title: Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials.
abstract: OBJECTIVE
  Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH).
  
  
  RESULTS
  In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (-26.4 [-42.8, -5.4] versus -0.0 [-10.7, 15.3]; P<0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ≤30 or ≤50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (r=0.43; P<0.001) and low-density lipoprotein cholesterol and Lp(a) (r=0.36; P<0.001) plasma levels.
  
  
  CONCLUSIONS
  Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
authors.forename: Alberico L
authors.initials: AL
authors.lastname: Catapano
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.affiliation: From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.). stsimikas@ucsd.edu.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D017326:Clinical Trials, Phase III as Topic; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D009841:Oligonucleotides / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: C569471:APOB protein, human; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D015415:Biomarkers; D017270:Lipoprotein(a); D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; C524142:mipomersen
keywords: antisense oligonucleotide; coronary artery disease; dyslipidemias; hyperlipoproteinemia type II; hypolipidemic agents