title: Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab.
abstract: Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain.
  
  
  
  We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period.
  
  
  
  At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, -55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person-years).
  
  
  
  In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .).
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Amarenco
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: William
authors.initials: W
authors.lastname: Duggan
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Glynn
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: John J P
authors.initials: JJP
authors.lastname: Kastelein
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Albert M
authors.initials: AM
authors.lastname: Kim
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Steven
authors.initials: S
authors.lastname: Nissen
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: James
authors.initials: J
authors.lastname: Revkin
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Rose
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Pamela F
authors.initials: PF
authors.lastname: Schwartz
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shear
authors.affiliation: From Brigham and Women's Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) - both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.).
authors.forename: Carla
authors.initials: C
authors.lastname: Yunis
mesh_terms: D000906:Antibodies / Q000097:blood*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000276:immunology; D007279:Injections, Subcutaneous / Q000009:adverse effects; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000097:blood / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D008055:Lipids; D000091362:PCSK9 Inhibitors; C000598888:bococizumab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9