KISS: Inclisiran

What is Inclisiran and how does it work?

• Inclisiran is a novel drug that lowers LDL-C by interfering with the production of the PCSK9 protein.
• The PCSK9 protein inhibits LDL receptor recycling predominantly in the liver; thus by interfering with the production of PCSK9 more LDL receptors are available to increase LDL clearance from the blood.
• The PCSK9 inhibitors (e.g. alirocumab and evolocumab) are monoclonal antibodies that bind to the PCSK9 protein to inactivate it, allowing up-regulation of LDL receptors.
• Inclisiran works in a different way - it is a 'small interring RNA' drug (siRNA) that interferes with the PCSK9 RNA causing PCSK9 breakdown, leading to up-regulation of LDL receptors which increases LDL clearance from the blood and lowers LDL-C levels.

Who is it for (NICE guidance - see below for Scotland) and how is it administered?

• Inclisiran is recommended as an option for primary hypercholesterolaemia or mixed dyslipidaemia (as an adjunct to diet) if:
• History of any of the following CVD events - ACS, coronary or other arterial revascularisation, CHD, ischaemic stroke, PAD, AND
• LDL-C persistently ≥2.6 mmol/mol despite maximal lipid-lowering therapy:
• That is max tolerated statin with or without other lipid-lowering therapies, or 
• Other lipid-lowering therapies when statins are not tolerated or contraindicated.
• It is NOT recommended for primary prevention (including those with familial hypercholesterolaemia), unless part of a research trial.
• It is administered via subcut injection.
• First 2 doses 3 months apart then twice yearly, leading some to liken it to a cholesterol 'vaccine'. 

Side Effects, interactions and precautions:

• Thus far no significant difference in any side effects vs placebo has been noted, apart from local injection site reactions (8.2% Inclisiran vs 1.8% placebo) with only 0.2% withdrawing.
• Renal/hepatic impairment - no dose adjustment; BNF advises avoiding in severe renal/hepatic impairment.
• Elderly? No dose adjustments; overall in studies 54% were ≥65 and 13% were ≥75.
• Inclisiran is not expected to have clinically significant interactions with other drugs (inc. statins).

Supporting evidence:

• The 2 key studies are ORION-10 (atherosclerotic CVD and LDL-C ≥1.8mmol/mol) and ORION-11 (mixed secondary prevention as per ORION-10 plus some primary prevention with risk factors and LDL-C ≥2.6).
• Most patients were on statins (89% in ORION-10 and 95% in ORION-11) with the majority on high intensity statins (69% in ORION-10 and 78% in ORION-11), although only small numbers were on ezetimibe (11% and 9% respectively).
• Both placebo controlled RCTs showed a reduction of LDL-C of ~50% maintained by 18 months.
• It's important to note 2 important caveats to the data so far: 
• We have NO hard CVD outcome data yet on this drug - all studies so far have used LDL-C as a surrogate marker; a UK based study (ORION-4) is planned to report in 2026 with CVD outcomes.
• We have NO comparative data comparing this drug to any current lipid-lowering therapy.

Why has NICE made this recommendation?

• NICE clearly feel there is a 'gap' in treatment for those at high risk of CVD (i.e. secondary prevention) who still have elevated LDL-C ≥2.6 despite statins (or due to intolerance of statins), and who are not eligible for the PCSK9 inhibitors (need LDL-C ≥ 3.5 or 4.0 depending on high risk/very high risk).
• They also note significant barriers to PCSK9 inhibitors even if eligible - v expensive and have to be prescribed by specialists, lack of such services/capacity issues and need for injections every 2-4 weeks.
• Crucially there is a cost reduction agreement with Novartis allowing this to be deemed cost-effective, and NICE specify that this drug can only be used if 'the company provides inclisiran according to the commercial arrangement'. This agreement is inevitably commercially sensitive and has not been put into the public domain.

Potential implications for primary care:

• NICE are clear 'Inclisiran is likely to be used in a primary care setting'.
• We will need to do LDL-C levels in those with CVD (rather than current guidance using non-HDL-C).
• NHS data suggests 300,000 patients will be eligible for this - potential significant workload implications for us in primary care. 
• How this rollout will actually happen in practice is still very uncertain, with many questions still to be answered, including:
• Where the final cost of the drug will lie - primary care, secondary care or both? 
• Will it just be primary caregiving this drug or will secondary care also have access to it?
• What about monitoring of side effects, given this is a novel drug?

What about Scottish recommendations?

Inclisiran has also been accepted by NHS Scotland for use, however, there are much tighter restrictions on use, including higher LDL levels, and importantly is restricted to specialist use only (unlike NICE recommendation for England/Wales which looks set for implementation in primary care), although they are recommending use in some patients with familial hypercholesterolaemia for primary prevention (unlike NICE). 

• SMC restriction: for specialist use only in patients at high cardiovascular risk as follows:
• Patients with heterozygous familial hypercholesterolaemia (HeFH) and LDL-C ≥5.0mmol/L, for primary prevention of cardiovascular events or,
• Patients with HeFH and LDL-C≥3.5mmol/L, for secondary prevention of cardiovascular events or,
• Patients with high risk due to previous cardiovascular events and LDL-C≥4.0mmol/L or,
• Patients with recurrent/polyvascular disease and LDL-C≥3.5mmol/L.