Investor Update

Oct 27, 2020

Thank you all for joining us today for our virtual R and D roundtable covering the Toledo program. I'm Elizabeth Goodwin, Investor Relations, also representing colleagues in our IR, R and D, and communications team who have worked hard to bring you this information today. This recorded zoom webcast is accessible via the Galapagos website homepage and will be available for replay later on today. Sell side analysts and professional investors are invited to pose questions at the end of our call. I'm going to give you a dial in number now. That's 44 for the UK, 2071928 338. That's 442071928338. And the code is 3312849. I'll give that number again a little bit later. There will be additional numbers visible on the webcast player screen when we come to that part of the, of the event. And now moving on to our forward looking statements. I would like to remind everyone that we will be making forward looking statements during today's webcast. These forward looking forward looking statements include remarks concerning future developments of the pipeline, the Toledo program in particular, our company and possible changes in the industry and competitive environment. Because these forward looking statements involve risks and uncertainties, Glapagos' actual results may differ materially from the results expressed or implied in these statements. And now I'd like to go over the agenda for today. Our program will last approximately 1 a half hours. First, we'll start with the talk. CEO, one of them is Dolpa will introduce our innovation approach. CFO, Pete Leifink, we'll talk about our innovation with the Toledo program, CMO, Walidah SAB will discuss our clinical strategy, and then Anna will come back to wrap up. You'll see a PowerPoint presentation on screen during their talk and again, this will be followed by a Q and A session. We'll you'll get more instructions at that point. So that's all for our logistics today. Now it's time for us to get into what you've all really been waiting for. I'd now like to hand over to Anna to tell us more about the approach to innovation at Galapagos. Thank you, Elizabeth. Very excited to to finally take away the apps around the Toledo targets and the Toledo story. So we are going to highlight that today. In in the session. Thanks for joining this. It's a very positive session. We're all very excited about sharing this information with you. Innovation is really in the DNA of this company. We have been focused on, innovating, innovating, and innovating since the start 22 years ago. We pushed these scientific boundaries. We are very much science driven, science is so crucial for anything we do in this company. We follow the biology along the way. We find a target developed at work. And see what, areas it can be best used for, and the Toledo group is is a very good one. We're exploring various diseases that potentially could benefit from the Toledo, drugs that we are in, in clinical trials with at the moment. We're clearly very innovative. We are focusing on new methods there, and always always focus on new model actions. So our approach to innovation, as I said, is, novel targets that we identify with our platform, combined with chemistry, always supported by biology, with, technologies to very rapidly go into clinical trials to identify, the target as, the right target to, treat various diseases. We have a very ambitious path in deliverables. Our objectives are to come up with 6 new targets per year, bring that to 4, 3 to 4 preclinical candidates per year, 3 proof of concepts, and then that should lead to 1 phase 3, start every year. So it's an ambitious program for a small biotech with Galapagos still is, but we are delivering and we are getting more and more programs into the clinic. It all boils down to the target discovery platform that we started 22 years ago based on adenoviral technology. What we did is putting a small piece of human DNA into an adenovirus backbone that when it enters a cell, a human cell, it will actually stop one specific protein being produced in that cell. And by doing that with over 6000 different genes of the human genome, we can rapidly zoom into those, genes in the human genome that are responsible for certain diseases. And when we identify such a target, a hit then we can, develop and work that ultimately will do similar, to the antivirus an interest to sell, when an interest to human body actually will, regulate and, stop the specific protein that's over produced in that specific disease. It's a very robust platform that has delivered many interesting targets so far and the Toledo Group is, is clearly, one of them. If you can see here on the slide on the right is actually the Toledo protein for those, chemists, embryologists, you can now identify the target based on this, this graph. You can get to the next slide. And clearly, our innovative approach with Toledo is, is now coming into and, into a stage where we are going to get results in patients. And it has been a long way where we initially identified the targets, and then got excited because of the dual mode of action. We confirmed that in in animal models and also in the in human, phase 1, healthy volunteer studies. And we are now launching a broad phase 2 program to see how this, family of drugs behaves, in various inflammatory and fibrotic diseases. So very exciting for us. And the question is can we can we make a difference? And, of course, you never know until you're actually, in the clinic in late stage trials It's always in the, a tough, decision in what diseases to go for, but the inflammatory diseases are clearly our need for new classes with, better efficacy. If you look at psoriasis than 20 years ago, it now has much better drugs available for treatment where the majority of or up to 90% of the patients react very favorable to treatment. However, in other inflammatory diseases, this improvement has not gone as fast as with psoriasis. And there's a clear need, unmet medical need, a need for better, safe and effective, treatment options. And that is the, the difference that we would like to make inflammatory disease with the Toledo group. You all know, we have forgotten it, on the market here in Europe and and and shortly in Japan, which is a very exciting work as well. But, clearly, we would like to, go another step into treatment of these inflammatory diseases. And, we hope to develop, the Toledo group, of molecules as a next generation in treatment of inflammatory diseases. We can get the next slide. Then it's my pleasure to hand it over to my CSO, Pete Wiesering, to give you the background on the Toledo program before we will actually continue with Valeed on our path to patient data. Pete Flozures. Thank you, Oulu. So we promised to raise the curtain on our Tahira program today, and we plan to do much more. I hope that by the end of this presentation, you will share with me our enthusiasm around this noble mechanism of action. We call it a master switch. This is new because Toledo acts in another way. It's x in a way which is different compared to current drugs. The novelties that has dual action. It blocks on the one hand side of damage and stimulates the repair. That's what I want you to remember at the end. Our body can only work because it's full of systems that act and control. There's always a balance. That's also true in the immune system. We need cytokines and covered here as orange ones. That act when we get an infection when a virus infections are back to you. This is the 1st phase of the fight. The 12 day I've done the job. We come into a second phase, and then we need the green ones. These are anti-in- in front of the cytokines and players. And they take care of the healing. So when Zenny when when there is an infection, we always have a fighting face and a healing face. It's important that those 2 are well balanced because in patients, what do we see, the fighting phase that's going well. But the heating phase is not there because the balance is lost. As a consequence, our cytokines, ourselves are going to damage the body that will cause ulcer spending without our bonds. So current therapies all are based on the same principle. They try to damage, the excess of the pro in front of the cytokine. They take away that excess to restore more or less the balance to avoid that the healing can take place. So they're going to take away and make sure that the small amount of the anti inflammatories can do the job and can eliminate damage. With Toledo, we have different ambition and we've seen those data and I'll share them with you. We want to play or replay with Toledo at both ends of this balance. We, on the wireless side, limited damage by creating the number of throm inflammatory cytokines cells, but at the same moment, we increase the anti inflammatory cytokines and cells. That's what I'm going to show to you today and that's why they're so enthusiastic about this class. How do we find this level of existing targets? Well, those amongst you who fell off from time low, it's a long way. It all starts with these ESSC. So on the left to see here, a cartoon of the guts. And talking about the gut is always fun. Because while the good is not the inside of the body, it's affected outside of the body. And to protect the body, we need to layer. These are these screens still tightly connected epithelial bank cells. And you also see that, purple start like cell, which spikes with the values. This effect is a dendritic cell and the active sensor. And not extremely smart sensors because when a bacteria passes, which does not cause harm, they don't act. But when noxious bacteria passes, they will give an alarm signal and then the whole immune system is activated. And the recruiters. So rather than setting up different models, one for the epithelial layer, one for dendritic cells, one for the macrophages, we decided to go for a more complex model and make our IBD asset, which was a bilayer model. And in fact, on top here, the barriers where we can measure whether it's really fairly sticky and nothing leaks true. And below we put down those sensor cells, the dynamic cells. And in fact, this is an extremely cool mold because if you will add lactobasilos, which is part of Houston, our buried comes stronger. While on the other hand, if we had a dangerous vacuum like Ecola, the bearing networks. So really a model which in terms of adherence and the complexity we had seen before. So, at this point, it allows now to us to knock our targets into immune cells and measure the impact of nucleotide targeting an immune system on the APK at the battery. Means by screening this type of models, and let's say that we discovered the Toledo. Early on, we were intrigued and we were lucky that we could find a non selective tool compound It has told you that non selective two compounds early on, we could prove that in fact the barrier was maintained. We could put in as much as bacteria as we want if you compensated with compounds, if you block the targets in terriers the barriers state in Egypt. So we started to measure all of the cytokines in these models, and we saw that many were going down. And also our surprise with you were going up. And this was something we had never seen before. So we wanted to confirm that. And we then set up a Macrophage asset where in fact indeed we could confirm in the 2nd type of, immune cells that with an increase of dose we saw decrease of the pro inflammatory cytokines and an increase of IL-ten, which is a prototype of the umpteen. In in inflammatory side. And so it was the first time that we say, wow, this is cool. I don't think anybody ever got this. So this target really did something special. So now I'm jumping 5, 6 years. To first give you a bit of the breadth. We've optimized cold parts. We then started to look broadly in all types of immune cells. And to a surprise effect, you can see on the left, you see there the macrophage is more sized. You see a decrease of Tiara Balfa a decrease of IL-twelve, a decrease of IL-one beta. And as in our model, we see an increase of IL-ten. When we go to the to the dendritic cells, we see similar picture to different cytokines. Yeah. ValFA going down, Ultra is going down, R23 going down, R10 column. So all of the drugs that we currently have, in fact, they react as well to the Toledo and on top, we increase R10. In T cells, we see a decrease of IL-two and interferon gamma only. And in B cells on the right, we see again a decrease of TNF alpha. Any piece of outbound. So this is a switch, a master switch, which in many cells of the immune system has a similar action. It really does something which we have never seen before. So that's why we call this our master switch in the image system. So I'm not going to keep you waiting until the end of the presentation to reveal the targets, and we're going to let know. So we call it toll 1 to 2 or 3, but behind that code, in fact, and many of you guessed that right, are the SIT ones, SIT 2, and SIT 3. These are names sold inducible kinases. Somewhat has told to do with the story. In fact, extremely little. The 1st member of the family, SRK1 was discovered in 99, when animals were fed a high school diet, and then one of the enzymes that they showed that was popping up was SIP 1. And as I click 2 and as I click 3, there is no link at all with soap. So soap and use kind is the name which is of serial link to our story. We selected 3 we are working on 3 Peter Takaal Peter can race currently. You can see GLPG-three thousand nine hundred and seventy. And that is the focus of today. I will only show data of 3970 because as a component moves into patients, blocks both as I give 2 and as I give 3. For 6 or 5 has a single profile, and I will not discuss today. 4999 is a bit of a strange, compound. It's selected on, on as I kid 3. Only it has a bit of a different profile that's also for a later discussion. So we'll not be, discussed further today. Oh, you have, you have to move in? Yeah. Okay. So how does SI case work? You can see that in the movie, you see the yellow and green strains. In fact, these are the MRNA scoring for the anti inflammatory and the pro inflammatory cytokines. And in immune cell at rest, They are in balance. This whole system in effect is under control of SIK and SIK controls on the left, the HVACs, and the CRTCs. Give me a minute here. So AgeX, in fact, they are blocking NFAPAviso if they reach the nucleus where you see the DNA strength of the NF Kappa B program, they will block that. CRTCs, they have the opposite function. If they can get to the cell, they will activate the threat system. But SIK is a kinase, so it adds a phosphate group to both age that in the CRTC and both stay out of the nucleus and they don't work. And so there is a basal functioning of NF Kappa B. And CRTC. And this gives us a kind of balance. So the next slide, well, so when there's inflammatory trigger. What happens now is that this whole LITA system is biased, and it is a direct activation of NF Kappa B. And you will see a vast increase on the left from the proinflammatory cytokines. So what happens now if you switch switch off this master's slides as I gave with it on your next slide. Well, then you get 2 opposite functions. So, the SDK is blocked. It's not phosphorylating anymore, HZAC and CRTC. Age drugs go to the nucleus and they block NF Kappa B, so you have a vast decrease of prefabody cytokines. While CRTCs also go to the nucleus. They activate the crepsicles, and you'll see an increase of anti inflammatory cytokines. And this is why this mechanism is so unique that with the single switch of the button, you're going to completely invert what is normally happening during an inflammatory process. You play at both ends and you avert completely the picture. That is the heart of the matter our LRK swaps. Next. So let me go back to the presentation. Next slide. So we discovered this target quite a while ago, so it was around 2012. And we will later add to the presentation a number of external references, and you will see the first up here as well in 2012. With those novel macro actions, as you're a pioneer. In fact, the work is going slow because we don't have any tools to confirm. So it took us a while Within 2014, we set up an HTS cleaning. And as soon as we had first hit the effect our chemistry team starts to work, And from 2017 onwards, we've been making a preclinical candidates and up to the area 4, and we plan to do much more and even increase the speed. Over the coming months. Because we have those 3 members, as Iq1, as Iq2, as Iq3, and in fact, we're going to combine all of them over the coming months. Site. We have effects set up for our company a massive effort, a massive effort, sorry, we've dedicated the largest chemistry team ever. We've dedicated the largest team to understand this mechanism of action ever. We synthesized a couple of 2000 openings. We initiated our chemistry work on more than 10 different cities. And we're really chasing every selectivity profile that we can take off. So we've been firing patterns and more Currently, about, 1four of the company directly or indirectly in research works on this program. And we really want to push this to the max. So you can see on the right, we have the different profiles. My ambition is in a couple of years. We have a plenty of compounds with different profiles blocking as I case selective in 1, 1 only jewels and triple zed. Next slide. Just to give you an example on how the chemistry worked and what the chemistry did on the left, you see The typical output of the screen. So those orange dots were only a few axes are sitting in the left corner there. Meaning they have low potency and they are not selective because they have the same distance to to to to any access. On the right, you'll see how with this chemistry effort, we have grown our seas, both in terms of policies and in terms of selling. We have selective as a key 3. Jules, we worked on selective as a key 2 series. We worked on selective as a key one series. So this will be a maintained effort and we will come with whatever profile we unleash is sufficiently interesting to be put in patients. Let's now go back to our IDP model. So this is a cartoon of an inflamed call. And you can see by the fact that the bacteria, the green dots that are stained the lumen as well, they pass and put through our barrier, which at the moment is leaky. The synthetic cells their sense of the presence and they activate the whole immune system. They're going to activate the macrophage, the neutrophils, and also they will recruit the T cells, th1 th2 th17. And all of them will, that produce many cytokines to form and to attack those bacteria. So what you see as well in the car too, there's only 1 or a few amounts of teed extras. So what happens now when we block with the two label, You're going to block both the DG cells, the macrophages, and you will see the balanced turn. You suddenly see a large amount of key rays. We see suddenly the green cytokines appear, and we don't see any of the protein in inflammatory cytokines. So, visit Toledo, you can locally distort completely reversed and interplay and barriers will restore and integrity will be restored as well. So bacteria from now on with state index. Let's now go to some Avito data. Today, we only show data of 3970. So the pictures might look very similar to what I've shown shown before, but that was with different compounds. Today, all data are around 3970. These are 3 IVD models and the uniqueness of the Toledo family, it affected that these compounds work in all three models. We've seen good activity with jacking visitors to all the mechanisms in 1 of 2 of those models. Never in the three models, but the same ones. On the left QMs, DSS, and that's in fact a barrier model. In this model with a chemical, you will, damage the battery integrity and you'll see how quickly a compound can restore that battery integrity. And T970 net scores as much as our internal positive control. In the middle, you have the T cell transfer model, an effect that is more unbalanced model because you may take healthy animals, you're going to infuse a mix of activated T cells, you you distort the balance. Now, as a consequence, you get all of the damage, on the call. Also, the reference is a diesel blocker, a buffer set here. Again, you see that 3070 is doing nice in the job to block the damage in the T cell transfer model. On the right, the NDR 1 model, it's less used It is quite close to disease. In fact, it's a model where you have sensitive animals, you would drink it under the bacterium, and their colon, and their colon will get in claims. And even more, I'll say the teen antibiotics in this model, versatile disease, like the clinical clinic while IL-twenty three, antibodies will work. So it's a quite relevant model. And also in this model, 39s and a 0 as shown night activity. Next month. So now we'll dive a bit deeper into what we've seen in the T cell transfer model in the tissue. So now I'm going to show you really experimental data, and let's start with the macrophages here. What you see here on the left are the activated, the pro inflammatory M1 macrophages, and on on treatment, you see the number going down. Same mode on the right, what you see here, is that, the 2 macrophages, the heating ones, when we induce the disease, their amount is quite low. By turning the switch here, return the program and the M2 screen kits. So we really have proof, continuity proof that we play on both ends of the pilots here. Excellent. So we've also made it locally, cytokines, These are there's no measurements in the cold tissue after treatment. On the left you see the TNF levels, So we start with the healthy animals unchallenged. We're going to challenge them with with T cell mix and you've seen increase of TNF. In the coal tissue. This is coal tissue. I must stress that you those animals, or you treat animals Toledo, and you'll see a retard to almost the the the healthy learners of before of TNF alpha. So a very strong blockage of the pro inflammatory cytokines. In the middle, the same, but the opposite story for IL-ten, I'll tell you, it's the cytokine that's going to induce the the heating in the disease state. These levels decrease. They are low. We apply to Leila and again, we see an increase to almost no. So you need to play before this data, I'll show you a play on both ends. Of the patents. Take the anti valve and R10 were only the prototypes of a multidroid panel. On the right, you see, you see on the top total panel of the pro in in inflammatory cytokines. We measured upon treatment. They all decrease. Below, you see 2 members of the family of the anti inflammatory cytokines and again upon treatment both members increase. So we see across cell types, across cytoplans, the system pictures, we play at both ends of the back. To Toledo works on multiple immune is also active in multiple disease phones. We've tested, I've shown you the models of IIT team. We've done, I will show you the data for psoriasis so that arthritis are a, we've tested Bluetooth models, we've tested all a models. It's not everywhere. I if you can see, for a, we don't see activity with with our compounds. Show you the most important one. Our next slide's first. Next, so the Anti inflammatory models with next in the second pair as well start to be interested in the fibrosis models. And also there, 3970, shows nice. Activity in 2 models of fibrosis, I'll show you the data. But again, we'll concentrate today on explaining switch how this molecules work in a in a fibrotic setting, I promise you to take it as well at the next. Okay. Next slide. Data on psoriasis. This is in fact a local model, we are going to inject IL-twenty three in the ear, and there's a very easy measurement to just measure how much the ear is swelling and you can improve then that your compound has an anti inflammatory activity. You can see that here, 330 scores as good as our positive control in this model after oral dosing. It's oral dosing company is repetitive to your body, go into the skin, And locally, it does, due to this activity there and clearly shows an activity as good as a positive control, which was a thick tooling able to push. Okay. Now two models of our strides. And effect on the left here at the CIA, on the right, sorry, arthritis model, and effect 2 quite different models. Although it's both bone and joints. The CIA model is a model where disease is driven by B And T cells. While the psoriatic arthritis model is driven by other cells. So, but as I showed at the beginning, Toledo shows an activity in T, B cells, macrophages, and ethics. So CIA is clearly check the promise of B and T cells that are coming through. And you can see over here that 3970 score as good as MREL in this model. So this is a harsh setting. We wait long before we start to dose so that there is good disease. It's the therapeutic setting as we call it. And then we start to see, yeah, we start to dose and we see effective decrease of the disease with these compounds. The phonetic arthritis model is a bit of a different model that Now we inject IL-twenty three, let's say, in a systemic mode, when you get an inflammatory response on the bones and certain of the tendons as associated with bonds, typically for the disease as well. It came there, and this is becoming a repetitive story, 370 of scores as good other positive control. Finally, in terms of animal models, I just told that we have a show activity in 2 5 process models. On the on the left, you see the bleomycin. The models what it is, the Windows small. Between 90 and 0, here was even better than Nina Teddonic, which is a positive control. So clearly an indication that there is an anti fibrotic activity ongoing here. There's a good rationale, but as I said, I'll keep that first, an extra long tape session. On the right, a chronic draw of course is a hospital, whereas well, you can see that the tornado lies discourse and even better scores than telemetry. So next to the auto immune, which is start in of the program, we as well plan a later wave of anti of fibrotic indications but on it, it will tell you more about this. So what do we have today ongoing? We have 3170, SIK 23 starting phase 2, we start to those patients only to expand breadth and the and thinking behind the program. 4999 in SiK3 Selective, we are IND ready. We wait for approval and we will start phase 1. 4, 6, or 5, it's very specific as likely to treat compound, explain as well later. It's kind of a backup. It has different properties compared to 3970. Beyond these three compounds, we plan to keep on as I said before, looking selective as I key ones, as I key twos as I key threes, and then as I key ones combined with 2 and 3. Whatever we can, when we find compounds that show an interesting profile, different effects are there in the clinic, we will push it forward. We've put 3970 in in in preclinical testing. And from there, we we go to the clinic. So we've performed the phase 1 single ascending dose, multiple ascending dose, and, in fact, the compounds in terms of PK performed. Excellent. It's a once a day compost. Absorption is fast. We've seen those proportional exposures. So and, based on the off life, once a day dosing really is our way for As well, what we see with the compound, the chance that we'll, enter dragon interaction programs are issues later. Is quite low. In terms of exposure and dosing, this is an easy compound to move forward. The more interesting compounds our data came in effect from the PD effects that we've been measuring in this phase 1, and you will see now graphs on the left on the TNF alpha levels, day 1 on the left, day 14 on the right, and then I'll tell as well, left day 1 right t40. So what we do here is we take blood samples out of those healthy volunteers at specific time points. We go into 3 years the whole blood and then measure whether Tiena Balfa is there or not an iontech. And as you can see, orange is Sibo, we don't see any effect on either Kiawalfa IL-ten. Do not those effects already gave any effects in TNF alpha, not yet on file or a very unusual IL-ten, But from the second dose effect onwards, we were clearly seeing robust, decrease of the pro inflammatory cytokines and a nice increase of as well of the anti inflammatory cytokines. In terms of safety, I can be very short This was a quite boring phase 1 study. So we've seen what you typically see and we've seen nothing special. So all lights on green to move forward into the clinic. And with that, I want to give the word to wallet. Thank you, Pete. Good morning. Good afternoon, everybody. I hope you can hear me well. I hope we got you very excited about what we've seen so far with this program and I'm really excited to walk you through the, clinical story and our approach there. So can I have the next slide, please? So when this slide that you've seen before and as we've been talking about the foundation of what we do and what guides us, Galapagos is signed. So when we set out to figure out how we wanna approach this, platform and how we wanna learn that's We looked at, the broad application that we have in inflammation. And as you can see here, between innate immunity, innate, and adaptive immunity you can see on the left hand side, these indications that are more close to innate, like psoriasis, UC, and CD in in in IBD space, And on the right hand side, you have rheumatoid arthritis, lupus chakra. And in the middle, getting, you know, from both worlds, you have psoriatic arthritis. And to a great extent that colors the way we're gonna go forward. But at the same time, we were taking a broad approach so that we can learn from the lead compounds so that the follow on compounds could be better positioned and potentially could move faster so that we can make these, promising SIK inhibitors, available to the patients as soon as possible. If I can have the next slide, So the first step here, and that's that's the first orange wave. So the first wave is to cast a wide net, in looking at a number of diseases across the innate and adaptive immunity space And in in a series of signal detection study to understand the biology, link that to what we've seen in end of phase 1, effect as well as an animal study. And then the next wave will be to, potentially go further in those areas where we have a clear effect in in these, signal detection study and go into those range finding study. But as well, expand into other indications. For example, if you start with, ulcerative colitis in the first wave, you can go into Crohn's disease If you start with the psoriatic arthritis, you can go with ankylosing spondylitis and so on. I'm sorry. We're staying at the same slide, and then you have that 3rd phase where we can further develop and go into confirmatory program, for the studies, the indications where we have effect in the the dose range finding study, but also initiate our, fibrosis platform as as Steve described. You know, so now let's dig a little bit in more details. I'm not gonna have the next slide, please. So for the trip for to validate this this initial space, we started with the psoriasis study. And and and psoriasis is not really an indication that we plan to continue developing, based on the way we think right now. But the reason why we started with it is because it lends itself to very quickly be evaluated and generate clinical data for us to indicate where we need to go next because we can do this in a phase 1 setting because most patients are relatively healthy, with the exception of some, the skin modification of their psoriasis. Many if I can have the next, click piece, then you can see we're gonna be casting a white net across that platform that we talked about. Looking at signal detection studies in ulcerative colitis and rheumatoid arthritis as well. And then later, which is gonna be starting, later next year. I'll show you on the on on subsequent slides. We're gonna be expanding into more challenging indication, but also very interesting to understand the biology, lupus, and and girdre syndrome. Next, then you will have a set of studies where we can go and do those range counting studies in RA and UC. For psoriatic arthritis, I'll talk to you a little bit more further on, that's an indication that we're actually trying to accelerate faster because it promises to, make these, potential therapeutic agents available to patients as quickly as possible. And then when we do go into indication expansion, you can see the adjacent indications that I talked about. Grows, ankylosing spondylitis, but there are also some others. That's why we didn't label that last one. There could be others that we we will find out more and learn more along the way and be informed by that 1st wave of signal detection. And lastly, you have that phase 3 where, you can go into confirmatory studies, for inflammatory diseases, but also, start exploring the fibrosis indications and other product indications that we're gonna go after. Next slide. This digs a little bit deeper on the timeline. Give you a sense of the parallel sets of signal detection proof of concept studies starting with the psoriasis study, which is again, in additional cohorts in our phase 1, the ulcerative colitis and riton arthritis are 2 studies. I'll talk about them in subsequent slides. And then later, we're gonna come up come out with, Lucas and Gerbrand in beginning of 2021. So 3 of those studies are already active and recruiting, and the other 2 will be, coming up, shortly, by by the end of this year, early next year. So we have 5 different proof concepts to investigate a broad negative action to be able to get a good sense of the overall biology and casting a wide net and and learning from it. We expect to have top line from these studies uh-uh, as as of the beginning of as of the middle of 2021. Now there's a there's a caveat there is that COVID is a bit uncertain. We're hoping that we're gonna be able to move according to the place that we want to, but there could be some some difficulties that we would see along the way. In the case of psoriatic arthritis, if you if you remember, I have a picture of the of the top of the, you know, innate and adaptive immunity immunity, and then Eric arthritis is there in the middle. And based on the number of studies that we've done frequently and that people have gone through some of them, today, we believe very strongly that the biology support this indication, and we have a very good conviction that we have a good probability of success. So as a result, we decided to prioritize this to take a bet, a bigger bet on this. And instead of waiting until we do things very sequentially. We plan to start immediately into those same 20 study in psoriatic arthritis, in the middle of next year. And and then with that, move as fast as possible, into phase 3, with the expectation that if our bet is correct, we will make available these potential medicines to the patients in about a year and a half to 2 years earlier than otherwise. Now let me take, some time to walk you through a bit of the design of these signal detection studies. So you have the first one called Kawasoma, which is the psoriasis study. As you will see across the board, those are small signal detection study in in in order for us to be able to cast a wide net and learn we must, do these smaller studies so that we can get initial information and not spend a lot of money at risk, but at the same time, also not take a long time to get the results back. But with that, also, you have to bear with us when you experiment of potential for some studies to have better results than others. So when we start talking to you about them next year, you guys should should expect also that some of them will look very good, but maybe some maybe not as good. And we should we need to be fully aware of it. And and we are going there with eyes wide open. So this, this study is essentially, we're gonna have 25 patients, then on active, therapy on placebo and 15 on act And and these are typical patients with moderate to severe psoriasis with, I have a baseline of at least 12 and above and body surface area coverage of 10% or more. And and we will look at, of course, safety and tolerability as we often do, but also at efficacy in the usual pausing scores and so on and so forth to get a sense of the activity. In addition, with those trials, we'll always look at biomarkers and things of that sort, as well. The next one is the C Turtle study in ulcerative colitis. And and that study again is is a similar design, generally, it's a 6 iteration, 10 on active on 20 on placebo. These are patients with mother to severe UC who have been exposed to treatment before, of course. And the key outcome is the usual stuff that we look at the endoscopy biopsy. We look at the male score and the partial male score. And and, of course, we will look at biopsies. And with those, we get pharmacodynamic endpoint as well to link back to the clinic, link back to the healthy subjects and learn from this. And lastly, this signal, the II study is the lady box study, which is a study in rheumatoid arthritis. Again, it's a study 15 patients on active on 10 placebo. It's a bit reminiscent of our first, study, that we've done a long time ago in Moldova with with Filgotinib, and we're hoping that we're equally gonna get some fantastic data with that study that will get us excited about going forward there with this one. So these are, again, patients who are methotrexate IR. They have mothers to severe active RA, and we usually look at the the usual symptoms of of RA that you know very well. So I hope, I can go to the next slide that I was able to communicate to you that the approach that we have taken in this, program is an ambitious, but also an in in informed development strategy where we take first, the fastest way that we can get clinical data in a psoriasis study in the phase 1b setting so that we can quickly get that information we also can take a bet on psoriatic arthritis based on our belief in in the biology and and also on the data that we have accumulated part, particularly the pharmacodynamic endpoint from the phase 1 study, and that could make the drug available truly patients, potentially after 2 years earlier. Then the learning approach that we take by taking the lead compound and linking back to the biology and translating back to the lab also to the healthy subjects and and have cross learnings will help us to position these follow on molecule, giving you an example follow on molecule comes in and based on preclinical data, we expect it to work in in in such, in a, let's say, in RA, be pharmacodynamic profile that we get, in phase 1, looks very much like what we expected to see in in compounds that would work in RA. It would be different than our our SIK 2, free. Then we can quickly go into a dose range finding study and a and and not have to do a a proof of concept study. And again, sort of speed development but not only that, also positioned for the right conclusion. So this is the approach that we're taking. And with every study that we do, our knowledge is gonna grow and ultimately, we will really unleash the potential of this brand new pharmacology and what could it it, what it could offer to patients. And lastly, we're going there with eyes wide open. So we know that this program is early. We are monitoring everything very carefully. We've been monitoring, for example, safety and and we look at the biology of this. From the beginning, we have a a large, group dedicated to monitor safety across all the trials so that we can detect signals very, very early and so on and so forth. We understand the promise of the novel pharmacology, but we also understand the potential, unknowns And we have all the systems in place to be able to, deal with this and and and solve any issues or if there were to happen, very early on. So I I want to tell you that we're going there with eyes wide open, knowing full well about the exciting parts, but also knowing for well that there are certain things that are not known because of the, of the novel pharmacology, and and we are gonna be watching this very careful. And with that, I will turn over to Ono to, to wrap up this very exciting story today. Thank you, Valit, and thank you, Pete. I hope you all share our excitement with this program. Clearly, we are, extremely excited and optimistic regarding Toledo. It is, it is short, its development still. It's early days with all the data, they point into the right direction. And I think it's really the totality of the Toledo data that makes a difference here. It convinces very much. It started with the, identification of the target with a very complex essay we saw in the literature that the mechanism made perfectly sense to focus on this one for, inflammatory diseases. We got the preclinical data in as speed has shown to you, where time after time, we saw very good and robust efficacy, something we have never ever seen with a more you before. And then lately the phase 1 data, where we saw luckily very good data in healthy volunteers, but we also a proof of principle with the fact that we, we could see a dose related effect on, on IL-ten and TNF. So altogether, we believe that we have a very strong package here, that warrants a hefty investment in a further steps towards, the patient. And if we go to the next slide, it's clear that we, potentially have a a real master switch for inflammation, different from anything anybody has shown so far much broader in its application and and hopefully much more effective than anything that's that is out there at the moment. We have, of course, with all the work that we have done over the past couple of years, a very broad and strong IP protection intellectual property protection with the patents. We have confirmation of the mode of action in in the phase 1 that we did with 30 1970 with a very, very good safety package. So that gives us a lot of confidence that we have a right window, to go into the clinic and into, the patient files. As Lalit has just outlined, we are going to into a very, smart path in clinical development, which should accelerate to bring this drug to, to the patient and hopefully shorten the development time substantially so that we can reach the market, much earlier than, than the other programs that they have been working on. All this, you could question why we have kept this under the wraps along with Toledo as a code name. Is all to, not make the competition wiser than, than needed. Clearly, we have a massive had started on the competition being in phase 2 where as far as we know, no other molecules for inflammation have been in the clinic based on, on this set of targets, on the SIK targets. So, that competition lead will help us to secure an important market share whenever this actually would get to the market. So a new class that potentially could change the way laboratory disease and fibrotic diseases are being treated. But what can you expect on the news flow, this year we, we were very pleased that 30, 1970, finished phase 1. So successfully, we're starting the proof of concept studies first one, underway, the second recruiting. So that's all going, in the right direction. Very, proud on the teams that worked on this especially in view of the whole COVID situation that, we didn't get, delays here. We're starting the next phase 1 for 4999, which data will come, of course, in 'twenty one. But in both you see in 'twenty one, the readouts, which are, of course, very important, of the proof of concept studies 3 preapproved concept studies will readout in 'twenty one and the rest will readout in 'twenty two. So, will be a lot of data that hopefully confirm what we are, what we are expecting. We, do you see a lot of other stuff happening phase 1 starts, phase 1 readouts. But look in 'twenty 2, where at the moment, we are planning the 1st phase 3, which would be a fantastic result if we achieve that. Then we have really accelerated the the speed of this program with a couple of years. And it's all possible now for Galapagos to do this, whereas in the past, we were always dependent on partners to finance the road forward. But as you know, with, the the cash that we received through the Gilead transaction, we can make our own development plan move forward as fast as possible and decide on the progression of these programs by ourselves. Which clearly helps to speed up the programs. So, I truly believe that this is a once in a lifetime opportunity for Galapagos something all these, people that work on this within Galapagos think is it is the project of their life. It is, something so new so promising that, this can change the way these diseases are being treated and that this happening at Galapagos makes us extremely excited and extremely proud. Of course, we still need to deliver on it, and it's a risky program because it's early. But, all the signals are bright green, and we're looking forward to sharing more information as we go along the way. With that, we, would like to end the formal part of the presentation. I hand it over to Elizabeth for the Q And A. Thank you. So thank you, to our speakers. That concludes the presentation portion of the video webcast. We do invite sell side analysts and professional investors to post questions. I'm going to give you the dial in number again that 44 for the UK 2071-928-338, and the code is 331289. There some additional numbers also listed in the webcast player interface. You should be able to access those. I ask that folks who dial in to please mute your PC while you're speaking on the telephone. Otherwise, we're gonna have some some terrible feedback there. And now folks who are interested in posing a question, you press star 1 on your telephone. And then you'll come into the queue. So I'll give folks just a moment to do that. Star 1 on your telephone. For the first speaker is Brian Abrahams from RBC Capital Markets. Go ahead, Brian. Hi. Thanks very much for taking my questions and, congratulations on all the innovative work that you guys are doing. Two questions for me. My first is, I'm curious, as you sort of look across that, look at this mechanism, I'm sort of curious what shapes the differences and how you guys are planning to target different compounds towards different indications. For instance, I noticed that, both 3970 and 4605 are, 623 selective and yet they seem to have different profiles in terms of what the, what diseases they work best in in the in the preclinical model. So I'm wondering if you could talk what explains, what might explain that mechanistically and what, guides your decision on on, on targeting each compound? And then I had a follow-up question. Okay. You can hear me now. Yeah. Thank you, Brian, and you get the target well many, many months ago. So congrats on that. 3970 and 4605. Hollywood complete different chemicals, scaffolds, and they behave completely different in the body as well. And that's probably what's going to guide 4, 6, or 5 to a couple of specific diseases because we see and dispositions that compound in higher months in certain tissues only, while 3970 is a compound that's coursed everywhere. So with ForsX Surviv is correct, it's the same as IQ2, as IQ3 profile, but the behavior in in in in in the body is is is quite different, and that's due to the chemicals. Thanks. Got it. That's really helpful. And then, maybe a question if if you Oh, as we lose Brian? Apologies, Brian. That was, let's say we've lost Brian. Brian, if you can just dial back in, we'll, we'll come back to you. I'm so sorry. So the next speaker is Phil Nadeau from Cowen And Company. Go ahead, Phil. The line is open. Let me add my congratulations on your progress on this interesting target. I guess two questions for me. The first is that there is a suggestion of sick, the, dysregulation in cancers, have you completed your preclinical carcinogenicity studies and and what have they shown? And then, second kind of a technical question, are are all the compounds that you're developing kinase inhibitors or are there other ways to regulate the activity such as interfering with the AMP binding domain? Thanks. Phil, thanks for the question. Like any drag up place in autoimmunity, you need to be careful indeed because your work on balances where indeed, if you take away too much, of throwing in in, in flounder, cytokines, for cancer. Those studies haven't started yet. They are I we we need to, we typically perform them later during phase 3. But from what we've currently seen in preclinical, it's not that we are heavily boring. I guess, yeah, that's, let's keep it to that. And then the second question, you wanna know what old tricks we try to do to block, the the the panels? Okay. We are open to novel modality. So if that's, so we've we've explained last yet R and D there that we will try ASOs and products. So if you're successful with one of those, it would, it should not be surprised that programs included. So thanks. So our next question comes from Evan Seagerman from Credit Suisse. Go ahead, Evan. Airline should be open now. Thanks, Elizabeth, and thank you everyone for the great presentation today. So, a few questions. 1, can you hear me? Hello? Yes. Yes. Yes. Are you good? Okay. Perfect. Sorry. Just to hear you. So looking at the Saraya Looking at the psoriasis indication, there's been, obviously, we did the PDP PDE4 inhibitor with Otezla, but there's been a lot of interest in Bristol's TIC 2. You know, how do you think your asset compares to these other kind of other modalities? And my second question is, is there any synergy benefit in combining, say, 1690 with 1 of your, 623 inhibitors in IPS. Well, if you take the first question. Yeah. Let me take the first one and then, toss it back to Pete for the second one. I our approach for psoriasis and and and this will be seen in also other programs that we're developing is is to use them as a as a signal detection. So, for us, and to better understand actually, how the biology is is comparing, we we do not know. I mean, if you look at at what is what is the unmet need now on psoriasis, I think we find the bar very high and and we're not necessarily thinking currently about developing our molecules, in psoriasis, afterwards. So, so this is truly to teach us about the biology and then, and and then, sort of complete our our, sort of, taking multiple shots across the adaptive and innate immunity that we see, we see in there. And our preclinical studies, as you saw, from Pete's presentation, the data looked very good. Now we'll we'll wait to see what what will happen in the clinic. Pete? Yeah. Thank you. Then on the second question, does it make sense to combine the tornadoes with 6090? Well, from mechanism action point, they're completely different. So in that sense indeed, it makes it makes clearly sense to, at a certain moment, combine those So for our fibrosis franchise, we have an ambition to bring multiple drugs to the markets and then come with an ideal combo pill at the end. So that that completely blocks the progression of diseases like Life Sciences. And from an acoustic point of view, for sure, this makes sense. Thank you. Great. Thanks so much. I appreciate it. Okay. Our next question will be from congrats on the progress with the Toledo program. So maybe I'll keep it two questions on my end. Just going back through the the timeline of the program, the original asset was 3312, which is Pantalito. It seems now that you're the program's avoiding sick ones specifically. I was just curious for your thoughts on, one avoiding that target or potential issues running into hitting that target, maybe selectivity of these next gen Toledo program assets over SIC 1. And then secondly, was also interested in, and, stick to as the backbone of, these compounds and was curious to get your thoughts in terms of what's been described as maybe pleiotropic activity and expression within tumor cells, and how you think about some of these in relation to what's been understood within the field of oncology. Okay. So the first question is on SiK1. If you look carefully to the chemistry slide, you can see that we have families with selective SiK1s. So in that sense, I don't think the conclusion that we've given up on EsaQ Van, EsaQ-one is a correct one. So, I probably didn't tell but during when we screen, in fact, in multiple immune systems, if you check all our data, we've picked up every ASIN K member in 1 or another screen. So I'm not going to say picked all three up in the in the IBD call center, but we've picked up every SIK in one of our screens so that SIK 1 has its place there that is for sure whether you can drag it well and safely that is a different question. So we are not yet there otherwise. We would have that, profile currently available. For oncology, as I said, so we are everybody playing our work in this field is, is is aware. Are we heavily concerned no. So there are many publications pointing into many directions that when we do the preclinical tox, we watch all of those tissues with special attention, and there is nothing where in today's day, guys. This is not this is not moving forward. So but thanks for the question. All right. Our next question comes from Rimal Kapadia from Bernstein. Go ahead, Ramal. Great. Thanks. Thanks very much. Take my question. Ramal Kapadia from Bernstein. Just go ahead. Firstly, just come back to uh-uh. Alright. Can you hear me? Yes. Yes. Hello? Yes. Okay. Great. So just kinda just coming back to a a a earlier question. You know, when I'm thinking about the outlook for many of the disease you are targeting. You know, there are now multiple MOEs on the market, and the bar is really only increasing for future molecules so, you know, what really gives you confidence that Toledo surpasses that bar so that when the product does come to the market in several years' time, you actually will gain traction. And it's tied to that. Now how would your plans change should some of the more advanced products in the clinic such as Dimituzumab also demonstrate great outcomes in in in indications like psoriatic arthritis given this is one of the reasons you just mentioned for not pursuing psoriasis. So that's the first question. And then my second question is just, you know, clearly very exciting in terms of trial outlook. How should we think about the R and D spend trajectory, tied to Toledo? Oh, no. You just mentioned hefty investment, in your presentation. So any additional color or, you know, on how on how R and D will be impacted, and the trajectory moving forward would be great. Thank you. Yeah. Yeah. Okay. Well, look, I I think this, again, we we we we are guided by science and data. So so far, our preclinical data suggests that, you know, this platform could make a big difference and actually be a paradigm changer. That's why we we we describe it the way we describe it. That's why we're so excited. That's why we've been investing a lot into it. And we will, see how the data look in the clinic, whether our story, which happens from now, has been lining up very well. When we take the next step to to go into the, the various diseases, whether we see the same, promising efficacy In the end, we will base our decision, on whether to progress or not, on the magnitude of effect, whether the chance we're gonna be and making a big difference in in in the states. As you saw that there's a huge, room in in inflammatory diseases, whether they are in methodology or APSA, but also an IVD, where there's a huge, room for us to to go up, like, what happened in the psoriasis field, 10, 20 years ago, and and our hope is that we're gonna be in that ballpark. Now, of course, if if the landscape changes, with new medicines really lifting the door, then we just have to clear that one. You know, we cannot we cannot be developing. We have zero interest in developing molecules with minimal incremental, change. This is something that, we we we truly fundamentally believe in it, at Kamathalos. But, again, we let the data guide us, and then that's how we will we will be, we're looking forward to see what we have. And with that, adjust our our label. Yeah. Well, with regard to the cost associated with it, clearly, this is an hefty investment. It has been an hefty investment for the last couple of years. However, if in the totality of, what Galapagos is spending, he says 2 trials, are not going to break the bank. As you know, we are very well realized, we got the money from from Gilead to invest in, innovative new research. And the this is clearly right in the street spot here. So we believe that it's warranted to continue in this broad phase 2 trial, and we'll see if the data justify going into multiple phase 3, we'll clearly do that. It will then be likely in a combination with Gilead. Gilead has the right to this program after completion of phase 2. They will have to opt in per molecule and after that, cost are shared 50.50. So it's up to them to, to join, but they are extremely excited about this program as you can imagine. So, I'm not concerned that the cost of this program, will go out of control and make our P and L suffer too much. So for now, we believe it's a very doable program financially. Great. Thank thank you very much. K. Thanks, Jamal. And our next question comes from Peter Welford at Jefferies. Go ahead, Peter. Hi, yes, thanks. Just have a question, follow-up really on the 1st generation of compound or the first compound 3312. I wonder if you can give us some more details on why that was deprioritized and what it was that you saw, whether you think that is a chemical specific. And perhaps you could then just follow-up there. Could you tell us with regards to the, I think, the 10 chemical series you said you developed are are all of these for 331239743399, and I think 4675, are they all different chemical series, or perhaps you could just put them for us in terms of chemistry, in in the various buckets that you've outlined to give us an idea of, I guess, or how sort of you've covered that that spectrum of drugs so far. Thank you. Okay. Let me start on the different chemical theories. 4299, G12, and 3970 came from, same family. So that is a small variation. So the seed is going behind. They are much more diverse if you want to have a selective SiK 2, I can tell you we've tried a number of things, so there is not an easy task. So if you want to select it as I give out as well, we've tried to note the seed. So, there are 2 to get this activity right. You need multiple seals. But the current, they are from a broader family. You can see the differences Our specialist is easily discriminated, but broadly speaking, they come from the same family. They don't treat it well, so treat it well as a pancake compounds, not that selective. And, we got a very full was a bit with early successes that if you targeted this to the colon, in the particular space, this one extremely easy and extremely just successful and we told Daniel as a proof of concept. If you can expose a call on all needs, give our maximum chances of success to validate this target early on. Unfortunately, when we took this is when we took it in the clinic, we hit 1 technical problem after the children and then the program became so terribly low that I effectively 9700 in space. It's internal speed took it over and then we we we decided to progress a faster program overall slower because I wasn't we could have done it faster with 2012, but then the next would have taken again a couple of long rounds of optimization. And in terms of speed, this was not going to be competitive and learning of so much. So it was a porting error we've made out of the deal. Thank you. So now our next question comes from Jason Gerberry from the Bank of America. Go ahead, Jason. Thanks, Elizabeth. Thanks, guys. So, Are you still with us, Jason? Picture. Yeah. Go ahead. Thinking of yeah. Can you hear me? Yes. Can you hear me, Elizabeth? Yes. Alright. Great. Yes. Yeah. Just, I guess, big picture, some of some of the more high profile, INI markets where you're moving forward with Pluto IBD RA. You know, obviously there's there's been a lot of success with, oral therapies in the clinic, is the idea broadly to sort of replicate the efficacy, but, you know, achieve that without systemic safety issues here with with the Toledo program. And then, as we think about, the the the program modulating and and IL10. Can can you talk a little bit about the the dual, the dual action there, the potential for any offsetting effect, if you dosed Toledo too high, Just wondering if you can comment on some of the dosing considerations there. Thanks. Yeah. I can get started there. In a way, I think if the mechanism toledo as you're playing on both ends, should allow us to dose a higher onto those response curve in a safe way. So in that sense, I had a bit of a different vision than, the fears that that I think I could pick up in your question, but the fact that you play on both ends of that balance in feel you should be able to go higher on the dose response because you will not exhaust the system. And in that sense, I believe that in terms of, both efficacy and safety, there is room there to improve. Of course, if we unhelp with a profile, which is similar as a check-in with a similar safety profile, then this is not a success. It's intrinsically this this this has the problems of being much, much better than what is currently altered because we play out those both ends. Another other question that I missed out. No. Thank you for the question. The first one? Yes. Okay. Thank you very much. Next question comes from Emily Field from Barclays. Go ahead, Emily. Hi. I just have a very, very high level question. I know you touched on this in one of the previous answers, but just, you know, it would see, it would seem that, you know, part of the issue with 3312 was, was a lack of selectivity. And so just just thinking about this from a high level, would it be right to assume that the he progresses the next generations and iterations of Toledo that that that that would be of increasing selectivity. And, And as you go about that, would you still plan to start with the broad indication set or kind of as you move through the next generation of the compound would would there be more selectivity also in terms of the relevant indications that you think that those potential assets might be relevant for. Sorry. Very high level, but Yeah. Oh, no. Thank you. And I will take the questions and activities. So indeed when I looked at the presentation and the history of CD12, you get the impression the way forward here to improve is easy. You just make more effective components. So you're not doing about 6 years of chemistry here, and it has been a long and an extremely interesting journey with a lot of surprises in that sense that as you have 3 players with similar or working around the same activity, it's it's full of surprise. So I do not exclude that one day combined as I K 123 will be the best molecule especially early on when we look to the selective profiles of 200 trees. It is not such an easy picture as it's, as one might think, just improve your productivity and you will then you would get there. No. The picture is quite complex with anybody who wants to try and is welcome, of course. But it's, it is a quite intriguing story and we learn every day. So I was thinking that only the selective profile out of future years you're not there today. Well, maybe you take on the indications that we want to take forward. Yeah. Sure. Thank you. Yeah, Emily, with regard to the indications, I think, the our ambition is that the lead compound is gonna be generating a lot of information that we can then use to back translate and position the the the ones that are coming behind, and and use essentially the, for lack of better word, the the pharmacodynamic fingerprint of each molecule to guide us in a in in a in a in a given path based on, you know, which which cytokines are changed, and and, also based on the preclinical data. So the first one is gonna be casting white net. The others are gonna probably are gonna be benefiting from that and actually going narrower, in indications or maybe exploring other indications as well. But it's It's hard to tell now before we have the data so that we can react to it, but it will be data driven. That's what it is. Great. Thank you. Yeah. Thanks. Thanks, Emily. So now we go to Matthew Harrison from Morgan Stanley. Go ahead, Matthew. Great. Thanks, Elizabeth. Hello, everybody. So I guess 2 things from me. First, maybe, can you just talk a little bit about formulations here. And I assume depending on which disease state you might be targeting, I don't know if you're looking at different formulations for these. So maybe if you could just walk through what you're doing in terms of formulation and bio availability to different key tissue sets. And then Second thing, I know in the past when you've discussed this, you've talked about really wanting to have a significantly differentiated clinical bar. Could you maybe just comment on how you're thinking about that and what you think you'll be able to know from that perspective when you have some of these proof concept studies? I'll take the question on the formulation. Well, the formulation attempts you need was limit 23, 312 at the beginning, and we we had the idea that's hit it hard in the call and that failed. So, but for the rest, 3970 is a relatively easy compounding with those at all as a solution, but you have a fast absorption, 49.9 So in that sense, that's a sort of combination. So I think it's 3 to 12, which is first of all, so we wanna look forward But did you take the second question on the indications? Yeah. No. I mean, I think, I I think, the the the these are gonna be small signal detection studies. And and usually the way we do this and just doesn't apply just for the Toledo program, for sing small sing signal detection, you can have free out comes, one where there's nothing, and then you'd say, okay. Well, we went down the the wrong path. I would need to go look somewhere else. Or you have, data that really knocks the ball out of the park and and and and then you clearly see that you have very promising Avenue, then you go and go fast in that in that direction, or you have data where it shows you that that you have a signal that's worthwhile further, you know, pushing in. Maybe you need to select your population better. Maybe you need to, focus with the next study looking at different endpoints to be able to tease that apart. But our ambition is that and and there's there's a lot of room. I mean, let let me take IBD, for example, when when you have, you know, looking at, you know, these EBS remission rates that we talk about and you have a difference from Placebo or anywhere between 10 to 15% after 10 or 12 weeks induction, the bar is is very low right now. We have huge room for improvement. And even when you look at maintenance to look at you know, steroids free survival, uh-uh, at the end of the trial, it's about 30 40%. And we're very excited about this because It's better than anything that that has been seen so far, but I like to see 90% security survival. I want you know, none of the patients to remain on steroids longer term. So then there's a huge room for us to do, much more. And and, you know, these initial trials are gonna send us toward that, but then we will have to confirm it with the with the with the larger trials. But that is our ambition. Our mission is to move the needle clearly visibly, appreciably, meaningfully, not not just small increments. Okay. Thanks very much. Matt, you. Our next question comes from Greg Sivanovate from Goldman Sachs Group. Greg, go ahead. Thanks, Elizabeth, and thanks team for the opportunity to ask questions. It was a great event. I've got two questions, if I could. The first one was just around the comments around safety, I believe the comment was we're seeing or you're seeing what you typically see. And I'm just wondering if you could just and on on what that means in your mind. And then second, any, what the initial discussions and it might be premature right now, but any initial discussions with Gilead as to what their level of interest is in Toledo and you know, how should we think about, what their level of interest might be in light of what's happening with Filgotinib and then, you know, the unfortunate disappointing readout for 1972. Thanks. Please, one safety. So we had no volunteers dropping out. We had no events that cost any concern. So, and there will always be somebody who'll be dizziness forever or higher, but that is normally, and you've always seen one headache or something that it is what I do a really an extreme boring phase 1 where we haven't seen anything, which is specific to Sorry, so it's a bit difficult to talk about boring things. I'll see you. Okay. Oulu, you take the question. Well, in this case, boring is very good. So, thanks for that phase 1 to be boring. Yeah, Gilead is clearly very excited about this. They after, the CRL with Filgotinib in the U. S, they have expressed their commitment for inflammation long term and they see this as the next big thing. So, yeah, you don't have to worry about, their interest to step on board when the time is there. It will take a while because they have the option after, completion of the phase 2 studies but I'm, I'm sure they're eagerly, following these developments and, we inform them on a regular basis, and they will be ready to act when the data are there. And, I fully expect them to, to join and will share the Phase III cost with us when the time is there. Okay. Thanks very much, Greg. So our next question comes from Michael Acunovich from the Maxim Group. Go ahead, Michael. Hi there. Thanks for taking my question. So it seems like P and is a big part of the dual mechanism. So I'd like to see, would you expect Toledo to work best in patients with disease phenotypes that are likely to respond to TNF therapy, or is the dual mechanism likely to expand the population, which is likely to respond? For a great question. Yeah. Well, the Toledo profile before we see the slides that we don't care hub, but there is a large array of, pretty standard clients. We're working for staff off same question, IL12, IL23. And, as I said, I believe that by playing on both ends, we should be capable of showing activity with more patients to start with, I hope. And I think that is the question, but I I know that that the slides were around TNF, particularly have made slides on on on the cytokines that is a beauty of this program. I mean, it is quite interesting. It really blocks the whole NFCouple B, program there, which, which, which is triggering a large variety of the cytokines. So it's it is not limited to our kinects. Also, we want to clean some iron on beta interferes or whatever. So In that sense, we should have a client portal for you on where it can play. But it's my belief that is profile in the end, we should be able to any higher on the dose response and that will give us a better Thank you. All right. Thank you. And then one more, if you don't mind. I'd just like to touch on, you have the dual mechanism, which essentially rebalancing the immune system rather than pure suppression. So would you anticipate that you would avoid many of the side effects associated with traditional anti inflammatories? All right. Thanks very much, Michael. Our next question comes from our first question poser today. That's Brian Abrahams of RBC. Thanks for your patience, Brian. Your line is now open. Thanks, Elizabeth, and thanks for taking my follow-up questions. So, I think studies have shown that sick one may play a role in maintaining muscle health, and I think studies have also shown topical pan sick inhibitors maybe associated with increased skin pigmentation. So, I guess I'm I'm curious specifically about whether you're looking at some of the param some parameters along those lines like, perhaps CK, or or pigmentation in the ongoing studies and if you've seen anything of note so far. And then also with, respect to therapeutic window, I'm curious where you're expecting to dose and the ongoing proof of concept studies relative to the equivalent dose levels, at which you saw the impressive activity, in the animal models. Thanks. Yep. So thanks. I'll I'll I'll take those. So, yes, essentially, as I as I mentioned, you know, commensurate with the size of our investment, we were also not just looking at, to understand the biology just in terms of efficacy, but I'm sending the biology period with whatever effect that that are in humans. So you can imagine we had a large team dedicated to it both, preclinical and clinical looking at this. And we monitor, all of these, elements that you mentioned. We're we're quite aware of the, you know, the the work that's being done with with topical use of the, SIK inhibitors. In terms of therapeutic window, the the preclinical data or, I mean, I'm sorry, the pharmacodynamic phase 1 data that Pete shared with you, showed you very nicely that that we we do have a a very good response both on on innate and adaptive immunity and changes in IL-ten and Terra Alpha. And and so with those, when when we dose in the clinic, we're gonna be picking a dose, at least in the signal detection that will be, they're targeting both because that's actually what, what we believe is needed, to show the better efficacy in the dose range finding studies, we will we will have a broader exploration so that we can see the the relative, impact of of the various inhibition of, you know, the TNF alpha, but also adding other cytokines as well as well as the increase in IL-ten as well and and whether more increases better or we we how do we characterize it as a response curve? So that's gonna be, also very interesting data that we'll be generating from our dose range finding That's really helpful. Alright. Thanks so much to everyone who's participated. This does conclude the Q and a part of our r and d round table. Please reach out to my to me or to Sophie Von Caisel. If you still have questions or if and or if you'd like to obtain some of the references mentioned during the webcast. Our next scheduled financial results call will be for the Q3 results at 8 am Eastern 1400 Continental Time in Europe on 6th November. We'll publish our results the evening before after a U. S. Market close. We thank all callers for their participation and, please, all of you stay safe and well. Thank you very much. Goodbye.