Anti-PCSK9 Monoclonal Antibodies: The Future Lipid-Lowering Agent of Choice?

There is an established link between elevated circulating low-density lipoprotein cholesterol (LDL-C) levels and the atherosclerotic burden associated with cardiovascular disease (CVD).1,2 While statin-based LDL-C lowering has been a cornerstone of secondary prevention of CVD,3,4 many individuals fail to adequately lower their LDL-C levels, either due to insufficient response or intolerance to statin therapy. Statin-related adverse effects have been reported in approximately 5-10% of patients,5 and it is estimated that approximately 10-20% of patients on high-dose statins perceive muscle-related adverse effects.6 While ezetimibe also reduces cardiovascular events after an acute coronary syndrome,7 the effects of ezetimibe on LDL-C (~20% reduction)8 and clinical events (6.4% relative risk reduction) are modest in subjects who already have a baseline LDL-C of ~70 mg/dL.9 Thus, more potent novel lipid-lowering agents could play an important role as supplemental medications in patients who fail to reach their target LDL-C level despite optimal statin therapy +/- ezetimibe.

Normally, circulating LDL-C is removed once it binds the LDL receptor (LDLR) on hepatic cells.10 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilisin family of serine proteases that binds to the LDLR promoting LDLR degradation, thereby resulting in less LDL sequestration and increased levels of circulatory LDL-C.10 The targeted inhibition of PCSK9 would promote LDL catabolism and, thus, allow for a reduction of LDL-C to levels below those commonly achieved to date.

PCSK9 inhibition, in the form of anti-PCSK 9 antibodies, such as alirocumab (SAR236553/REGN727), evolocumab (AMG145), and bococizumab (PF04950615/RN316), represents a novel approach to LDL-C lowering. As antibodies, these drugs must be delivered parenterally, although small-molecule oral PCSK9 inhibitors are in early developmental stages.

There are a number of clinical trials with PCSK9 monoclonal antibodies demonstrating their excellent efficacy and short-term safety profile in a variety of patients, including those with elevated cardiovascular risk, patients with heterozygous or homozygous familial hyperlipidemia, and statin-intolerant patients. In phase 2 trials (Table 1 below), the LDL-C reductions versus placebo have ranged from 50-70% with the top doses of PCSK9 inhibitors.11 In addition, statistically significant reductions in total cholesterol (26-38%), apolipoprotein B (ApoB) (34-52%), triglycerides (12-26%), and lipoprotein(a) (15-31%) have been reported.12 There appears to be little (2-8%), if any, increase in HDL-C.12 Longer-term follow-up up to two years demonstrates persistence in these effects without attrition over time, notably in the Open-Label Study of Long-Term Evaluation Against LDL Cholesterol (OSLER)13 and the ODYSSEY LONG TERM trial.14

The aforementioned phase 2 trials have been reinforced by phase 3 trials (Table 2 below). The efficacy of evolocumab as a monotherapeutic agent was demonstrated in the Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 (MENDEL-2) trial, a phase 3, randomized, controlled clinical trial. Among 614 patients, monotherapy with evolocumab reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p <0.001 for all comparisons).15 Similar results of a phase 3, randomized, double-blinded trial with alirocoumab demonstrated a ≥50% LDL-C reduction in the majority of patients who received 24 weeks of alirocumab (75 mg every two weeks) versus ezetimibe therapy alone.16 Statin-intolerant patients in the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects -2 (GAUSS-2) study, a phase 3, randomized, placebo-controlled clinical trial studying 370 patients, showed a reduction of LDL-C from baseline by 53% to 56% with evolocumab, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001).17

A longer phase 3 trial of evolocumab over the course of 52 weeks randomized 901 individuals with an LDL-C of at least 75 mg/dL, despite previous treatment with various agents. Each of the doses of evolocumab achieved a significant and sustained reduction in LDL-C compared to placebo, with an overall mean reduction of 57.0 ± 2.1% (p <0.001) at 52 weeks.18 Similarly, the OSLER trial, a 52-week, phase 3, open-label extension study that enrolled patients from four previous phase 2 parent studies of evolocumab, randomized patients to either evolocumab 420 mg every four weeks with standard of care (SOC) (evolocumab + SOC, n = 736) or SOC alone (n = 368).13 Patients who received evolocumab during the OSLER trial had a mean reduction in LDL-C of 52% at week 52 (P <0.0001), whether they had received placebo or evolocumab during the preceding 12-week parent study.13 On the other hand, patients randomized to SOC only (and discontinued evolocumab on entry into the OSLER trial) had a return of LDL-C levels to baseline levels prior to initial entry into the parent study,13 illustrating the importance of maintaining patients on a steady regimen in order to sustain optimal LDL-C levels.

There are four large phase 3 outcomes studies currently ongoing with three different PCSK9 inhibitors on top of background statin therapy. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial is a randomized, double-blinded, placebo-controlled study that is following 27,500 patients treated with statins who have prior MI, ischemic stroke, or peripheral arterial disease for approximately three to four years to evaluate the impact of LDL-C reduction on major cardiovascular events with evolocumab versus placebo. The ODYSSEY OUTCOMES trial is a randomized, double-blinded, placebo-controlled study in 18,000 patients comparing the effect of monoclonal antibody alirocumab with placebo on the occurrence of cardiovascular events in patients who have experienced an acute coronary syndrome (ACS) event four to 52 weeks prior to randomization and are treated with evidence-based medical and dietary management of dyslipidemia.14

The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1) trial is an ongoing study in 17,000 patients evaluating the PCSK9 inhibitor, bococizumab compared to placebo, in reducing the occurrence of major cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization, in high-risk subjects on background lipid-lowering therapy with an LDL-C of 70-100 mg/dL or non-HDL-C of 100-130 mg/dL. The SPIRE-2 trial has a similar design but will enroll 9,000 high-risk patients with an LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL.

The efficacy and early safety of PCSK9 inhibitors via the use of monoclonal antibodies to achieve lower LDL-C concentrations appears promising to date. However, the future of these agents as a potentially widely used medication depends on the outcomes of the ongoing phase 3 trials currently underway and their ability to lower CVD risk. Nonetheless, the excitement surrounding anti-PCSK9 antibodies as a potential breakthrough agent is warranted as it may potentially change the paradigm surrounding the treatment and management of patients for years to come.

Selected Phase 2 Trials of PCSK9 Inhibitor

Study Focus: Efficacy as a combination therapy with a statin

Trial: LAPLACE-TIMI 5719
Patients: N = 631 with LDL-C ≥ 2.2 mmol/L on stable statin dose
Study Design: 12-week, randomized, double-blind, dose-ranging, placebo-controlled study of evolocumab at various doses, when added to statin therapy distributed every 2 or 4 weeks.
Results° (LDL-C concentration reduction): Evolocumab every 2 weeks added to statin therapy: Mean 41.8% to 66.1%
Evolocumab every 4 weeks added to statin therapy: Mean 41.8% to 50.3% (p <0.0001).20

Trial: Roth21
Patients:N = 92 with LDL >100 mg/dL on atorvastatin 10 mg for ≥7 weeks
Study Design:16-week study (8-week therapy/8-week follow-up), randomized to atorvastatin at various doses plus therapy or placebo every 2 weeks
Results° (LDL-C concentration reduction): Atorvastatin 80 mg daily plus Alirocumab every 2 weeks: 73.2±3.5% reduction from baseline
Atorvastatin 10 mg daily plus Alirocumab every 2 weeks: 66.2±3.5% reduction from baseline
Atorvastatin 80 mg daily plus placebo every 2 weeks: 17.3±3.5% reduction from baseline

Trial: Stein22
Patients: N = 77 with HeFH and LDL-C ≥100 mg/dL on stable diet and statin dose, with or without ezetimibe
Study Design:12-week, randomized, double-blinded, assigned patients to receive alirocumab at various doses every 4 weeks, or 150 mg every 2 weeks, or
placebo every 2 weeks in addition to a statin with or without ezetimibe
Results° (LDL-C concentration reduction): Alirocumab, 150 mg every 4 weeks: 28.9% (SE 5.08) (p = 0.0113)
Alirocumab, 200 mg every 4 weeks: 31.54% (4.91) (p = 0.0035)
Alirocumab, 300 mg every 4 weeks: 42.53% (5.09) (p <0.0001)
Alirocumab, 150 mg every 2 weeks: 67.90% (4.85) (p <0.0001)
Placebo every 2 weeks: 10.65% (5.04)

Trial: McKenney23
Patients: N = 183 with LDL-C ≥100 mg/dl on stable-dose atorvastatin 10, 20, or 40 mg for ≥6 weeks
Study Design:12-week, randomized, double-blinded, assigned to subcutaneous placebo or alirocumab 50, 100, 150 mg every 2 weeks or alirocumab 200 or 300 mg every 4 weeks alternating with placebo, in addition to statin therapy
Results° (LDL-C concentration reduction): Alirocumab 50 mg every 2 weeks: 40%
Alirocumab 100 mg every 2 weeks: 64%
Alirocumab 150 mg every 2 weeks: 72%
Alirocumab 200 mg every 4 weeks: 43%
Alirocumab 300 mg every 4 weeks: 48%
Placebo at week 12: 5%.

Trial: Ballantyne24
Patients: N = 351 with LDL-C ≥80 on statin therapy
Study Design:24-week, randomized, double-blinded, assigned to subcutaneous placebo or bococizumab. 50, 100, 150 mg every 2 weeks or bococizumab 200 or 300 mg every 4 weeks in addition to statin therapy
Results° (LDL-C concentration reduction): Bococizumab 50 mg every 2 weeks: 34%
Bococizumab 100 mg every 2 weeks: 45%
Bococizumab 150 mg every 2 weeks: 53%
Bococizumab 200 mg every 4 weeks: 28%
Bococizumab 300 mg every 4 weeks: 45%

Study Focus: Efficacy in statin intolerant patients

Trial: GAUSS11
Patients: N = 160 with an intolerance to ≥1 statin because of muscle related events
Study Design: 12-week study, randomized to different groups including, evolocumab alone at various doses, evolocumab in addition to oral daily ezetimibe, or oral daily ezetimibe alone. Evolocumab was distributed every 4 weeks.
Results° (LDL-C concentration reduction): Evolocumab 280-mg: –67 mg/dL (–41%)
Evolocumab 350-mg: –70 mg/dL (–43%)
Evolocumab 420-mg: –91 mg/dL (–51%)
Evolocumab 420-mg/ezetimibe: –110 mg/dL (–63%)
Placebo/ezetimibe: –14 mg/dL (–15%) (p <0.001).11

Study Focus: Efficacy as monotherapy

Trial: MENDEL25
Patients: N = 406 with LDL-C 100-190 mg/dL
Study Design: 12-week study, randomized to evolocumab injections alone at various doses vs. subcutaneous placebo injections vs oral daily ezetimibe. (Evolocumab and placebo injections were every 2 or every 4 weeks)
Results° (LDL-C concentration reduction): Evolocumab 70 mg every 2 weeks: -41·0%
Evolocumab 105 mg every 2 weeks: -43·9%
Evolocumab, 140 mg every 2 weeks: -50·9%
Evolocumab 280 mg every 4 weeks: -39·0%
Evolocumab 350 mg every 4 weeks: -43·2%
Evolocumab 420 mg every 4 weeks: -48·0%
Placebo every 2 weeks: -3.7%
Placebo every 4 weeks: 4.5%
Oral Ezetimibe 10mg/day: -14.7% (p <0.0001 for all doses vs placebo or ezetimibe).25

Study Focus: Efficacy in HoFH

Trial: TESLA A26
Patients: N = 8, with LDL receptor-negative (n = 2) or receptor-defective (n = 6) HoFH on stable drug therapy with LDL-C ≥130 mg/dL and triglyceride concentration ≤400 mg/dL.
Study Design: Treated with evolocumab subcutaneous 420 mg every 4 weeks for 12 weeks, an additional 12 weeks at 4-week intervals, and then every 2 weeks for an additional 12 weeks
Results° (LDL-C concentration reduction):
Receptor-negative patients: No reduction
Receptor-defective patients: -19.3±16% and -26.3±20% with 4- and 2-week dosing, respectively (P=0.0313).

LAPLACE-TIMI 57 = LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy–Thrombolysis In Myocardial Infarction 57; evolocumab is a fully human monoclonal immunoglobulin antibody which is distributed subcutaneously and binds specifically to human PCSK9 and inhibits its interaction with the LDLR;4 GAUSS = Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects; HoFH = homozygous familial hypercholesterolemia; HeFH; LDL-C = low-density lipoprotein cholesterol.
°The primary endpoint for each trial was percentage reduction in LDL-C concentration.

 

Selected Phase 3 Trials of PCSK9 Inhibition Classified by Drug

Study Name: MENDEL-227
Population: Patients with an LDL-C ≥100 mg/dL and <190 mg/dL and Framingham risk scores ≤10%.
Randomized to various groups:

  1. Oral placebo and SC placebo biweekly
  2. Oral placebo and SC placebo monthly
  3. Ezetimibe and SC placebo biweekly
  4. Ezetimibe and SC placebo monthly
  5. Oral placebo and evolocumab biweekly
  6. Oral placebo and evolocumab monthly.

N: 614
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg once monthly
Percentage of LDL-C reduction:
At 12 weeks vs. placebo:
-55% to 57% with evolocumab
At 12 weeks vs. ezetimibe:
-38% to 40% with evolocumab
(P <0.001 for all comparisons)

Study Name: GAUSS-217
Population: Patients (62 ± 10 years of age) with an average LDL-C 193 ± 59 mg/dL.
Randomized to: 
SC evolocumab + daily oral placebo or 
SC placebo + daily oral ezetimibe
N: 307
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg once monthly
Percentage of LDL-C reduction:
At 12 weeks:
Evolocumab reduced LDL-C by -53% to 56%, corresponding to treatment differences vs. ezetimibe of 37% to 39% (P <0.001).

Study Name: OSLER-213
Population: 81% of the eligible 1359 patients randomized and dosed in the 4 evolocumab phase 2 parent studies elected to enroll.
Randomized to: 
evolocumab+SOC or SOC alone.
N: 1,104
Drug: Evolocumab
Dose: 420 mg once monthly
Percentage of LDL-C reduction:
At 52 weeks:
Patients who first received evolocumab in OSLER experienced a mean 52.3% reduction in LDL-C (P <0.0001).

Study Name: FOURIER
Population: Patients 40 to 85 years of age with CVD at high risk for a recurrent event with any of the following:

  • LDL-C ≥70 mg/dL
  • Non-HDL-C ≥100 mg/dL
  • Fasting triglycerides ≤400 mg/dL

N: 27,500
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg once monthly
Percentage of LDL-C reduction: Ongoing**

Study Name: TESLA B28
Population: Patients with HoFH with LDL-C ≥130 mg/dL and triglyceride concentration ≤400 mg/dL
Randomized to:
evolocumab or placebo
N: 49
Drug: Evolocumab
Dose: 420 mg once monthly
Percentage of LDL-C reduction: At 12 weeks vs. placebo:
-30.9% reduction with evolocumab (P <0.0001).

Study Name: LAPLACE-229
Population: Patients with any of the following screening LDL-C levels: 
≥150 mg/dL (no statin at screening)
≥100mg/dL (nonintensive statin at screening) or
≥80 mg/dL (intensive statin at screening) and fasting triglyceride ≤400 mg/dL

Randomized to a daily, moderate-intensity or high-intensity statin.
After a 4-week lipid-stabilization period, patients were randomized again to:
evolocumab + statin therapies + placebo or 
evolocumab + statin therapies + ezetimibe.
N: 2067
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg once monthly
Percentage of LDL-C reduction: At 12 weeks vs. placebo:

High-intensity statin groups: 
Biweekly: -68.3-76.3% 
Monthly: -55.0-70.5%

Moderate-intensity statin groups: 
Biweekly: -68.2-71.4%
Monthly: -59.2-64.5%

At 12 weeks vs. ezetimibe:

High-intensity statin groups: 
Biweekly: -47.2%
Monthly: -38.2%

Moderate-intensity statin groups: 
Biweekly: -39.6%
Monthly: -41.1%

Study Name: DESCARTES18
Population: Patients with hyperlipidemia stratified according to the Adult Treatment Panel III  risk categories and started on 4 weeks of background lipid-lowering therapy with: 

  • Diet alone
  • Diet + atorvastatin 10 mg 
  • Atorvastatin 80 mg
  • Atorvastatin 80 mg + ezetimibe 10 mg

Those with an LDL ≥75 mg/dL were randomized to:
evolocumab or placebo.
N: 901
Drug: Evolocumab
Dose: 420 mg once monthly
Percentage of LDL-C reduction:
At 12 weeks: -57.5 ± 1.6%
At 52 weeks: -57.0 ± 2.1%

At 52 weeks on background therapy with:
Diet alone: -55.7 ± 4.2%
Atorvastatin 10 mg: -61.6 ± 2.6%
Atorvastatin 80 mg: -56.8 ± 5.3%
Atorvastatin 80 mg + Ezetimibe: -48.5 ± 5.2%

(P <0.001 for all comparisons)

Study Name: RUTHERFORD-230
Population: Patients with HeFH on stable lipid lowering therapy for at least 4 weeks.
Those with an LDL-C ≥100 mg/dL were randomized to: 
evolocumab or placebo.
N: 331
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg monthly
Percentage of LDL-C reduction:
At 12 weeks vs. placebo:
Biweekly: -59.2% 
Monthly: -61.3%
(P <0.0001 for all comparisons)

Study Name: YUKAWA-231
Population: High-risk Japanese patients initially randomized to atorvastatin 5 or 20 mg daily.
After a 4-week stabilization period, patient remained on their designated statin and underwent a second randomization to:
evolocumab or placebo.
N: 404
Drug: Evolocumab
Dose: 140 mg biweekly or 420 mg monthly
Percentage of LDL-C reduction:
At 12 weeks vs. placebo:

Atorvastatin 5 mg groups:
Biweekly: -72.3%
Monthly: -59.3%

Atorvastatin 20 mg groups:
Biweekly: -73.1%
Monthly: -66.9%

Study Name: ODYSSEY LONG TERM32
Population: Patients with hypercholesterolemia at high or very-high CV risk, including those with HeFH treated with lipid-modifying therapy, all on background of maximally tolerated statin ± other lipid-lowering therapy

Randomized to:
alirocumab or placebo.
N: 2,341
Drug: Alirocumab
Dose: 150 mg biweekly
Percentage of LDL-C reduction:
At 24 weeks vs. placebo:
-61.9% reduction with alirocumab
At 52 weeks vs. placebo:
-61.3% reduction with alirocumab
(P <0.0001)

Study Name: ODYSSEY OUTCOMES19
Population: Patients with an index hospitalization for acute myocardial infarction or unstable angina. Treated with maximally tolerated and approved dose statin and fulfill any of the following criteria:

  1. LDL-C ≥70 mg/dL
  2. Non-HDL-C ≥100 mg/dL
  3. Apolipoprotein B ≥80 mg/dL

Randomized to:
alirocumab or placebo beginning 1 to 12 months after an index hospitalization.
N: 18,000
Drug: Alirocumab
Dose: 75-150 mg biweekly
Percentage of LDL-C reduction:
Ongoing*

Study Name: ODYSSEY CHOICE II
Population: Patients with primary hypercholesterolemia (heFH or non-FH) inadequately controlled with their non-statin lipid modifying therapy or diet.
N: 200
Drug: Alirocumab
Dose: Monthly injections
Percentage of LDL-C reduction:
Ongoing data collection with a primary outcomes measure of percentage change of LDL-C from baseline to 24 weeks****

Study Name: ODYSSEY COMBO II33
Population: Patients with hypercholesterolemia at high CV risk and had inadequate LDL-C reduction at baseline despite stable maximally tolerated statin therapy for at least 4 weeks.
Randomized to:
alirocumab as add-on therapy or ezetimibe.
N: 720
Drug: Alirocumab
Dose: 75 mg biweekly, increased to 150 mg if needed to reach pre-specified LDL-C levels.
Percentage of LDL-C reduction:
At 12 weeks vs. ezetimibe:
-30% reduction with alirocumab group compared to ezetimibe group (P <0.0001).

Study Name: ODYSSEY FH II34
Population: Patients with HeFH, not adequately controlled with their lipid-modifying therapy.
Randomized to:
alirocumab or placebo.
N: 249
Drug: Alirocumab
Dose: 75 mg 
biweekly with dose up-titrated to 150 mg biweekly at week 12 if week 8 LDL-C was ≥70 mg/dL.
Percentage of LDL-C reduction:
At 24 weeks vs. placebo:
-49% reduction from baseline in LDL-C levels in alirocumab group compared to an increase of 3% in FH II placebo groups (P<0.0001).

Study Name: ODYSSEY MONO19
Population: Patients not receiving statin or any other lipid-lowering therapy for at least 4 weeks prior to screening with an:

  1. LDL-C 100–190 mg/dL
  2. 10-year risk of fatal CV events of ≥1% and <5%, based on the ESCRE.

Randomized to:
alirocumab or ezetimibe.
N: 103
Drug: Alirocumab
Dose: 75 mg 
biweekly with dose up-titrated to 150 mg biweekly at week 12 if week 8 LDL-C was ≥ 70 mg/dL
Percentage of LDL-C reduction:
At 24 weeks vs. ezetimibe:
-32% reduction with alirocumab compared to ezetimibe (P <0.0001).

Study Name: ODYSSEY ALTERNATIVE35
Population: Statin intolerant patients to be followed for 24 weeks.
Randomized to one of the following groups:

  1. Alirocumab 
  2. Ezetimibe 10 mg daily
  3. Atorvastatin 20 mg daily (statin re-challenge)

N: 314
Drug: Alirocumab
Dose: 75 mg biweekly with dose up-titrated to 150 mg biweekly at week 12 depending on  week 8 LDL-C level.
Percentage of LDL-C reduction: Ongoing***

Study Name: SPIRE-1
Population: Patients with high risk of CV event on background lipid lowering therapy with an LDL-C ≥70 mg/dL to <100 mg/dL.
Randomized to:
bococizumab or placebo.
N: 17,000
Drug: Bococizumab
Dose: 150 mg biweekly
Percentage of LDL-C reduction: Ongoing***

Study Name: SPIRE-2
Population: Patients with high risk of CV event on background lipid lowering therapy with an LDL-C ≥100 mg/dL.
Randomized to:
bococizumab or placebo.
N: 9,000
Drug: Bococizumab
Dose: 150 mg biweekly
Percentage of LDL-C reduction: Ongoing***

CV = cardiovascular; GAUSS = Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects; OSLER = Open-Label Study of Long-Term Evaluation Against LDL-C; FOURIER = Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; ESCRE = European Systematic Coronary Risk Estimation. HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; SPIRE = The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects.
* The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1,613 primary end point events have occurred with minimum follow-up of at least two years, providing 90% power to detect a 15% hazard reduction.
** The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first.
*** Four-way composite endpoint of: CV death / Non-fatal MI / non-fatal stroke / hospitalization for unstable angina needing urgent revascularization.
**** Preliminary data suggests an approximate -56% reduction with alirocumab 75 mg biweekly and 150 mg monthly vs. placebo at 24 weeks.

References

  1. Delahoy PJ, Magliano DJ, Webb K, Grobler M, Liew D. The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis. Clin Ther 2009;31:236-44.
  2. McPherson R, Frohlich J, Fodor G, Genest J; Canadian Cardiovascular Society. Canadian Cardiovascular Society position statement: recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006;22:913-27.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
  4. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
  5. Pohjola-Sintonen S, Julkunen H. Muscle-related adverse effects of statins. Duodecim 2014;130:1622-7.
  6. Bruckert E, Hayem G, Dejager S, Yau C, Be´gaud B. Mild to moderate muscular symptoms with high dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14.
  7. Cannon CP on behalf of the IMPROVE-IT Investigators. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin vs simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Late-Breaking Session Presented at American Heart Association Scientific Sessions; Chicago IL: 2014 Nov 17.
  8. Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012;223:251-61.
  9. Cannon CP on behalf of the IMPROVE-IT Investigators. IMPROVE-IT study final results. Presented at American Heart Association Scientific Sessions; Chicago IL: 2014 Nov 17.
  10. Lagace T A, Curtis D E, Garuti R., et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006;116:2995-3005.
  11. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497-506.
  12. Stein EA, Giugliano RP, Koren MJ, et al. Efficacy and safety of evolocumab (evolocumab), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J 2014;35:2249-59.
  13. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (evolocumab) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-43.
  14. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J 2014;168:682-89.
  15. Koren MJ, Lundqvist P, MD, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2531-40.
  16. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 2014;176:55-61.
  17. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.
  18. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19.
  19. Kohli P, Desai NR, Giugliano RP, et al. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol 2012;35:385-91.
  20. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 20128;380:2007-17.
  21. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Eng J Med 2012;367:1891-900.
  22. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, alirocumab/Alirocumab to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36.
  23. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, Alirocumab/alirocumab, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53.
  24. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol 2015;115:1212-21.
  25. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012;380:1995-2006.
  26. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013;128:2113-20.
  27. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2531-40.
  28. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.
  29. Robinson JG, Bettina S, Nedergaard BS, et al.The LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870-82.
  30. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.
  31. Kiyosue A, Honarpour N, Xue A, Wasserman S, Hirayama A. Effects of evolocumab (AMG 145) in hypercholesterolemic, statin-treated, Japanese patients at high cardiovascular risk: results from the phase III YUKAWA 2 study. J Am Coll Cardiol 2015;65(10_S):A1369.
  32. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
  33. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J 2015;36:1186-94.
  34. Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, Gipe DA, Baccara-Dinet MT. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther 2014;28:281-9.
  35. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8:554-61.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Prevention, Vascular Medicine, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Diet

Keywords: Acute Coronary Syndrome, Angina, Unstable, Antibodies, Monoclonal, Apolipoproteins, Apolipoproteins B, Azetidines, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cholesterol, HDL, Coronary Disease, Cost of Illness, Double-Blind Method, Fasting, Hepatocytes, Heptanoic Acids, Hospitalization, Hypercholesterolemia, Hyperlipoproteinemia Type II, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, LDL, Myocardial Infarction, Outcome Assessment (Health Care), Peripheral Arterial Disease, Proprotein Convertases, Pyrroles, Random Allocation, Receptors, LDL, Risk, Risk Factors, Secondary Prevention, Serine Endopeptidases, Serine Proteases, Standard of Care, Stroke, Subtilisin, Triglycerides


< Back to Listings