In January 2020, the UK Government's Department of Health and Social Care (DHSC) announced ‘a ground-breaking, in-principle agreement with Novartis’, namely, the introduction of inclisiran, (DHSC, 2020). Inclisiran interferes with RNA ‘to prevent synthesis of the enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9), leading to lower serum concentrations of low-density lipoprotein cholesterol (LDL-C)’ (Byrne et al, 2020).
Byrne et al (2020) note that the NHS-Novartis agreement announced access to an unapproved drug at the start of the drug's clinical trial, and that ‘the government press release included no contact details for further information. Despite this, large clinical benefits are being claimed, even before the NHS trial has begun.’
On 9 December 2020 the European Medicines Agency (2020) approved inclisiran's use throughout the European Union (of which the UK is not a member). In January 2021 it was observed that Novartis would be attempting ‘to recoup some of the $9.7 billion it spent in acquiring the drug's developer, The Medicines Company’ (Anonymous, 2021); and in September 2021 it was reported that the National Institute for Health and Care Excellence (NICE) had approved ‘Leqvio® (inclisiran) following a Phase III trial that showed that the drug provided effective and sustained LDL-C reduction in two sub-populations of atherosclerotic cardiovascular disease: established cerebrovascular disease and polyvascular disease’ (Begley, 2021). Endorsing inclisiran as a ‘potential game-changer in preventing thousands of people from dying prematurely from heart attacks and strokes,’ NICE's deputy chief executive Meindert Boysen was clear that this ‘could see as many as 300 000 people with high cholesterol or mixed dyslipidaemia who have already had a previous cardiovascular event receive the drug over the next three years’ (Begley, 2021).
Can such optimism be justified? For instance, by January 2021 it was reported that ‘it will take several more years before a fuller understanding of the clinical value of Leqvio emerges’ (Anonymous, 2021), which could have quelled premature exuberance over possible outcomes. In August 2021, the University of Oxford (2021) highlighted a clinical trial that would aim ‘to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to treat blocked arteries’, stating that the estimated primary completion date is July 2026, with an estimated study completion date of … 2049.
There is no evidence that inclisiran has any impact on heart disease whatsoever. Rather, a surrogate endpoint – LDL-C concentration – has been used from which arguably over-optimistic inferences have been drawn. For example, BBC News had no hesitation in announcing the ‘life-saving cholesterol jab recommended on NHS’ (Roberts, 2021).
Perhaps the media ought to modify unnecessarily optimistic, and possibly misleading headlines, especially when they appear to rest on rather shaky evidential foundations. By contrast, there is mounting evidence that high concentrations of LDL-C may not be as dangerous as is widely supposed. For example, following a review of the literature, Ravnskov et al (2018) found that ‘[d]espite the fact that LDL-C is routinely referred to as the “bad cholesterol”, we have shown that high LDL-C levels appear to be unrelated to the risk of cardiovascular disease, both in familial hypercholesterolaemia individuals and in the general population and that the benefit from the use of cholesterol-lowering drugs is questionable.’ It seems incumbent on those who might reject the outcomes of such reviews to adduce persuasive evidence to the contrary.
On 15 September 2021 consultant cardiologist and chairman of the Public Health Collaboration Dr Aseem Malhotra, together with seven co-signatories – including Past President of the Royal College of Physicians Sir Richard Thompson, and President of the International Society of Vascular Surgeons Prof Sherif Sultan – wrote to NICE expressing their concerns, and highlighting what they considered to be a lack of transparency in the NICE's decision-making process, and the absence of long-term data on effectiveness or safety. They recommended ‘that a full appraisal of the inclisiran trial data and marketing license be obtained by UK's Medicines and Healthcare products Regulatory Agency prior to rolling out the drug to patients in the NHS’ (Malhotra, 2021).
Such a cautious approach to the introduction of a new drug, whose ability to combat heart disease remains unproven, seems to be a sensible application of the scientific process, rather than participating in what could be seen as an unseemly rush to market.