October Horizon Scanning Research & 2016 Intelligence Centre Bococizumab for primary hyperlipidaemia and mixed dyslipidaemia – adjunctive to statin therapy and/or diet NIHR HSRIC ID: 6837 Lay summary Bococizumab is a new drug to treat high levels of fat and cholesterol in the bloodstream (primary hyperlipidemia and mixed dyslipidemia). These conditions can cause a build-up of fatty deposits (plaques) in the arteries, which may lead to heart attacks and strokes. Bococizumab is given by subcutaneous injection. Some studies have suggested that this drug in combination with other cholesterol lowering drugs may help to reduce the risk of heart attacks 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 GROUPS • Primary hyperlipidaemia: heterozygous familial and non-familial – adjunctive to diet; in combination with statin. • Mixed dyslipidaemia – adjunctive to diet; in combination with statin. • Primary hyperlipidaemia or mixed dyslipidaemia: statin-intolerant, or patients in whom statins are contraindicated – adjunctive to diet. TECHNOLOGY DESCRIPTION Bococizumab (PF-04950615; RN316) is one of a new class of lipid regulating drugs, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Unlike others in its class, which are fully human (e.g. evolocumab and alirocumab), bococizumab is a humanised IgG2Δa monoclonal antibody (mAb) that targets this serine protease. The accumulation of low-density lipoprotein-cholesterol (LDL-C) in the blood can result in atherosclerosis, which may lead to cardiovascular disease (CVD), e.g. coronary heart disease (CHD) or stroke1. The low-density lipoprotein (LDL) receptor binds LDL-cholesterol to mediate its clearance from the circulation. Recent studies suggest that gain-of-function mutations in PCSK9 increase LDL-C levels, and thus the risk of cardiovascular events; conversely, genetic variations linked to reduced PCSK9 function decrease plasma LDL-C, subsequently lowering risk2,3. The PCSK9 protein interferes with the clearance of LDL-C by binding to, and inducing the degradation of the LDL receptor2. Bococizumab inhibits the PCSK9 protein, preventing PCSK9-mediated degradation2. Bococizumab is intended to treat primary hyperlipidaemia (heterozygous familial and non-familial) and mixed dyslipidaemia as an adjunctive to diet and statins, or primary hyperlipidaemia or mixed dyslipidaemia as a monotherapy in those who are statin-intolerant, or for whom statins are contraindicated. Bococizumab is administered by subcutaneous (SC) auto-injector device at 150mg given once every two weeks in combination with statins and/or diet on a continuing basis. It is not currently licensed in the EU for any other indication. INNOVATION and/or ADVANTAGES PCSK9 inhibitors, like bococizumab, are intended to prevent cardiovascular events. While statin therapy considerably reduces the risk of CVD, cardiovascular morbidity and mortality still occur in a significant portion of subjects receiving this therapy, in particular those with familial hypercholesterolemia (FH) – characterised by extremely high levels of LDL-C4,5. If licensed, bococizumab has the potential to reduce residual cardiovascular (CV) risk in those with primary hyperlipidaemia and mixed dyslipidaemia; or reduce CV risk in those who are statin-intolerant, or for whom a statin is contraindicated, a group with few well-tolerated effective therapies available. DEVELOPER Pfizer Limited. Horizon Scanning Research & Intelligence Centre AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Dyslipidaemia encompasses a number of conditions in which disturbances in fat metabolism lead to changes in lipid concentrations in the blood. These include hypercholesterolaemia, hyperlipidaemia and mixed dyslipidaemia. Hypercholesterolaemia is defined as raised levels of cholesterol in the blood, typically including elevated LDL-C. Hyperlipidaemia refers to raised cholesterol and/or raised triglycerides (TG) – hypercholesterolaemia and/or hypertriglyceridaemia. Mixed dyslipidaemia is defined as hyperlipidaemia with elevations in LDL-C and TG accompanied by decreased levels of high-density lipoprotein cholesterol (HDL-C)6. Primary dyslipidaemia may be caused by a mixture of environmental factors and genetic predisposition; these include homozygous or heterozygous mutations in the LDL cholesterol receptor gene (a cause of FH) and lipoprotein lipase gene (a cause of familial hypertriglyceridaemia), or more commonly, by the interaction of several genes with dietary and other factors such as smoking or physical inactivity (non-familial dyslipidaemia)6. Most people with hypercholesterolaemia have cholesterol concentrations that are only mildly or moderately elevated, and show no clinical symptoms. However, severe hypercholesterolaemia can cause xanthomas (lesions on the skin containing cholesterol and fats), arcus corneae (cholesterol deposits in the eyes), and significantly increased risk of atherosclerosis and therefore CVD6. 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/litre (68.5mg/dL)7. People with FH have marked elevations in cholesterol and are at particular risk of developing premature CVD6. CLINICAL NEED and BURDEN OF DISEASE It is estimated that 6 in 10 adults in England have cholesterol levels above 5.0mmol/litre (193mg/dL), a leading risk factor for CVD8. In England, there were 383,640 admissions for the four main types of CVD (ICD10: CHD I20–I25; stroke I61–I64; peripheral arterial disease I73.9; and aortic disease I71) in 2014-159. CHD is the leading cause of death in the UK, responsible for more than 73,000 deaths each year. About 1 in 6 men and 1 in 10 women die from CHD. In 2012-2013, there were around 2.3 million people living with CHD (around 1.3 million people affected by angina, the most common symptom of CHD), 1.2 million people recovering from a stroke, around 1.1 million living with atrial fibrillation, and just over 480,000 with heart failure in the UK8,10. Primary non-familial hypercholesterolaemia affects about 4% of the adult population, totalling approximately 1.5 million people in England, of whom an estimated 600,000 are diagnosed and 460,000 are receiving treatment. Primary heterozygous FH affects an estimated 1 in 500 people, totalling 106,000 in England (although only 15–17% are diagnosed)6. In June 2016 alone, 5,541,338 items of lipid-regulating drugs were dispensed in England at a net ingredient cost of around £17.1 million11. It has been estimated that 12,088 people with non-familial hypercholesterolaemia and 1,749 with FH will have LDL-C levels that are not adequately controlled by their current lipid- 3 Horizon Scanning Research & Intelligence Centre regulating treatment12. However, the proportion of those with severe hypertriglyceridaemia that is not adequately controlled by current lipid-regulating drugs is not known. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia (TA394). June 201613. • NICE technology appraisal. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia (TA393). June 201614. • NICE technology appraisal. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia (TA385). February 201615. • NICE clinical guidelines. Cardiovascular disease: risk assessment and reduction, including lipid modification (CG181). July 20147. • NICE clinical guidelines. Identification and management of familial hypercholesterolaemia. (CG71). August 200816. • NICE quality standard. Cardiovascular risk assessment and lipid modification (QS100). September 201517. • NICE quality standard. Familial hypercholesterolaemia (QS41). August 201318. NHS England Policies and Guidance • NHS England. 2013/14 NHS Standard Contract for Severe and Complex Obesity (All Ages). A05/S/a. • NHS England. 2013/14 NHS Standard Contract for Insulin-Resistant Diabetes Services (All Ages). A03/S(HSS)/b. • NHS England. 2013/14 NHS Standard Contract Paediatric Medicine: Endocrinology and Diabetes. E03/S/e. • NHS England. Clinical Commissioning Policy: Complex and Specialised Obesity Surgery. NHS ENGLAND/A05/P/a. April 2013. Other Guidance • European Society of Cardiology. European guidelines on cardiovascular disease prevention in clinical practice. 201619. • American College of Cardiology. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. 201620. • 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. 201321. • European Society