October Horizon Scanning Research & 2016 Intelligence Centre

Anacetrapib in combination with a for patients with primary hypercholesterolaemia or mixed dyslipidaemia – adjunctive therapy

NIHR HSRIC ID: 5243

Lay summary

Anacetrapib is a new drug that may reduce the level of fats, like cholesterol, in your blood. High cholesterol can increase the risk of diseases such as heart attack and stroke, which are the main cause of death in the UK, accounting for over a quarter of all deaths each year. Anacetrapib is given as a tablet in combination with another drug (a statin), which is already used to lower ‘bad’ cholesterol. If anacetrapib can increase ‘good’ cholesterol, it may help reduce deaths and illness caused by heart disease and strokes.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.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.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia: patients unable to reach low-density lipoprotein cholesterol goals with the maximum tolerated dose of HMG-CoA reductase inhibitor (statin) therapy – adjunctive therapy to diet; in combination with a statin.

TECHNOLOGY

DESCRIPTION

Anacetrapib (MK-0859) is a selective cholesterol ester transfer protein (CETP) inhibitor. CETP plays a major role in promoting the transfer of cholesteryl esters from antiatherogenic high-density lipoprotein cholesterol (HDL-C) to proatherogenic apolipoprotein B-100- containing lipoproteins such as triglyceride-rich lipoproteins and low-density lipoprotein cholesterol (LDL-C). A low level of HDL-C is considered a risk factor for the development (CVD) and anacetrapib may increase HDL-C and decrease LDL-C. Anacetrapib is administered orally at 100mg once dailya.

Anacetrapib does not currently have Marketing Authorisation in the EU for any indication.

Anacetrapib is in phase III clinical trials for the reduction of CVD mortality and morbidity in patients at high risk of CVD events.

INNOVATION and/or ADVANTAGES

If licensed, anacetrapib will offer an additional oral treatment option for patients with primary hypercholesterolaemia and dyslipidaemia.

DEVELOPER

Merck Sharp and Dohme Corp.

AVAILABILITY, LAUNCH OR MARKETING

Anacetrapib is being evaluated in a phase III cardiovascular outcomes trial.

PATIENT GROUP

BACKGROUND

Dyslipidaemia describes a wide range of lipid abnormalities and disturbances in lipid metabolism that lead to changes in plasma lipoprotein function and/or levels. Along with other cardiovascular risk factors, this may lead to the development of atherosclerosis and CVD1. Epidemiological studies show a strong relationship between increased LDL-C (or increased non-HDL-C) and reduced levels of HDL-C with the development of CVD2. Total cholesterol (TC) and LDL-C levels constitute the primary targets of therapy as evidence showing that reducing TC and LDL-C can prevent CVD is strong and compelling. However,

a Company provided information. Horizon Scanning Research & Intelligence Centre

several other types of dyslipidaemias also appear to predispose of premature CVD. The atherogenic lipid triad, associated with insulin resistant states or type 2 diabetes, is a common pattern found in premature CVD. It consists of increased very low density lipoprotein (VLDL) particles manifesting in clinical laboratory measurements as mildly elevated triglycerides (TG), increased small density LDL particles, and reduced HDL-C levels, often accompanied by raised levels of apolipoprotein B-1001,b. This lipid phenotype is associated with overactivity of CETP and hepatic lipase activities and underactivity in lipoprotein lipase activity3.

Hypercholesterolaemia is characterised by a high cholesterol concentration in the blood. Primary hypercholesterolaemia is associated with an underlying genetic cause. This may be a specific genetic defect, as in monogenic familial hypercholesterolaemia (FH), or the interaction of multiple genes with dietary and other risk factors, such as smoking and physical inactivity (non-familial hypercholesterolaemia). FH is present from birth, has an autosomal dominant pattern of inheritance, and may lead to early development of atherosclerosis and coronary heart disease4. If untreated, about 50% of men and 30% of women with heterozygous FH will develop coronary heart disease by 55 years of age5. The majority of people with primary hypercholesterolaemia have mildly or moderately elevated cholesterol levels and exhibit no clinical symptoms. Severe hypercholesterolaemia can cause xanthomas and arcus corneae. However, the increased risk of CVD is the most significant problem associated with hypercholesterolaemia6. The risk of CVD is directly related to blood cholesterol levels and it is estimated that more than 50% of CVD in developed countries is a result of blood cholesterol levels higher than 3.8mmol/L7.

CLINICAL NEED and BURDEN OF DISEASE

Primary non-familial hypercholesterolaemia affects around 4% of the adult population of England (approximately 1.5 million people), of whom an estimated 600,000 are diagnosed and 460,000 are receiving treatment8. Primary heterozygous-familial hypercholesterolaemia is less common (1 in 300) and affects about 106,000 people in England, although only an estimated 15-17% are diagnosed8.

People with hypercholesterolaemia have an increased risk of CVD as in the long term raised cholesterol levels accelerate the development of atherosclerosis. Approximately 5.9 million people in England are currently living with CVD9. Healthcare costs relating to CVD are estimated to be £11 billion each year9. In 2015 in England, there were 69,731,400 prescription items dispensed for lipid-regulating drugs, with a total net ingredient cost of £238 million10. In England, approximately 4.4 million people are currently prescribed statins7. CVD is the most common cause of death in the UK and is a major cause of illness, disability and reduced quality of life. In the UK, CVD accounts for around 1 in 3 of all deaths (180,000) each yearError! Bookmark not defined..

PATIENT PATHWAY

b Expert personal communication.

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RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Ticagrelor for secondary prevention of atherothrombotic events after myocardial infarction (ID813). Expected December 2016. • NICE technology appraisal. for treating primary hypercholesterolaemia and mixed dyslipidaemia (TA393). June 2016. • NICE technology appraisal. for treating primary hypercholesterolaemia and mixed dyslipidaemia (TA394). June 2016. • NICE technology appraisal. for treating primary heterozygous-familial and non-familial hypercholesterolaemia (TA385). February 2016. • NICE technology appraisal. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (TA210). December 2010. • NICE clinical guideline. Cardiovascular disease: risk assessment and reduction, including lipid modification (CG181). July 2016. • NICE clinical guideline. Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease (CG172). November 2013. • NICE quality standard. Cardiovascular risk assessment and lipid modification (QS100). September 2015. • NICE public health guidance. Cardiovascular disease prevention (PH25). June 2010.

NHS England Policies and Guidance

• No relevant guidance identified.

Other Guidance

• European Atherosclerosis Society. Guidelines on management of dyslipidaemia. 201611. • European Society of Cardiology/European Atherosclerosis Society. European guidelines on cardiovascular disease prevention in clinical practice. 201612. • American College of Cardiology. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk: a new paradigm supported by more evidence. 201313. • European Society of Cardiology. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. 201314. • European Society of Cardiology. ESC/EAS Guidelines for the management of dyslipidaemias. 20111.

CURRENT TREATMENT OPTIONS

Managing hypercholesterolaemia involves dietary and lifestyle changes (such as smoking cessation, weight loss and increased physical activity), and treatment with a lipid-regulating drug if appropriate8. Starting drug treatment is generally based on an assessment of the person's CVD risk8.

Current lipid modification therapy options for hyperlipidaemia in the primary prevention of CVD include7,15,16: • Statin therapies licensed for the use in the UK include: o o o

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o o • Ezetimibe – monotherapy is recommended as an option for treating primary (heterozygous-familial or non-familial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated. • Evolocumab and alirocumab – recommended by NICE as options for treating primary hypercholesterolaemia or mixed dyslipidaemia if LDL-C is ≥3.5mmol/L in patients at very high risk of CVD, and ≥4.0mmol/L in patients at risk of CVD. Statin therapy has been shown to decrease LDL-C by approximately 25-50%, with a corresponding 24-40% risk reduction in CVD events which equates to a relative risk reduction of 21% in CVD events for a reduction of 1mmol/L in LDL-C17,18.

Current treatment options for hyperlipidaemia in the secondary prevention of CVD include7: • . • may be considered for secondary prevention in people with CVD who are unable to tolerate statins or in FH in combination with a statin. They are also used in the treatment of severe isolated hypertriglyceridaemia (TG >10mmol/L), but where this co- exists with hypercholesterolaemia (i.e. in mixed hyperlipidaemia), LDL-reduction remains the priority and thus statins tend to remain first-line. • Bile acid sequestrants and anion exchange resins for reduction of LDL-C in patients unable to tolerate other agentsc.

EFFICACY and SAFETY

Trial REALIZE, NCT01524289, MK-0859-020, 2011-004525-27; anacetrapib vs placebo; phase III. Sponsor Merck Sharp & Dohme Corp. Status Ongoing. Source of Publication19, trial registry20, manufacturer. information Location EU (incl UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Participants n=306; aged 18-80 yrs; heterozygous familial hypercholesterolaemia; treated with an optimal dose of statin for at least 6 wks; no homozygous familial hypercholesterolaemia. Schedule Randomised to anacetrapib 100mg oral once daily; or placebo oral once daily. Follow-up Active treatment for 52 weeks. Primary Percentage change from baseline in LDL-C. outcome Secondary Percentage change from baseline in HDL-C, non-HDL-C, apolipoprotein B, outcomes apolipoprotein A1, and lipoprotein. Key results For anacetrapib vs placebo groups, respectively: change in mean LDL-C concentration from baseline to week 52, 3.3mmol/L to 2.1mmol/L vs 3.4mmol/L to 3.5mmol/L. The placebo-adjusted change to LDL-C was -21.9% and on HDL-C was 53.0%. Adverse For anacetrapib vs placebo groups, respectively: participants with AEs, 76 vs 78%; effects participants with AEs leading to discontinuation, 6% vs 5% (p=0.7174). There was an (AEs) increased incidence of skin-related AEs in the anacetrapib group compared with placebo (9% vs 2%, p=0.0162). Expected Study completion date reported as Oct 2018. reporting date ESTIMATED COST and IMPACT

c Expert personal communication.

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COST

The cost of anacetrapib is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other: reduced hypercholesterolaemia and  No impact identified dyslipidaemia, which should lead to reduced CVD events.

Impact on Health and Social Care 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 and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

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

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion states that safe and effective first, second and third line alternative therapies are already available and have been recommended by NICE, therefore they currently see no clear place for this therapy in the treatment of hypercholesterolaemiad. Furthermore, the large HDL particles generated by anacetrapib may prove to be pro-atherogenic, not anti-atherogenic, so the ability of the drug to reduce LDL-C cannot be taken as a surrogate measure of benefitd.

REFERENCES

1 Reiner Z, Catapano A, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal 2011;32:1769-1818. 2 Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. Journal of the American Medical Association 2009;302(18):1993-2000. 3 Chapman M, Ginsberg H, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European Heart Journal 2011;32(11):1345-1361.

d Expert personal communication.

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4 National Institute for Health and Care Excellence. Clinical knowledge summaries: hypercholesterolaemia – familial. www.cks.nice.org.uk/hypercholesterolaemia- familial#!topicsummary Accessed 14 October 2016. 5 British Heart Foundation. Focus on: familial hypercholesterolaemia. www.bhf.org.uk/heart- matters-magazine/medical/familial-hypercholesterolaemia Accessed 14 October 2016. 6 National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. NICE technology appraisal overview TA385. London: NICE; February 2016. 7 National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. NICE clinical guideline CG181. London: NICE; July 2014. 8 National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. NICE technology appraisal pre- meeting briefing (review of TA132). London: NICE; February 2016. 9 British Heart Foundation. CVD statistics – BHF UK Factsheet. www.bhf.org.uk/research/heart- statistics Accessed 14 October 2016. 10 Health & Social Care Information Centre. Prescription cost analysis data, England 2015. www.hscic.gov.uk 11 Catapano A, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal 2016; doi:10.1093/eurheartj/ehw272. 12 Piepoli M, Hoes A, Agewall S et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal 2016; doi:10.1093/eurheartj/ehw106. 13 Robinson J and Stone N. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk: a new paradigm supported by more evidence. European Heart Journal 2015; doi:10.1093/eurheartj/ehv182. 14 Norata G, Ballantyne C and Catapano A. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. European Heart Journal 2013; doi:10.1093/eurheartj/eht088. 15 Patient. Lipid-regulating drugs (including statins). www.patient.info/doctor/lipid-regulating-drugs- including-statins#ref-41 Accessed 14 October 2016. 16 National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. NICE technology appraisal TA394. London: NICE; June 2016. 17 Canadian Agency for Drugs and Technologies in Health. Anacetrapib for the treatment of dyslipidemia. www.cadth.ca/anacetrapib-treatment-dyslipidemia Accessed 14 October 2016. 18 Fulcher J, O-Connell R, Voysey M et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385(9976):1397-1405. 19 Kastelein J, Besseling J, Shah S et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo- controlled, phase 3 study. The Lancet 385(9983):2153-2161. 20 ClinicalTrials.gov. Study to assess the tolerability and efficacy of anacetrapib co-administered with statin in participants with heterozygous familial hypercholesterolaemia. www.clinicaltrials.gov/ct2/show/ NCT01524289 Accessed 14 October 2016.

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