Evolocumab and Clinical Outcomes in Patients with ... · Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease, March 20171 Further Cardiovascular Outcomes Research

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease, March 20171

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) By: Shermaine Ngo, LMPS Resident; Ambulatory Cardiology Rotation with Susan Buchkowsky

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CLINICAL QUESTION

In patients with atherosclerotic cardiovascular disease and LDL >1.8mmol/L or non-HDL > 2.6mmol/L, how does evolocumab (either 140mg SC every 2 week or 420mg SC monthly) compare to matching placebo SC injections in reducing a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization?

CONTEXT

Evolocumab (RepathaTM

): human monoclonal ab that binds to and inhibits free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) o PCSK9 binds to LDL receptors on hepatocytes to ↑ degradation of LDL receptors within the liver

∴ inhibiting PCSK9 ↑ LDL receptor ↓circulating LDL

“Whether [Evolocumab] prevents cardiovascular events is uncertain.” EVIDENCE TO DATE EVOLOCUMAB (REPATHA)

DESCARTES2014

: Phase 3 trial – In pts (N=901) with LDL>1.94mmol/L & fasting TG<4.52mmol/L (excl. HF, recent MI, recent/planned revasc), evolocumab 420mg SC qmosx52wks, added to diet alone, ator. 10mg daily, ator. 80mg daily + ezetimibe ↓ LDLs (by 48.5-61.6%)

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OSLER2015

: 2 open-label RT – In pts from 12 Phase 2/3 trials (N=4465), evolocumab x11.1mos + standard tx vs. standard tx alone (70% on statin) SS ↓ LDL by 58.4%. A pre-specified exploratory analysis showed SS ↓ in composite of death, MI, USA requiring hospitalization, coronary revasc., stroke, TIA, and HF hospitalization (HR: 0.47, (95% CI 0.28-0.78), P=0.003)…but trial was not powered for this outcome

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GAUSS-32016

: 2 staged DB RCT – In pts with muscle-related statin intolerance, 4-wk wash-out Stage 1

(Ator 20mgx10wk vs. Placebo x10wk) Stage 2 N=218 statin-intolerant

(evolocumab qmos vs. ezetimibex24wk), evolocumab had a greater ↓ in LDL than ezetimibe (LS mean diff: 36.1%) Muscle-related AEs: ezetimibe 28.8%, evolocumab 20.7%

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STATIN

IMPROVE-IT2015

: DB RCT – In pts acutely post ACS, simvastatin 40mg daily (mod-dose statin) + ezetimibe vs simvastatin alone ↓ average LDL from 1.8 to 1.4 mmol/L and SS ↓ a composite of CV death, MI, USA requiring hospitalization, revasc. or stroke (NNT = 50/7yrs)

CCS GUIDELINES 2016

“We suggest that PCSK9 inhibitors be considered to lower LDL-C level for patients with atherosclerotic CVD in those not at LDL-C goal despite maximally tolerated statin doses with or without ezetimibe therapy (Conditional Recommendation; Moderate-Quality Evidence).”

“We recommend a target LDL-C consistently <2.0mmol/L or >50% reduction of LDL-C …to lower risk of CVD events and mortality…for recent ACS and established coronary disease, consideration should be given to more aggressive targets (LDL-C <1.8 or >50% reduction)”

Methodology

Study design Multi-national, double-blinded, placebo-controlled, randomized phase III trial (Feb 2013 – Jun 2015)

Randomization Randomized 1:1 via central computerized system, with stratification, according to final screening LDL (< 2.2 or > 2.2mmol/L)

Allocation concealment Site representative will call to Voice/Web response system to assign a randomization # to subject

Blinding Double Blinded (“matching placebo as SC injections”); Investigators, Patients, Clinical Events Committee

Power N of 22,500 (1620 endpoint events) for 90% power to detect a 15% RRR in the key secondary endpoint with evolocumab as compared with placebo

Loss to follow-up Evolocumab (n=5,<0.1%) vs. Placebo (n=13,<0.1%)

Analysis Efficacy analysis: Intention-to-treat (ITT); Safety analysis: modified ITT

Outcomes Primary Outcomes:

Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization

Secondary outcomes:

Composite of cardiovascular death, myocardial infarction or stroke

Individual components of primary endpoint

All-cause mortality

Composite of cardiovascular death or hospitalization for heart failure

Cholesterol Treatment Trialists Collaboration composite endpoint of major coronary events (coronary heart death, non-fatal MI), stroke or coronary revascularization

Subsets including composite of coronary heat death, non-fatal MI, ischemic stroke or urgent coronary revascularization, composite of coronary heart death, non-fatal MI or stroke, composite of fatal or non-fatal MI or stroke

AEs: Muscle-related, cataracts, injection site, allergic and neurocognitive, new onset diabetes, LFTs, CK, FBS, HbA1c and anti-evolocumab antibodies

Funding Amgen (Role: Collaborated in trial design, responsible for data collection, but no involvement in data analysis)



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I: Evolocumab vs. C: Placebo

Setting 1242 sites in 49 countries

Inclusion criteria

40 to 85 years old

Clinically evident atherosclerotic CVD (i.e. history MI, non-hemorrhagic stroke, symptomatic peripheral artery disease, or additional risk factors (see appendix below))

LDL > 1.8mmol/L, or non-HDL > 2.6mmol/L, while taking at least atorvastatin 20mg daily or equivalent + ezetimibe

Relevant exclusion criteria

Within 4 wks of MI or stroke

Planned cardiac surgery/revasc. w/in 3 mos

NYHA III or IV HF, or last known LVEF < 30%

History of hemorrhagic stroke

Use of CETP inhibition treatment, mipomersen or lomitapide in previous 12 months

Fibrates, except for fenofibrates are prohibited. If taking, must be on stable fenofibrate tx x 6 wks

Prior use of PCSK9 inhibitors other than evolocumab or use of evoloc. in previous 12 wks

LDL or plasma apheresis within previous 12 mos

CK > 5x ULN

eGFR < 20mL/min/1.73m2

Active liver disease or hepatic dysfunction

Pregnant or breast feeding

Study size 27,564

“Average” patient

Evolocumab (N=13,784) | Placebo (N=13,780) Demographics/History:

Age 62.5 yo ● North America 16.6%

Male 75.5% ● Europe 62.9%

White 85% ● Latin America 6.6%

Wt 85 kg ● Asia Pacific/South Africa 13.9%

Atherosclerotic Disease Evolocumab Placebo

MI Median time from MI Non-hemmorhagic stroke Median time from stroke Peripheral Artery Disease

80.9% 3.4(1.0-7.4) 19.5% 3.2(1.1-7.1) 13.5%

81.3% 3.3(0.9-7.7) 19.2% 3.3(1.1-7.3) 12.9%

CV Risk Factors

Hypertension Diabetes mellitus Current smoking

80.1% 36.7% 28.0%

80.1% 36.5% 28.5%

Median Lipid Measure (IQR)

LDL – mmol/L Total Cholesterol – mmol/L HDL – mmol/L Triglycerides – mmol/L Lipoprotein(a) – nmol/L

2.4(2.1-2.8) 4.3(3.9-4.9) 1.1(0.9-1.4) 1.5(1.1-2.1) 37 (13-166)

2.4(2.1-2.8) 4.3(3.9-4.9) 1.1(0.9-1.4)

1.5(1.1-2.0) 37(13-164)

Lipid-Lowering Therapies Evolocumab Placebo

High-intensity Statin Moderate-intensity Statin Low/unknown intensity Statin Ezetimibe

69.5% 30.2% 0.3% 5.3%

69.1% 30.7% 0.2% 5.2%

Other Cardiovascular Medications Evolocumab Placebo

Aspirin, P2Y12 inhibitor or both Beta-blocker ACEI/ARB, MRA or both

92.7% 75.8% 78.4%

92.0% 75.4% 77.9%

No clinically-relevant baseline between-group differences

PRIMARY OUTCOMES

Evolocumab n (%)

Placebo n (%)

Hazard Ratio

95% CI (P)

✓1o Composite (CV death, MI, stroke,

hospitalization for USA or coronary revasc.)

1344 (9.8%) 1563 (11.3%) 0.85 0.79-0.92

(P < 0.001)

SECONDARY OUTCOMES

Evolocumab

n (%) Placebo

n (%) Hazard Ratio

95% CI (P)

✓2o Composite (CV death, MI, stroke)

816 (5.9%) 1013 (7.4%) 0.80 0.73-0.88

(P < 0.001)

✘CV death 251 (1.8%) 240 (1.7%) 1.05 0.88-1.25 (P=0.62)

✘All-cause death 444 (3.2%) 426 (3.1%) 1.04 0.91-1.19 (P=0.54)

✓MI 468 (3.4%) 639 (4.6%) 0.73 0.65-0.82 (P<0.001)

✘USA

hospitalization 236 (1.7%) 239 (1.7%) 0.99

0.82-1.18 (P=0.89)

✓Stroke 207 (1.5%) 262 (1.6%) 0.79 0.66-0.95 (P=0.01)

✓Ischemic

Stroke/TIA 229 (1.7%) 295 (2.1%) 0.77

0.65-0.92 (P=0.003)

✓Coronary revasc. 759 (5.5%) 965 (7.0%) 0.78 0.71-0.86 (P<0.001)

✘CV death or HF

hospitalization 402 (2.9%) 408 (3.0%) 0.98

0.86-1.13 (P=0.82)

✓CTTC composite 1271 (9.2%) 1512 (11.0%) 0.83 0.77-0.90 (P<0.001)

LDL REDUCTION

Evolocumab

q2wk % (95%CI) Evolocumab

qmos % (95%CI) Evolocumab vs. placebo

@12wks 61.1%

(60.5-61.7) 56.9%

(55.3-58.6)

@48wks

Mean absolute↓, vs. placebo: 1.45 mmol/L (95% CI, 1.43-1.47)

59% (58-60%) P<0.001

Evolocumab: 87%: <1.8mmol/L, 67%: <1.0, 42% < 0.65 Median LDL at 48 wks: 0.78 mmol/L

SAFETY OUTCOMES

Evolocumab

n (%) Placebo

n (%) Absolute risk

difference

Any AEs 10664 (77.4%) 10644 (77.4%) 0%

Serious AEs 3410 (24.8%) 3404 (24.7%) 0.1%

Injection-site rxn 296 (2.1%) 219 (1.6%) 0.5%

Muscle-related event 682 (5.0%) 656 (4.8%) 0.2%

Rhabdomyolysis 8 (0.1%) 11 (0.1%) 0%

Cataract 228 (1.7%) 242 (1.8%) 0.1%

New-onset DM 677 (8.1%) 644 (7.7%) 0.4%

Neurocognitive event

217 (1.6%) 202 (1.5%) 0.1%

AT >3xULN 1.8% 1.8% 0%

CK >5xULN 0.7% 0.7% 0%



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Limitations: Methods

Trial enrolled a specific population o On baseline statin therapy, preferably high-intensity statin but must have been on at least the equivalent of atorvastatin 20mg daily o Excluded patients acutely post-MI (within 4 weeks) or planned revascularization/cardiac surgery o Run in period with placebo SC injections to confirm tolerance to SC administration

Background lipid therapy had to be stable for at least 4 weeks o ?# of pts who recently started statin and other lipid-lowering therapies

Different regimens of evolocumab o Depending on patient preference, patients could be on evolocumab 420mg SC monthly or 140mg SC every 2 weeks o Comparison between two regimens: 140mg Q2W + statin ↓ mean LDL up to 77%, 420mg QM + statin ↓ mean LDL up to 67%

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Powered for secondary efficacy outcome

Funding Bias: AMGEN involved in design and data collection Results

Patient Population – Generalizability o Caucasian

85% male

75.5% from Europe

62.9% on high-intensity statin

69%, anti-platelet tx

92%, BB

75%, ACEI/ARB/MRA

78%

o Treatment: ~90% on q2wk regimen, and compliant to treatment

Median duration of Follow-up was 26 months (IQR: 22-30) o Other lipid-lowering trials’ follow-up have averaged approximately 5 years o Event rate ~50% higher than initially estimated led to a shorter required duration of f/u (initial plan = 4 years)

Event rate predominantly MI (61%) shorter duration might have limited trial’s ability to capture mortality benefit o Lacking information on long-term safety

Sub-group analysis o Efficacy in 1

o outcome lost in Latin Americans, Polyvascular disease, LDL >2.37 mmol/L, in pts on ezetimibe, in pts on evolocumab q mos

o Efficacy in 2o outcome lost in Latin Americans, Polyvascular disease, in pts on ezetimibe, in pts on evolocumab q mos

Patient population who switch over to monthly = possible unknown confounding factors? Compliance issues? Study’s Conclusion: “Inhibition of PCSK9 with evolocumab on a background of a statin therapy lowered LDL to a median of 0.86 mmol/L and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.” My Conclusion and Applicability to clinical practice:

For patients on a moderate to high-intensity statin with a LDL > 1.8 mmol/L and on other secondary preventative therapy for CAD, evolocumab 140mg SC every 2 weeks for 2.2 years compared to a moderate to high-intensity statin alone reduces the risk of myocardial infarction and stroke. There are no significant mortality benefits.

APPENDIX

I. Additional Information on Inclusion Criteria:

Major Risk Factors (1 Required for inclusion): o diabetes (type 1 or type 2) o age ≥ 65 years at randomization (and ≤ 85 years at time of informed consent) o MI or non-hemorrhagic stroke within 6 months of screening o additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke o current daily cigarette smoking o history of symptomatic PAD (intermittent claudication with ABI < 0.85, or peripheral arterial revascularization procedure, or

amputation due to atherosclerotic disease) if eligible by MI or stroke history

Minor Risk Factors (2 Required for inclusion): o history of non-MI related coronary revascularization o residual coronary artery disease with ≥ 40% stenosis in ≥ 2 large vessels o Most recent HDL-C < 40 mg/dL (1.0 mmol/L) for men and < 50 mg/dL (1.3 mmol/L) for women by central laboratory before

randomization o Most recent hsCRP > 2.0 mg/L by central laboratory before randomization o Most recent LDL-C ≥ 130 mg/dL (3.4 mmol/L) or non-HDL-C ≥ 160 mg/dL (4.1 mmol/L) by central laboratory before

randomization o metabolic syndrome



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II. Study Design

The study consists of 2 periods: (1) Screening, lipid stabilization, and placebo run-in period, (2) double-blind treatment and follow-up period III. Statin Intensity for FOURIER

IV. Results for FOURIER



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IV. PCSK9 inhibitors

PCSK9 inhibitor

Dose for hyperlipidemia

Pharmacokinetics Cost Comments

Evolocumab (Repatha

TM)

140mg SCQ2wk 420mg SCQmos

Non-linear pharmacokinetics Median Tmax: 3-4 ds F: 72% Cmax: - 18.6 + 7.3 ug/mL (140mg) - 59 + 17.2 ug/mL (420mg) AUC: - 188 + 98.6 day*ug/mL (140mg) - 924 + 346 day*ug/mL (420mg) Effective half-life: 11-17 days Metabolism: expected to degrade to small peptides and individual amino acids Max suppression: 4 hours

$7844/year Store in fridge (allow to stand at room temp for at least 30 mins prior to use) Financial Assistance Program: RepathaREADYadvance

Alirocumab (Praluent®)

75mg SC Q2wk (may ↑to 150mg SC Q2wk if inadequate response within 4-8 wks)

Median Tmax: 3-7 ds F: 85% Cmax: - 1.54 + 1.02 ng/mL (150mg) AUC: - 129 + 35.7 day*mg/L (75mg) Effective half-life: 17-20 days Metabolism: expected to degrade to small peptides and individual amino acids Max suppression: 4-8 hours

$7844/year Store in fridge (allow to stand at room temp for at least 30 mins prior to use) Financial Assistance Program: MyPraulent ODYSSEY

2015: D Phase II DB RCT, P High

CV risk pts on statin, I Alirocumab 150mg SCQ2k, C Placebo O ↓LDL -62%, post hoc analysis showed evidence of ↓ CV events (not powered)

Bococizumab « during the conduct of these two outcomes trials…bococizumab was commonly associated with the development of high-titer antidrug antibodies that resulted in substantive attenuation of LDL-cholesterol lowering over time. In addition, the trials showed that bococizumab was associated with a wide variation in LDL-cholesterol lowering, even among patients who were antibody negative.5 On the basis of the SPIRE lipid-lowering data, the sponsor elected to discontinue further development of bococizumab on November 1, 2016. »

REFERENCES (1) Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017

Mar 17. (2) Blom DJ, Hala T, Bolognese M, Lillestol MJ, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. (3) Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of

evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1500-9. (4) Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the

GAUSS-3 randomized clinical trial. Jama. 2016 Apr 19;315(15):1580-90. (5) Dosing Information | Repatha® (evolocumab) [Internet]. Repathahcp.com. 2017 [cited 12 April 2017]. Available from: https://www.repathahcp.com/dosing/



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(6) https://www.uptodate.com/contents/image?imageKey=CARD%2F109030&topicKey=CARD%2F106888&rank=1~18&source=see_link&search=pcsk9%20inhibitor (7) http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/evolocumab-3419-info.pdf (8) http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/alirocumab-3457-info.pdf (9) SPIRE http://www.nejm.org/doi/full/10.1056/NEJMoa1701488#t=article

https://www.uptodate.com/contents/image?imageKey=CARD%2F109030&topicKey=CARD%2F106888&rank=1~18&source=see_link&search=pcsk9%20inhibitor

http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/evolocumab-3419-info.pdf

http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/alirocumab-3457-info.pdf

http://www.nejm.org/doi/full/10.1056/NEJMoa1701488#t=article

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Evolocumab and Clinical Outcomes in Patients with ... · Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease, March 20171 Further Cardiovascular Outcomes Research