pcsk9 inhibitors
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Hyperlipidemia and PCSK9 inhibitors.
Presentation by: Terri Newman, PharmD Candidate 2015
Understand the mechanism of action of PCSK9
inhibitors
Examine the relationship between statins + PCSK9
inhibitor therapy in the treatment of hyperlipidemia
Identify the place in therapy and proposed benefits of
PCSK9 inhibitors
Examine the gap in knowledge regarding these new
agents and explain what needs to be addressed before
implementation of these new agents
Objectives
JP is a 62 year old male with a PMH significant of:
HTN, unstable angina, TIA, MI, carotid artery disease, CAD
JP’s past surgical history includes:
7 CABG, 48 stents, and 52 cardiac catheterizations
Patient Case
Patient still has chest pains occasionally and has been to the cath lab 2 times in 2014. His current treatment regimen includes:
Aspirin 81 mg
Diltiazem 240 mg
Isosorbide mononitrate 60 mg
Metoprolol succinate XL 25mg
NTG patch
NTG spray
Prasugrel 5mg
Ranolazine 1000mg
Rosuvastatin 20mg
Trandolapril 1mg
Patient Case
Lipid Panels
Male, over the age of 55, FH of CVD (mother had a stroke), hypertension, dyslipidemia
ASCVD risk score
Patient has clinical ASCVD.
Patient Case
Date 11/24/14 5/14/14 5/8/13
TC 153 152 108
HDL 45 45 30
LDL 79 88 51
TG 147 96 138
Statins gold standard of therapy
4 statin benefit groups:
LDL > 190 mg/dl
Clinical ASCVD
Diabetes
10 year ASCVD risk >7.5%
Lipid guidelines
Stone NJ, Robinson JG, Lichenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2014; 129: S1-S45.
Proprotein convertase substilisin/kexin
Mechanism of action
PCSK9 Inhibitors
Picture of PCSK9 mechanism of action. Google image. January 28, 2015.
SREBP responds to sterol content and regulates PCSK9 and LDLR
Relationship between statins & PCSK9 inhibitors
American Heart Assocation. Commentaries on cutting edge science. Available at: http://circres.ahajournals.org/content/111/3/274/F1.expansion.html. Accessed January 28, 2015.
LAPLACE-2: Effect of Evolocumab or Ezetimibe Added to
Moderate or High-Intensity Statin Therapy on LDL-C Lowering
in Patients With Hypercholesterolemia
Study drug: Evolocumab 140mg bi-weekly or 420mg monthly,
SQ
Design: Phase III, 12 week, double-blind RCT, 1,896 patients
Objective: To determine efficacy and tolerability of Evolocumab
in combination with moderate or high intensity statin.
Primary outcome: % change in LDL from baseline to the mean
of weeks 10 and 12 and at week 12.
LAPLACE-2
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Male or female, 18-80 years of age, fasting TG
<400mg/dL, with:
LDL 150mg/dL or greater
LDL 100mg/dL or greater on non-intensive statin
LDL 80mg/dL or greater on intensive statin
Inclusion criteria
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Baseline Characteristics
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Randomized patients to receive statin
Rosuvastatin 5mg
Rosuvastatin 40mg
Evolocumab 140mg SQ q2 wks
Placebo SQ q2 wks
Evolocumab 420mg SQ monthly
Placebo SQ monthly
Simvastatin 40 mg
Atorvastatin 80mg
Evolocumab 140mg SQ q2wks + placebo
Evolocumab 420 SQ monthly + placebo
Placebo SQ q 2 wks + placebo po qd
Placebo SQ monthly + Placebo po qd
Ezetimibe 10mg po qd + placebo SQ q 2 wks
Ezetimibe 10 mg po qd + placebo SQ monthly
Atorvastatin 10mg
LAPLACE-2 Treatment groups
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Results
Percent reduction in LDL across all
statin groups:
2 week dosing of Evolocumab: 59%-66%
reduction from baseline
Monthly dosing of Evolocumab: 62%-65%
reduction from baseline
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Results
Treatment LDL % reduction from baseline
Ezetimibe 10mg
17-24%
Evolocumab q2wks
61-62%
Evolocumab qmonthly 62-65%
Patients treated with atorvastatin (10mg or 80mg)
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Moderate intensity statin
High intensity statin
Results
Evolocumab q2wks
Evolocumab qmonthly
Baseline LDL(mg/dL) 115-124 123-126
Treatment LDL(mg/dL) 39-49 43-48
Evolocumab q2wks Evolocumab qmonthly
Baseline LDL (mg/dL) 89-94 89-94
Treatment LDL (mg/dL) 35-38 33-35
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Results Percent change in LDL for Evolocumab vs. placebo or ezetimibe at mean of 10 & 12
weeks
Every 2 weeks Monthly
Atorvastatin 10mg vs. placebo -70 (-75.4 to -64.5) -62.8 (-69.1 to -56.6)
Atorvastatin 10mg vs. ezetimibe
-37.5 (-43 to -32) -43.5 (-49.7 to -37.3)
Simvastatin 40mg vs. placebo -69.4 (-74.9 to -64) -68.5 (-76.7 to -60.2)
Rosuvastatin 5mg vs. placebo -66.9 (-72.7 to -61.1) -66.6 (-72.6 to -60.6)
Every 2 weeks Monthly
Atorvastatin 80mg vs Placebo -74.9 (-84.5 to -65.4) -74.8 (-83 to -66.6)
Atorvastatin 80mg vs Ezetimibe
-44.9 (-54.3 to -35.6) -43.8(-52.1 to -35.6)
Rosuvastatin 40mg vs placebo -65.7 (-73.2 to-58.1) -62.9 (-71.4 to -54.5)
High Intensity Statins
Moderate Intensity Statins
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
High-intensity Evolocumab q2wks Evolocumab qmonthly
% of patients with LDL <70mg/dl Ezetimibe: 51-62%
94 93-95
Moderate intensity Evolocumab q2wks Evolocumab qmonthly
% of patients with LDL <70mg/dl Ezetimibe: 17-20%
88-94 86-90
Results Percentage of patients with LDL < 70mg/dl
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Safety & Tolerability
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Evolocumab reduced LDL at the mean of weeks 10 and 12 in patients
with hypercholesterolemia on background statin therapy
No differences noticed among moderate intensity or high intensity
Patients randomized to evolocumab in addition to atorvastatin
therapy experienced greater LDL reductions than those on ezetimibe
LDL <70 mg/dl was achieved in a majority of patients on
evolocumab
Moderate intensity: 86-94%
High intensity: 93-95%
Well tolerated with comparable adverse events rates to placebo and
ezetimibe
Summary of trial
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
+ -
Showed efficacy of evolocumab across a multitude of statins, doses, and most common add on treatment.
Not an outcomes study. Can this drug reduce the outcome of CV events?
Correlated with 2013 ACC/AHA guidelines by focusing on percent lowering of LDL rather than specific numbers
Is a lipid stabilization phase of 4 weeks adequate?
Multicenter, large trial, evenly distributed baseline characteristics, ↑ external validity
Study was designed prior to the release of AHA/ACC 2013 lipid guidelines so patients weren’t identified based on 4 statin benefit groups. Patients may have been randomized to a treatment that may have been suboptimal based on new guidelines.
Discussion
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
Statins used were 3 most commonly prescribed statins and
doses correlated with moderate-high intensity statins based
on ACC/AHA guidelines
Regardless of statin type, dose, or intensity the addition of
Evolocumab led to similar LDL reductions
Evolocumab outcomes study
1. Does additional lowering of LDL due to addition of PCSK9
inhibitor reduce atherosclerotic CV disease more than what is
observed with maximal statin therapy?
2. *In a patient whose LDL is <100mg/dl and is on a high-
intensity statin, does additional lowering with PCSK9 inhibitor
reduce CVD events even further?
3. Is very low LDL harmful?
Discussion
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883
SPIRE-HR: Randomized Clinical Trial
Of Bococizumab (PF-04950615; RN316) In Subjects With
Hyperlipidemia Or Mixed Dyslipidemia At Risk Of
Cardiovascular Events
Objective: determine efficacy, safety, and tolerability of
bococizumab in lowering LDL
Design: Phase III trial
Estimated completion: April 2016
Inclusion: statin treatment, LDL >70mg/dL, very high risk
of having a cardiovascular event.
Outcome: % change from baseline in LDL
Patient’s clinical trial
Pfizer, Inc. Randomized Clinical Trial Of Bococizumab (PF-04950615; RN316) In Subjects With Hyperlipidemia Or Mixed Dyslipidemia At Risk Of Cardiovascular Events (SPIRE-HR). Available at : https://clinicaltrials.gov/ct2/show/NCT01968954?term=spire+hr&rank=1. Accessed January 28, 2015.
Pfizer investigating pill form. First trial in humans this year.
Evolocumab under FDA review with expected response on August 27th.
Upcoming trials: FOURIER: Further outcomes research with PCSK9 inhibition in subjects
with elevated risk Subjects: clinically evident cardiovascular disease Treatment arms: Evolocumab Q2W or QM + effective statin vs Placebo +
effective statin Primary endpoint: is the time to cardiovascular death, myocardial
infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first.
Completion: February 2018
SPIRE-1: Evaluation of bococizumab in reducing major CV events in high risk subjects Subjects: High risk of CV event on statin therapy Treatment arms: Bococizumab 150mg Q2W vs placebo Primary endpoint: time to major cardiovascular event & confirmed
occurrence of a major cardiovascular event (CV death, non- fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization)
Completion: April 2018
Future events
Pfizer, inc. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1). Available at: https://clinicaltrials.gov/ct2/show/NCT01975376?term=spire-1&rank=1. Accessed: January 28, 2015. Amgen. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). Available at https://clinicaltrials.gov/ct2/show/NCT01764633?term=evolocumab&rank=19. Accessed January 28, 2015.
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or
high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2
randomized clinical trial. JAMA. 2014;311(18):1870-1883
Pfizer, Inc. Randomized Clinical Trial Of Bococizumab (PF-04950615; RN316) In Subjects With
Hyperlipidemia Or Mixed Dyslipidemia At Risk Of Cardiovascular Events (SPIRE-HR). Available at :
https://clinicaltrials.gov/ct2/show/NCT01968954?term=spire+hr&rank=1. Accessed January 28, 2015.
Pfizer, inc. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major
Cardiovascular Events in High Risk Subjects (SPIRE-1). Available at:
https://clinicaltrials.gov/ct2/show/NCT01975376?term=spire-1&rank=1. Accessed: January 28, 2015.
Amgen. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk
(FOURIER). Available at https://clinicaltrials.gov/ct2/show/NCT01764633?term=evolocumab&rank=19.
Accessed January 28, 2015.
American Heart Assocation. Commentaries on cutting edge science. Available at:
http://circres.ahajournals.org/content/111/3/274/F1.expansion.html. Accessed January 28, 2015.
Stone NJ, Robinson JG, Lichenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2014; 129: S1-S45.
References