Author + information
- Received July 27, 2013
- Revision received August 27, 2013
- Accepted September 19, 2013
- Published online February 11, 2014.
- Nihar R. Desai, MD, MPH∗,
- Robert P. Giugliano, MD, SM∗,
- Jing Zhou, MS∗,
- Payal Kohli, MD†,
- Ransi Somaratne, MD‡,
- Elaine Hoffman, PhD∗,
- Thomas Liu, PhD‡,
- Robert Scott, MD‡,
- Scott M. Wasserman, MD‡ and
- Marc S. Sabatine, MD, MPH∗∗ ()
- ∗TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- †Division of Cardiovascular Medicine, University of California at San Francisco, San Francisco, California
- ‡Amgen, Inc., Thousand Oaks, California
- ↵∗Reprint requests and correspondence:
Dr. Marc S. Sabatine, TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, 350 Longwood Avenue, Boston, Massachusetts 02115.
Objectives This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program–Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals.
Background Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy.
Methods In 282 subjects from the LAPLACE–TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non–high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl.
Results During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal.
Conclusions PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.
The National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) recommends that low-density lipoprotein cholesterol (LDL-C) concentration be lowered to <100 mg/dl in patients with established cardiovascular (CV) disease or CV disease equivalents. In 2004, the guidelines were updated with an optional goal of <70 mg/dl (1). However, contemporary analyses demonstrate that many patients at high risk for adverse CV events are unable to achieve an LDL-C level of <70 mg/dl, even with high-potency statin therapy (2,3). Thus, additional treatment options are needed.
AMG 145, a fully human, monoclonal, immunoglobulin G2 (IgG2) antibody to proprotein convertase subtilisin kexin type 9 (PCSK9), led to significant, dose-dependent reductions in LDL-C of up to 66% in the LAPLACE–TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial Infarction 57) trial (4). We sought to define the ability of treatment with AMG 145 to enable subjects at high risk for adverse CV events in the LAPLACE–TIMI 57 trial to achieve NCEP-ATP III LDL-C and other lipid goals.
The design and primary results of LAPLACE–TIMI 57 have been reported previously (4). Briefly, the study was a phase 2, double-blind, placebo-controlled, dose-ranging study comparing AMG 145 (in doses of 70, 105, and 140 mg every 2 weeks or 280, 350, and 420 mg every 4 weeks) versus placebo in 631 subjects with hypercholesterolemia and LDL-C concentrations >85 mg/dl on a stable dose regimen of statin therapy with or without ezetimibe. LDL-C was measured by preparative ultracentrifugation (UC-LDL-C) at baseline, day 1, and week 12 and calculated using the Friedewald equation on a fasting lipid sample at weeks 2, 4, 6, 8, and 10. This pre-specified subgroup analysis included 282 subjects at high risk as defined by NCEP-ATP III guidelines (i.e., with coronary heart disease [CHD] or CHD risk equivalents) who received the study drug and had LDL-C measurements taken at the end of the study.
The primary outcome of this analysis was the proportion of subjects who achieved the NCEP-ATP III recommended LDL-C concentration of <70 mg/dl at week 12, measured with UC-LDL-C. Secondary outcomes included the proportion of subjects who simultaneously achieved an UC-LDL-C <70 mg/dl, a non–high-density lipoprotein cholesterol (HDL-C) concentration of <100 mg/dl, and an apolipoprotein B (ApoB) concentration of <80 mg/dl and the proportion of subjects who achieved ≥50% reduction in UC-LDL-C at week 12.
A Cochrane-Armitage test for trend was used to analyze the differences among all the groups in the proportion of patients who achieved the lipid goals described above. For all analyses, p values of <0.05 were considered significant. See the Online Appendix for further details.
Of the 631 randomized subjects in the LAPLACE–TIMI 57 trial, 284 (45%) were high-risk patients based on NCEP-ATP III definitions. There were no significant differences in baseline characteristics across the randomized treatment arms or among patients when pooled for placebo versus AMG 145 treatment (Online Table 1).
Of the 284 high-risk patients, 282 (99.3%) received at least 1 dose of the study drug and had LDL-C measured by UC at week 12. Among this group, each dose of AMG 145 significantly reduced UC-LDL-C from baseline to week 12 compared with placebo (Online Fig. 1) by up to 64% for the AMG 145 group treated every 2 weeks and up to 45% for the AMG 145 group treated every 4 weeks (p < 0.001 for each dose compared with placebo). The lowest mean ± SD of the UC-LDL-C levels achieved at week 12 were 47 ± 30 mg/dl and 59 ± 29 mg/dl, respectively. The distribution of baseline and UC-LDL-C levels achieved at 12 weeks among subjects receiving an AMG 145 dosage of 140 mg every 2 weeks is shown in Online Figure 2.
Compared with placebo, each dose of AMG 145 significantly increased the proportion of patients who achieved the NCEP-ATP III recommended LDL-C of <70 mg/dl at week 12 (p < 0.001 for each dose) (Fig. 1), with 90% and 70% of subjects who received the top doses every 2 and 4 weeks, respectively, achieving this lipid goal.
Because monoclonal antibodies to PCSK9 yield U-shaped LDL-C reduction over their dosing intervals, the LDL-C measurements at week 12 represent the nadir of efficacy. For patients receiving doses every 4 weeks, the sampling of LDL-C every 2 weeks also permitted an examination of LDL-C reduction (using LDL-C calculated via the Friedewald equation) at the midway point during the dosing interval (Online Fig. 3). Up to 90% of subjects receiving AMG 145 every 2 weeks and up to 97% of subjects receiving AMG 145 every 4 weeks (p < 0.001 for each AMG 145 dose compared with placebo) were able to attain the NCEP-ATP III recommended LDL-C of <70 mg/dl at week 10 (Fig. 2).
There were also step-wise increases in the proportion of subjects who achieved a reduction in UC-LDL-C of ≥50% (p < 0.001 for each dose compared with placebo) (Online Fig. 4). Furthermore, all AMG 145 dose regimens were also significantly more likely than placebo to achieve non–HDL-C <100 mg/dl or ApoB <80 mg/dl or to achieve all 3 lipid targets (p < 0.001 for each AMG 145 dose vs. placebo for each lipid goal) (Online Fig. 5). Further analyses performed at week 10 demonstrated that up to 90% and 97% of high-risk subjects treated with AMG 145 every 2 weeks and every 4 weeks, respectively, were able to achieve this triple goal (p < 0.001 for each AMG 145 dose vs. placebo for each lipid goal at week 10) (Online Fig. 6).
There were no significant differences in the rates of serious adverse events, treatment-related adverse events, elevations in creatine kinase >5× upper limit of normal (ULN), or asparate aminotransferase (AST)/alanine aminotransferase (ALT) elevations >3× ULN across treatment groups (Online Table 2). There was no evidence of an association between UC-LDL-C achieved at week 12 and the frequency of serious adverse events, muscle events, AST/ALT elevations >3× ULN, or other events of interest (Online Table 3).
Our analysis from the LAPLACE–TIMI 57 trial of subjects with established CHD or CHD risk equivalents demonstrates that the addition of AMG 145 to background lipid-lowering therapy with a statin, with or without ezetimibe, significantly increases the ability of high-risk subjects to achieve NCEP-ATP III LDL-C and other lipid parameter goals. We observed that ≥90% of high-risk subjects in our study were able to achieve an LDL-C level of <70 mg/dl at some time during the dosing interval with both of the top AMG 145 doses every 2 weeks and the top dose every 4 weeks.
There are over 71 million adults with hypercholesterolemia in the United States, of whom it is estimated that 17% are at high risk and would potentially be candidates for the more aggressive NCEP-ATP III 2004 updated LDL-C goal of <70 mg/dl (2). Contemporary observational analyses demonstrated that approximately 35% of high-risk patients actually attain the NCEP-ATP III LDL-C goal (2,3). Because PCSK9 inhibition with AMG 145 offers additional robust LDL-C reduction in addition to existing statin therapy, the introduction of PCSK9 inhibition into clinical practice would represent a significant advancement enabling the vast majority patients with CHD and CHD risk equivalents to achieve optimal LDL-C levels.
Over 12 weeks of treatment, AMG 145 was well tolerated, with no dose-related or dose-frequency–related increases in the rates of serious adverse events, treatment-related adverse events, or incidence of significant elevations in creatine kinase or AST/ALT. Furthermore, we found no evidence of an association between LDL-C level achieved at week 12 and the incidence of adverse events. These observations are consistent with those of longer-lasting clinical trials of statins that have demonstrated the safety of achieving low levels of LDL-C (5).
Our results are in accord with the overall findings from the LAPLACE–TIMI 57 trial and observations from a study of another monoclonal antibody against PCSK9 (6). However, there were relatively few high-risk patients in the latter study, and high-intensity statin therapy was used in only 24% of subjects.
There are several limitations to our analysis worth noting. Background lipid-lowering therapy was determined by the treating clinician at the time of screening and was to remain constant during the trial. However, the use of intensive lipid-lowering therapy and the LDL-C levels at baseline among high-risk patients were similar to those reported in contemporary registries and cross-sectional population studies. The reductions in UC-LDL-C at week 12 are at the end of the dosing interval and likely underestimate the true biological effect. In supporting analyses conducted at week 10, we observed that up to 97% of high-risk subjects were able to attain an LDL-C concentration of <70 mg/dl. However, the 10-week measurements were made using the Friedewald equation to calculate LDL-C and thus may represent an underestimation of LDL-C and hence an overestimation of the proportion of patients who achieved the target. With treatment for only 12 weeks, we have only short-term safety and tolerability data.
PCSK9 inhibition with AMG 145 enables most patients at highest risk for adverse CV events to achieve the most stringent recommended lipid goals. If this therapy demonstrates efficacy for reducing CV events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.
The LAPLACE–TIMI 57 trial was supported by a research grant from Amgen, Inc., to the TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts. Dr. Giugliano has received research grant support through Brigham and Women's Hospital from Daiichi Sankyo and Merck; and honoraria for consulting from Amgen, Daiichi Sankyo, and Merck. Drs. Somaratne, Liu, Scott, and Wasserman are employees of Amgen and own Amgen stock. Dr. Sabatine has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi-Aventis joint venture, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Roche Diagnostics, Sanofi-Aventis, and Takeda; and honoraria for consulting from Aegerion, Amgen, AstraZeneca/Bristol-Myers Squibb Alliance, GlaxoSmithKline, Merck, Pfizer, Sanofi-Aventis, and Vertex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- apolipoprotein B
- coronary artery disease
- coronary heart disease
- high-density lipoprotein cholesterol
- low-density lipoprotein cholesterol
- NCEP-ATP III
- National Cholesterol Education Program-Adult Treatment Panel III
- National Health and Nutrition Examination Survey
- upper limit of normal
- Received July 27, 2013.
- Revision received August 27, 2013.
- Accepted September 19, 2013.
- American College of Cardiology Foundation
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