Category Archives: PCSK9

Cholesterol lowering – proven or not?

Repatha

Just before I head off on holiday for a couple of weeks, I thought I should make a quick comment on the Repatha trial (PCSK9- inhibitor). I have written much about this new class of cholesterol lowering drugs, and I have been highly skeptical that they would have any benefits on cardiovascular disease. [Mainly on the basis that I don’t believe raised LDL causes CVD, and these drugs have one action – to lower LDL].

As many of you will be aware, the data from a clinical trial on Repatha has just been released. It was reported by the BBC thus

‘Huge advance’ in fighting world’s biggest killer.’

An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors. The results of the large international trial on 27,000 patients means the drug could soon be used by millions.

The British Heart Foundation said the findings were a significant advance in fighting the biggest killer in the world. Around 15 million people die each year from heart attacks or stroke. Bad cholesterol is the villain in the heart world – it leads to blood vessels furring up, becoming easy to block which fatally starves the heart or brain of oxygen.

It is why millions of people take drugs called statins to reduce the amount of bad cholesterol . The new drug – evolocumab – changes the way the liver works to also cut bad cholesterol. “It is much more effective than statins,” said Prof Peter Sever, from Imperial College London.

He organised the bit of the trial taking place in the UK with funding from the drug company Amgen. Prof Sever told the BBC News website: “The end result was cholesterol levels came down and down and down and we’ve seen cholesterol levels lower than we have ever seen before in the practice of medicine.”

And so on, and so forth. So, the Repatha trial was a huge success. Obviously, it certainly lowered LDL to levels never seen before. Or, maybe it was not quite such a huge success. Michel de Logeril, a professor of cardiology in France – who set up and ran the famous, and successful, Lyon Heart Study sent me this comment.

‘This is just junk science.

The calculated follow-up duration required to test the primary hypothesis was 4 years as written by the authors themselves (but only in the second last paragraph before the end of discussion…) but the actual median duration of follow-up has been 2.2 years; it is thus a biased trial (a similar bias as in JUPITER: 1.9 years instead of 4 years): early stop!

In addition, contrary to the misleading claims in the medias, there was no effect on both total [444 deaths with evolocumab vs. 426 with placebo] and cardiovascular [251 vs. 240] mortality; which is not unexpected with a so short a follow-up.

They pretend that they are differences for non-fatal AMI and stroke but there is no difference in AMI and stroke mortality… Very strange… It would be critical to get access to the raw clinical data to verify the clinical history of each case in both groups.

Well, in my opinion and given the present state of consciousness among US doctors, FOURIER is a flop!

Best

Michel’

What he is saying, is that there was a reported reduction in non-fatal heart attacks and stroke. And less need for revascularization procedures e.g. PCI/stents. As you may gather Professor de Logeril would like to see the raw data to verify this. There is very little chance that this will be made available.

Anyway, that was the upside.

The downside is when you look at cardiovascular deaths.

The total number of deaths from cardiovascular disease in the Repatha group was 251
The total number of deaths from cardiovascular disease in the placebo group was 240
So, 11 more people died of cardiovascular disease in the Repatha group

The overall mortality data

The total number of, overall, deaths in the Repatha group was 444
The total number of, overall, deaths in the placebo group was 426
So, there were 18 more deaths in those taking Repatha.

The differences here are not large enough to be statistically significant. However, there were more, not less, deaths in the Repatha group, and more, not less, CV deaths. This study was also terminated early, which is extremely bad news for any clinical trial, and casts enormous doubt on any findings. It was supposed to last four years, but was stopped at 2.2 years. Why? Were the mortality curves heading rapidly in the wrong direction.

Alongside this, should be set the knowledge the Pfizer also had a PCSK9-inhibitor undergoing clinical trials, and they pulled the plug, right in the middle of it all.

Pfizer Ends Development Of Its PCSK9 Inhibitor

‘November 1, 2016 by Larry Husten

Immune issues and diminishing efficacy doomed the new drug.

Pfizer announced on Tuesday that it was discontinuing development of bococizumab, its cholesterol-lowering PCSK9 inhibitor under development.

“The totality of clinical information now available for bococizumab, taken together with the evolving treatment and market landscape for lipid-lowering agents, indicates that bococizumab is not likely to provide value to patients, physicians, or shareholders,” the company explained.

Pfizer said that it would halt two very large ongoing cardiovascular outcome studies with bococizumab, the 17,000 patient SPIRE 1 trial and the 10,000 patient SPIRE 2 trial. The trials were fully enrolled.’

Pulling the plug when 27,000 patients had been fully enrolled. What on earth did they see. Something more than slightly worrying. I guess we will never really know, but that is one hell of a write off.

It is also interesting to note that Amgen – the company selling Repatha, has announced that:

‘Amgen to refund cholesterol drug if patients suffer heart attack

Pledge aims to convince insurers to pay for $14,000-a-year medicine.’ ²

As reported in the Financial Times.

This is a big vote of confidence … not! I think, perhaps, we are looking at a doomed drug. Probably a doomed class of drugs. Has the cholesterol hypothesis been verified, or contradicted? I know I am biased, but I know what I think.

1: http://cardiobrief.org/2016/11/01/pfizers-ends-development-of-its-pcsk9-inhibitor/

2: https://www.ft.com/content/34154cdc-0a86-11e7-ac5a-903b21361b43

Lowering cholesterol – an urgent Christmas appeal

143 Replies

A reader of this blog sent me this e-mail message that she had just received:

“This is a special Cholesterol e-News Bulletin asking for your help to draw your urgent attention to a recent decision by NICE that is of great concern to us.

There has been significant progress in the management and treatment of cardiovascular disease (CVD) over the past two decades, which has resulted in an overall decline in CVD deaths in the UK. Heart disease still remains one of the UK’s biggest killers. Over half of all UK adults have raised cholesterol increasing their risk of cardiovascular disease; leading to heart attacks and strokes. Not only does it have a devastating impact on patients and their families, but it also places significant burden on our health service and wider economy.

Innovative new medicines, such as PCSK9 inhibitors, are an exciting development in the treatment of cholesterol, with little known side effects and very good scientific evidence that they work to significantly reduce the levels of bad cholesterol in those at high risk of CVD.

NICE reviewed the first of these PCSK9 medicines and recommended that it should not be available for NHS patients.

HEART UK is concerned by NICE’s recent decision to turn down the use of the first of the PCSK9 medicines. This means patients will not have access to the best possible treatment options to help lower the levels of bad cholesterol, particularly those at high risk such as people with an inherited high cholesterol condition called Familial Hypercholesterolaemia.

NICE are conducting a second round of consultation, closing on Tuesday 8th December, before issuing final guidance. On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.”

NICE = The National institute for Care and Health Excellence. Let us not dwell for too long upon that self-aggrandizing title. NICE was set up in the UK, initially to look at whether or not various healthcare interventions represented good value for money, or poor value for money.

For reasons beyond the understanding of man, they plucked a figure from the sky one day (well not a figure, a range) from £20 – £30K ($33 – $48K) per year. If the intervention cost more than £20 – £30K/year to provide one added year of full quality life, then they turned it down. [One year of full quality life = 1 QALY (quality adjusted life year)]. And breathe.

Of course, NICE make all sorts of exceptions (all cancer drugs get funded no matter how much they cost, or how useless they are – go figure) and the way NICE words out how much interventions actually cost/ per QALY is complete nonsense in many cases. Be that as it may, they do make an effort to say ‘How much!’ ‘You must be joking,’ Reject…bong!

If NICE do say, reject, bong! This basically means that the drug will not be prescribed to anyone in the UK. In addition, such is the influence of NICE that many other countries use their decisions as an important guide for what they will do with regard to funding. So if NICE turn a drug down, this is very bad news from the manufactures or said drugs.

Now, when it comes to the new cholesterol lowering agents (PSCK-9 inhibitors) the manufacturers have a problem. Which is that they cost around £4 – £8K ($6.4 – $12.8) per year, per patient. Now, at those sort of costs, you are going to have to have some seriously impressive benefits. At present, however, the manufacturers have no data on mortality, or morbidity. Which makes the current cost per QALY = infinity. Just slightly above the NICE thresholds.

For those who read my blog you will know that I wrote the following in ‘Changing the definition of Familial Hypercholesterolaemia.’

At present I would think that the response of NICE (to PCSK-9 inhibitors) would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

As it turns out NICE did turn down the first PCSK9-inhbitor, no surprise there. And this is where HEART UK comes in….

Before going any further I should state that there are, currently, two PCSK9-Inhibtors launched/launching. They are Repatha ‘evolocumab’ made by Amgen. And Praluent ‘alirocumab’ to be co-marketed by Sanofi and Regeneron. They are, to all intents and purposes, identical drugs doing identical things. Remember the names Amgen and Sanofi. Amgen and Sanofi….

Now HEART UK states that it is a charity. ‘HEART UK – The Cholesterol Charity – campaigns to increase general public and policy makers’ awareness of raised cholesterol as a major public health concern. We campaign to keep action on cholesterol at the forefront of the health debate.’ ¹

Where do HEART UK get their funding from. Difficult to tell precisely. They claim to get money from public donation… how much? It’s a secret. What I do know is that they receive a very large amount of funding from companies that have cholesterol lowering products. So, for example Nestle, who make Shredded Wheat, pay HEART UK money, and HEART UK says stuff like

‘HEART UK dietician Linda Main said: “Shredded Wheat and Shredded Wheat Bitesize are low in saturated fat and can play an important role in a heart healthy diet and HEART UK is delighted that these products are supporting National Cholesterol Month and the Great Cholesterol Challenge.’²

Kerching!

Of course, when it comes to cholesterol lowering PCSK9-Inhibitors are the big daddies, with the big, big, budgets. So, you would expect that Amgen and Sanofi would be very, very, close to HEART UK. Well, if you expected that, you would be right. If you want to visit the HEART UK website, and look at the sponsors of their conference we have³:

Sanofi: Exclusive conference sponsor

Amgen: Sponsored symposia 1

Sanofi: Sponsored symposia 2

Amgen: Privileged sponsor…etc.

And now, to bring the two strands of this little tale together. NICE have just turned down the first PCSK9-inhbitor and so we have HEART UK reaching out to everyone that they know, or have contact with, to plead with them to sign a petition ‘On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.’ Sob. But what about Tiny Tim?

Some people, were they to be truly cynical, would allege that HEART UK may not be trying to get NICE to reverse their decision on PCSK9 – inhibitors, for the great good of humankind. But because they are being paid large sums of money by the manufacturers of PCSK9-inhbitors. Shame on anyone for thinking such a thing. With Christmas coming this should be a time of peace and happiness. Such cynicism has no place in my thoughts. No sirree.

[And for my Christmas quiz the reader with the best answer to the following question will have it published on my blog. ‘What is a health charity, and should they be allowed to accept sponsorship from pharmaceutical companies?’]

1: http://heartuk.org.uk/policy-and-public-affairs

2: http://heartuk.org.uk/latest-news/article/press-release-shredded-wheat-to-support-heart-uks-national-cholesterol-mont

3: http://heartuk.org.uk/news-and-events/meetings-conferences/heart_uk_annual_conference/sponsors

Changing the definition of Familial Hypercholesterolaemia

218 Replies

I am grateful to Mike Sheldrick, a reader of this blog for spotting some news, that was not entirely expected by me. For reasons that I will explain later. As you may know two new cholesterol lowering drugs have now launched. Two PCSK9 inhibitors. I call them the ‘dreaded’ PSCK9 inhibitors. I have written about them a few times. There has been surprisingly little noise about them so far, at least in the UK. Not sure about the US or the rest of the world. They are called Repatha and Praluent. Catchy eh!

These drugs have two major problems at present, at least from a money making perspective. They have no outcome data, by which I mean that they have not been shown to reduce the risk of heart attacks, strokes… or anything else for that matter. (They have been launched purely on their ability to lower LDL to violently low levels). They are also extraordinarily expensive. In the UK Praluent will cost between four thousand to eight thousand pounds ($6 – $12K) per year, depending on the dose¹.

Which means that the NHS can, if it so wishes, pay eight thousand pounds a year for a drug that does not actually do anything – other than lower a surrogate marker for heart disease. Now, this may not be seen as bargain of the year. I can imagine great battles are going on right now between the pharmaceutical companies and NICE. The organisation that decides if a drug is cost effective, or not.

At present I would think that the response of NICE would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

So, what to do? You have this amazing cholesterol lowering super-drug that does nothing, and it is enormously, eye-wateringly expensive. Come on, come on. Think!

To be frank, I thought that the primary marketing tactic would be to claim that statins actually have many, many horrible side-effects – that no-one noticed until…. there were new drugs to be launched of course. Which would mean that all those people who were ‘statin intolerant’ would need to take PCSK9 inhibitors instead. To get that horrible, damaging LDL level down. There is no doubt that the attack on statins is currently happening, but there has been more resistance to this than expected.

So, what else can you do? Well, there is one population where cholesterol lowering is seen as absolutely essential. The population is those who have familial hypercholesterolemia (FH). This group has always been considered at such a high risk of dying from heart attacks and strokes, that no clinical trials have even been done. You just do anything, and everything, to get the cholesterol (LDL) levels down, no questions asked. [No evidence of benefit needed either]

At present about one in five hundred people have FH and, when I started thinking about, I realised that this is really a big enough market for PCSK9 inhibitors. Just to do some simple sums. There are sixty-five million people in the UK at present. If one in five hundred has FH, that represents an FH population of 130,000. If every single one of these people goes on the higher dose of one of these drugs, the total sales would be £1Bn/year. In the UK alone. That is a blockbuster in anyone’s eyes.

If we transpose these figures to the US. The total population in the US is three hundred and twenty million. Which means that 640,000 people will have FH. With Praluent selling at $14,000/year, that would be $9Bn/year in sales in the US alone. Worldwide we are talking tens of billions a year. Of course, there are two virtually identical drugs out there, Praluent and Repatha, so divide the market by at least two – and there are more PCSK9 inhibitors in the pipeline.

Reducing this market still further, not everyone will take an injectable medication every two weeks, no way. And so the total market, though still massive, shrinks down ever further. Realistically, you might get a maximum of a quarter of those with FH on your drug. Amgen, for example would have to cope with piddling sales of $10Bn/year worldwide. Which will not do, not at all. More money must be made.

Of course, the simplest thing to do, to get round the problems with market size is simple. Make the market bigger. And the easiest way to do this is to widen the criteria for Familial Hypercholesterolaemia (FH). And lo, it has come about. The American Heart Association has stated that the level of LDL at with FH can be diagnosed is to be lowered:

“More people may be diagnosed with familial hypercholesterolemia (FH) using criteria contained in a new scientific statement published by the American Heart Association. The expanded definition could also mean more patients will be eligible to receive expensive cholesterol-lowering drugs, including the new PCSK9 inhibitor drugs, (Repatha from Amgen and Praluent from Sanofi/Regeneron)….

The new criteria for heterozygous FH sets an LDL level of at least 190 mg/d L (4.9mmol/l) for adults who have a similarly affected first-degree relative, premature coronary artery disease, or a positive genetic test. According to Mann, 3% of the population has LDL levels over 190 mg/dL level, but, she points out, “less than 1% of the population has FH. You could have docs diagnosing people with HeFH or HoFH* solely so that their insurance will cover a medication, such as PCSK9 inhibitors. That could be very confusing for patients.”²

*HeFH = Heterozygous Familial Hypercholesterolaemia (affects 1:500 – high LDL levels)

*HoFH = Homozygous Familial Hypercholesterolaemia (affects 1:1,000,000 – super-high LDL levels)

In one simple stroke, the market for PCSK9 inhibitors in the US has been increased from 640,000 to 1,920,000. Or, in monetary terms, $9Bn to $27Bn. There, that’s more like it. In the UK the market goes up to 400,000, with max PCSK9 sales going from one billion to three billion pounds sterling. A clever little trick.

I must say that I, possibly the most cynical human on the entire planet, never thought they would do this. I discounted as just too brazen. It would just be likely to be laughed out of court. Silly me. No-one is laughing. Experts are rubbing their chins and nodding sagely at the wisdom of this move. New swimming pools all round, is what they are probably thinking.

Do you think that the American Heart Association’s (AHA) decision here may have been affected by commercial sponsorship? This, of course, would be impossible to say – without getting sued senseless for libel.

However, I had a little look around the AHA, and Amgen, also the ‘non-profit’ FH Foundation and Amgen, and suchlike. Here is one statement from the AHA site. ‘Amgen is a proud sponsor of the American Heart Association’s Heart360 Toolkit^3. Ho hum Needless to say. Amgen are also ‘proud’ sponsors of various AHA meetings.

In addition, Amgen are also a foundation ‘corporate sponsor’ of the FH foundation⁴. They are probably very proud of that too. Finding these financial relationships can be a little tricky, as they are usually hidden in the depths of various websites. Perhaps other mike care to improve on this list…. Probably not that hard to do.

‘Money makes the world go around, the world go around, the world go around.’

1: http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5687

2: http://cardiobrief.org/2015/11/05/new-definition-of-familial-hypercholesterolemia-could-expand-patient-population-for-expensive-cholesterol-drugs/

3: golowcholesterol.com/tag/amgen/

4: https://thefhfoundation.org/about-us/sponsors/

A tale of mice and men

83 Replies

(PCSK9 and diabetes)

I look into my crystal ball and I see…. I see another wave of diabetes. Yes, the great Nostrokendrickos has spoken. Why do I predict this? Well, I see those given PCSK 9 inhibitors developing diabetes. I see the pharmaceutical companies telling us that this was completely unexpected, a paradox, and not clinically relevant anyway. Hold on…. no the vision is fading….it is gone.

Being an old fashioned type of person I have this strange belief that the body does not produce complex enzymes for a laugh. It takes a lot of energy and resources to make enzymes, or any another form of highly structured protein. If there is no need for them, and what they do, the body sighs with relief and stops making them. Then, over the years, evolution gets rid of the enzyme altogether. It’s kind of how evolution works.

So when we do have an enzyme Proprotein convertase subtilisin/kexin type 9 (PCSK9) I think: What is its purpose? Can it simply be there by mistake? To be frank, I am not entirely sure what the purpose of this enzyme is, but I now know that if you do not have it, bad things can happen. Here is a study which looked at what happens to mice with no PCSK9:

‘Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet b-cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4 months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets¹.’

Sorry, I realise that the language is a bit technical, so here is a quick interpretation.

PCSK9 is an enzyme that degrades/destroys LDL receptors, so cells cannot absorb so much LDL (a.k.a. ‘bad’ cholesterol)
Without PCSK9, beta-cells in the pancreas (where insulin is made) absorb too much LDL
These LDL ‘overfilled’ beta cells were found to be malformed, dying (apoptosis) and inflamed
Mice without PCSK9 which had these ‘overfilled’ beta-cells were also glucose intolerant, did not produce enough insulin and were hyperglycaemic a.k.a. there were diabetic

That was mice, what of men? (And, of course women). Well, if we look at people with familial hypercholesterolemia (FH), they have a lack of LDL receptors, or the receptors don’t work so well due to malformations, or both. Therefore, you get less LDL inside cells, including beta-cells. Therefore:

‘In the cross-sectional analysis from the Netherlands, patients with familial hypercholesterolemia were found to have a 51% lower odds of having type 2 diabetes compared with relatives without the cholesterol disorder, and diabetes prevalence varied by gene mutation type…. Hovingh and colleagues hypothesized that this reduced risk occurs because pancreatic beta cells in people with the condition have decreased cholesterol uptake and improved function and survival².’

Hovingh was almost certainly right.

Now some people will, no doubt, grab hold of this research to tell us that ‘As we told you all along LDL is dangerous and damaging, it even causes diabetes by harming beta-cells.’ I am sort of waiting for an ‘expert’ to tell us this. Maybe they already have. At which point I shall approach them from behind, then hit them repeatedly with a large wet kipper. I shall then announce, with great satisfaction…

‘No, you idiot, what this shows us is that excess LDL inside cells is damaging and dangerous, but that has absolutely nothing whatsoever to do with having a high LDL level in the bloodstream…..you idiot.’

Anyway, adding this information together with the study on mice, it seems that the basic function of PCSK9 may simply be to ensure that cells do not absorb too much LDL from the bloodstream, thus protecting them from: malformation, inflammation and death. It certainly seems to be true of beta-cells in the pancreas. Is it true for all other cells – who knows, but it is a bit worrying is it not?

What is certainly true is that PCSK9 inhibitors will almost certainly increase the risk of diabetes, to an even greater extent than statins. This seems entirely predictable; in fact I predict it now. I also predict that the increased risk of diabetes will take years to emerge. This will be for various reasons that I would like to go into, but fear libel suits.

However, when this adverse effect does eventually emerge I know that it will greeted with astonishment and surprise by the ‘experts’ and, at least in public, by the pharmaceutical companies marketing these drugs. Although I am perfectly certain that they know all about this research… they always do. They ain’t stupid.

The great Nostrokendrickos has spoken. Put this article in a time capsule, to be opened when PCSK9 inhibitors are found to cause diabetes.

References:

1: Majambu Mbikay, Francine Sirois, Janice Mayne, Gen-Sheng Wang, Andrew Chen, Thilina Dewpur, Annik Prat, Nabil G. Seidah, Michel Chretien Fraser W. Scott: ‘PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities.’ FEBS Letters 584 (2010) 701–706

2: http://www.medpagetoday.com/Cardiology/Diabetes/50429

P.S. I wonder what other research they are aware of? I think I might go and find out.

Here they come – take cover

126 Replies

Apart from Rosuvastatin/Crestor, all the statins have lost patent protection, and so the world has changed. I probably need to explain a bit about Patent Protection. If a pharmaceutical company discovers a new, potentially beneficial chemical/drug, it can claim patent protection for twenty two years from the date of first registration of that new chemical compound. Then the clock starts ticking.

So you need to get going to do all sorts of testing on your new chemical to make sure that it actually does something considered useful e.g. kill bacteria, or attack cancer cells, or control progression of rheumatoid arthritis. You also need to ensure it doesn’t kill people, using the sort of doses you would give to achieve a clinical effect. You should ensure that it doesn’t react badly with other commonly used drugs, and on and on.

This all takes time, and costs a lot of money. Companies tell you it costs hundreds of millions to get a drug to market, perhaps even a billion, but their figures are always held tightly to their chest. It certainly costs a lot. How much exactly…no idea. As for the amount of time? Probably about eight to ten years from discovery to launch.

After launch, the companies then have around twelve to fifteen years to sell the drug as hard as they can, whilst they have an effective monopoly. During this window of opportunity they can fix the price wherever they like. This is usually bang on what medical systems think they can afford, or just a sneaky bit more. ‘Oh go on, you know you want it.’

However, once patent protection is gone, generic drug manufacturers that have been waiting in the wings like vultures, can make that exact same drug and sell it, in competition with the company that discovered the drug in the first place – or any other company that wants to make it.

Because generic companies have not had to go through the hugely expensive drug development process, their costs are much less, therefore they can afford to sell the drug far cheaper and still make money. At which point the big companies such as Glaxo, or Pfizer lose interest. Their business model requires enormous profits to support their equally enormous overheads. Selling drugs at a 5% margin is not what they do. They have a workforce of tens of thousands to support.

Getting back to the point in hand. Statins are now, effectively, out of patent. They were the most profitable drugs in the history of the pharmaceutical industry. Lipitor/atorvastatin made tens of billion dollars in profit each and every year it was in patent, and turned Pfizer into the biggest drug company in the world. But statins are now cheap as chips.

Various attempts have been made to combine statins with drugs such as ezetimibe and carry on the patents – you get extra protection for combinations. A few billion has been added here and there. However, the seam of gold has effectively been hollowed out.

So what to do? Shrug your shoulders and move on to a different therapeutic area. Or…? Over the years, billions upon billions have been spent making the statin market into something absolutely massive. This market could also be described as the ‘cholesterol lowering market.’ Everyone, or just about everyone, knows their cholesterol level. They have been trained to be terrified of having a high cholesterol level, and they want it brought down. Bell rings, dog salivates.

In parallel with successfully raising the spectre of having a high cholesterol, the level of cholesterol considered ‘high’ has also been inexorably driven down. Years ago a high level was something over 7.5mmol/l (~300mg/dl). In Europe anything about 5.0mmol/l is now consider high. In the US it is 5.2mmol/l, otherwise known as 200mg/dl (the US and the rest of the world use different units of measurement). However, even that has been further lowered. In those at ‘high risk’ the cholesterol level needs to be below 4.0mmol/l.

The average cholesterol level of human is about 5.5mmol/l (very broad brush stroke), which means that we find ourselves in the weird, yet unquestioned situation, where around 85% of the entire population of the world is now considered to have a high cholesterol. Boy that is some market. Almost every one alive, and with a pulse, should be taking a statin. And people almost demand them ‘I must get my cholesterol level down, now!’

As a pharmaceutical company you certainly do not want to walk away from that, the land of milk and honey…and money. A perfectly prepared market, desperate for anything that lowers cholesterol. Even gaining one percent of that market would mean about twelve million people worldwide… in counties rich enough to pay. If your drug costs a thousand pounds, dollars, or Euros a year, that is still twelve billion pounds dollars or Euros each and every year. Twelve billion profit a year. Be still my beating heart.

And to access that market, all you need to do is to find another way of getting cholesterol down. [Using new drugs that can be patented, and sold at a price that makes a whopping profit]. As a quick aside, the HDL ‘good’ cholesterol raising agents all crashed and burned before you ever knew they existed. They raised HDL and also raised the rate of death from heart disease at the same time. Ooops. So maybe HDL isn’t ‘good’ cholesterol after all. Shhhh, let that be our little secret.

So the industry looked around, and studied everything they could, and they have come up with Proprotein convertase subtilisin/kexin type 9 inhibitors. However, you must ensure that you don’t ever call them that, or everyone’s eyes will simply glaze over followed rapidly by sleep. So this moniker has been shortened to PCSK9 inhibitors. Very catchy.

How do they work? Put as simply as I can. Low Density Lipoprotein (LDL) a.k.a. ‘bad’ cholesterol I is removed from the circulation by binding to an LDL receptor, which is then pulled into the cell. The LDL is ‘unpacked’ and the receptor broken down by PSCK9. However, if you block PCSK9, the receptor lives to fight another day. It is sent back out to the surface of the cell, binds to LDL again and pulls it in. With more and more receptors waving about, the LDL is more rapidly removed from the circulation and the ‘cholesterol’ level drops.

It is true that if you give people a PSCK9-inhibor the LDL/cholesterol levels certainly drop very dramatically. Even more so than with statins. Hoorah! LDL levels can reach virtually zero. Hoorah! Drool! Kerching! As you might expect, a number of pharmaceutical companies have decided to develop their own, very slightly different versions, of PCSK9 inhibitors, and they will all be launching shortly. The one hitting Europe and the US first is likely to be Praluent. Made by Sanofi and Regeneron. It will be given a more catchy brand name when it launches. Cholestegon, or something of the sort.

Of course the hype is going to be monstrous. Newspaper front pages will hail these drugs are life savers, super-statins, Governments must fund them, blah, blah, blah. Billions upon billions will be spent marketing them. Well, you have to speculate to accumulate don’t you.

Experts a.k.a. rent-a-quote dancing bears will do their thing…. ‘Roll up, put money in the jar and the bear will sing and dance any tune you like…’ Yes, experts will dance the tune, and sing the songs required of them by the industry….kerching, kerching, kerching, ker-bloody-ching. ‘Why can’t I see my reflection in the mirror any more mummy?’

Papers will appear in journals that will be reproduced, and repackaged, to be presented to doctors; giving all the scientific reasons why PCSK9-inhibitors need to be used. There are, however, one or two little problems to be resolved.

Statin hype
Cost
Injectable
No outcome data

Statin hype

Having spent billions convincing everyone that statins are uniquely effective, have no side effects, and also cure cancer, bacterial infections, HIV, the Ebola virus, bad breath, poor conversational ability, and other things too numerous to mention, your main competitor is the ‘wonder’ drug you created in the first place. Which is also now very cheap.

So, dear pharmaceutical companies, you are going to have to attack statins to create some space in the cholesterol lowering world. We can already see this happening, with sad looking ‘experts’ confirming how terribly disappointing it is that some people just cannot tolerate statins…when I say some, I mean about 25%. ‘But I thought you said statins had no adverse effects.’

Expert: ‘I know, that is what I once thought, but it seems…sob…that many patients have difficulties…sob. Sorry, I am very emotional about all this.’

Pharmaceutical company executive whispers: ‘It’s OK, you can have your money now. There there, don’t get so worked up. You can have your swimming pool.’

Cost

Statins now cost about thirty pounds a year. PCSK9 inhibitors will be in the region of five to ten thousand – so I have been told. If so, health authorities are going to be very, very, unhappy. They will see budgets spiralling out of control. This could kill these products stone dead in many countries. However, the companies will be very careful to ensure that they will only be looking for them to be used in a very small sub-set of high risk, statin intolerant patients. [And if you believe that, you will surely believe anything].

Injectable

These drugs impact on processes within the cell nucleus itself, so they are monoclonal antibodies. They cannot be taken orally, as they would be broken down in the stomach/gut, so they have to be injected. Every two weeks or so, you will need to have an injection. This can be painful and also inconvenient. This will limit uptake. Then again, some people believe that if you inject something, it must be more powerful.

No outcome data

Whilst PCSK9 inhibitors definitely lower LDL, there is no data on their effect on cardiovascular mortality, or any other form of mortality either. They are launching purely on their cholesterol lowering ability. A surrogate outcome. This, of course, saves the tiresome and costly requirement of demonstrating that they actually work. But it may make it rather tricky for them to gain full approval without any proof of efficacy. Or maybe not.

Despite the problems listed above these drugs are coming. Will they be a success? Well those working in pharmaceutical companies are not stupid. They would not be spending billions unless they were pretty certain of success.

What will success look like? Well, frankly, I am sure that they would be happy with one percent of the population taking PCSK9 inhibitors. That would be about three million in the US, four million in Europe, five million in the rest of the world – in countries that have enough money to pay. This is a total market of one hundred and twenty billion pounds/dollars a year. Not bad. Three drugs sharing one hundred and twenty billion is forty billion each, per year, for fifteen years. That is $600Bn lifetime drug earnings.

If they were to succeed in squeezing the market up to ten per cent, that would be a market of one thousand two hundred billion a year. Greater than the GNP of almost every country in the world, up to about Canada. My guess is that they will get to about two to three percent. This market will consist of those with very high cholesterol levels who are ‘statin intolerant’. Yes, be ready for the phrase ‘statin intolerant’, it is how those poor unfortunates who cannot take statins due to adverse effects will be described in future.

Speculating wildly, if they did manage to get everyone on a statin to convert to a PSCK9 inhibitor then the entire GNP of nations would be gone. In the UK, twelve million, or so, are ‘eligible’ for statins. Twelve million times ten thousand is one hundred and twenty billion pounds. That is slightly more than the entire budget of the NHS. Money well spent?

You have been warned.