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This study is testing a medicine called inclisiran which helps to lower bad (LDL) cholesterol in the blood. Doctors hope that giving this injection every 6 months for several years will lower the number of heart attacks and strokes, but they do not know this for certain. Inclisiran is given as an injection into the tissue just under the skin every 6 months, with an extra injection 3 months after starting the treatment. Inclisiran is an investigational drug. This means that it is currently not approved by the Medicines and Healthcare Products Regulatory Agency for use in the UK.

How does inclisiran lower bad cholesterol levels?

Inclisiran blocks the production of a protein called PCSK91 in the liver. PCSK9 has an important role in the control of blood cholesterol levels. Higher levels of PCSK9 lead to higher levels of bad (LDL) cholesterol in the blood. This is because of how PCSK9 effects LDL receptors. LDL receptors on the surface of the liver cells remove bad (LDL) cholesterol from the blood stream. PCSK9 attaches to the LDL receptor which causes the liver cell to destroy the LDL receptor instead of reusing it. If PCSK9 levels in the blood are high, there are fewer LDL receptors on the liver cells and more bad (LDL) cholesterol in the blood stream.  

How does inclisiran block the production of PCSK9?

Inclisiran is a small interfering RNA which blocks the production of the protein PCSK9. The instructions for how to make every protein are held in the DNA inside the cell. To make a protein, first, the cell makes a copy of the DNA. The copy of the DNA is called messenger RNA. The messenger RNA is then converted into a sequence of amino acids, the building blocks that make up proteins. Small inferring RNAs prevent the messenger RNA from being converted into the protein. This video from Alnylam - a pharmaceutical company that specialises in small interfering RNA medicines - helps to explain how this process works. Alnylam is not involved in the ORION-4 study or the development of inclisiran.

PCSK9 — proprotein convertase subtilisin/kexin type 9