Poolbeg Pharma PLC (GB00BKPG7Z60.SG) Earnings Call Transcript & Summary

Good afternoon, ladies and gentlemen. Welcome to the Poolbeg Pharma plc investor presentation. [Operator Instructions] 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 Poolbeg, Jeremy, Liam. 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 taking about 25, 30 minutes or so to give you a background and context to our kind of recent activities, recent news and obviously, future planning. And then we'll have 10 or 15 minutes or so for Q&A at the end. So as stated, if you want to ask questions, please drop them in. So we'll start off the usual legal disclaimer. And then I just want to ground everybody may be new attendees to Poolbeg, 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 001 clinical trial that's upcoming. And we're also developing an oral patient-friendly obesity treatment. So we're tackling 2 very large markets with significant unmet medical needs. 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 transactions at the end because as you see, there will be a trend coming through where we'll be partnering is a very core focus 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 say we've teed this up, these programs are attractive for pharma partnering. We've always kind of said from a Poolbeg's standpoint, we were capital light. We want to generate 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 longer, more lengthy clinical trials and ultimately on the market because obviously, we want to get these drugs into patients at the end of the day. But I'd say pharma are always looking to fill their pipeline of products. So we want to tee that up with our clinical trials. We've announced our unaltered interim results today. We've got a cash runway into 2027, which then funds these 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 said, to move forward with our 2 attractive and exciting programs. As mentioned, partnering is a key focus at Poolbeg. We have a lot of experience in this space. We generate 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 IIa POLB 001 CRS prevention trial and then the oral GLP-1 study. Again, the high-quality and compelling human data is really what moves the needle for these companies. And as I said, partnering then flows and follows on that. And that's our strategy. And I'd say we'll go into detail on these particular clinical trials shortly. This is the pipeline as it stands today. Again, high value is a key takeaway from here as I say in 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 from these partnering standpoints. We'll spend quite a bit of time tonight, and I would say Liam will spend quite a bit of time tonight talking about POLB 001. Our p38 MAP kinase inhibitors is already delivered. And we're positioning this as a preventative, as a prophylactic for cancer immunotherapy-induced cytokine release syndrome. And as mentioned in the RNS late last week and reiterated this morning, we're commencing Phase II here, and we put a lot of pieces in place to achieve this. And again, importantly and happily, we got FDA Orphan Drug Designation for this back in May, which we've mentioned in the past, and I'll talk about later on multiple significant benefits to getting that designation. So on the right-hand side, the key milestones here is a trial at 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, et cetera. A lot of work going on to get this clinical study up and running. We did, again, announced last week, we've received or approved bispecific antibody. We've secured this for the clinical trial. And again, that's at no cost to Poolbeg, which is quite important because these drugs are quite expensive. And I think that shows the kind of commitment and interest from pharma that they too want to see this solution for CRS and they're willing to give us their drug to test POLB 001, as I say, to reduce or eliminate CRS from these studies from these drugs. I would say the plan then from a time line is relatively short term. Phase IIa interim data is expected summer of 2023 (sic) [ 2026 ]. And that will give us a good read into 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 the oral GLP-1, we mentioned, we'll discuss this briefly today, but this is a clinical trial preparation as well. So we're progressing towards trial commencement. Again, a lot of activities called this morning around the manufacturing front, et cetera. 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 a rapid study that will be run at the University of Ulster. And that's in partnership with partners at AnaBio, who have this terrific encapsulation technology. And then on the bottom, we won't discuss today, but we do are exploring partnerships around novel drug discovery aspects that we did using 2 AI collaborations previously around pretty impressive influenza clinical challenge data with group CytoReason and then RSV with OneThree. So it's potential drugs, potential drug targets that we're discussing for potential partnerships, not something we'll drive forward ourselves. So that's where Poolbeg is today. I say very excited about POLB 001, which we'll discuss. And again, I just want to 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 recently about progress that the industry has made for cancer therapies, cancer treatments. We've mentioned on various panels that not too long ago, the 50s and 60s, 1950s, 1960s, where they were discovering chemotherapies, and that was like a blunt approach for many, many years. 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 recently now, we're moving into the world of the realm, where we're using the body's own immune system to go after the tumor. And that is where these cancer immunotherapies have been quite impressive when it comes to efficacy data over the last 10 years or so. I would say 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 nasty and unwanted side effect. And again, these are severe and potentially life-threatening. Approximately 70% 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 we always give the example that somebody rural has to come up to the city to get their cancer treatments, have to stay there for maybe a week or 2, 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 Cytokine Release Syndrome. So it is an unmet need, and it's been recognized by the industry that are looking for solutions. Right now, it's more in a reactive setting, in that if the CRS develops, they come in with drugs to try and quash or calm down the immune system, calm down that inflammatory response. So there's nothing approved for the prevention of it. We believe that POLB 001 can play a role here. So I'd say right now, they're using drugs like tocilizumab, which is an antibody against the target called interleukin-6, which they use to kind of block that immune or cytokine response. And again, data for prevention is pretty scattered and unimpressive. So now we're looking for something that's oral. And as I say, we look at POLB 001 as an oral drug, so patients can take this from home. So it doesn't have to be given in a hospital like these IV infusions of antibodies like tocilizumab. And as I said, we feel it's going to selectively present excessive inflammation and importantly, without causing immunosuppression. So you're not blunting the immune response, you're just blocking that inflammatory response and ideally blocking that Cytokine Release Syndrome. The drug itself, POLB 001, we have an extensive data set on that. So we've demonstrated favorable safety and 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 our pharma partner. So that's setting the scene of cancer immunotherapies and CRS and why 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 market and the strategy. Liam, over to you.

Thank you, Jeremy. And yes, 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, we're going to prevent Cytokine Release Syndrome. So it's quite important from a development perspective that we're differentiated, and we have a reason to believe that this can be very successful in the clinic. So POLB 001 is a p38 MAP kinase inhibitor. So just very briefly, what does p38 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. And importantly, what we've seen not just with our molecule, but with the inhibition of p38 in general is that we can have a potent decrease in a wide range of pro-inflammatory cytokines without ablating the immune system. So what this is doing is preventing the hyperinflammation without preventing inflammation altogether. And this is very important in the use case of Cytokine Release Syndrome because obviously, these patients have tumors, have blood cancers, and a lot of those cancers carry risks 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 p38, 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. And we also see some evidence that we can potentially enhance tumor clearance with p38 inhibition. So just briefly on the bottom, I have 4 rows shown, and tocilizumab and dexamethasone are existing treatments for Cytokine Release Syndrome, not used preventively, only reactively. 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 p38 inhibition compared to these other effects. Steroids notoriously have wide effects, but somewhat unknown in an immune context. They have both inflammatory and anti-inflammatory effects. Tocilizumab is really affecting downstream. So it's an IL-6 receptor antagonist. So it's very specific. But when we go a p38, 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 involves multiple immune cells within the body. And we believe that having this systemic effect and a broader effect is a reason why we could see superior effects in the clinic. So very important that we have a novel and differentiated mechanism of action. To the next slide. So briefly, just to mention some of the preclinical data that we have, and I'm showing some of the important data on this slide. But as Jeremy mentioned, the molecule itself has a very extensive nonclinical and preclinical package of pharmacology and safety pharmacology. So POLB 001 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 would be used in the acute condition and potentially something in the setting of oncology where a lot of existing drugs 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 this 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 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, a CD28 challenge. So this allows us to investigate POLB 001 in a model really closely aligned to what we're trying to tackle in the clinic, which is really important. So -- on the top is the design. So 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 CD28 superagonist. 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 a technical artifact. But importantly, in the red, you can see that when we introduce CD28, actually, you get this increase in the CRS score. So the CD28 is driving Cytokine Release Syndrome. And as we introduce POLB 001 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 an anti-TNF antibody is a really robust comparison, robust because antibodies 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 001 that's not designed for animals actually only lasts for a couple of hours. So it's quite difficult even to get the exposure 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 001 was as effective as the gold standard prevention 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 IL-6 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 lower than blue in the IL-6 and even lower than with the anti-TNF antibody. You will notice on the right-hand side, anti-TNF was lower, but there is a technical artifact that because we're comparing against an anti-TNF antibody, TNF levels will be lower because it's quenched in the body. So really enthused by these results preclinically with POLB 001 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 I data we have. So here, I'm showing the Phase Ib LPS human challenge study that we did. And there was also a first-in-human trial done. In both studies, the molecule had an excellent safety and tolerability profile. What I'm shown here is the LPS human challenge study and more of the pharmacological effect. So why we think it's going to be effective as we move towards the Phase II in Cytokine Release Syndrome? So again, on the left-hand side, so we use LPS, which is -- it's a component of the bacterial cell wall. But in a science perspective, again, it's really potent way of activating the immune system. It binds to toll-like receptor agonist 4 and drives hyper potent responses and is a really effective way for us to measure p38 inhibition and the effects of it. So what we did was we pre-dosed the volunteers for 6 days. So on the left-hand side, you can see day 1, 2, 3, 4, 5. They were pre-dosed with POLB 001 twice daily. And on day 6, we introduced this intravenous dose. There is day 4, 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 going to go into that today. So just on the middle and right-hand side, I'm showing a selection of this data. We presented it more extensively previously. But what we could see is across a range of markers that are all quite important in Cytokine Release Syndrome, including IL-8 and TNF not shown here, is 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. So 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 patients' 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 an effect in 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, symptom to patients, and it's going to suggest that these patients will be better off taking 001. 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 and as we introduced POLB 001, 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 70 mg and 150 mg were both highly effective and probably as effective as we wanted 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 trial, we've been quite active in this space, and it's really, really important to us that we do make sure there's a strong unmet need that this is something patients and clinicians really need, and we positioned 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' interest in supporting POLB 001 and really support in any way they can that we can get it through the clinic as quickly as possible and get access to them. But from their perspective, myeloma, in particular, is in an incredible spot at the moment where for some patients, they are discussing functional cure. So myeloma is typically considered non-curable. It's very difficult to get rid of the clonal disease. But actually, 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 -- 50% of patients will be diagnosed with multiple myeloma at the age of 68 onwards and some of the emerging data for first-line therapy. So bear in mind, in myeloma, there is 3, 4, 5 effective lines of therapy. With first-line therapy, some of the latest results they've seen is a progression-free survival in the range of potentially 17 years. So first-line therapy can be really effective for a lot of people. And I think a lot of the interest is changing from all patients to really categorizing those who get multiple myeloma younger or get a high-risk form of disease and how we can treat these differently and also how we can bring immunotherapies into a frontline setting. So to really benefit from the immunotherapies, the hypothesis is that you really want to fit immune system because as cancers progress, it generally breaks down your immune system. It makes it quite difficult to generate an immune response. So giving these immunotherapies to late-stage 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. 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 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 treatment selection. So things like staying close to home, reducing treatment-related toxicities and staying with existing health care teams. And 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 lot of pain. 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, patient preference is playing a larger role than ever. So the 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 we get the best for patients. And on the bottom I have here, outpatient delivery of certain immunotherapies is not feasible. So this is largely done in the U.S., and they're really investigating how to make these treatments more available, but it's just so difficult with something like Cytokine Release Syndrome that can progress so rapidly. And even with massive philanthropic grants, the top centers are struggling. It's really only for the fitter patients, those who have a full-time caregiver that they're able to do it. So a lot of major hurdles 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 a massive challenge as we move forward and really needs novel solutions. So speaking about solutions, POLB 001. The trial we're -- we're advancing first in-patient Phase IIa trial. So shown on the bottom here, I'll go straight into Dr. Emma Searle, a Consultant Hematologist at the NHS Christie Foundation Trust in the U.K. 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 that 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 Emma's leadership, and we'll be using all U.K. 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 at the IMS conference in Toronto. And those patients will be receiving an approved bispecific antibody. So these bispecific antibodies typically induce Cytokine Release Syndrome up to 70% of patients. So it's a really strong position for us to investigate POLB 001 and its ability to prevent this potentially life-threatening side effect in about 30 patients. So it's going to be rapid. Our focus is getting proof-of-concept data out. I'll go into it in more depth on subsequent slides. But 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 U.K., and they've been embedded in the U.K. hematology community for some time. They actually have existing networks in 15 U.K. 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 U.K. hematology community. And 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're a really good balance of having that network, having the understanding of the molecule, being able to produce high-quality data that's going to be attractive to partners as well. And importantly, they are driven by a mission to improve outcomes for cancers -- for patients with blood cancers. So they're a very specialist organization, purely there for blood cancers within the U.K. with a mission to drive outcomes 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 001, 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. So the trial itself, as I mentioned, it's in multiple myeloma. So it is Phase IIa open-label, single-arm trial. So no randomization, and this means that everybody is going to be given the drug. And there's going to be no blinding. So we're going to see data come out really quickly next year. The trial itself, so on the left-hand side, I have a schematic here showing how it works. And again, this is an artifact of Cytokine Release Syndrome that bispecific antibodies actually have to be given in 2 step-up doses, they're called in myeloma patients. And these step-up doses are actually microdosing. 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 of about 3%, and then about 30% and then 100%. This process takes about a week to 10 days to actually dose the patient up to the level they need to get to. And by giving these microdoses, they get the body used to it, and it mitigates the risk for Cytokine Release Syndrome. But even with this step-up dosing, they still, as I mentioned, get about 70% of Cytokine Release Syndrome. So we're going to be given POLB 001 twice daily, and there's going to be about 30 patients, and we're going to be using an approved bispecific antibody, as Jeremy mentioned. So the supply of approved bispecific antibody has been secured at no cost to Poolbeg, very important to us. And again, we're ready to proceed at pace into this. So we have a supply of GMP-grade POLB 001 ready to go. So really, we're in a really strong position. Everything is at an advanced stage of preparation, and we are expecting interim data in the summer of next year. And 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-up dose of the bispecific antibody. So we're dosing during that high-risk period for CRS, which typically lasts for about 2 to 3 days after the first 3 doses. So 99% of Cytokine Release Syndrome will actually happen here between day 1 and 7 there on the slide or 8, 9, 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 001. We'll be able to really quickly get data from this trial after the first 14, 28 days, we're going to know 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 patient. We also want to confirm the safety and pharmacokinetics of the drug. So again, first time going into patients, we'll just confirm that the exposure of the drug itself is sufficient. And we're also going to 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 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 nearly all centers, that step-up dosing is actually happening in an inpatient environment. And what that means the patient has to come in and they will come in for the full 5, 7, 8, 9, 10 days. And if they have CRS, that kicks that out. It's incredibly challenging. Typically, oncology wards throughout the world are full and they try to reserve beds. 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 the bed in the oncology ward. So this is really a bottleneck for the patients and the fact that we're able to do a trial potentially where we limit that inpatient duration is going to be really attractive to the hospitals, again, just emphasizing that this is a trial that is going to be really attractive to investigators and to patients to participate on. I really like to touch, we're not 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.

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 chomping at the bits ready to get going this into patients. Again it's a nice milestone for any biotech company, but obviously from a Poolbeg's standpoint. Again I want to you know take a step kind of backwards and just talk about, again, context here. We talked about bispecifics and CAR T cells. We've engaged the T cells to go after the tumor. And again, as I mentioned earlier on in the last 10 years or so, it really has exploded on the scene and fantastic efficacy with these kind of side effect issues that we're trying to resolve. But because of their efficacy, their revenue generation is increasing somewhat exponentially. And there's a forecast like 2030, there'll be $120 billion 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 001 to come in. So effective CRS management, we could achieve that. So that's the reason why we're driving forward with this. I mentioned earlier on about receiving Orphan Drug Designation from the U.S. FDA. This was terrific for the company and fantastic as the outcome from the hard work of the team to achieve this. It is kind of, I think, quite impressive validation that the FDA looks at this and sees the unmet need here. The benefits are 7 years in the U.S. market exclusively following approval. You get a waiver of new drug application fees, typically in the range of $4 million, again, when you get this Orphan Drug Designation, earlier access to the special protocol assessments. Again, it's just speeding your way through the FDA is one way to look at it and then tax credit for qualified clinical trials. Now we say like this is what's attractive to our partners. They see that we have this and the bispecific antibody supplier, when they saw this news, they kind of got back in touch with great to see because they can see down the road that's a benefit to them, sort of add value to the program. So again, very excited about that and a reminder of potential first approved preventive therapy for cancer immunotherapy-induced CRS. Now again, we're not working in a vacuum here. We did a lot of external key opinion leader talks and talked to 10 or so different myeloma docs globally, U.S., France, U.K., talking to them about the unmet need is one thing. But 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 talked about the middle here, where, as Liam said, patients are kind of coming in, they're taking up beds. So I don't mean that in the bad way. It's like they have to remain in hospitals for 1 week or 2 for fear that CRS develops. So we're looking at 500,000 patients for diffuse large B-cell lymphoma and multiple myeloma only. And that's, again, patients diagnosed estimates in the U.S. and the EU- 5. So this bottleneck here, not enough patients are getting the life-saving drugs. So we think if you remove the CRS, you remove this bottleneck and again, we'll be able to kind of obviously charge for POLB 001. And if you kind of fast -- if you could do the analysis of the number of patients versus what you could charge for a drug like this, and there are comparables out there, we're looking at a potential $10 billion market. So I think that's kind of quite exciting. Again, as I say, getting that 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 he sums it up well. Martin is a myeloma specialist with The Royal Marsden. 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 drugs into the community setting away from the dedicated, let's say, cancer trials or clinical units. So again, as I say, if that can fall away, it makes life a whole lot better for many, many people. So they said, POLB 001 has the potential to transform the cancer immunotherapy by expanding administration of cancer immunotherapies themselves from the specialist cancer centres into the community. So we always kind of refer instead of coming down to London, for example, patients can stay in their hometown or their home village or their home cities and get their treatments. So I think that we can have a significant impact on the space, on the fields and on patients here. And obviously, it will be a sizable significant market. From that point, I'll let -- Martin Kaiser, as I mentioned, has a few words on the recent panel that we spoke of.

CRS plays into this, for example, because at the moment, it needs such a specialized knowledge with the way how it is 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 they document for and that they can deal with it.

So CRS is a big problem.

Yes. CRS is a big problem.

And potentially, it would enable immunotherapy to come into the more sort of local area hospitals as opposed to specialists.

For the existing therapies at the moment, yes, that...

So as I say, Martin is a highly regarded, highly respected myeloma doc. So we leave the last word for him. I do want to just kind of mention briefly our oral -- I'm cognitive of time, we have kind of run over a little bit. So just one slide on the oral GLP-1 program. So as I say, we're moving forward with this. Again, another proof-of-concept clinical trial that will be pretty rapid in generating data. So we expect top line data in the first half of next year. As I mentioned earlier on, it's a proprietary delivery technology to encapsulate the GLP-1 peptide, which normally be digested, so it protects it from the gut and gets it into the site of action. The trial investigator Professor Carel le Roux, he'll be running this at the University of Ulster. I just want to make sure that GLP-1 gets into systemic circulation. So again, a very straightforward analysis of the pharmacokinetics and pharmacodynamics. We will look at glucose tolerance test. And we're looking at 20 obese subjects here. So a 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 Metsera around getting access to GLP-1 programs. There is RYBELSUS, only one orally delivered GLP-1 receptor agonist on the market. And that has its own issues with only about a 1% bioavailability. So we believe we can improve on that. So I say very excited about seeing that moving forward as well. And again, I'm just going to wrap up and certainly leave a few minutes for questions. But again, a reminder, partnering focused, an excellent team. I myself has been in the industry for 20-plus years and have gotten more recently an exit back in 2020 with the last company, Inflazome. So I know how the process works from deals and collaboration standpoint. As mentioned at our interims today, cash balance of $10 million as of the 30th of June. So again, that pushes us, giving us a runway into 2027. So again, multiple catalysts from an investor standpoint, this clinical data coming up, as I say, the POLB 001 Phase II initiation and interim analysis and then top line data and then the Oral GLP-1 as well. So well capitalized to get to these catalyst-rich areas. So again, I'll leave it there. You can take -- can read on that, okay, but that just reiterates. So what we'll do now is just transition and I know some questions have been coming in and I can see them on the screen here. So we'll get through as many as we can in the next 5 or 6 or 7 minutes or so. So again, apologies for running over with the presentation, but I do want to get to some of the questions.

And Liam, I'll read these out, Liam and see what's -- I'll assign for me or you, and I'll try not to make things too challenging. But anyway, first question here, during the POLB 001 trial, will any information on progress be released? I think you're on mute there, Liam.

I'm back. Sorry. Absolutely is the short answer. We will keep you guys updated as we can. And so as I mentioned, we're in a really advanced stage 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 when we have the trial starting, first patient in, data coming out next year, we intend to give as many updates as we can throughout that process. So stay tuned.

Brilliant. Thanks, Liam. 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 clinical trial, as Liam said, is open label. So we will see the data first. They'll be involved. For first mover, we've deliberately kept the door open. We didn't want to close the door where we'll just only do a deal with this company and nobody else. So we've been doing outreach with all of the large pharmas who have bispecific or the CAR Ts, just engaging with them, telling them about 001. As I said, the announcement last week will certainly help and accelerate discussions that we're on firm footing with the Phase IIa. So we've kept the door open. Of course, the fact that they're providing drug, I think, gives strong indications that, number one, they want to resolve their CRS issue that they have. So -- and we know, as I say, what they have in their pipeline is other CAR Ts and bispecifics and drugs that -- where CRS is an issue. So first mover is a good way to say this. I mean, they'll have an insight. They're obviously committed, but working with the door open where others could, I guess, essentially come in and overbid, if you want to put it that way. So again, I appreciate the question. Next question, if POLB 001 trial, if successful, what monetization options are on the table, company buyout, partnering agreement with pharma or many pharmas, expansion into other diseases? Again, it's a great question. We could spend quite a bit of time talking about that. But what I will focus on is that, as I mentioned earlier about keeping the door open. So we -- this could potentially be a license agreement where they could take the drug from us and apply it in, as I say, a much larger, let's say, Phase IIb or Phase III. We'll receive upfronts for the work that we've done, the derisking that we've done for the program, and then generate downstream milestones and sales royalties on successful development. That's one structure you can do. You're right. I mean, they may come in and say we just want to buy whether it is the company or whether it is the program. Maybe they don't have an interest in GLP-1 as an example, they just want to buy the program and then you negotiate an agreeable price for that and maybe some downstream contingent value rights, CVRs, some milestones, et cetera. So that option is on the table as well. Going it alone, that's a no. We always thought that 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 III trials and ultimately getting on the market. And 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 CRS. We've had questions about sepsis, et cetera. I do think that with pharma companies when you license a drug, they like to take control of everything. So essentially it will be up to them to decide what disease areas they progress on. So again, thank you. That's a terrific question. I appreciate that. Next question, when is the oral GLP-1 trial expected? And what is trial data to do? I think we covered that earlier on. There's a lot of work going on right now. I was on a call this morning around the manufacturing of both the encapsulated GLP-1 and the placebo and then getting all the documentation needed for that. So there's kind of studies and assets 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, and you're going to compare their kind of glucose tolerance test, so very straightforward. And so again, we're looking forward to getting that data in hand as well. A question here. What is your opinion on the disappointing share price response to the excellent POLB 001 trial news? I won't say -- I don't mean to be [indiscernible] you tell me, but I think we're working really hard in the background and moving the programs forward, as I mentioned, derisking the programs. I do think we had a fundraise earlier this year. Maybe people are taking a bit of profit off the table from that. But I still think we're kind of -- heads are down, we're fully focused. I mean I'm a shareholder myself. So I want to see this kind of drive forward. So disappointing is a word. But I think when the markets see what we're doing, when they see the market size, when they see the progress we're making, hopefully, there will be kind of a turnaround with an acknowledgment of what the team is doing here and the value that we're bringing to derisking the program, bringing value to shareholders. So we're hoping that is acknowledged. So I appreciate that. Question. Liam, I'll pass this over to you. This is tricky. How confident are we that POLB 001 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 could give your opinion, Liam, maybe I'll add it.

Yes. I would love to put a figure on it. Our results today are incredibly promising. You've seen them 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 this or similar areas might have failed for things actually unrelated to how effective they are, can be things like infection or something else, which really isn't tolerable. So a lot of people have faith in the p38 pathway. I'll say that. There's a lot of results. So we're quite confident on. And really, as we move forward, we'd be very optimistic that 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 we know we're hitting all the right markers as we move into this trial. We know we have good exposure. So look, I guess, watch this space, we have a lot of confidence on this side, and we're very optimistic as we move forward, but clinical development.

Brilliant. Liam, thanks for that. And maybe I'm just going to 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?

No, absolutely not. We're in a really strong position as we move into this from a regulatory perspective and also from our own pharmacology perspective, we use some of the best models available for Cytokine Release Syndrome. So nothing else planned before the study.

All right. Thank you for that. Another one for you, Liam. I'll leave it you. 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, I could harp on all day about this, but this is a really well-defined condition. Cytokine Release Syndrome only came out about 10, 15 years ago when all these immunotherapies started to get approved. But there's a lot of CD3-engaging bispecific antibodies, where not just high rates of Cytokine Release Syndrome are also very similar, very similar timings, very homogenous disease. So really promising as we move forward for looking at something like a broad label. But that also means that it's really well defined when these patients are going to have Cytokine Release Syndrome. It's going to 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 treatment here, especially in this Phase IIa. There's a lot of data out there on our molecule and p38 inhibition that that's all we're focused on. The first couple of weeks of treatment, do we prevent Cytokine Release Syndrome? We don't need to follow them. They might continue to get the bispecific antibody for longer, but the trial will not continue any longer than the first cycle or 2.

Let's take a deep breath. Liam, next one is yours as well. They're actually the next couple of questions, and I say I'll give 2 more minutes just and again apologies for running over time, but you know we do want to address as many as possible. From Marcus is this a double-blinded trial? I guess CRS is so significant placebo, no SIBO effect, may not damage the data?

It's a Phase II trial. We're in a really strong -- so short answer is not double blinded. It's not blinded at all. It's open labeled and single armed. And we know because we're going into a condition where 70% of patients have it. It's really defined. It's going to be quite apparent how quickly these are getting. So Cytokine Release Syndrome in this setting is really all defined by the timing. So if you have a fever within the first day or 2 after given a step-up dose, it's almost certainly Cytokine Release Syndrome. So we don't actually have too many concerns. If the drug is effective, it's going to be apparent in this trial. We don't expect a placebo effect to be preventing Cytokine Release Syndrome.

Yes. Great. I'll take the next one, Peter, 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 for multiple myeloma, we can say that. But as I say, we'll be talking further about that. But I think it's important, it's very difficult to do clinical trials where 2 unapproved drugs. Obviously, POLB 001 is one is unapproved for now, and we're trying to prove that the validity of moving it through the clinic. So yes, the bispecific is already approved and on the market in both. Let's go with the last question here. Was it -- how many sites will be involved in the trial?

The short answer is it's not going to be a lot. It's a handful of sites. The advantage of using ACT is that they are incredibly well set up in the U.K. already. They're already networking into the biggest sites. We know what sites are going to be using the bispecific antibodies we're doing. That means that we can do this in a relatively small number led by the Christie, which is again, the biggest -- I can stress that's the biggest single site cancer center in Europe. So really are able to do this without expanding out 20, 30 sites. It's going to be small. We will share the sites in due time.

Brilliant. Let's call it. That there are a few more questions. We can address those offline perhaps. And really greatly appreciate everyone's time. It's -- Poolbeg, as we've been through just the last 40, 50 minutes or so, we have nice momentum now. As I said, we have funding to take us through our clinical milestones we spoke to in 2027. Very excited to get this trial going. We talk about pieces in place, similar with the oral GLP-1. So there's a lot of, say, data points with these clinical milestones in the very near future. Team is working very hard to get us there and achieve that. So -- and again, to the point, hoping that the share point reacts to the same. But I think we're on a nice track. We've got a very good mission. As I said, we're trying to change cancer immunotherapy treatment, get it away from these dedicated cancer clinics into the community. So it's a worthwhile venture. We're very proud to be doing it. And 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'll now automatically redirect you for the opportunity to provide your feedback in order that the company can better understand your views and expectations. It's going to take a couple of moments to complete, but I'm sure will be greatly valued by the company. On behalf of the management team of Poolbeg Pharma plc, we'd like to thank you for attending today's presentation.