INCLISIRAN

Day 1: Approved in Europe in 2020, the novel lipid lowering drug #inclisiran acts on PCSK9, a known lipid pathway target; this gene therapy ‘switches off’ the enzyme (mimicking the natural mechanism of protein synthesis inhibition) which favours low density lipoprotein cholesterol (LDL-C) receptor up-regulation, thus lowering plasma LDL

Day 2: #inclisiran is for use in adults with primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet. NICE approval is for sub-optimal LDL-C levels after statin use (can stay on the statins) or when statins can't be used. Also if there is a history of cardiovascular events e.g ACS. #inclisiran is given s.c 284 mg as a single injection (usually abdo) on day 1, day 90 and then every 6 months

Day 3: Kinetics. Moderate Vd & protein binding. #inclisiran localises in the liver re technology targeting a hepatocyte receptor for uptake. It is metabolised by non-specific nucleases into inactive substances; can use in hepatic impairment (no data re use if severe). Elimination t½ 9 hrs. No adjustment needed for renal impairment. The reason(s) for long action (~6 months) unclear; possibilities include that the silencing complex formed between the drug & enzyme PCSK9 mRNA have been shown to remain active after drug cleared. Also, intra & extracellular PCSK9 enzyme levels are affected (MABs extra-cellular only)