Instant Genius - The future of drug discovery

Episode Date: October 1, 2023

If we learnt anything from the COVID-19 pandemic it was that, as a society, we owe a huge debt to the scientists around the world that work, day in, day out, on developing medicines to keep us healthy and to fight disease. But how does this process work? In this episode we catch up with Prof Simon Ward, Director of the Medicines Discovery Institute at Cardiff University. He tells us about the journey a new medicine has to take, starting from its initial inception in the lab, through various rigorous clinical trials before it can finally be used in clinics and hospitals around the world to save lives. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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delivering digital precision with analogue warmth. So you can experience exceptional sound at home. Music just as the artist intended. Visit name audio.com. to learn more. Hello and welcome to Instant Genius, a bite-sized masterclass in podcast form. Each week you'll hear world-leading scientists and experts

talking about the most fascinating ideas in science and technology today. I'm Jason Goodyear, commissioning editor at BBC Science Focus magazine. We humans depend on the Earth's natural resources for our very existence, so it's vital that we take care of them. However, it's abundantly clear that the environment isn't in great shape at the moment. In this special six-part series, we explore the different factors affecting the sustainability of our natural resources, investigate what their current state is, and discuss what we could be doing to take better care of them. If we learnt anything from the COVID-19 pandemic, it was that, as a society, we owe a huge debt to the scientists around the world that work day in, day out,

on developing medicines to keep us healthy and to fight disease. But how does this process work? In this episode, we catch up with Professor Simon Ward. director of the Medicine's Discovery Institute, a Cardiff University. He tells us about the journey a new medicine has to take, starting from its inception in the lab through various rigorous clinical trials, before it can finally be used in clinics and hospitals around the world to save lives. So before we get going, can you tell me a bit about your background?

Drug discovery seems to be a very sort of multi-disciplinary process these days. So how did you get into it and what's your day-to-day like? Yeah, so I got into drug discovery, first of all, by doing a degree in chemistry. So I went to Cambridge University to study natural sciences and specialised in chemistry while I was there. And then after that, did a little bit of work in a small biotech company in Cambridge. And this was right at the start of the big biotech boom. There was lots of money in the area, lots of excitement. There was champagne crates arriving after work. It was a very heady days of the biotech industry. And I went back from there to do a PhD. And that was the time that really shaped my mind in terms of where I wanted to go with chemistry.

Because although I was enjoying the challenges of chemistry and the challenges of synthetic chemistry, which is really making new molecules, molecules people haven't ever created or seen before, I felt it was a little bit without purpose. And I really wanted to do. use those skills towards bringing new medicines into reality. So that's, that was the sort of the path I took from a more pure chemistry background coming forward into a drug discovery environment. Yeah, so as briefly as possible, could you sum up what your role is? So my role now is running an institute in Cardiff University where we're trying to discover and develop new medicines. That's the simplest definition possible, I think.

Well, that's super exciting stuff. So before we get sort of into the meet of this conversation then, I understand that you're a member of the Royal Society of Chemistry. So why did you decide to join and, you know, what benefits has that brought you? So I decided to join when I was in my first job in the biotech industry. So back before I even did my PhD. And for me, it was a community of like-minded professionals. It was a way to understand what were the key developments in the area. But more important than that, it was a way to understand what jobs were available, where I could maybe go and work. And in the early days, get some help and advice in terms of career, mentoring, and actually get a bit of a foothold of starting to work as a chemist in the area. Because it's not like medicine or law where you have big professional bodies which you're obliged to join. It's optional to join the RSC. So it was very much around my personal career benefits at the time. And you found it helpful?

It's been something which I've been part of for a long time now. It's been an organization that at times I've had a lot of contact with and I've got a lot out of in terms of career benefits. And at other times I've contributed back more in terms of being parts of committees or organizations, setting up conferences and so forth. So it's been a community of people which has been essential, I think, as I've jumped around from job to job to job, the network of people you know and the community you can build is absolutely key to going forwards. So then, let's get into that career and that community then, the process of drug discovery. So this is really fascinating. So let's start at the very, very initial stages then. How do you even come up with an idea for a new drug? You know, where do you start? What is the starting point?

So the starting point is really trying to understand the disease or the condition you're trying to treat. I think it's fair to say that a lot of the drugs we take, a lot of the drugs that a lot of us are familiar with, drugs which came about by chance, by serendipity. So the drugs which have, we've sort of stumbled across over our lives. And that makes it quite difficult really to then think, okay, well, if I don't want to go out this just by, like going into the casino, just by a game of chance, how do I actually go about this in a targeted way? And the way forwards there is to really understand the disease. So you have many, many years of maybe quite basic

biology research and clinical research that is forming a hypothesis of, well, so what is wrong in schizophrenia, in leukemia, in whatever the disease might be, and actually by understanding that better than how can we come up with an approach where we might be able to think of a drug intervention which would help? Yeah, so let's have a look at that stage. I think that's really interesting. So let's say we've identified the disease. We know what we want to tackle. then how do we go about choosing what actually we're going to tackle that with, the molecules, the chemicals, etc? Yeah, so it's basically a series of hypotheses and a series of coming up with a question you want to ask and thinking of a way to answer that question. So we might say, are we think that this enzyme is involved in this disease?

And if we inhibit this enzyme, for instance, that will improve the disease. and then essentially we need to find some chemical tools to help us probe that question. So we then, as a medicinal chemist, would help find ways to design tool molecules, probe molecules. We'd inhibit the enzyme. We'd see whether that does help in our model systems. And if it doesn't, we'd refine the hypothesis, maybe come back with a different enzyme to target. Or if it does, we'd then maybe start a drug discovery program. So it's an iterative cycle of questions and answers based off hypotheses. So you mentioned the chemical tools that you use there, the tools of the trade, as we might say.

So is there a kind of simple way that you can explain how some of those work and what approaches you take with them? What's very challenging when you're thinking about making a drug molecule is clearly that you need to be considering so many different aspects. And you'd already hit the nail on the head and said that this is a multidisciplinary sport. a game where lots and lots and lots of different disciplines come together and lots of experts come together. Because what we're trying to do is essentially influence something within a person, which is such an incredibly complicated organism and situation, that no single discipline or single scientists can ever bring forward anything which is going to be meaningful just on their own. So when we're talking about a chemical tool, we're having to think not just about maybe the biological

effects that the molecule might have. So can we bind to a certain protein? Can we inhibit a certain enzyme? But we're also having to think about all the physical properties, all the solubility and stability and toxicities, and ultimately how the drug might have to get to the right part in the body. And what we're bringing to bear, there are lots and lots and lots of different properties of the molecule with lots of different scientific disciplines. And we're trying to drive a design strategy based off this complex, multi-parametric, as we'd call it up, so multilateral. multifaceted problem. So you used like a nice sports analogy there. So can we say like what does a typical team look like if there is such a thing? So typically in drug discovery programs, you have

teams of chemists and biologists as the core to that team working together. So the biologists have got the better knowledge of what's happening within the human body and how the disease actually works and the chemists have the better knowledge of what sorts of molecules might be possible, what sorts of things might be possible to consider as drugs. And so you evolve and work across that, that gap in your knowledge to try and build this drug discovery hypothesis. And then you bring in around that other people such as clinicians who obviously understand the disease. You bring in patient groups to understand the need that you're working with. You bring in experts in pharmacology, that solid form, the crystallinity of the disease. You're bringing in patient groups.

the materials and you bring in lots of different scientific disciplines around it. And one of the things that for me is super, super exciting. And there's always been a real bonus of this sort of work is working with this group of people where you need each other's expertise to achieve the task together. So you've got no single person who could do it all. And you actually have to work across this boundary. So you're always learning. You're always finding new things. You're always challenging each other. And it's a really stimulating environment to work in. So I think one really interesting thing about drug discovery is where they come from. So people will know like the famous stories about penicillin or things like that. But, you know, how does that work in practice for

somebody like you who works in the field today? So one of the big challenges is that there are the famous stories of the eureka moments, which could either be, as you said, the penicillin discoveries or can be the discoveries. Viagra is one of the hugely common ones that are talking about now where you have a drug starting to be developed for angina, suddenly being developed for a completely different reason from really quite surprising observations going on in the clinical trials. And those things were not predicted. So it's very difficult to say to somebody, we'll come into a rational drug design, but be prepared for something so unexpected. You've no idea where you're going to go. So we have to keep our eyes open and our minds open because

as we're going through these complex experiments, every now and again, we see something, You think, oh, okay, well, that's not what we were aiming at. That's not really where we thought we were going. But actually, we can see a real opportunity here. And that happens more and more. And you see it a lot nowadays where maybe a program starts towards a particular type of cancer. But as you're developing the understanding, you think, actually, this is going to be a more effective therapy in Huntington's disease or something very, very, very different. But there is some surprising chain of logic which takes you down that path.

So I think having a really open mind is absolutely key to that. Business owners in California know there's a lot to keep up with. The rules change constantly. Guidance shifts. Even a small payroll mistake can turn into an expensive problem. And that's why so many business owners visit guardianhr.com for practical, reliable, HR help when they need it most. Guardian HR is local in L.A.

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This podcast is sponsored by Name, Audio and Focal. With over 100 years of combined expertise, Name and Focal have been bringing music to listeners just as the artist intended. Since day one, this mantra has shaped every innovation in high-fi design, technology and acoustic engineering, balancing craftsmanship and tradition with pioneering thinking. Name Audio pushes cutting-edge technology

to ensure digital precision whilst sustaining. Pratt, pace, rhythm and timing, the elusive quality that makes music feel alive and gives it emotional texture. Today, in partnership with French acoustic specialist focal, name audio creates systems that deliver exceptional sound and unforgettable listening experiences at home. Try it for yourself at a focal powered by name boutique. Visit focal powered by name.com for more information. So you mentioned there the different phases of clinical trials. So I think that's something people will have heard of, but perhaps they're not familiar with that. So can you run us through the sort of journey of a drug as it goes from its initial idea to actually featuring in clinics and hospitals?

Just a quick overview and then we can drill into each stage a little further. Yeah, so the journey is essentially one of mitigating risk and building confidence. So you start with an initial hypothesis of how. you might want to treat the disease. You start to develop a molecule which you think would be able to do so and you build confidence in its profile. Once you have a molecule, which you think has the ability to progress into the very expensive clinical trials, you can start the process of then phase one trials, so is the molecule safe to be taken? So generally healthy volunteers through to phase two trials, which are generally where you start to test the molecule in a patient population, and then big phase three

trials which are multi-centred around the world where you've got a very broad population base to try and test the drug in the widest possible clinical setting and then approval and marketing and then onward development from there. So that sounds like a terribly complicated process. Can you even say like a ballpark figure how long that would take? Possibly 12 years on average, I'd say. There are a number of steps in there which are are determined by regulatory authorities and a lot of the safety intolerabilities, there's a lot of steps in there which are built into legal frameworks of lots of our countries, which require essentially a certain level of caution and a certain slowness in the process

to be able to have confidence that we're moving forward acceptably. But it could take decades and decades where maybe we fail in the clinical trials, we learn why, we go back and start again, and there are a number of programs which have been running over many, many, many years now. So let's have a look at something that I think a lot of people would be interested in knowing the answer to. So we mentioned there trials in human volunteers and then human patients. But if you read the science news, you'll often read about studies being carried out in mice. So it seems to be a very common thing. So why do we do that? Why are mice so useful in this

application? So mice are used in a lot of fundamental biology work. because they are easy to manipulate genetically. And that allows a very good platform to ask very precise and specific biological questions. So the mice are not, from my perspective, part of the drug discovery in development process as much, but they're very, very critical to the fundamental hypothesis generation in the first place.

So you have lots of labs that will use mice to be able to generate those key, is this target, this protein critical to this disease question. So let's have a look at the phase one trials then. You mentioned healthy volunteers. So how do we go about finding those? So this is a very interesting point. I'm running a phase one trial at the moment

and the recruitment to that is absolutely key to this success. So essentially what you're asking people to do is to step forwards and volunteer to take a medicine that hasn't been taken by people before. So it's a big scary thing to do. When I first started working, it was something where it was common practice for the lead chemist to be part of that trial.

And that was an interesting perspective, really, because in some ways that was quite good, that we're saying, well, if you believe in this program, you step forwards and be part of the trial. But I think as time went on, there was a realization that if you were leading the project from the chemistry side, you had a vested interest in the project really, so you weren't coming at it with a neutral

perspective. But essentially, what we have to do is to advertise and adverts go out on all the usual social media channels and networks to try and encourage people to step forwards and be willing to take part in a trial for which they will have no personal benefit, but they're just contributing to the broader enabling of drug development that's going on. Yeah, so somebody is perhaps interesting and helping out in this way. What can we say to sort of assure them that this process is safe? You know, what gets a sort of nascent drug up to this point where we can say, we're happy to carry out phase one trials on this? So one of the enormous challenges from my point of view is how do you get a molecule out of the discovery phase, so the lab phase and into the development phase,

so decide what we're doing these clinical trials. And part of the reason that's difficult is that there are so many checks and balances, so many criteria you have to meet before you can progress. And these checks and balances have evolved over decades, and a lot of them have evolved because trials have gone wrong in the past or drugs have given side effects in the past. And as people have learned from those, and as the regulators have learned from those, they've basically put the bar higher and higher and higher and higher in terms of what you need to have to get a molecule safely through. So when you want to start a clinical trial, so in the UK you have to write to the Medicines Health Regulatory Agency, the MHRA, and you have to submit a big dossier showing not just why you think the molecule is going to be useful in the disease, but you have to submit huge amounts of information around why the molecule is safe, why you think it'll be well tolerated, and a lot of justification of the doses you want to use in the clinical trial. And when you start the trial, you start incredible.

cautiously with a huge amount of scrutiny and huge amount of oversight. So it's a very, very cautious, hugely cautious approach. So what sort of level of success can we say do we need to get from phase one into phase two? Yeah, so the success rates in drug development, drug discovery are a huge topic of discussion and debate because the costs are enormous as you go forwards. So even small failure percentages actually in real terms cost a lot of money. So about half of drugs that start phase one get through to phase two, which is a pretty reasonable number, but the number that get through phase two is more like 20 or so. And then again, only 40, 50% make it through phase three. So you've got about a 10% chance of starting

clinical development to getting a drug on the market at the end. So you mentioned there, roughly 50% of drugs get through phase one. So what happens if a drug does fail phase one? Is that the end of the road or can we go back and tweak it and try again? Yeah, so there's two things that can happen. One could be that it fails for some reason that doesn't actually stop it going forward for a different disease, but maybe stops it going forward for the primary disease. So you may have heard of repurposing and this is a word that we use a lot in terms of can we reposition molecules in different diseases. So can we reuse, basically build and get some value from all the money and the work that's gone into the drug? But you're absolutely right. The other side would be

maybe we'd give the drug to people and find it was metabolized too rapidly. And so perhaps unexpectedly, the levels of drug in people who were very low and we could understand why and go back and then chemically modify that drug to be more stable. The problem is then you have to restart all of the safety and all of the work to make that clinical trial application again. So you go back, but you're going back at least three years. So presumably there's a whole multitude of reasons why a drug can't make the grade at this point. There's fewer reasons in the phase one, which I guess is why the success rates are a little bit higher, because the only two things you're wanting to check really are, does the molecule get absorbed if you're giving it as an oral medicine?

So does it get absorbed and distributed around the body, as you'd hoped it would do? And is it well tolerated? And if you've done enough work beforehand, those two questions are probably a little bit more, you have a bit more confidence behind them than you do for some of the questions that come later in the clinical phase. Okay, so let's have a look at that then. Let's have a look at phase two. So this is on people actually suffering from the disease. Is that correct? Yeah, generally, yeah. So how do these compare in scale and in sort of how strict the criteria are that the drug needs to proceed under the next phase? Yeah, so this, for most of us, is the key experiment. So we do all this work in the lab and we do all this hypothesizing and all these idea generating and clever thinking. but fundamentally what we need to know is in a person who has the particular disease,

is this drug potentially useful? And that question is the key question and the challenges, we often don't ask it until maybe seven or eight years after starting the program. So what's key is that you can ask that question in a way which is quite simple. And you could imagine maybe if we were developing a drug which was helping with blood pressure or with heart rate, you've got very, very, very, straightforward, objective, clear measures you could use in your phase two trial to say, I'm giving this drug, has the person's blood pressure come down? And you've got a very, very simple

measure to do that. But if you compare that with situations such as schizophrenia, such as Alzheimer's disease, situations where you've got diseases, which are much more complicated, far less well understood, you've got often much more challenging readouts. A good example is neuropathic pain, so real chronic pain that people live with. But we often assess pain on the basis of a questionnaire. And obviously, people's perception of pain is very different depending on all manner of factors. And so the more subjective you make the trial, the more variability you put into the trial. And so the harder it is to see a clear signal in that trial. So you mentioned earlier then that phase three is pushing out of the drug to a worldwide setting.

So what's the difference between a phase three drug and one that's finally approved? So once you finished phase two, you know that your molecule has the potential to work in patients, but you've generally only done maybe 100 patients and maybe you've selected a group that's as similar in characteristics as possible to give you the best chance to see your signal. So once you've done your phase three trial, you've maybe done the same trial across 1,000 patients or across 10 different countries. So you've got good confidence that there's reason to believe your drug would work. But of course, your drug then might be given to millions of people after that globally, with all differences in people's backgrounds and genetic compositions. And so what generally happens then is what we'd call phase four trials.

So this is after the drug is approved, and this is a continuous process of monitoring the effectiveness and the safety of the drug. And it's the safety that's the big concern after marketing, because as you go to a wider population, rarer and rarer types of people, every now and again there's going to be somebody, for some reason, that drug isn't suitable for. And it's monitoring and understanding that that's key to the post-marketing success of a drug. So this series is based on the theme of sustainability. So we've talked there for quite a long time about what a lengthy, complicated process this is. What sort of concerns are there around sustainability? Can we make this process more efficient? What do we do to make it more efficient?

These are questions that have plagued the pharmaceutical industry for its entire existence. And that comes in part from the fact that a lot of the industry that drive, these processes are our shareholder-driven companies, and they come with their own timelines and financial and market pressures to deliver on timeframes, which are clearly very different to the timelines that drug discovery and development work on. So the sustainability there and the ability to know when to stick with an area and when to jump strategically is absolutely critical. And one of the things that's very challenging, one of the things I've experienced personally, is you can be in an area of really quite promising science,

drug discovery and development, but there will be a strategic or financial pressure on the company which will cause it to shift. So you've seen over the last few years, again from personal experience, neuroscience being downgraded in terms of a priority area within the farmer industry because the success rates are more challenging.

So you have not just perhaps scientific challenges to getting molecules through to development, but you can also have significant business and strategic decisions coming in and actually changing the whole landscape you're working in. So having said all of this, then, what does the future of drug discovery look like? So at the moment, we're talking a lot about AI.

You know, what roles are these emerging technologies going to pay? I mean, are they going to be able to streamline the process? I think every few years, there is hope that some revolutionary technology is coming through. And I suppose through my lifetime, it's been automated synthesis where we can make millions of compounds. It's been high-thruput screening where we can screen millions or billions of compounds. And now we have the AI side. And all of these contribute.

So AI has been part of drug discovery for a long time. It's been there in different guises. It's more recently come to the fore in terms of how it's described. but the computational algorithms have been a component of how we've done drug discovery for many, many years. And it's going to be a useful tool. It's not going to be the be all and end, or it's not going to be the ability to, with a few clicks of the button, actually get to a drug in some lightning fast time.

But it does allow us to wrestle with enormous, complex data sets much more productively than we can just with our minds alone. So it's going to be another very very, very, very, very useful tool in the armoury, but we are still through these cycles of hope and hype, I think, with all of these technologies. Yeah, so at the end of day, really, the goal here is to effectively combat disease. So sort of by way of closing, how optimistic are you for the future of drug discovery? You know, can we beat things like antibiotic resistance?

Well, we'll be able to develop more effective drugs to treat deadly diseases. I think the field has developed in the last decade or so. to bring a lot of sensible scientific developments together. So moving from fields of hype and hope, it's actually capitalised on a huge amount of developments in molecular biology to really allow us to progress drugs and develop drugs in ways we couldn't do before. So I think scientifically, actually, the area looks very, very encouraging and very promising. I think the area where there's the biggest challenge is the funding side of this,

because fundamentally, the big disease areas, the big companies in these areas are and have to be motivated by commercial return. And so when we're considering how we respond to new pandemics, how we respond to future bacterial crises, there have to be mechanisms in place to fund these outside just relying on the big farmer. And so I think the government and broader charity activity in terms of funding is going to be key to drug discovery and development more so than just the scientific discoveries. Thank you for listening to this episode of Instant Genius, brought to you from the team behind BBC Science Focus. That was Professor Simon Ward, director of the Medicines Discovery Institute at Cardiff University.

The current issue of BBC Science Focus magazine is out now. Pick up a copy wherever you buy your favourite magazines or download us on your preferred app store. You can also find us online at www. sciencefocus.com. This podcast is sponsored by Name, Audio and Focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name Audio believes you can have digital precision

with analogue warmth. Alongside French acoustic specialist focal, Name creates high-end audio systems, combining innovation with craftsmanship, so you can listen to music, just as the artist intended. Discover more at Name audio.com.