Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, after Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I)

C. Michael Gibson, Serge Korjian, Pierluigi Tricoci, Yazan Daaboul, Megan Yee, Purva Jain, John H. Alexander, P. Gabriel Steg, A. Michael Lincoff, John J P Kastelein, Roxana Mehran, Denise M. D'Andrea, Lawrence I. Deckelbaum, B. Merkely, MacIej Zarebinski, Ton Oude Ophuis, Robert A. Harrington

Research output: Contribution to journalArticle

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Abstract

Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.

Original languageEnglish
Pages (from-to)1918-1930
Number of pages13
JournalCirculation
Volume134
Issue number24
DOIs
Publication statusPublished - Dec 13 2016

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Apolipoprotein A-I
Myocardial Infarction
Safety
Renal Replacement Therapy
Placebos
Alanine Transaminase
Kidney
Bilirubin
Coronary Artery Disease
Creatinine
Cholesterol
CSL112
Animal Diseases
Liver
Incidence
Serum
HDL Cholesterol
Pharmacokinetics

Keywords

  • alipoprotein A-I
  • myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, after Acute Myocardial Infarction : The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). / Gibson, C. Michael; Korjian, Serge; Tricoci, Pierluigi; Daaboul, Yazan; Yee, Megan; Jain, Purva; Alexander, John H.; Steg, P. Gabriel; Lincoff, A. Michael; Kastelein, John J P; Mehran, Roxana; D'Andrea, Denise M.; Deckelbaum, Lawrence I.; Merkely, B.; Zarebinski, MacIej; Ophuis, Ton Oude; Harrington, Robert A.

In: Circulation, Vol. 134, No. 24, 13.12.2016, p. 1918-1930.

Research output: Contribution to journalArticle

Gibson, CM, Korjian, S, Tricoci, P, Daaboul, Y, Yee, M, Jain, P, Alexander, JH, Steg, PG, Lincoff, AM, Kastelein, JJP, Mehran, R, D'Andrea, DM, Deckelbaum, LI, Merkely, B, Zarebinski, M, Ophuis, TO & Harrington, RA 2016, 'Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, after Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I)', Circulation, vol. 134, no. 24, pp. 1918-1930. https://doi.org/10.1161/CIRCULATIONAHA.116.025687
Gibson, C. Michael ; Korjian, Serge ; Tricoci, Pierluigi ; Daaboul, Yazan ; Yee, Megan ; Jain, Purva ; Alexander, John H. ; Steg, P. Gabriel ; Lincoff, A. Michael ; Kastelein, John J P ; Mehran, Roxana ; D'Andrea, Denise M. ; Deckelbaum, Lawrence I. ; Merkely, B. ; Zarebinski, MacIej ; Ophuis, Ton Oude ; Harrington, Robert A. / Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, after Acute Myocardial Infarction : The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). In: Circulation. 2016 ; Vol. 134, No. 24. pp. 1918-1930.
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abstract = "Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2{\%} received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4{\%}. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5{\%}. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.",
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TY - JOUR

T1 - Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, after Acute Myocardial Infarction

T2 - The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I)

AU - Gibson, C. Michael

AU - Korjian, Serge

AU - Tricoci, Pierluigi

AU - Daaboul, Yazan

AU - Yee, Megan

AU - Jain, Purva

AU - Alexander, John H.

AU - Steg, P. Gabriel

AU - Lincoff, A. Michael

AU - Kastelein, John J P

AU - Mehran, Roxana

AU - D'Andrea, Denise M.

AU - Deckelbaum, Lawrence I.

AU - Merkely, B.

AU - Zarebinski, MacIej

AU - Ophuis, Ton Oude

AU - Harrington, Robert A.

PY - 2016/12/13

Y1 - 2016/12/13

N2 - Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.

AB - Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.

KW - alipoprotein A-I

KW - myocardial infarction

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U2 - 10.1161/CIRCULATIONAHA.116.025687

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