How Does a Molecule Become a Medicine? Drug Discovery & Clinical Trials

[00:02:34][Music] hello and welcome to the show how does a molecule become a medicine brought to you by the pond of science team nottingham i'm sebastian or seb your host and i'm a phd student at the university of nottingham studying studying small proteins called cytokines that coordinate our immune system in the in its find against pathogens and speaking about pathogens i'm sure most of you have had enough from this one little bug that has kept us on our toes for more than a year now but thankfully with unprecedented speed multiple vaccines have been developed that touch wood will soon enable us to return to normal lives as before the pandemic but how exactly does one develop such a drug or vaccine and what can we do to improve the process and keep up the pace even for other drugs as well we've invited two fantastic speakers stan bukowski and peter scorse from nottingham based pharmaceutical companies signature discovery and quotient sciences who will take you on the journey a molecule has to take before becoming a fully authorized medicine then we'll start with his talk on modern early drug discovery and pre-clinical testing using the antiviral lena kapavia as example and after this peter will take over to tell us all about the clinical trials and how regulators actually decide if the medicine is fit for treatment of patients and while we're very sad not to bring these talks to you in our usual collection of pubs and bars panda science chapters from all across the uk have have made up for this and created a number of exciting online shows that will be streamed live here on youtube throughout the four days of the festival so if that sounds interesting make sure to have a peek into the program at pintoscience.co.uk and also check out the science art gallery in a tab on the website and finally this show is made for you so please get involved by asking loads of questions and commenting using the stream chat our speakers will be happy to answer any questions in the q a sessions following their talks and furthermore please let us know about the most interesting drug related or drug discovery related facts you took from today's show by tweeting at point of science using the hashtag pine21 and hashtag molecule to medicine and now without further ado i'm delighted to hand over to dr daniel bakowski principal scientist at signature discovery for his talk over to you dan thank you sebastian for the very kind opportunity to talk about drug discovery and feel very very kind introduction um so i think to really understand how early drug discovery works it's probably useful to sort of to go back in time first the roots of medicine may run deep um and it's it's it's easy to be very patronizing about our forebears i mean here you can see bloodletting and leeches it's very easy this is a mock the state of scientific knowledge then but it's also important to recognize that even then there is a history of empiric empiricism of astute's observation and in fact it was this astute observation it was the only means by which we used to be able to find new medicines where essentially it's just a matter of seeing that a novel substance or a novel treatment could exert a beneficial or desired effect i.e it made the disease better and you can hopefully understand the advantage of this and that it requires absolutely no understanding of biology it's simply requires someone to be able to show that a remedy works and on the right here i've got one such astute observation and this was from 1763 and it's a it's a rather lovely letter to the royal society by um uh by uh it was his name was edward stone and what he showed or he reported was that willowbach an extract from that was very good at treating egg or fever um if you actually look at his the rationale for why he tried it's rather charming and certainly not very scientific but nevertheless he showed this is probably what we could describe as a very very early clinical trial and our next stop then from sort of history way back in the past is the late 19th century 1897 to be exact leverkusen in germany and by 1897 chemists had identified the active factor in willow bark there's a compound called salicylic acid but salicylic acid it does reduce fever it's an antibiotic it reduces essentially fever symptoms but it's not a very nice drug it's extremely bitter and it's very very corrosive so the chemists buyer and it's important to understand this is not only the birth of modern drug discovery it was the birth of the modern organic chemical industry what this chemist did is they deliberately synthesized some derivatives of salicylic acid and they thought well can we improve on its properties can we find a better drug and we might very generously call this a library today and the chemists they synthesize the grand total of five derivatives so it's not very ambitious in terms of modern chemistry and what they found was that one of these and that's the the top derivative this this the acetyl uh derivative of salicylic acid acetal salicylate turned out to be far far better than the parent molecule in fact it was so good they decided that within two years it was being sold to patients and it's the world's first blockbuster drug and even in 2021 a billion people a year still take this drug and what i want to say is that the reason i've introduced this is that it's an interesting sort of process we have this concept of a lead it's a compound start with we do a bit of chemistry around it we generate a library and then we look for the best of these can we improve on it screening and this really is the process of modern drug discovery this is late 19th century remember so um oops excuse me um but a lot has happened in the 120 years since and ultimately it's a question of scientific advances and there have been huge huge advances in both chemistry and biology so if you will recall the biochemists they generated a library of five compounds now a big pharma company would have a drug discovery library of perhaps a million unique compounds it's unimaginable scale and also there have been significant advances in biology in fact science as a whole has moved at a pace and in directions the early chemists early pharmacists who probably have unimagined they simply couldn't have imagined this the pace and the scale of scientific advances but what the what this improvement this understanding and biology really offers is it gives the option of target-based drug discovery so instead of just throwing chemicals at a disease and looking for a phenotypic improvement we can actually identify a specific target and decide okay we're going to drug this particular protein this particular enzyme and it's all based on a scientific rationale by understanding how the disease works if you can understand physiology if we can understand pathophysiology we can understand maybe there's a good way to develop a modern drug but the modern drug discovery is very very different from the from the late 19th century to in other ways most first and foremost it's incredibly slow and it's extremely expensive drugs will commonly take longer than a decade to take to the clinic and easily over a billion dollars and worse attrition is very very heavy in this industry most projects will fail and this attrition because of the huge cost and time investment required it discourages innovation and inflates drug prices we're all familiar with stories of big pharma and drugs so this has led to the concept of well okay we have to accept the risk attrition from various reasons so what if we can fail fast fail smart and fail cheap that way we can recognize that there is attrition but we can mitigate it and that's understanding the process having a good drug development process we can actually reduce the impact of this and hopefully get drugs to clinic faster and more cheaply so what does the modern process of drug discovery look like so let's just recall it takes over a decade and billions of dollars to get drugs to market so i've simplified it somewhat here it's just the four initial events and it's a process with many moving parts so first and foremost for target-based drug discovery we need to have a target we need to have confidence that interference this target inhibiting it or stimulating it will give us a beneficial effect in a disease and we hope everyone here will appreciate the importance of basic research for this we need to elucidate the biological pathways which let us understand the molecular mechanism mechanisms of disease by understanding those we can then identify vulnerabilities in those diseases places where soft points where perhaps we can intervene pharmacologically this is all hypothesis-driven when science drives every aspect of modern drug discovery we need confidence that modulating this target is going to work but having a target is just part of the puzzle the next thing we need to do is to have an assay an assay through which we can interrogate this target to see whether drugs work whether or not they inhibit or they stimulate depending on the target identification and validation we might want to inhibit some we might want to stimulate others in primary assays they come in many many flavors they can be biochemical let's say purified protein the target itself they can be cell based and they have many many different readouts but what's important they all share is that they are very very robust they're reliable they're efficient they're miniaturizable because what we want to be able to do ideally is throw hundreds of thousands or millions of compounds against this target to see what hits what works this is something we call a high throughput screen [Music] so following a primary assay we'll then have secondary assays and these come in again many many different flavors we'll have a selection of orthogonal assays so these just give us confidence that what the primary essay is telling us is true if we've identified a novel chemical compound that looks like it's hitting our targets we need to confirm is that genuine or is it some peculiarity of the assay itself is it a false positive so secondary assay will give us confidence there they will also show us whether any compounds are toxic to cells obviously a toxic compound it's probably not going to make it to the clinic it's not going to be very nice drug and finally selectivity assays and that's because drugs are very very promiscuous things indeed in fact it's vanishingly unlikely that a given drug will only target will only bind to and modulate the target we're interested in so target based drug discovery there are for each target we're looking at there are tens of thousands of off targets where we might not want to drug for example some of the proteins the ion channels involved in regulating the heartbeat we clearly don't want to target those with an immuno modulator for example and finally the final stage is something we just call add me dmpk which is fantastically confusing to anyone new to the field but ultimately all it means is drug fate so for a drug to work we have to be able to deliver it to the target we have to get it on board the patient we also want to make sure that it might it stays on in the patient for long for as long as we need to have its exerting effects many drugs that are fantastic in early in vitro assays in the prime yeah in the secondary assay they would never ever make it to the clinic because some of them will simply not be absorbed by a patient or others will have a very very short half-life which means they're cleared from the body they leave the body very very quickly they're either excreted or they're metabolized so having an understanding of this is crucial to modern club discovery and finally the most important thing about this cascade as we like to call it is that it's iterative so what we can do is we can throw a million random compounds at a target and we'll get a get a few hits a few thousand compounds that are quite interesting but what we can do is we put those through this cascade and we tell chemists okay these compounds are interesting they're not good drugs they're not very potent they're not very selective but can you do anything with them and the chemists will then tweak they'll modify them just like buyer did for salicylic acid and then we put those back through these assays and we say is it any better just like buyer did and ultimately with enough iterations here hopefully the plan the goal is to get a much better compound a much more drug-like molecule and with each iteration each generation when we operate this we improve our knowledge around the drug this concept of structure activity relationships to understand how the chemistry works how it binds to our target and we've got access to all sorts of magnificent fantastic scientific techniques we can visualize we can actually visualize drugs binding to targets with techniques like cryo electron microscopy x-ray crystallography really really fantastic these are things that biochemists would never even have imagined what was possible so i want to give you a case study now about modern drug discovery and i've selected this compound here lena capovir i'm pretty confident that not many of you will have heard of this compound and so so why why pick this compound that no one's ever heard of and there are three reasons the first is is that it's an antiviral what 2020 2021 is still showing this is that everyone is trying to become an embryologist almost uh it's so really it's it's an interesting target it's also a chance to rehabilitate small molecules which is what drug discovery is largely about as antivirals and for covid19 it's been a very very complex murky past everyone here will have heard of hydroxychloroquine ivormectins zinc being sold as as cures panaceas to cover 19 and the truth is they simply aren't they simply don't work very well and a proper discovery cascade would show this and it has shown this and yet still we see these compounds having traction when they really shouldn't lend a cap of it was also voted small molecule of the year in 2020 so it's a really it's an exciting interesting molecule for many reasons and finally there are quite a few twists in the discovery tear which is quite nice so let's step back to this process of drug discovery it's a target id in validation what is lenicapavia meant to be doing so what i've got here is a very very simplified life cycle of the hiv virus selena capovia is an antiviral use for the treatment of aids so it's obviously a very very different viral disease to cope with 19 but one which is of probably very similar sort of burden to society it's a catastrophic chronic disease heavily stigmatized and this is the process the life cycle you have to understand that we've got huge knowledge about how this virus works and each of these steps is the virus binding to a target cell being imported releasing its genetic material and enzymes and then going through the process of replication budding and then generating many many more viruses to infect many other cells by understanding the steps here from basic science each of these is a vulnerability that we can potentially target with drug discovery and the target that lena capovic has picked is quite an interesting one it's this thing here the capsid and the capsid is essentially the packaging for the hiv virus it's it's a really beautiful structure it's it's a fullerene cone and it forms as a polymer basically of this of a capsid protein here and it forms a little protein coat that contains dna and enzymes and the rationale is well it's quite obvious if we can somehow prevent this coats forming we can immediately interfere with several steps in the hiv life cycle so it should be an antiviral and this is this is a program that is that was run by gilead and all of this data is in the public domain it's well worth reading out it's really fascinating story of drug discovery and the assays that they used to support this was an in-vitro capsid maturation so simply took purified protein and thought oh can we stop it these these capsids and the first twist is no they couldn't they couldn't stop it forming with inhibitors they just couldn't generate compounds or active enough but does this mean the program failed and the answer is no because there's a very very interesting finding and that was that they could generate accelerated accelerators of capsid maturation they could actually give these these proteins to form this coat helping hand they could accelerate it it turns out that this is also a very very effective antiviral mechanism in fact much more effective than you might intuitively think by giving the virus a helping hand we actually it's the capsule forms so quickly it does not form properly and so it's not a competent package of the of the rna of the um the genetic material the enzymes of the virus so the virus cannot replicate it cannot do its normal life cycle as well so this is the first lesson that leonard capovic provides we get unintuitive mechanisms of action but this drug discovery strategy could pick that up again it's this understanding that it's informed by basic science understanding what we're doing and how we're targeting um so this this slide shows it's basically going to tell you another little sort of trick that leonard capps shows and this is leni capovia i mean look at the complexity it doesn't take a medicinal chemist here to say well this is a lot more complex than than aspirin minus is a really really complicated molecule and it turns out that over decades of drug discovery chemists have sort of built up a selection of rules or more guidelines as to what constitutes a good drug if you will recall if you want to make a good drug we need to get it into a patient we need to be able to deliver it and chemists have come up with a list of rules they like to call them or guidelines molecular descriptors are the physical properties of a drug that make it an effective oral drug something you can take every day and it's going to be absorbed that's the big big challenge for many many drugs and you can see that leonard capovia okay it violates most of these rules in fact it violates them really quite severely but it's a huge huge molecule so what's what's the twist what does any catholic tell us here does it tell us that these rules don't work no the rules are fine lena capovir is a truly terrible oral drug but there's the qualifier all of them although it doesn't work as an oral drug you can inject lenicate and in fact what is remarkable is that you only need to inject it once every six months six months this is a drug it's fine forget and and i think that's the most remarkable thing about this drug it's an appreciation of by the the biologists the chemists of the disease the drug was being used to treat the indication hiv aids remember this is a chronic lifelong condition it's heavily stigmatized and for a normal oral drug if someone forgets to take a dose one day there's a chance that you can get resistance evolving in the virus there's a chance of viral transmission but here you simply have one injection every six months and you have this sustained antiviral activity and so yes so i think that that's that's that's a key key thing to remember here um it's it's this understanding that drug design is not about just generating a molecule that can totally stimulate or inhibit your target it's about understanding well how will this drug be used in the clinic so yes lena capovir deservedly small molecule of the year i've just put side-by-side asp in 1897 and essentially in a bit later this is what medicinal chemists are capable of and it's it's just completely a clinical trial at the moment and it's looking extremely promising it's first in class really exotic chemistry um incredibly potent novel mechanism of action a reminder that drug discovery is about understanding where you can bend rules where you can break them and yet still get a fantastic drug out at the end and above all it's an understanding that modern pre-clinical and clinical drug discovery is an appeal an appreciation of what you are trying to treat so i shall leave that there and if you do have any questions i'd be happy to try to answer them thank you thanks uh that was a great and very interesting talk yeah i didn't realize that yeah that drugs can break so many rules and still make it to the clinic yeah very interesting um so as then already said if you have any questions please type them in the chat and i'm sure them is happy to answer them um but i've actually got a question myself um not about lena carpenter actually though um so you've mentioned uh in the early part of your talk that the failure rate is very big so the the common thing to do for pharmaceutical companies is now to fail easy and fail cheap but um is there also is someone looking in at bringing this failure rate down or is that basically left there's there are many many efforts and try to understand how drugs fail and it's very interesting if you look at the reasons for why drugs have failed historically it was largely toxicity and often this would be idiosyncratic toxicity but only once you get it into the clinic you start realizing that your drug unfortunately may kill people more than it can help them and there are because many many stories of drugs have failed in this way interestingly for modern drugs they tend to fail because they don't work which is very very interesting and that's this is why the concept of target identification and validation is so important important the idea is we have to do this properly to understand that is our target really involved in a disease and also are we looking at it are the models we have of disease are they adequate and the simple answer is that in many cases they're not they're not predictive but there is a change i mean it's nice that drugs are failing for different reasons but the there's still a lot of work to do yeah yeah i hope yeah because it will obviously also bring the cost down wouldn't it yeah so yeah yeah 90 programs that cost tens of millions of dollars before you reach that critical failure point it's it's a very uncomfortable position to be in yeah okay thanks for that um so as i can see we've got quite a few questions uh in the chat we'll answer a few of them i'm not sure if we can answer all of them okay so let's jot start with gemma who asks uh do you think that ai can help with target in identification yeah that's a very very interesting question the answer is yes um simply by as we understand the biology more we can do sort of ontology we can understand which targets appear to be associated with certain diseases we can do a genome-wide association studies to identify this and of course this is big data it's absolutely fantastic for ai but i think in the in the short term the the contribution of ai is more likely to be in the medicinal chemistry side to make these esoteric leaps in chemistry to say well we what about trying this different molecule it might bind it might be an improvement of what you already have is that better than the medicinal chemist there have been some lovely papers showing that ai can actually be just as good as a medicinal chemist i don't know to all my medicinal chemist friends i want to say that yes we still need definitely human eyes to look at these things yeah probably they will work next to each other at some point hopefully uh okay let's see whatever other questions we have um so sarah asks uh i was wondering in what ways do you think it will be possible in the future to shorten the time it takes for molecules uh from when it's discovered uh until it reaches the clinic yeah that that's another that's another very good question we know it's possible and of course the example are covered vaccines we can get medicines into the clinic incredibly quickly i think it's once we have confidence in these safety studies that we can get drugs quickly through the long-term effects it's clearly there will always be questions about that and lots of the the problems we've had historically have been these longer-term emergent problems with drugs these idiosyncratic effects that early discovery early clinical studies simply aren't powered to detect but it would be it is possible certainly unfortunately as we get more and more scientific techniques there's more more science we can do in this early drug discovery stage that people will expect to be able to do before we can advance over the pre-clinical stage so in a way we're kind of lengthening the drug discovery process there's a danger of that too okay great and i think we've got time for one last question parameter asked how much can organize health organoids help in drug discovery and what are the caveats that organize spring and um are they actually used already much in the in the discovery process another nice question so organ organoids are they're an attempt in an in-vitro system to try to recapitulate a target organ so many of the criticisms that are very very fairly thrown at drug discovery projects and the assays we use they're not predictive they're not close enough to a living person they're remote from the true genuine physiology and an organoid is an attempt to try to correct that that golf a gulf of physiology so organoids they're like an organoid is like a bit of a gut you can use um stem cells to form guts like organoids where hopefully you've got a much more native light tissue and it's more native-like than you hopefully expect to be more predictive for drug discovery but this comes to the cost and the cost here is one of opportunity and the time it takes to run these so they're not very good for doing the kind of large scale high throughput screening but they're absolutely probably really really very very powerful for later stage discovery when you're when you've identified your hit your lead you know you've got an interesting chemical series and you really want to understand it better then they're very nice good question okay thanks and unfortunately we won't have time for any more questions um i hope we can get these questions answered in another way uh i think we'll we'll probably figure something out um but for now thank you dan for your exciting talk and answering all these questions in such great detail it was really nice to have you on pleasure thank you for inviting me it's really turbo thanks okay and now before we continue with our next speaker we will explore explore some of the rather unconventional ways how drugs have been discovered uh i think dan has mentioned it and many of you will know that some of the most famous pharmaceuticals actually didn't undergo the classical drug discovery process um but were discovered purely by accident or through the occurrence of side effects during treatment of another disease and to test your knowledge on this we've created a small quiz which i would like to invite you all to participate in um so if you know the answer please type it in the chat and let us know how well you did at the end okay so let's dive right into the first question i think that's a fairly easy one that many of you will know so question one is who discovered penicillin once again type the answer in the chat if you know it um and i'm quite sure many of you know to know the story behind this as well so that person that we were looking for was a microbiologist working on bacteria and at some point when they checked their petri dishes with where bacteria usually grow on they discovered a fungal contamination and that had the bacteria less region around it and it turned out that the fungus released penicillin to kill these bacteria um so let's have a look in the chat i can see a lot of questions already most of you a lot said alexander fleming and that is of course correct um yeah he was the discoverer of the first antibiotic okay uh so question number two which is a bit harder so uh the blood thinner warfarin was derived from from which plant was it a fennel beet sweet clover or sea milk thistle i think that's a bit harder and the reason why you can see cows on this on the screen right now is the story behind this um because it was farmers in in the us and canada that complained um to about their cattle bleeding to death after just undergoing minor procedures such as dehorning and it turned out all of these cows had eaten from the moldy plant in question which contained the active compound the commercial and this was then further investigated and eventually led to the development of this blood thinner that saved countless lives okay let's see uh in the chat a lot of people responding i can see a lot of bees uh someone said see as well okay let's see who was right it was indeed bee sweet clover um yeah who would have thought that cattle um yeah were the discoverers discoverers of uh a modern day drug okay so for our last question we have a quite funny one i would say for which disease was viagra originally intended for so was it a uh angina was it b depression or was it c alzheimer's disease and um so i personally found that uh the story behind this um quite funny um so the viagra was originally actually synthesized in the uk in one of faiza's lab labs and when it undergo underwent clinical trials for the original disease it should treat a very observant nurse reported that a lot of men were laying on their stomachs when coming into the clinic for checks for obvious reasons i guess and then father soon realized that this is an excellent way to to treat uh previously unmet need um to treat uh erectile dysfunction and so it became the first oral drug for this okay let's have another another look in the chat i think the chat is um saying a and gina i think there's a couple of people that think otherwise but let's see what the right answer is yeah so you were right it's an indeed an angina great um i think uh everyone did very well in this quiz let us again let us know how well you did and i'm sure you appreciate that sometimes luck can beat the most elaborate scientific method to discover drugs but nevertheless even that the drugs that were discovered by accident have to show that they're safe and effective before making it to the market and you've probably guessed it that's exactly the topic for our next talk and i'm really excited to welcome dr peter scholes cso at quotient sciences will tell us all about clinical trials and the late stages of drug development so over to you peter thank you seb hi everyone um thank you for the opportunity to uh present and virtually meet with everybody it's a shame we're not all down the pub of course but uh hopefully next year um it will be fairly whistle stop tour through clinical development um so thinking about the best place to start and as always it's a case of start with the end in mind is a is a good good maximum good saying and you what is ultimately what is the purpose of clinical research what's the final outcome from from those labors over many years and in some respects it's shown on the slide here albeit just for one of you know hundreds of medicinal products of course but a local one here in nottingham that was in invented discovered by uh by boots ibuprofen uh brand name of neurofen of course but the two screenshots are really the you're the outcomes of many many years of research in terms of information that's given to patients and information that's given to prescribers and physicians so first of all we have the patient information leaflet that's a little bit of paper in our packs of medicines we get from the pharmacy or the doctors which i'm sure we uh read rigorously but in essence it explains to the patient what the drugs for how it should be taken how it should be stored what potential side effects are and the summary of product characteristics the smpc is a more detailed i guess more scientific version of that for the for the medical doctor which goes into more detail on on the therapy areas the dosage regimens how the drug should be given in particular populations for example but really explaining um how hopefully that medicine can be prescribed to that patient to cure the disease or believe the symptoms and really everything we do is gained at yes it's gated by regulators but it but it's aimed at providing the information to allow drugs to be prescribed safely to treat or indeed prevent disease as dan's already said it's a long journey typically 10 to 12 years and daniel did a great presentation on the left-hand side covering discovery and pre-clinical into clinical trials i'll cover that bit in the next few slides of course before the end of the runway reviewed by regulators prior to market approval and when a new drug becomes commercially available for patients i think the thing to note here is there's some numbers um which start to illustrate this attrition this high failure rate i think dan mentioned 98 but you can see here you start with thousands of compounds in the laboratory just to get one product on the pharmacy shelves and time often equates to money in life of course um and just some numbers to it to reflect that this was a um quite a key publication from 2016 where some researchers used you know a really elaborate um pharmacoeconomic model to understand the cost of drug development and this is both the cost to get a drug to market but also it includes the cost of all the failures on the way all those that don't make it to the destination and the estimates then in 2016 was over two and a half billion dollars to get one product to market which again uh without necessarily seeking to justify you know starts to indicate how the cost has to be recuperated somehow uh on that journey to fund the next generation of innovative medicines other research papers more recently have indicated the cost could be higher bottom line it's an expensive process the good news is pharma and biotech industries are not dissuaded by that the left-hand plot here shows um actually there's more potential new drugs being researched now than ever before indeed there's over 18 000 in development as we speak across the globe at various stages is to bring new products through to market for unmet clinical need the right hand side is the sobering view of new products actually get over the line and looking back over the 10 years this is in terms of new drugs approved in the united states the average is less than 50 per annum perhaps in the last couple of years this has been a slight uptick but again a further emphasis of you know the need to get more efficient for we as an industry to move more products from the left to the right and get them into the hands of patients to treat unmet clinical need so what's required ultimately to get a new drug to market i'll mention a few times about the regular independent regulatory oversight so what do regulators look for before they will sanction a product as being suitable for for being prescribed and there's three main pillars of that the safety efficacy and the quality the safety dan's started to describe uh you know the fundamentals about the drug interacting with the target and minimizing off-target interactions or side effects the efficacy are really the fruits of the clinical research which i will uh i will describe shortly um does the work does the drug work clinically do the benefits overcome the risks for those patients quality perhaps doesn't get as much air time but in essence that's around the product you know the tablet the inhaler the injection that gets administered to us how can that be made to a high quality and a reproducible standard the beauty of a live event that's the phone i do apologize and indeed how can the product on the pharmacy shelf be reflective of that which was used in clinical research which proved the product worked in the first place how do we tie that together the first clinical development um a lot of detail on this slide which i won't necessarily read out but up into the point of the regulatory view there's three really clear phases phase one phase two phase three and we can see here the time base to those your 12 months for phase one research two years of phase three typically three years to phase two typically three years of phase three but also as we go through those stages there's a shift from healthy volunteers in phase one research typically in small numbers you know less than a hundred phase two we get into hundreds of patients and then phase three and thousands of patients and the purpose of the research is to answer some fundamental questions in order to get that product to market there's a recurring theme of safety you know the um the intensity and the scrutiny is relentless is the drug safe at every stage of clinical development in phase one though you know the focus in addition is really understanding what the body does to the drug these are volunteers they're not patients but can we understand how the body processes the the power the body eliminates the drug in phase two when we're in uh patients we can start to study you know how does the drug work does it just is the pharmacology working is what we hoped what would happen based on um computer models or animal models you do we start to see those um interactions clinically in vivo and how much should be given what's the dose for how often for how long to start to answer some of those fundamental questions and then phase three of the larger trials multinational multi-center thousands of patients um often comparing the drug to a placebo or the current best practicing care you're really to prove once and for all the therapeutic potential for that new molecular entity the following the regulatory approval and hopefully um the other commercialization as products research can indeed continue safety is always still monitored and other indications perhaps can be pursued for that medicine the last row i think also picks out just one one final time attrition and this is a real totally simple representation if for example a hundred molecules make it as far as clinical research so go through the work dan described then at the end of phase one on average 64 will still be alive at the end of phase two 20 will will still be in development and then 12 will go to the regulators and 10 may get approved so basically there's a 10 chance of success even if it gets as far as phase one clinical research and by the end of phase two eight out of ten drugs will have failed so that's a real focus for us i think a real opportunity one of the earlier great questions was how can we improve drug development reduce attrition so some questions perhaps to help answer that from a clinical perspective how can we start human trials quickly and show the drug is safe perhaps faster how can we get that new drug into patients sooner to see if it's going to work again in terms of time reduction cost reduction and don't forget the product um we talk about drug as a generic term but from a pharmaceutics perspective we would view that as the white powder the product is actually formulated composition of that drug which is delivered to the patient and often often contains other ingredients to achieve the desired therapeutic outcome most drugs are delivered orally obviously the example dan showed was ended up being an injection but most drugs are delivered orally and if we just think about human physiology and human evolution and there's a little schematic there to show esophagus into the stomach into the small intestine the colon we really need the drug unless it's for local disease to be absorbed into the bloodstream for the drug to work and if you think about it the reason we exist today as human beings is that evolution has helped our gastrointestinal system be tremendous barrier to foreign chemicals to stop poisons being absorbed into our bloodstream which is great on one hand but not great for new medicines so pharmaceutically we have to get that say the tablet to disintegrate in the stomach the drug to dissolve and then the drug to be absorbed across biological membranes into the blood and just showing one graph i can't help myself is a typical what we call a pharmacokinetic profile this is the blood concentration in the plasma against the time course over say a 24-hour period after taking that tablet and this would be ideal rapid absorption not too much drugs the peak plasma doesn't cause side effects the zener decay as the body starts to metabolize and eliminate the drug but it would stay above a certain concentration threshold over one over 24 hours suitable for a once a day therapy but life's not like that of course most drugs are poorly soluble some drugs are poorly permeable some drugs are broken down too quickly so a tablet is not just a tablet often a tablet contains these of the other excipients ingredients to try and overcome some of those challenges that we have to live with in terms of drug chemistry so i was trying to think of a metaphor for the talk today about um you know again ways we could we can go about addressing this and hopefully it's acting meaningful on a day like today where uh rules relax and social distancing eases a little bit thinking about going to the local cafe or restaurant and uh to order a meal and we expect things to come quickly don't we uh you know the ingredients are there the products bake there and we eat it there maybe if we don't like it we'll send it back to the kitchen but the pharmaceutical industry isn't integrated like that we have the drug substance the white powder there's the product to develop and make and then we ingest we test it clinically but they're very discreet activities often in or typically in discrete locations and what that can mean is a very convoluted supply chain and a lot of time to get a drug turned into a product to dosed in people often 12 18 months actually and the results of that can in effect be a game of snakes that matters that if if the drug and the product doesn't elicit the response we need we have to go back to the start and develop another one so it's a very very inefficient process because of these silos so again there's a lot of in industry interest about breaking down those silos and um here in nottingham um you know there's a we've been a pathfinder in some of that and really integrating the manufacturing of pharmaceutical products to a high standard and then the clinical testing of that i'm really doing that in a matter of days rather than a matter of months and uh the quotient where i work we've run over 400 studies over the last decade with that very model making and dosing quickly and safely and that's driven a lot of documented time and cost savings but scientifically of course even better than that we use human data to make decisions human clinical data that those pharmacokinetic data or biomarker data if we're looking for some assessments of pharmacology rather than in silico computer models or animal models which run the risks of not being predictive for the human response so then we can start to re-engineer early clinical development for example so the left-hand sketch shows a typical first in human study in healthy volunteers what's called a single ascending dose where the dose of a new drug is escalated carefully slowly and and with high medical observations and as well as doing that what we can now do is introduce the ability to look at different formulations of that drug if needed you look at different technologies if say solubility is a problem or permeability is a problem or the metabolism or half-life is a problem so in phase one remember yes we answer the question is the drug safe is it tolerated by humans yes we understand the pharmacokinetics but we also gain great insights early into the product so we can make and supply product with confidence into those initial phase two studies so we can you know in a better way look for signals of efficacy in patients and all this i hope will start to reduce that attrition rate of 80 of drugs failing by the end of phase two so quick case study uh this is work we did it at quotient in nottingham for a san diego biotech called mei pharma they had a new molecule heading out of discovery into clinical development um but there was solubility concerns there was uncertainty as to what formulation they should make which remember could take many months to dose in humans um to make sure the drug would be absorbed and be bioavailable so by integrating activities yes we did some computer-based modelling and some laboratory formulation studies but we identified three potential formulations to dose in this first study um without going into too much detail one way we reduce the particle size of the drug to make it dissolve faster one where we include fatty lipidic excipients which can improve the solubility and one where we turn the drug from a crystalline form which often needs a lot of energy to dissolve to be absorbed into an amorphous form which is a is a a better energetic state for the compound and then in the first in human study we had the chance to look at these different formulations as well as ascend the dose and the good news is we we found a really relatively simple formulation um which gave adequate bioavailability to adequate levels of the drug in the blood which were verified by a biomarker which the mei hopefully hoped would be predicted an efficacy in patients and that allowed us i mean in 12 months to get phase two testing underway with a drug product which maximized the potential for success and this drug is in phase two trials today and your fingers crossed um enjoying some successful results in some rare blood cancers so hopefully in a few years time this will this will make it to market last minute or so just just mention about regulatory oversight um of the whole process not just phase one trials or phase two trials but the you're the final regulator review prior to marketing authorization in the uk our regulatory body is the mhra the medicine healthcare research authority and each clinical trial needs a separate clinical trial application and there's a sister process in the us overseen by the the food and drug administration so sponsors of studies have to submit a lot of information for every clinical study about the drug substance the drug product the previous clinical and non-clinical history and the clinical protocol they wish to execute and perform to answer the next question during development but each study doesn't just need regulatory review and approval it also needs independence ethics and again in the uk there's independent ethics committees which review similar information but look through the lens of the volunteer um you look at what information the volunteer will be given make sure the volunteer whether they be a true volunteer or or a patient participating in a study make sure their welfare is protected and their safety is assured as well so my last slide hopefully um what we've gone through both both dan and myself have indicated that your medicines development it's a long journey takes a long time costs a lot of money and it's high failure but you as a as a complete industry um we are looking ways to improve the efficiency of drug development while staying within a really robust system of checks and balances and really integrated research i think is a way of breaking down some of those barriers to reduce time and cost and maximize potential for success and of course and today being a case in point in that and the last 12 months um certainly putting us all under magnifying glass you know the importance of new medicines has never been more um you know had more attention than it does have today and with that hand back to yourself said please uh for any questions in the last five minutes great thank you that was very interesting and i actually didn't realize that nottingham or yeah specifically quotient is uh on the forefront of um yeah clinical testing and new yeah developments in that area as well um so i've seen we've got a lot of questions uh that have come in um i think we'll go straight on to these we don't have much time um but we'll try to answer as many as possible so the first question would um would you expect aspirin aspirin to be approved today um um good question i hope it would yes uh again it would as with any new medicine uh the same is true past presence and futures those basic tenants is the drug safe is it efficacious do the benefits outweigh the risks and also is it is it a cost-effective treatment treatment compared to other other standards of care so it's those same those same litmus tests if you like those same basic questions which the clinical development plan would have to be good to generate the evidence for so i'm sure it would be the case for aspen to be proved today it still plays a key role in um in the treatment of some illnesses and some aches and pains as we know yeah i think especially on a day where um there's a quite a few of relaxation in in the uk regarding indoor pump um yeah visitors and stuff that would help quite a bit okay so next question um when an existing drug is found safe for one an illness and it's then um found to be useful for another illness does it have to be tested all over again and potentially or just parts of it have to be again a great question so if it's the same product the same tablet the capsule no that's that's safe that's a high quality product it'll be a say two three year shelf life so that the quality is already boxed off if it's the same route of delivery then um you typically the same um your no additional safety or toxicological testing would be would be needed what would what would have to be performed is that other leg on the stool the the efficacy assessments you would have to do trials in that new additional patient population to prove the drug works and again if the product changes or if it's a different route of administration then other work in those other areas may be required so again it will depend on the level of change that would be required okay thanks and i think we don't have time for any more questions um so thanks again to you peter and also to dan for your lovely talks and also thank you to everyone behind the scenes who have uh worked incredibly hard to make this all possible um so there's plenty of more shows coming up in the next three days of the festival so make sure to check out our website um for the program in the next few days and also please let us know how you liked talks and what you've taken from them by tweeting panda science uh using the hashtag pint21 and hashtag molecule to medicine and i think that's it so thanks again for tuning in and have a lovely rest of your evening from everyone in the science nottingham team and see you next year hopefully in person again bye [Music] you