Poolbeg Pharma (LSE:POLB) — POLB 001 Phase 2a Trial Update

0:01 Good afternoon, ladies and gentlemen. Welcome to the POLBEG PHARMA PLC Investor Presentation. The company may not be in a position to answer every question received during the meeting itself. However, the company can review your questions submitted today and will publish those responses where it's appropriate to do so. Before we begin, we'd like to submit the following poll. I'm sure the company would be most grateful for your participation. I'd now like to hand over to the presenting team from POLBEG, Jeremy, Liam. Good afternoon. Good afternoon. Good afternoon, and thank you for that introduction. Good afternoon, everybody, and thank you for joining us for this presentation today. The plan of action is Liam and I will go through a set of slides, probably take you about twenty five, thirty minutes or so to give you a background and context to our kind of recent activities, recent news, and obviously future planning.

0:57 And then, we'll have ten or fifteen minutes or so for, for q and a at the end. So, as stated, if you wanna ask questions, please, drop them in. So we'll start off, usual legal disclaimer, and then I just wanna ground everybody, maybe new attendees, to pull back who we are, and I think why it's an exciting company to invest in and, our plans for the future. So we are a clinical stage biopharmaceutical company with a core focus on transforming the cancer immunotherapy field. We'll talk about that in-depth in detail later on with our POLB zero zero one clinical trial that's upcoming. And we're also developing an oral patient friendly obesity treatment. So we're tackling two very large markets with significant unmet medical needs.

1:43 The investment case in the middle of this slide here, we have a very experienced team with a proven track record of both clinical development and then transact at the end. Because as you see, there'll be a trend coming through where we'll be partnering as a very core focus for for POOLBEG right now. As mentioned, we've got high value programs targeting significant critical unmet needs in the oncology and the metabolic disease, settings. And as I said, we've teed this up that these programs are attractive for pharma partnering. We've always kinda said from a POLBEG standpoint, we were, you know, capitalized. We wanna generate this, proof of concept clinical data proving that the science is verified and valid, and then partner with PHARMA who takes it forward from there in the the longer, more lengthy clinical trials and ultimately on the market. Because, obviously, we wanna get these drugs into into patients at the end of the day. But as a pharma are always looking to fill their their pipeline of products, we wanna tee that up with our clinical trials.

2:42 We've announced our in on altered interim results today. We've got a cash runway into 2027, which then funds these near term near term clinical value inflection points in this oncology and obesity setting. So I think we're well positioned from a financial standpoint, and as I say, for you know, to move forward with our two attractive and exciting programs. As mentioned, partnering is a key focus to POOLBEG. We've had a lot of experience in this space. We are we generate a high value programs with strong intellectual property. We spend a lot of time generating and filing our intellectual properties and announced, you know, several this year. We've gotten granted in various territories. As I said, running these proof of concept clinical trials, this is an ask. It's always an ask from pharma companies when you bring some exciting science to them. These are very busy people, and they're looking for clear and compelling and exciting human data that they can then take to their senior management to get deals and transactions approved. So that's exactly what we're doing with our phase two a, POLBEG zero one CRS prevention trial, and then the oral GLP one study.

3:46 Again, the high quality compelling human data is really what moves the needle for these companies. And and as I said, partnering then flows and follows on that. And that's our strategy. So we're going to detail on these these particular clinical trials shortly. This is the pipeline as it stands today. But, again, high value is a is a key takeaway from here. I was saying some multiple near term clinical value inflection points that not only drives shareholder value, we believe, but also drives that interest in partnering as the data is what really what moves the needle set from these partnering standpoints. We'll spend quite a bit of time tonight, and I'm obviously, Liam will spend quite a bit of time tonight talking about POL zero zero one our p thirty eight MAP kinase inhibitors is already delivered, and we're positioning this as a as a preventative, as a prophylactic for cancer immunotherapy induced cytokine release syndrome.

4:34 And as mentioned in the in late last week and reiterated this morning. We're commencing phase two here, and we put all a lot of pieces in place to to achieve this. And, again, importantly and happily, we got FDA orphan drug designation for for this back in May, which we we've mentioned in the past. I'll talk about later on multiple significant benefits to getting that designation. So on the right hand side, the key milestones here is the trials of the advanced stage of preparation. Those in the industry know that there's a lot of work going on in the background with regards to various regulations, manufacturing, formulations, etcetera. A lot of work going on to to get this clinical study up and running. We did and again announced last week. We we've received or we approved by specific antibody. We've secured this for the clinical trial. And, that's at no cost to POOLBEG, which is quite important because these drugs are quite expensive.

5:29 And I think that shows the kind of commitment and interest from pharma that they too wanna see this solution for a CRS, and they're willing to give us their drug to test POLB zero zero one, as I say, to to reduce or eliminate CRS from from these these studies from these from these drugs. I say the plan then from a timeline is relatively short term. Phase two interim data is expected summer of twenty twenty three, and that'll give us a good read into the the efficacy of the drug. Safety, yes, we'll check as well, but a good read into the efficacy. And as I say, that then will accelerate the partnering discussions. For menorah GLP one, we've mentioned we'll discuss this briefly today, but this is a clinical trial preparation as well. So we're progressing towards trial commencement. Again, lot of activities caused this morning around the manufacturing front, etcetera. So, again, we're looking this is a very short study. Top line proof of concept data is expected in the first half of next year. So rapid study that'll be run at the University of Ulster, and that's in partnership with partners at who have this terrific encapsulation technology. Then on the bottom, we won't discuss today, but we do are exploring partnerships around novel drug discovery aspects that we did using two AI collaborations previously around pretty impressive influenza clinical challenge data with group cidereason and then RSV with one three. So it's our potential drugs, potential target drug targets that we're discussing for potential partnerships, not something we'll drive forward ourselves.

6:54 So that's where POOLBEG is today. It's very excited about the POLB zero zero one, which we'll discuss. And, And, again, I just wanna talk briefly about the reasons why we're doing this. So the potential to make cancer immunotherapy safer and more accessible. So we've talked, you know, recently about progress that the industry has made for cancer therapies, cancer treatments. We've mentioned on on various panels that not too long ago, you know, the fifties and sixties, ninety fifties, ninety sixties, where they were discovering chemotherapies, and that was like a blunt approach for many, many years. But, again, the cancer biologists understanding the disease progression came up with more targeted treatments where they're able to inhibit pathways, for example, that tell the cells to replicate. But, again, more recent now we're moving into the world of the realm where we're using the the body's own immune system to go after the tumor. And that's where these cancer immunotherapies have been quite impressive when it comes to efficacy data over the last ten years or so.

7:51 But I'd say we we have an issue with regards to these when you're activating the immune system against the tumors, you're getting this cytokine release syndrome as a as a nasty and unwanted side effect. And, again, these are severe and potentially life threatening. Approximately seventy percent of patients undergoing CAR T or bispecific treatments can be affected by this. And this puts a lot of strain and issue strain on the health care system. Obviously, on the patient, that goes without saying. But because of that, the treatment is restricted to these specialist cancer centers. So, you know, we always give the example that, you know, somebody rural has to come up to the city to get their cancer treatments, have to stay there for maybe a week or two, you know, highly inconvenient for themselves and the families, but obviously adds burden to the health care system as well. So extended hospitalization, high consumption of health care resources, that's an issue with with cytokine release syndrome. There So is an unmet need, and it's been recognized by the industry. They're looking for solutions.

8:46 Right now, it's more in a reactive setting in that if the CRS develops, they come in with drugs to try and quash, you know, calm down the the immune system, calm down that inflammatory response. So there's nothing approved for the prevention of it. We believe that POLB zero zero one can play a role here. So let's say right now, they're using drugs like tocilizumab, which is an antibody against a target called interleukin six, which they use to kinda block that immune or cytokine response. And, again, your data for prevention is is pretty scattered and and unimpressive. So now we're looking for something that's oral. And I said, we look at POLB zero zero one as an oral drug, so patients can take this from home. So it doesn't have to be given in a hospital like a like these IV infusions of antibodies like tocilizumab. And as I said, we feel it can selectively present excessive inflammation and, importantly, without causing immunosuppression.

9:37 So you're not blunting the immune the immune response. You're just blocking that inflammatory response and ideally blocking that cytokine release syndrome. The drug itself, POLB zero zero one, we have an extensive data set on that. We've demonstrated favorable safety and top tolerability. And we've got patent coverage out to at least 2043 from filings that we did back in 2023. And as mentioned earlier on, I'll talk about later on, FDA orphan drug designation, which again makes us a very attractive approach for for our pharma partner. So that's setting the scene where cancer immunotherapies and CRS and why the the the industry and the market indeed is looking for a solution here. So what I'll do, I'll pass you across to Liam now to dive into the science aspects and our clinical trial and our partners, and then I'll be back later on to talk more around the the the the market and the strategy. Liam, over to you.

10:28 Thank you, Jeremy. And, yeah, as Jeremy mentioned, I will speak you through some of the existing data that we have and then also some of our upcoming clinical plans and the trial that we announced just last week. So I guess first thing off, you know, we're going to prevent cytokine release syndrome. So it's quite important from a development perspective that we're differentiated and and, you know, we have a reason to believe that this can be very successful in the clinic. So POLB zero zero one is a p thirty eight MAP kinase inhibitor. So just very briefly, what does p thirty eight MAP kinase generally do in the body? So it's an inflammatory protein, and it's a gatekeeper to inflammatory responses. And, generally, it's perceived as a gatekeeper to hyperinflammatory responses. So when the body needs to amplify immune response to have a really potent quick response.

11:14 And importantly, what we've seen not just for our molecule, but with the inhibition of p 38 in general is that we can have a potent decrease in a wide range of pro inflammatory cytokines without ablating the immune system. So so what this is doing is preventing the hyper inflammation without preventing inflammation altogether, and this is very important in in the use case of cytokine release syndrome because, obviously, these patients have tumors, have blood cancers. A lot of those cancers carry risks of of things like infections that can really impact not just their quality of life, but actually their outcomes as well. And what we importantly see as well is that we can actually inhibit p thirty eight, inhibit these hyperinflammatory responses without having any impact on T cell responses. T cells being a core component of the immune system, and the hope is with these immunotherapies that you're harnessing the immune system. So it's really important for us that we are not actually preventing those effective breakthrough immunotherapies from having their full potential.

12:11 And we also see some evidence that we can potentially enhance tumor clearance with p thirty eight inhibition. So just briefly on the bottom, I have four rows shown, entoslizumab and dexamethasone are existing treatments for cytokine release syndrome, not used preventively, only reactively, and tocilizumab is only approved for the treatment of CAR T cell induced cytokine release syndrome. And what you can really see here is that there's a wider range of cytokines inhibited by p 38 inhibition compared to these other effects. Steroids notoriously have wide effects, but somewhat unknown in an immune context. They they have both inflammatory and anti inflammatory effects. Tocilizumab is really affecting downstream, so it's an IL six receptor antagonist.

12:59 So it's very specific. But when we go p 38, what we actually see is that there's a whole raft of cytokines that we can prevent from going into this hyperinflammatory state, and this is important because cytokine release syndrome is a systemic condition. So it involves multiple immune cells within the body, and we believe that, you know, having this systemic effect and a broader effect is is a reason why we we could see superior effects in the clinic. So very important that we have a novel and differentiated mechanism of action. Let's go to the next slide. So briefly just to mention some of the preclinical data that we have, and I'm I'm showing some of the important data on this slide. But as Jeremy mentioned, the molecule itself has a very extensive nonclinical and and preclinical package of of pharmacology and safety pharmacology.

13:45 So POLB zero zero one was initially developed for chronic autoimmune diseases, so the safety package supports use in a low morbidity disease, which generally means it has to have a much cleaner profile than something that we use in the acute condition and potentially something in the setting of oncology where a lot of existing drugs are are somewhat harsh compared to other indications. But we're going in a really strong position with a molecule with an excellent safety profile. So what's been shown here on the slide is actually an animal experiment that we did of cytokine release syndrome. These are quite difficult to do, so we need to use humanized mice, and humanized mice essentially have the full human immune system. So the the mice are bred without a functional immune system. There is a residual immune system that's taken out, and actually human cells are inserted. So these really have the full range of the human immune system that we want to look at. And this model can also recapitulate cytokine release syndrome when we induce something like LPS challenge or, in this case, the c d h twenty eight or c d twenty eight challenge.

14:48 So this allows us to investigate POLB zero zero one in a model really closely aligns to what we're trying to tackle in the clinic, which is really important. So on on the top is the design. So, you know, in short, there's a lot of detail there, but we humanize the mice just meaning we give the human immune system, and then we actually give them a tumor again to mimic what we're trying to do in the clinic, and then we induce cytokine release syndrome. In this case, we use a c d twenty eight super agonist. What does that mean? It's just a really potent way of activating a lot of immune cells in the body at the same time. So on the bottom left, what we can see is actually the blue is background, so these mice will have a level of graft versus host disease. It's it's a technical artifact. But importantly, in the red, you can see that when we introduce c d twenty eight, actually, you get this increase in the CRS score. So the c d twenty eight is driving cytokine release syndrome. And as we introduce POLB zero zero one in increasing doses, so from light blue to dark blue to green, what we see is actually almost all of the doses we gave are highly effective in mice. And we also compare this against anti TNF. Antibody is a really robust comparison.

15:55 Robust because antibodies in in mice will have a half life of days or weeks. They stay in the system for a long time. A small molecule like POLB zero zero one that's not designed for animals actually only last for a couple of hours. So it's quite difficult even to get the exposure in in the mice at the same level. But even with all of these technical challenges in the experiment, what we can see is that POLB zero zero one was as effective as the gold standard prevention of it in this model. So, again, really enthused by these responses. On the right hand side, we validated that that is actually part of the prevention of cytokine release syndrome, what we are seeing. So I l six and TNF alpha that are highly responsible for driving cytokine release syndrome. Here, we can see that actually we were able to reduce them in a dose dependent effect with our drug. So the green being being lower than blue in in the I l six and even lower than with the anti TNF antibody.

16:46 You will notice on the right hand side, anti TNF was lower, but there is a technical artifact that because we're we're comparing against an anti TNF, antibody TNF levels will be lower because it's quenched in in the body. So really enthused by these results preclinically with POLB zero zero one and a really strong position as we move forward into the clinic. So moving into the clinic, just to recap some of the existing phase one data we have. So here I'm showing the phase one b LPS human challenge study that we did, and there was also a first in human trial done. In both studies, the the molecule had an excellent safety and tolerability profile. What I'm showing here is the LPS human challenge study and more of the pharmacological effects of why we think it's gonna be effective as we move towards the phase two in cytokine release syndrome. So, again, on the left hand side, so we use LPS, which is a it's a component of the bacterial cell wall, but in a in a science perspective, again, it's really potent to activate in the immune system.

17:46 It binds to toll like receptor agonist four and drives hyper potent responses and is a really effective way for us to measure p 38 inhibition and and the effects of it. So what we did was we predosed the volunteers for six days. So on the left hand side, you can see day one, two, three, four, five. They were predosed with POLB zero zero one twice daily. And on day six, we introduced this intravenous dose. There is day four, which is blue there as well. That's because we also did a skin challenge to see how effective the molecule is in preventing tissue inflammation, which is quite important, but we're not gonna go into that today. So just on on the middle and right hand side, I'm I'm showing a selection of this data. We presented them more extensively previously, but what we could see is across a range of markers, they're all quite important in cytokine release syndrome, including IL eight and TNF not shown here.

18:37 It's actually what we saw was a dose dose dependent reduction. And what we didn't see was a complete ablation, as Jeremy mentioned, which is very important to us, though. We're not completely knocking out the immune system here. What we're doing is bringing it down to a safe level so we get a normal immune response, not a pathogenic immune response, not an immune response that's going to threaten a patient's life. On the right hand side, again, we're showing heart rate. The reason I'm showing heart rate here is because it's one thing to show effect on cytokines, but what we really want to show is that effect on cytokines can actually have an impact on clinically meaningful variables. So something that's causing a symptom in the clinic, a symptom to patients, and it's gonna suggest that these patients will be better off taking zero zero one. So right hand side, we're showing heart rate, and what we can see is in the gray line, which is LPS only. When we give an LPS challenge, they have a massive spike in heart rate, which is expected.

19:29 And as we introduce POLB zero zero one, so the green line is the lowest dose, the blue line is the middle dose, and the red line is the top dose. What we see is that the green line brings down heart rate, and then the blue and the red almost completely overlap. And what this just means is that in this model, at least with the timing of the doses, that the seventy one fifty make for both highly effective and probably as effective as we want them to be. So this gives us great hope that we have the potential to potentially prevent cytokine release syndrome while also preserving key immune system functionality. Right. So just to quickly mention before I go into the the trial, you know, we've been quite active in this space, and it's really, really important to us that we do make sure there's a this strong unmet need that this something patients and clinicians really need, and and we position this molecule correctly. So a couple of weeks ago, I was over in Toronto at the International Myeloma Society, really enthused by not just clinicians interested in supporting POLB zero zero one and really support in any way they can that we can get the get it through the clinic as quickly as possible and and get access to them. But from their perspective, myeloma in particular is in an incredible spot at the moment where for some patients that they are discussing functional cures, so myeloma is typically considered non curable.

20:49 It's very difficult to get rid of the the global disease. But, actually, they're they're now questioning whether or not they have functional cures because the overall survival is far exceeding, the average age of onset. So a lot of patients will have fifty percent of patients will be diagnosed with multiple myeloma at the age of 68 or onwards, and some of the emerging data for first line therapy. So bear in mind in myeloma, there is three, four, five effective lines of therapy. With first line therapy, some of the latest results they're seeing is a progression free survival in the range of potentially seventeen years. So first line therapy can be really effective for a lot of people, and I think a lot of the the interest is changing from from all patients to really categorize in those who get multiple myeloma younger or get a high risk form of disease and and how we can treat these differently, and also how we can bring immunotherapies into a frontline setting. So to really benefit from the the immunotherapies, the the hypothesis is that you really want to fit immune system because as cancers progress, it generally breaks down your immune system. It it makes it quite difficult to generate an immune response. So giving these immunotherapies to late late stage re re response refractory treatments is difficult. And if you bring it back into frontline when you have a more immunocompetent body, you can actually get much more effect out of the immunotherapy.

22:12 So what they're trying to do at the moment is to broaden access and extend learnings, how they have the academic centers, and how to deliver these immunotherapies and and broaden access to them, very challenging. As I mentioned, there are a lot of lines of therapy that are effective, and that means the patient preference plays a massive role in in treatment selection. So things like staying close to home, reducing treatment related toxicities, and staying with existing health care teams. One of the ways I always like to think of it is the actual definition of multiple myeloma is when you have symptomatic disease. So there is a precursor condition known as smoldering myeloma, which is essentially the same thing, but when you don't have symptoms. So these patients will commonly have bone disease, weak bones, a a lot of pain.

22:58 And as this goes on, it really is important that you look at quality of life in addition to survival. And now with so many options, you know, patient preference is playing a larger role than ever. So same with existing health care teams who they trust, and also, as I mentioned, reducing those treatment related toxicities because it's one thing to survive, but this is really about how how we get the best for patients. And on the bottom, have here outpatient delivery of certain immunotherapies is not feasible. So this is largely done in The US, and they're really investigating how to make these treatments more available. But it it's just so difficult with something like cytokine release syndrome that can progress so rapidly. And even with massive philanthropic grants, the the top centers are struggling. It's really only for fitter patients, those who have a full time caregiver that they're able to do it. So a lot of major hurdles as they as they try to do that even in a resource rich environment. So being able to migrate this out to environments where they aren't as resource rich is is a massive challenge as we move forward and really needs novel solutions.

23:59 So speaking about solutions, POLB zero zero one. The trial we're we're advancing first in patient phase two a trial. So shown on the bottom here, I'll go straight into it. Doctor Emma Searle, a consultant hematologist at the NHS Christie Foundation Trust in The UK in Manchester. So it's one of the largest cancer centers in Europe. It is actually the largest single site cancer center in Europe, and we're really excited to have Emma on board. Not just does she really believe in the molecule and the unmet need, but also she has so much fabulous experience with early stage trials to really accelerate this trial, design it properly, and get the most out of it. So we're using accelerating clinical trials. They're a specialist blood cancer trials organization to support with Emma's leadership, and we'll be using all UK sites to complete the trial, a handful of sites along with the Christie NHS Foundation Trust. And the goal of the trial is we're looking at multiple myeloma patients, as I mentioned, the last trial over the IMS conference in Toronto, and those patients will be receiving approved bispecific antibody.

25:07 So these bispecific antibodies typically induce cytokine release syndrome up to seventy percent of patients, so it's it's a really strong position for us to investigate POLB zero zero one and its ability to prevent this potentially life tracking side effect in about thirty patients. So it's gonna be rapid. Our focus is getting proof of concept data out. I'll go into it in some more depth in in subsequent slides. We're we're really excited as we move forward into this trial. So just a little bit more on accelerating clinical trials or ACT for short. So they are specialist trials delivery organization dedicated to blood cancers, work solely in The UK, and they've been embedded in The UK hematology community for some time. They they actually have existing networks in 15 UK hospitals covering a massive number of cancer patients. So really strong position and relationship, not just with the investigators who are going to be on our trial, but also with the wider UK hematology community.

26:08 They have extensive, as I mentioned, a positive relationship with those leading centers, which is really important for us to be able to recruit this trial rapidly and equipped to provide registrational standard trials and an ideal profile to complete the topical trial. So they they they're a really good balance of having that network, having the understanding of the molecule, being able to produce high quality data that's gonna be attractive to partners as well. And importantly, they are driven by mission to improve outcomes for cancers with for patients with blood cancers. So they're very specialist organization, purely there for blood cancers within The UK with a mission to drive outcomes and and trials that they really believe in. So, again, it's a testament to the unmet need for cytokine release syndrome and the potential for POLB zero zero one, really not just to prevent cytokine release syndrome, but as a net effect to actually broaden access to these immunotherapies and improve patient outcomes across the board.

27:06 So the trial itself, as I mentioned, it's in multiple myeloma, and so it is phase two a open label single arm trial. So no randomization, and this means that everybody's gonna be given the drug, and there's gonna be no blinding. So we're gonna see data come out really quickly next year. The trial itself so on the left hand side, I I have a schematic here showing how it works. And, again, this is an artifact of cytokine release syndrome that these bispecific antibodies actually have to be given in two step up doses, they're called, in myeloma patients. And these step up doses are actually micro dosing. So if you gave a first dose of a bispecific antibody to a patient, what they will have is uncontrollable potentially lethal cytokine release syndrome. So to avoid this, what they give is a small dose, and then they give a bigger dose, about three percent, then about thirty percent, and then a hundred percent. This process takes about a week to ten days to actually dose a patient up to the level they need to get to.

28:07 By giving these micro doses, they get the body used to it, and it mitigates the risk for cytokine release syndrome. But even with this step of dosing, they still, as I mentioned, get about seventy percent of cytokine release syndrome. So we're gonna be given POLB zero zero one twice daily, and there's gonna be about thirty patients, and we're gonna be using an approved bispecific antibody as Jeremy mentioned. So the supply of approved bispecific antibody has been secured at no cost to POLBEG, very important to us. And, again, we're ready to proceed a pace into this. So we have a supply of GMP grade POLB zero zero one ready to go. So so, really, we're in a really strong position. Everything's at an advanced stage of preparation, and we are expecting interim data in in the summer of next year. So the actual endpoints on the study so as I mentioned, the dosing will be given before the onset or before the administration of the first step of dose of a bispecific antibody.

29:03 So we're dosing during that high risk period for CRS, which typically lasts for about two to three days after the first three doses. So ninety nine percent of cytokine release syndrome will actually happen either between day one and seven there on the slide or eight, nine, 10. So after that high risk period, the risk of CRS actually goes down massively. So this is actually a really focused position where we can investigate POLB zero zero one. We'll be able to really quickly get data from this trial after the first fourteen twenty eight days. We're we're gonna know if if the drug has been effective or not. So the key endpoints that we're looking at is obviously the incidence of CRS, the severity of CRS, safety because we're first in patients. We also want to confirm the safety and pharmacokinetics of the drug. So, again, first time going into patients, we'll we'll just confirm that the exposure of the drug itself is sufficient.

29:54 And we're also gonna be examining CRS management and tocilizumab usage, again, to get a real idea of how effective our drug is, but also how effective our drug is at preventing the need for additional treatment for these patients. Because, typically, if they do have CRS, the hospitalization is longer. If they have CRS after the first step of dose, they can't get the second step of dose until it's resolved. So that hospitalization period really gets pushed on, and in nearly all centers, that step up dosing is actually happening in an inpatient environment. And what that means is the patient has to come in, and they will come in for the full five, seven, eight, nine, ten days. And if they have CRS, that kicks that out. This is incredibly challenging. Typically, oncology wards throughout the world are full, and they try to reserve beds and and even in this sense where you can plan when the patients will come in. It's still very challenging because a lot of centers will actually have patients even in the emergency room waiting to come up to a bed in the oncology ward. So this is this is really a bottleneck for the patients, the fact that we're able to do a trial potentially where we limit that inpatient inpatient duration is gonna be really attractive to the hospitals.

31:06 Again, just emphasizing that this is a trial that's gonna be really attractive to investigators and to patients to participate participate on. Really light touch. We're not trying to cure cancer with this drug, so we don't need to follow the patients out until survival. The only period of interest we have is in the first month or so, and the trial will be quite short after that. Super. That's great, Liam. And with that, I will pass back to Jeremy. Thank you. Thank you for that overview, Liam. Again, you can hopefully sense, the excitement that we have. We're we're chomping at the bit to really get going at this in the patients. Again, it's a nice milestone for for any biotech company, but, obviously, from a pool based standpoint. Again, I wanna, you know, take a step kind of backwards. We just talk about the again, context here. You know, we talk about bispecifics and CAR T cells. These engage the T cells to go after the tumor. And, again, as I mentioned earlier on, the last ten years or so, it really has exploded onto the scene and fantastic efficacy with these kind of side effect issues that we're trying to resolve. But because of their efficacy, their their revenue generation is is increasing somewhat exponentially.

32:13 There's a forecast, like, twenty thirty, there'd be a 120,000,000,000 roughly in revenue of these t cell engagers. So you can imagine the market we're playing in. I mean, if each one of these has a CRS issue, they're looking for something like POLB zero zero one to to come in. So effective CRS management, you know, we could achieve that. So that's, you know, the reason why we're we're driving forward with this. I mentioned earlier on about receiving orphan drug designation from the US FDA. This was terrific for the company and fantastic as the outcome from the the the hard work for the team to achieve this. It is kind of, I I think, quite impressive validation that the FDA looks at this and sees the the unmet need here. The benefits are seven years of The US market exclusively following approval. You get a waiver of neutral application fees, typically the range of 4,000,000, again, when you get this orphan drug designation.

33:00 Earlier access to these special protocol assessments, again, it's just, you know, speeding your way through the FDA is one way to look at it, and then tax credits for qualified clinical trials. Now we say, like, this is what's attractive to our partners. You know, they see that we have this and, you know, the the the bispecific antibody supplier. You know, when when they saw this news, you know, they kind of got back in touch with They're great to see because they can see down the road as a benefit to them, so that values the program. So, again, very excited about that and a reminder of potential first approved preventative therapy for cancer immunotherapy and GRS. Now, again, we're we're not working in a vacuum here. We did a lot of external key opinion leader, you know, talks and talked to, you know, 10 or so different myeloma docs globally, US, France, UK. Talked to her about the unmet need is one thing. You know? But we've we've done our own kind of in-depth analysis of where we would fit in here. And the feedback generally was like this bottleneck we was talking about the middle here, whereas Liam said, patients are kinda coming in. They're taking up beds.

33:57 So I don't mean that in a bad way. It's like they have to remain in hospitals for a week or two for fear that CRS develops. So we're looking at five hundred thousand patients for diffuse large b cell lymphoma and multiple myeloma only, and that's, you know, again, patients diagnosed estimates in The US and the The EU five. So with this bottleneck here, you know, not enough patients are getting the the life saving drugs. So we think if you remove the CRS, you remove this bottleneck. And, again, you know, we'd be able to kind of obviously charge for POLB zero zero one. And if you kind of fast you know, if you could do the the analysis of the number of patients versus what you could charge for a drug like this, there are comparables out there. We're looking at, you know, potential $10,000,000,000 market. So I think that's gonna quite excite you. And, again, as I said, getting that, you know, proof of concept data now in this clinical trial is really what's exciting us. I think Martin Kaiser we'll hear from Martin shortly in a video, but, you know, he sums it up well. And Martin's a myeloma specialist at the Royal Marsden.

34:48 So if there's a therapy that was already delivered, a whole lot of the infrastructure requirements fall away. And we talk about getting it into the community, getting the the the the drugs into the the community setting away from the from the dedicated, you know, as I say, you know, cancer trials or clinical units. So, again, you know, as I say, if that can fall away, it it makes life a whole lot better for for many, many people. So I said POLBEG a potential to transform cancer immunotherapy by expanding administration of the cancer immunotherapies themselves from these specialist cancer centers into the community. So we're always gonna refer instead of coming down to London, for example, you know, patients can stay in their hometown or their home village or their home cities and get their treatments. So I think that we we could have a significant impact on the space, on the fields, and on patients here. And, obviously, it'll be a sizable significant market.

35:36 From that point, I'll let you we'll Martin Kaiser, as I mentioned, has a few words of recent panel that we spoke of. That CRS plays into this, for example, because at the moment, it needs such a specialized knowledge with the way how it is deal dealt with at the moment that it is limited to very specialized centers. In some economies like The U. S, for example, the treatment centers have to even apply for a license to be able to give these drugs because of CRS so that they demonstrate and that the document for and that they can deal with it. So CRS is a big problem? CRS is a big problem. Yeah. Yeah. Potentially, it would enable immunotherapy to come into a more sort of local area hospitals as opposed to specialist cave for the existing therapies at the moment? Yes. That.

36:31 So as I say, Martin is a highly regarded, highly respected myeloma doc. So, you know, we we'll we'll leave the last word for him. I do want to, just kinda mention briefly our oral and I'm confident of time. We have kinda run over a little bit. So, you know, just a one slide on the oral GLP one program. Let's say we're moving forward with this, getting again, another proof of concept clinical trial that that'll be pretty rapid in generating data. So we expect top line data in the first half of next year. As as mentioned earlier on, it's proprietary delivery technologies to encapsulate the the GLP one peptide, which normally be digested, so it protects it from the gut and gets it into the side of action. There's trial investigator professor, He'll be running this at the University of Ulster. Just wanna make sure that the GLP one gets into systemic circulation.

37:17 So, again, a very straightforward analysis of the pharmacokinetics and pharmacodynamics. We will look at glucose tolerance test. And we're looking at 20 of these subjects here. So very focused clinical trial, but it gets us the data that we need to facilitate partnering. And you saw Pfizer did a big deal during the week with Metcera around getting access to to GLP one programs. There is a Rybelsus only one orally delivered GLP one receptor agonist on the market. And, you know, that has its own issues with only about a 1% bioavailability. So we believe we can improve on that. So it's very exciting by seeing that moving forward as well. And, again, I'll just gonna wrap up and certainly leave, you know, a few minutes for for for questions. But, again, reminder, partnering focused, an excellent team. You know, I myself been in the industry for twenty plus years and have gotten more recently an exit back in 2020 with the last company, Infosome.

38:08 So I know how the process works from deals and collaboration standpoint. As mentioned in our inference today, cash balance of 10,000,000 as of the June 30. So, again, that pushes us giving us a runway to 2027. Again, multiple, you know, catalysts from an investor standpoint, this clinical data coming up. Let's say the policies here on phase two, initiation and interim analysis, and then top line data, and then the oral GLP one as well. So well capitalized to get to these catalyst rich areas. So, again, I'll leave it there. You know, you could take you read on that. Okay. But I'll just reiterate. So what we'll do now is just transition, and I know some questions have been coming in. I can see them on the screen here. So so we'll get through as many as we can in the in the next five or six to seven minutes or so. So, again, apologies for running over with the the presentation, but I do wanna get to to some of the questions.

38:57 And, Liam, I I'll read these out, Liam, and see what's what I've assigned for me or you, and I I'll try not to make things too challenging. But, anyway, first question here, during the POLB zero zero one trial, will any information on progress be released? Think you're on mute there, Liam. Thanks. I'm back. Sorry. Absolutely is the short answer. We will keep you guys as updated as we can. So as I mentioned, we're in a really advanced state of preparation. And as we have all of the additional so there'll be some additional information on trial design that we'll be excited to announce. The other sites that we're going to use, we'll announce them in time. And also, you know, when we have the trial starting, first patient in, data coming out next year, we we intend to give as many updates as we can throughout that process.

39:49 So stay tuned. Brilliant. Thanks, Next question, will the bispecific provider have first mover advantage if the trial progresses successfully? That's a really good question because it gives kind of insight into, I guess, the fact that they have committed drug. We talked earlier about the value being significant. The the clinical trial, as Liam said, is open label. So we we will see the the data first. You know, they'll be involved. For first mover, we've deliberately kept the door open. You know, we didn't wanna close the door where we'll we'll just only, you know, do a deal with this company and nobody else. So we've been doing outreach with all of the the large pharmas who have bispecific CAR Ts Just, you know, engaging with them, telling them about zero zero one. As I said, the announcement last week will will certainly help and accelerate the discussions that were on firm footing with the phase two a. So we've kept the door open. Of course, you know, the fact that they're providing drug, I think, gives strong indications that, number one, they wanna resolve their CRS issue that they have. So, you know and we know is, as I said, what they did what they have in their pipeline is other CAR Ts and bispecifics and drugs that where CRS is an issue.

40:56 So first mover is a good way to state it. I mean, that they'll have an insight. They're obviously, you know, committed, but working the door open where others could, I guess, essentially come in and overbid, if you wanna put it that way. So, again, appreciate the question. Next question. If POL two zero one trial is successful, what monetization options are on the table? Company buyout, partner agreement with one pharma, many pharmas, expansion into other diseases go along. That's again, that's a great question. We could spend quite a bit of time talking about that. But what I will focus on is that, you know, as I mentioned earlier about keeping the door open. So we you know, this could potentially be, you know, a license agreement where they could take the drug from us and apply it in a, let's say, much larger, let's say, phase two b or phase three. You know, we'll receive upfronts for the, you know, the work that we've done, the derisking that we've done for the program, and then generate downstream, you know, milestones and sales royalties on, you know, successful development.

41:51 That's one structure you could do. You're right. I mean, they may come in and say we just wanna buy, you know, whether it is the company or whether it is the program. You maybe they don't have an interest in GLP ones as an example. They just wanna buy the program, and then you negotiate and and agree with price for that. And maybe some, you know, downstream, you continue value rights, your CVRs, you know, some milestones, etcetera. So that option's on the table as well. Going it alone, that's a no. We always thought that, you know, we generate this proof of concept data, and then we look to big pharma companies to take it on board and bring it forward. Because it gets very expensive in these large phase three trials and and ultimately getting on the market. And, you know, big pharma have that expertise. We acknowledge that. So the goal alone would not be, but the other disease is a good question. We've had questions before about, you know, CRS. We've had questions about sepsis, you know, etcetera.

42:37 I do think that, you know, with pharma companies, when you license a drug, they like to take control of everything. So, essentially, it'd be up to them to decide what disease areas that progress on. So, again, thank you. That's a terrific question. Appreciate that. Next question. When is the oral GLP one trial expected, and when is trial data due? I think we covered that earlier on. There's a lot of work going on right now. I was on a a call this morning around the manufacturing of both the, you know, the encapsulated GLP one and the the placebo, and then getting all the documentation needed for that. So there's kind of studies and assays going on with that. But as mentioned, the data in the first half of next year. As mentioned, it's a very straightforward clinical trial. 20 of these subjects, they get a placebo one day. They get the encapsulated drug the next day, you're gonna compare their kind of glucose tolerance test. So very straightforward. And, you know, so, again, we're we're looking, you know, looking forward to, you know, getting that data in hand as well.

43:29 Question here. Are these yeah. What is your opinion on the disappointing share price response to the excellent POLBEG while trying news? It's you know, I I won't say I don't I don't mean to be clear by you telling me, but I think we're working really hard in the background and, you know, moving the programs forward, as much as derisking the programs. I do think, you know, we had a fundraise earlier this year. Maybe people are, you know, taking a bit of profit off the table from that, but I still think, like, we're we're kind of, you know, heads are down. We're fully focused. I mean, I'm a shareholder myself, so I wanna see this kinda drive forward. So, you know, disappointing is a word, but I think, you know, when the markets see what we're doing, when they see the market size, when they see the progress we're making, hopefully, there'll be a kind of a turnaround and an acknowledgment of what the the team is doing here and the value that we're bringing to you know, derisking the program, bringing value to shareholders. So we're hoping that is acknowledged. So appreciate that.

44:18 Question. Liam, I'll pass this over to you. How hard this this is tricky. How confident are we that POLBEG zero zero one will deliver the positive results we all hope for, and can we put a percentage on this? I love that. You're putting on a spot, but, listen, you you you could give your opinion, Leo. Maybe I'll add it. Yeah. Would love to put a a figure on it. Our results today are incredibly promising. You've seen them. All all the experiments we do point in the same direction. There's also a lot of positivity going to a pathway, which is extremely well researched. Other molecules that might have failed in in this or similar areas might have be might have failed for things actually unrelated to how effective they are. It can be things like infections or something else, which really isn't tolerable.

45:06 So a lot of people have faith in the p thirty eight pathway. I'll say that. You know, there's a lot of results that we're quite confident on. And, really, as we move forward, we'd be very optimistic that this this is not just differentiated. It's also building on things that we know are somewhat effective in the clinic, like anakinra and tocilizumab. There's overlaps in the pathways, which is very important for us. So so we know we're hitting all the right markers as as we go into this trial. We know we have good exposure. So, look, I I guess, watch this space. We we've a lot of confidence on this side, and we're very optimistic as we move forward, but clinical developments. Brilliant. Liam, thanks for that. And maybe I'm just gonna sit down here for a while because the next one, I'll pass across to you as well. Are there any more preclinical studies that you need to do?

45:53 No. Absolutely not. We're in a really strong position as we move into this from a from a regulatory perspective and also from, you know, our own pharmacology perspective. We've used some of the best models available for cytokine release syndrome, so nothing else planned before the study. Alright. Thank you for that. In order for you, Liam, I'll leave it to Why is the trial so short? The trial is so short because we're only focused on that cytokine release syndrome risk period. And, again, you know, I could I could harp on all day about this, but this is a a really well defined condition. Cytokin release syndrome only came out, you know, about ten, fifteen years ago when all these immunotherapy started to get approved, but there's a lot of, you know, c d three engaging bispecific antibodies where not just high rates of cytokine release syndrome, but also very similar, very similar timings, very homogenous disease.

46:47 So really promising as we move forward for looking something like a broad label. But that also means that it's really well defined when these patients are gonna have cytokine release syndrome. It's gonna be at the start of treatment so we can do our study adequately powered all within the first month. We're not trying to cure the the treatments here, especially in this phase two a. You know, there's a lot of data out there in our molecule and p 30 eight inhibition that that's all we're focused on. But the first couple of weeks of treatments, do we prevent cytokine release syndrome? Yep. You don't need to follow them. That that they might continue to get the bispecific antibody for longer, but the trial will not continue any longer than the first cycle or two. Got it. Let's take a deep breath, Liam. Next one is yours as well. Everything they're actually the next couple of questions. And I say I'll give two more minutes just that, again, apologies for running over time. But, you know, we do want to address as many as possible. But from Marcus, is this a double blinded trial?

47:39 I guess, CRS is so significant placebo, no SIBO effect may not damage the data. It's a phase two trial. We're in a really strong so short answer, it is not double blinded. It is not blinded at all. It's open labeled and single arms. We know because we're going into a condition where seventy percent of patients have it, it's really well defined. It's gonna be quite apparent how quickly these are getting it. So cytokine release syndrome in this setting is is really all defined by the timing. So if you have a fever within the first day or two after give after me giving a step up dose, it's almost certainly site cytokine release syndrome. So we don't actually have too many concerns. If the drug is effective, it's gonna be apparent in this trial. We don't expect a a placebo effect to be preventing cytokine release syndrome. Yeah. Great.

48:27 I'll take the next one. Peter M. Thank you. Is the cancer drugs you're using FDA or EMA approved? And the short answer to that is yes. This is an approved bispecific antibody on the market, you know, for, you know, ultramyloma. You know, we can say that. But as I say, we're we'll we'll be talking further about that. But I think it's important. It's very difficult to do clinical trials where two unapproved drugs. Obviously, POLBEG is here. One is unapproved for now, and we're trying to prove that, you know, the validity of, you know, moving a truth in the clinic. So, yes, the the bispecific is already approved and on the market in both. Let's go with the the last question here. Was it how many sites will be involved in the trial? Short answer is it's not gonna be a lot. It's a handful of sites.

49:14 You know, the advantage of using act is that they are incredibly well set up in The UK already. They're already networked into the biggest sites. We know what sites are gonna be using the bispecific antibodies we're doing. That means that, you know, we can do this in a relatively small number led by the Christie, which is again, you know, the biggest can't stress that the biggest single site cancer center in Europe. So really are able to do this without expanding out, you know, twenty, thirty sites. It's gonna be small. We will share the sites in due time. Great. Listen. Let let's call it there are a few more questions. We can we can address those offline perhaps. And really greatly appreciate everyone's time. It's, you know, POOLBEG as as we've been through just the last, you know, forty and fifty minutes or so. You know, we're we have nice momentum now. As I say, we have funding to take us through to our clinical milestones we spoke to into 2027.

50:04 Very excited to get this trial going. We talk about pieces in place, simply with the oral GLP one. So there's a lot of, let's say, data points, you know, with these, you know, clinical milestones in the very near future. Team is working very hard to get us there and achieve that. So and, again, to the to the point, you're hoping that the the SharePoint reacts to the same. But I think we're on a nice track. We've got a very good mission. As I say, we're trying to, you know, change cancer immunotherapy treatments, you know, get it away from, you know, these dedicated cancer clinics into the community. So it's a a worthwhile venture. We're, you know, very proud to be doing it. As I say, looking forward to benefiting patients in the future and shareholders as well. So thank you all for your time, and we look forward to give you future updates. That's great. Jeremy, Liam, thank you once again for updating investors. If I could please ask investors not to close this session as we now automatically redirect you for the opportunity to provide your feedback in order the company can better understand your views and expectations.

50:55 So it'll take a couple of moments to complete, but I'm sure it'll be greatly valued by the company. On behalf of the management team of POLBEG PHARMA PLC, we'd like to thank you for attending today's presentation.