The headline in the UK Times newspaper on January 14th, 2020 was "New cholesterol 'vaccine' could save thousands of lives a year" (Ref 1). The BBC headline was "NHS to pioneer cholesterol-busting jab" (Ref 2). The BMJ reported: "Inclisiran: UK to roll out new cholesterol lowering drug from next year" (Ref 3).
The media story may have been a UK one, but the drug that it featured is very much a global phenomenon. The coverage was also interesting because it wasn't the result of a press release about findings from a research trial, which is normally the case. It was a PR/marketing story about a "novel partnership" between the pharmaceutical company, Novartis, and the UK National Health Service "which will see patients receive accelerated access to its groundbreaking cholesterol-lowering drug inclisiran" (Ref 4).
This "novel partnership" appears to have made headlines for two reasons. First, because the UK Health Secretary, Matt Hancock, was quoted as saying "this collaboration has the potential to save 30,000 lives over the next ten years." The notion that lives can be saved always gets the front page. Secondly, when providing a comment about the collaboration, Professor Naveed Sattar, used the word 'vaccine', which is even more emotional. Sattar's conflicts of interest were reported as Amgen and Sanofi - the pharmaceutical companies with currently approved cholesterol lowering injections. His comment was: "Doctors are excited by inclisiran and the potential to 'vaccinate' against high cholesterol in some patients, with obvious benefits to compliance and uptake" (Ref 5).
Let's look at the drug - inclisiran - what it does, the evidence for benefit and why the 'vaccine' positioning is particularly insidious.
Inclisiran and PCSK9 inhibitors
This is the most important thing to note up front: "Inclisiran is not yet approved for use by the FDA or any other regulatory authority."
The company's own web site has these words in bold at the top of the main page (Ref 6). The pharmaceutical magazine informs us that inclisiran "has been submitted for review with the FDA, and Novartis has said the drug is also set for submission with the EMA in the next few weeks" (Ref 7). (The FDA is the US regulating body and the EMA is the European one).
Inclisiran is one of a group of medicines called PCSK9 inhibitors. (PCSK9 stands for proprotein convertase subtilisin/kexin type 9.) It is important to know the normal function of the PSCK9 gene and protein. The PCSK9 gene provides instructions for making a protein to help regulate the amount of cholesterol in the bloodstream. The PCSK9 protein controls the number of low-density lipoprotein (LDL) receptors, which are proteins on the surface of cells. These receptors play a vital role in regulating blood cholesterol levels. The receptors bind to particles called low-density lipoproteins (LDLs), which are the main carriers of cholesterol in the blood. LDL receptors are particularly abundant in the liver, the organ responsible for removing most excess cholesterol from the body. The number of LDL receptors on the surface of liver cells determines how quickly cholesterol is removed from the bloodstream. The PCSK9 protein breaks down LDL receptors before they reach the cell surface, so that more cholesterol can remain in the bloodstream (Ref 8).
That's what PCSK9 is designed to do. Inclisiran is designed to stop this: "Inclisiran is designed to prevent the production of PCSK9 at its primary source in the liver" (Ref 9).
The body has a process and inclisiran has the function of stopping that process. Do you know the consequences of this happening? I don't. I'm a simple soul when it comes to the body. I think that the body is utterly marvellous and quite exquisitely designed and balanced. Its ability to regulate everything from temperature to pH levels to blood pressure to blood glucose (when not abused by the host) is quite extraordinary.
I have fundamental concerns when humans 'play God' and think that a natural function should be impaired. I hold the same view with statins. The body has a pathway called the mevalonate pathway. Statins impair the operation of this pathway. They don't block it entirely and eliminate the production of cholesterol entirely. If they did, the first person to take a statin would have dropped dead. They impair it enough to lower, but not eliminate, cholesterol and consequences arise. One of the indisputable consequences is a loss of a coenzyme called "Coenzyme Q10." CoQ10 is a compound that helps to generate energy in cells. CoQ10 production is downstream of the point in the mevalonate pathway at which statins operate. Hence statins impair the production of CoQ10. (Manufacturers know this, which is why early statin patents applied for CoQ10 to be added to the statin, but this was never done). This helps to explain why side effects of statins include energy and muscle pain issues.
Back to Inclisiran - this is the latest PCSK9 inhibitor, but not the first. The drug company, Amgen, has a drug called Evolocumab, which has the brand name Repatha®. Sanofi/Regeneron has the drug Alirocumab, which has the brand name Praluent®. Both of these are injected every two weeks. The perceived advantage of inclisiran is that it only needs to be injected twice a year. This would likely be more tolerable to patients, thereby increasing compliance.
Repatha® and Praluent® work in very similar ways to each other. Inclisiran works slightly differently to both of them. Inclisiran blocks the genetic expression of the PCSK9 protein, while Repatha® and Praluent® block it after it has already been produced in the body.
Repatha® and Praluent® were both originally approved for use in Familial Hypercholesterolemia (FH). There are two types of Familial Hypercholesterolemia (FH) - heterozygous and homozygous. The first is rare and the second is incredibly rare. The prevalence of heterozygous FH was held to be 1 in 500 and the prevalence of homozygous FH was held to be 1 in 1,000,000. These numbers are continually being revised, with current estimates of 1 in 200 to 1 in 500 for heterozygous FH and to 1 in 160,000 to 1 in 1,000, 000 for homozygous FH (Ref 10). I suspect that these revisions (to diagnose more people with FH) are related to the fact that some drugs have only been approved for those with FH.
As typically happens with drugs approved for one condition (FH), there is 'creep' and further approvals are given for more common conditions in the same illness category. In December 2017, the US FDA approved Repatha® "to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease" (Ref 11). In April 2019, Praluent® was approved "to reduce the risk of heart attack, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular (CV) disease" (Ref 12). Both drugs moved quickly from being approved for the rare condition of Familial Hypercholesterolemia to being approved for general use for secondary prevention - Repatha® within one year and Praluent® within two years.
As I showed in this post, "there is no evidence of benefit for Evolocumab [Repatha®] in any circumstance for which NICE [the UK guidelines body] recommends it" (Ref 13). Benefit is defined, as it should be, of making a difference to actual events - deaths, heart attacks etc. The UK Telegraph newspapers reported on my findings, but this has not stopped Repatha® being prescribed (Ref 14).
Inclisiran - the evidence and the trials
There is no evidence whatsoever that inclisiran has any impact whatsoever on heart disease. All trials thus far have been to demonstrate the cholesterol lowering impact of inclisiran (in people already taking statins and/or other cholesterol lowering medications).
Knowing what inclisiran is designed to do, I am not at all surprised that it lowers LDL-cholesterol substantially. The surprise is that drugs are approved in the field of heart disease before having demonstrated any benefit for actual heart disease. Drug companies have long achieved the situation whereby a surrogate end point (one's cholesterol) has sufficed for people to be given powerful drugs, which may have no impact on actual events.
A summary of the clinical trials for inclisiran is as follows (Ref 15):
- ORION-11 was conducted in the EU (including the UK), South Africa and the Ukraine on 1,617 people with Atherosclerotic Cardiovascular Disease (ASCVD) and elevated LDL-cholesterol. It involved the administration of inclisiran vs placebo injections on day 1, day 90 and every 6 months thereafter. The main outcome measures were i) the percentage change in LDL-cholesterol from baseline to day 510 (18 months follow-up) and ii) the time‐adjusted percentage change in LDL‐cholesterol levels from baseline after day 90 and up to day 540 (this reviews the impact of ongoing cholesterol lowering after 2 injections in 3 months). First results were reported at the European Society of Cardiology's ESC Congress 2019 in Paris. It was reported that "Inclisiran achieved 54% LDL-C lowering with time-adjusted reductions of 50% sustained over 18 months of treatment" (Ref 16).
- ORION-10 was the same trial as ORION-11 but conducted in the US on 1,561 people with Atherosclerotic Cardiovascular Disease (ASCVD) and elevated LDL-cholesterol. The injections (day 1, 90 and every 180 days) and outcome measures (LDL-cholesterol lowering) were the same as in ORION-11. First results were presented at the American Heart Association Scientific Sessions, 2019. It was reported that "Inclisiran achieved 58% LDL-C lowering with time-adjusted reductions of 56% sustained over 18 months of treatment in patients with atherosclerotic cardiovascular disease (ASCVD)" (Ref 17).
- ORION 9 was conducted on 482 people with heterozygous familial hypercholesterolaemia in the EU (not the UK), Canada, USA and South Africa. This had the same inclisiran vs placebo injection intervention and the same primary end points. First results were presented at the American Heart Association Scientific Sessions, 2019. It was reported that "Inclisiran achieved 50% LDL-C lowering with time-adjusted reductions of 45% sustained over 18 months of treatment in patients with heterozygous familial hypercholesterolemia (HeFH)" (Ref 18).
- ORION 8 is not due to be completed until Aug 2023. It is due to be conducted on 3,700 people who have already been involved in one of the many inclisiran clinical trials. This trial is twice as long - 1,080 days and the primary end points are i) the proportion of subjects reaching LDL‐cholesterol targets of <70 mg/dL and ii) the proportion of subjects reaching LDL‐cholesterol targets of <100 mg/dL. This is still a trial looking at surrogate end points; it is not looking at events.
- ORION 4 is the first trial that is intended to measure things that actually matter - events. This is not due to report back before January 2024. It is being conducted on 15,000 patients in Europe (primarily the UK) and North America. The primary outcomes are due to be a composite of major adverse cardiovascular events defined as the time to first occurrence of: Coronary heart disease (CHD) death; Myocardial Infarction (heart attack); Fatal or non‐fatal ischemic stroke; and urgent coronary revascularisation (stent) procedure. The latter already favours the drug group, as patients are more likely to be given a stent if their LDL-cholesterol is higher and their cholesterol will be higher if they are on the placebo.
Concerns and observations about inclisiran
1) The accelerating move towards PCSK9 inhibitors helps to explain an article from April 2019, which asserted that statins don't work well for half the people that take them (Ref 19). That study was funded by Amgen. It is in the interests of pharmaceutical companies to criticise one drug when there is a more lucrative one to promote instead.
Establishing the notion that half of people don't benefit from statins, opens the door to half of people being given PCSK9 inhibitors - even if they don't have the conditions for which PCSK9 inhibitors were approved (FH or Atherosclerotic Cardiovascular Disease). This paves the way for drugs, which were originally only intended to be for the rare condition of Familial Hypercholesterolemia, to be used in primary prevention (in people who don't have heart disease). That's the holy grail of market potential and in a drug that makes the profits from statins look like petty cash.
2) Talking of 'lucrative', the main objections to PCSK9 inhibitors thus far have been cost related. Both drugs entered the market costing approximately $14,000 per patient per year. The list price for Repatha® is $1,117 per month, although not many people pay that much apparently (Ref 20). In February 2019, the list price for Praluent® was cut by 60% to $5,850 a year (Ref 21). The main objections to these drugs should have been that their long term consequences are unknown and the benefits for things that matter, events, are largely unproven.
3) There is no patient leaflet for inclisiran as yet, because it has not been approved. Using another PCSK9 as a guide, the most common side effects (may affect up to 1 in 10 people) of Repatha® include: flu or flu-like symptoms; symptoms of the common cold (runny nose, sore throat etc); back pain; joint pain (arthralgia); high blood sugar levels (diabetes); redness, pain or bruising at the injection site; feeling sick; allergic reactions including rash (Ref 22). It is interesting that, as with statins, diabetes appears to be the most serious known side effect.
There is an additional issue with inclisiran, beyond the currently approved PCSK9 inhibitors. Repatha® and Praluent® are injected every two weeks. If someone has a bad reaction following the first injection, they can stop, and things should be back to normal within a fortnight. If someone has a bad reaction to inclisiran, its effects appear to last six months and will take a lot longer to clear their system.
4) Have you heard of bococizumab? I hadn't, until researching for this note. Bococizumab was a PCSK9 inhibitor, which was in development by Pfizer. Development was stopped because of an unexpected decrease in LDL-cholesterol lowering over time, high levels of immunogenicity and high rates of injection-site reactions (Ref 23). Have other PCSK9 trials been long enough to enable discovery of all unintended consequences?
5) The vaccine reference made me particularly uncomfortable. Vaccines are made from the same germs that cause disease. They are intended to stimulate your immune system to make antibodies to the disease, so that you become immune to the disease.
LDL-cholesterol is not a disease. PCSK9 inhibitors are not vaccines. The only thing they have in common with vaccines is that they are injected (and make money). No antibodies can be made to LDL-cholesterol. The comparison is absurd, but deliberate and calculated.
Vaccines have an accelerated approval process. Vaccine manufacturers in the US are not liable for any harm resulting from a vaccine (Ref 24). The European position was complicated by a 2017 ruling (Ref 25). The biggest benefit of positioning a drug as a vaccine is surely that nothing negative will ever be said about that drug. Observe mention of any vaccine and you will notice that there is zero tolerance of anything critical being said about any vaccine. Imagine how beneficial it could be to have a cholesterol lowering injection protected in the same way? Especially when that drug has known and unknown side effects, questionable benefits and eye watering costs?
The vaccine inference, although made by Sattar in connection with this marketing story, is not new. A US article from 2015 was entitled: "New cholesterol-lowering vaccine could help tackle heart disease" (Ref 26).
Back to the story
The UK health secretary, Matt Hancock, was quoted as saying: "this collaboration has the potential to save 30,000 lives over the next ten years." It doesn't. No lives can be saved - we're all going to die.
The best that cholesterol-lowering medications can do is to extend lives. By how much? We have no evidence for events, let alone life-extension, for inclisiran. We have some independent evidence for statins, in studies where they were taken for several years. A non-industry funded paper from 2015 found that, "The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1days, respectively" (Ref 27). This would then need to be weighed up against any side effects experienced for several years.
My examination of Repatha® - following the publication of the first data on events - showed that it would cost £654,545 to delay one event - which could happen the day after (Ref 28). That's just the financial cost. What's the human health cost? What's the genetic cost? Or the epigenetic cost? What's the long term cost of 'playing God', Mr Hancock?
References
Ref 1: https://www.thetimes.co.uk/article/new-cholesterol-vaccine-could-save-thousands-of-lives-a-year-ghkpvmmlx
Ref 2: https://www.bbc.co.uk/news/health-51091083
Ref 3: https://www.bmj.com/content/368/bmj.m139
Ref 4: http://www.pmlive.com/pharma_news/novartis_links_up_with_nhs_for_speedy_access_to_cholesterol_drug_inclisiran_1322299
Ref 5: https://www.sciencemediacentre.org/expert-reaction-to-announcement-that-a-new-heart-disease-drug-inclisiran-will-be-available-for-nhs-patients-pending-approval/
Ref 6: https://www.themedicinescompany.com/clinical-development/
Ref 7: http://www.pmlive.com/pharma_news/novartis_links_up_with_nhs_for_speedy_access_to_cholesterol_drug_inclisiran_1322299
Ref 8: https://ghr.nlm.nih.gov/gene/PCSK9
Ref 9: https://www.themedicinescompany.com/clinical-development/
Ref 10: Singh & Bittner. Familial hypercholesterolemia-epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015. https://www.ncbi.nlm.nih.gov/pubmed/25612857
Ref 11: https://www.drugs.com/newdrugs/fda-approves-amgen-s-repatha-evolocumab-prevent-heart-attack-stroke-4655.html
Ref 12: https://www.drugs.com/newdrugs/fda-approves-praluent-alirocumab-prevent-heart-attack-stroke-unstable-angina-requiring-4955.html
Ref 13: https://www.zoeharcombe.com/2017/04/evolocumab-nice-guidelines/
Ref 14: https://www.telegraph.co.uk/news/2017/05/06/nhs-wasting-tens-thousands-year-wonder-drug-stroke-heart-attacks/
Ref 15: http://www.io.nihr.ac.uk/wp-content/uploads/2019/06/12058-Inclisiran-for-Primary-Hypercholesterolaemia-and-Mixed-Dyslipidaemia-V1.0-MAY2019-NON-CONF.pdf
Ref 16: https://www.themedicinescompany.com/investor/pr/4000045/
Ref 17: https://www.themedicinescompany.com/investor/pr/4151966/
Ref 18: https://www.themedicinescompany.com/investor/pr/4152740/
Ref 19: https://heart.bmj.com/content/105/13/975 and https://www.zoeharcombe.com/2019/04/statins-dont-work-well-for-half-those-who-take-them/
Ref 20: https://www.repatha.com/repatha-cost/
Ref 21: https://www.reuters.com/article/us-sanofi-fr-regeneron-cholesterol/sanofi-and-regeneron-cut-list-price-of-cholesterol-drug-by-60-percent-idUSKCN1Q019M
Ref 22: https://www.medicines.org.uk/emc/files/pil.6962.pdf and https://www.repatha.com/repatha-side-effects/
Ref 23: https://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor
Ref 24: https://www.law.cornell.edu/uscode/text/42/300aa-22
Ref 25: http://law.emory.edu/elj/content/volume-67/issue-3/articles/liability-vaccine-injury-united-european-world.html
Ref 26: https://www.journals.elsevier.com/vaccine/news/new-cholesterol-lowering-vaccine-could-help-tackle-heart-dis
Ref 27: https://bmjopen.bmj.com/content/5/9/e007118
Ref 28: https://www.zoeharcombe.com/2017/04/evolocumab-nice-guidelines/
Comment: See also: