Big Pharma: How drugs get made

How do drugs get from the bench to your bedside?
12 September 2017

Interview with 

Mene Pangalos, AstraZeneca


Drugs are mainly mass produced by pharmaceutical companies based on very detailed knowledge of the mechanisms of diseases and how our bodies work. AstraZeneca, one of the world’s largest pharmaceutical companies has just moved to Cambridge. So Chris Smith took the opportunity to ask Mene Pangalos, Executive Vice-President of AstraZeneca’s Innovative Medicines and Early Development Biotech Unit, about how a company like his invents and markets medicines in the modern era...

Mene - Turning science into medicine is probably the hardest journey we go on in our careers, and what actually gets us out of bed every morning. If we take a disease like heart failure where we’re trying to regenerate the heart, or reduce the damage in the heart after a heart attack, we'll take a cell from the heart and we’ll try and understand how that cell works, how it survives, and how we can try and affect its survival in a positive way.

We may find a receptor on the surface of that cell. I would think about it like a lock that we can open with a key, the key being the drug. If we can find a molecule that’s able to turn that lock open so the receptor gets switch on and, as a consequence of switching it on, we’re able to keep that cell alive, that’s how you start to think about generating a therapy that can regenerate the heart.

Chris - So what do you do then? You think we know what that receptor looks like, so then you go to your chemist and say I want you to design me just umpteem molecules that might engage with that lock, and then we’ll try them - what’s the process?
Mene - It’s long and arduous and, of course, we’re simplifying it to the ‘nth’ degree but that’s exactly right. You say I understand the shape of that lock, find me some keys that fit it, but when you find those keys please make sure they don’t fit any other locks that are on the cell, which are the other receptors that you don’t want to hit. Because, if you hit them you have side effects, you have toxicities, so this is why the process is complicated and difficult.

Then if you add the complexity on top of that of - and by the way, the key has to be able to penetrate the stomach and not be dissolved by all the acid in the stomach. It has to get just to the heart and not to the liver and the kidneys. It’s got to be available for 24 hours during the day so that you only have to take it once a day. That adds the complexity to what our magical chemists have to do in terms of designing those molecules that unpick that particular lock, and only that particular lock, but also do it in a way that doesn’t cause you lots of side effects when you take it.

Chris - At what stage do you actually start putting it into a living thing, whether that’s an animal or a person?

Mene - It takes quite a long time because the keys or the molecules have be stable, they have to be selective, and so that can take years before you get it into an animal. Then optimising that key to make it suitable for going into people, that can take probably another two to three years. Then you have to do all the toxicology experiments, which will take you another year or so. So you can see how very, very quickly you get to a journey that’s somewhere between five and ten years.

Chris - What fraction actually make it?

Mene - Less than 5%. So from when you’ve created the key to the lock and it’s ready to go into people, less than 5% if those keys ever become medicines.

Chris - So there must be a big price tag if we’re talking ten years plus of investment to get to that state, the amount you must spend for that 5% success rate must be humongous?

Mene - Our industry invests billions. AstraZeneca invests over 6 billion dollars a year just on research and development. So it’s a huge, huge investment and, of course, the risks are incredibly high, so when we do get a drug that’s successful we get very, very excited.

Chris - How long do you have in order to recoup what you’ve had to spend and then have enough of a war chest, effectively, to invest in the next arsenal of chemicals that are going to become the next blockbusters - we hope?

Mene - From the time we identify that key, we generally file a patent. And given how long it takes us to move that molecule into clinical trials, and then develop it through the clinical trials and ultimately get it approved as a medicine. I would say, on average we’re probably in the region of around ten years of patent exclusivity when you have that molecule, that key to yourself and no-one else can copy it. But once the patent expires, ten years down the road for example, then anyone else can make that key. And, of course, once that happens you get what’s called generic erosion and the price for the molecule goes down very, very steeply, and it become pretty much free for the rest of eternity.

Chris - It’s the 5th September today, and in Brussels this European initiative called DRIVE-AB is having it’s final meeting. DRIVE-AB is this initiative which is designed to drive reinvestment in research and development and responsible use of antibiotics because antibiotic resistance is a massive problem. But to cite DRIVE-AB’s statistics, they say there are just four pharmaceutical companies that have maintained investment in the development of new antibiotics. Why has the industry shifted away from what is clearly a massive demand area?

Mene - For us, it’s was an area we can’t spread ourselves too thin, so one of the areas where we think we can compete globally and do very, very well. I think one of the dangers that we have in our industry is that you could try and do everything and then you don’t do anything particularly well. So, for us, it was a decision that in oncology, cardiovascular, respiratory disease, we can compete globally.And the antimicrobial space, it’s a very, very challenging area. If you think about how antibiotics are used today in the terms of the fact that new antibiotics tend to be reserved as a last resort which means that, therefore, your medicines are not adopted early and, therefore it become difficult to justify any returns on your investment. But, ultimately, companies have to make the choice of where they think they can compete and actually be successful.


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