O ne of the therapeutic analysts. Joining me on stage are Peng Lu, Chief Medical Officer, and Wim Souverijns, Chief Commercial Officer of Pharvaris. I hope I got that right. Perfect. I swear I did not practice. All right, so since I officially do not cover the company, maybe it'll be very helpful for the audience to get a quick overview of the company and where you are. Excellent. I can take that one. The company was founded by people that have a long history in hereditary angioedema. You might be familiar with FIRAZYR or icatibant, a drug which was commercialized today by Shire, Takeda for HAE. And the inventor of that drug was our Chief Scientific Officer, Jochen Knolle. When they sold the company to Shire in 2008, he walked away with the idea, it's great to have an injectable to treat HAE attacks, but wouldn't it be fantastic to have an oral version? And so it's been in his brain. He worked with his chemist. And then in 2015, they found an idea. They thought, we can do this. In 2016, Pharvaris was founded with the purpose to really bring, as we say, pioneering science for patient choice, but ultimately to bring to the market an oral therapy for hereditary angioedema. One of the interesting things that Jochen did is that he not only developed a drug or wanted to develop a drug for treatment of HAE attacks, but he also was smart enough to develop two formulations, which gives us an opportunity now to have one active ingredient under two brands, two products, one to treat attacks and one to prevent attacks. Currently, we're in our phase III for both the on-demand study, and we'll be initiating by the end of the year the phase III for prevention as well. Awesome. So can we just talk about the safety first, given the experience that you have both in the phase I and II setting, because that, I believe, was one of the concerns? Yes, that's an excellent question. We were always being asked the safety because, as mentioned, B2, we are actually the first B2 receptor antagonist to use for long-term prophylactic treatment compared to all the other competitors. Competitors Competitors always target more upstream about the plasma kallikrein or factor XII, the pathway there. And so far, as we mentioned, that we have two different formulations, and for on-demand and for prophy, that no matter for on-demand and prophy, the drug was very well tolerated, no matter in the healthy volunteer studies or HAE patients. So far, for example, for healthy volunteer, we've already had over 300 healthy volunteer data. And for HAE patients, we also shared the data for over one year, long-term safety data from HAE patients. Overall, that the drug was very well tolerated. We highlighted again. And also, we did not notice any drug-related adverse events or signal there. Got it. So we've been working on this HAE landscape for a while now. One thing that comes across in every physician conversation we have is patients are looking for convenience, and the efficacy seems to have maxed out. So given that paradigm, you have two really interesting programs. So how are you thinking about the commercial landscape when you first launch the on-demand first and then come in with the prophy? It's a great question. I would probably give a bit more nuanced answer than this just about convenience. I think we've seen tremendous progress in HAE over the last 15 years. It took a long time before the first therapy actually got to the U.S., the C1 inhibitor. Then we started with on-demand. We had different products coming there, C1 inhibitor, KALBITOR. FIRAZYR became the standard of care there. Then with the arrival of prophylactic therapies with HAEGARDA, the sub-Q version of BERINERT, as well as then TAKHZYRO or ORLADEYO, we've seen a ton of advantage for patients. I mean, this is a rare disease. There are less than 10,000 patients in the U.S. Having so many drugs on the market is really fantastic. However, the reality is that till today and in the foreseeable future, people living with HAE and their doctors, they have to make an uncomfortable choice. If you're really set on, I want to have the most efficacious therapy, you are required to inject yourself. Whether you do that every two weeks, every month, or maybe in future every two months, you still got to inject yourself, and me personally, I will avoid every injection I can get. I hate the dentist for that reason. On the flip side, if you say, for me, it's more important to actually avoid the needle and be having a more convenient therapy, you don't get the efficacy. You don't have a therapy today that can show injectable-like efficacy in an oral form. So the market, I would say, if you're a patient that is focused on efficacy, you want to have that convenience. And so indeed, bring to market an oral product like deucrictibant, which has the potential to be showing injectable-like efficacy, is really an interesting alternative, valuable proposition. But at the same time, for the many patients that have shown to us that they want to have an oral, there the game is actually efficacy. And again, with what we've shown till now, we think we can compete very well in that space as well. I think the on-demand side is slightly different in the sense that on-demand, it treats attacks. Now, whether that attack is mild, moderate, or severe, it's a breakthrough attack, or you're just on on-demand therapy, fundamentally, clinically, they're all the same. So what you're looking for with on-demand is the most optimal therapy there. And what we have learned from the community is in our research, in our day-to-day talking to patients and doctors, is what they're looking for in on-demand is very rapid onset of symptom relief. That's psychologically enormously important. But they also want to have quick resolution of the attack so they can go back, move to normal life again. And finally, they want to have the confidence that they can do that with one administration. If I know that one pill is going to work, that's really my optimal scenario. And I would say, if you look at the data that we've shown in the phase II and also in the long-term extension study, we're very well positioned to, in that on-demand space, really also be a leading figure. Got it. So on the on-demand side, the way the current market is, I believe it's about 70%, at least in the United States, it's 70% prophy, 30% on-demand. And it's sort of moved from 60% prophy to 70%. Do you think we are sort of at that cusp now where that 30% is going to stabilize, especially with the availability of oral fast-acting on-demand therapies? Yeah. I think it's a very interesting situation. I want to answer that with a story in a second. But fundamentally, if you look at the guidelines, what the community, the HAE community wants to achieve is that no patient should suffer any attack. That's the mantra. That's the mindset that they have. And that's only possible with prophylaxis. You can't do that. If you just sit there, don't treat, and wait till an attack is happening, you're going to have attacks. So I think that is a driver for this shift from on-demand to prophylaxis. And if you look at some of the market data, you see that this is happening. It's slowly. We're at the 70% right now. We're not going to go to 95%. I don't believe that. Are we going to 75%, maybe 80%? We'll see. It's slowly trending in that way. I'll tell you a story. I met with a patient a couple of years ago before we had our phase II data. And he was on lanadelumab prevention. And he told me, he said, if your drug, your pill gives me confidence that it can really address an attack immediately, I'll switch tomorrow from lanadelumab to your drug because I don't want to have this drug in my body all the time. In the same sentence, he said, but my daughter, who's in her 20s, she had a horrible high school time because she had plenty of attacks treating with icatibant. Her life was saved by lanadelumab. To switch her from lanadelumab to anything else, it's going to be extremely difficult. So ultimately, what it means is HAE is a very personalized condition. People living with HAE make their own choices. You can't just say all of them will go left or right. You really have to profile. You really have to segment. And you really have to speak to their psyche, to their mind, what is important to them. And so in that sense, there will always be on-demand just because any patient needs to have any on-demand on them in case of a breakthrough attack. But we do think that the majority of the market will really move to prophylaxis. Yeah. I also want to add one bullet that just like we mentioned here, that we, at the beginning, we just mentioned that we really pioneer science for patient option here. That's exactly as we mentioned that for different patients you talk, they really have individual preference and even individual scenarios. Some patients, maybe for this period of time, they would think on-demand is the best for them. However, if they deal with wedding, some important events, this all will trigger more frequent attack. Then these patients think at this time, I maybe need prophylactic treatment. Then they maybe consider prophylaxis treatment for this period of time. But when scenario changes, their mind may be still back for the on-demand. That's also we talk about the short-term prophylaxis, all the different scenarios. That's exactly as we mentioned, we consider two different options here. One is oral capsule. One is icatibant tablet. We can combine the different scenarios that really provide all the different options for our patients. So when I think about the prophylactic market, there are two things too that I sort of peg on. Attack reduction from baseline and patients who are completely attack free, right? So when you think about the patients who are completely attack free, we are somewhere in the 50%-60% range with the best data right now. So does that mean that the remaining patients, or since you can't really predict who's going to be attack free, right, because there is no correlation between knockdown of plasma kallikrein with attack resolution, everybody carries a pill in their bag. Is that the way to think about how it's going to happen, especially if you have a very fast onset, fast-acting on-demand? Maybe if you want to talk about the attack. Actually, from the clinical research part, I really have to say both attack reduction, attack free, are very important assessments. Meanwhile, before Wim gave the detail, you know that sort of like you have your own assessment there. From my side, really attack free is a relatively more subject assessment. The reason I mentioned is because attack free is always related to duration. For example, some patients can attack free for one month. Some patients can attack free for three months. And some patients may be attack free for one year, even two years there. So that's a really different scenario to talk about attack free. Overall, as Wim also highlighted, from our purpose, from HAE guideline, our eventual goal is a patient can live in a normal life. That's the goal. And how patients interpret normal life. Some patients maybe think no any attack is normal life. Some patients think even they have one or two mild attacks, there is no any interfere. Their daily life or their daily job, they also feel that's normal life. That's great for them. That's exactly what in my mind, really both attack reduction and attack free are important. But meanwhile, we feel that pretty much attack reduction is more objective can show how really treatment effect, no matter from which angle. Yeah. It's interesting because we have an IIT running at the moment in the Netherlands in acquired angioedema, which is similar to HAE. There are four patients on that study who have one-year data and an open-label extension part. I was very disappointed. We cannot say all these patients are attack free. Why? Because one of the patients had one attack the second day of the study. All the rest, they were attack free. We cannot claim that patients on deucrictibant are attack free. But what does that mean in the context of the value that you provide to those patients? That's why it's a more subjective endpoint, attack free days versus attack reduction, which is a clear comparison with your placebo, which is probably more meaningful from a scientific perspective. Yeah. Regarding the story we mentioned here, we have four patients in an acquired angioedema study. As we mentioned, one patient had attack, mild attack at day two. Then all these four patients, right, attack free over one year after that. However, if you look at and see whether these all patients attack free for the entire study or not, we cannot. But all the four patients are really happy, really feel that the deucrictibant really transformed their life here. That's exactly what we mentioned with attack reduction, attack free. Both are very great assessment for the clinical research. Maybe we should integrate them together when we evaluate the efficacy of the treatment. Got it. So let's talk about the commercial landscape. This is about a $2.5 billion-$2.8 billion market currently. It's growing. It's growing. It's probably going to be whatever, $4 billion-$5 billion within the next few years. But 80% + of the sales are in the United States. Europe has been very slow to adopt any of these therapies. So what needs to change in Europe, given that you're a European company? You're absolutely right. Partly it's adoption. To a large extent it's also price. There's a huge difference in the value that the U.S. is putting into these drugs compared to Europe. There's a huge difference in the value that the Europeans put on these drugs. Now, and that's the reason why the adoption of some of these more innovative therapies, particularly in prophylaxis, are taking time to get adopted. We see that changing. It's much slower than the U.S. Germany, France, also the U.K. already now, they're starting to see more and more modern prophylactic therapies, lanadelumab, ORLADEYO, coming to market there more frequently. It's hard work. It's hard work. You need to convince, on the one hand, the payers. And secondly, you need to have a very close. You have strong communication with the patients. I think HAE is starting to become consumer marketing. As I said before, every patient has their own wishes and own desires. You cannot just bombard the market with one singular message, so that takes time and effort. Got it, so you have two studies. One, which is already underway. The other is supposed to be underway soon? Yeah. Our prophylactic pivotal study, CHAPTER-3 study, will be initiated in the coming weeks, by the end of this year. This is your standard whatever, 90-120 patients kind of study? Yeah. Actually, for our on-demand study, it's ongoing. Altogether, we target enroll 120 patients. And for our prophylaxis trial, we target enroll around 80 patients there. Enrollment is spread roughly equally between the United States and Europe? Excellent question. Actually, for both studies, actually a global trial, we targeted to enroll U.S., Europe, Asia-Pacific, and also a lot of Latin American countries. Overall, we think a majority of patients may be from ex-U.S. However, the ratio may be slightly different. For on-demand, we can expect maybe 20%-30% that U.S. patients. For prophylaxis, that may be slightly less because a majority of patients in U.S. has been on prophylaxis treatment already. Got it. And from a data readout or cadence of data readout, anything in 2025? Or it's more of a 2026 readout? Yeah. Currently, we do not provide really the guidance regarding the pivotal trials and also our top-line readout yet. But based on that, our competitors just wrap up study, for example, KONFIDENT study for on-demand or garadacimab or other studies, your assumption sounds reasonable. Got it. So how are you thinking about the commercial launch? Would you license out the European segment like a lot of the other companies have done and then hold on to U.S. rights? Yeah. We haven't made any decision yet on that front. But it's clear, as you said before, the bulk of the value comes from the U.S. And in the U.S., with a relatively small investment, 100 people, you can really commercialize and get a very profitable business. Outside of the U.S., you can do that, but it takes much longer. And so it's a question of the risk appetite. Do you want to invest in that and wait for that revenue to compensate for that and make profit in a longer time frame? Or do you find, at the end of the day, another player, whether that's a distributor or a licensed partner, to get that drug to patients? Because I think that's the most important thing which drives us is we are fundamentally believing that deucrictibant, this oral and injectable like efficacy, is something that needs to get in the hands of patients as soon as possible. And if there's somebody better placed to do it than us outside of the U.S., we would definitely consider that. Awesome. Anything I'm missing that I should be asking? No, I don't think so. Awesome.