Bococizumab for Primary Hyperlipidaemia and Mixed Dyslipidaemia – Adjunctive to Statin Therapy And/Or Diet

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 of Cardiology. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. 201322. • The Endocrine Society. Evaluation and treatment of hypertriglyceridemia: An endocrine society clinical practice guideline. 201223. • European Society of Cardiology. ESC/EAS Guidelines for the management of dyslipidaemias. 201124.

4 Horizon Scanning Research & Intelligence Centre

CURRENT TREATMENT OPTIONS

Guidelines recommend that patients with primary hyperlipidaemia should undergo a formal risk assessment (such as the Framingham risk equation) to ascertain their risk of developing CVD. This incorporates factors such as the patient’s age, sex, systolic blood pressure, total cholesterol (TC), HDL-C levels, smoking status, and left ventricular hypertrophy. For those patients judged to be at high risk, the first step is to instigate lifestyle changes, including dietary modification, smoking cessation, and exercise where possible. Lipid-regulating drug therapy may be considered where this is ineffective, or in patients with FH.

Current pharmacological treatment options for primary hypercholesterolaemia and hypertriglyceridaemia include the following 7,16,20,25,26,27,28:

• Statins – e.g. atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin. • PCSK9 inhibitors – e.g. alirocumab, evolocumab . monotherapy – for non-familial hypercholesterolaemia or mixed dyslipidaemia if LDL-C >4.0mmol/litre (in those with CVD at high riska of subsequent events) or LDL-C >3.5mmol/litre (in those with CVD at very high riskb of subsequent events); for primary heterozygous FH if LDL-C >5.0mmol/litre (in those without CVD) or >3.5mmol/litre (in those with CVD). . adjunctive to statin or other lipid modulating drug. • Ezetimibe . adjunctive to statin - for heterozygous-FH or non-familial hypercholesterolaemia not adequately controlled by maximal dose statin. • Fenofibrate . adjunctive to statin – for hypertriglyceridaemia if triglycerides remain high. • Nicotinic acid group – e.g. nicotinic acid, acipimox . adjunctive to statin – for hypertriglyceridaemia if triglycerides remain high. • Lomitapide . adjunctive to diet and other lipid-regulating drugs - for homozygous FH.

Where statin therapy is contraindicated or not tolerated: • Ezetimibe . for heterozygous FH or non-familial hypercholesterolaemia. • Bile acid sequestrants – e.g. colestyramine, colesevelam, colestipol. • Nicotinic acid group. • Fibrates – e.g. gemfibrozil, bezafibrate, ciprofibrate, fenofibrate. • Omega-3 fatty acid compounds.

Where serum-triglyceride concentration is >10mmol/litre: • Fibrates.

In addition, specialist treatment for homozygous FH, and in exceptional cases, for heterozygous FH: • LDL lowering apheresis may be given in the event of an inadequate response to lipid modifying drug therapy. • Liver transplantation after lipid modifying drug therapy and LDL apheresis.

a High risk of CVD is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; chronic heart disease; ischaemic stroke; or peripheral arterial disease. b Very high risk of CVD is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease).

5 Horizon Scanning Research & Intelligence Centre

EFFICACY and SAFETY

Trial SPIRE-AI, SPIRE-SI, SPIRE-HF, NCT02458287, NCT02135029, NCT01968980, B1481046; bococizumab B1481030; statin B1481021, 2013- vs placebo, both in intolerant; bococizumab 002644-87; bococizumab combination with a statin; vs atorvastatin vs vs placebo, both in phase III. placebo; phase III. combination with a statin; phase III. Sponsor Pfizer. Pfizer. Pfizer. Status Complete but Complete but Complete but unpublished. unpublished. unpublished. Source of Trial registry29, Trial registry30, Trial registry31, information manufacturer. manufacturer. manufacturer. Location USA. USA and Canada. EU (incl. UK), USA, Canada and other countries. Design Randomised, Randomised, Randomised, placebo-controlled. active- and placebo- placebo-controlled. controlled. Participants n=299; aged ≥18 years; n=184; aged ≥18 years; n=370; aged ≥18 years; primary hyperlipidaemia dyslipidaemia; fasting heterozygous familial or mixed dyslipidaemia; LDL-C ≥70 mg/dL fasting hypercholesterolaemia; fasting LDL-C ≥70mg/dL TG ≤400 mg/dL; statin fasting LDL-C ≥70 mg/dL and TG ≤400mg/dL; intolerant. fasting TG ≤400 mg/dL; treated with a statin. high or very high risk of incurring a cardiovascular event; treated with a statin. Schedule Randomised to Randomised to Randomised to bococizumab 75mg or bococizumab 150mg SC bococizumab 150mg SC; 150mg via SC every 2 wks; or or placebo SC; all given autoinjector; or placebo atorvastatin oral once every 2 wks in 75mg or 150mg via SC daily; or bococizumab combination with a statin. autoinjector; all given placebo SC every 2 wks. every 2 wks in combination with a statin. Follow-up Active treatment for 12 Active treatment for 12 Active treatment for 12 wks; 6 week follow-up. wks; 6 week follow-up. wks; 6 week follow-up. Primary LDL-C (150mg dose); Fasting LDL-C. LDL-C. outcomes delivery system success rate. Secondary LDL-C (75mg dose); Fasting TC, LDL-C, Apo Mean TC; ApoB; non- outcomes delivery system success B, non-HDL-C, HDL-C; Lp(a); HDL; rate (75mg) and observer Lipoprotein (a) (Lp(a)), ApoA-I; ApoA-II; very low assessment tool; mean high density lipoprotein density lipoprotein TC; plasma bococizumab (HDL), TG, apolipoprotein (VLDL); TG; TC/HDL and PCSK9 A-I (ApoA-I), and ratio; ApoB/ApoA-I ratio; concentrations; apoliprotein A-II (ApoA- LDL; proportion of apolipoprotein B (ApoB); II); proportion of subjects subjects achieving fasting non-high density achieving fasting LDL-C LDL-C ≤100mg/dL and lipoprotein cholesterolc ≤100mg/dL and ≤70mg/dL; plasma PF- (non-HDL-C). ≤70mg/dL; 04950615. pharmacokinetics; antidrug antibodies

c non-HDL cholesterol level = total cholesterol - HDL cholesterol

6 Horizon Scanning Research & Intelligence Centre

No quality of life (ADA); proportion of No quality of life measurement included in subjects discontinuing measurement included in trial outcomes. treatment due to trial outcomes. musculoskeletal AEs.

No quality of life measurement included in trial outcomes. Key results Not reported. Not reported. Not reported. Press release states ‘Met Press release states ‘Met Press release states ‘Met primary endpoint’. primary endpoint’. primary endpoint’. Adverse Not reported. Not reported. Not reported. effects (AEs) Press release states “safe and well tolerated”. Expected Study completion date Study completion date Study completion date reporting date reported as Feb 2016. reported as Nov 2015. reported as Apr 2016.

Trial SPIRE-LL, SPIRE-HR, SPIRE-LDL, NCT02100514, NCT01968954, NCT01968967, B1481045, 2014-000478- B1481019, 2013-002642- B1481020, 2013-002643- 20; bococizumab vs 37; bococizumab vs 28; bococizumab vs placebo, both in placebo, both in placebo, both in combination with a statin; combination with a statin; combination with a statin; phase III. phase III. phase III. Sponsor Pfizer. Pfizer. Pfizer. Status Complete but Complete but Complete but unpublished. unpublished. unpublished. Source of Trial registry32, Trial registry33, Trial registry34, information manufacturer. manufacturer. manufacturer. Location EU (incl UK), USA, EU (not UK), USA, EU (incl UK), USA, Canada and other Canada and other Canada and other countries. countries. countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled. Participants n=749; aged ≥18 years; n=727; aged ≥18 years; n=2,139; aged ≥18 years; primary hyperlipidaemia high cholesterol; fasting hyperlipidaemia or mixed or mixed dyslipidaemia; LDL-C >70mg/dL and TG dyslipidaemia; fasting fasting LDL-C >100mg/dL ≤400mg/dL; high or very LDL-C >70mg/dL and TG and TG ≤400mg/dL; high high risk of incurring a ≤400mg/dL; high or very or very high risk of cardiovascular event; high risk of incurring a incurring a cardiovascular treated with a statin. cardiovascular event; event; treated with a treated with a statin. statin. Schedule Randomised to Randomised to Randomised to bococizumab 150mg SC; bococizumab 150mg SC; bococizumab 150mg SC; or placebo SC; all given or placebo SC; all given or placebo SC; all given every 2 wks and in every 2 wks and in every 2 wks and in combination with a statin. combination with a statin. combination with a statin. Follow-up Active treatment for 52 Active treatment for 52 Active treatment for 52 wks; 8 wks follow-up. wks; 8 wks follow-up. wks; 8 wks follow-up. Primary Fasting LDL-C. LDL-C. LDL-C. outcome

7 Horizon Scanning Research & Intelligence Centre

Secondary Fasting TC; Apo B; non Mean TC; Apo B; non TC; mean TC; Apo B; outcomes HDL-C; LDL-C; LDL-C HDL-C; LDL; LDL by TG non HDL-C; LDL; LDL-C stratified by TG level (≤ or level; HDL; TG; ApoA-I; stratified by TG level (≤ or ≥200mg/dL); Lp(a); HDL; ApoA-II; Lp(a); proportion ≥200mg/dL); Lp(a); HDL; TG; ApoA-I; ApoA-II; of subjects achieving TG; VLDL; VLDL-C; VLDL-C; proportion of fasting LDL-C ≤100 ApoA-I; ApoA-II; subjects achieving fasting mg/dL and ≤70 mg/dL; proportion of subjects LDL-C ≤100 mg/dL and pharmacokinetics. achieving fasting LDL-C ≤70 mg/dL; ≤100 mg/dL and ≤70 pharmacokinetics. No quality of life mg/dL; pharmacokinetics. measurement included in No quality of life trial outcomes. No quality of life measurement included in measurement included in trial outcomes. trial outcomes. Key results Not reported. Not reported. Not reported. Press release – ‘Met primary endpoint’ AEs Not reported. Not reported. Not reported. Expected Study completion date Study completion date Study completion date reporting date reported as Jul 2016. reported as Apr 2016. reported as Jul 2016.

Trial SPIRE-1, CV OUTCOMES 1, CV SPIRE-2, OUTCOMES 2, OUTCOMES 2, NCT01975376, NCT01975389, B1481038, 2013- B1481022, 2013-002646-36; 002795-41; bococizumab vs placebo, bococizumab vs placebo, both in both in combination with a lipid lowering combination with a lipid lowering therapy; phase III. therapy; phase III. Sponsor Pfizer. Pfizer. Status Ongoing. Ongoing. Source of Trial registry35, manufacturer. Trial registry36, manufacturer. information Location EU (incl UK), USA, Canada and other EU (incl UK), USA, Canada and other countries. countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=17,000 planned; aged ≥18 years; n=11,000 planned; aged ≥18 years; high risk of incurring a CV event; fasting high risk of incurring a CV event; fasting LDL-C ≥70mg/dL or non-HDL-C LDL-C ≥100mg/dL or non-HDL-C ≥100mg/dL; treated with lipid lowering ≥130mg/dL; treated with lipid lowering medication. medication. Schedule Randomised to bococizumab 150mg Randomised to bococizumab 150mg SC; or placebo SC; all given once every SC; or placebo SC; all given once every 2 wks in combination with a lipid 2 wks in combination with a lipid lowering therapy. lowering therapy. Follow-up Active treatment until confirmed CV Active treatment until confirmed CV outcome or for up to 60 months; 40 outcome or for up to 60 months; 40 days follow-up. days follow-up. Primary Time to major CV event (defined as CV Time to major CV event. outcome death, non-fatal myocardial infarction (MI), non-fatal stroke, and hospitalisation for unstable angina needing urgent revascularisation). Secondary Time to first occurrence of a composite Time to first occurrence of a composite outcomes endpoint of CV death, non-fatal MI, endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalisation for non-fatal stroke, and hospitalisation for unstable angina; circulating biomarkers unstable angina; circulating biomarkers (lipids and high-sensitivity C-reactive (lipids and hs-CRP); EQ-5D Health protein [hs-CRP]); EQ-5D Health Questionnaire. Questionnaire.

8 Horizon Scanning Research & Intelligence Centre

Expected Study completion date reported as Jun Study completion date reported as Jul reporting date 2018. 2017.

Trial NCT01592240, B1481015, EudraCT 2012-001226-10; bococizumab vs placebo, both in combination with a statin; phase II. Sponsor Pfizer. Status Published. Source of Publication2, trial registry37, manufacturer. information Location USA. Design Randomised, placebo-controlled. Participants n=356; aged ≥18 years; hypercholesterolaemia; fasting LDL-C ≥80 mg/dL, fasting TG ≤400 mg/dL; treated with statin. Schedule Randomised to bococizumab 50mg, 100mg, 150mg or placebo once every 2 wks; bococizumab 200mg, 300mg or placebo once every 4 wks; all given SC and in combination with a statin. Follow-up Active treatment for 24 wks; 8 wks follow-up. Primary LDL-C. outcome Secondary LDL-C; ADA; pharmacokinetics; LDL-C <100mg/dL, <70 mg/dL, <40mg/L, outcomes <25mg/dL; TC; ApoB; ApoA1; ApoAII; Lp(a); HDL-C; VLDL; TG; non-HDL-C.. No quality of life measurement included in trial outcomes. Key results Outcomes at 12 wks p<0.05 for each compared to placebo

Administration once every 2 wks: for placebo (n=47) vs bococizumab 50mg (n-43- 44),100mg (n=42-44),150mg (n=46), respectively: Mean (SD) change in mg/dl LDL-C, -2.8 (29.2), -35.4 (26.6), -52.3 (31.3), -54.2 (27.0); TC, -5.6 (29.6), -35.8 (24.7),-52.7 (32.7), -58.6 (32.9); non-HDL-C,-5.7 (-2.3), -37.5 (-28.3), -55.0 (-38.5), -59.6 (-44.9) Median (Q1, Q3) change in mg/dl Triglycerides, -18.0 (-52.0, 13.0), -12.0 (-40.0, 9.0), -13.0 (-43.5, 10.0), -21.0 (-43.0, 9.0)

Administration once every 4 wks: change in mg/dl (% change) for placebo (n=46- 47) vs bococizumab 200mg (n=48), 300mg (n=50), respectively: Mean (SD) change in mg/dl LDL-C, -1.3 (37.2), -21.3 (28.0), -38.3 (41.3); TC, -0.4 (40.0), -19.5 (27.4), -37.6 (43.6); HDL-C, -1.0 (7.4), 3.4 (9.2), 3.1 (7.7); non-HDL-C, 0.6 (38.0), -22.9 (29.1), - 40.7 (44.9). Median (Q1, Q3) change in mg/dl Triglycerides, 5.0 (-23.0, 32.0), -9.0 (-35.0, 11.5), -14.5 (-51.0, 13.0). AEs Administration once every 2 wks: for placebo (n=49) vs bococizumab 50mg (n- 50),100mg (n=51),150mg (n=49), respectively: treatment related AEs, 29%, 24%, 31%, 37%; treatment related serious AEs, 0%, 0%, 0%, 2%. Administration once every 4 wks: placebo (n=51) vs bococizumab 200mg (n=50), 300mg (n=51), respectively: treatment related AEs, 16%, 28%, 33%; treatment related serious AEs, 0%, 0%, 0%.

Most frequent AEs (≥10%) included nasopharyngitis, upper respiratory tract infection, diarrhoea, urinary tract infection, bronchitis, arthralgia, injection site erythema, injection site reaction, gastroesophageal reflux disease, cough, and anaemia.

9 Horizon Scanning Research & Intelligence Centre

Trial NCT01342211, NCT01350141, B1481012; NCT02055976, B1481005; bococizumab vs placebo, B1481036; bococizumab vs both in combination with bococizumab vs placebo, both in maximum dose ezetimibe vs placebo, with combination with high atorvastatin or or without atorvastin; dose atorvastatin, rosuvastatin; phase II. phase II. rosuvastatin, or simvastatin; phase II. Sponsor Pfizer. Pfizer. Pfizer. Status Complete but Complete but Complete but unpublished. unpublished. unpublished. Source of Trial registry38, Trial registry39, Trial registry40, information manufacturer. manufacturer. manufacturer. Location USA and Canada. USA and Canada. Japan. Design Randomised, placebo- Randomised, placebo- Randomised, active- and controlled. controlled. placebo-controlled. Participants n=93; aged ≥18 years; n=46; aged ≥18 years; n=218; aged ≥20 years; hypercholesterolaemia; hypercholesterolaemia or hypercholesterolaemia; fasting LDL-C dyslipidaemia; fasting LDL-C not controlled by a ≥100mg/dL, fasting TG LDL-C ≥80mg/dL, fasting stable dose of ≤400 mg/dL; on a stable TG <400 mg/dL; on atorvastatin, or naïve to daily dose of atorvastatin 80mg or lipid lowering therapy. atorvastatin, rosuvastatin 40mg for a rosuvastatin or minimum of 45 days prior simvastatin. to study. Schedule Randomised to Randomised to Atorvastatin-refractory: bococizumab 10mg/mL bococizumab (dose not Randomised to intravenous (IV) infusion stated) as a 60 minute IV bococizumab 50mg, with dose based on infusion; or placebo 60 100mg, or 150mg SC weight; or placebo IV minute IV infusion. every 2 wks; or ezetimibe infusion. 10mg oral once daily; or placebo SC once every 2 wks; all given in combination with atorvastatin (dose not stated) once every 2 wks.

Lipid lowering drug-naïve: Randomised to bococizumab 50mg, 100mg, or 150mg SC; or placebo SC all given once every 2 wks. Follow-up Active treatment for 85 Active treatment for 85 Active treatment for 16 days; follow-up 56 days. days; follow-up 56 days. wks, follow-up 8 wks. Primary LDL-C. LDL-C. LDL-C. outcome Secondary TC; HDL-C; non-HDL-C; TC; HDL-C; non-HDL-C; TC; ApoB; ApoA-I; ApoA- outcomes TG; ApoB; ApoA1; TG; ApoB; ApoA1; II; Lp(a); HDL-C; VLDL-C; Lp(a); treatment treatment emergent AEs TG; Non-HDL-C; TC/HDL- emergent AEs (TEAEs); (TEAEs); clinical C ratio; ApoB/ApoA-I clinical chemistry, chemistry, haematology ratio; proportion of haematology and and coagulation subjects having LDL-C coagulation assessments; vital signs; <100 mg/dL, <70 mg/dL, assessments; vital BP; ECG; ADA. <40 mg/dL, <25 mg/dL, signs; blood pressure <10 mg/dL; ADA. (BP); electrocardiogram No quality of life (ECG); ADA. measurement included in No quality of life

10 Horizon Scanning Research & Intelligence Centre

trial outcomes. measurement included in No quality of life trial outcomes. measurement included in trial outcomes. Key results Not reported. Not reported. Not reported. AEs Not reported. Not reported. Not reported. Expected Study completion date Study completion date Study completion date reporting date reported as Jul 2012. reported as Jun 2012. reported as Jan 2015.

ESTIMATED COST and IMPACT

COST

The cost of bococizumab is not yet known, however the annual costs of other PCSK9 inhibitors are as follows:

Drug Dose Annual cost41 Alirocumab 75mg or 150mg single-use prefilled pen once every £4,383 2 wks. Evolocumab 140mg prefilled pen or syringe once every 2 wks. £4,448.60

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other: reduced LDL-C levels and  No impact identified dyslipidaemia resulting in decreased risk of CVD.

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: need for SC injections. Training  None identified required for patients and staff. Some patients may be unable to self-administer.

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

11 Horizon Scanning Research & Intelligence Centre

REFERENCES

1 Dorey E. Cholesterol-busting PCSK9 drugs. The Pharmaceutical Journal. April 2015. http://www.pharmaceutical-journal.com/news-and-analysis/features/pcsk9-inhibitors-the-next- cholesterol-lowering-blockbusters/20068181.article 2 Ballantyne CM, Neutel J, Cropp A et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose- ranging study in statin-treated subjects with hypercholesterolemia. The American Journal of Cardiology. 2015;115(9):1212-1221. 3 Cohen JC, Boerwinkle E, Mosley TH Jr et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. The New England Journal of Medicine. 2006:354(12): 1264–1272. 4 Mahdy Ali K, Wonnerth A, Huber K et al. Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities. British Journal of Pharmacology. 2012; 167(6):1177–1194. 5 Zimmerman MP. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control? American Health and Drug Benefits. 2015;8(8):436–442. 6 National Institute for Health and Care Excellence. Evolocumab for treating hyperlipidaemia and mixed dyslipidaemia (excluding homozygous familial hypercholesterolaemia). Technology appraisal (TA394). Final Scope. London: NICE; June 2015. 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 NHS Choices. Coronary heart disease. http://www.nhs.uk/conditions/Coronary-heart- disease/Pages/Introduction.aspx Accessed 10 October 2016. 9 Health & Social Care Information Centre. Hospital Episode Statistics for England. Admitted Patient Care, 2014-15. www.hscic.gov.uk 10 Bhatnagar P, Wickramasinghe K, Williams J et al. The epidemiology of cardiovascular disease in the UK 2014. Heart. 2015;101(15):1182-1189. doi: 10.1136/heartjnl-2015-307516. 11 NHS Business Services Authority. Prescription Cost Analysis (PCA) Data: 2016 Data. June 2016. http://www.nhsbsa.nhs.uk/PrescriptionServices/3494.aspx 12 National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal (TA394). Resource impact report. London: NICE; June 2016. 13 National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal (TA394). London: NICE; June 2016. 14 National Institute for Health and Care Excellence. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal (TA393). London: NICE; June 2016. 15 National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. NICE technology appraisal TA385. London: NICE; February 2016. 16 National Institute for Health and Care Excellence. Identification and management of familial hypercholesterolaemia. Clinical Guideline (CG71). London: NICE; August 2008. 17 National Institute for Health and Care Excellence. NICE. Cardiovascular risk assessment and lipid modification. Quality standard (QS100). London: NICE; September 2015. 18 National Institute for Health and Care Excellence. NICE. Familial hypercholesterolaemia. Quality standard (QS41). London: NICE; August 2013. 19 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. 20 Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 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: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology. 2016;68(1):92-125. 21 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.

12 Horizon Scanning Research & Intelligence Centre

22 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. 23 Berglund L, Brunzell JD, Goldberg AC et al. Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism. 2012;97(9):2969-2989. 24 Reiner Ž, Catapano AL, De Backer G et al. 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 25 Joint Formulary Committee. British National Formulary. BNF February 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com 26 NICE Pathways. Managing familial hypercholesterolaemia. June 2016 http://pathways.nice.org.uk/pathways/familial-hypercholesterolaemia#path=view%3A/pathways/ familial-hypercholesterolaemia/managing-familial-hypercholesterolaemia.xml&content=view- node%3Anodes-drug-treatment-in-adults Accessed 3 October 2016. 27 Guidelines in Practice. Controlling triglyceride levels can reduce risk of CVD and pancreatitis https://www.guidelinesinpractice.co.uk/jul_10_merriman_triglycerides_jul10 Accessed 10 October 2016. 28 Patient.co.uk. Lipid-regulating drugs. July 2014 http://www.patient.co.uk/doctor/lipid-regulating- drugs#ref-41 Accessed 10th October 2016. 29 ClinicalTrials.gov. Efficacy, safety, tolerability and actual use study of bococizumab and an autoinjector (pre-filled pen) in subjects with hyperlipidemia or dyslipidemia (SPIRE-AI). https://clinicaltrials.gov/ct2/show/NCT02458287 Accessed 27 September 2016. 30 ClinicalTrials.gov. Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects who are intolerant to statins (SPIRE-SI). https://clinicaltrials.gov/ct2/show/NCT02135029 Accessed 27 September 2016. 31 ClinicalTrials.gov. A 52 week study to assess the use of bococizumab (PF-04950615; RN316) in subjects with heterozygous familial hypercholesterolemia (SPIRE-FH). https://clinicaltrials.gov/ct2/show/NCT01968980 Accessed 27 September 2016. 32 ClinicalTrials.gov. Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with primary hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events (SPIRE-LL). https://clinicaltrials.gov/ct2/show/NCT02100514 Accessed 27 September 2016. 33 ClinicalTrials.gov. Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events (SPIRE-HR). https://clinicaltrials.gov/show/NCT01968954 Accessed 26 September 2016. 34 ClinicalTrials.gov. Randomized Clinical Trial of Bococizumab (PF-04950615; RN316) in Subjects With Hyperlipidemia or Mixed Dyslipidemia at Risk of Cardiovascular Events (SPIRE-LDL) https://clinicaltrials.gov/ct2/show/NCT01968967 Accessed 27 September 2016. 35 ClinicalTrials.gov. The evaluation of bococizumab (PF-04950615;RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-1). https://clinicaltrials.gov/ct2/show/NCT01975376 Accessed 27 September 2016. 36 ClinicalTrials.gov. The evaluation of bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-2). https://clinicaltrials.gov/ct2/show/record/NCT01975389 Accessed 29 September 2016. 37 ClinicalTrials.gov. Monthly and twice monthly subcutaneous dosing of PF-04950615 (RN316) in hypercholesterolemic subjects on a statin. https://clinicaltrials.gov/ct2/show/NCT01592240 Accessed 30 September 2016. 38 ClinicalTrials.gov. A multiple dose study of PF-04950615 (RN316) in subjects on high doses of statins. https://clinicaltrials.gov/ct2/show/NCT01342211 Accessed 30 September 2016. 39 ClinicalTrials.gov. A multiple dose study of PF-04950615 (RN316) in subjects on maximum doses of statins. https://clinicaltrials.gov/ct2/show/NCT01350141 Accessed 30 September 2016. 40 ClinicalTrials.gov. Dose ranging study of bococizumab (PF-04950615; RN316) in hypercholesterolemic Japanese subjects. https://clinicaltrials.gov/ct2/show/study/NCT02055976 Accessed 27 September 2016. 41 National Institute for Health and Care Excellence. Press and Media. NICE draft guidance recommends new drugs for cholesterol disorder. May 2016. https://www.nice.org.uk/news/press- and-media/nice-draft-guidance-recommends-new-drugs-for-cholesterol-disorder Accessed 11 October 2016.