Poolbeg Pharma (LSE:POLB) — POLB 001 Update

0:01 Good afternoon, and welcome to the POOLBEG PHARMA PLC investor presentation. Throughout this recorded presentation, investors will be in listen only mode. Questions are encouraged and can be submitted at any time by the q and a tab situated at the right hand corner of your screen. Just simply type in your questions and press send. The company may not be in a position to answer every question it receives during the meeting itself. However, the company can review all questions submitted today and publish responses where it is appropriate to do so. Before we begin, I'd like to make the following poll. I'd now like to hand you over to Jeremy Skillington, CEO. Good afternoon, sir. Good afternoon, and thank you.

0:32 Good evening. Can we say good evening? Actually, can we say happy New Year to everybody who joins us? I know we're the middle of January, but, obviously, our first chance of POOLBEG to to speak to our investors and would be investors. We had a very productive week last week at the JPMorgan conference in San Francisco. So it's nice to be back and to to give everybody an update on our most recent activities around POLB zero zero one, as you know, our our lead program, our lead asset. So, as, as an anchor, I just wanna start and, remind you how well POOLBEG is positioned for, for success. We've had a very exciting, 2023. I think we've made a lot of progress in our pipeline. We've built out our team.

1:18 Again, we started with with strength with our chairman, Colin Friel, Ian O'Connell, CFO, and myself. And, again, a lot of experience in the industry, both building and indeed exiting companies. But very happy towards the in q four, bringing on three new colleagues, three very experienced new colleagues in, John McEvoy, who's heading up legal, Laura Marr, who's gonna head up our clinical. And joining us here tonight is, David Albans, our chief business officer. And, you know, I think the the purpose of tonight is to give you an update on zero zero one, around the, CRS induced by cancer immunotherapies, recent data we've generated. Again, talk about the, you know, the clinical, requirements and then ultimately the the market. And I think there's a you know, David has been doing a terrific amount of work with the team to analyze that in greater detail.

2:07 So, again, great to have the Armour team on as as we build for the future. I think right now as a company, we're focused on, number one, moving our pipeline forward, but, obviously, as well, looking for near term revenue generators. Interesting time in the industry as, you know, 2023 has been challenging for most. Again, a good year for for POOLBEG. But, again, focusing in parallel on, on partnering discussions, which, as said, we've been very busy and active on, towards the end of, last year, of course, at JPMorgan last week. So, again, I do I will remind you of our pipeline of high value programs. Zero zero one, we'll speak about in-depth tonight. And the most exciting aspect of that of late is its application to cancer immunotherapy, the in cytokine release syndrome associated with cancer immunotherapy, and we'll talk about that. Also have a program going into the clinic this year, oral GLP one agonist. Again, the GLP ones have been excited in in the obesity and diabetes space of late, and we have an oral delivery program going into the clinic. And then lastly, our AI program, very wonderful collaborations to bring us through to having new novel drugs and targets for respiratory infectious diseases. As a reminder, we've got a very strong cash balance, 14,100,000 as of the middle of last year. And, again, as I said, pivoting towards revenue generation to be wholly independent as well. Apologies for my voice as well, this lingering cold following Christmas.

3:28 So, again, as a snapshot of our pipeline, high value programs, zero zero one, as I say, we'll talk about tonight. Positive phase one day one b data from our LPS challenge study last year and more recently, in vivo data confirming, I guess, the you know, strengthening our conviction that progressing into cytokine release syndrome is the way to go. And I'll share some of some some data on that later on. But as I say, we're phase two ready. We have a pretty robust, you know, package for, your for, the regulators to review. So moving that right in, of course, partnering ready. Also looking at, you know, at severe influenza, this is our starting point in respiratory viral infections. We see a a great application there for the same product, for the same drug in that space, let's say, on the back of our LPS challenge study last year. There's a great progress and promise.

4:14 The oral encapsulated GLP one is a proof of technology clinical trial will begin and finish this year. So, again, these are short, trials where we get a lot of human data, ultimately making that available to for partnering purposes. And, again, progressing through the, the the candidate drug candidates and drug targets identified in our AI collaborations. Other collaborators do in the background, other works going on. We have a an encapsulation technology collaboration with a Nasdaq listed company that's going quite well and sent along some some samples to them for for analysis and, of course, progressing our oral vaccine program, was funded by the Irish government. So exciting enough in that regard. But let's focus on zero zero one. It's a phase two ready or p thirty eight MAP kinase inhibitor. Again, are looking now at the cytokine release syndrome associated with cancer immunotherapies.

5:08 And so Martin Kaiser will talk about, you know, from a clinician standpoint, what's happening in that space and the issues involved and how we could resolve that. But as a reminder, we have phase two ready and say excellent bioavailability, very strong preclinical package, safe and well tolerated. Everything that you want in a drug, in a molecule, you can check those boxes. Good strong efficacy in our human phase one LPS challenge study. And again, looking at an in vivo model specifically in cytokine release syndrome, we've gotten quite exciting data as well there that I'll talk about. Interestingly around this industry, patents are critical. We have oncology patents filed last year, which gives us protection if granted out to 2043. This new data will actually enhance the the robustness and the the excitement around these patents and, again, focusing in on CRS. Again, we have granted patents out to 2038 for the use of p thirty eight inhibitors, for severe influenza.

6:05 But focusing in on the cancer immunotherapies, I'd say this is the next generation of of cancer therapies. You know, if you're more recall, we started with the the chemotherapies progressed forward to small molecules, antibodies. But immuno oncology is, you know, quite recent, but instead, most exciting part of, the industry where we're actually seeing cures, you know, which, is getting the both the, the the industry and the health care system and the patients very excited. But the challenge with these immunotherapies is when you give them, you develop the cytokine release syndrome requiring the patients to stay in hospital. So that puts, you know, a lot of pressure on the health care system to manage these patients as they're, you know, in the hospital system. It actually, know, gives a bit of a bottleneck, which kind of doesn't allow new patients to come through because beds are taken up because of this CRS issue. As I say, we see and this is we talked previously about treatment of CRS, but now that we have these new patents filed, we can actually talk about prevention. This is something we didn't want to about previously.

7:01 But we can actually be in a position to prevent the onset of cytokine release syndrome, again, the patients to receive their immuno your neuro oncology therapy and then progress through the hospital system a lot quicker. Indeed indeed, being a small molecule and orally available, they can take these drugs

7:19 home and take it from there. So again, we'll Martin will talk a lot about that and the the the benefits of of our drug. So very excited about where we are right now from a data standpoint, from an IP standpoint, you know, with recent filings. As said, we see a great market opportunity, which Dave will talk about later on. As I say, lot of activity going on in the analysis of that market space. This is the data that recently came out again validating the role of inhibiting p thirty eight to reduce cytokine release syndrome. And very briefly on the right hand side with these graphs, these are a variety of cytokines that are activated in response to this cytokine release syndrome. We have interferon, TNF, interleukins and MIPs. What we're seeing here is without any treatment, without any p38. In the red line, we see this dramatic increase of the expression, the release of these cytokines.

8:12 Once you give POLB-one in the other colored lines, let's say we have three different doses here, you're seeing this reduction or reduced expression of this of these variety of cytokines. So again, as I mentioned earlier on, this gives us great confidence that our molecule is doing what we wanted to do or what we expected to do, and it could play a significant role in the prevention and, as said, treatment of cytokine release syndrome. And again, the world kind of opens up now as to where we can put this drug, particularly in the immuno oncology space. So I say that the data strengthens and facilitates the expansion of our patent applications, which, again, critical for this industry, you know, in the cancer immunotherapies space. So very excited about the direction that we're taking right now. So appreciate your time. I will pass you on to Martin. Again, Martin has been a fantastic collaborator with us.

8:57 He's worked very closely with with Dave looking at the clinical, you know, analysis, clinical applications, you know, giving us guides on on commercial applications as well. So, Martin, I'll I'll pass across to you, and I look forward to hearing your your presentation. Thank you very much, Jeremy. Thanks. Yes, I'm very happy to present here as a clinician. I'm a hematologist, hematologist at the Royal Marston Hospital in the Institute of Cancer Research. I value myself as very happy that I have been active in this field in a time where there has been so much progress. I'm working specifically on multiple myeloma. One of the uncommon cancers where I think there has been relative to patient numbers as many new mechanisms of treatment and as many new drugs licensed as in hardly any other oncological indication.

9:50 I am a clinical trialist both on the academic and the industry side and I think it's a pleasure to work on so many trials where there is really progress is being made, new progress not only on the treatment side but also on a symptom mitigation side as we are speaking here today. And in my policy roles, I'm also having a very clear view on what implications sometimes relatively small changes in terms of the management, especially of side effects, can make in terms of patient having access in different healthcare systems, but also in different reach systems in terms of, reaching patients that are living potentially in rural or remote areas and they can make a huge difference to, the benefit that we make to patients with our treatments.

10:36 So, speaking about that I've been working in a field that has really been at the forefront of developments, I think what we have been blessed in haematology with is that we have been working and developing a lot of treatments that are really leveraging T cell and immune system activity against the tumor cells. And that is reflected in the number of CAR T cell therapies that are now licensed and in everyday use across haemato oncology. The B cell malignancies at the moment leading, but of course there is a lot of other developments ongoing and as we're seeing in my trust for example across the board developments in solid oncology, meaning that the patient numbers will only increase over time. And the same is to be said about the bispecific antibodies that have really, in my disease, multiple myeloma, taken, I think, the management of the disease by storm in terms of showing new response levels that we've not seen before, which we will go into in more detail.

11:39 But all of these drugs and that's not only limited to hemato oncology, that is also true in where we are seeing them used in solid oncology are leading to CRS cytokine release syndrome. And you can see listed here on the bottom three drugs that are currently available, but they all come with their downsides of either being intravenous drugs or not being completely efficacious in terms of mitigating side effects or even causing other side effects. That, does, open an unmet need in this field to really, facilitate the delivery of all of these, new immune therapies that are coming our way, both in hematology and solid oncology. Now, giving a bit of background what is cytokine release syndrome? I'm of course very familiar with it because I see it on a day to day basis, but, it is a side effect that is very common with, these new immunotherapies, specifically these immunotherapies that are using T cells to attack the cancer cells, either through a bispecific antibody or by modifying the T cells into genetically modified CAR T cells.

12:40 And it is a severe inflammatory response, which effectively has to do with that we're leveraging a very effective part of the immune system, primary purpose of which is to cause an inflammation to fight infection. But this time, of course, we are artificially triggering it by directing these cells against the tumor cells. And in some sense, a lot of these symptoms in the early stages mitigate what we see in an infection. As you can see on the right hand side is fever, heart rate, hypoxia, sometimes hypertension. That's the typical type of picture that we get in simple to severe infections. But because it is not an infection and certain stopping mechanisms that normally stop an infection are not in place here, these symptoms can really progress to a broad range of really severe symptoms that can affect quite a number of organ systems, including neurotoxicity in the form of eye cancer that's often linked with a cytokine release syndrome, so effectively a state where people can get seizures or, a reduced cognition, or awareness actually that can really be very serious to manage and to reverse as well.

13:48 So as with many of these conditions, you ideally want to prevent it entirely or you at least want to stop such a condition in the early stages because it is normally a cascade, a a thing that is actually like a chain reaction that increases if not mitigated early on. Now why does this play a role? And why is it something that we are wanting in some sense to stimulate, although we need to mitigate it at the same time, is because it is part probably of the positive effects that we're seeing, with these new treatments that are unprecedented, really. This year is one of the treatments that has already got a license for multiple myeloma by specific antibody called teclistamab, which is really effectively giving T cells new eyes, guiding them to the bone marrow to attack the myeloma cells, as many of you will be aware of.

14:38 And the response rates that we're seeing here with the single agent drug in multiple myeloma, have a lot of active drugs, but we normally need to combine them in three or four drug combinations to reach over response rates, as we see with this drug here of over sixty percent. And this is actually already in patients that are refractory to get against everything else and we're seeing already in earlier lines of treatment the efficacy of these drugs even being better. But inherently the efficacy of these drugs is linked to cytokine release syndrome, as you see on the right hand side. It is we're we're we're we're really redirecting a very powerful part of our immune system, and seventy percent of patients do develop, a CRS. Fortunately, with the bispecifics, these are mostly low grade CRS, but they're nevertheless meaning that we need to be prepared to mitigate and to treat them. And that is actually what we're coming to in some of the next slides, bringing up challenges logistically. Now, one of the thoughts that has already been going into with the currently available drugs, the ones that I showed you on the slide before, one of them being tocilizumab, an anti interleukin-six antibody that was originally developed for rheumatoid arthritis and similar inflammatory conditions, but is now being used here reactively quite well was if we give these up front, so if we give a drug like atosanizumab as a preventative, can we actually completely abrogate cytokine release syndrome? And this is from another study again conducted in multiple myeloma with a different bispecific antibody that has a similar high

16:09 incidence of cytokine release syndrome again, distribution of grade one and grade two, so less severe or severe more severe CRS. And here the drug

16:20 the existing currently standard of care tocilizumab SATACA release treatment was given as a prophylactic beforehand. And the hope was, of course, that with that CRS would be completely non existent. But that's not true. So we still see forty percent of patients develop a CRS and we do still see about the same proportion of patients developing a medium grade, and even some patients developing higher grade Sierra. So, there's clearly, despite, this encouraging sign that we can do something, about it, not currently a treatment that would really be giving us the confidence that we can manage this prophylactically. On the right hand side you see the very encouraging signal that came out of the study, however, regardless is that the overall response rate does not seem to be affected at all by giving prophylactic tocilizumab.

17:12 It might even be slightly higher, although I think that's a small study to make such a statement. Now, why this having an impact on how we can manage patients? Well, most of these drugs that I've mentioned already, the mitigating drugs currently, are IV drugs. So we can only give them really by having patients as inpatients while starting the T cell engager or CAR T cell therapy. And most of these drugs are given in a dose ramp up phase which means that patients have to stay in hospital for at least set duration. And that's all fine if the patient does not develop any CRS. So this is kind of like the example of patient one that you can see here on the top. We can plan. It's still taking away resource of course if we have to have the patient in and often it's just the fact that the prophylactic drug is not available as an oral drug that keeps the patient in the first place. So that's actually already a very important thing to reflect on. But then you can see with patient two and patient three what happens with their inpatient stay if the patient does indeed develop cytokine release syndrome because suddenly it's not only that we have to give the IV drug to mitigate or to reduce the symptoms of the cytokine release syndrome but the stay of the patient in the hospital is getting extended as well because we need to make sure that there is no recurrence with the next dose and that the patient does not need tocilizumab, for example, or even some of the other drugs that we have in the repertoire

18:42 later down the line. Which means in the worst of circumstances you can have inpatient stay that are more than tripling in duration to what you were originally planning. And that makes of course inpatient planning reach especially in smaller hospitals the potential in smaller hospitals to deliver those treatments or in the community really, really challenging. So I think in summary and this is of course where the excitement comes from with an oral management potential oral management of cytokine release syndrome as we are now seeing the first signs here with POLB001 is that CRS is as such a serious condition and at the moment we need to use quite a lot of healthcare resource to manage this because of the drugs that we have to give needing qualified medical personnel to give an IV infusion, but there is still a remaining mortality risk per se. There is still no complete abrogation of cytokine release syndrome.

19:40 We do know there's a rapid growth of these drugs. This problem will and we're already seeing it in my trust definitely in solid oncology with the first bispecifics in lung cancer approaching. We're seeing this becoming a universal problem. So at the moment that limits really the delivery of these immunotherapies to cancer specialist centers. That's quite interesting, particularly in large markets like The US. It still often comes with a, pre registering, for even for academic centers to be able to deliver these drugs, really, limiting their reach at the moment. And this is all linked to really that all of this can be managed in a hospital setting. So really an oral therapy that could prevent the CRS or even just treat the CRS by the patient at home would be highly highly beneficial to patients' healthcare systems and really, I think, have a big impact on reach and access to such treatments.

20:33 Thank you for your attention. That's great, Mark. Thanks a lot. Thanks so much, Martin. Good morning, good afternoon where where you may be based, everybody. Dave Ullman, chief business officer. I just wanna now take you through a few final slides around the the unmet need in the market opportunity, and thanks, Jeremy and and Martin, for for for for lining this up. But just to underline the point, I think, that Martin eloquently made is we are talking here about a a a very very high frequency of CRS occurring overall, whether it's grade one or above, but it can be seventy to ninety five percent of these patients.

21:19 And therefore, I think the under the underlining point I take away from Martin's presentation is even the the lower grades can be problematic in terms of efficient, broader delivery of these breakthrough therapeutics. So the severe cases, they're rare, but they can occur. And so as we as we've now developed additional data, I'll I'll remind you in a second around the LPS challenge study we we completed ahead of ASH and presented at ASH. But along with the additional preclinical data, we feel feel now we're in a very strong position to advance into phase two, really looking at this oral product as a as a preventative measure for CRS to be an enabler to the broader use of bispecific immunotherapies.

22:07 So coming back to the LPS study, Jeremy today in his presentation highlighted some new data generated in in mouse models, which again showed us this dose dependent reduction in in key pro inflammatory cytokines, dampening their effect, but not ablating immune function. The LPS study was the first in human l phase one normal volunteer study we ran in the lead up to ASH and had accepted at ASH. And I'll show I'll show you the abstract as a reminder. But really also showed that as a as a reminder for everyone, it had a a very clean safety profile. So an oral therapy with clean safety profile, reductions in the key inflammatory markers, but not ablation. So we were not destroying immune function that is key in these sensitive patients, but really stopping hyperinflation, which is what, in fact, CRS We had a very clear demonstration of the on target in inhibition, therefore confirmed, and it was a dose dependent relationship.

23:12 And and, actually, that was submitted to ASH. Next slide. So we we we were we attended ASH, as Jeremy said, just prior to JPMorgan, had some very positive interactions with the key opinion leader community, research community, and the pharma industry with with these evolving data. So going forward, it is our focus with POLB001. We, of course, have a great opportunity in severe influenza, but really our priority is in the cancer space going forward, both with our own investments that we continue to make, but also seeking partners to drive the program forward.

24:01 It depends what you read if if you want to be specific about numbers of overall market opportunity. And we and I've chosen, I think, you know, what one or couple of sources that give us an indication. But the the way way I think about immunotherapies in cancer, and Martin alluded to this in his talk, really, it's not just about hematological malignancies. It's it's gonna be about solid tumors, and it will also be about immune inflammatory disease in the future. And if we just look at bispecific antibody and CAR T therapies in in the cancer space, there are estimates they range. But here, we're we're talking a a $100,000,000,000 market as we get into the 2030s. '20 And probably 80% of that will be bispecifics.

24:48 As you may be aware, CAR Ts offer great promise for patients, but autologous CAR Ts is somewhat limited in its breadth of application US, but the bispecifics are becoming gradually more more ubiquitous more ubiquitously adopted worldwide. And this estimate is therefore the eighty twenty that they will be a major factor in the future of cancer care as we saw in the past, if you remember the curves around monoclonal antibodies on a similar trajectory. This is this burgeoning growth is is exponential.

25:26 So from our own perspective, as we think about the target profile, target product profile for POLB zero zero one as a preventative measure for CRS induced by cancer immunotherapies, taking a relatively conservative view, just looking at three hematological malignancies in third line plus, so later lines of therapy. As Martin said, the these the these treatments are moving up the lines, but we we've stuck to third line plus populations with a with a with a a a growth over time. We've we've estimated that this market opportunity is greater than a billion US dollars if POLB zero zero one could hit its profile, and that that would exclude the the any expansion into the solid tumor space or immune inflammatory disease, which would be make this a significant upside beyond the the 1,000,000,000.

26:18 So I think the takeaway from this is regardless regardless of the specific numbers of the overall market and of this specific number, this is a huge opportunity, and we're we're very encouraged with our early data to to to prioritize this asset going forward. And it's it goes without saying, really, that when when we create you know, do our internal strategizing and hypothesizing, that's fantastic. And and, you know, we we need a vision. We need a strategy. But we must go to the outside world, including Martin, but a a range of top international key opinion leaders are from The UK, from France, from The US, and from Canada.

27:06 Couple of the key millionaires mentioned here, Martin, we've met today, professor Morgan in The US, a whole range of other physicians, some key payers and clinical trials experts in the cancer space. We are confident now that we have confirmed, as we've described today, the unmet need here is clear. There are there are interventions available, but they will not fully solve the problem, either because they're IV or not completely abrogating c CRS risk, but also because there are licensing issues. So, you know, some of these therapies are not licensed for such uses because they were actually developed for other purposes. So there is a very clear need for a new oral therapeutic and or prophylactic to assist or enable the broader delivery of bispecific therapies in cancer, perhaps CAR T therapies in cancer also in the future. So we're very grateful to the input from our experts around the world to confirm that opportunity.

28:14 And in summary, we we now feel that we've got a growing and comprehensive preclinical and initial clinical data package from the from the phase one LPS study. We're now now in a phase two design, phase two ready situation. We are we have absolutely confirmed the CRS opportunity, and we've seen this clean profile from a safety perspective and the dose dependent reductions in hyper inflammation in all of the preclinical and the clinical study that we've run. We've taken international key opinion leader advice on this and confirmed some of the thinking here is on target, is on track, and we see a major market opportunity.

29:03 So, yes, we continue to invest on our side, but we are already also seeking pharma partners. We've we've been looking at that at ASH, been continuing those discussions at JPM, and we'll continue to do so as a as a priority going forward. But thanks so much for your time. And perhaps, Jeremy, we could open up for for some q and a. Perfect. Let me just jump in at at this point and just thank you all for your for the presentation. Ladies and gentlemen, please do continue to submit your questions just by using the q and a tab, which is situated on the top right hand corner of your screen. But just while the company take a few moments for your questions questions submitted today, I'd like to remind you that recording of this presentation along with a copy of the slides and the published q and a can be accessed via your investor dashboard. Jeremy, as you can see, we have received a number of questions throughout today's presentation. And if I could just hand over to you just to read out those questions and provide response to it's appropriate to do so, I'll pick up from you at the end. No.

29:56 Happy to do that. And, firstly, thanks to to Martin and Dave for going through that. I hope, you know, those listening kind of appreciate the, I guess, the excitement. You know, the fact that we're we we've opened up, I think, a new opportunity here. You know, we we've kinda seized on, you know, the opportunity of these cancer immunotherapies by specifics in particular. There are even try specifics out there at, good discussions at at JPMorgan, but they realize that CRS is an issue. Yes. Their oncology drugs or immuno oncology drugs are are efficacious, but they could be safer. So I think that's where POOLBEG comes in, and we have a a nice niche to to exploit now from the data we've generated and the IP that we've filed. So I appreciate, Martin and and and Dave's time for for going through their perspectives. So, yes, we appreciate the questions coming in. So what we'll do is I'll read out these questions, direct them to either myself, to to David, to Martin, and we we'll take it from there. And we'll, you know, we we'll go through with, you know, as I say, four or five, you know, questions. So, again, appreciate people's time this evening.

30:54 From Niall P, what was the investor sentiment like at JPMorgan conference, both POOLBEG specific and general market mood? I think that's a really good question because, you know, we've been in the kind of the the doldrums a little bit over the previous two years. But there was a little bit of a rush towards the end of the year where, number one, the XBI, the the kind of biotech index, you know, from Nasdaq, increased. I think it was something like 40. Let me get this right. 48% or so between the November 1 and the start of JPMorgan. So the sentiment to biotech has improved, which is really good. I think that's mainly on the back of big pharma getting back into the m and a, you know, the mergers and acquisition by us. Some significant, you know, companies, you know, deals were done towards the end of the year. So I think, you know, biotech in particular, particularly private biotech is a is a cycle where VCs invest, you know, biotech or pharma companies buy their companies and then they reinvest in other biotechs. So it's a cycle. So that cycle had been broken for a little while, but now it's picking up again. So the sentiment, I think, was was quite buoyant, and I think there's optimism certainly for 2024 that that trend will continue.

32:01 But, again, from a POOLBEG specific standpoint, to Dave's point, we you know, we've been discussing at various meetings all through the year about our our ambitions and our strategies. But it was a nice, I think, time gap between the early December discussions at ASH where, you know, primarily clinicians are are in the room talking about POLB zero zero And then a month or so later, we're at JPMorgan where it's the business development teams were talking about. So it's a nice kinda laying the groundwork to carry on the conversation with different groups. But I think there was a lot I wouldn't say there was a lot of nodding in the room when I was talking. I was presenting, showing them our data, our strategy, our ambitions, and they see the CRS issue. So they see this as kinda something that they need to fix because if you look at various pharma's pipelines, and maybe we'll do another presentation on that, but bispecifics, trispecifics, CAR Ts are populated throughout a lot of big pharmas. So they know this is an issue, and they know it needs to be resolved. They do rely on tocilizumab before this, but when they see that there's a small molecule that can be given, like, primary prophylactic given, you know, in advance of treatment to block CRS before it starts, there's a lot of nodding. So I think there's a lot of enthusiasm about what we're doing. And as you say, yeah, those discussions will continue at base.

33:09 Thank you, Nile, for that question. Nathan, is there scope for accelerated route route to use in clinic via FDA breakthrough status based on historic data for zero zero one under its previous use case for rheumatoid arthritis and similar for chronic inflammation? I I'd I'd say kinda yes, but from a different reason. I think that, you know, there is a significant unmet need. We're looking at this even from an orphan drug standpoint. There is, you know, we have a terrific, regulatory colleague, Bruno Speedo, working with here who's having those dialogues with the EMA and FDA and kinda moving things forward like that. We're we're kind of on the ball when it comes to getting this moving as quickly as possible. I'd say running that as Dave's point in parallel with our own clinical ambitions and our partnering ambitions. And, obviously, you know, when we speak with pharma, you know, we can talk about what our regulatory path is looking like. That's something, yes, we're definitely pursuing there.

34:01 Nathan had a second question. Don't be greedy now, Nathan. Any applications for patent allowance for sepsis use case for zero zero one? Really good question. I mean, sepsis is very challenging as as a disease, as an indication. The use of, your zero zero one in sepsis, there's a potential possibility. I think from an IP or patents, your protection standpoint, that may already be out there, so there might be prior art in that space. But I think from an indication, from a disease standpoint, I think, you know, Dave spoke to this, like, the oncology direction is is a significant market. So as happens a lot of drugs, go into somebody where you have a better chance of success and then expand from there. So there could be some, say, an IP standpoint, we'll have to look into that a bit deeper. But, getting success, getting efficacy in in one indication, we can, you know, branch out from there. But certainly, sepsis is somewhere where it's a tricky disease to go after, but huge unmet need without question.

34:57 Thank you for that, Nathan. Robin, seems like all these questions are for me. Maybe I'll, you know, try and find one. Would it be fair to say that the cancer indication is now the central focus of BD activity for POLB zero zero one? I think, you know, Dave did speak to this. I'll take this, Dave. I'll take this. But if you I can take it. You can carry on. I'll I'll take it. I I Go. Go. Go. Yeah. Robin, I I yes is the answer. You know, we in any any asset you're developing where you have or every company has limited resources, both people and and money, you you pick your horses. Right? The you know, I hope you know, we we know from what we've shared with you today, our excite our primary excitement is in the cancer immunotherapy space as an enabler to safer, safer, broader use of these amazing therapeutics.

35:46 We've got the capability to input. We we we we see a huge opportunity, and we've got some great data on the asset. It doesn't mean, to Jeremy's earlier point, that we're uninterested in severe influenza or, a, another life cycle indication. If we have the IP and if we had the collateral to then go into life cycle opportunities, we would certainly love to be in that position. But the answer is yes. It is our priority now given given the amount of work we've done to uncover the opportunity and and work with stakeholders in the space. That's great. Thanks, Dave. I think that leads nicely to a question James has posed, James c. Will POD zero zero one be sold or partnered separately for cancer and respiratory treatments? Or would it be sold, partnered as one drug with multiple uses? And we we've talked about that before. We've discussed internally that there is the possibility. Now pharma prefer to take one drug and do what they want with it. You know, that helps them with their, you know, as I said, their life cycle managements, their regulatory paths, etcetera. But I've seen deals in the past where the same drug, one may be given intravenously, which we believe zero zero one would be applicable for severe influenza.

36:56 But then on the other hand, you know, for CRS in particular, that'll be an orally delivered drug. So you can kinda carve things up in that regard. But, ideally, I think from a pharma standpoint, from a POOLBEG, if the one company the drug and then developed it in multiple indications, I think that's where the, you know, the I think the the world would be better off for for all concerned. And do you want me to take the regulatory question? Sure. Yeah. Okay, Robin. Yes. So, you know, with with all these things, I'll put a I'll put a caveat around it. Of course, we would see Can you read can you read it out first, Dave? Yeah. So the question is what would it what would be possible to would it be possible to design a regulatory trial of POLB zero zero one for CRS? Sufficient to show reduction in the rate of severity of CRS, or would there have to be a survival endpoint? So the the answer, at least from the company perspective, is that is is is yes. We we believe it would would be possible to design a study to demonstrate efficacy on reduction of overall rates of CRS and and certain grades of CRS. So, you know, we'd have to set the parameters parameters and and size of study appropriately to show beyond statistical doubt that we could achieve, you know, what would be clinically meaningful reductions overall and of of severe forms of CRS secondary endpoints, which would probably be more related to health care resource utilization, hospitalization, the use of other interventions and, you know, to to manage these patients who who will end up staying in hospital

38:28 for longer. So I don't believe that you you would need a survival endpoint. However however, I do believe that one would need to further study and confirm that there is no negative impact on on the the therapeutics, we have very strong preclinical rationale for why that would not be the case. And in fact, in CAR T, there is a potential that it could be an enhancement to CAR T quality, but that needs to be looked at. So I think that's a good you make a good point in your question that I think it's less about a survival trial, but it's certainly more about absolutely ensuring you've got at least neutrality on the the efficacy of of the therapeutic, but but absolutely managing the risk of CRS down to a level that clinicians like Martin would say that is clinically meaningful. And and I and we would take regulatory advice, with the FDA and the EMA to to confirm our thinking.

39:24 If we get orphan status on this, which we will consider going forward, I would love that to be one pivotal trial as as we we can can get get for for products for rare conditions. But that that's work we're we're we're undertaking. Yep. Good discussions. Thanks for that, Dave. We'll just take a couple of more. I think, Sparky again, appreciate Sparky. He's he's on these calls regularly and comes up with really good questions. It's a long one, so bear with me. Hi, Jeremy. Well done on progress so far. We keep hearing of near term revenue generating. Where is it gonna come from? Is it all partnering, which we don't seem to be beating big pharma away from the door at the moment? Are we looking for the right deal and being offered lower amounts, or have we had on the offers one would think from a PR from zero zero one, the prospective partner would be afraid to miss out? There's a lot there's a lot to take in there. There's a lot to take in there. I won't do one by one. I'll just say generally, you know, obviously, you know, we we don't or we're not allowed to talk about this stage of, discussions with pharma. But I I will say again, I reiterate what I said earlier on.

40:23 We we've talked to all the big pharmas. I spent, you know, fifteen, sixteen thousand steps a day around San Francisco going from hotel to hotel, up floors and down floors. Again, sharing the data, sharing the information. There is genuine interest, I think, with a CR solution. I did talk about, you know, tocilizumab, which accidentally, this is a Roche drug. It's an antibody. It has to be given infusion, you know, to, you know, to to manage CRS. It kind of it fell into, you know, their labs and that, know, when CRS was being developed by these relatively new drugs, this was out there that's used. But they see that what would be better is a small molecule. What would be better is, you know, orally delivered and then take it from home. So where you know, we can check all those those boxes. Interestingly and maybe it's it's questions alluding to is that, you know, from a rush standpoint, everyone is using their drug even though they a different company owns the the the bispecific that causes the CRS. So we can see the same situation here where every company uses our drug. And I think where you build up that competitive tension is where they see that, you know, we could answer a solution for, you know, one pharma's particular bispecific, but we could use you know, they could use our drug for everybody else's. So they're kinda corny a bit of a market there.

41:32 So I think that, you know, just they are happy with the with the discussions, happy with the level of engagement, and, obviously, we kinda, you know, go up the ladders from there. Jeremy, could I just add Please, Sylvia. So if I'm reading the question correctly, excuse my interpretation, I'm also seeing a a general question there about m and a activity beyond the POLB zero zero one that that Jeremy has described as a, you know, as where we have interest from a a range of partners, both clinical and and pharma industry. But from an m and a perspective, you know, I I think Jeremy Jeremy described when he opened up today, it is a corporate priority to move towards revenue generation.

42:17 And therefore, we're very active in a bunch of discussions now where where we're looking for in in the the or less in the rare and orphan space, where you see high unmet medical need, meaningful assets often alone or with limited competition, and where you see narrower customer base because they're specialized, chronic therapy because these are often genetic diseases. Yeah. And you might say, well, how are you gonna find one of those? Well, we see quite a lot right now because, unfortunately, during the pandemic, you know, companies didn't get fully out of the gate and have found themselves in a tough capital position, or they have one asset, and that's not really adequate from a portfolio point of view. So can you get it gushed out of, you know, one plus one equals three? So we we are we are now you know, if I was to describe it, I'm I'm talking for for our chairman now, Carl Friedel, but if I describe probably top two priorities, it's look for revenue generating opportunity with a meaningful asset in a high unmet medical need, probably rare orphan disease that could be global or US.

43:27 And then secondly Yeah. POLB zero zero one. There There are are other other things things we're we're doing, doing, but I just really wanted to underline that. Good point, Dave. Yeah. Thanks for bringing that up. I know Martin has a hard stop at, 645. I will take one last question. It's for me, Martin, so you're gonna be up to but it's it's a short one, so we'll kinda wrap up as of that. But it says, will pending patents hold back potential deals with pharma? Good question, and the short answer is no. I think farmers know that, you know, sometimes they like to get into the pending patent and shape it themselves. But, I've done deals in the past where you have a pending patent. Once you get that first patent in, you know, obviously, you kinda negotiate for for the grant, but I think you're you've you're on the start line, you know, before everybody else. They can't you know, you've got the the head start as it were. So listen. Let let's wrap it up there. Again, appreciate everybody's time, our first IMC of the year. Thanks everybody for attending. There'll be many more to come as we make our progress. And, again, appreciate the lots of questions and the support for the company. And, you know, as I say, exciting year ahead. 2023 was was busy, exciting, and 2024 looks like it's gonna be pretty much the same. So thanks everybody for for attending, and thanks again, David and Martin. Appreciate your time. Thanks so much. Thanks, everybody. Good luck. Perfect. Jeremy, David, Martin, thank you very much for updating attendees today. Could I please ask investors not to close the session? I should now be automatically redirected to provide your feedback in order that the management better understand your views and expectations.

44:48 This then take a few moments to complete, and I'm sure it'll be greatly valued by the company. On behalf of the management team, POLBEG PHARMA PLC, we'd like to thank you for attending today's presentation, and good evening to you all. Yep. Good evening. Good evening. Thank you, guys. Thank you.