Author + information
- Received February 28, 2014
- Revision received March 18, 2014
- Accepted March 19, 2014
- Published online June 17, 2014.
- Erik Stroes, MD, PhD∗∗ (, )
- David Colquhoun, MD†,
- David Sullivan, MD‡,
- Fernando Civeira, MD§,
- Robert S. Rosenson, MD‖,
- Gerald F. Watts, DSc, PhD, DM¶,
- Eric Bruckert, MD#,
- Leslie Cho, MD∗∗,
- Ricardo Dent, MD††,
- Beat Knusel, PhD††,
- Allen Xue, PhD††,
- Rob Scott, MD††,
- Scott M. Wasserman, MD††,
- Michael Rocco, MD‡‡,
- GAUSS-2 Investigators
- ∗Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
- †Wesley Medical Centre, Auchenflower, Australia
- ‡Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia
- §Hospital Universitario Miguel Servet, Zaragoza, Spain
- ‖Cardiometabolic Disorders Department, Icahn School of Medicine at Mount Sinai, New York, New York
- ¶Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
- #Hopital Pitie-Salpetriere, Paris, France
- ∗∗Preventive Cardiology and Rehabilitation, Cleveland Clinic, Cleveland, Ohio
- ††Amgen, Thousand Oaks, California
- ‡‡Cardiovascular Medicine Department, Cleveland Clinic, Cleveland, Ohio
- ↵∗Reprints and correspondence:
Prof. Erik Stroes, Department of Vascular Medicine, F4.211, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
Objectives This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses.
Background Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients.
Methods The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12.
Results Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups.
Conclusions Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905)
Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular risk (1,2). Although statins are well tolerated, statin-related adverse events have been reported more commonly than in the randomized trials, reaching up to 10% to 20% of patients (3). Although Zhang et al. (3) reported that a substantial proportion of patients with side effects to 1 statin tolerated a re-challenge to a second statin, failure to achieve treatment target in patients intolerant of multiple statins is expected to translate into lower benefits in cardiovascular risk (1–4). The cholesterol absorption inhibitor, ezetimibe, is well tolerated, but yields only a minor reduction in LDL-C. Other therapies include bile acid sequestrants and nicotinic acid, but these agents are usually poorly tolerated. Novel potent LDL-C lowering therapies, such as the apolipoprotein-B synthesis inhibitor and the microsomal triglyceride transfer protein inhibitor, are characterized by marked side effects, limiting wider usage (5,6).
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein involved in regulating low-density lipoprotein receptor (LDLR) recycling (7–9). Evolocumab (AMG 145) is a fully human monoclonal antibody that binds to PCSK9 and inhibits its interaction with the LDLR, resulting in increased receptor recycling and LDL clearance. In a phase 2 dose-finding study, evolocumab reduced LDL-C in statin-intolerant patients and showed favorable short-term tolerability (10). We now report on the GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial (11), a phase 3 study that compared the effects of evolocumab with ezetimibe in statin-intolerant hypercholesterolemic patients. Compared with GAUSS, which included patients intolerant to at least 1 statin, the present phase 3 trial evaluated evolocumab compared with ezetimibe using a placebo-controlled design in patients intolerant to at least 2 statins.
GAUSS-2 enrolled patients aged 18 to 80 years on no or low-dose statins. Participants had LDL-C above their National Cholesterol Education Program (NCEP) Adult Treatment Panel III goal (12). Participants had previous intolerance to ≥2 statins, defined as inability to tolerate any dose or increase the dose above the smallest tablet strength because of intolerable muscle-related side effects (11).
Study design and oversight
The institutional review boards approved the protocol, and all patients provided written informed consent. GAUSS-2 was a randomized, double-blind, phase 3, placebo- and ezetimibe-controlled study (11). Patients were randomized 2:2:1:1 to subcutaneous evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe. Patients and all study personnel were blinded to treatment assignment. An independent data monitoring committee reviewed all data.
Study procedures were similar to those listed in the MENDEL-2 (Anti-PCKS9 Monotherapy for Hypercholesterolemia: The MENDEL-2 Randomized, Controlled Phase III Clinical Trial of Evolocumab) study (13).
Efficacy and safety evaluations
Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12. Co-secondary efficacy endpoints at the same time points included change from baseline in LDL-C, percent of patients with LDL-C <70 mg/dl, and percent change from baseline in non–high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, total cholesterol/HDL-C ratio, apolipoprotein B/apolipoprotein A-I ratio, lipoprotein(a), triglycerides, HDL-C, and very low-density lipoprotein (VLDL-C) (10). Safety endpoints included treatment-emergent and serious adverse events, creatine kinase (CK) and hepatic enzyme elevations, and anti-evolocumab antibodies.
Planned enrollment of 300 patients (200 on evolocumab) had ≥92% power to detect superiority of evolocumab regimens over ezetimibe based on a 2-sided t-test with 0.05 significance level for co-primary endpoints. Statistical analyses were similar to those in the MENDEL-2 study (13).
Between January and August 2013, 307 patients were randomized to evolocumab (n = 205) or ezetimibe (n = 102) (Table 1, Online Table S1). Patients had a baseline LDL-C of 193 ± 59 mg/dl. Lipid-lowering therapy was used by 33% of patients; 18% received a low-dose statin. Fifty-six percent of patients were at high risk of coronary heart disease (CHD) according to the NCEP. Treatment was completed by 96% of patients on evolocumab and 86% of patients on ezetimibe. Eight patients discontinued evolocumab (4%) for adverse events (n = 6), patient request (n = 1), or loss to follow-up (n = 1). Fourteen patients discontinued ezetimibe (14%) for adverse events (n = 11), patient request (n = 2), or other reason (n = 1). The study was completed by 290 patients (94%) (Online Fig. S1).
Low-Density Lipoprotein Cholesterol
Evolocumab yielded significant reductions in LDL-C (Table 2). Mean percent reductions from baseline at a mean of weeks 10 and 12 were 56.1% (95% confidence interval [CI]: 59.7% to 52.5%) with 140 mg Q2W and 55.3% (95% CI: 58.3% to 52.3%) with 420 mg QM, corresponding to treatment differences versus ezetimibe of 36.9% (95% CI: 42.3% to 31.6%) and 38.7% (95% CI: 43.1% to 34.3%), respectively (p <0.001). Mean percent reductions from baseline and treatment differences at week 12 were similar (p < 0.001). Reductions in LDL-C were sustained throughout the trial (Fig 1). Evolocumab-treated patients were more likely to achieve LDL-C target levels than ezetimibe-treated patients (Fig. 2).
Treatment-emergent adverse events are listed in Table 3 and the Online Appendix. Adverse events led to study drug discontinuation in 8% (evolocumab) and 13% (ezetimibe) of patients. Myalgia occurred in 8% of evolocumab-treated patients and 18% of ezetimibe-treated patients. Patients using low-dose statin therapy were more likely to develop myalgia in the ezetimibe (statin vs. no statin: 21% vs. 17%) and the evolocumab group (statin vs. no statin: 17% vs 6%). Discontinuation rates due to musculoskeletal side effects were 5% (evolocumab) and 6% (ezetimibe). No binding or neutralizing antibodies to evolocumab were detected.
In the GAUSS-2 study, evolocumab administered over 3 months yielded a significant reduction in LDL-C in hypercholesterolemic patients who were unable to tolerate effective doses of at least 2 statins, reflecting a population with a true unmet need.
Evolocumab treatment resulted in a 53% to 56% reduction in LDL-C, with comparable reductions between dosing regimens. In GAUSS-2, 82% of patients used no statin, leading to markedly elevated LDL-C levels (mean of 193 mg/dl) comparable to those observed in early secondary prevention trials (14). Of evolocumab-treated patients at high risk, more than 75% achieved LDL-C <100 mg/dl compared with less than 10% of ezetimibe-treated patients. In the context of the American College of Cardiology/American Heart Association guidelines (15), these findings imply that evolocumab could be a promising alternative agent to lower LDL-C in statin-intolerant patients with markedly elevated LDL-C levels.
Compared with the dose-finding phase 2 trial (GAUSS) (10), GAUSS-2 enrolled a population at a higher cardiovascular risk, with more patients intolerant of at least 2 statins, leading to the inclusion of patients with a truly unmet clinical need. In the upcoming results of the outcome trial with evolocumab (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk; NCT01764633), the observed 100 mg/dl reduction in LDL-C can be expected to reduce cardiovascular risk, given the 22% risk reduction per 39 mg/dl LDL-C decrease reported for statins (1,2).
In GAUSS-2, ezetimibe was selected as comparator based on its favorable tolerability and widespread use in statin-intolerant patients (16). The majority of patients using ezetimibe were unable to achieve LDL-C target levels, as evidenced by the 2% rate of achieving LDL-C <70 mg/dl. Moreover, benefit of ezetimibe-induced, LDL-C lowering awaits confirmation in the ongoing outcome study (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]; NCT00202878) (17).
Evolocumab also reduced lipoprotein(a) levels by 27% (Q2W) and 22% (QM) at week 12, consistent with lipoprotein(a) reductions reported in previous studies using PCSK9-targeting programs (18–20). Further studies on the mechanism of lipoprotein(a) lowering and the benefit of evolocumab in patients with elevated lipoprotein(a) levels are warranted.
Evolocumab was well tolerated with 96% of patients completing treatment. With all patients having historically experienced muscle-related side effects during statin therapy, myalgia incidence was low (18%, 7%, and 9% of patients in the ezetimibe, evolocumab Q2W, and evolocumab QM groups, respectively). In the MENDEL-2 study (13), these rates were 1%, 1%, and 1%, respectively. Notwithstanding the higher rate in statin-intolerant patients, there was no increase in muscle-related side effects in the evolocumab- compared with ezetimibe-treated patients. This suggests that the pathways contributing to statin-associated myalgia and/or myositis (21,22) are distinct from those contributing to PCSK9 antibody-mediated LDL-C lowering. Because the study was short term, these data await confirmation in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; NCT01764633) outcome study. The incidence of treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups.
A limitation of this study includes the absence of a blinded statin re-challenge. We used a real-life definition of patients who experienced intolerable muscle-related side effects to ≥2 statins, with the majority unable to tolerate ≥3 statins. A placebo-controlled blinded statin re-challenge has, however, been included in the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3; NCT01984424) study. Another limitation is the short study duration in patients needing life-long treatment; however, patients were eligible to enroll in the open-label extension study (Open Label Study of Long Term Evaluation Against LDL-C Trial-2; NCT01854918) following GAUSS-2.
Evolocumab treatment yielded a robust reduction in plasma LDL-C in hypercholesterolemic patients with statin intolerance. The low incidence of muscle-related side effects in GAUSS-2 underscores evolocumab as a useful therapy for hypercholesterolemic patients who presently have few tolerable treatment options, provided that benefit is confirmed in the ongoing endpoint trial (FOURIER; NCT01764633).
The authors thank Meera Kodukulla and Laura Evans (on behalf of Amgen) for editorial support and Colin Weller, Julie McGinnis, Tony Jack, and Mary McCombie (Amgen) for assistance with trial management.
This study was funded by Amgen Inc. Dr. Stroes has received (nonsubstantial) lecturing fees from Amgen, Merck, Novartis, Regeneron, and sanofi-aventis. Dr. Sullivan has received research funding from Amgen, Abbott Products, AstraZeneca, Merck, Sharp, and Dohme, and sanofi-aventis; educational program funding from Abbott Products, AstraZeneca, Merck, Sharp, and Dohme, Pfizer Australia, and Roche; and travel support from Merck, Sharp, and Dohme. Dr. Sullivan has served on advisory boards for Abbott Products, Merck, Sharp, and Dohme, and Pfizer Australia. Dr. Civeira has received a research grant from Merck; consulting fees from sanofi-aventis; and honoraria from Merck and Amgen. Dr. Rosenson has participated on advisory boards for Aegerion, Amgen, AstraZeneca, CVS Caremark, GlaxoSmithKline, Novartis Pfizer, Regeneron, sanofi-aventis, and Sticares InterACT; has received institutional research grants from Amgen, Novartis, and sanofi-aventis; has received royalties from UpToDate, Inc.; and is a stockholder of LipoScience, and Medicines Company. Dr. Watts has received honoraria for advisory boards and lectures from Amgen, sanofi-aventis, Abbott, and AstraZeneca. Dr. Bruckert has received honoraria for meetings or presentations from AstraZeneca; Merck, Sharp, and Dohme, Aegerion, Danone, Amgen, Novartis, and sanofi-aventis. Dr. Cho has received research funding and consulting fees from Amgen. Dr. Rocco has received research funding from Amgen and Eli Lilly; and consulting fees from Abbott, Pfizer, Bristol-Myers Squibb, and Amarin. Drs. Dent, Knusel, Xue, Scott, and Wasserman are employees and stockholders of Amgen. All other authors have reported that they no relationships relevant to the contents of this work to disclose.
- Abbreviations and Acronyms
- coronary heart disease
- confidence interval
- creatine kinase
- high-density lipoprotein cholesterol
- low-density lipoprotein cholesterol
- low-density lipoprotein receptor
- National Cholesterol Education Program
- proprotein convertase subtilisin/kexin type 9
- every 2 weeks
- very low-density lipoprotein cholesterol
- Received February 28, 2014.
- Revision received March 18, 2014.
- Accepted March 19, 2014.
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