Pitch over there. Yeah, that wasn't me. That was the conference organizers. Great. Great. Okay, well, thanks so much, everyone, and welcome to the next session. I'm Steve Seedhouse from the biotech team here at Cantor. And it's really a privilege of me to introduce our next presenting company, Pharvaris. I'm joined on stage by CCO Wim Souverijns and the CMO Peng Lu. I'm really looking forward to the conversation. Obviously, Pharvaris is developing deucrictibant, a very exciting molecule for HAE. And in lieu of me saying more, I would love to maybe pass it off to either Peng or Wim, if you'd like, just to make some opening comments and introduction to the company and to yourselves and sort of where the current state of affairs is at Pharvaris. And then we'll get right into Q&A. So, and thank you very much for welcoming us here. My name is Wim. I'm the Chief Commercial Officer. So Pharvaris, we are a late-stage pre-commercial biotech company. We're developing one active ingredient with two products for both the treatment and the prevention of bradykinin-mediated attacks. We've got a very exciting period ahead of us because we have data readouts at the end of this year, Q4. We'll have filing next year. We have another phase III readout the second half of next year. So we're all gearing up for getting these products to patients and here together with Peng. Yeah, as we can hear me. Great. This is Peng Lu here. I'm the Chief Medical Officer joined Pharvaris around 2020. Just like Wim mentioned, it's a really exciting moment to witness the compound really first entering to human until this stage. We target to really see how about the top-line result for our first indication on demand that Q4 this year, and also exciting that we also will initiate a new trial not only for hereditary angioedema patients, but also for acquired angioedema patients by the end of this year. Hopefully, eventually we can bring deucrictibant for the bradykinin-mediated angioedema patients, not only provide the next generation new breakthrough, hopefully that for HAE patients, but also can address type 3, normal C1 patients, and also acquired patients who don't have any approved treatment yet. Great. Yeah, and that'll be very interesting, obviously, to follow and exciting development for the really unaddressed populations here, the bradykinin-mediated angioedema. It's certainly unique to you guys. We'll come to that. Certainly want to focus also on the more regular way HAE studies upfront. Also the space in general, really exciting time. There's been a lot of new approvals. I think that's really a rising tide situation in terms of just more options for patients. Would love to get your perspective upfront on just the positioning of deucrictibant in each of those markets and whether that's changed at all or just your current thinking on sort of how your positioning stacks up to the current market landscape, including the emerging new treatments. I would say that if we confirm our phase II results in the phase III, then we're going to be very well positioned to be a leading product for HAE, both for on-demand as well as for prophylaxis. I think there is a clear expectation, there's a clear desire in the community for effective oral treatments. I think that what we have shown till now really meets those demands. On the on-demand side, we have a very comprehensive addressing of an attack from very early onset to really getting quickly to complete attack resolution and doing that with a single dose in most of the cases. For prophylaxis, I think I was a bit surprised when we read out our phase II data because we hadn't anticipated that injectable-like efficacy, the ability to deliver the same efficacy seen with injectables, Takhzyro in particular, at that time. And so if we confirm that in our phase III, I think it'd be going to be an extraordinarily powerful tool to really change the landscape and really make oral therapies the dominant use in prophylaxis. Just on the overall market, I guess, across both, obviously there's a new launch in on-demand that's oral. The oral market vis-à-vis Orladeyo in prophylaxis has been quite resilient to new entrants. And actually the growth itself has been quite resilient. Has that been as you expected? I mean, obviously you went in the oral route. And then in addition to that, I'm curious if, like, why hasn't there been more innovation on the oral side behind Pharvaris? Because clearly that's an opportunity that's been resilient. And it looks like you guys are the sort of last and best oral option in development here. Yeah, I think it's very interesting. If you would have run market research before the launch of Orladeyo, you would probably never have predicted their success. Because if you talk to doctors, if you talk to patients, the first thing that matters is efficacy, efficacy, efficacy. Reality has shown that actually a lot of patients out there are willing to sacrifice some of that efficacy and tolerability for an oral option. And so I think that bodes very well for a product like us, where we kind of offer both the efficacy, tolerability, as well as the convenience in one package. So I think that is important. There is a clear desire for that. Why haven't others done it? Well, I can tell you that Pharvaris was founded in 2016, but the actual seed of the company was planted in 2008. Because at that time, our Chief Scientific Officer from Jerini, the company that developed icatibant or Firazyr, was at a patient meeting and spoke to patients. Patients said, "Oh, thanks so much to have Firazyr because it's a subQ option rather than an IV." But in the same sentence, they said, "Can you please make us an oral icatibant?" So here in the way, thinking, if you go through the patent literature, all the big pharma companies have tried to make an oral B2 receptor antagonist. Nobody succeeded until Jochen and his chemist, Chris, were actually able to find a scaffold that was able to do that. So to answer your question, why don't we see more? It's very difficult. It's not trivial. Yeah. Absolutely. I just want to mention that because we target a B2 receptor, the receptor itself has a large pocket that, you know, that the peptide can be potent and still stable there. But the small molecule is indeed a very challenge. That's indeed that we mentioned several companies, even big pharma tried, but failed. That's exactly you can see our name is deucrictibant, means deuterium. That's innovation. We use stable compound and create crict is crystal that our chemists use very three steps that innovation there to generate deucrictibant is not only highly potent, but also is druggable and have a great compound until we're today. Fantastic. Let's put a pin in and discuss the phase III on-demand therapy data, obviously, because that's upcoming in fourth quarter. Generally speaking, I guess to start, what type of product profile are you hoping to demonstrate ultimately in the phase III on-demand trial? I think that Wim have already stated there. We always believe we can bring injectable-like efficacy, placebo-like safety, and great convenience that as a new oral treatment for both on-demand and prophylaxis. If we relate to the on-demand treatment specifically, you know, Wim already mentioned that we really have high confidence. We can confirm all the observations from our phase II trial. That means once deucrictibant can treat on-demand, you know, attack there, that it can bring that fast onset of symptom relief. We expect the patient the first time can feel that the, you know, that attack progress be halted within 15 minutes- 30 minutes, then can feel the symptom relief that between 1 hour and 1.5 hours. That's also the primary endpoint we will assess in our pivotal trial. Meanwhile, the patient may be expected to see the attack severity reduction from severe to moderate, moderate to mild between two to three hours, and also eventually achieve complete that symptom resolution, no any symptom anymore within 12 hours. So that's a profile we target to be confirmed with our pivotal trial. Also, we expect it over 85% attack will be resolved completely with a single dose of deucrictibant treatment to really show very good sustainability and durability there. Just on the two, so the onset to symptom relief, obviously, which is the primary endpoint, as you mentioned, and would sort of be maybe the predominant data that would appear in a label. Can you talk about that versus the sustainability of effect and complete resolution? Do you think you'll be more differentiated versus competition, whether it's injectable or oral on one or the other or on both? Or what would you emphasize and what do regulators emphasize, I guess, in terms of sort of which is more important or which is more salient? Excellent question. Actually, there'll be a great discussion with all the regulatory agencies there. But from our trial design part, from pivotal trial, we covered all the endpoints, either in the primary endpoint or key secondary endpoint. If compared to all the standard of care or even act early, just approved here, that we've already included from time to onset the, you know, PGIC a little better, as mentioned, and also several that attack severity, attack resolution, single dose use in our trial design. Therefore, that we are in a very good position to include all these data, efficacy data in the label. Meanwhile, I also want to highlight here, we also have an innovative endpoint we invent ourselves. It's end of progression. So this is a first line I mentioned to show that how fast deucrictibant can work. This we also included in our key secondary endpoint, but we'll be pending on the further discussion with the agency to be unique that, you know, ethics assessment in the label. That would presumably, you'd expect that to occur within minutes, I guess even, right? I mean, how early are you assessing that? Exactly. Very good point that if from our pharmacokinetic profile and from our phase II that post hoc analysis, we expected it will be between 15 minutes -30 minutes. Okay. Can you actually comment on just the assessment of attack progression and then ultimately resolution? Like how often is that performed in phase III? And And is it the same as what was done in phase II in terms of assessing symptoms? Exactly. It's very consistent from our study design that phase III compared to phase II. Only difference is that because we try to capture the different endpoint here, we have more intensive assessment in phase III. That means we have more time points to capture that response for onset, for the attack severity reduction and also resolution there. Therefore, indeed, it's a challenge trial and we have very dedicated site staff and patients there to ensure we get a high-quality data. Okay. And more frequent, including at those very early time points in the first hour, importantly. I can give you an example here for the first of four hours. The first time point is 15 minutes, then every 30 minutes up to four hours, then every hour assessment up to 12 hours, then every two hours up to 24 hours. You can tell that 25 time points within 24 hours is indeed quite intense. Indeed. Okay. And then, so assuming positive data, can you talk about just the preparations the company is making to file for approval? How fast post data do you think you can file? Obviously, a competitive space, time is valuable here. So any guidance or sort of loose expectation of when you could launch this product ultimately if everything goes well? Maybe I will start and we hand it over, Wim, regarding the launch. Currently, we expect the top-line data available in Q4, then that really depends on the top-line available time. We expect to file that in US first and it will be the first half of 2026. If no surprise, early 2027, we will prepare for launch. Yeah. So we are. I've been financially very prudent. So at the moment, we have a very small team, but virtually every one of them has very longstanding relationship in HAE. So both our GM for the US, our sales and marketing, people in market access, patient advocacy, medical affairs, all of those have been working for a long time with HAE. And that's quite peculiar and very important in this area because HAE is a relationship-driven therapeutic area. I used to work a lot in hematology, very different. Here you really need to be connected. So these people have been working on building the relationship at the top level, tier one, starting in tier two now. And so from next year on, indeed, we'll be starting preparing for our commercial launch, expanding the organization and really making sure that we get coverage up until tier three level doctors in the U.S. Okay, and ultimately, you mentioned that the U.S. filing, I think being first, ultimately, is Pharvaris planning on launching deucrictibant globally or are you looking to? We've seen some partnerships recently in the space, so there's certainly some strategic interest, but how are you thinking about that? So the first principle for us, which is the most important, is to get this product to patient as soon as possible in the best possible way. And so for the U.S., it's very straightforward. An organization of less than 100 people, you can really commercialize a very attractive opportunity. Outside of the U.S., particularly due to the pricing level, which are very different in the U.S., it's much more challenging. So that's why we're looking at different options, including partnerships to do that. In the meantime, the things that are on the critical path, for instance, all the preparations from a market access perspective, these are happening so that we can slot them in in whatever scenario that will unfold later on. Great. Maybe we can for now, certainly we can come back time permitting, but would love to talk about the prophylaxis opportunity as well because that's potentially larger, certainly as today, although we'll see how both segments sort of evolve. But one of the big changes you've made clinically here, obviously, in the prophylaxis program, which I think would be expected to play in your benefit, is the extended-releas formulation, which you didn't have available during the phase II. So can you just talk about your confidence in that formulation change and ultimately how you think that will impact safety and efficacy in the prophylaxis setting versus the data that you generated in phase II? Yes, that's indeed excellent questions that we will use extended-release formulations at 40 milligram once daily there that in our pivotal study and before that we use that, you know, that the new formulations that in our pivotal trial. Actually, we conduct the five different pharmacokinetic profile and pharmacokinetic studies in healthy volunteers to ensure that the pharmacokinetic profile of extended-release formulation is consistent with our expectation compared to the 20 milligram BID twice daily that we used in the phase II. Actually, the PK profile for extended-release formulation further optimized the peak and the trough ratio and potentially reduce any, you know, long-term chronic use that safety concerns and also increase the trough there and further potentially boost efficacy. That's from PK pharmacokinetic profile. In addition, we have four acquired angioedema patients have been used extended-release formulation up to two years. You know, for these four patients, all of them are frequent attacker patients before that on deucrictibant treatment. After these four patients on the extended release formulation, only one patient reported one mild abdominal attack on day two. After that, all four patients attack-free up to two years and also deucrictibant is very well tolerated, so therefore, not only PK side, but from efficacy and safety side, we are quite confident that extended release formulation is most appropriate and feasible for prophylactic use. Those four patients are obviously a great precedent to gain confidence from. How did the bradykinin levels compare in those patients versus like any of the typical subgroups of HAE patients? Yeah. And because it's competitive inhibitor, right? So are they a good surrogate for the PD at the molecular level that you would expect in HAE as well? Excellent question. Here maybe I can briefly introduce with acquired angioedema patients. We talk about it because we are very familiar with hereditary angioedema patients, especially type one and type two. This is due to the SERPING1 genetic mutation, then hereditarily have either lack of the C1 inhibitor, that amount of function there. Acquired angioedema, they have very similar symptoms of HAE patients. They also have the low C1, that amount of function there, but it's not due to hereditary disease. It's due to the underlying disease. For example, if lymphoma patients or lupus patients, autoimmune patients, they increase the consumption of the C1. So therefore, generally the pathogenesis of acquired and HAE patients are very similar. It's due to C1 deficiency there. It's one is due to genetic mutation, the other due to underlying disease. Therefore, that we believe is a very good surrogate for the HAE patient assessment. Got it. Have you, just on the point you made on the pharmacokinetics and the trough concentration obviously being higher and more persistent, have you been able to model, like do you have a way to predict or project or guide people in terms of how that would translate to attack rate? Like just how much benefit could that afford you on efficacy? Yeah, for the trough level currently for extended-release formulation for the 40-milligram once-daily, we expect trough level is about two to three times higher here. We do not guide that direct translation, but meanwhile, we just want to mention that the high trough there can cover the variability from the patients. As we know, a lot of drug development, right, from phase II to phase III, always being questioned how about the variability of the patient population and how about the, you know, the global use, global trial. Therefore, that if give us that definitely sufficient buffer from phase II to phase III development, that's exactly our guidance for efficacy. Will be our phase III pivotal trial efficacy will be at least comparable, but have potential even further boost attack reduction, the pivotal results. Okay. I'm fascinated by this market and want to ask your opinion on just the various segments of it and just how you think deucrictibant is going to fit in specifically within them. So you have like patients currently on injectable prophylaxis. You have patients currently on Orladeyo oral prophylaxis who may be doing well because they've stayed on it. Then you have patients who tried Orladeyo, it's not as effective, it looks like, as deucrictibant, they've discontinued it. That's a substantial number of patients. And then of course, you have the new switches that maybe are going on to some of these new therapies. So where do you think deucrictibant will sort of land in terms of preferential use in those segments? Do you have a certain segment that you would target more directly with your marketing effort early on? Talk to me about that. For us, there are four segments and I think you kind of called them out already. Our belief is that prophylaxis at equilibrium many years from now will be led by oral products. And the reason for that is that we anticipate that oral products will become the first line therapy for prophylaxis. Today already we know that Orladeyo takes the lion's share of the new patients in the U.S. There are about 150 new patients -250 new patients every year, HAE patients. Those also flow through to prophylaxis. And with deucrictibant as a profile, we believe that we have a very good shot at taking the majority of those patients. And if you take the majority of those patients on a year-to-year basis and we confirm this very high efficacy in the phase III, we anticipate to see much less dropout than we've seen with Orladeyo. And so over time, you build up a pancake. It becomes a really significant share in the market. And because of our first line ability for orals without dropouts, we think that ultimately orals become at least 50%, 55%, maybe 60% of the total market. In the second segment, so that segment is the first segment we want to go out. The second segment is the patient you mentioned. By the time we will be launching, about a thousand patients will have tried Orladeyo and come off. David is in the audience here. If we hit a thousand patients in the first year, we'll be very, very happy. So second segment, absolute clear target for us because there's patients that have shown they won't have an oral. They weren't satisfied. We can maybe offer them something better. Thirdly, you have the Orladeyo patients. And you're right, in brackets will tell you these patients are sticky, they're stable. If you look through the real-world evidence of patients on Orladeyo, you still see that they have half to one attack breakthrough attack per month. Now that for me is not enough. We can do better. And for those patients, we really want to go aggressively after them and saying, we can give you the same oral, but the efficacy that you see with injectables. And I'm sure there will be a residual part of patients that will stick to Orladeyo because they've been there, they've found something, but others will be willing to switch. And lastly, I would say the injectable segment. There's probably a lot of patients out there that stuck with Haegarda or Takhzyro and didn't move to Orladeyo because they didn't want to sacrifice on the efficacy. But if they have an option that can give them the same efficacy, they might be swayed. And so that's kind of our strategy to go after these markets. The last segment is probably the hardest and we might kind of phase that a little later. The other ones are really very early on, we're going to be very aggressively going after. What do you think of? It's a great overview and thanks for that. What do you think of? I have this hypothesis that now with the availability of oral on-demand therapy and so that's already available now for patients and presumably deucrictibant will get there as well sooner than later, as you mentioned early 2027, that that would be a tailwind for oral use and prophylaxis as well because this is the first time that a patient would be able to just take an all-oral regimen. They might be able to switch to Orladeyo, but I'm going to have breakthrough attacks and I'm going to need an injection at that point anyway. That would be maybe once a month or once every other month. That changes when you can just say, well, let me just go all the way to a pill. Do you see it the same way? Is there any evidence of that, maybe even already post the recent oral on-demand launch or even before that, just a sense of that dynamic? There is already an expectation and a desire from the community for that. I mean, three years ago, one of the key conferences in HAE, they called the C1 Inhibitor Workshop in Budapest. One of the KOLs got the question when he presented our data, our phase II data. He got asked the question, so does that mean that we're going to have the same product for prophylaxis and on-demand? And he said, isn't that what we're all dreaming of? So I think that's really something that can radically change this market because as you rightly said, if you're on Orladeyo and you have to take Firazyr, you still have this injection. Combining that with an effective oral, that makes the whole different life. And the sort of patient demand dynamic and on-demand, once two orals are available, deucrictibant, when it enters the market will sort of be competing with another oral as it will with Orladeyo, but the efficacy difference there, I think I would argue is much more profound. It's just obvious that deucrictibant is more efficacious. It may be closer, one could say, in on-demand. Do you think it's a situation where patients will sort of try both and see what works best for them? And if in fact your effect is more durable, maybe you get complete resolution more rapidly, they'll just feel that and they'll know it and they'll gravitate to deucrictibant? That's absolutely how we anticipate it. On-demand is relatively easier to switch because you don't have a prescription for a whole year of drug. You got a prescription, a month, two months of therapy, you go back to the doctor and then you can say, oh, why don't you try the other one? So that ability is definitely playing in our favor in on-demand. So we anticipate that it clearly will do well because there's a huge desire for orals, but I think it doesn't preclude us from kind of, if the product effectively is perceived better by the patient community, to really make that switch. And also since our on-demand we are launched first, right? That on-demand, the patient can feel really that quick, you know, that response there is also paved a good way for patients to consider later on adapt to the prophylactic use, right? It's about only nine to 12 months apart. In the last couple of minutes, let's circle back to just the bradykinin-mediated angioedema, the orphan drug designation, and then you have an assay obviously that you presented at a recent analyst day that sort of helps you identify patients in the broader bucket of bradykinin-mediated angioedema. So you've been approaching this in a pretty comprehensive way. I'm just curious if you have an expectation ultimately that would manifest in an initial drug label either with FDA or ex-US, or would this be something that you would expand the label into with data down the road? Help us understand strategically how Pharvaris is going to leverage that angle to differentiate the product label or the product profile. Yes, it's indeed a very interesting and tough question here. And ideally, you can see all we map out our development plan. We would like to target that for prophylactic indication. If possible, we will target bradykinin-mediated angioedema indication. It will be strongly differentiated from the current indication part or other competitors. That's exactly that we currently have the acquired angioedema that the trial initiated by the end of this year parallel to our prophylactic trial. Meanwhile, we also included the normal C1 patients, as you mentioned, in our pivotal trial for HAE. Therefore, we covered all the major subtypes of the bradykinin-mediated angioedema part. We move this way because if you see, even though it's a very crowded market, no matter approved treatment or that under development, all the current compound or treatment options are targeted plasma kallikrein pathway, upstream there, upstream there. And the deucrictibant is the only one to target downstream to block bradykinin and B2 receptor. We can cover not only plasma kallikrein dependent pathway, but also plasma kallikrein independent pathway there. That's a huge differentiation compared to other treatments and also can bring really the benefits for the patients who are not, you know, respond to any treatment yet. That's exactly we work hard there. Mainly it's to consider what the patient needs. Indeed. And the study you mentioned that's enrolling that broader population, that's a CREATE study and. That's CREATE study. That'll start later this year. Do you have a sense? I'm good. Do you have a sense of just when data would start to accrue from that, how you'd be able to package that up and present it if it would inform potentially an HAE filing? I would imagine you expect that you'll be able to find patients pretty readily for that study. Is that fair? That's fair to say because the CREATE study is a smaller study that we're only driven by efficacy assessment. And meanwhile, that's because currently there is no any approved treatment, no any, you know, that AAE trial available, therefore the competition is much less. That's exactly if we also shared the study design that in the past conference year. So we will start for that trial prophylaxis first, then go to on-demand. That's exactly what we mentioned for the prophylactic indication part. We think we do have a hope to target a bradykinin-mediated angioedema indication. Just in general, do you have a sense of maybe the relative size of that group of patients versus the currently on-label HAE patients? So there's a very good paper published just two months ago, I believe, from the HAEA on the US epidemiology, which showed that in the US, there are about 9,700 patients that are using therapies for HAEA. They did an adjudication and they found that about 7,600 are HAE patients, both type 1, type 2, and type 3. It means that about 2,000 patients are not HAE patients. We assume that at the moment, about 800 of those are acquired angioedema patients. Now, that is the tip of the iceberg potentially because the only reason why these patients get picked up is that a doctor who's treating lymphoma or who's treating lupus has the reflection in case of an angioedema attack to send this patient to an allergist. Then they get treated. We were on that board in May. One of the doctors said, yesterday I got a patient in, he had attacks for five years before the hematologist sent them to me. So there is no, there's very little awareness, very little knowledge among these different specialties about what bradykinin-mediated angioedema is and acquired and that it can be treated. So by having a development program and potentially a label, we'll be able to communicate, promote that, build more awareness. And so potentially there might be many more patients coming out of the woodwork than what we currently see. It could be very meaningful, yeah, and obviously we're looking forward to following the progress there and Pharvaris is leading the way, so kudos on that. We're up on time, but we'd just like to say, obviously we're excited about the upcoming data in the fourth quarter and all the progress that you'll be making thereafter and looking forward to following along. Thanks so much for joining us at the conferences here and thanks to everyone on the webcast and in the room for listening in. Thanks, Steve. Terrific. Thanks, everyone.