Inclisiran: A New Hope, or Too Much Hype?

Back in October 2021 NICE took everyone by surprise when they recommended a novel lipid lowering drug inclisiran for use in primary care NICE TA733 Oct 2021. The response to this from primary care was, at best, lukewarm; but since then inclisiran has been introduced into General Practice (in some areas of England) as discussed by Dr Jim Moore, chair of the Primary Care Cardiovascular Society, on Neals podcast last month. But for those of us who are not using inclisiran, what is this new drug, why all the hype and controversy, and for those using (or contemplating using) it, what do we need to be aware of?

What is Inclisiran? Inclisiran is a novel lipid lowering medication, given by 6 monthly subcut injections, which interferes with synthesis of the PCSK9 protein, leading to up-regulation of LDL receptors which increases LDL clearance from the blood and lowers LDL levels. It works in a different way from the PCSK9 inhibitors (e.g. alirocumab) by working at an intracellular level (‘small interfering RNA’ drug) causing reduced synthesis of the PCSK9 protein.

What have NICE recommended? Inclisiran is recommended by NICE NICE TA733 as an option for SECONDARY prevention of CVD events if LDL-C is persistently ≥2.6 mmol/mol despite maximal lipid-lowering therapy. It is NOT recommended for primary prevention (including those with familial hypercholesterolaemia), unless part of a research trial. NICE also state that ‘inclisiran is likely to be used in a primary care setting.’ Inclisiran has also been accepted for use in Scotland SMC 2021, but is restricted to specialist use only.

Show me the evidence…The evidence is based on 2 key trials - ORION-10 (atherosclerotic CVD and LDL ≥1.8mmol/mol) and ORION-11 (mixed secondary prevention as per ORION-10 plus some primary prevention with risk factors and LDL ≥2.6). Most patients were on statins. Both placebo controlled RCTs showed a reduction in LDL of approx 50%, maintained by 18 months. More recently in Jan 23 exploratory analysis of the data so far suggests ‘potential benefits for MACE reduction’ with inclisiran, but ‘these findings await confirmation in the larger CV outcomes trials of longer duration’.

A 50% reduction in LDL sounds impressive, but It’s important to note two important caveats to the data so far: We have NO hard CVD outcome data yet on this drug and we have NO data comparing this drug to any current lipid-lowering therapy. The lack of clinically meaningful CVD outcome data is a concern BMJ 2021;375:n2462., and a recent review in the DTB (DTB 2023;61:86) concludes ‘there is no meaningful cardiovascular outcome data for inclisiran’. Two UK placebo controlled trials (ORION4 VICTORION-2P) assessing CVD outcomes in people with established CVD will report in 2026 and 2027.

Is it safe? The simple answer is that we have no idea. This is a novel drug that has only been in use for a few years, so we have no idea if there will be any long term side effects or problems. Studies repeatedly show the drug is generally ‘well tolerated’, apart from some injection site reactions, but this is not synonymous with it being ‘safe’. Tolerability of a drug is important for concordance, but this does not necessarily equate to safety in the longer term. Reports are already starting to emerge of possible dermatological side effects of inclisiran, including alopecia.

OK, so there are still some unanswered questions, but an LDL reduction of 50% is very impressive which could equate to significant CVD reductions - should we really have to wait until 2026/27 before rolling this drug out in primary care?

This is an argument that has been proposed by some given the (potentially) significant CVD improvements this drug could have. But (M’Lud) there are some important practical and ethical considerations that we need to consider before diving in with inclisiran in General Practice, aside from the lack of clinically meaningful outcome and safety data:

1. Inclisiran is a black triangle drug, so the recommendation from NICE to roll it out immediately to primary care is highly unusual. As the BMA/RCGP position paper makes clear, if we consider prescribing this drug we ‘take full responsibility for the prescribing.’ In addition we need to fully consent patients ‘documenting the lack of long-term evidence and unknown long term safety profile of this new and novel medication’ and we need to report all possible side effects of the drug however minor (even if we aren’t sure if the drug caused the side effect) to the “yellow card” reporting site.
2. Effect attenuation over time - given the nature of the drug there is a risk that antibodies may develop over time attenuating treatment effect, even if it is effective initially. Over the 18 months of treatment in the trials rates of anti-drug antibodies to inclisiran went up from 1.8% to 4.9% and the DTB cites other lipid lowering drugs that have been withdrawn due to the development of anti-drug antibodies.
3. Concerns over erosion of the usual regulatory and consultation frameworks. It is probably a significant understatement to say that the process by which inclisiran was introduced was ‘questionable’. The best part of 12 months before this drug was even licensed, NHSE boldly announced via press release that due to a ‘ground-breaking, in-principle agreement with Novartis, introduction of inclisiran on the NHS following approval has the potential to save up to 30,000 lives over the next 10 years’. This all felt like a fait accompli with NICE duly following suit with their recommendations, despite the lack of clinically meaningful outcome data. Given the opaque commercial nature of the agreement, cost-effectiveness analyses cannot be properly scrutinised either. This trend for announcing ‘behind closed doors’ agreements on new drugs, often via press release and increasingly before data has been published or peer reviewed (e.g. molnupiravir), is a worry. As the brilliant book Empire of Pain highlights, documenting the oxycontin scandal, there are significant risks if boundaries between drug company, regulatory bodies and politicians get eroded. The RCGP/BMA position statement says they have ‘not been reassured by the answers provided by NHSE/I’, and the DTB conclude that CVD outcome data is needed ‘before raising expectations of the unproven long-term clinical benefits and unknown long-term adverse effects of a drug that has been hyped as ‘revolutionary’ and ‘cutting-edge’ on the UK Government’s website.’

So, whether you think this is innovation, or dereliction of duty, and whether you are a glass half full/glass half empty/glass volume yet to be adequately confirmed person, it is clear there are still a lot of questions to be answered about inclisiran. Whether it will turn out to be ‘A New Hope’ and a genuine novel block buster, or simply too much hype, only time will tell.

Finally, for a wider review of lipids, we have recently updated our lipid management CPD module, which provides a comprehensive overview for all of us. This update is especially beneficial for those in England who are now working with the new QoF lipid targets!