A new anti-cholesterol drug could soon be offered to hundreds of thousands of people in England and Wales on the NHS.NHS England says inclisiran, given as a twice-a-year injection, could save about 30,000 lives within a decade. Despite numerous public health campaigns and an expanding choice of lipid-lowering drugs, deaths from cardiovascular disease (CVD) remain common. According to the British Heart Foundation (BHF), 163,379 people in England, Wales, Scotland and Northern Ireland died from heart and circulatory diseases during 2019. Of these, 62,962 died from coronary heart disease (CHD).1 That’s about one death from CHD every 8.5 minutes.
There are, of course, numerous CVD risk factors: researchers have identified more than 300.2 Some cannot be modified: age, genes, sex and so on.2 Recent research confirmed, for example, that premature menopause is a risk factor for atherosclerotic CVD, such as fatal and non-fatal CHD and stroke. White and black females who experienced the menopause before 40 years of age (9.8% and 17.4% respectively) were 28% and 24% respectively more likely to develop atherosclerotic CVD than those who went through the menopause at the usual age, after allowing for other risk factors.3
Treatment and lifestyle modification reduce the risk from some other factors, for example, smoking, hypertension and abnormal lipid profiles.2 But such modifiable factors are still common. The BHF estimates, for instance, that high levels of low-density lipoprotein cholesterol (LDL-C) accounted for 43.9% of CHD cases and 13.8% of strokes in 2019.1 Indeed, 43% of people aged 16 years and older in England in 2018 had raised cholesterol levels (at least 5 mmol/l).1
Lowering LDL-C by 39 mg/dl (1 mmol/l) reduces the risk of cardiovascular death by 20%, the need for coronary revascularisation by 19% and all-cause death by 10%.4 In practice, however, more than 70% of people with atherosclerotic CVD do not reach LDL-C less than 70 mg/dl (1.8 mmol/l), partly because of poor compliance.4 To help address persistently high lipid levels, NICE approved inclisiran for adults with primary hypercholesterolaemia or mixed dyslipidaemia.
A bowl of petunias
Inclisiran’s roots lie, perhaps surprisingly, in a bowl of petunias with light purple petals. Researchers wanted to create deep purple petals. So, they introduced extra copies of the gene that carries the code for the enzyme that produces the purple pigment. To their surprise, the petals lost their colour.5,6 The observation led, indirectly, to inclisiran.
To understand why means looking at a cell’s genetic machinery. Put rather simply, genes carry instructions to produce a protein. Based on these instructions, the cell makes messenger RNA from genes on the one of the two DNA strands (transcription). Messenger RNA leaves the nucleus carrying the code for the protein from the DNA to the ribosome in the cytoplasm. The ribosome constructs the amino acid chain that forms the backbone of proteins.1
The modified petunia cells expressed the added and normal (wild type) genes. But this meant there was ‘too much’ messenger RNA. So, the cell destroyed the messenger RNA before it reached the ribosome, producing colourless petals.5 The experiment was the first time biologists identified a process called RNA interference (RNAi).
It’s hard to overstate the importance of RNAi to life on Earth. Apart from petunias and other plants, fungi, fruit flies (Drosophila), nematodes (a group of worms) and humans use RNAi to detect and degrade foreign RNA.5-7 So, RNAi protects us from viruses and potentially harmful genes that ‘jump’ from one part of the genome to another (transposons).5,2
As RNAi is a fundamental biological mechanism, it’s a tempting target for pharmacologists investigating new ways to treat several diseases. Treatments based on siRNA are approved for some in-born errors of metabolism, acute hepatic porphyria and hypercholesterolemia.8
LDL carries cholesterol, which the body needs to make, for instance, cell membranes and certain hormones. Receptors on the cell surface recognise and ingest LDL-C. LDL releases its cholesterol payload inside the cell. The LDL receptors then return to the cell membrane. So, in general, the greater the number of receptors the lower the LDL-C level.9
Statins reduce cholesterol production by liver cells (hepatocytes). Cells want a steady supply of cholesterol. So, the number of LDL receptors increases. This clears more LDL-C from the blood and into hepatocytes.9 Another lipid-lowering drug, ezetimibe, potently and selectively inhibits cholesterol absorption from the gut. This reduces the amount of cholesterol delivered to the liver. In response, the liver produces more LDL receptors. So, ezetimibe typically reduces LDL-C levels by more than 20%. Ezetimibe also improves HDL-C and triglyceride levels.10
Many tissues, such as the brain and liver, produce a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 binds to LDL receptors forming a complex that lysosomes inside cells break down.9 The freed LDL receptor re-inserts into the hepatocyte cell membrane.8 In other words, PCSK9 and LDL-C compete for the same receptor. Reduce PCSK9 and there are more receptors available to bind LDL-C.
The therapeutic antibodies alirocumab and evolocumab bind to active PCSK9. This increases the number of LDL receptors.9 So, alirocumab and evolocumab ‘markedly decrease LDL-C levels and significantly reduce cardiovascular risk’.4 But alirocumab and evolocumab need biweekly or monthly subcutaneous injections.4,11 A recent review suggested that this regimen ‘has generated concerns for patient compliance’.4
Healthcare professionals give inclisiran as a twice-yearly subcutaneous injection as monotherapy or to patients taking concurrent statins or other lipid-lowering drugs. In hepatocytes, inclisiran triggers the breakdown of the messenger RNA for PCSK9. So, LDL receptor density rises.8 This reduces circulating LDL.
The ORION programme of clinical studies assessed inclisiran’s safety and efficacy. The ORION-10 and -11 studies, for instance, enrolled patients with atherosclerotic CVD (both studies) or at an equivalent risk (ORION-11 only) with raised LDL-C despite receiving maximum tolerated statin doses. At day 510 (about 17 months), inclisiran reduced LDL-C levels by 52.3% in ORION-10 and by 49.9% in ORION-11. The results were consistent across subgroups, such as intensity of statin treatment, age, BMI, diabetes and renal function.12
Combining results from ORION 9, 10 and 11 and adjusting for placebo, inclisiran reduced LDL-C by 51% at day 510. Inclisiran also reduced PCSK9 levels by between 61% and 70% compared with increases of between 14% and 18% with placebo. Other lipid parameters also improved.8,13 The pooled analysis showed a 2.5% decrease in major cardiovascular events with inclisiran compared with placebo (7.1% and 9.4% respectively).8,13
A recent analysis of ORION 9, 10, and 11 included 3660 people with familial hypercholesterolemia. Because of their genes, people with familial hypercholesterolemia have very high LDL-C levels and are at particularly high risk of CVD. At day 510, inclisiran reduced LDL-C by 50.7%, after correcting for placebo. At this time, 61.5% of patients receiving inclisiran showed at least a 50% reduction in LDL-C from baseline compared with 2.2% of the placebo group.14 While these results are promising, NICE notes that no data directly compare inclisiran with ezetimibe, alirocumab or evolocumab. NICE adds that there is no long-term evidence assessing inclisiran’s effect on cardiovascular outcomes. These studies are, however, underway.
In general, early evidence suggests that inclisiran is well tolerated. The pooled analysis reported that 20% and 23% of inclisiran and placebo users respectively experienced at least one serious treatment-emergent adverse event (TEAE).8,13 Injection-site reactions (ISR) were more common with inclisiran than placebo in ORION-10 (2.6% and 0.9% respectively) and ORION-11(4.7% and 0.5% respectively).12
In the study of people with familial hypercholesterolemia, TEAEs lead to 2.5% and 1.9% of patients discontenting inclisiran and placebo groups respectively. ISRs were also more frequent with inclisiran than placebo: 5.0% and 0.7% respectively. About a quarter (26.4%) of the ISRs were moderate and there were no severe reactions. According to the SmPC, 8.2% and 1.8% of inclisiran and placebo patients respectively reported ISRs in the pivotal studies. Again, while promising, further studies and long-term observations are needed to characterise safety fully.11
NICE approved inclisiran for primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. Patients need to meet a range of criteria, including a history of one of the following:
- Acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)
- Coronary or another arterial revascularisation
- Ischaemic stroke
- Peripheral arterial disease.
Eligible patients also need to have LDL-C concentrations that are persistently at least 2.6 mmol/l, despite maximum tolerated lipid lowering therapy.
Inclisiran costs £1,987.36 a dose. After an initial injection, patients receive inclisiran at 3 months and then every 6 months. Because of the potential economic bill, inclisiran is available to the NHS with a undisclosed discount. One goal of the agreement is to use inclisiran to lower LDL-C by about 50% in approximately 300,000 of the about 3.3 million people with atherosclerotic CVD over three years. Among other initiatives, the agreement aims to develop or improve lipid management pathways, optimise uptake of lipid-lowering therapy and increasing awareness of lipid management in primary care.
Researchers identified the link between dietary fats and CVD in the 1930s.15 Some 90 years later, high LDL-C levels still account for two in every five of cases of CHD and one in every seven strokes.1 Clearly, there’s no simple answer to this long-established problem. After all, it’s encoded in our genes and in our atherogenic diets and lifestyles. The launch of drugs modulating RNA open a new chapter in the fight against atherosclerosis.
Mark Greener is a freelance writer
1. British Heart Foundation. Heart and Circulatory Disease Statistics 2021 Available at https://www.bhf.org.uk/what-we-do/our-research/hea... Accessed September 2021.
2. Gupta S, Gudapati R, Gaurav K, Bhise M.Emerging risk factors for cardiovascular diseases: Indian context. Indian J Endocrinol Metab. 17(5):806-14. https://doi.org.10.4103/2230-8210.117212
3. Freaney PM, Ning H, Carnethon M, et al. Premature menopause and 10-Year risk prediction of atherosclerotic cardiovascular disease. JAMA Cardiology. 2021. https://doi.org.10.1001/jamacardio.2021.3490
4. Hardy J, Niman S, Pereira E, et al. A Critical Review of the Efficacy and Safety of Inclisiran. Am J Cardiovasc Drugs. 2021. https://doi.org.10.1007/s40256-021-00477-7
5. Iwasa J, Marshall W. Karp’s Cell Biology: Global Edition: Wiley. 2018.
6. Baulcombe D. RNA silencing. Current Biology. 2002. 12(3):R82-R4. https://doi.org.10.1016/S0960-9822(02)00665-6
7. Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nature Reviews Genetics. 2009. 10(2):94-108. https://doi.org.10.1038/nrg2504
8. Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong X-b. The growth of siRNA-based therapeutics: Updated clinical studies. Biochemical Pharmacology. 2021. DOI: 10.1016/j.bcp.2021.114432. https://doi.org.https://doi.org/10.1016/j.bcp.2021...
9. Ritter J, Flower R, Henderson G, Loke Y, MacEwan D, Rang H. Rang and Dale’s Pharmacology 9th ed: 2020. Elsevier.
10. Bruckert E, Giral P, Tellier P. Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption. Circulation. 2003. 107(25):3124-8. https://doi.org.10.1161/01.Cir.0000072345.98581.24
11. Nambi V, Agha A. Inclisiran: A game changer in a changing game? J Am Coll Cardiol. 2021. 77(9):1194-6. https://doi.org.10.1016/j.jacc.2021.01.008
12. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020. 382(16):1507-19. https://doi.org.10.1056/NEJMoa1912387
13. Wright R. Inclisiran for Subjects With ASCVD and Elevated Low-Density Lipoprotein Cholesterol - ORION-10 Presented at American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019 Available at https://www.acc.org/latest-in-cardiology/clinical-... Accessed March 2021.Available at https://www.acc.org/latest-in-cardiology/clinical-....
14. Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021. 77(9):1182-93. https://doi.org.10.1016/j.jacc.2020.12.058
15. Willett WC. Dietary fats and coronary heart disease. Journal of Internal Medicine. 2012. 272(1):13-24.