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
- No outcome data
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.’
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].
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.