PCSK9 Inhibitors: When Statins Aren't Enough

THERAPY REVIEW ■

PCSK9 inhibitors: when statins aren’t enough

STEVE CHAPLIN

The proprotein convertase subtilisin/kexin type 9 70 5mg 10mg 20mg 40mg 80mg (PCSK9) inhibitors, 60 evolocumab and alirocumab, are novel 50

lipid-lowering agents that 40 can produce a further substantial reduction in 30

LDL cholesterol in patients 20 who cannot reach target

using standard therapy % reduction in LDL cholesterol 10 with statins and 0 ezetimibe. This article Atorvastin Fluvastatin Pravastatin Rosuvastatin Simvastatin examines the current approaches to lipid- Figure 1. Percentage reduction in serum LDL cholesterol according to daily dose of statin in clinical trials8 lowering for primary and cardiovascular risk. Between 1961 and secondary prevention of 2012, the proportion of deaths in the UK cardiovascular disease and caused by cardiovascular disease fell the place of these new from 50% to 28%.4,5 Many factors have agents in therapy. contributed – less smoking, treatment for hypertension and diabetes, antiplatelet therapy, increased physical activity – but, igher blood levels of LDL cholesterol with about 80% of people with athero- Hmean higher rates of coronary heart sclerotic disease now prescribed a sta- disease, for different populations and at tin6 and nearly 68 million prescriptions various concentrations of LDL choles- dispensed in 2016 in England alone,7 terol.1 For example, LDL cholesterol con- these drugs are likely to have played a centrations typically exceed 13mmol/L big part. The statins are more effective in individuals with homozygous familial than any of the cholesterol-lowering drugs hypercholesterolaemia and they can preceding them: intensive statin therapy develop coronary events by their 20s or can halve LDL cholesterol levels by up to 30s.2 In people with heterozygous hyper- 2mmol/L (about half the population have cholesterolaemia, LDL cholesterol can a level of about 4mmol/L).1 Randomised be above 8mmol/L and coronary events controlled trials have shown that each occur in the mid-50s.3 1mmol/L reduction in LDL cholesterol Since the launch of the statins in the with a statin reduces the rate of major mid-1990s, and in particular the introduc- vascular events by about a quarter annu- tion of the government’s National Service ally from the second year of treatment. Framework for Coronary Heart Disease A 2mmol/L reduction in LDL cholesterol in 2000, lipid-lowering has been an inte- for five years in 10,000 patients would gral and very successful component of prevent major vascular events in an esti- pharmacological strategies to reduce mated 1000 patients with pre-existing

prescriber.co.uk Prescriber October 2017 ❚ 21 ■ THERAPY REVIEW l PCSK9 inhibitors

vascular disease (as secondary prevention) and in 500 people at increased risk 0 140mg evolocumab every two weeks as primary prevention.1 420mg evolocumab every month Beyond statins -20 Not all statins were created equal. Pravastatin and fluvastatin offer a rel- -40 atively modest reduction in LDL cholesterol, inferior to that of simvastatin and well below the high-potency ator- -60 vastatin and rosuvastatin (see Figure LDL-C (%CFB) 1).8 For some time, when high-potency -80 statins were available only as branded products and were priced accordingly, management guidance recommended -100 simvastatin – first at a ‘standard’ dos- 8 9 10 11 12 age (20–40mg daily) then at a high dos- Nominal time (weeks) age (80mg daily). Following the expiry of patent protection for Lipitor (atorvastatin) Figure 2. Percentage change from baseline (%CFB) in LDL cholesterol (LDL-C) during 12 in 2011, the tables turned: atorvastatin weeks’ treatment with evolocumab in addition to statin/ezetimibe in patients with primary prescribing has been growing by 20% hyperlipidaemia or mixed dyslipidaemia26 annually and it is now set to surpass simvastatin as the most frequently pre- LDL cholesterol is less than hoped for in clinical practice is a moot point and a scribed statin.9 about 20% of patients.14 different analysis put the risk of adverse So, as resources allowed, the effects of all severities at 18%.15 In the approach to lipid-lowering therapy has Adverse effects and adherence USA, the National Lipid Association become more aggressive. NICE now Some people can’t take statins, and Statin Safety Task Force concluded:16 recommends initiating atorvastatin at a some people won’t. The tolerability of “The clinician should acknowledge that dosage of 80mg daily for secondary pre- statins became a controversial topic statin intolerance is a real phenome- vention of cardiovascular disease, pro- when, in 2014, NICE recommended ator- non, manifesting mostly as an array of vided the risk of drug interactions and vastatin for primary prevention in people muscle-related symptoms that include adverse effects is acceptable, and sub- with a ≥10% 10-year risk of developing aching, stiffness, proximal motor weak- ject to patient preference.10 (The recom- cardiovascular disease.10 The balance ness, fatigue, and back pain. Estimates mended dosage for primary prevention of risks and benefits was undisputed for of the frequency of muscle symptoms is 20mg daily.) The aim is to reduce non- secondary prevention but a review of clin- verifiably related to statin use range HDL cholesterol by 40%. The strategy is ical trial data concluded that it was unfa- from 1% to 10%. Severe myopathy with similar for people with familial hypercho- vourable for primary prevention.15 objective weakness and/or markedly ele- lesterolaemia, with the aim of reducing This raised the profile of the adverse vated muscle enzymes is rare. Reliable LDL cholesterol by 50%.11 effects of statins, prompting a detailed research designs are only beginning to Evidently, even high-intensity statins rebuttal by advocates of wider use.1 This address the actual frequency of statin are not sufficient in some cases. There is response, which for the moment is the muscle intolerance in populations.” variability between patients in the reduc- last and most comprehensive word on the However, investigators from the tion of LDL cholesterol achieved12 and, in subject, concluded that there is convinc- Anglo-Scandinavian Cardiac Outcomes clinical practice, many do not achieve the ing evidence only that statins increase Trial (ASCOT) recently implied that statin desired level.13 Why should statin mono- the risk of myopathy (by five cases per intolerance is less than real: their anal- therapy not deliver an adequate reduction 10,000 patients treated for five years), ysis of adverse events (AE) reported in in LDL cholesterol? Very high cholesterol diabetes (by 50–100 cases) and haemor- the trial showed “an excess rate of mus- levels, as may occur in people with famil- rhagic stroke (by 5–10 cases). The abso- cle-related AE reports only when patients ial hypercholesterolaemia, will still be lute excess of adverse events associated and their doctors were aware that statin high even after a 50% reduction. Adding with statins is about 1%–2%, it added, therapy was being used and not when its ezetimibe, which exerts a complementary and there is “good evidence” that they use was blinded… most AEs associated mechanism of action by inhibiting intesti- do not cause symptomatic effects such with statins are not causally related to nal absorption of cholesterol, increases as muscle pain and weakness (known as use of the drug...”17 the proportion of patients achieving the “statin intolerance”). How well the safety The concept of statin intolerance is target LDL cholesterol reduction but, findings of clinical trials in populations now established in the public conscious- even with this strategy, the reduction in selected for lower morbidity translate to ness and in regulatory decision-making

22 ❚ Prescriber October 2017 prescriber.co.uk ■ THERAPY REVIEW l PCSK9 inhibitors

(it is a licensed indication for some alter- The enzyme PCSK9 binds to LDL a statin; or alone or in combination with native lipid-lowering agents). Adverse receptors and promotes their degrada- other lipid-lowering therapies in patients effects are cited as a major factor behind tion by hepatocytes, which has the effect who are statin intolerant, or for whom a low adherence to statin therapy,18 esti- of raising LDL cholesterol. Gene muta- statin is contraindicated. Evolocumab is mates of which range from 40% to 80% tions that increase PCSK9 function occur also licensed for use, in combination with of days covered by prescribed medica- in some individuals with familial hyper- other lipid-lowering agents, in adults and tion.19-22 Observational studies consist- cholesterolaemia; conversely, mutations young people over 12 years with homozy- ently report increased cardiovascular that decrease PCSK9 function are associ- gous familial hypercholesterolaemia. disease and mortality associated with ated with low levels of LDL cholesterol.25 low adherence23 showing that, whatever PCSK9 inhibitors prevent the formation Dosage and administration the rights and wrongs regarding the evi- of the enzyme-receptor complex, preserv- Both PCSK9 inhibitors are administered dence, the consequences are real. ing LDL receptors and thereby increasing by subcutaneous injection but the dose hepatic LDL uptake from the circulation. regimens for primary hypercholestero- PCSK9 inhibitors – a new kind They also increase levels of favourable laemia are slightly different. The initial of lipid-lowering agent HDL cholesterol in the circulation. dosage of evolocumab is 140mg every The lipid-lowering effect of statins is Two PCSK9 inhibitors were introduced two weeks or 420mg monthly (the dos- mediated by an increase in the expres- in the UK in 2016 as adjuncts in lipid- ages are clinically equivalent, see Figure sion of the LDL receptor in the liver lowering therapy. Evolocumab (Repatha) 2). Alirocumab is usually initiated at a (following inhibition of cholesterol synthe- and alirocumab (Praluent) are mono- dosage of 75mg every two weeks but a sis), thus enhancing the uptake of LDL clonal antibodies that bind to PCSK9, higher dosage of 150mg every two weeks cholesterol from the circulation and its producing a profound reduction in circu- (or 300mg every month) can be used if a subsequent catabolism. This is, in fact, lating LDL cholesterol (see Figure 2).26 greater initial reduction in LDL cholesterol the common final pathway by which other Both are licensed for use in adults with is required. For patients with homozygous lipid-lowering agents act, and the reduc- primary hypercholesterolaemia (heterozy- familial hypercholesterolaemia, the initial tion in cardiovascular risk associated gous familial and non-familial) or mixed dosage of evolocumab is 420mg monthly, with different agents correlates with the dyslipidaemia as an adjunct to diet. increased after 12 weeks if necessary to extent to which they consequently reduce They can be used in combination with a 420mg every two weeks. LDL cholesterol.24 The proprotein con- statin (alone or with other lipid-lowering Both PCSK9 inhibitors have been vertase subtilisin/kexin type 9 (PCSK9) agents) in patients who cannot achieve marketed in prefilled single-use pens. inhibitors reach this common point via a the required reduction in LDL choles- A 300mg dose of alirocumab requires new mechanism. terol at the maximum tolerated dose of the use of two pens; the evolocumab SureClick pen contains 140mg and three Without CVD With CVD pens are needed for the 420mg dose (or High risk of CVD1 Very high risk of a 420mg cartridge is also available). CVD2 No dose adjustment is recommended for older people (though experience in Primary non-familial Not recommended Recommended Recommended the over-75s is limited) or in patients hypercholesterolaemia or at any LDL-C only if LDL-C only if LDL-C with mild or moderate renal impairment mixed dyslipidaemia concentration concentration is concentration is or mild hepatic impairment. Evolocumab persistently above persistently above should be monitored closely in patients 4.0mmol/L 3.5mmol/L with moderate hepatic impairment because total exposure is lower and the Primary Recommended Recommended only if LDL-C effect on LDL cholesterol levels may be heterozygous familial only if LDL-C concentration is persistently above reduced. There is little experience with hypercholesterolaemia concentration is 3.5mmol/L either drug in patients with severe renal persistently above or hepatic impairment. 5.0mmol/L Clinical use 1 High risk of CVD is defined as a history of any of the following: acute coronary syndrome NICE has recommended evolocumab and (such as myocardial infarction or unstable angina needing hospitalisation); coronary or other alirocumab as options for treating primary arterial revascularisation procedures; coronary heart disease; ischaemic stroke; peripheral hypercholesterolaemia or mixed dyslipid arterial disease aemia when LDL cholesterol is persis- 2 Very high risk of CVD is defined as recurrent cardiovascular events or cardiovascular events in more than one vascular bed (that is, polyvascular disease) tently above specified thresholds (see Abbreviations: CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol Table 1) after maximal tolerated lipid- lowering therapy.27,28 This is conditional Table 1. NICE LDL cholesterol thresholds for treatment with the PCSK9 inhibitors evolocumab and alirocumab27,28 on price discounting via confidential

24 ❚ Prescriber October 2017 prescriber.co.uk PCSK9 inhibitors l THERAPY REVIEW ■

patient access agreements. The recom- mendation for evolocumab is limited to 0 the fortnightly 140mg dose. Evolocumab -10 has not been appraised for homozygous familial hypercholesterolaemia. -20 NICE based its conclusions on clinical trials showing that these agents sig- -30 nificantly reduced LDL cholesterol levels -40 when added to statin monotherapy (by 60%–70%) or a statin/ezetimibe combi- -50 nation (by 30%–40%) in studies lasting six months to one year. These effects -60 are sustained during long-term use for 29 -70

up to three years (see Figure 3). In one Mean (SE) % change from baseline recently published study in patients with -80 atherosclerotic heart disease and LDL 0 12 24 36 52 64 76 88 100 112 124 136 148 cholesterol levels ≥1.8mmol/L, evolo- week cumab lowered LDL cholesterol by 59% to a median of 0.78mmol/L and reduced Figure 3. Mean % change in LDL cholesterol from baseline, during long-term treatment the risk of cardiovascular events (cardio with alirocumab when added to statin±ezetimibe therapy in patients with heterozygous vascular death, myocardial infarction, familial hypercholesterolaemia29 stroke, hospitalisation for unstable is about £4400. Against this, there are trials was 1.9% with evolocumab (vs 2.3% angina or coronary revascularisation) by likely to be savings by reducing the num- with controls); in the case of alirocumab, 15% after two years.30 ber of patients with severe hypercholes- it was 5.3% vs 5.1% with placebo and In clinical practice, both PCSK9 inhib- terolaemia and coronary heart disease 8.8% vs 9.7% with ezetimibe.26,34 itors are likely to be prescribed as add-on who need lipoprotein apheresis. NICE did therapy to statins and ezetimibe for peo- not consider monotherapy with a PCSK9 Summary ple who are at a high risk of cardiovas- inhibitor and it is likely the expense com- Reducing LDL cholesterol is crucial cular disease. NICE concluded that the pared with a statin/ezetimibe will make to lowering the risk of cardiovascular large reduction in LDL cholesterol would this a rare choice for prescribers. events and for most people, lifestyle probably offer a substantial benefit but change, statins and ezetimibe are effec- it acknowledged uncertainty about the Adverse effects tive. However, about one in 12 patients long-term effectiveness of PCSK9 inhib- A meta-analysis of 25 trials of evolo- with non-familial hypercholesterolaemia, itors because of the theoretical risk that cumab or alirocumab involving a total and one in seven of those with familial neutralising antibodies may develop. In of 12,200 patients found that the over- hypercholesterolaemia, do not reach the clinical trials, neutralising antibodies all rate of treatment-emergent adverse desired reduction in LDL cholesterol with were identified in 0.1%–0.4% of patients events was similar to that reported with this approach. NICE has recommended a but this did not reduce the efficacy of ezetimibe and placebo over 12–52 weeks new treatment step with the addition of treatment. (50%–70%) and rates of specific adverse evolocumab or alirocumab, both of which In a resource impact report, NICE events were not statistically significantly offer a further substantial reduction in estimates (based on data provided by different.32 The most frequently reported LDL cholesterol and, on the basis of cur- alirocumab manufacturer Sanofi) that events were musculoskeletal disorders rent evidence, good tolerability. The addi- 8% of people with non-familial hypercho- (10%–17% of patients), including back tional cost to the NHS is being withheld lesterolaemia and 14% of those with the pain, arthralgia, muscle spasms and but, on the basis of the standard price of familial form do not have adequate con- myalgia, nasopharyngitis and gastrointes- each agent, it is likely to be high. trol of LDL cholesterol with statins and tinal disorders. Injection-site reactions ezetimibe and are thus eligible for treat- were reported by about 2% of patients References ment with alirocumab or evolocumab.31 using evolocumab (vs 2% with placebo) 1. Collins R, et al. Interpretation of the evi- The number of people likely to be treated and about 6% with alirocumab (vs 4% dence for the efficacy and safety of statin ther- with alirocumab or evolocumab in the with placebo). Prescribing information apy. Lancet 2016;388:2532–61. current financial year is 4500 and this for alirocumab states that most injection 2. Cuchel M, et al. Homozygous familial hypercholesterolaemia: new insights and is estimated to rise to almost 14,000 by site reactions were transient and of mild guidance for clinicians to improve detec- 2020/21. NICE does not estimate the intensity, resulting in discontinuation in tion and clinical management. A position 33 cost impact because it won’t reveal the 0.2% of patients (vs 0.3% in controls). paper from the Consensus Panel on Familial confidential discount but the basic NHS Overall, the frequency of discontin- Hypercholesterolaemia of the European cost of a year’s treatment with each agent uation due to adverse events in clinical Atherosclerosis Society. Eur Heart J prescriber.co.uk Prescriber October 2017 ❚ 25 ■ THERAPY REVIEW l PCSK9 inhibitors

2014;35:2146–57. tin, or rosuvastatin compared with titrating europa.eu/docs/en_GB/document_library/ 3. Nordestgaard BG, et al. Familial hyper- statin monotherapy. Vasc Health Risk Manag EPAR_-_Public_assessment_report/ cholesterolaemia is underdiagnosed and 2013;9:719–27. human/003766/WC500191400.pdf undertreated in the general population: 15. Abramson JD, et al. Should people at low 27. National Institute for Health and Care guidance for clinicians to prevent coronary risk of cardiovascular disease take a statin? Excellence. Evolocumab for treating primary heart disease: consensus statement of the BMJ 2013;347:f6123. hypercholesterolaemia and mixed dyslipi- European Atherosclerosis Society. Eur Heart J 16. Guyton JR, et al. An assessment by the daemia. TA394. June 2016. Available from: 2013;34:3478–90a. Statin Intolerance Panel: 2014 update. J Clin https://www.nice.org.uk/guidance/ta394. 4. British Heart Foundation. Trends in coronary Lipidol 2014;8 (3 Suppl):S72–81. NICE guidance is prepared for the National heart disease, 1961–2011. February 2011. 17. Gupta A, et al. Adverse events asso- Health Service in England, and is subject to Available from: www.bhf.org.uk/-/media/ ciated with unblinded, but not with blinded, regular review and may be updated or with- files/research/heart-statistics/bhf-trends- statin therapy in the Anglo-Scandinavian drawn. NICE has not checked the use of its in-coronary-heart-disease01.pdf Cardiac Outcomes Trial—Lipid-Lowering Arm content in this article to confirm that it accu- 5. British Heart Foundation. Cardiovascular (ASCOT-LLA): a randomised double-blind pla- rately reflects the NICE publication from which disease statistics 2014. December 2014. cebo-controlled trial and its non-randomised it is taken. Available from: www.bhf.org.uk/-/media/ non-blind extension phase. Lancet 2017. 28. National Institute for Health and Care files/publications/research/bhf_cvd-statis- DOI: http://dx.doi.org/10.1016/S0140- Excellence. Alirocumab for treating primary tics-2014_web_2.pdf 6736(17)31075-9 hypercholesterolaemia and mixed dyslipi- 6. Steen DL, et al. Retrospective exami- 18. Cohen JD, et al. Understanding statin daemia. TA393. June 2016. Available from: nation of lipid-lowering treatment patterns use in America and gaps in patient education https://www.nice.org.uk/guidance/ta393. in a real-world high-risk cohort in the UK in (USAGE): an internet-based survey of 10,138 NICE guidance is prepared for the National 2014: comparison with the National Institute current and former statin users. J Clin Lipidol Health Service in England, and is subject to reg- for Health and Care Excellence (NICE) 2012;6:208–15. ular review and may be updated or withdrawn. 2014 lipid modification guidelines. BMJ 19. Benner JS, et al. Long-term persistence in NICE has not checked the use of its content in Open 2017;7(2):e013255. DOI: 10.1136/ use of statin therapy in elderly patients. JAMA this article to confirm that it accurately reflects bmjopen-2016-013255. 2002;288:455–61. the NICE publication from which it is taken. 7. NHS Digital. Prescription cost analysis, 20. Virani SS, et al. Is high-intensity statin 29. Dufour R, et al. Open-label therapy with England – 2016. March 2017. Available from: therapy associated with lower statin adher- alirocumab in patients with heterozygous http://www.content.digital.nhs.uk/catalogue/ ence compared with low- to moderate-inten- familial hypercholesterolemia: Results PUB23631 sity statin therapy? Implications of the 2013 from three years of treatment. Int J Cardiol 8. Law MR, et al. Quantifying effect of stat- American College of Cardiology/American 2017;228:754–60. ins on low density lipoprotein cholesterol, Heart Association Cholesterol Management 30. Sbatine MS, et al. Evolocumab and clini- ischaemic heart disease, and stroke: sys- Guidelines. Clin Cardiol 2014;37:653–9. cal outcomes in patients with cardiovascular tematic review and meta-analysis. BMJ 21. Lin I, et al. Patterns of statin use in a disease. N Engl J Med 2017;376:1713–22. 2003;326:1423–7. real-world population of patients at high car- 31. National Institute for Health and 9. NHS Digital. Prescriptions dispensed in the diovascular risk. J Manag Care Spec Pharm Care Excellence. Resource impact report: community, statistics for England 2005–2015. 2016;22:685–98. Alirocumab (TA393) and evolocumab (TA394) July 2016. Available from: http://content. 22. Bellows BK, et al. Antihyperlipidemic for treating primary hypercholesterolaemia and digital.nhs.uk/catalogue/PUB20664 medication treatment patterns and statin mixed dyslipidaemia. June 2016. Available 10. National Institute for Health and Care adherence among patients with ASCVD in from: https://www.nice.org.uk/guidance/ Excellence. Cardiovascular disease: risk a managed care plan after release of the ta394/resources/resource-impact-report- assessment and reduction, including lipid 2013 acc/aha guideline on the treatment of pdf-2543362381 modification. CG181. July 2014 (updated blood cholesterol. J Manag Care Spec Pharm 32. Zhang X-l, et al. Safety and efficacy of September 2016). Available from: https:// 2016;22:892–900. anti-PCSK9 antibodies: a meta-analysis of www.nice.org.uk/guidance/cg181 23. De Vera MA, et al. Impact of statin adher- 25 randomized, controlled trials. BMC Med 11. National Institute for Health and Care ence on cardiovascular disease and mortal- 2015;13:123. DOI 10.1186/s12916-015- Excellence. Familial hypercholesterolaemia: ity outcomes: a systematic review. Br J Clin 0358-8. identification and management. CG71. August Pharmacol 2014;78:684–98. 33. Sanofi. Praluent Summary of Product 2008 (updated July 2016). Available from: 24. Lloyd-Jones DM, et al. 2016 ACC Expert Characteristics. December 2016. https://www.nice.org.uk/guidance/cg71 Consensus Decision Pathway on the Role 34. European Medicines Agency. Alirocumab 12. Adams SP, et al. Atorvastatin for lower- of Non-Statin Therapies for LDL-Cholesterol (Praluent). Public Assessment Report. July ing lipids. Cochrane Database of Systematic Lowering in the Management of Atherosclerotic 2015. Available from: http://www.ema. Reviews 2015;3:CD008226. DOI: Cardiovascular Disease Risk: A Report of the europa.eu/docs/en_GB/document_library/ 10.1002/14651858.CD008226.pub3. American College of Cardiology Task Force on EPAR_-_Public_assessment_report/ 13. Marrett E, et al. Limitations of real-world Clinical Expert Consensus Documents. J Am human/003882/WC500194524.pdf treatment with atorvastatin monotherapy for Coll Cardiol 2016;68:92–125. lowering LDL-C in high-risk cardiovascular 25. Latimer J, et al. PCSK9 inhibitors in patients in the US. Vasc Health Risk Manag the prevention of cardiovascular disease. J Declaration of interests 2014;10:237–46. Thromb Thrombolysis 2016;42:405–19. None to declare. 14. Foody JM, et al. Changes in LDL-C levels 26. European Medicines Agency. Evolocumab and goal attainment associated with addi- (Repatha) Public Assessment Report. May Steve Chaplin is a medical writer tion of ezetimibe to simvastatin, atorvasta- 2015. Available from: http://www.ema. specialising in therapeutics

26 ❚ Prescriber October 2017 prescriber.co.uk