Okay, welcome everyone. It's my pleasure to lead this fireside chat with Pharvaris, and we're very pleased to have CEO Berndt Modig with us today. Thanks so much for coming here and giving us an update. Yeah, thanks, Joe. Good to be here. Thanks for having us. Nice to be in a warm place compared to Switzerland. Exactly. Super exciting time for the company. Maybe you can bring us up to date on all the recent progress and the goals for the coming year to start. Yeah, so we are now very excited about being in two phase III studies ongoing. We announced at the beginning of the year that we had initiated the prophylactic phase III trial, and the on-demand trial was initiated a year ago. That is a key focus for the company. We are really in an execution mode for 2025, also preparing for launch and also building up, looking at infrastructure and supply chain. Another exciting thing that we also announced recently is their intention to potentially expand the footprint of deucrictibant into other forms of bradykinin-mediated angioedema. They announced the intention to do a small study in acquired angioedema, which is a completely different indication for which there is nothing approved today. That is, if approved, could be a potential label expansion of the deucrictibant. Great. Let's talk about the data that you've generated so far, since that'll frame the opportunity. Can you remind us of what does the profile look like and how will this help the HAE space evolve? Yeah, maybe just to set the stage and remind everyone a little bit about HAE. People living with HAE are fundamentally looking for three pillars or three very important things. The first one, of course, is efficacy. The second one is tolerability, safety, and also tolerability in dealing with the therapy in the lifelong setting and the treatment burden and how to live with the therapy and the burden of treatment and what it means to what the impact is on your daily life. Those are three fundamental things that someone living with HAE is looking for. Today, even in spite of all the developments that we've seen in this space, I mean, I was involved in a company that developed icatibant 20 years ago. It's been interesting to observe the different therapy options that have come to market in recent years. Even today, there's nothing that really scores fully on all these three parameters. What we're aiming for is basically the combination of all three. With an oral therapy, the convenience is, of course, obvious, and the efficacy is paramount and also safe to tolerability. We are looking to fill an unmet need to maintain the level of efficacy that we have achieved now with some of the injectable therapies and in combination with the oral convenience. It's a first for a company to be able to have both treatment options in a pill for on-demand and prophylactic use. How do you think about taking advantage of that opportunity and leveraging that unique aspect of the Pharvaris story? Yeah, so yeah, that's a good point. We have deucrictibant, this is our molecule. And so we have with that molecule, it's a B2 receptor antagonist, and it's similar, same mechanism as icatibant, but a completely new chemical entity, new IP. And it's also different compared to icatibant in the properties of the molecule. It makes it suitable for prophylactic development because it has a longer, significantly longer half-life. With that molecule, then we have two distinct products, the immediate-release capsule for on-demand and extended-release tablet for prophylaxis. That in combination, we see that that could give the treating physicians and patients the possibility of making the right decision for the patient, whether you want to be something on demand or you want to be on prophylaxis or maybe different phases in your life. Even if you prefer the on-demand and then you have an important event, an exam or a procedure, you can then take, I think, move over to prophylaxis. It gives a lot of options for patients. That is the idea. Also, the early diagnosed, typically in the adolescent age, start out with an on-demand therapy and can then start with an immediate-release capsule. If they do well, then decide to go to prophylaxis at some point. We see, as you said, we are the only company that offers both products, both for on-demand and prophylaxis. Yeah, exciting. Earlier this year, the company provided guidance for the phase III pivotal data in the on-demand setting. I think it's expected in the first quarter of 2026 that we'll get that data. Can you talk a little bit about how that trial has been progressing and what assumptions are baked into that guidance? Yeah, as I mentioned earlier, the trial was initiated a year ago, and we are very pleased with how enrollment is going. We noticed a difference also compared to phase II. I think that's attributable to the data in phase II that we saw and also bigger, higher visibility of the program in general. The study design is only treating two attacks and with a crossover design, so one with drug, one with placebo. We also allow for a certain percentage of patients to be on prophylactic during the trial, which is then, of course, less disruptive for patients joining a clinical trial and not have to go off their therapy and makes it attractive, especially for somebody who's interested in an oral option. That is going well. As I said, the current guidance is Q1 2026. Okay. How has enrollment been trending in terms of the types of patients that are in the trial? Can you talk a little bit more about that? Just given there are many different prophylactic options available for patients, how does that influence what the event rate might be that underlies and what do you hope to see in terms of a treatment effect? Yeah, I think we would expect to be very similar to the phase II. I mean, of course, as always, you have to see what the actual data tells you, but we expect that to be very similar. I mean, also given the results that we did see in the phase II. What we also do in our trial, which is the same as in the phase II, is to make sure that we qualify attacks to make sure we treat so-called real attacks in the clinical setting in order to provide data to demonstrate efficacy. All in all, that's going good. Okay. Can you talk a little bit more about the primary endpoint and what did you see in phase II and how does the phase III primary endpoint compare and what does that? Yeah. What is the powering assumptions that you're using to design the phase when you design the phase III? Yeah, powering is, I mean, the effect size is expected to be similar. We have not talked in details about powering, but of course, the patient numbers and everything has also been in line with the regulators and to satisfy the powering assumptions. We have also in the phase II trial, we used an endpoint called VAS AMRA at four hours. In the phase III trial, we are using an endpoint called PGI-C, which is a little better. I mean, the endpoints and the measurements in an on-demand trial is essentially measuring the same thing fundamentally. It is asking the patients as an endpoint, do you feel better or you ask the patients to make a score in the case of AMRA on a scale of one to one hundred, how the severity of symptom is. There is also another endpoint that we are including in the phase III, which is called end of progression. What we have seen in our data so far is that the end of progression looks like it is about 25 minutes. That is an endpoint in our protocol that we have not seen in any other studies. I think that also is an earlier, even earlier time point where you can have a demonstration that the drug is acting. Yeah. Is that important for patients? Yeah. The end of progression, I mean, what we hear from clinicians is that that is the first point that the patient experiences that the drug is doing something for them. To have that sense of security that the drug is starting to work is clinically meaningful. That is why I really believe that that is in our phase III study, that is in the secondary endpoint. If positive, we think that that also is a significant differentiator potentially in our label. Okay. Great. Staying with the on-demand for another minute or two, the size of this market has been a bit of a debate in the investment community. I'm wondering, how do you think the market will evolve and how large do you see this market once we have a couple probably new treatment options in a pill for on-demand as well as more prophy options? Yeah. What we have, what else I wanted to mention also in the on-demand, in addition to that, is what is important. You mentioned the icatibant earlier, which is a drug that is very efficacious, but quite a few patients need a second dose. Another step in the demand segment to sort of filling an unmet need for improving therapy is the sustainability of efficacy. I think that's, I encourage you to take a look at the data that we have generated so far on that particular aspect. It's not just only the onset of symptom relief, it's really the ultimate resolution of the attack. We have seen that in the on-demand, as I mentioned earlier, not much innovation has taken place in the on-demand segment in the last 10 years. We believe that an oral option for on-demand is something that is potentially very attractive for patients. We believe that there definitely is a market for on-demand in the future. In the case of the prophy segment, the market, the competition or the sort of a lot of intensity of new therapy options tends to be in the longer acting injectable side versus in the oral segment is just us and another company at the moment. The longer acting, we see the market fundamentally in two different patient profiles. Somebody who is looking to prefer an injectable and maybe see if they can do better with the longer acting injectable is somebody who is fundamentally okay with needles. You have the oral segments, which is a patient profile that definitely would not want to be on needles. I think we see that also in the recent uptake of the first prophylactic oral option that has very clear unmet need for an oral option. We see the future of the market in those two segments and within which then we also think that potentially an oral could be the clearly preferred option. Right. Okay. Can we talk a little bit about your commercialization strategy? How much work have you done on that front? Where are you in terms of preparing for the launch? Yeah. We are now, this is one of the key activities in 2025, which is a very execution year for Pharvaris to develop our thinking about a go-to-market strategy and develop the ideas on supply chain infrastructure, etc. It is our strategy certainly for the U.S. market to go it alone and to commercialize on our own. In other territories, in that evaluation of the go-to-market strategy, we may, if we think it makes sense, work with a partner collaboration in certain markets or territories where it could make sense from a business perspective. Can you talk a little bit about how the product will be presented to patients and packaged actually? Because again, you're in a unique situation where you have both the on-demand and the prophylactic options. I know they'll be launched at different times, but once they're both available, is there any way that the company can take advantage of having both treatment options? Yeah. We expect it to have two different brands. They also need to be clearly distinguished from each other also for safety. That makes sure that the patient takes the right product, prophylaxis or on-demand. I think the whole treatment paradigm is with having the possibility to have your on-demand therapy always on hand. There is guidance that any person living with HAE should always have at least two on-demand acute treatments available to them any time. The ability to, we haven't talked much about the details in packaging, but as you can imagine, a very small soft gel capsule is very convenient to carry with you compared to a prefilled syringe or anything else. The idea is then for the patients then to, whether you're on prophylactic and then you can have, even if you're whatever prophylactic treatment you're on, also to have a small soft gel capsule that you can take anytime should you need it. Yeah. It's very interesting that you have both of these options. Switching gears to prophy then, you recently initiated the phase III CHAPTER-3 study. Can you start us off there by giving us an overview of that trial design and how does the phase III compare to the phase II? Yeah. The phase III trial in terms of the protocol is looking at the reduction of attacks compared to placebo. It is a very straightforward trial design and two-to-one randomization using the 40 mg dose from the phase II. In the phase III trial compared to the phase II, we're also moving from BID in phase II with the soft gel capsule to our XR, extended-release tablet formulation, which is then the prospective commercial formulation for prophylaxis in phase III. Okay. How does what you saw in phase II frame what you'd like to see in phase III? Yeah, we saw in the phase II trial, we saw a very good level of efficacy, around 87% reduction in attacks in the primary endpoint and even higher in the percentage of over 90%. I think it was 93% or 96% even in the moderate to severe attacks. In that territory, of course, it would be our ambition to also have in our phase III trial. I think that that is the level that you also see now already in the current approved therapies for injectables. I think that, as I said in the beginning, patients are looking for a high level of efficacy in combination with the lower treatment burden. Okay. You mentioned that in extended-release tablets being used in the phase III. Can you talk a little bit more about what we know about how that behaves and could that influence the results in any way relative to what you saw in phase II? It's a different formulation. We have looked at the PK profile of that. If you have an opportunity to take a look at our corporate presentation, you will find a slide in there that shows you the PK profile of the XR formulation compared to the XR. The objective here in this setting is to maintain exposure level above the plasma concentration that's associated with therapeutic efficacy as defined in our case as EC85. It's about 13.8 nanograms per milliliter. What you see in the PK profile of the XR is that it maintains that exposure over a 24-hour period. Whereas in the phase II trial with the BID, with the on-demand capsule, it's more like a yo-yo effect. You go up and then you go down at the 12, of course, because the on-demand has a shorter duration. It goes up again. You get closer to the trough level maybe in the BID versus with the extended- release. That gives us some confidence that that would also be seen in the phase III trial. There is another trial that you can take a look at in more detail in our corporate deck. It is an investigator trial at the Amsterdam Medical Center in the acquired angioedema with only four patients. It is a very small trial. In that trial, the patients took the XR formulation and have seen basically no attacks in the period except for one attack right at the beginning. In over 18 months, these four patients had zero attacks. That is another indication that suggests that we will about the outcome of the phase III. Of course, if the trial as such has to tell us what we'll see when we get it. Right. Exactly. Very interesting. I think CHAPTER-3 is designed to enroll around 81 patients. Given that's less than pivotal studies for several other key trials in the space, I'm just wondering if you can talk about how you're able to get alignment with the FDA on that feature and how does that influence the powering? In fact, as you pointed out, 81 patients in 80 sites globally. It's not really powered. It's primarily powered for safety and less so for efficacy because if you compare the number with the phase II trial in the 40 mg, we had two dose groups in the 40 mg. In the phase II trial, we had something like 10 or 15 patients. We had a P value of 0.0008. Now we have 80 patients in the same one dose group. I think for purposes of powering, I think we are in a good spot there. As I said, it's more focusing on building the number of patients to build the safety database. That makes sense. Okay. Earlier this year, you provided us guidance that data from CHAPTER-3 would be out in the second half of 2026. I think there is a 24-week endpoint. This implies full enrollment in the first half of 2026, which is a little bit over a year. Does that sound right in terms of the progression that we should expect for CHAPTER-3 execution? Yeah. I think if you compare it, the prophylactic trial versus on-demand, once you have the last patient in, it becomes much more predictable when you have the endpoint, of course. The key there is enrollment. Once you hit the 24 weeks after the last patient in, then you are at your normal evaluation of the locking databases and all that stuff. I think that is sort of how you should look at it. In the on-demand trials, enrollment is the first step. The second step is actually investigating the attacks. That adds another variable that you do not have in the prophylactic trial. Right. What's going on in acquired angioedema? You alluded to some of the data that you saw there. What's the company's plans to does the company have plans to develop? Yeah. We now see an intention to also do a study in acquired angioedema. We are currently in discussion with the regulators about the details of such a study. What I can say is that it's expected to be quite a compact or small study and also pivotal so that if it works out, the idea would be then also in terms of timing could be similar to the hereditary angioedema program. If approved, then could be an expansion of the deucrictibant label. Acquired angioedema is an indication for, it's a form of bradykinin-mediated angioedema for which there is nothing approved today. It's estimated to be about 10% of the HAE market. These patients are referred to HAE treating or allergists or patients treating HAE patients from other doctors because the symptoms are caused by underlying disease in autoimmune disease or lupus and other underlying disease. It causes dysfunction or C1 deficiency, then results in acquired angioedema. It is basically mechanistically the same as the hereditary form. Right now, the patients are there's nothing approved. Patients, the most common treatment is icatibant actually for these patients. Interesting. Is there something about the bradykinin mechanism that lends itself particularly well to this indication? I mean, some of these other bradykinin mediated, I mean, it's also relatively complex that there is a presumption that bradykinin inhibition could have an advantage there. It's not necessarily the case, but it could have a, there's been studies looking at other forms of angioedema or surveys, I should say, that suggest that bradykinin inhibition is a good way to deal with this. It seems like you'd have separate on-demand and profit studies like you have in your current HAE program? Yeah. That's something we are discussing, exactly how that would look like or if you have like story, we want to roll over to the next. This is the exact design of this, to be more to talk more about later. I think the point is that it's a small trial. It's expected to be pivotal. The number of patients in small trial also doesn't have, it's not a huge impact on our cash usage. Right. Okay. How about we talk about the commercialization strategy and what kind of resources do you need to bring to bear in order to be impactful and be able to commercialize this? Yeah. Yeah. I mean, this is a space where the commercial footprint can be very compact in terms of focusing on the key physicians. I think it's something along the lines of order of magnitude, like 50 people in a commercial organization in a market like the U.S. It is relatively compact and certainly doable for a small company. How do you think about, I know it's early, but how do you think about pricing, particularly because you have both on-demand and prophylactic? Yeah. Yeah, of course, as I said, it's early to talk about pricing. We can also not give too real guidance there, but of course, I mean, of course, we would be looking at the pricing to value and the benefit for patients. Okay. I mean, basically, the expectation to what you see currently today. I think this is not a disease where I think you would be competing on price. Yeah. There's a lot of precedent for healthy price levels here. Okay. Great. Anything we didn't touch on that we should make sure that we mentioned before we go? I think, I mean, what we think is key is, of course, I think that the concept of two products is a factor that makes us a little bit different in the space. I think also to really understand what patients are looking for, it's not just sort of one particular endpoint or one particular list. It's really the totality of the patient experience. The patient today could say that they're doing well, but what does that really mean? It means that they're doing okay with what they have because there's nothing better out there. I think one last point I'd like to make is that sometimes there's a debate whether this is a sticky market or not. We think that it's not a sticky market. I think you've seen data that there is quite a bit of churn. Data has suggested about 5% of the patient population is looking for switching therapies presumably because they'd like to try something better that works better for them. I think the key point here is also that HAE, there is no real sustainable first mover advantage. It's really about providing the best therapy for patients. That will be the success for any company in the end. Yep. That makes sense. Thank you so much, Berndt. Really appreciate the update. Yeah. Thanks. Thank you, Joe. It's good to see you. Yeah. Likewise.