JOURNAL CLUB

DR.PRAVEEN NAGULA

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Update on the evidence for

PCSK9 inhibition to lower LDL

cholesterol

NEJM,2014 May 8 ;370:1811.2

Background

For patients who are eligible for statin therapy but are considered

to be statin intolerant,inhibition of proprotein convertase

subtilism/kexin type9 (PCKS9) has been proposed as an

alternative mechanism of action for lowering LDL cholesterol.

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Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76:3330-3337.Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

LDL receptor

AMG 145, a fully human monoclonal antibody that binds PCSK9,

was well tolerated and lowered LDL in phase Ia and Ib studies (Dias CS, JACC published online Oct 17, 2012. http://dx.doi.org/10.1016/j.jacc.2012.08.986)

Qian YW, et al. J Lipid Res. 2007;48:1488-1498.Horton JD, et al. J Lipid Res. 2009;50:S172-S177.Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.

PCSK9 Regulates the Surface Expression of LDLRs by Targeting LDLRs for Lysosomal Degradation

“Proprotein Convertase Subtilisin/Kexin type 9.”

5The PCSK9 protein appears to control the number of low-density lipoprotein receptors

• Evolocumab,a monoclonal antibody that inhibits PCKS9 and is

administered subcutaneously,was recently tested in several

manufacturer – funded phase 3 trials..

• The bottom line findings of them are….

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DESCARTES trial

Durable Effect of PCSK9 antibody CompARed wiTh placEbo Study

(NCT01516879)

About 900 pts with hyperlipidemia

Started on 4-12 weeks of background lipid lowering therapy

according to risk categories from the Adult Treatment Panel III of

the National Cholesterol Education Program.

Patients with an LDL cholesterol ≥75 mg/dl, assigned randomly in a

2:1 ratio to receive evolocumab(420 mg) or placebo every weeks.

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Background lipid-lowering therapy

• diet alone

• diet plus atorvastatin,10 mg daily,

• Atorvastatin ,80 mg daily,

• Atorvastatin ,80 mg daily plus ezetimibe, 10 mg daily,

Time period of 4 to 12 weeks.

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Results

At 52 weeks, mean LDL reduction was 57% lower with

Evolocumab than with placebo, with significant advantages (49-

62%) across the various background therapy subgroups.

Also significant reduction of Apo B, non–HDL, lp(a) and TGs.

The most common adverse events were nasopharyngitis, upper

respiratory tract infection, influenza, and back pain.

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CONCLUSIONS

At 52 weeks, evolocumab added to diet alone, to low-dose

atorvastatin, or to high-dose atorvastatin with or without

ezetimibe significantly reduced LDL cholesterol levels in

patients with a range of cardiovascular risks.

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GAUSS -2 trial

• GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9

Antibody in Statin Intolerant Subjects)

• Evolocumab vs Ezetimibe in 307 statin intolerant patients.

• Evolocumab reduced LDL cholesterol by 53 -56% (compared

to Ezetimibe it was 37-39%advantage),the advantage was

dependent on the dosing intensity and schedule.

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MENDEL -2 trial

• 614 Statin naive patients.

• Evolocumab reduced LDL levels by 55% to 57% compared

with placebo ( a 38% to 40% advantage over ezetimibe)

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LAPLACE TIMI 57 trial

• Achievement of LDL C target goals in high risk groups.

• In 282 subjects,at high risk according to NCEP-ATP III criteria, the

proportion of subjects achieving the recommended LDL-C goal

of <70 mg/dl across treatment arms were compared.

• Other outcomes included the triple goals of LDL-C <70 mg/dl, non–

high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and

apolipoprotein B (ApoB) <80 mg/dl.

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Objectives

To compare 12 weeks of AMG 145 (given SC Q2 or Q4

weeks) vs placebo in stable patients with

hypercholesterolemia on a statin ± ezetimibe:

– Primary: % change in LDL-C*

– Secondary: changes in other lipoproteins

pharmacokinetics/pharmacodynamics

tolerability and safety

* measured using ultracentrifugation in a central core laboratory

Study Design

Kohli P, et al. Clin Cardiol. 2012;35:385-391.

78 centers5 countries

934 screened 631 random. 629 treated( *2 subjects assigned placebo Q4W received no study drug)

Screening and Placebo Run-in

Period

Subcutaneous injection of 6 mL

placebo

Fasting LDL-C 5-10 days before

randomization

Maximum 6 weeks

Day 1Visits: Week 2 Week 8 Week 12Week 6Week 4 Week 10 Week 14

70 mg AMG 145 SC Q2W 79 Subjects

105 mg AMG 145 SC Q2W 79 Subjects

140 mg AMG 145 SC Q2W 78 Subjects

Placebo SC Q2W 78 Subjects

Q2W:

280 mg AMG 145 SC Q4W 79 Subjects

350 mg AMG 145 SC Q4W 79 Subjects

420 mg AMG 145 SC Q4W 80 Subjects

Placebo SC Q4W 77 Subjects

Q4W:

Primary EndpointAssessed

• Results During the dosing interval, more than 90% of subjects in

both of the top dose groups every 2 weeks and every 4 weeks attained

this lipid target over the dosing interval, with similar success rates for

the triple lipid goal.

Conclusions PCSK9 inhibition with AMG 145 enables high-risk

patients to achieve established lipid goals. If this therapy demonstrates

efficacy for reducing cardiovascular events with a favorable safety

profile in ongoing phase 3 trials, we believe it will have major public

health implications.

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The LAPLACE-2 Study

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LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition

Combined With Statin ThErapy – 2 (NCT01763866)

Design:

A 12-week, randomized, double-blind, placebo- and ezetimibe-

controlled, phase III study

Objective:

To evaluate the efficacy and safety of evolocumab administered

biweekly (140 mg) or monthly (420 mg) in combination with a statin

in hypercholesterolemic patients

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The RUTHERFORD-2 Study

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RedUcTion of LDL-C with PCSK9 Inhibition in HEteRozygous

Familial HyperchOlesteRolemia Disorder (NCT20110117)

Design:

A 12-week, randomized, double-blind, placebo-controlled,

multicenter phase 3 study

Objective:

To evaluate the efficacy and safety of evolocumab (AMG 145)

140 mg Q2W and 420 mg QM administered subcutaneously in a

large cohort of HeFH patients unable to achieve an LDL-C < 100

mg/dL despite statin therapy with or without ezetimibe

RUTHERFORD-2: Conclusions

• Evolocumab was well tolerated, with no notable difference

in the AE profile compared with placebo.

– The rate of nasopharyngitis and muscle-related adverse

events (AEs) was higher in the evolocumab group.

• The imbalance in the overall set of muscle-related AEs was not due to

significant imbalances in any individual muscle-related event (i.e., creatine

kinase).

• Evolocumab may offer a new and effective treatment option

to further reduce LDL-C in HeFH patients.

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FOURIER phase 3

• Further Cardiovascular Outcomes Research With

PCSK9 Inhibition in Subjects With Elevated Risk

(FOURIER)

• 22,310 pts higher risk group

• Above statins

• Any benefit in ACS

• First received: January 8, 2013

• Last updated: May 7, 2014

• Last verified: May 2014

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Comment

• Evolocumab significantly lowered LDL cholesterol and had a

generally favorable side effect profile in several different patient

populations with varying background therapies.

• Still cannot be recommended as primary therapy,as these LDL

reductions whether assosciated with improvements in cardiovascular

outcomes is not proven(need long term studies).

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ODYSSEY trial

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TAKE HOME MESSAGE

• Hypercholesterolemia management beyond statins has taken a

considerable development….results are satisfactory..

• The results applicability to the long term benefits needs further

studies.

• Statin intolerant patients have better options for treatment in the

near future.

• Evolocumab is near recognition for FDA approval once the

results of FOURIER trial are released.

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DES OUTCOMES :

SORT OUT III TRIAL

The Winner of the Sprint does not necessarily Win the Marathon

Lancet 2014,March 14(e pub ahead of print)28

Background

• Limitations of early DES such as late stent thrombosis and evidence

of delayed neointimal healing have prompted the development of

DESs with new platform materials, thinner stent status, more

biocompatible or more biodegradable surface polymer coatings, and

less potent antiproliferative drugs.

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The winner of sprint…..

• In SORT OUT III trial ,risks for both definite stent thrombosis and

target vessel revascularisation (TVR) were significantly higher with

the second generation zotarolimus eluting stent (ZES) than with the

first generation sirolimus eluting stent (SES) during the first year

after implantation.

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5 yr clinical outcomes …

• 99.7 % of the 2232 patients who were randomly assigned to

receive ZESs or SES s were followed up clinically (Danish

national registry).

SES s ZES s P value

MACE AT 5 YEARS 15.6% 17.0% 0.40

Outcomes between 1 and 5 years

12.3% 9.9% 0.07

Definite Stent thrombosis

1.8% 0.1%

TVR 7.0% 4.1%

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Not won the marathon…

• The superiority of the SES to the ZES at 1 yr follow up was lost at

5 years because of higher rates of late stent thrombosis and TVR

with the first generation stent.

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