Darapladib for Cardiovascular Risk Reduction in Patients with Coronary Heart Disease

Horizon Scanning Centre May 2013

Darapladib for cardiovascular risk reduction in patients with coronary heart disease – add on therapy

SUMMARY NIHR HSC ID: 2237

Darapladib is intended to be used as add on therapy for cardiovascular risk reduction in high-risk patients with coronary heart disease (CHD), including patients with acute coronary syndrome. If licensed, it will represent the first in a new class of treatments for this patient group. Darapladib is a selective This briefing is inhibitor of lipoprotein-associated phospholipase, a key enzyme involved in lipid metabolism and inflammation which circulates with lipoprotein particles based on and is carried into arterial walls with low-density lipoproteins during the information progression of atherosclerosis. It is not licensed for any other indication. available at the time

of research and a Diseases of the heart and circulatory system (cardiovascular disease or limited literature CVD) are the main cause of death in the UK and account for almost 191,000 search. It is not deaths each year – one in three of all deaths. The main forms of CVD are intended to be a CHD and stroke. The prevalence of CVD in the UK increases with age and is definitive statement higher in men than in women. There are over 1.6 million men and over 1 on the safety, million women in the UK with CHD, giving a total of nearly 2.7 million people. efficacy or Nearly 1.6 million of these people are less than 75 years of age. In 2011-12, effectiveness of the there were 282,569 admissions for coronary heart disease in England, health technology resulting in 1,163,109 bed-days and 409,508 finished consultant episodes. covered and should 64,435 deaths were registered in England and Wales during 2011. not be used for commercial Treatment of CHD aims to prevent recurrent cardiovascular events by purposes or reducing individual patients’ cardiovascular risk. This includes lifestyle commissioning changes such as dietary modification, smoking cessation, and exercise. without additional Current pharmacological treatment options for the prevention of information. cardiovascular events in high-risk patients include lipid lowering therapies, antiplatelet therapy and antihypertensive therapy. Darapladib is currently in two phase III clinical trials comparing its effect on time to first occurrence of major adverse cardiovascular events, against treatment with placebo. These trials are expected to complete in November 2014.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Cardiovascular risk reduction: high-risk patients with coronary heart disease (CHD), including patients with acute coronary syndrome (ACS) – add on therapy.

TECHNOLOGY

DESCRIPTION

Darapladib (SB-480848) is a selective inhibitor of lipoprotein-associated phospholipase-A2 (Lp-PLA2). Lp-PLA2 is a key enzyme involved in lipid metabolism and inflammation which circulates with lipoprotein particles and is carried into arterial walls with low-density lipoproteins (LDL) during the progression of atherosclerosis. Within the vessel wall, LpPLA2 stimulates macrophage recruitment leading to rupture of atherosclerotic plaques. Inhibition of Lp-PLA2 may help prevent the expansion of the necrotic core of plaques, preventing rupture1. Darapladib is intended to be used as add on therapy for cardiovascular risk reduction in high-risk patients with CHD, including patients with ACS. Darapladib is administered orally at 160mg once daily in combination with standard therapy.

Darapladib is also in phase II clinical trials for diabetic macular oedema.

INNOVATION and/or ADVANTAGES

If licensed, darapladib will represent the first in a new class of treatments for this patient group.

DEVELOPER

GlaxoSmithKline.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

The accumulation of LDL cholesterol in the intima (inner lining) of arteries2 and associated inflammatory reactions gradually lead to the formation of atherosclerotic plaques within the arterial tree2. Atherosclerotic plaques in the coronary arteries obstruct blood flow and reduce oxygen supply to the myocardium, which in turn produces the typical symptom of CHD, chest pain (angina pectoris)2. Other symptoms include exertional dyspnoea and fatigue, arrhythmias, and heart failure. Chronic stable angina and acute coronary syndrome (ACS) are clinical manifestations of CHD2. ACS refers to a spectrum of clinical presentations, ranging from ST-segment elevation myocardial infarction (STEMI) to presentations found in non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA)3. The key behavioural risk factors for CHD include smoking, physically inactive lifestyles, poor diet,

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excess salt, obesity and alcohol consumption4. Medical risk factors include high blood pressure, high blood cholesterol, being overweight and obese, and diabetes5.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to the National Service Framework for Coronary Heart Disease (2005).

CLINICAL NEED and BURDEN OF DISEASE

Diseases of the heart and circulatory system (cardiovascular disease or CVD) are the main cause of death in the UK and account for almost 191,000 deaths each year – one in three of all deaths5. The main forms of CVD are CHD and stroke. The prevalence of CVD in the UK increases with age and is higher in men than in women5. There are over 1.6 million men and over 1 million women in the UK with CHD, giving a total of nearly 2.7 million people. Nearly 1.6 million of these people are less than 75 years of age5.

An estimated 233,600 people are diagnosed with ACS annually in the UK3. The overall prevalence of angina in the UK is approximately 5% in men and 4% in women (8% of men and 3% of women aged 55 to 64 years and about 14% of men and 8% of women aged 65 to 74 years)5. It is estimated that there are around 1.5 million people who have previously suffered a myocardial infarction in the UK5, and nearly 600,000 individuals of each sex who have had a stroke5. Risk of CHD is directly related to blood cholesterol levels. It is estimated that around 60% of CHD is due to increased total blood cholesterol levels5. The proportion of people with high cholesterol (total cholesterol levels of 5mmmol/l and over) in England ranges between 54% and 64% for men and 56% and 68% for women5.

In 2011-12, there were 282,569 admissions for coronary heart disease (ICD-10 I20-I25) in England, resulting in 1,163,109 bed-days and 409,508 finished consultant episodes6. 64,435 deaths were registered in England and Wales during 20117. CVD is estimated to cost the UK economy around £30bn a year5.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Ticagrelor for the treatment of acute coronary syndromes (TA236). October 20118. • NICE technology appraisal. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (TA210). December 20109. • NICE technology appraisal. Statins for the prevention of cardiovascular events (TA94). November 200810. • NICE technology appraisal. Drug-eluting stents for the treatment of coronary artery disease (TA152). July 200811.

• NICE clinical guideline. Management of stable angina (CG126). July 201112. • NICE clinical guideline. Unstable angina and NSTEMI (CG94). March 20103. • NICE clinical guideline in development. Myocardial infarction with ST-segment elevation – the acute management of MI with ST-segment elevation. Expected date of issue, July 201313.

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• NICE clinical guideline. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (CG67). 200814. • NICE clinical guideline. Secondary prevention in primary and secondary care for patients following a myocardial infarction (CG48). 200715.

• NICE quality standard. Quality standard for stable angina. (QS21). 201216. • NICE public health guidance. Guidance on the prevention of cardiovascular disease at the population level (PH25). 201017.

Other Guidance

• European Society of Cardiology and the European Atherosclerosis Society. ESC/EAS guidelines for the management of dyslipidaemias. 201118. • Hamm et al. Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. 201119. • World Health Organisation. Prevention of cardiovascular disease: pocket guidelines for assessment and management of cardiovascular risk. 200720 • Scottish Intercollegiate Guidelines Network. Management of chronic heart failure (95). 200721. • Scottish Intercollegiate Guidelines Network. Management of stable angina (96). 200722. • Scottish Intercollegiate Guidelines Network. Acute Coronary Syndromes (93). 200723. • Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease (97). 200724. • Bassand et al. Guidelines for the diagnosis and treatment of non-ST-segment-elevation acute coronary syndromes. 200725. • National Cholesterol Education Program. Detection, evaluation, and treatment of high blood cholesterol in adults: adult treatment panel III. 200226.

EXISTING COMPARATORS and TREATMENTS

Treatment of CHD aims to prevent recurrent cardiovascular events by reducing individual patients’ cardiovascular risk. This includes lifestyle changes such as dietary modification, smoking cessation, and exercise. Current pharmacological treatment options for the prevention of cardiovascular events in high-risk patients include5,25,27:

• Lipid lowering therapies, which include statins (simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin), fibrates (bezafibrate, ciprofibrate, fenofibrate and gemfibrozil), nicotinic acid and anion exchange resins. • Antiplatelet therapy: aspirin, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, tirofiban. • Antihypertensive therapy which include, ACE inhibitors, angiotensin-II receptor antagonists, thiazides and calcium channel blockers. • Beta blockers such as propranolol, timolol and metoprolol.

Current guidelines may also recommend revascularisation procedures in appropriate patients3: • Percutaneous coronary intervention (PCI) angioplasty with stent placement, • Coronary artery bypass grafting (CABG).

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EFFICACY and SAFETY

Trial SOLID-TIMI 52, NCT01000727, STABILITY, NCT00799903, 100601; 480848/033; darapladib vs placebo; darapladib vs placebo; phase III. phase III. Sponsor GlaxoSmithKline. GlaxoSmithKline. Status Ongoing. Ongoing. Source of Publication28, trial registry29. Trial registry30. information Location EU (inc UK), USA, Canada and other EU (inc UK), USA, Canada and other countries. countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=13,000 (planned); adults aged ≥18 yrs; n=15,828 (planned); adults aged ≥18 yrs; hospitalised for ACS within 30 days of chronic CHD; current treatment with study randomisation; concomitant statins unless study doctor deems background medication including statins, inappropriate; at least one of the antiplatelet drugs and beta-blockers; at following: ≥60 yrs, diabetes mellitus least one of the following: ≥60 yrs, requiring pharmacotherapy, HDL-C myocardial infarction (MI) prior to ≤50mg/dL, current smoker or smoking qualifying ACS event, diabetes mellitus cessation within the last 3 months, requiring pharmacotherapy, significant significant renal dysfunction, renal dysfunction, cerebrovascular cerebrovascular disease or PAD. disease or peripheral artery disease (PAD). Schedule Randomised to darapladib 160mg once Randomised to darapladib 160mg once daily or placebo, in addition to standard daily or placebo, in addition to standard therapy. therapy. Follow-up Study continues until approximately 1,500 Study continues until approximately 1,500 primary endpoints have occurred. Median primary endpoints have occurred. Median treatment duration anticipated to be treatment duration anticipated to be approximately 3 yrs. approximately 3.5 yrs. Primary Time to the first occurrence of any Time to first occurrence of major adverse outcome/s component of the composite of major cardiovascular event. adverse cardiovascular events Secondary Composite of major coronary events; Major coronary events; total coronary outcome/s composite of total coronary events; events; individual components of the individual components of the primary end primary end point; all-cause mortality. point; composite of all-cause mortality; all- cause mortality. Expected Estimated study completion date Nov Estimated study completion date Nov reporting 2014. 2013. date

Trial NCT00268996, SB-480848/026; NCT00269048, LPL104884; darapladib vs darapladib vs placebo; phase II. placebo; phase II. Sponsor GlaxoSmithKline. GlaxoSmithKline. Status Complete but unpublished. Published. Source of Trial registry31. Publication32, trial registry33 . information Location EU. EU, Canada, USA and other countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=300 (planned); adults aged 18 to 80 n=959; adults aged 18 to 80 yrs; stable yrs; successful PCI or uncomplicated CHD or CHD-risk equivalent (defined as diagnostic cardiac catherterisation; diabetes mellitus requiring antiplatelet therapy. pharmacotherapy, carotid stenosis >50%, prior carotid surgery or stenting, PAD, or

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10 year risk for coronary events >20% according to Framingham Risk Score).

Schedule Randomised to darapladib 10mg once Randomised to darapladib 40mg, 80mg or daily or placebo. 160mg once daily, or placebo, all in combination with atorvastatin 20mg or 80mg. Follow-up Active treatment period 1 year. Active treatment period 12 weeks.

Primary Intravascular ultrasound (IVUS) based Sustained inhibition of plasma Lp-PLA2. outcome palpography and high-sensitivity C- reactive protein. Secondary Endothelial function plaque volume by Other biomarkers and safety. outcomes quantitative coronary angiography and intravascular ultrasound, circulating biomarkers. Key results - For darapladib 40mg, 80mg and 160mg respectively compared with placebo, % change (95% CI): Lp-PLA2 activity, -43.0, -55.0 and -66.0 (p<0.001); high-sensitivity C-reactive protein, -6.0 (-22.0 to +13.0), -0.3 (-18.0 to +20.0), -13.0 (-18.0 to +5.0); interleukin -6, -7.8 (-18.0 to +4.0), -2.3 (-12.0 to +10.0), -12.3 (-22.0 to +1.0) (p=0.028); myeloperoxidase, +1.6 (-9.0 to +14.0), +0.9 (-10.0 to +13.0), +4.7 (-6 to +17); matrix metalloproteinase-9, -0.8 (-14.0 to +15.0), -9.8 (-22.0 to +4.0), +4.8 (-9.0 to +21.0); P-selectin, +1.0 ( -6.0 to +8.0), -3.0 (-10.0 to +4.0), 0 (-7.0 to +7.0); CD40L, -3.9 (-11.0 to +14.0), -3.9 (-11.0 to +14.0), +3.4 (-13.0 to +22.0); urinary 11-dehydrothromboxane B2, -4.5 (-16.0 to +8.0), -0.6 (-12.0 to +13.0), 0.2 (-12.0 to +13.0). Treatment with darapladib did not modify total cholesterol, LDL-C, HDL-C or triglyceride levels compared with placebo. Adverse - No AEs associated with vital signs, effects (AEs) electrocardiograms or laboratory data were reported. Serious AEs were reported in 3% of the placebo (n=7), darapladib 40mg (n=6) and darapladib 80mg (n=7) groups and 2% of the darapladib 160mg (n=5) group. The most commonly reported AE was angina. Expected Previously reported as August 2007. - reporting date

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ESTIMATED COST and IMPACT

COST

The cost of darapladib is not yet known. The cost of selected lipid-regulating drugs are summarised below:

Drug Dose (oral) Annual cost34 Atorvastatin (Lipitor) 10mg, once daily £24.57 Simvastatin 40mg, once daily £15.21 Rosuvastatin (Crestor) 20mg, once daily £338.26 Pravastatin 40mg, once daily £30.68 Fluvastatin 80mg, once daily £105.82

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs: add on  Reduced drug treatment costs therapy.

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments.

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Corson MA. Darapladib: an emerging therapy for atherosclerosis. Therapeutic Advances in Cardiovascular Disease 2010;4(4):241-248. 2 Evidence Based Medicine. Coronary Heart Disease (23.4) 2010. http://www.ebm- guidelines.com/ebmg/ltk.free?p_artikkeli=ebm00080#s6. 3 National Institute for Health and Care Excellence. Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. Clinical Guideline CG94. London: NICE; March 2010. 4 Department of Health. The National Service Framework for coronary heart disease. London: DH; 2004.

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5 British Heart Foundation Statistics Database. Coronary heart disease statistics 2012 edition. University of Oxford: Department of Public Health. 6 NHS. Hospital episode statistics. NHS England 2011-12. HES data 2012. www.hesonline.nhs.uk 7 Office for National Statistics. Mortality statistics. Deaths registered in 2011 (Series DR) Table 5. www.ons.gov.uk 8 National Institute for Health and Care Excellence. Ticagrelor for the treatment of acute coronary syndromes. Technology appraisal TA236. London: NICE; October 2011. 9 National Institute for Health and Care Excellence. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. Technology appraisal TA210. London: NICE; December 2010. 10 National Institute for Health and Care Excellence. Statins for the prevention of cardiovascular events. Technology appraisal TA94. London: NICE; November 2008. 11 National Institute for Health and Care Excellence. Drug-eluting stents for the treatment of coronary artery disease. Technology appraisal TA152. London: NICE; July 2008. 12 National Institute for Health and Care Excellence. Management of stable angina. Clinical guideline CG126. London: NICE; July 2011. 13 National Institute for Health and Care Excellence. Myocardial infarction with ST- segment elevation – the acute management of MI with ST-segment elevation. Clinical guideline in development. Expected date of issue July 2013. 14 National Institute for Health and Care Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical guideline CG67. London: NICE; May 2008. 15 National Institute for Health and Care Excellence. Secondary prevention in primary and secondary care for patients following a myocardial infarction. Clinical guideline CG48. London: NICE; May 2007. 16 National Institute for Health and Care Excellence. Quality standard for stable angina. Quality standard QS21. London: NICE; August 2012. 17 National Institute for Health and Care Excellence. Guidance on the prevention of cardiovascular disease at the population level. Public health guidance PH25. London: NICE; June 2010. 18 European Society of Cardiology. ESC/EAS Guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). European Heart Journal 2011;32:1769-1818. 19 Hamm CW, Bassand JP, Agewall S et al. Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal. 2011;32:2999-3054. 20 World Health Organization. Prevention of cardiovascular disease: pocket guidelines for assessment and management of cardiovascular risk. Geneva: WHO; 2007. 21 Scottish Intercollegiate Guidelines Network. Management of chronic heart failure. Clinical guideline 95. Edinburgh: SIGN; February 2007. 22 Scottish Intercollegiate Guidelines Network. Management of stable angina. Clinical guideline 96. Edinburgh: SIGN; February 2007. 23 Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. National clinical guideline 93. Edinburgh: SIGN; February 2007. 24 Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease. Clinical guideline 97. Edinburgh: SIGN; February 2007 25 Bassand JP, Hamm CW and Ardissino D. Guidelines for the diagnosis and treatment of non-ST- segment elevation acute coronary syndromes. European Heart Journal. 2007;28(13):1598-660. 26 National Cholesterol Education Program. Detection, evaluation, and treatment of high blood cholesterol in adults: adult treatment panel III. National Institutes of Health. NIH publication No.02- 5215. September 2002. 27 Steg G, James SK, Atar D et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal 2012;33:2569-2619. 28 O’Donoghue ML, Braunwald E, White HD et al. Study design and rationale for the stabilization of plaques using darapladib – thrombolysis in myocardial infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. American Heart Journal 2011;162(4):613-619.

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29 ClinicalTrials.gov. A clinical outcomes study of darapladib versus placebo in subjects following acute coronary syndrome to compare the incidence of major adverse cardiovascular events (MACE). http://clinicaltrials.gov/show/NCT01000727 Accessed 20 May 2013. 30 ClinicalTrials.gov. The stabilisation of atherosclerotic plaque by initiation of darapladib therapy trial (STABILITY) http://clinicaltrials.gov/ct2/show/NCT00799903?term=NCT00799903&rank=1 Accessed 20 May 2013. 31 ClinicalTrials.gov. Integrated biomarker and imaging study – 2. http://clinicaltrials.gov/ct2/show/NCT00268996?term=SB-480848&rank=5 Accessed 20 May 2013. 32 Moller ER (3rd), Ballantyne CM, Davidson MH et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent. Journal of the American College of Cardiology 2008;51(17):1632-1641. 33 ClinicalTrials.gov. A multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of SB-480848, an oral lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, in subjects with stable coronary heart disease (CHD) or CHD-risk equivalent to examine chronic inhibition of Lp-PLA2. http://clinicaltrials.gov/show/NCT00269048 Accessed 20 May 2013. 34 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 65. London: BMJ Group and RPS Publishing, March 2013.