Inclisiran: A Novel Therapeutic for Long-Term Lowering of LDL Cholesterol?

By Connor Emdin
May 18, 2017

Elevated low-density lipoprotein cholesterol (LDL cholesterol) is a leading cause of coronary heart disease and death worldwide.1 When LDL cholesterol particles become oxidized, they can invade the endothelium of blood vessels and attract macrophages, forming atherosclerotic plaques. Over a lifetime, high levels of LDL cholesterol can lead to the formation of numerous unstable atherosclerotic plaques, potentially leading to myocardial infarction, stroke, and death from cardiovascular disease (CVD).2

Statins are the current mainstay of therapy for LDL cholesterol lowering in CVD. However, many high risk individuals struggle to maintain adherence to statin therapy, even after suffering a myocardial infarction or stroke.3

A novel approach to LDL lowering is through inhibition of proprotein convertase subtilisin–kexin type 9 (PCSK9). Recently identified, PCSK9 is a protease that promotes degradation of the low density lipoprotein (LDL) receptor.4 Highly expressed in the liver, the LDL receptor mediates uptake of LDL cholesterol particles from the blood. Higher levels of LDL receptor lead to greater uptake and lower blood LDL cholesterol levels. In promoting degradation of the LDL receptor, PCSK9 acts to increase blood LDL cholesterol levels.4 Individuals with genetic mutations that damage PCSK9 have naturally extremely low levels of LDL and are protected from cardiovascular disease.5 Several large, recently published studies have shown efficacy of monoclonal antibodies targeting PSCK9 in lowering LDL and reducing risk of CVD.6

[Keep up with current trends in cardiology from Harvard Medical School.]

Results from a small phase-2 trial (ORION-1) published in the New England Journal of Medicine suggests a potential novel therapy, inclisiran, to lower LDL cholesterol.7 Unlike current therapies which are antibodies against PCSK9, inclisiran is a small interfering RNA (siRNA) that inhibits production of PSCK9 protein; siRNA are double-stranded RNA molecules that contain an RNA sequence complementary to the messenger RNA sequence of the protein of interest (in this case PCSK9).8 When introduced into a cell, the siRNA (incslisiran) binds to the PCSK9 messenger RNA and causes it to be degraded, preventing production of the PCSK9 protein. Thus, in contrast to normal drugs that bind to the target protein and disrupt its function, siRNA prevent the target protein from being produced at all.8 A single dosage of inclisiran can prevent production of PCSK9 over extremely long periods (up to 210 days).7

In ORION-1, 501 individuals were randomly assigned to one of eight different arms: two placebo arms and six intervention arms of escalating doses and varied dosing interval.7 Levels of PCSK9, cholesterol, and lipoproteins in the blood were then measured at 180 days. At time of enrollment in the trial, all individuals were receiving maximum dose statin therapy and were at high cardiovascular risk (with either a history of CVD or greater than 20% risk of a cardiovascular event over ten years).

Both the single-dose and two-dose regimen of inclisiran significantly lowered LDL and total cholesterol levels (Table). At 180 days, a single dose of inclisiran 500 mg lowered blood PCSK9 levels by 59.3%, LDL cholesterol levels by 41.9%, and total cholesterol levels by 26.6% (p<0.001). This dose also significantly lowered triglyceride levels and increased HDL cholesterol levels by 8.8% (p<0.05). Inclisiran was well tolerated with similar numbers and proportions of adverse events reported in the inclisiran and placebo arms. Injection site reactions occurred in 4% of individuals.7

Table. Effect of inclsiran on cholesterol measurements at 180 days

Single-Dose Regimen Two-Dose Regimen
Placebo 200 mg Inclisiran 500 mg Inclisiran Placebo 200 mg Inclisiran 300 mg Inclisiran
PCSK9 Levels 2.2% -56.0%* -59.3%* -1.2% -66.2%* -69.1%*
LDL Cholesterol 2.1% -27.9%* -41.9%* 1.8% -44.9%* -52.6%*
Total Cholesterol 1.8% -17.6* -26.6* 0.7% -26.8%* -33.2%*

*Significant at p<0.001 when compared to placebo.

These results raise the intriguing possibility that inclisiran may be a therapy which can reduce LDL cholesterol over the long term without the low adherence observed with statin therapy in many patients. One could imagine patients receiving an injection of inclisiran along with their yearly flu shot and having long-term CVD prevention. However, larger trials will be required to demonstrate the cardiovascular effectiveness of inclisirian before it can be approved for wide use.


  1. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224-2260. doi:10.1016/S0140-6736(12)61766-8.
  2. Libby P, Geng YJ, Aikawa M, et al. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996;7(5):330-335.
  3. Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long-term statin therapy? Curr Atheroscler Rep. 2013;15(1):291. doi:10.1007/s11883-012-0291-7.
  4. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11(10):563-575. doi:10.1038/nrcardio.2014.84.
  5. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013.
  6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. March 2017:NEJMoa1615664. doi:10.1056/NEJMoa1615664.
  7. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430-1440. doi:10.1056/NEJMoa1615758.
  8. Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet. 2015;16(9):543-552. doi:10.1038/nrg3978.

Connor Emdin_headshot_150x127Connor Emdin is a post-doctoral research fellow in Sek Kathiresan’s lab at the Broad, specializing in the genetics of cardiovascular disease. He completed his doctorate in cardiovascular epidemiology at the University of Oxford from 2009-2013.


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