Problem patients in primary care Patient 4: Peripheral artery disease

Problem patients in primary care Patient 4: Peripheral artery disease Dr Terry McCormack Hambleton Richmond Whitby Clinical Commissioning Group Research Lead 01/05/2014 Delivering clinical research to make patients, and the NHS, better

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

A Case History MW now 55 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 3

A Case History MW now 55 1997 Lipid Treatment None Total Cholesterol mmol/l Triglycerides mmol/l 11.4 4.7 HDL mmol/l 0.88 LDL mmol/l 8.35 4

A Case History MW now 55 Lipid Treatment 1997 2013 La Place II None Atorvastatin 80 mg and ezetimibe 10 mg Total Cholesterol mmol/l Triglycerides mmol/l 11.4 4.92 4.7 2.89 HDL mmol/l 0.88 0.98 LDL mmol/l 8.35 2.62 5

La Place II FH patients - Evolocumab Autoinjector/Pen 140 mg (1 injections of 1 ml @ 140 mg/ml) Q2W Q2W Autoinjector/Pen 420 mg (3 injections of 1 ml @ 140 mg/ml) QM 3.5 ml Personal Injector + CZ Cartridge 420 mg (3.5 ml @ 120 mg/ml) QM QM OR: 6

A Case History MW now 55 Lipid Treatment 1997 2013 La Place II None Atorvastatin 80 mg and ezetimibe 10 mg Total Cholesterol mmol/l Triglycerides mmol/l 11.4 4.92 4.7 2.89 HDL mmol/l 0.88 0.98 LDL mmol/l 8.35 2.62 7

A Case History MW now 55 Lipid Treatment 1997 2013 La Place II None Atorvastatin 80 mg and ezetimibe 10 mg 2014 Osler II A80 + E10 +evolocumab 420 mg (AMG 145) Total Cholesterol mmol/l Triglycerides mmol/l 11.4 4.92 1.90 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) 8

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

Hepatic LDLR Plays a Central Role in Cholesterol Homeostasis 10 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.

Recycling of LDLR Enables Efficient Clearance of LDL Particles Increased LDL-R surface concentration Lysosomal degradation LDL-R recycling 11 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.

PCSK9 Regulates the Recycling of LDLR by Targeting the LDLR for Degradation Decreased LDLR surface concentration LDLR/PCSK9 routed to lysosome 12 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

PCSK9 is a Novel Regulator of Hepatic LDL Receptor Expression Absence of PCSK9 Presence of PCSK9 More LDL-R Lower plasma LDL-C Less LDL-R Higher plasma LDL-C Inhibition of PCSK9 is a compelling new hypercholesterolemia target 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 13

AMG 145 is a Fully Human Monoclonal Antibody Against PCSK9 and Blocks PCSK9/LDL-R Interaction AMG 145 Increased LDL-Rs and Lower LDL-C Increased LDL-R Recycling 14 1. Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.

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. 400 350 300 250 200 150 100 50 0 MEN AGED 35-74 1997 1998 1999 2000 2001 2002 2003 2004 2005 North East Yorkshire and Humberside West Midlands South East London Wales 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 12 th 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

FOURIER 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 19

Study Design and Treatment Schema Subject on stable ( 4 weeks) optimised lipid lowering therapy No Lipid Therapy Titration (Titration visits approximately Q2W as needed to optimise lipidlowering therapy) Yes Placebo Injection Final Screening LDL-C 1.8 mmol/l or Non-HDL-C 2.6 mmol/l Randomisation 1:1 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 Placebo Q2W or Q4W (per subject preference) Optimal lipid lowering therapy, including an effective dose of atorvastatin, rosuvastatin or simvastatin ~ 11,250 Subjects End of Study Maximum approximately 15 weeks IP administered Q2W or Q4W Atorvastatin dispensed: Q12W Laboratory assessment: Day 1 Week 4 Week 12 Week 24 HDL-C = high-density lipoprotein-cholesterol; ; QD = once daily; Q2W = every 2 weeks; Q4W = once 4 weeks; Q24W = once every 24 weeks; EP = endpoints; 2 0 = secondary. Data on file, Amgen; [AMG 145 Protocol 20110118 Amendment 4; July 16, 2013]. Q24W Number of key 2 0 EPs achieved 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. 20

Identifying Eligible Patients I Adult aged 40-85 Post-MI Post-stroke (non-haemorrhagic) Symptomatic PAD intermittent claudication (ABI < 0.85) peripheral revascularisation, or amputation due to atherosclerosis with one or more of the following major risk factors Diabetes (type I or II) Age 65 (and 85) Daily smoker Index episode within 6 mts Previous MI or stroke before index episode Symptomatic PAD (MI/stroke patients) Lipid stabilisation period 21 PAD: Peripheral Arterial Disease Limit to proportion of patients with index event > 5 years ago

Identifying Eligible Patients II Adult aged 40-85 Post-MI Post-stroke (non-haemorrhagic) with 2 of the following minor risk factors: Symptomatic PAD intermittent claudication (ABI < 0.85) peripheral revascularisation, or amputation due to atherosclerosis 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) Lipid stabilisation period PAD: Peripheral Arterial Disease Limit to proportion of patients with index event > 5 years ago 22

Evaluating lipid levels: Inclusion Criteria 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) 23 *per local regulatory approval

FOURIER Amendment 4 Background lipid therapy Atorvastatin, simvastatin or rosuvastatin all eligible as background statin therapy. Only atorvastatin (20 mg, 40 mg and 80 mg) is provided by Amgen Background Statin Atorvastatin Simvastatin Rosuvastatin 20 mg 40 mg 5 mg Acceptable Doses 40 mg 80 mg 80 mg 10 mg 20 mg 40 mg 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) 24

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