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Increasing the use of PCSK9 inhibitors in patients with uncontrolled LDL-C supports national efforts to address one of the UK’s greatest health burdens.

The sombre facts and figures regarding cardiovascular disease (CVD) across the UK are hard to ignore:

Every three minutes someone will die from CVD

Every day 435 people will lose their lives to CVD

Every year CVD has associated annual healthcare and economic costs of around £9 and £19 billion respectively

The impact that CVD, the second-largest cause of death in the UK, has on patients, society and our economy is sobering indeed.

Although the widespread use of lipid-lowering therapies (including statins) has helped in the fight to reduce the risks associated with high cholesterol, over 60% of high-risk patients in the UK do not reach target low-density lipoprotein (LDL-C) levels with this treatment. Looking at the continued societal and economic effect that CVD has across the country; the fight against high cholesterol is still an important one. The job is not yet done.

Currently statins are the most common lipid-lowering therapy prescribed for the treatment of uncontrolled high levels of circulating low-density lipoprotein cholesterol (LDL-C). With some statins becoming generic, this has helped increase their use.

Statins have decades of clinical data to show that the class can lower LDL-C levels and in turn the risk of CVD, but statins don’t work for everyone; either because of tolerability issues or because they provide insufficient lipid lowering efficacy to reach guideline-based targets.

In particular, patients with the inherited condition familial hypercholesterolaemia (FH), and patients diagnosed with clinical atherosclerotic cardiovascular disease, may still fail to reach their LDL-C targets when treated with statins. A refreshed focus on individual patients and tailored treatment is one of the possible solutions to this problem.

PRALUENT▼ (alirocumab), a proprotein convertase subtilisin-kexin (PCSK9) inhibitor, lowers LDL-C by binding to and inhibiting the hepatic protease PCSK9 that promotes degradation of LDL receptors. It is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:

• In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,

Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

The effect of alirocumab on cardiovascular morbidity and mortality has not yet been determined.

The ODYSSEY LONG TERM trial measured the percentage change in calculated LDL cholesterol level from baseline to week 24 in 2,341 patients at high risk for CV events. The patients had LDL cholesterol levels of 70mg/ dL (3.9mmol/L) or more and were receiving treatment with statins at the maximum tolerated dose, with / without other lipid-lowering therapies.

Patients given bi-weekly injections of 150 mg alirocumab (usual starting dose is 75 mg) showed a 61% reduction (1.25 mmol/litre versus 3.08 mmol/litre) (P<0.001) in LDL-C from baseline compared to a 0.8% increase (3.6% absolute increase) in patients receiving placebo after 24 weeks of treatment. A goal of less than 70mg/dL (3.9mmol/L) LDL-C after 24 weeks was met in 79.3% of patients receiving alirocumab, compared to 8% of patients receiving placebo.

PCSK9 inhibitors have acceptable efficacy and tolerable safety profiles, based on initial evidence. The most common (≥1/100 to <1/10) adverse events associated with alirocumab are local injection site reactions, upper respiratory tract signs and symptoms and pruritus.

Despite figures included in the NICE impact report regarding the use of PCSK9 inhibitors, the uptake is still below the institution’s original estimate of 4,500 people in England during 2017/18.

Demonstrable efficacy in reducing LDL-C in patients uncontrolled on statins, coupled with NICE recommendation, means that the uptake of PCSK9 inhibitors is likely to increase over the next five years. By recognising the potential value of PCSK9 inhibitors, we can help patients across the UK achieve their target LDL-C levels.

Prescribing Information: Praluent® ▼ (alirocumab)

Please refer to the Praluent Summary of Product Characteristics (SPC) for full prescribing details.

Presentations: Praluent 75mg or 150mg solution for injection in pre-filled pen contains 75mg alirocumab in 1ml solution or 150mg alirocumab in 1ml solution, respectively. Indications: Praluent is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non- familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. The effect of Praluent on cardiovascular morbidity and mortality has not yet been determined.

Dosage and Administration: Secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephrotic syndrome, hypothyroidism) should be excluded prior to initiation of Praluent. Praluent is injected as a subcutaneous injection into the thigh, abdomen or upper arm. The usual starting dose is 75mg, once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150mg once every 2 weeks or 300mg once every 4 weeks. A dose of 300mg should be given as two 150mg injections consecutively at two different injection sites. If a dose is missed, the patient should administer the injection as soon as possible and thereafter resume treatment on the original schedule. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration). If additional LDL-C reduction is needed in patients treated with 75mg once every 2 weeks or 300mg once every 4 weeks (monthly), the dosage may be adjusted to the maximum dosage of 150mg once every 2 weeks. Praluent should not be injected into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections. Praluent must not be co- administered with other injectable medicinal products at the same injection site. The patient may either self-inject Praluent, or a caregiver may administer Praluent, after guidance has been provided by a healthcare professional on proper subcutaneous injection technique. Praluent pre-filled pens should be allowed to warm to room temperature for 30 to 40 minutes prior to use.

Special populations: Elderly: No dose adjustment needed. Children and adolescents (<18 years): No data are available. Hepatic impairment: No dose adjustment is needed for patients with mild or moderate hepatic impairment. Praluent should be used with caution in patients with severe hepatic impairment (Child-Pugh C). Renal impairment: No dose adjustment is needed for patients with mild or moderate renal impairment. Praluent should be used with caution in patients with severe renal impairment.

Contraindications: Hypersensitivity to the active substance or to any of the excipients.

Precautions and Warnings: General allergic reactions, including pruritus, as well as rare and sometimes serious allergic reactions such as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in clinical studies. If signs or symptoms of serious allergic reactions occur, treatment with Praluent must be discontinued and appropriate symptomatic treatment initiated. Interactions: no pharmacokinetic effects of alirocumab on other medicinal products and no effect on cytochrome P450 enzymes are anticipated. Statins and other lipid lowering therapies can increase clearance of alirocumab; however LDL-C reduction was maintained on two weekly alirocumab administrations. Pregnancy, Lactation and Fertility: There are no data from the use of Praluent in pregnant women and is expected to cross the placental barrier, thus use of Praluent is not recommended during pregnancy unless the clinical condition of the patient warrants it. Praluent is not recommended in breast-feeding women when colostrum is produced; for the rest of the breast-feeding period, a decision should be made whether to discontinue nursing or to discontinue Praluent. There are no data on adverse effects on fertility in humans.

Adverse Reactions: Common (≥ 1/100 to < 1/10): local injection site reactions (including erythema/redness, itching, swelling, pain/tenderness), upper respiratory tract signs and symptoms (oropharyngeal pain, rhinorrhea, sneezing), and pruritus. Rare (≥1/10,000 to <1/1,000): Hypersensitivity, hypersensitivity vasculitis, urticaria and eczema nummular. Not known: Flu-like illness. Please refer to the SPC for full details on adverse reactions. Special precautions for storage: Store in a refrigerator (2°C to 8°C). Keep the pen in the outer carton in order to protect from light. Legal Category: POM. List price: 1x 75mg or 150mg pre- filled pen £168. 2x 75mg or 150mg pre-filled: £336. Marketing Authorisation (MA) Numbers: 1x 75mg pre-filled pen: EU/1/15/1031/001, 2x 75mg pre-filled pens: EU/1/15/1031/002, 1x 150mg pre- filled pen: EU/1/15/1031/007, 2x 150mg pre-filled pens: EU/1/15/1031/008. MA Holder: Sanofi-Aventis groupe, 54 rue La Boétie, F - 75008 Paris, France. Further information is available from: Medical Information Department, Sanofi, One Onslow Street, Guildford, GU1 4YS, Tel; 0845 372 7101. Date of Preparation: July 2018

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard

Adverse events should also be reported to Sanofi Tel: 0800 0902314.

Alternatively, send via email to UK-drugsafety@sanofi.com