Delivering clinical research to make patients, and the NHS, better

Problem patients in primary care Patient 4: Peripheral artery disease Dr Terry McCormack Hambleton Richmond Whitby Clinical Commissioning Group Research Lead

01/05/2014

Declaration Of Interests

•   Research Grants – Amgen, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, NIHR, Servier

•   Advisory Boards and Speaker Fees –Alere, Astellas, AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Lundbeck, MSD, Roche, Sunovian

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•   Intermittent Claudication aged 39 –   Stops smoking –   Total cholesterol 11.4 mmol/l = mixed hyperlipidaemia –   Left and right saphenous-femoral angioplasty

•   Family History –   Father suffered MI age 49, died aged 58 MI –   Aunt died age 47 MI –   Grandfather died age 47 –   Brother lost leg to peripheral arterial disease

•   TIA age 44 •   ACS and coronary artery stent age 48 •   Long term depression

A Case History – MW – now 55

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A Case History – MW – now 55

1997

Lipid Treatment

None

Total Cholesterol

mmol/l

11.4

Triglycerides mmol/l

4.7

HDL mmol/l

0.88

LDL mmol/l 8.35

5

A Case History – MW – now 55

1997 2013 La Place II

Lipid Treatment

None Atorvastatin 80 mg and ezetimibe

10 mg

Total Cholesterol

mmol/l

11.4 4.92

Triglycerides mmol/l

4.7 2.89

HDL mmol/l

0.88 0.98

LDL mmol/l 8.35 2.62

6

La Place II – FH patients - Evolocumab

3.5 mL Personal Injector + CZ Cartridge 420 mg (3.5 mL @ 120 mg/mL) QM

Autoinjector/Pen 420 mg (3 injections of 1 mL @ 140 mg/mL) QM

Autoinjector/Pen 140 mg (1 injections of 1 mL @ 140 mg/mL) Q2W

QM

Q2W

OR:

7

A Case History – MW – now 55

1997 2013 La Place II

Lipid Treatment

None Atorvastatin 80 mg and ezetimibe

10 mg

Total Cholesterol

mmol/l

11.4 4.92

Triglycerides mmol/l

4.7 2.89

HDL mmol/l

0.88 0.98

LDL mmol/l 8.35 2.62

8

A Case History – MW – now 55

1997 2013 La Place II

2014 Osler II

Lipid Treatment

None Atorvastatin 80 mg and ezetimibe

10 mg

A80 + E10 +evolocumab

420 mg (AMG 145)

Total Cholesterol

mmol/l

11.4 4.92 1.90

Triglycerides mmol/l

4.7 2.89 2.73

HDL mmol/l

0.88 0.98 0.62

LDL mmol/l 8.35 2.62 0.13 (0.54)

History  

•   Nikolai  N.  Anichkov  (1885–1964)  links  cholesterol  and  atherosclerosis  in  1913  

•   Scandinavian  Simvasta@n  Survival  Study  1993  

•   Nature  Gene+cs  34,  154  -­‐  156  (2003)  ...  Marianne  Abifadel  et  al  discovers  role  of  PCSK9  

10

Hepatic LDLR Plays a Central Role in Cholesterol Homeostasis

1.  Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:3330-3337. 2.  Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547. 3.  Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

11

Recycling of LDLR Enables Efficient Clearance of LDL Particles

1.  Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:3330-3337. 2.  Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547. 3.  Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

Increased LDL-R surface concentration

LDL-R recycling

Lysosomal degradation

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PCSK9 Regulates the Recycling of LDLR by Targeting the LDLR for Degradation

1.  Qian YW, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498. 2.  Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177 3.  Rashid S et al. PNAS 2005;102:5374-5379

Decreased LDLR surface concentration

LDLR/PCSK9 routed to lysosome

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PCSK9 is a Novel Regulator of Hepatic LDL Receptor Expression

Inhibition of PCSK9 is a compelling new hypercholesterolemia target

•   Less LDL-R •   Higher plasma LDL-C

•   More LDL-R •   Lower plasma LDL-C

Absence of PCSK9 Presence of PCSK9

•  Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:3330-3337.

•  Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547.

•  Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

•  Qian YW, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498.

•  Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177

•  Rashid S et al. PNAS 2005;102:5374-5379

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AMG 145 is a Fully Human Monoclonal Antibody Against PCSK9 and Blocks PCSK9/LDL-R Interaction

1.  Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.

Increased LDL-Rs and Lower LDL-C

Increased LDL-R Recycling

AMG 145

0  

50  

100  

150  

200  

250  

300  

350  

400  

1997   1998   1999   2000   2001   2002   2003   2004   2005  

   North  East  

   Yorkshire  and  Humberside      West  Midlands      South  East  

   London  

Wales  

Age-standardised death rates from CHD per 100,000 population by Country and Government Office Region, 1997 to 2005, United Kingdom Office  for  Na@onal  Sta@s@cs,  General  Register  

Office  for  Scotland,  Na@onal  Sta@s@cs  and  Research  Agency,  N  Ireland.

MEN AGED 35-74

WOMEN AGED 35-74

•   LDL/HMG  CoA  •   HDL/CETP  •   Triglycerides/tredap@ve  

•   Eze@mibe  •   PCSK9  

Four PCSK9 Inhibitor Compounds

•   AMGEN – Evolocumab 7820 •   Pfizer – Bococizumab 3439 •   Sanofi/Regeneron - Alirocumab 4892 •   Lilly ?

Further Cardiovascular OUtcomes in Research with PCSK9 Inhibition in Subjects with Elevated Risk

Welcome to this Online FOURIER meeting Dec 12th 2013 2.30-3.00pm

1.  If you can see this slide and you are logged in correctly. The meeting will start shortly. 2.  If you are unable to hear the presentation, please check that you have enabled audio on

Lync and that you have turned up the volume in your computer’s settings both for the computer’s own speaker and specifically for the Lync programme. If still can’t hear via your computer, you can join by phone on 0207 594 1111 conference ID: 674561

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•   Further Cardiovascular OUtcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk

•   A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-Cholesterol Reduction on Major Cardiovascular Events When AMG 145 is Used in Combination with Statin Therapy in Patients with Clinically Evident Cardiovascular Disease

FOURIER

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Study Design and Treatment Schema

Day 1 Q24W Week 24 Week 12 Week 4

Laboratory assessment:

Number of key 20

EPs achieved

HDL-C = high-density lipoprotein-cholesterol; ; QD = once daily; Q2W = every 2 weeks; Q4W = once 4 weeks; Q24W = once every 24 weeks; EP = endpoints; 20 = secondary. Data on file, Amgen; [AMG 145 Protocol 20110118 Amendment 4; July 16, 2013].

Placebo Q2W or Q4W (per subject preference)

Optimal lipid lowering therapy, including an effective dose of atorvastatin, rosuvastatin or simvastatin

~ 11,250 Subjects

En

d of

Stu

dy

AMG 145 SC 140 mg Q2W or 420 mg Q4W (per subject preference)

Optimal lipid lowering therapy, including an effective dose of atorvastatin, rosuvastatin or simvastatin

~ 11,250 Subjects

Subject on stable (≥ 4

weeks) optimised

lipid lowering therapy

Plac

ebo

Inje

ctio

n Fi

nal S

cree

ning

LD

L-C

≥ 1

.8 m

mol

/l or

N

on-H

DL-

C ≥

2.6

mm

ol/l

IP administered Q2W or Q4W Atorvastatin dispensed: Q12W

Lipid Therapy Titration

(Titration visits approximately

Q2W as needed to

optimise lipid-lowering therapy)

Ran

dom

isat

ion

1:1

No

Yes

Maximum approximately 15 weeks

•   Study will end when 1630 subjects have experienced a key secondary endpoint of cardiovascular death, myocardial infarction or stroke. (3550 primary endpoints expected). End of study estimated to be 40 months after last patient is enrolled.

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Identifying Eligible Patients I

PAD: Peripheral Arterial Disease

Adult aged 40-85

Post-stroke (non-haemorrhagic)

Post-MI

Diabetes (type I or II)

Symptomatic PAD •   intermittent claudication (ABI < 0.85) •   peripheral revascularisation, •   or amputation due to atherosclerosis

•   Index episode within 6 mts

•   Previous MI or stroke before index episode

Age ≥ 65 (and ≤85)

with one or more of the following major risk factors

Lipid stabilisation period

Daily smoker

§ §

§ Limit to proportion of patients with index event > 5 years ago

Symptomatic PAD (MI/stroke patients)

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Identifying Eligible Patients II

PAD: Peripheral Arterial Disease

Adult aged 40-85

Post-stroke (non-haemorrhagic)

Post-MI Symptomatic PAD •   intermittent claudication (ABI < 0.85) •   peripheral revascularisation, •   or amputation due to atherosclerosis

Lipid stabilisation period

§ §

§ Limit to proportion of patients with index event > 5 years ago

Metabolic factors •   LDL-C > 3.4 mmol/L or non-HDL-

C ≥ 4.1 mmol/L •   HDL-C < 1.0 mmol/L in ♂

or < 1.3 mmol/L in ♀ •   hsCRP > 2.0 mg/dL •   Metabolic syndrome

Coronary factors •   Non-MI related coronary

revascularisation •   Residual CAD (≥40%

stenosis in 2 or more large vessels)

with ≥2 of the following minor risk factors:

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At Screening: •   Fasting triglycerides ≤ 4.5 mmol/L (400 mg/dL)

After 2 weeks of stable lipid-lowering therapy, subject eligible for inclusion if:

•   Fasting LDL-C ≥ 1.8 mmol/L (≥ 70 mg/dL) OR

•   non-HDL-C ≥ 2.6 mmol/L (≥100 mg/dL)

Evaluating lipid levels: Inclusion Criteria

*per local regulatory approval

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•   Atorvastatin, simvastatin or rosuvastatin all eligible as background statin therapy.

•   Only atorvastatin (20 mg, 40 mg and 80 mg) is provided by Amgen

–   Where locally approved, highly effective statin therapy (at least atorvastatin 40mg/day or equivalent) is recommended. As a minimum, all subjects must receive at least an effective statin dose (at least atorvastatin 20mg/day or equivalent).

–   For subjects with LDL-C >2.6 mmol/l not receiving highly effective statin therapy, investigator must attest that higher dose statin therapy is not appropriate for this subject (e.g. subject refused, dose not tolerated, other significant concern)

FOURIER Amendment 4 Background lipid therapy

Background Statin Atorvastatin Simvastatin Rosuvastatin

Acceptable Doses

20 mg

40 mg

80 mg

40 mg 80 mg

5 mg 10 mg 20 mg 40 mg

Any  Ques+ons?