 So good morning everybody, I hope that you all had a nice night and are all rested and ready for this. So, because now you need to keep awake. This is going to be a lecture book type of story in introduction that's what Lars asked me to do to sort of set the scene. It's not going to be extremely exciting spoiler, but I'm going to do my best to keep you awake still. So drug development always it starts with a great idea and I'm going to talk a little bit about the whole process as Lars just did but in a little bit more detail and try to highlight where this group actually can contribute and there are many places as Lars has already said. That was you, not me. Yeah, okay. I'll see if this one works. Yeah. So, just first, the project idea is, is, of course, you need to, you need to start there. And what I mean here is the project idea and some kind of target mechanism disease patient need market opportunity. These are the guiding words. Okay, I'll try. No. So, okay, please. What I mean with the target the idea is, and what I usually find works the best if you try to focus on a mechanism or pathway that when modulated generates a positive effect to a medical problem sounds like a complicated sentence. It's really sometimes people just come up with a target and they don't really know where it takes. So they want to work on this target but they haven't yet identified what is the medical need that this is going to help us with. Or they come up with a medical need and they have no idea where to start with a target. So once you have solved this rather simple question then you can start the project. And then you. Okay. So then you have your target molecule. You need to start thinking about should I activate, or should I inhibit it. What is the disease and patient need what is it really that this drug is going to achieve. We have a market place for this. And for us as scientists this doesn't come always naturally, because we think if, if something is good, there will always be a place for it. But in drug development, and in the type of economical situation that we live in the systems. There's not always a place, even though it can work. There needs to be a market opportunity. And this needs to go into the thinking. And from all of these questions you can start drafting something that is sort of the guide map through a drug development project. You can get product profile TPP and I would say always start this early. Once you have just these, you have your draft path. And then you can go from there and you can expand your knowledge and you can fill this with all the details that it eventually needs, and will have when you get to your final drug. So just to tease a little bit about sort of this with where this assembly can can really make some difference. Of course, a lot of the targets that you will work on have crystal structures. And these can come in very, very handy and we'll come back to that later. But in understanding the mode of action for your drug, eventually, and where to position. The structure one drug target molecule that is worked on here in London. So, please. Then it comes to identifying a drug molecule. You need to have a pharmacological approach. I said before, activating or inhibiting. You also need to understand, does your target become modulated best by a small molecule or by logic. This is quite early on a decision you will have to make a route of administration is actually also something that is good. You always have an idea about early. And that may change, because the molecules don't behave as you want. But it's good to have an early target picture and image. Again, this can really be linked to the market opportunity if you need to change administration route, the market opportunity may be gone. It's important to try to understand. This is not the right presentation. So, hmm. Let's go anyway. Small molecules. No, it's, yeah. It's just not the right presentation, but it's fine. Small molecules. So these are chemically synthesized low molecular weight inhibitors or agonists of your target. They're usually metabolized, and they can then create toxic intermediates. This is something that you always have to keep in mind working with small molecules. However, they are nice in a way that they are usually non immunogenic so the body doesn't really react immunologically to them. They can interact with multiple cells and organs intracellular extracellular. And they often have an acceptable species, sort of non selectivity so it can be used between different species. The biologics and here I count antibodies there's spaces here in the front. So by logics antibodies peptide scaffold proteins, all of these, they are, they have in common that they are derived from living cells. So that also makes makes them much more heterogenic in their nature. They are generally degraded into just building blocks of the natural proteins. So non toxic things. You know acids, glycol salation pieces. And one of the drawbacks though is that they may initiate an immune response and they are recognized as foreign. So that this is something to keep in mind and try to work on. It's possible to really achieve very high selectivity with, for example an antibody, which is often more tricky with a small molecule. And this is why they they are sometimes really preferred type of drug when you really need this very very tight specificity. The drawback though is that that specificity also leads to that homologous molecules across different species are not recognized. So a human specific antibody cannot be tested in the mouse or a rat that we commonly use in the lab. And that is of course creating a problem. How do you then find these hits and leads small molecules struck tractor based design fragment by screening. HTS published leads a patent busting. And that's not this illustration was quite nice to put put up here because this is really an illustration of where you have a nice crystal structure of your target. And you can use that to co crystallize your small molecule and get hints for how to improve it. And one caveat with this that we've seen several times in in in projects. And that is that using this method. If there are, if you then use a new class of small molecule. And really, you can open new pockets and change, make introduce bigger changes in your target molecule. These are often very difficult to predict, however, and despite that that there are now computational sort of methods that can really predict quite a lot. There are more bigger structural changes when you open up the structure in a different way are often very difficult to predict. And hence, still there is a room for these things like HDS, for example for finding completely novel structures interfering with a molecule in a completely not novel way. Yes, we can go to next one. You can also do analytics. Traditionally, immunization of an animal to generate an antibody and from there you can generate monoclonals. You can also do antibody library selections, which is a more molecular way to generate leads. And it's illustrated by this little cartoon. I'm not going to go into that but this is a phage display. This is a library or selection mechanism, and that can actually be used both for antibodies but also for peptides or scaffold proteins and scaffold proteins are then new and improved variants of antibodies. You can debate if it's improved or not, but they do have some properties that actually makes them better drugs. They are generally better, have better stability, they can be almost some of them can be almost boiled. So they actually present an intermediate between the natural immune system and the artificial drug. There are also natural molecules that that you can sort of use. So cytokines chemokines and modify them in different ways and mimetics of these. So then we go into the preclinical development part. We've now found our molecule and here we're going to establish efficacy of the molecule. We're going to start our journey on how to formulate it. And here comes in again the question, which is your route of administration because that will really affect your formulation. And safety. These are the top deliverables from this phase. In some more detail. How do you turn your lead that generated the early phase, the first molecule that binds and that's what you think it should. How do you make it really the drug. How do you optimize it. So for efficacy, you really need to find the right potency and efficacy and why do I say both isn't isn't potency and efficacy the same thing. Not really. I'm not going to draw any of these those response curves to you. But I usually do. Potency is how low you can really go and it still has its effect. So usually expressed as some kind of IC 50 inhibiting concentration that introduces a 50% inhibition or activation if it's an easy 50. And, and, and you will get the non molar or picomolar concentration that is required to get this 50%. The efficacy, however, is for an inhibitory molecule usually only talk about good molecules. They really inhibit 100%. There's, there's, there's nothing. So for, for those types of approaches, efficacy is never really in the picture. But there are four agonists on the other hand, many agonists you may not want to have 100% activation. You may just want to modulate and this is where you find your pharmacological sweet spot. And that's when you start talking about efficacy, the natural ligand may actually introduce 100%. But you may just want to moderate it. You may just want to have an 80% or 60%. And, and, and this is really where again it's important to be able to understand your molecule, how it binds. And some of this work can actually be very much aided by structure. Rational structure design where you can see, well, I need to move a certain, a certain helix in my protein, a certain way. That's when I get my perfect pharmacological effect. In this phase, you also need to establish a maximal and minimal effect doses, and this is for your further development to really understand, where do I have my safe dose. And where can I start dosing without the risk of harming my patient. And where should I put my tox doses. Here you also characterize the pharmacokinetic profile. So how fast is the drug taken up? How does it distribute? How is it spread through the body? I'm sure that it really reaches its target. Many drugs have failed because there is not enough drug in the target organ. And this has been a saga for many of the early antibody projects. Antibodies are big. The tumors have natural defenses towards taking up big molecules, macromolecules, and actually many of the first antibodies for oncology did never penetrate enough the tumors to have this intended effect. And here you demonstrate something that we talk about as proof of concept. I'll come back to that. I'm not going to say a lot about the CMC, so the formulation and more chemical development apart from this, but you really need to do appropriate formulation for the intended route. And here again, some of the types of technologies that are really the specialty of this group and you can perform at places like the Max Four, and later on hopefully at ESS, is around sort of understanding crystallinity, understanding that you get the right size and the right shape of your particles to generate formulation that can be taken up rapidly and or not rapidly, if that's your intention, but the way that your pharmacological mechanism really intensifies. Here you also establish a manufacturing process that ensures that you have a pure and stable API. Another important part here is the safety. I'm not going to go into details of safety testing, because it's an area of itself. It is important that you can establish a maximal tolerated dose that you can understand how long time you can expose an animal, which is in the safety studies to predict that it's also safe for when you go into humans. And therefore you make a series of different tests, usually conducted in two animal species, a rodent and a non rodent, or for macromolecules like antibodies in non human primates, since the crossover between species doesn't allow the pharmacology to actually happen in the species. Just a few words on pharmacology, so because I see that I've talked too much, as usual. Overall aim is to predict and deliver a safe and effective dose and this is really the main aim of this whole package. Safe and effective. And I think sometimes we focus too much on one of them, and others in the team focus too much on the other. But they really need to go together. You need to establish an effective dose in order to understand that that dose is the one that is safe as well. Please, Tico. And I also just want to say you should think of structuring your studies in a way that you actually can build the individual pieces of information into a chain of evidence that your drug is really going to work. Because at one end, you need to convince the physicians to take on and try this drug in the clinic. And then you need to have some rather good evidence behind yourself that this is going to work. Otherwise, it may not even be ethical to do the human test. So think of relevant cells, primary cells, disease tissues, correlations between in vitro and vivo, we touched upon this and correlation between species. Use sensitivity when you need to make sure that your data is reproducible and quantitative. So these are slides that and pharmacokinetics, what the body does to the drug and pharmacodynamics, which is in the next one. No, we take this. So I'm sorry, this is not the presentation, the final so it's a, I'm not 100% sure what's going to come that's why PK so the pharmacokinetics and this is this is just a very, very crude image. This is a very simple method, you label a peptide that is your drug in this case. And you give it to an animal and you can actually follow it online. How it distributes. And of course, a lot of it will go to the, to the metabolizing organs or excreting organs. In this case, actually the key thing that we were interested is is is rather up here. So at five minutes. This is the salivary glands. And at five minutes there's almost nothing at four hours you actually see quite a lot 24 hour. This is when you see the maximum, and then at 48 hours, it's almost gone. This is this is really a very nice neat way that you can illustrate these types of processes and see them online. Please. So pharmacodynamics then is the efficacy part. So what the drug does to the body, how it affects it, how it affects the process that you wanted to affect. So you can go to the next one. These are just a few, few words that that everybody in drug development will, will talk about. That's why I wanted you to just hear them. If you haven't heard them 100 times before. And that depends of course on your background, but PK PD, what we just discussed. I think and pharmacodynamics together understanding when you have enough of the drug at the place so that it can actually have its effect. Proof of mechanism this really relates to making sure that it works on the molecular target proof of concept, really, that it works on the concept of the disease. And make sure that when you establish a proof of concept of proof of mechanism that is actually in a relevant animal model. Many models are nice to have, but maybe not so relevant for the final intention. And I couldn't resist so this is this is this is an animal model of lung fibrosis. And here you can debate is it is it relevant. What part of it is. And this is this is work we've done together with Irma and Leo within a Tristan project where we we have where we have induced lung fibrosis. And I just wanted to show it to illustrate how image different types of imaging modalities can really be of use and be implemented. And since we're, we're here, you, you can see. This is, this is the tissue, the difference here is that you have a lot of photographic tissue up here. You can also see this in the M R pictures. And this is this is really a finding that I want Irma to talk about later on so we'll leave it because I have only one minute left. Please, please, please. Life will cover this so that's that's not the problem. biomarkers I just wanted to introduce biomarkers and imaging is a biomarker methodology that shouldn't be forgotten. And that really can be established in the pre clinical and then taken into the clinic and that makes it unique. So please. clinical. I will just stay at this one because phase one phase two and phase three clinical trials is what awaits you if you want to get to a registered. Phase one is all about safety, it's all about safety, making sure that the drug is safe that you can establish a dose that is safe. It's all about efficacy, making sure that you can also find within that margin of safety, a dose that actually efficacious and delivers the mechanism that you want to have the pharmacological mechanism. And phase three is mostly about establishing that you have an efficacy that is comparable and actually better than competition and standard of care. And I think this is where we put it all back to this. There needs to be a market opportunity. And this is where, where you see this, and you don't want to find this out down here that there wasn't. There wasn't even space because patients are very, very people. I leave you because I don't think that my last slides were the correct ones so.