent change in LDL-C from baseline to Week 24 in the intent-to-treat (ITT) population, using all LDL-C values regardless of adherence to treatment (ITT estimand). The percent change was defined as 10Ox
  • the baseline calculated LDL-C value was the last LDL-C level obtained before the first double-blind IMP injection.
  • the calculated LDL-C at Week 24 was the LDL-C level obtained within the Week 24 analysis window. All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) between Weeks 8 to 24 were allowed to be used to provide a value for the primary efficacy endpoint, if appropriate, according to above definition.
  • pre-treatment period was defined from the signed informed consent up to the first dose of double-blind IMP injection
  • treatment emergent adverse event (TEAE) period was defined as the time from the first dose of double-blind IMP injection to the last dose of IMP injection + 70 days (10 weeks) as residual effect of treatment is expected until 10 weeks after the stop of double-blind IMP;
  • (c) post-treatment period was defined as the time starting the day after the end of the TEAE period up to resolution/stabilization of all SAE and AESI, whichever came last.
  • AE was any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment.
  • AESI Abnormal event of special interest
  • allergic events allergic drug reactions and/or local injection site reactions deemed to be allergic by the Investigator (or have an allergic component), that required consultation with another physician for further evaluation of hypersensitivity/allergy as per the Investigator's medical judgment should be reported as an AESI;
  • pregnancy pregnancy occurring in a female patient or the partner of a male patient (if permitted by the female partner and by local regulatory authorities) during the study or within 70 days following the last dose of study drug. Pregnancy was recorded as AESI in all cases. Pregnancy was qualified as an SAE only if it fulfilled one or more SAE criteria. In the event of pregnancy of a female patient included in the study, study product was discontinued. The follow-up of the pregnancy was mandatory until the outcome has been determined;
  • symptomatic overdose with IMP.
  • An overdose (accidental or intentional) was an event suspected by the Investigator or spontaneously notified by the patient (not based on systematic injection counts) and defined as at least twice of the intended dose within the intended therapeutic interval (i.e. , 2 or more injections are administered in ⁇ 7 calendar days), to be reported using the term "symptomatic OVERDOSE (accidental or intentional), indicating the circumstance in parentheses (e.g., "symptomatic overdose (accidental)” or “symptomatic overdose (intentional)”).
  • the patient was monitored and appropriate symptomatic treatment instituted. The circumstances of the overdose were clearly specified in the verbatim and symptoms, if any, entered on separate AE/SAE forms.
  • Asymptomatic overdose was requested to be reported as a standard AE;
  • neurologic events neurologic events that require additional examinations/procedures and/or referral to a specialist were requested to be reported as an AESI. If the event did not require additional examinations/procedures and/or referral to a specialist, it was requested to be reported as a standard AE; and
  • Neurocognitive events all neurocognitive events were considered as AESI.
  • the window period for Week 0 was +3 days.
  • the window period for Weeks 8, 12 and 24 was ⁇ 3 days.
  • the window period for Weeks 4, 20, and 32 was ⁇ 7 days.
  • AII blood sampling including the blood sampling for determination of lipid parameters (e.g., TC, LDL-C, HDL-C, TG, non-HDL-C, Apo A, Apo B, Apo C-lll, Lp(a), LDL particle size and number) and also for plasma glucose, was performed in the morning, in fasting condition (i.e. , overnight, at least 10 to 12 hours fast and refrain from smoking), and before IMP injection for all site visits throughout the study. Alcohol consumption within 48 hours and intense physical exercise within 24 hours preceding the blood sampling were discouraged. If the patient was not in fasting conditions, the blood sample was not collected, and a new appointment was given to the patient for the day after (or as close as possible to this date), with instructions to fast (see above conditions).
  • lipid parameters e.g., TC, LDL-C, HDL-C, TG, non-HDL-C, Apo A, Apo B, Apo C-lll, Lp(a), LDL particle size and number
  • hematology all visits except Weeks 4 and 20; may be performed at Week 0 as applicable and based on the clinical discretion of the Investigator;
  • HbA1 c screening and Weeks 0, 12, and 24;
  • liver panel all visits except Visits 3 and 6; may be performed at Week 0 as applicable and based on the clinical discretion of the Investigator. In case of total bilirubin values above the normal range, differentiation into conjugated and non-conjugated bilirubin will occur automatically;
  • hepatitis C antibody at screening and Week 24; in case of ALT increase during the study, hepatitis C antibody should be determined. If Hepatitis C antibody was positive during the study, reflexive testing was performed;
  • Microscopy was evaluate for the presence of red blood cells (RBC), RBC clumps, white blood cells (WBC), WBC clumps, epithelial cells (transitional, renal tubular, and squamous), casts (hyaline, epithelial, WBC, RBC, granular, fatty, cellular, broad, waxy), crystals (triple phosphate, calcium oxalate, calcium phosphate, calcium carbonate, uric acid, amorphous, ammonium biurate, bilirubin, leucine, tyrosine, cystine), bacteria, yeast- budding, yeast-hyphae, trichomonas, oval fat body, fat, mucous, and sperm.
  • RBC red blood cells
  • WBC white blood cells
  • WBC clumps epithelial cells
  • epithelial cells transitional, renal tubular, and squamous
  • casts hyaline, epithelial, WBC, R
  • BP Blood pressure
  • the iTAQ was a patient reported outcome (PRO) measure to assess treatment acceptability over the 4-week period prior to the completion of the questionnaire. It was requested to be completed by the patient at the Weeks 8 and 24 visits.
  • Percentages are calculated using the number of patients randomized as denominator.
  • Percentages are calculated using the number of patients randomized as denominator.
  • Table 4 Demographics and patient characteristics at baseline - Patients with Type 1 Diabetes as per IVRS
  • Table 5 Demographics and patient characteristics at baseline - Patients with Type 2 Diabetes as per IVRS
  • T1 DM patients exhibited a percentage reduction from baseline in LDL-C particle number (LS Mean) of 40.7% at week 12 and 44.4% at week 24 and percentage reduction in LDL-C particle size of 2.3% at week 12 and 2.3% at week 24. ApoC3 was reduced in these patients by 6.9% at week 12 and 7.5% at week 24.
  • Lipoprotein-(a) (mg/dL)
  • Apolipoprotein B (mg/dL)
  • Apolipoprotein A1 (mg/dL)
  • T2DM patients exhibited a percentage reduction from baseline in LDL-C particle number (LS Mean) of 37.6% at week 12 and 38.3% at week 24 and percentage reduction in LDL-C particle size of 2.6% at week 12 and 2.8% at week 24. ApoC3 was reduced in these patients by 6.3% at week 12 and 5.8% at week 24.
  • the duration of hypercholesterolemia was generally similar between treatment groups and between patients with T1 DM and T2DM.
  • T1 DM and T2DM patients were treated with high and moderate intensity statins in both treatment groups with a higher proportion of patients were treated with moderate intensity statins (58.9%). Overall, 59.0 % of T1 DM and T2DM patients were on treated with statin.
  • Bile acid sequestrant 0 1 (0.3) 1 (0.2)
  • Omega 3 fatty acids > 1000mg/day 17 (9.9) 16 (4.6) 33 (6.4)
  • High intensity statin corresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily or simvastatin 80mg daily.
  • Moderate intensity statin corresponds to atorvastatin 10 to 20 mg daily or rosuvastatin 5 to 10 mg daily or simvastatin 20 to 40 mg daily or pravastatin 40 to 80 mg daily or lovastatin 40 mg daily or fluvastatin 80 mg daily or pravastatin 2 to 4 mg daily.
  • Low intensity statin corresponds to simvastatin 10 mg daily or pravastatin 10 to 20 mg daily or lovastatin 20 mg daily or fluvastatin 20 to 40 mg daily or pravastatin 1 mg daily.
  • % calculated using the number of patients randomized as denominator except for each intensity of statins where % is calculated using the number of patients on statins as denominator and for each daily dose category where % is calculated using the number of patients taking that particular statin as denominator.
  • the proportion of individuals achieving LDL-C ⁇ 70 mg/dL ( ⁇ 1 .8 mmol/L) was 76.4% in the alirocumab group and 7.4% in the placebo group (P ⁇ 0.0001)
  • the proportion of individuals attaining LDL-C of ⁇ 50 mg/dL (1 .3 mmol/L) was 50.7% in the alirocumab group and 2.4% in the placebo group (P ⁇ 0.0001).
  • the sensitivity analysis on the primary efficacy endpoint showed similar results in both populations (data are not shown) .
  • Least-squares means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis.
  • the model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, and the interactions treatment group-by-time point, strata-by-time point, treatment group-by-strata and treatment group-by-strata-by-time point, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline value-by-time point interaction.
  • MMRM model run on all patients in the ITT population (i.e. Type 1 and Type 2 Diabetes patients).
  • MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
  • Least-squares means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis.
  • the model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, and the interactions treatment group-by-time point, strata-by-time point, treatment group-by-strata and treatment group-by-strata-by-time point, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline value-by-time point interaction.
  • MMRM model run on all patients in the ITT population (i.e. Type 1 and Type 2 Diabetes patients).
  • MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
  • the p-value is followed by a '*' if statistically significant according to the fixed hierarchical approach used to ensure a strong control of the overall type-l error rate at the 0.05 level.
  • Table 13 Percent change in key secondary efficacy endpoints from baseline - Patients with Type 1 Diabetes
  • Apo apolipoprotein
  • ITT intention-to-treat
  • LDL-C low-density lipoprotein cholesterol
  • Lp(a) lipoprotein (a)
  • LS least squares
  • non-HDL-C non-high-density lipoprotein cholesterol
  • TRL-C triglyceride-rich lipoprotein cholesterol
  • SE standard error
  • SD standard deviation
  • Non-HDL-C (Week 24) 0.7 (2.0) -37.9 (1 .4) -38.7 (2.4)
  • Triglycerides (Week 24) ⁇ 0.0 (2.7) -5.7 (2.0) -5.7 (3.4)
  • Apo apolipoprotein
  • ITT intention-to-treat
  • LDL-C low-density lipoprotein cholesterol
  • Lp(a) lipoprotein (a)
  • LS least squares
  • non-HDL-C non-high-density lipoprotein cholesterol
  • TRL-C triglyceride-rich lipoprotein cholesterol
  • SE standard error
  • SD standard deviation
  • n (%) number and percentage of patients with at least one TEAE.
  • the most frequently reported TEAEs (> 2%) in the placebo group and with a difference > 0.5% incidence from the alirocumab group were: influenza (2.3% versus 2.9%), pain in extremity (1 .7% versus 2.9%), hypoglycemia (1 .7% versus 2.4%), cough (1.5% versus 2.9%), musculoskeletal pain (1 .2% versus 2.4%), upper respiratory tract infection (0.9% versus 2.4%), hyperglycaemia (0.9% versus 2.4%), and pneumonia (0.6% versus 2.4%).
  • SAEs (at PT level) reported in more than 1 patient in either treatment groups were pneumonia (in 1 patient (0.3%) in the alirocumab group versus 2 patients (1 .2%) in the placebo group), vertebral foraminal stenosis (in 2 patients (0.6%) in the alirocumab group versus no patients in the placebo group), and urinary tract infection (in 2 patients (0.6%) versus no patients in placebo group).
  • One death due to myocardial infarction was reported in a T2DM patient of the placebo group, 1 month after the first IMP dose administration (Visit 3).
  • AESI adverse events of special Interest
  • Neurologic events meeting AESI criteria were defined as neurologic events that require additional examinations/procedures and/or referral to a specialist. Such events were reported in 1 patient (0.3%) in the alirocumab group (paraesthesia) versus 1 patient (0.6%) in the placebo group (dysphagia). Both events were reported in T2DM patients.
  • AII neurocognitive events were considered as AESI. Neurocognitive events as per sponsor or FDA grouping were reported in 4 patients (1 .2%) in the alirocumab group versus no patients in the placebo group. All events were reported in T2DM patients: a cognitive disorder was reported in 2 patients (0.6%), and memory impairment and amnesia in 1 patient (0.3%) each. Of note, the 2 cognitive disorders also led to permanent treatment discontinuation.
  • Local injection site reactions meeting AESI criteria were defined as either local injection site reactions that were allergic and required consultation with another physician or local injection site reactions that were non-allergic that were clinically significant (e.g.
  • LISR confirmed per investigator as related to IMP ('per eCRF') were reported in 6 patients (1 .7%) in the alirocumab group versus 8 patients (4.7%) in the placebo group (injection site reaction of the placebo for alirocumab). No local injection site reactions (LISR) meeting AESI criteria, defined as reactions that require consultation with another physician for further evaluation, were reported.
  • Example 3 Analysis of Individuals with Type 2 Diabetes Mellitus and ASCVD from Odyssey DM-lnsulin Clinical Trial
  • LDL-C low-density lipoprotein cholesterol
  • non-HDL-C non-high- density lipoprotein cholesterol
  • ApoB apolipoprotein B
  • LDL-PN low-density lipoprotein particle number
  • ASCVD atherosclerotic cardiovascular disease
  • ASCVD coronary heart disease
  • Ml acute and silent myocardial infarction
  • ischemic stroke or peripheral arterial disease.
  • Efficacy analysis included Week 24 percentage reduction from baseline in non-HDL-C, LDL-C, ApoB, and LDL-PN, and percentage of individuals achieving non-HDL-C ⁇ 100 mg/dL ( ⁇ 2.59 mmol/L), LDL-C ⁇ 70 mg/dL ( ⁇ 1 .81 mmol/L), and ApoB ⁇ 80 mg/dL at Week 24.
  • Intention-to-treat (ITT) analysis included all randomized individuals with a baseline LDL-C value and at least one LDL-C value up to Week 24.

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US12269897B2 (en) 2008-12-15 2025-04-08 Regeneron Pharmaceuticals, Inc. Anti-PCSK9 antibodies
US11246925B2 (en) 2011-01-28 2022-02-15 Sanofi Biotechnology Human antibodies to PCSK9 for use in methods of treating particular groups of subjects
US12083176B2 (en) 2011-01-28 2024-09-10 Sanofi Biotechnology Human antibodies to PCSK9 for use in methods of treating particular groups of subjects
US11673967B2 (en) 2011-07-28 2023-06-13 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-PCSK9 antibodies
US11904017B2 (en) 2015-08-18 2024-02-20 Regeneron Pharmaceuticals, Inc. Methods for reducing or eliminating the need for lipoprotein apheresis in patients with hyperlipidemia by administering alirocumab

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