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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.

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://ruo.mbl.co.jp/g/product/metabolic/pcsk9.html&ei=hEPJVLy4Eou2yASB44LwBg&bvm=bv.84607526,d.aWw&psig=AFQjCNGkXoNXZNIaoNLSBLDAkyr6xFfVVA&ust=1422562539866430

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.

http://circres.ahajournals.org/content/111/3/274/F1.expansion.html


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


Baseline Characteristics


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


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


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)


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


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


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


Safety & Tolerability


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


+ -

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


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


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.

https://clinicaltrials.gov/ct2/show/NCT01968954?term=spire+hr&rank=1


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.

https://clinicaltrials.gov/ct2/show/NCT01975376?term=spire-1&rank=1




https://clinicaltrials.gov/ct2/show/NCT01764633?term=evolocumab&rank=19


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







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