Poolbeg Pharma PLC (POLB) Earnings Call Transcript

Good afternoon, and welcome to the Poolbeg Pharma PLC Investor Presentation. [Operator Instructions] Before we begin, I'd like to submit the following poll. I'd now like to hand you over to Jeremy Skillington, CEO. Good afternoon, sir.

Good afternoon, Lillian, and thank you for that introduction. Good afternoon to everybody, and thank you for joining us today at lunch time. Hopefully, you have your sandwich or [ bowl of soup ] in front of you as we want to give you some very exciting, very important updates from Poolbeg just over the last short while. So my name is Jeremy Skillington, the CEO of Poolbeg Pharma. I'm delighted to be joined today by Professor Brendan Buckley, who sits on our Scientific Advisory Board and as an NED as well; and Dr. Liam Tremble, our Principal Scientist. So today, I do want to go through and give you a sense of where Poolbeg are. I know we're familiar to many of you. But for those maybe not so familiar, we are a very highly experienced team with a proven track record, lots of years in the biotech and pharma industries. We've got a very exciting pipeline of high-value programs targeting critical unmet needs, and we're going to go through in great detail today POLB 001, our lead program, which just recently got announced to get orphan drug designation from the U.S. FDA. So a very exciting time for that. I think importantly, for investors, we've got multiple near-term value inflection points, and these are clinical value inflection points, and we'll talk about those as we go through. I'd say right now, we're focused on execution of these clinical trials and ultimately, leading to partnering. And we can touch upon this maybe in the Q&A, but lots of good discussions with pharma partners who are very excited to see us execute on the POLB 001 CRS clinical trial, which we'll speak to and again, leading to partnering thereafter. We did announce last week a fund raise, GBP 4.865 million of conditionally raised, obviously, pursuant to a general meeting at the end of June. But this added to our cash balance of GBP 6.2 million that we had at the end of March, gives us a really nice cash runway into 2027, I'd say, to execute on these clinical trials and then importantly, achieve these milestones and partnering. This is the Poolbeg pipeline as we stand today, the lead program, POLB 001. It's a p38 MAP kinase inhibitor. This is a master regulator of the immune system of the immune or inflammatory response. And we are pursuing this drug in cancer immunotherapy-induced cytokine release syndrome, and it's a really significant or serious issue for patients who are already undergoing cancer therapy, but their immune system goes awry, it gets overexcited, you could say, and causes significant issues to these patients. So we've got a small molecule orally available drug to prophylactically to prevent CRS, which we're putting into clinic later this year. And as I mentioned, very exciting news that came through to us late on Friday that the FDA has granted us orphan drug designation. And thankfully, Professor Buckley will go through the details of that later on. But I mentioned the clinical milestone is very important. So we're on track. The first patient to be dosed in the second half of this year, H2 2025 in this Phase IIa trial. So yes, that will be in multiple myeloma patients, and that was specifically a request from pharma company. They want to see the safety and efficacy of this drug in patients. And this is a very rapid trial. So we'll have interim analysis, interim readouts from a subset of these patients in the first half of next year. So again, looking to see the cytokine release syndrome, how POLB 001 impacts or prevents CRS in the first half of next year. And then the full top line data in the second half of next year. So again, we have a nice momentum of milestones. But I think importantly, we're going to get really good data quite quickly, essentially quite quickly. The second program we won't touch upon today, we've got an oral encapsulated GLP-1 program. I think the world is getting very excited and acknowledging the importance of this GLP-1 receptor agonist. Those on the market, the majority of which are given by injection, and we've got an oral encapsulated version of that, again, planning to take this into the clinic for a proof of concept, a proof of technology clinical trial again later this year with top line data, again, very rapid in the first half of next year. And then 2 AI programs that come from kind of our legacy collaborations with CytoReason and OneThree around identifying new novel drug targets to influenza and novel drugs to RSV, respiratory syncytial virus. That's the pipeline as it stands right now. But I'd say the majority of the focus today will be on POLB 001 because, as I say, on the back of this orphan drug designation given by the FDA on Friday. So I'll walk you through CRS, cytokine release syndrome, the dramatic impact it has on patients. But I think importantly as well, the benefit that we could bring to the marketplace and ultimately contribute to a market that we've estimated to be over $10 billion. So cytokine release syndrome, CRS, this is a severe potentially life-threatening side effect of cancer immunotherapies. Now cancer immunotherapies do a terrific job of reorienting your immune system to go after a tumor. Not an easy thing to do because that's your cell tissue, your cell tumor, but they do a really good job, particularly in the hematological cancers of increasing surviving of these, for example, multiple myeloma patients. But you do have the side effects, upwards of 70% of the patients receiving either a bispecific antibody or a CAR T cell therapy develop cytokine release syndrome, CRS. This is a significant issue for the patients themselves, obviously, they're not feeling well. They're on cancer treatment anyway, but they're not feeling well. And these CRS can escalate where these patients are -- essentially, they're on respirators to begin with ventilators and their low blood pressure. But ultimately, this can go down to multi-organ failure. So it's a significant issue that needs to be stopped. As I said, with a small molecule POLB 001, we feel we could potentially prevent this from happening in the first place. So there are no approved therapies for the prevention of CRS. Right now, it's kind of managed in a reactive manner where these patients are given tocilizumab. This is an interleukin-6 antibody that's already in the market for rheumatoid arthritis. So they give it as a rescue to try and manage that CRS symptoms that they receive. But I say nothing is out there yet to prevent CRS, particularly Grade 2. And we, as I said, planning a clinical trial later this year to demonstrate that proof of concept. So we've done some independent analysis last year. We talked to a lot of key opinion leaders. We talked to clinicians, we talk to payers. And we estimate that we can potentially enter into a $10 billion market opportunity. And I'll touch upon this in greater detail later on. But I think right now, we're at a really interesting time with the growth essentially of these bispecific and T-cell engagers and CAR-Ts. But as I say, if we can manage CRS as a support therapeutic, but I think we'll have a very exciting market ahead of us. I do want to comment on Poolbeg as we were. Many of you know, we started off looking in infectious diseases. We spun out of hVIVO in 2021. And I think we really kind of opened up a very exciting opportunity in the oncology space. So we were pursuing POLB 001 for severe influenza. And many of you will remember, we got terrific data using an LPS challenge study. Liam will present some data on that later on. But I think it kind of what grabbed your attention a few years ago was this urgent need to prevent CRS in this oncology, in this immuno-oncology setting. So we kind of dived into that deeper, and it became very clear to us that this would supersede by an enormous factor, the market for influenza. So we pivoted in that direction. We were rapid in 2023 filing patent applications in this immuno-oncology space. And at the time, we had data coming through from our LPS challenge study that we presented at the American Society of Hematology Conference in the U.S. And that got the attention of the hematologists, recognizing that here could be something of benefit to their patients who receive these bispecifics and CAR-Ts, but unfortunately, also develop CRS. So again, we did our analysis in 2024, $10 billion market opportunities, talked to a lot of key opinion leaders. We generated additional preclinical data in a mouse model of CRS. We presented that at the ASH conference, American Society of Hematology again back in December. Again, that was very well received. So we're building a nice momentum and getting a very good network. And where we are today, as I mentioned, we are Phase II ready, planning to go into the clinic later this year, first patient dose in the second half of this year. I would say, strong indications that colleagues at big pharma, who we -- from a business development standpoint, have talked to, updating them regularly on our activities. Strong indications, they'll provide us with a bispecific antibody for that clinical trial free of charge. Again, they see the benefits that this could improve the outcomes in their -- the safety outcomes in their drug. So they're willing to give us this antibody free of charge, then we can take that forward into our study in combination with POLB 001, say, study that CRS aspects of these multiple myeloma patients. I think excitingly then for the company, we announced just yesterday after receiving news late on Friday that the FDA has granted us orphan drug designation for the prevention of T cell engaging bispecific antibody-induced CRS. So that was a really nice way to end the week last week. I say, we're building on the momentum that we've generated over the last 3, 6, 12 months. So on that, I do want to pass across to Professor Brendan Buckley now. Brendan will talk you through the aspects of the FDA orphan drug designation. Brendan, over to you.

Thank you, Jeremy. I'm a Non-Executive Director of Poolbeg and also direct the scientific advisory team. My background in orphan drugs is that I was a member of the Committee for Orphan Medicinal Products at the European Medicines Agency and also was a faculty member for a good number of years on an advanced course on clinical trials in rare diseases that the FDA used to run for their internal staff. I'm a former Professor of Medicine and Pharmacology and also former Chief Medical Officer of ICON. Next slide, Jeremy. So what's the significance of orphan designation? The first thing to say is it's not a license from the FDA to put the drug on the market yet, but it essentially gives us a lot of incentives and help to develop what they regard now as a drug with plausible promise. In 1983, during the Reagan presidency, an Orphan Drug Act was passed to facilitate development of drugs for rare diseases. These are defined as diseases affecting fewer than 200,000 persons in the U.S. at any given time. And they provide for financial and other incentives to develop the drugs to treat, diagnose or prevent these diseases and conditions. So the act tells us what we have to do to designate these drugs. And effectively, we have to prove the incidents that are fewer than 200,000 a year in the U.S., but they also make us show that it is plausible that these drugs will work, but they have a good prospect of turning out to be effective in the disease and the condition. So in a sense, a regulator granting orphan drug designation is an external review of the plausibility of what we're doing and it confirms that we're on the right track in our supposition that this will work. And again, to reiterate, granting orphan designation isn't a license to market the drug. That comes later at the end of trials. Next one, Jeremy, please.

Thanks, Brendan. You froze there a little bit Brendan. Can you do your last couple of sentences there, please?

Sorry. So the -- we have to provide data to the FDA, which demonstrates to them that we have a plausible basis for expecting the drug to work in this indication. So the fact that we've got orphan designation tells us that the FDA are happy that we're proceeding in the right direction, and we're not following a dream. We're following something which is highly plausible that may work. The orphan designation is, of course, is not a license. I'll reiterate that again. So why are we so happy? Why was it a great Friday? Well, the benefits of this designation, the kind of highlight ones come both during development of the drug and when the drug is on the market. So importantly, we sit into a nice relationship with the American regulator in that, for example, by designation of orphan, we don't have to pay regulatory fees. And that is a considerable benefit. It's of the order of more than USD 200 million. Anybody who normally applies for a drug to get a new -- an NDA to go into clinical trials or to proceed towards a market authorization application has got to pay very hefty fees. Basically, the drug developers pay the drug regulators. And we have a favorable regulatory engagement with the FDA, and this includes free advice from them on how appropriate or otherwise the protocols that we're going to use in the clinical trials are to getting us to the endpoints that we're looking for. And finally, for qualified clinical trials, there are tax credits down the line in the U.S. So this is very helpful during development and again, extends our runway considerably. Once the drug gets on the market, if we are successful in that, we have Uncle Sam protecting our intellectual property to an extent for 7 years. So nobody else can compete with us in this area if they have a drug which works similarly to us. So the orphan designation protects us from [ me too's ]. So somebody can't come along with a drug that is subtly different in molecular structure but works the same way to POLB 001 and get it on the market. We're protected by the regulator from that. Also, it's recognized that during drug development, you lose patent life. And the orphan designation allows the clock to be rewound to start later so that your loss of patent life begins much later than if we didn't have orphan designation. And this can add several years to the patent along the line. The effect of the Orphan Drug Act in the United States was really to start the whole biotech industry. So companies like Genentech and so forth, they all started off with the Orphan Drug Act, which enables them to develop drugs for rare diseases that otherwise were considered not worthwhile commercially. So you can see why we are really incentivized by this and very energized by it now. Thanks, Jeremy. We'll move next to Dr. Liam Tremble, and Liam is our principal scientist who is in charge of this program, and he has a very strong background in immunology. And I would have to say he's probably one of the best drug development scientists I've ever worked over the years.

Thank you, Brendan, and [ high ] praise. Hopefully, I can live up to some of that. But thank you all for your time today. And I'm just going to speak through some of the existing preclinical and clinical data that we have so far and some of our clinical plans as we move forward. So on the slide in front of you, I'm just going to take a little bit of time that -- the result is straightforward and that we were able to show that in a mouse model, in a humanized mouse model that POLB 001 was effective in reducing CRS. But the detail on the slide, I'll just go through and explain it in a little bit more detail. And essentially, cytokine release syndrome is quite challenging technically to study in animals. This is largely because they need to be humanized, so to induce a human immune system. So in the top bar, this is what we're looking at, that we use a special strain of mice that have genes knocked out, including major histocompatibility complex. So they don't have any rat or mouse immune cells. And what happens is we give some human immune cells, and we preselect these for high reactivity. And we give them about 5 days before we induce cytokine release syndrome to allow those cells to go into the tissues to mature and to really make the mouse humanized in terms of we're studying in the human immune system rather than the mouse immune system. And similar to what our plans are in the clinic, we prophylactically dosed with POLB 001. And then what we did in this case was we induced CRS with a CD28 super antibody. CD28 binds on T cells and essentially to get a very vigorous and violent activation of T cells to stimulate your cytokines and then drive symptoms. And that's the important part that we really wanted to study and that we weren't just interested in the prevention of cytokines, but we really wanted to test if POLB could reduce cytokines and have a clinical improvement. So this model is quite specialized. The Jackson Labs in the U.S. do it first, and they have a special strain of mice, where one of the challenges with a humanized mouse model is you always get a residual level of immunogenicity against the human immune system. So this is called background graft-versus-host disease with the mouse immune system, residual immune system still recognize the human immune system. And we can basically minimize that because the symptoms overlap with cytokine release syndrome. And that allows us to see cytokine release syndrome physically manifest in these animals over what we would see in background graft-versus-host disease. So in the graph on the left-hand slide, as you're looking at it, the difference between the navy and the red lines, this is essentially without POLB 001. We had a CRS score of 2, which is no CRS really. It's background graft-versus-host disease. And what we can see is when we introduce CD28 into the rat, we see actually the clinical score increase where they have symptoms of cytokine release syndrome. And then you can see we introduced 3 different doses of POLB 001. And actually, what we saw was that it brought the CRS right down to the background graft-versus-host disease, indicating that we completely reduced or diminished the cytokine release syndrome. In this model, we also used an anti-TNF antibody. And so in the clinic, as Jeremy introduced, there's an antibody tocilizumab, which is anti-IL-6 receptor use. And in this case, the difference is purely a technical limitation of the model and that an anti-TNF antibody is better than an anti-IL-6. So this is really the gold standard that we wanted to use in this model. And as you can see, it was also effective. And then when we look at the biomarker responses, we looked at a number of biomarkers, but for simplicity, I've only shown IL-6 and TNF alpha here. What we can see is that the red line where we induce CRS as we expect, we get an increase in various cytokines to increase with the clinical manifestations. And as we introduce POLB 001, what we see is these cytokines really go down greatly, almost in the terms of IL-6 to background levels of graft-versus-host disease of the navy line. Interestingly, in terms of the anti-TNF antibody, POLB also outperformed this antibody for almost all markers or for all markers with the exception of TNF. And that's because an anti-TNF antibody will quench TNF. So even the assay is going to be a little bit biased. So we were really impressed and promised and enthused by these results. So this is some new data that we haven't shared before, and we'll share a little bit more later this year. But essentially as part of the orphan application, one of the things we did really want to do was to say, well, look, we've looked at cytokine release syndrome in animal model using the CD28 stimulus, but we really wanted to use specifically a bispecific antibody as we intend to do in the clinic. So what we used here is a CD19xCD3 bispecific antibody, essentially equivalent to Blincyto, an acute lymphoblastic leukemia drug that's currently in the clinic. And the important part here is that it stimulates T cells by CD3. So it gives equivalent indications as to the other multiple myeloma drugs, which are BCMA/CD3 bispecific antibodies. And what I'm showing you here is similar to the last slide with IL-6. So this is a slightly shorter model just for technical limitations. But here, we can see that in this model as well, POLB greatly reduced IL-6 levels, giving us an indication that we will hopefully see clinical benefit as we move forward towards our planned clinical trial. On this next slide, this is one that some of you may have seen before. So I'm just going to give a brief summary of our previous LPS challenge trial that we conducted. This is a Phase Ib clinical trial where we use lipopolysaccharide, a component of the bacterial cell wall to induce an acute inflammatory stimulus and similar to how we intend to dose in our upcoming trial. We administered POLB 001 prophylactically for 4 days before we gave an intradermal and then an intravenous dose. I'm going to focus on the intravenous dose because that's more representative of a systemic inflammatory response, which is what we're kind of comparing to as we move forward with cytokine release syndrome. And as we can see here, again, I'll focus on IL-6 because we know this is a clinically important cytokine in cytokine release syndrome. What we can see is actually the 2 upper doses that we used in that trial of 70 milligrams and 150 milligrams twice daily were both highly beneficial to the patients or to the healthy volunteers in this indication. And one of the strongest parts of the LPS challenge study and its relevance as we move forward with cytokine release syndrome is LPS doesn't just induce cytokines, but these cytokines are coupled to clinical responses. So in our case, we were able to see a heart rate elevation and also an increase in heart rate, driven by the LPS. And as we introduce POLB 001, what we saw was that these elevations were actually decreased. Again, give us an indication that hopefully we'll be able to drive meaningful clinical benefit as we move towards the prevention of cytokine release syndrome. So I mentioned the trial we're hoping to do later this year or to start later this year. So this is a trial in multiple myeloma patients receiving a bispecific antibody. The bispecific antibody induces cytokine release syndrome. And what we're planning is prophylactic dosing to cover the entire step-up dose region, which generally occurs over the time course of 5 to 7 days. This is the highest risk period of cytokine release syndrome and currently requires patients normally to be given the bispecific in a hospital setting. So what we're interested in is obviously looking at the biomarkers as POLB 001 is introduced, but then also looking at the incidence of CRS, specifically Grade 2 or higher CRS, which tends to be more clinically severe, clinically challenging. And if we can reduce that or eliminate that completely, then obviously, the drug will have high value as we move forward. And then one of the other things that we're interested in is to see if we would still need the same level of tocilizumab usage for, as Jeremy said, rescue use of cytokine release syndrome. So the trial is designed as a simple rapid trial that will allow us to get proof-of-concept data as we move forward. So twice daily oral dosing, single-arm, open label using an approved bispecific. And we've really been focused on making sure that we design a trial that will allow us to get rapid clinical data. So for this trial, we have had strong indications from big pharma that they're willing to provide the bispecific antibody free of charge. And that's, again, a big boost in terms of making sure that this trial moves quickly and that it recruits quickly. So we are hoping to start in H2 2025, and we're hoping to have top line data in the second half of next year. We've had leading myeloma clinicians enthusiastic to participate on this trial, and that's something that I know I'm personally excited to be able to share later in the year. And so we'll definitely give you more updates as we're able to share more information. And we do have extensive engagement with myeloma experts and key opinion leaders in the field such as Martin Kaiser and Gareth Morgan, and they've all highly enthusiastically endorsed the program, which is really exciting for us at Poolbeg. As we move forward, I'll hand you back to Jeremy for the moment to go through some of the market opportunity.