Pharvaris NV Aktie

[Audio Gap] biotech analyst at the firm. It's my pleasure to have with us our next presenting company, Pharvaris. Up on stage with me are 2 members from Pharvaris. Thanks for making the trip guys. We've got David Nassif, who is Chief Financial Officer; as well as Maggie Beller, who is Head of Corporate and Investor Communications. Thanks, guys, again for flying over from Boston. So maybe we can start off with an overview of the company before we go into some specifics about updating on catalysts.

Sure. Well, first of all, thanks for inviting us. We really appreciate it and also the opportunity to have a chat with you. Before we get into the overview, maybe for those of you that don't know, this week, we priced a $132 million underwritten offering, which takes our cash runway into 2028. So now both launches, both ODT and Prophy are fully funded. Any overhang on the stock completely lifted. So we're looking forward to future data and approvals. As to the pipeline, I guess there are basically 3 updates.

On ODT, we are on track for the first half of 2026 filing of the NDA on -- as it pertains to prophy, we are still on track for top line readout by Q3 2026. And then on AAE, the enrollment is progressing well. So if you wanted to talk about differentiation of the products, basically, our story is we are a portfolio strategy at this point, where patients, payers professionals know they can use our products for a vast array -- or will be able to a vast array of indications. We have a single molecule supporting 2 formulations. We have once-daily dosing, we think, for the vast majority of cases. And so far, we've shown superior efficacy in ODT.

Okay. Great. So maybe we can go into a little bit more detail on some of these items that you just mentioned. So on demand, can you just remind us what the takeaways from the top line data were for the RAPIDe-3 study?

Yes. Thanks so much, Tazeen. So we read out our RAPIDe-3 top line data in December of last year. Out of that, we were pleased to hit our primary endpoint and all 11 key secondary endpoints with statistical significance in a hierarchical fashion. So that from our bio stats colleagues is very hard to do because if you miss the stat sig on one, you don't get it for any of the subsequent ones. What we are really proud of is that across the entire attack trajectory, we were able to show rapid onset of symptom relief, complete symptom resolution and single-dose durability. So there are some key endpoints within our 12 that I just talked about, including end of progression, which is the first time somebody stops feeling worse. It's a really important psychological moment for a patient because they know their drug is working. HAE is a stress-induced disease. And so if you're able to relieve some of the stress and anxiety, that could help you come to attack resolution faster.

We were able to put end of progression at 17.5 minutes. We are the first and only group to have done that in a prespecified manner. So depending on how our discussions go with the FDA, that could, in fact, be included on our label. Next is our primary endpoint. That is time to symptom relief as measured by PGI-C a little better. We were able to show that deucrictibant works at -- in about 1.28 hours for that primary endpoint. Next is substantial symptom relief. This, once again, is when people are able to kind of get back to their normal life, whether that's you're able to go to the grocery store, you're able to get your haircut, you're able to just get back to living. We showed across 2 different endpoints about 2.5 hours for that. And then lastly is complete symptom resolution. So that is when you are no longer experiencing any symptoms.

Deucrictibant was able to do that in less than 12 hours. That's really important because that means that somebody, if they feel an attack coming on at 7:00 p.m. at night, they could take a single dose of deucrictibant and be completely symptom-free by the time they wake up in the morning. You can get on a plane and feel better within 12 hours, right? That is just really impactful for patients, for physicians. So we think across the board, those are really key endpoints. And lastly is our single-dose durability. 83% of people were able to achieve these efficacy findings with a single dose of 20 mg deucrictibant. So all of those things, I know there's a lot of data, but we think that, that really across the board differentiates us not only from standard of care, which is deucrictibant, but also from a recently approved oral.

Okay. So maybe can you just talk us through what the demand in on-demand is just given that the prophy market continues to grow. There's continuingly new launches you expect to be one of them over time. But maybe can you talk to us about the latest market data that you have on TAM and some important metrics like what are the average number of breakthrough attacks patients having even if they're on a prophylactic drug?

Yes, that's a great question. So as we look at the on-demand market, I think we can say holistically, we think that the entry of an oral should actually grow the number of attacks that are treated because the treatment barrier is so much lower when you have an oral. Before there was this recently approved oral, people would need to excuse themselves, inject themselves, it's very painful. There's all sorts of stigma associated with injections. And we believe by removing the challenges around discretion, around portability and oral should allow people to treat more attacks. So before the summer of last year, about 70% of attacks were treated. That leaves 30% that are untreated. So we think that there could be more attacks treated. However, as you said, there have been recent oral -- recent entries in the LTP space that are really putting up great efficacy numbers.

You've got 80% to 90% attack reduction. Based off of our open-label extension data, we think that deucrictibant could have less than 1 breakthrough attack a year. So there could be a bit of an increase and then a decrease as you think about more attacks treated. In 2025, there are about 87,000 doses given. And that's an important distinction because some people require multiple doses to be able to completely address their attacks. So some standard of care takes 2 to 3 vials. We know that the oral takes -- about 38% of people have to take a second dose. So we believe that the total attacks treated is probably a little bit less than the number of doses taken. But once again, that's a flexing number right now as we think that there could be more attacks treated in the future.

Okay. Now can you talk about the heterogeneity of HAE and the type of attacks patients have? If they tend to have one type of attack, is that what they tend to get most of the time? Or can it be any variety of parts of the body that are impacted by an attack?

It's a great question. So when we think about an HAE patient, a person can have changes in their HAE throughout their lifetime, right? It tends to be stress-induced, as I said, hormonal changes can cause either more frequent attacks or more severe attacks. So somebody who -- even for me, you can have one attack that is a mild attack, maybe it's a peripheral hand swell. And then the very next attack could be a laryngeal attack, which is potentially life-threatening. So as you go throughout your life, that can change over time.

That's one of the benefits of deucrictibant is this ability to be able to address attacks depending on how a person and their physician decide to treat their HAE. At some point, there may be a situation where people don't want to be on long-term prophy all the time. And so you're able to quickly come off of deucrictibant XR and switch to maybe just treating on demand. Also important for women of child-bearing age or who are breast feeding, you shouldn't be on an HAE medication if you're pregnant or breast feeding. And so the ability to come on and off therapy is a unique selling point of deucrictibant's.

Okay. And then in terms of types of attacks, are there ones that patients feel like I don't need anything for this so if my pinky is swollen, I can deal with it. And if that's their current way of thinking, do you think that having an option like deucri could change their mind?

That's a great point is that we -- in fact, our goal right now is to change treatment expectations. Right now, somebody may, as you said, get a peripheral hand swell, it could be their left hand, I'm right-handed. You know what, I'm just going to deal with this because I'd rather save my medication for my next attack, which could be an abdominal attack, which is super painful, laryngeal attack or something that impacts my life more. As we said, with the decrease in treatment burden of an oral therapy, we believe that those decisions that people have to make when they forego treatment could be lessened if you're able to have something that's discrete, that's portable, that's easy to take, easy to swallow. And like I said, what we believe outperforms standard of care, though no head-to-head studies have been conducted.

Okay. So you do have a comp in the market, a recently launched comp of an oral for on-demand I'm sure you guys have been following that. What are you learning from that? And where do you think deucri can potentially perform better?

Great question. We believe EKTERLY's launch has gone really well. It confirms what we and the sponsor of EKTERLY had said beforehand, which is that there is a severe unmet need for oral therapies in on-demand. We think that they've done a great job being able to capture that market. For us, we view the on-demand commercial opportunity in 3 main segments. One is the people who are on icatibant right now, deucrictibant and icatibant utilize the same mechanism of action. However, deucrictibant is more potent than icatibant. That means -- and it has a longer half-life. That means that, as I was saying before, some people who take 2 to 3 vials of icatibant to fully treat their attack could now do that with just a single pill. So if people have been using icatibant since it was launched in the U.S. in 2011, they've built a trust in the mechanism. And now we can go to them and say, this is the same mechanism. It works for you because this is at the bottom of the HAE cascade.

However, it works in a single pill and it's oral. So that's sort of that first segment that we think we can go after. The second segment is people who are on a C1 replacement right now. The way that people are utilizing C1 replacement is to address patients with normal C1. So mechanistically, this shouldn't work, right? If you have normal C1, you add more C1, doesn't really work. However, that is an infusion that's done with a health care practitioner. So if there is a risk of an attack progressing to a laryngeal attack, which could cause association, at least there's a health care provider on site. We believe that with the mechanism of deucrictibant, our data in normal C1, which showed equivalent efficacy from normal C1 to type 1 and type 2 that, that whole 20% of the HAE market that's currently unserved could work well with deucrictibant.

And then lastly, as you said, EKTERLY is the oral that's on the market right now. We believe that although not head-to-head studies, we believe we have a differentiated profile there. We approach that market in providing people with a risk-free trial of treating their on-demand attack either with deucrictibant or if they're using EKTERLY, you can just say, try it once and see how your attack progresses. We've heard anecdotally that for physicians and patients who participated in both the Phase III study for confident and our Phase III study, RAPIDe-3, that there is a marked difference between these 2 drugs. We want people to experience the -- the 17.5 and the progression, the less than 12 hours complete symptom resolution, the single dose durability. And we think that with this differentiated profile that, that's how we're going to capture those oral switches as well.

Okay. So the 3 subgroups that you just mentioned to me, which are the ones that you think will be the fastest to onboard?

Based off of the mechanism, we believe that the icatibant switches and the RUCONEST switches are going to be the fastest. It will take more effort to be able to get in front of people who have already tried EKTERLY. That's probably the largest opportunity, but also maybe the more difficult to switch.

Okay. Got it. Now as you think about what type of commercial organization you'll need, assuming that it will be -- this launch is first and then prophy after, how big of a footprint do you think you're going to be needing?

So I'll take that one. We believe that by the end of this year, we'll have 70 people in commercial, ready to launch on demand sometime in '27. And then we think that we're going to need another 20 by the end of '27 to fully address the prophy market. So 90 people ultimately over the course of 2 years.

Right. And have you started the process of identifying people? And...

Oh, yes.

And then when would you start to hire people?

Yes, the sales force will come, call it, Q3, Q4. Some of the more senior people, we probably already hired 3 or 4 this year, and there are another 3 or 4 in the mix. So it's happening.

Okay, got it. And then from the time you get approved, let's say, your PDUFA is on a Tuesday, would you be able to launch on the Wednesday?

Well, the goal is to launch as soon as possible thereafter, which is why we want to make sure -- everyone's been hired and trained and product is available and we're ready to go. So we're hoping that it's virtually instantaneous.

Good. So maybe let's move on to prophylaxis. So maybe give us an update on the timing for the top line data that you're expecting to show us. Is it this summer?

Third quarter.

Third quarter. Remind us the design of the study and what would be good data or clinically meaningful data rather?

Absolutely. So our Phase III study is a global study. We enrolled approximately 81 people in a 2:1 fashion. So that helped us with approaching people that there was a higher likelihood that they would be on active drug. Our global footprint included the U.S., Europe, APAC, LatAm we included type 1, type 2 and normal C1 participants as well as adolescents, so 12 and up. The -- like I said, guided towards data in the third quarter. Now leading into our CHAPTER-1, our Phase II study, we had done some market research of what would be a meaningful efficacy number for us to be able to own the oral segment. Our market research indicated that we would need to put up at least 70% efficacy for percentage of attacks reduction monthly. When we flipped over the CHAPTER-1 data, we were happy to see 85%. That put us squarely within the other injectables in this space.

Right now, those injectable numbers are between 80% and 90%. Our goal would be to replicate that Phase II data. So if we could be between 80% and 85%, we think that, that not only significantly gives us ownership of the oral segment, but also enables us to compete with injectables. And then I can sort of talk about maybe our 4 segments that we have in the LTP space as well. So we know that 80% of physicians will start naive patients on an oral therapy, if all things are equivalent, efficacy, safety. So in the U.S., there are about 200 to 250 new HAE patients each year. If we're able to capture 80% of that, 200 and keep them on therapy, then each year, that's 200 stacking on top of one another. Now of course, we're not going to keep 100% of every new patient. But unlike another approved oral, which has about a 60% retention rate, we think we can be closer to 90% if we're able to put up our 80% to 85% efficacy. So that ends up just being a pancake effect over time.

The next segment is people who have tried an oral but come off of it. Based off of those retention numbers I was just stating, if 40% of people each year drop out, we believe by the time we could potentially get to market, there are 1,000 people who have tried an oral and come back off of it. So that's 1,000 people who have indicated they want an oral, but for whatever reason, efficacy, tolerability, they've moved back to their injectable. If we're able to go to those people and present an equivalent efficacy and tolerability profile, we believe that we could capture some of that market. The third segment is people who are on the oral right now, who maybe are foregoing efficacy and tolerability because they prefer their oral so much, whether it's they don't like injection or there's some sort of antidrug antibody with other therapies, they're foregoing their efficacy. So if we're able to say, you like your daily oral at 44% attack reduction, here's an 80% to 85% daily oral, we may be able to switch those patients there.

We know from data that's put out by another sponsor that those orals are still having about 1 to 2 breakthrough attacks a month. As I mentioned earlier, our open-label extension data indicates that we could be at less than 1 attack a year. So we're really excited about that opportunity to provide a potentially better efficacy and tolerability oral for people. And then the last segment is people who are staying on injectables right now because they don't want to forgo their efficacy and tolerability. We had done some market research questioning people on when they would prefer a daily oral to a long-acting injectable at the different injection rates right now. So once every 2 weeks, 4 weeks, 2 months, 3 months and then 6 months.

It's only when we get to daily oral versus once every 6 months that people tend to prefer about 50-50. So let's assume that another sponsor can put up a 6-month injectable that once again has the same efficacy and tolerability that we're seeing with these others. That prophy market, which is about a $4.7 billion market right now, splits evenly between 50% orals, 50% injectables. We believe with an efficacy profile that we could dominate orals. And then within the injection space, that tends to be a little bit of a crowded market, right? You've got about 9 injectables that are all going to be competing for that other 50%. So although we don't believe that 100% of the market will go to orals, we do think that we can have a strong market leadership for the prophylactic space.

Okay. So -- and also the split between on-demand versus prophylaxis, right? So you're going to further be differentiated in that you're going to offer patients in both segments' treatment. So what's your concern about cannibalization if you have a really strong prophylactic oral as you described with the outcome that you're hopeful for with the 80% plus reduction in attacks, kind of how do you think about what the on-demand opportunity would be for that same product?

Yes. So right now, 38% of the U.S. market is on on-demand only. We believe that, that will get smaller over time as more people add on prophylaxis to their treatment regimen. However, every HAE patient is an on-demand patient because you should still carry rescue medication with you in case you get breakthrough attacks. Now for us, we believe that we can really address both aspects of that, right? So it's not -- we're not as concerned of, oh, well, what happens if 80% of the market becomes prophy, Okay, we're good with that. We have a prophy. Well, what happens if on-demand takes over? Okay. We also believe that we have a dominant profile there.

And one of the things that we're working towards building a high level of data around is what if somebody was on deucrictibant XR? And then if and when they had a breakthrough attack, they could treat with deucrictibant IR. So we've pulled together some initial efficacy findings around mechanism on mechanism. So people from chapter 1 who had breakthrough attacks treated with icatibant, same mechanism of deucrictibant and had equivalent efficacy findings as people from placebo who treated with icatibant. We most recently put out some interesting safety margin data around people if somebody was -- who was modeled around if somebody was on XR daily and then they treated not only with IR tablet, but a second IR tablet right away, those safety margins were well within what we would expect of NOL. So we're thrilled with that.

Okay. Okay. So as you think about time lines for the data readout, what should we expect to see in 3Q when you top line the data?

We will be, of course, showing numbers around our percentage attack reduction, safety profile as well. I think one of the things that we've been seeing from other people and what is shifting in expectations on prophy is some data around either number of days that are attack-free, percentage of patients that are attack-free, right? Like the bar is being raised as these efficacy -- as the efficacy improves from all of our peers. And so I think the attack-free percentage and numbers will be important for us as well.

Okay. Now that 80% plus that you have the goal of achieving, as you expand from a Phase I/II to a pivotal study, the population is quite heterogeneous. So how do you get comfortable that with more patients enrolled in this pivotal study that you could do a similar number to what you had in that impressive smaller study?

Yes. Thank you. So one of our -- one of the items that we've implemented in the Phase III to be able to protect against this Phase II to Phase III efficacy degradation is we are switching our formulation from a twice daily immediate release capsule. -- so that has a very swift uptake of therapeutic exposure and then it sort of drifts until about hour 12 and then you take a second one. Now at around hour 12 and 24 in our CHAPTER-1 study, we believe that some patients could have been vulnerable to breakthrough attacks because there's an opportunity to drop below that therapeutic threshold of EC85, about 13.8 nanograms.

We have modeled our PK around the XR formulation, which is the formulation we're using in CHAPTER-3 as well as our intended commercial formulation and put out recent PK variability data, which indicates that even from patient to patient, the PK and therapeutic exposure is about 2 to 4x higher than that minimum EC85, where you're blocking 85% of the B2 receptor. Because the PK profile is much softer and you're not having these drastic peaks and troughs. We believe that, that is an optimized formulation for a once-daily prophylactic.

Okay. Got it. So if you want to go back to comparing versus Orladeyo, which would be your oral competitor in the space. Historically, the HAE market has tended to be sticky, which means if something is working for you, whatever it might be, even CINRYZE, which is an old drug, some people are still on it, you tend to stay on it. If it's not working for you, our feedback from physicians is that you tend to switch to something else pretty quickly. So what portion of the population are you really looking to have patients switch from? Because it's our understanding that for ORLADEYO, if it's not working for you, you've already moved on to something else. So would it be from the injectable population, at least initially that you would expect to see most of your uptake?

We believe -- I think we're in complete agreement. There is some brand loyalty that people have. However, I think that your point is very well taken, which is if it's working for you, they will stay on it. As I mentioned before, people in Orladeyo are still experiencing 1 to 2 breakthrough attacks a month. Based off of what we're seeing from the other injectables, that actually isn't working well for them, right? Like that is not the expectation that patients have when they take an injectable. So we believe that people are accepting a lower efficacy because they prefer an oral so much.

So we actually really do think that good is not good enough, right? Just because you are on an oral right now and putting up with breakthrough attacks doesn't mean that that's what you should be experiencing. So they -- Orladeyo was able to capture about 25% of the market in 5 years with the maybe not as compelling profile. So as much as people say that it's a sticky market, it's not that sticky if they're able to get 25% of the market in 5 years. We believe that people will switch to the better product for them.

Okay. And then maybe one more question about your point on switching. So it is true that if it's not that different, it's hard to get patients to switch unless they feel like something is really different. So going from an injectable to an oral would be one of those things where, hey, this is different enough, I want to try it. But what about the flip side of injectables? There's now a bunch of [Audio Gap]

To dominate 100% of the market. There are -- each patient and physician has the opportunity to choose what's best for them. There are benefits to being on a long-acting injectable and then there are trade-offs as well, right? We see that at the end of those long injection frequencies, there tend to be more breakthrough attacks as sometimes triggered by stress, right? You know that your next injection is coming up. The longer people have in between injections, the more likelihood that you're going to miss an injection, right? You can't remember if you took it in the first week of July or the second week of July.

And then lastly, the control that you forgo by just taking an injection and then having to wait for your next injection could actually be quite a deterrent for people. If somebody -- for example, like I said, for people who want to get pregnant, if you are on a 6-month injection, that means that you need to start family planning multiple half-lives before that. So you start to family plan 1.5 years to 2 years before you can actually begin that process. So we believe that the control around being able to say, each day, I wake up and I'm able to control my HAE by taking a daily oral is going to be really appealing to people as well. Like I said, not 100% of the market. There are going to be people who prefer to just get an injection every 6 months and not worry about it. That's okay. We're trying to provide patient choice.

Okay. All right. So when the top line comes out, assuming that is positive, what are the next steps with FDA?

Yes. So in addition to having our efficacy and safety from the randomized clinical trial portion, there's an open-label extension that's running where we need to be able to have enough people who were on deucrictibant for a full year. So we need to pull together that safety database. And then the other thing, as David mentioned, is our ongoing CREATE study. This is an acquired angioedema. Part 1 of that study is a 12-week prophylactic study that if the timing allows with the setup of 24 patients in that group, we could actually take the efficacy and safety from AAE, add it on to CHAPTER-3 plus the CHAPTER-4 safety database and submit that for a broader a broader submission on AEBK, which is bradykinin-mediated angioedema.

Okay. And when would that happen, do you think?

We haven't guided towards when that data is going to be. But once we get enough visibility into that, we'll provide a disclosure on it.

Okay. Perfect.

It's also true, I think, given that there are no approved AAE therapies that if we are able to put the 2 together in filing that we could get priority review.

Okay. Perfect. Well, with that, we're out of time. So thank you, guys, for spending the last 30 minutes with me. Thanks, everyone, for joining as well.

Thank you.

Yes, thanks. Thanks, Tazeen.

Good day and thank you for standing by. Welcome to the RAPIDe-3 topline data webcast. [Operator Instructions] I would now like to hand the conference over to your speaker, Maggie, please go ahead.

Thank you, and welcome to the top line data announcement of RAPIDe-3, a Phase III clinical study of deucrictibant immediate-release capsule for the on-demand treatment of hereditary angioedema attacks. My name is Maggie Beller, Head of Corporate and Investor Communications at Pharvaris. Please note that today's webcast is being recorded and the slides will be uploaded onto the Investors section of our corporate website immediately following this call.

Please note that the statements of our guests today are their own and not those of Pharvaris and Pharvaris makes no representation as to the adequacy, fairness, accuracy or completeness of the information in their comments. In addition, our presentation today will include forward-looking statements, including, but not limited to, statements regarding deucrictibant and its potential as well as our preclinical and clinical studies, regulatory interactions and future plans. Such forward-looking statements are subject to certain risks and uncertainties that could cause actual results to differ materially from those projected. For additional information regarding the various factors that could cause such differences, please see the section entitled Risk Factors in our annual report on Form 20-F and our other filings available on the SEC's website.

In addition, any forward-looking statements represent the company's expectations only of today, while we may elect to update these forward-looking statements, we specifically disclaim any obligation to do so unless required by law. During our call, Pharvaris' Chief Executive Officer, Berndt Modig, will speak to Pharvaris' continued journey to pioneer science for patient choice. We are joined by Dr. Marc Riedl, a Professor of Medicine at the University of California, San Diego and a principal investigator of the RAPIDe-3 study, who will share his perspective on these data as a worldwide recognized expert treating physician. Thank you, Dr. Riedl, for joining us. Pharvaris' Chief Medical Officer, Dr. Peng Lu, will go through the top line efficacy and safety findings from the RAPIDe-3 study. Additionally, Pharvaris' Chief Commercial Officer, Wim Souverijns is available for the Q&A portion of the call.

I'd now like to hand the call over to Berndt Modig. Berndt?

Thank you, Maggie, and good morning and good afternoon, everybody. Over 20 years ago, I started biotech in HAE at the company that developed icatibant, the current standard of care treatment for HAE attacks alongside Chief Scientific Officer, Jochen Knolle, who's the investor of deucrictibant. Shortly after the approval of deucrictibant in Europe, a person living with HAE approached Jochen at a patient meeting after declaring deucrictibant had changed their life, they ask Jochen if he could make deucrictibant in the pill version. That is at the moment Jochen recognized that the good was not good enough.

Ten years ago, with this unmet need in mind, Jochen and his lead chemist, Christoph Gibson, designed a highly potent small molecule with oral bioavailability that utilizes the same mechanism of action as icatibant. Also by the initial findings such as those bradykinin challenge studies, Jochen knew this asset could become a game changer, and that is the foundation of Pharvaris. Recognizing deucrictibant potential as we both in on-demand and prophylactic treatment, Jochen and his team went to step further and developed 2 distinct formulations and immediate release capsule for on-demand treatment and an extended-release tablet for prophylaxis.

Following rigorous clinical development, we are proud to announce data from Pharvaris' first pivotal Phase III study of deucrictibant, in which we met our primary end point and all secondary efficacy endpoint with a well-tolerated safety profile. The RAPIDe-3 data potentially position the capsule of deucrictibant to deliver their fastest symptom relief for vendor progression through the complete tax resolution, thereby offering beginning to end control of HAE attack rates. I'd like now to introduce Dr. Marc Riedl in a world-leading HAE expert effort to speak to his experience in treating HAE and the unmet needs in acute HAE treatment. Marc?

Thanks very much, Berndt, and good morning, good afternoon to everyone. I'm Dr. Marc Riedl. I'm a Professor of Medicine at UCSD and -- by way of quick background, I'm an allergist immunologist. I've been managing HAE patients for almost 25 years now. And I've also been very involved in HAE research, particularly in the clinical trials aimed at developing novel and improved therapies for HAE. So it's my pleasure to join the call today really to provide a clinical perspective on HAE and perhaps provide a few insights for context as we talk about the clinical trial data. So as people are well aware, HAE management has dramatically changed and evolved over the last 20 years or so. And during that time, we've seen great progress in HAE treatment options.

There has been considerable growth, particularly in the area of long-term prophylactic treatments, and we have seen, in fact, more patients moving towards preventative treatments. But what hasn't changed in HAE management is that all plans, all treatment plans must include effective on-demand HAE treatment. And this is without exception because patients continue to have HAE attacks that are unpredictable, that are debilitating and that are potentially life-threatening. We can never forget that aspect of HAE. So even with more effective long-term prophylactic treatments our patients with HAE continue to have attacks they continue to require on-demand treatment. And we see that the treatment responses to the preventative treatments are really quite variable.

So this variability in the response to preventative treatment leads to ongoing need for on-demand therapy. We still see attacks occurring. And we need treatment that is rapid, reliably effective. We have current on-demand treatments, and these have generally been effective, though the burden of treatment is relatively high, and this is particularly true with the long-standing subcutaneous and intravenous rescue treatments. So another remaining unmet need in HAE is a reduction in the treatment burden for the therapies that we can offer.

Historically, treatment burden and side effects have led to treatment delays or even treatment avoidance and this has long contributed to the morbidity and the risk of these HAE attacks. So the recent development of oral rescue medications for HAE has really been a substantial advance. This has reduced the burden and the barrier to treatment. For patients, the rapid onset of symptom relief as well as the reduction in tax severity and the durability of the relief are really the key components to successful on-demand treatment. And this brings me to a final point that I'd like to highlight that of mechanism of action. So bradykinin B2 receptor antagonism is a well-established and a recognized successful approach to stopping HAE attacks.

Both the physicians and the patients in the HAE community are really familiar with this mechanism of action. Because as you heard just now, subcutaneous icatibant has the same mechanism of action and icatibant has been widely used for HAE rescue treatment over the past 14 years or so. So this is a mechanism of action with a proven clinical track record. It's anticipated to be reliably effective for all forms of bradykinin-mediated angioedema. And so as we move towards reviewing the study data, I'll just make a final note that as a clinician, efficacy and safety of a treatment will always carry the day.

The most important questions for me and my patients are: number one, does the treatment work? And for HAE rescue medication, that's heavily dependent on how quickly and how durably a treatment works often assessed by the need for additional doses or additional treatment for that attack. And secondly, is the treatment safe or are there common substantial side effects. But currently, I would say, a third important question is treatment burden, is the treatment easy to administer? Is it portable? Will it fit into daily work, family and recreational activities? And it's in these areas where we continue to see progress and advances that really make me optimistic for the future of our HAE patients and their families.

So with that, I'd like to turn it over to Dr. Peng Lu. Peng?

Thanks, Marc. As Marc highlighted, people living with HAE seek unburdened control of their disease. What has been amazing is the combination of simplicity and speed in the moment of attack, coupled with the durable effects of single capsule. Today, that becomes a possibility. Let us work through the results of the RAPIDe-3 study. RAPIDe-3 was designed as a double-line crossover study. Each participant received deucrictibant or placebo in a randomized order to treat 2 qualified attacks. Adolescent patients also received a single-dose deucrictibant for PK and the safety assessment prior to randomization.

Along with the new guidelines published early this year, RAPIDe-3 is the first pivotal study to enroll all subtype of HAE. Expanding beyond type 1 and the 2, also patients with normal C1 inhibitor. In addition, the study enrolled both on-demand and prophylactic patients throughout the study, attacks with varying severities and across all body locations were treated to evaluate the therapeutic effect of deucrictibant. RAPIDe-3 was initiated in March '24. In total, 124 adults and 10 adolescent were recruited within 12 months. Among those enrolled 88 participants completed treatment and assessments of paired attacks. Therefore, they were included in the primary efficacy analysis.

As Pharvaris partnered with centers from 24 countries across 6 continents. This study included approximately 70% Caucasians, over 14% Asian and around 7% black or African American, make RAPIDe-3 the most representative HAE study to date. For the subtype of HAE patients, in addition to type 1 or 2, RAPIDe-3 also enrolled 4 HAE patients with normal C1 inhibitor, 2 with a Factor XI mutation and the 2 with the Plasminogen mutation. Among all participants, approximately 23 of patients received long-term prophylactic treatment with lanadelumab most frequently used, accounting for 42%. The demographics of the primary efficacy analysis set, 88 participants with paired attacks were comparable to the all randomized population presented here.

As a reminder, the HAE endpoints are measured by patient reported outcomes. Today, we will focus on the data from 2 validated and well-accepted skills, Patient Global Impression of Change, PGI-C, and the Patient's Global Impression of Severity, PGI-S. Both skills have been recommended and aligned with the regulators. Evaluating the effectiveness of on-demand treatment requires a holistic view. For people living with HAE, the aspects that matter most. First, fast onset of treatment response; second, short time to substantial symptom relief; and the third, early complete symptom resolution. The RAPIDe-3 study met statistical significance for the primary and all 11 secondary endpoints for the evaluation, which were assessed sequentially under the prespecified multiplicity control procedure.

During today's top line presentation, we will be sharing data from primary and several secondary efficacy and safety analysis. A comprehensive communication plan has been established for further scientific exchange at upcoming medical conference. The primary end point for RAPIDe-3 is the time to onset of symptom relief, defined as achieving at least a little better at the 2 consecutive time points within 12 hours. Deucrictibant demonstrate a significantly faster onset of symptom relief than placebo with a median time of 1.28 hours, well beyond 12 hours for placebo listed at NE, not estimable. As shown in the Kaplan-Meier curve, evident separation between the deucrictibant and the placebo curve emerged within the first hour.

By the 4-hour time point, approximately 85% deucrictibant-treated attacks had achieved onset of symptom relief compared with around 30% of placebo-treated attacks. Subgroup analysis on the onset of symptom relief shows consistent and robust results across subgroups, including patients with normal C1 inhibitor adolescence as well as all attack locations and severity. People with HAE and treating physicians report that the point at which attack symptoms stop progressing is the early sign that a treatment is working. The worst is over and things will get better.

Based on feedback from patients, advocates and treating physicians, we designed RAPIDe-3 to include end of progression as a prespecified efficacy endpoint. It is defined as the earliest post-treat time point, after which all subsequent PGI-C ratings are stable or improved. In the study, we are pleased to observe end of progression was achieved within 17.5 minutes for deucrictibant-treated attacks, confirming the rapid absorption and the PK/PD profile of the deucrictibant immediate release capsule.

As shown with the full attack trajectory, substantial symptom relief represents a key milestone between onset of response and complete resolution. Deucrictibant demonstrates fast and substantial symptom relief with PGI-C better with a median time 2.85 hours. Achieving both a little better and better quickly shows a robust pattern of treatment effect in the study population, demonstrating deucrictibant's ability to deliver rapid and durable symptom improvement beyond just onset of relief.

Substantial symptom relief was also measured by at least 1-level improvement on the PGI-S. Patient Global Impression of Severity sustained for 2 consecutive time points. Deucrictibant achieved this high bar with a median time of 2.41 hours, showing robust and consistent with the PGI-C assessment.

When treated with deucrictibant, earlier complete symptom resolution for acute attacks had been achieved within 12 hours. What does this mean for patients? Symptoms associated with nontreated HAE attacks can negatively impact patients for up to 5 days. Only 1 capsule with deucrictibant offers patients the potential to be symptom-free within half a day. During the RAPIDe-3 study, approximately 83% attacks were treated with a single capsule within 12 hours post treatment with deucrictibant and 93% attacks did not use rescue medication.

In the safety analysis with patients receiving any dose of study drug, deucrictibant was very well tolerated. Overall, a total of 24 and 17 participants observed at least 1 adverse event for attacks treated with deucrictibant or placebo, respectively. Most adverse events were mild or moderate in severity. There were 2 serious adverse events reported in each group. One was a miscarriage occurred 1.5 months after placebo treatment. The other was nontreated hospitalized HAE attack that occurred about 4 months after deucrictibant treatment. No participants discontinued study or treatment due to adverse events. No safety signals identified from adverse events, lab, ECG or vital signs.

In summary, the efficacy results clearly show the potential of deucrictibant's differentiation. Looking at the strength of the data, I'm truly excited and proud of what the study has accomplished and the impact deucrictibant may have for people living with HAE. After more than a decade working in the HAE space, it has been a privilege to witness and contribute to the remarkable progress in the new treatment development. that continue to address unmet medical need and improve the quality of life for HAE patients. Here, we would like to take this opportunity to sincerely thank the HAE community, especially study participants and their families, investigators and site staff, our study partners and all Pharvaris for their invaluable contributions to HAE clinical research, especially the RAPIDe-3 study.

Thank you, Dr. Riedl and Peng, for your insights on the RAPIDe-3 data presented today. I'd like to reiterate my appreciation on the team around the world who have collaborated to generate this data. Let me remind us of our journey to this day. Ten years ago, Pharvaris set out to develop an oral bradykinin beta receptor antagonist using our in vivo bradykinin challenge model, the left part of this slide, we define the dosing for both on-demand and prophylaxis and subsequently optimized 2 distinct products for one for each indication by our formulation work. Our aspiration was to show that these products could effectively address the unmet need in both the on-demand and prophylactic settings.

Today, we are excited that the results from RAPIDe-3 study represent a step towards realizing that aspiration. We're very proud of the team that made that possible, and we're looking forward to the results of the prophylactic study, Chapter 3 in the second half of next year. Additionally, CREAATE, the global Phase III acquired angioedema study initiated as planned this quarter is actively recruiting. Until then, we continue to work towards the planned submission of our first global marketing authorization for deucrictibant in the on-demand treatment of HAE attacks.

In closing, Pharvaris is steadfast in our mission to improve the standard of care for people living with bradykinin-mediated angioedema.

This has concluded the presentation section of the webcast. [Operator Instructions] Our first question comes from the line of Maxwell Skor from Morgan Stanley.

Great. Congratulations on the very encouraging data. So just to start off, could you discuss the strategic advantages of deucrictibant's potential to address both on-demand and prophylactic treatment of HAE? How might this dual indication approach enhance, let's say, market share and patient adoption compared to single indication therapies? And finally, any guidance around which medical meeting we could expect an update and what additional data we could look for in that update? Congrats again.

Yes. So thanks Mark, for the question -- Max. And on that topic, of course, I mentioned in our presentation, the to have 2 formulations with the same active ingredient for both on-demand and prophylaxis, of course, is the goal of that is to provide the choice of the patient how to best treat the condition. So that is -- should be a patient benefit in our -- potentially in our view. And of course, anything that benefits patients is also good for the company and market share, as you alluded to. So I'd like to also maybe invite Wim Souverijns to comment on that further as we are thinking about that strategy for launch of deucrictibant potentially in the future. So over to you, Wim.

Yes. Thanks, Berndt. I think it's a huge advantage for Pharvaris to have this 1 active ingredient in 2 forms that really covers all the needs of patients with bradykinin angioedema, whether they want to do only on treating their attacks on demand because they have very few of them or whether they really choose to go for prophylaxis and as a backup plan require a rescue medication and still use the same molecule. I think this is the wish and desire from the community. They see the benefits of this. And it really plays into our mission as a company.

Our tagline is pioneering science for patient choice. Well, this is exactly what we are offering here. We don't really want to force anyone in this market to go left or right. We have the tools for them to treat the way they want to. And I think that will be very appreciated by the community. There are scientific merit to that. So we think this is a big competitive advantage in the market.

Yes, [indiscernible] go ahead Peng...

Yes, exactly. You know that for the -- Max, that you mentioned the upcoming at the medical conference. Actually, as Dr. Riedl on the call here, actually that our -- the first data plan that to present the top line data and more detailed information is in the coming [ AAAI ] conference will be held in February '26 in Philadelphia.

Our next question comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the strong data. So a question for management and also Dr. Riedl. We've seen Ekterly have a strong launch so far as the first available oral on-demand treatment option for HAE. And since deucrictibant will be entering the market later, I was wondering which specific aspects of its clinical data or product profile do you expect to distinguish it further in the marketplace? And then Dr. Riedl, similar question. How has your practice been adopting Ekterly now that it's commercially available? And how do you expect market share to break down if and hopefully when deucrictibant is approved?

Yes. Thanks, Jo, and thanks for your question. So the -- what we also discussed here when we showed you the data is the -- what's important for the patient and what really makes an on-demand treatment stand out is, of course, the fast onset of symptom relief, but also extremely important, as Peng also mentioned, the holistic perspective is that what a patient is looking for is durability of the efficacy and up to the shortest possible complete resolution of the attack, so which is the time point when the patient can resume to normal life and continue what they were doing or going to that meeting or getting on that flight, whatever they need to do to have the attack behind them as quickly as possible. So onset is important and -- but of course, also durability is key here. And I think that's where we -- based on the data what we've seen today that potentially the deucrictibant can stand out.

So also to -- I'll hand over to Dr. Riedl also to add some comments on this topic.

Sure. Yes. Thanks for the question. As you might imagine, we've seen really significant interest in the oral rescue medications. And as you noted, with the oral kallikrein inhibitor that's now been approved, certainly lots of patient interest. Not surprisingly, people are really keen to use an oral medicine versus having to do an injection or an infusion. And so as you noted, we've seen pretty robust uptake of patients wanting to try the newly approved medication. I expect that to continue. And I think as you saw today, the data here looks very favorable for the efficacy and the safety of deucrictibant.

So I think in clinical practice, having options is really important. We go through a lot of data with patients and the shared decision-making process. And I think that will certainly be the case if and when deucrictibant is available to us that we'll be talking through the study data and making sure they understand the pros and cons of any treatment.

The only other thing I would add, and I alluded to this in my earlier comments is that patients are really familiar with bradykinin receptor antagonism. At least in our practice, icatibant has generally been the go-to treatment up until recently for many years. And so I think that may resonate with patients that, hey, I use that medicine and it worked for me, and this is the same mechanism of action. So we do discuss these things with patients. Some patients are more interested in that than others. Mostly, they just want it to work. But I think the familiarity with the mechanism here is something that they will recognize and we'll talk through as we make treatment decisions. So that's kind of our experience and my view on it.

Our next question comes from the line of Steven Seedhouse from Cantor.

Congratulations. What looks like the best onset of action ever reported across every single endpoint, really impressive. I wanted to ask directly about the competitor here and the comparison, just a couple of more details. First, specifically with reference to the drug-drug interactions and CYP3A4 inhibitors in that drug's label, can you comment on the strength of any CYP3A4 interaction with deucrictibant? Is it a substrate? Would you expect similar drug interaction language in an eventual label?

And then also the importance of a single capsule here for deucrictibant versus needing 2 tablets. Do you think that would be, albeit a small but potentially meaningful difference in the marketplace?

Yes. Thanks, Steve. So I'll hand over to Peng to comment on the CYP3A4 question you had. So start with that.

Yes, sure. Steve, good question here. Indeed, that deucrictibant is mainly metabolized by CYP3A4. Therefore, from the drug-drug interaction part, we would expect to avoid using deucrictibant with a strong CYP3A4 inhibitor or inducers. That's consistent with for most medications that are metabolized by CYP3A4.

Yes. So on the softgel capsule in the single pill, of course, what's relevant here is, of course, the -- in addition to the portability and the ease and simplicity of a very small softgel capsule, it's also important here is the need or lack of need for a second dose. I mean the confidence that the patient -- more confident the patient is that this taking one pill or tablet is going to take care of it and not have to worry about or have anxiety about should I take a second dose or not is a key factor here. So the convenience of a very small, simple softgel capsule in combination with the potential of resolving the attack with just one dose, I think will be the key parameters here that are important.

Could you -- just a follow-up, any chance you have data handy on what percent of the patient demographic were broke out between type 1 versus type 2? Like was the vast majority type 1? Just want to confirm that.

Yes, indeed, the majority is that patients around 90% are type 1 patients.

Our next question comes from the line of Jeff Jones from Oppenheimer.

Congrats on the data. Two quick technical questions and then a strategy one. Was there any difference in response rates based on HAE type, although, as you noted, 90% of them were type 1. And can you comment on the average time from the onset of attack to treatment in the study?

Peng, over to you.

Yes, sure. As just presented for the study that the majority patients are type 1 patients and around the 5% to 7% type 2 and then the 3%, 4% type 3 patients. And we indeed did a subgroup analysis and will be presented in the future conference that actually docs read out there and will be presented that maybe in the quality eye there. And currently, we can only share that the efficacy is consistent and robust across all the subtypes.

Okay. Any comment on the time to treatment?

Yes. Currently, because that we mainly work on the top line readout, we do not have the detailed information to summarize for the time to treatment because it's not included in the primary and secondary endpoints. But meanwhile, that we expect the time to treatment will be consistent as we ever observed for the Phase II study.

Okay. And then on strategy and next steps, can you comment on estimated timing for regulatory filings and any commentary on commercialization plans?

Yes. So I think the -- we also mentioned that I think in the press release, we aim to file here in the next year in '26 in the first half of next year. And of course, the team is working hard to get the file together as already started, of course, and to do that as fast as we can because we get this through the regulatory process and to patients as soon as possible.

Maybe to add to that, Jeff, from a commercial perspective, we have had a very prudent resource deployment strategy, which means that we have invested in top talent. So we have on our leadership, long-standing experience in HAE hired, people that have done the prework for the commercial launch. Anything that is on the critical path has been on track. So nothing is lost there. But obviously, the big increase in gearing will be for next quarter and the quarters thereon. But we're going to be launch ready for this product. We are super excited about this. The community is very excited. So it's going to be fun.

Our next question comes from the line of Laura Chico from Wedbush.

One on the baseline properties of the RAPIDe-3 population. If I contrast the -- on the primary endpoint, the response of the placebo group, the median time to reaching the PGI-C endpoint was greater than 12 hours. But if I compare that to the other oral therapy, it just seems like the RAPIDe-3 population might have been a tougher to treat population, even though you still did achieve a 1.28 hour median time. So I'm just kind of curious if there's any kind of qualitative comments you can make in terms of the severity of the RAPIDe-3 population? And then I have a follow-up for Dr. Riedl.

Thanks. That's an interesting question. So Peng, can you add some color on that?

Yes, sure. Actually, good question, Laura. I think that within this study, we covered that attacks that with varying severity and also our location there. And regarding the percentage, we have around 20% that mild attack and half that 5 -- 0% moderate attack and about 30% of severe and very severe attacks. It's very representative for all the attacks that typically treated with on-demand treatment. And here, indeed, that we are also surprised to see that the placebo group even did not achieve that onset within 12 hours.

There may be 2 factors. The first factor is actually it's 49% patients that achieved onset that around 12 hours, it just missed the medium time there. The second is that because that you can see from the other, that rescue medication use curve, around 44% that the placebo patients actually use the rescue medication. Therefore, they will be censored at the end of assessment window. That means that they're beyond the 12 hour there.

Okay. That's very helpful. And then one question for Dr. Riedl. There's been a narrative that we've heard from investors, not patients or providers, but that increasing availability of oral on-demand treatments might actually lower prophylaxis use rates. And I'm curious how you see that happening. I know you mentioned the burden of treatment, but do you see prophylaxis rates remaining at this level going forward? Or how are you thinking about that in terms of managing your own patients?

Yes, it's an excellent question. It's something I've actually thought about a fair amount. And I also had, I will say, had some suspicion that we might see some -- a little bit of erosion of long-term prophylactic therapy as on-demand treatment has become easier recently. I have to say, so far, that hasn't materialized. And so in the clinical space, we still see people very enthusiastic about long-term prophylactic therapy. I think there is a predictability to life that, that lens that's very attractive and allows them to get on with their lives without worrying so much about attacks.

So to answer the question, so far, no, we haven't seen this erosion of long-term prophylactic therapy. And that might also be due to the fact that, as we all know, the long-term prophylactic therapies have continued to evolve also less burden of treatment, longer, more durable medications, longer duration effect, easier to use and so forth. So we're still seeing not all, but the majority of patients on long-term prophylaxis.

I guess the last piece of commentary, which is just real life is I don't see people moving away from long-term prophylaxis. But if I put it in lay person's terms, they're cheating a little bit more maybe. They're maybe not dosing quite as often as prescribed with their long-term prophylactic therapy. And I think that's just human nature to try to use as little medicine as you might need to, but not going off long-term prophylactic therapy. We really haven't seen that so far.

Our next question comes from the line of Sushila Hernandez from Van Lanschot Kempen.

Congrats on the data. Could you elaborate on the importance that deucrictibant was explored in all HAE subtypes and what the potential approval means for these patients? And for Dr. Riedl, what are you looking out for, for the prophylaxis readout next year?

Yes, Sheila. So the -- the applicability to all forms of angioedema is primarily related again to the mechanism of action of bradykinin inhibition at the end of the pathway or the cascade at the receptor level, so which enables the treatment of potentially of all forms of angioedema. So that's the key point there. And I'm sure Peng also has some comments to add there as well.

Yes. As Dr. Riedl have already highlighted that for -- as a B2 antagonist that we expect that deucrictibant is able to cover all the angioedema needed by bradykinin. That's -- actually have a lot of discussion with the community. But that makes us excited is that for the study, we first actually enrolled really the normal C1 patients in the pivotal study and able to show the data and to really provide more information for the clinical practice that how we can help the normal C1 patients. But Marc, I will also hand it over to you for the question.

Sorry, the question was related to additional readouts? Or could you repeat the specific question?

Yes. So the importance of this potential approval for all HAE subtypes and also for the prophylactic readout next year, what are you looking out for?

Yes. Sorry. So yes, I think the subtypes of HAE, certainly, studies up to this point have largely focused on type 1 and type 2 C1 inhibitor deficiency patients. There is this, we think, rare form of HAE normal C1 inhibitor, which we used to call type 3. We're trying to get away from that terminology because that's clearly an umbrella of probably various different types of mostly bradykinin-mediated angioedema. So I think there's increased interest in looking at that population because there's a huge unmet need there. And you saw the inclusion of a small group of genetically defined HAE normal patients in this study, and there may be some additional studies with that sort of small population looked at.

So I think it's always difficult to say much about a few patients, but I do think that it looks that this was a favorable outcome for that subset of HAE as well. And that is a group of patients that need treatment, and we've had very little data to date. So the hope would be that we have data we can point to that will allow us to treat those patients with deucrictibant or other therapies, which will be very positive.

As far as additional readouts, I think in the coming year or so, certainly, you heard about the oral deucrictibant for long-term prophylactic therapy, the CHAPTER study. I think that will be very important. As I mentioned earlier, we've seen lots of interest in oral therapies, which has been borne out with berotralstat and sebetralstat and now deucrictibant. And I think an oral therapy with high efficacy for long-term prophylaxis would be another big step forward. So we look forward to that data.

I think beyond that, as people are aware, there may be additional data on the Intellia CRISPR/Cas9 program, we're looking forward to seeing. And then maybe a little further down, but Navenibart as the YTE modified monoclonal antibody and then siRNA therapies behind that. So I'm not certain on the time line for when those studies all roll out with their data, but certainly looking forward to seeing what those studies show.

Our next question comes from the line of Jacob Mekhael from KBC Securities.

Congrats On the data. I have one for Dr. Riedl. Maybe could you share or maybe quantify the proportion of your on-demand patients that you would expect to ultimately switch to oral? And maybe are there any patients that would still prefer an injectable option? And if so, what are the reasons behind some of those preferences?

And then I have a follow-up on maybe the prophylactic program. If you can share any updates with us on the recruitment there? And could you potentially be in a position to accelerate the time line for this readout as well?

So I maybe start, Jacob on the last question. So we -- our guidance for top line data for the PROphY study is second half of next year, and the enrollment is going as expected. And so we are also looking forward to that data readout next year. So that's all on track at this point. So -- and then on the other question, the line was a little bit weak. I couldn't hear exactly what the question. Would you mind repeating the first 2 questions?

Yes, sure. I can repeat that. That question was for Dr. Riedl. If you can quantify the proportion of your on-demand patients that you would expect to ultimately switch to oral? And are there any patients that would still prefer an injectable option? And if so, what would be the reasons behind some of those preferences?

Yes, sure. Happy to share my experience because this is, as you can imagine, something we're actively talking through now that we have some oral options. The vast majority of patients that I manage are interested in oral rescue treatment. It's just my experience, but if I had to put a number on it, I would say 80%, 85% are very interested in using oral rescue medicine. And our experience to date is that most, not all, but most of those patients have a good experience with that and tend to stick with it.

There is a subset of patients that continue on either subcu or intravenous rescue therapy. It's a small percentage, but there are people that say, you know what, I'm good with this treatment. I know how to use it. I don't have major intolerable side effects, and I trust this medicine. I know it works for me. So that is a small subset of patients. And then we have had another small subset of patients that have tried the existing oral therapy and decided that for whatever reason, it didn't work fast enough or well enough for them compared to their subcutaneous or intravenous treatment.

So there have been some that have trialed it and decided to go back to their previous rescue treatment. It's a small subset. It's not the majority. But those are some of the reasons, I think, either -- inertia is a strong thing. I'll stick with what I know and what I'm doing or the injected medicine simply worked better for me, faster, more durable, whatever the reason may be. So we have seen a minority, I would say, maybe 20% of patients sticking with the older, more conventional therapies versus the oral, but most have been -- have pretty quickly adopted the oral rescue medications.

Our next question comes from the line of Patrick Trucchio from H.C. Wainwright & Co.

Congrats on the data. The first is for Dr. Riedl. Just wondering on the 11 secondary endpoints that met significance, which do you view as the most clinically meaningful? End of progression, substantial relief or complete resolution?

And then just separately, can you share results from the adolescent performance in RAPIDe-3? And was the PK and efficacy profile consistent with adults?

And then just lastly, I was wondering what data specifically from this data set could inform expectations for CHAPTER-3?

Yes. So I think the first question was for Dr. Riedl. So over to you.

Yes, sure. So of those secondary endpoints, the end of progression is one that we're talking about a lot more, and I think has become an important one. And I think Peng talked about this a little bit in her presentation. But if you talk with patients, that's honestly what they're very interested in is at what point does the progression stop, meaning I'm not getting any worse because their experience with their attacks is that once that happens, they know that they're going to get better. And of course, they want to get better as quickly as they can. So those other endpoints are important, including up to complete resolution.

But psychologically, I think, and I don't want to speak for patients, but this is what they tell me, that end of progression is actually very important. And the faster that they can recognize that, the more confident they are that this attack is on its way out, and I can start to get back to my normal activities. So of all the data you saw outside of the primary endpoint, I think that end of progression one is something that's very meaningful to me as a clinician and also that's what I hear from patients.

So, Peng, about the adolescent PK.

Yes. Actually, I will give maybe the same answer as novel C1 here that we will definitely share the subgroup analysis data in the future conference. And -- but overall, I think the message is consistent that we did indeed the subgroup analysis and the data that especially for primary endpoint and others are consistent for the subgroup compared to overall population. Regarding the detailed data that we will not share today, but we will share soon in the medical conference there.

Regarding the -- your third question, the CHAPTER-3 data, I think that based on today's data and based on the -- from the science that to our journey of the clinical research, we do feel that the RAPIDe-3 data that even that confirmed with the findings from the RAPIDe-2. Actually, I have to acknowledge beyond my expectation is with a more heterogeneous population of the Phase III study, we still can demonstrate that as strong data as our Phase II that even boost our confidence for the CHAPTER-3 readout.

There are no further questions at this time. So I'll hand the call back to Maggie for closing remarks.

Thank you very much for joining us for the RAPIDe-3 top line data presentation. We're grateful to everyone who contributed to the study and to the outcomes that we see here today. If you had any questions, please let us know, you can reach out to me directly. This concludes our conference call.

Well, hello, everyone. I'm Max Skor, biotech analyst with Morgan Stanley. Before we get started, I just have to read some quick disclosures. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

And now I'd like to introduce Pharvaris. Very happy to have the team here, Berndt Modig, CEO; David Nassif, CFO. Welcome. Thank you very much for attending this year.

So just to kick things off, could you set the stage by walking us through deucrictibant's value proposition across both acute and prophylactic treatment of hereditary angioedema.

Yes. Thanks, Max, and great to be here again. So deucrictibant being an oral therapy option is -- fulfills a very specific unmet need in this space that we've seen over the years. And so that's a key feature, of course, the oral aspect of it. And you expect that the oral segment and the desire and the preference for oral in the patient community is very high and to have a more convenient therapy that function -- allows function and normalcy in patients' lives. But it doesn't -- it starts with oral, but it doesn't stop there, of course. The paramount proposition is for any therapy and especially also in HAE is efficacy.

So the -- to have an oral in combination with a high efficacy, we describe it as injectable-like efficacy based on the current therapies and the efficacy level that we see there. And to have that in combination with an oral is one of the key propositions. And then, of course, given that this is a lifelong treatment also a placebo-like tolerability and something that is not a big burden on patients and the side effect profile that's also, of course, key. So it's all about these 3 pillars, you could say, currently. Today, in our view, there is no therapy out there today that really meets all those 3 requirements fully.

Okay. That's great. So hereditary angioedema, it's an exciting space, a lot of new players and therapies are becoming available. But can you share your perspective on the evolving HAE market, particularly trends in treatment adoption and maybe talk to the incidence or prevalence rates in the United States and the mix between on-demand and prophylactic treatment?

Yes. So in recent years, I mean, of course, the prophylactic segment has grown and has been established with the -- primarily also with the introduction of injectables with a relatively low injection frequency like TAKHZYRO. And so the guidelines for treatment in patients living with HAE is to maintain as much as possible freedom from attacks and have as low attack rate as possible. And so the growth of the prophylactic segment that we see continue. I think it's about 67% in terms of the population today and growing and about 80% in terms of the value in the prophylactic segment.

But having said that, I think also the on-demand segment is also very viable in our view. It's a different way of treating. It has to have some flexibility that prophy doesn't have, especially if you're on the long-acting injectables, you have your drug in your system in a very long time. And so the innovation in the on-demand space is also important. We haven't seen that to the same degree in the last decade. So an efficacious oral therapy also for on-demand, we think is also a very viable proposition.

Okay. And there was a competitor in the on-demand space that recently launched. But what I think is interesting from a competitive perspective is deucrictibant based on 2 different formulations, you're able to potentially address both the prophylactic and on-demand. Can you potentially -- can you talk to that dynamic?

Yes. I mean that is the -- as also we say in our corporate presentation, science for patient choice. And so I think the decision how to manage the condition in HAE is a very individual decision and what your preference is and what your daily circumstances are. And it's not just calculating the number of attacks. It's about how the patient feels about the attack and what is the anxiety level of going through an attack and the unpredictability. So that all drives the decision whether a patient wants to be on prophy or on-demand.

And I think having the same active ingredient in 2 formulations gives us a clear differentiation in this space. And also newly diagnosed patients typically start out a good therapy in adolescent years and on-demand therapy might be practical for that patient population. And then as they continue and sometimes typically you see attack frequency goes up over the years. And then if the patient is comfortable with deucrictibant in one form, they can also then go over to prophy and have that maintain the comfort that they then could have potentially with one drug.

Okay. And based on your market research and talking to KOLs, what is their view on having 2 different formulations, but one option potentially?

I mean generally, that's perceived very well. I mean I think that that's -- there's also -- sometimes people ask about the -- if there's any sort of mechanistic differentiation there in terms of treating a breakthrough attack. So with the same compound. And then from a mechanistic perspective, that is not -- there's no difference. There's no specific rationale to use a certain drug in prophy and then another one to treat a breakthrough attack. You could -- because it's all about the maintaining the plasma exposure level that's associated with therapeutic efficacy. So that's just not unique to deucrictibant. That's true also for the other therapy.

Okay. And before we dive into the data, maybe just refresh our memory in regards to the mechanism of action, how it differs from the competitive approaches, bradykinin in general?

Yes. So the -- what -- we are the only company out there with as you mentioned, a formulation, both prophy and on-demand with the B2 receptor antagonist. And we started out with [ Pharvaris ], my co-founder is an inventor of icatibant. So a very deep understanding about the pathway and that receptor. And so we've seen the efficacy that's been able to be achieved with bradykinin inhibition at the end of the cascade.

It also has the advantage and the potential advantage to treat other subtypes of angioedema, not just the type 1 and 2. For example, patients with other mutations and normal C1, is call plasminogen are then have an overproduction of bradykinin and have the same clinical manifestations as type 1 and 2, but it's a very different pathway. It goes bypasses its kallikrein, it's kallikrein independent. So that being at the below at the end of the cascade with B2 receptor antagonist provides a mechanistic advantage.

And maybe we'll touch on that at the end, but that's an important point. So moving on to on-demand. You recently moved the RAPIDe-3 Phase III readout up to the fourth quarter of 2025. I believe it was initially you were guiding to the first quarter. So before we look ahead, can you walk us through the key efficacy and safety data reported to date? And what underpins your confidence in this readout?

Yes. So we were very excited when we saw the Phase II data, of course, I mean that -- the benchmark so far has been the efficacy level of the icatibant. And I think that the deucrictibant based on the data that we saw in the Phase II is it's, of course, the onset of symptom relief, which is the primary endpoint. That's the key parameter. But it doesn't stop there.

It's really also about the completion of the resolution of the attack, the need for a second dose. And on those parameters, the Phase II data that deucrictibant shows a clear differentiation, both against icatibant as well as against other therapies that we have seen for on-demand. So that is something that we, of course, hope to see similar data in our Phase III study.

Okay. That's very helpful. I think in your corporate deck, you do a great job kind of laying out the competitive landscape, what other options, both injectable and oral are out there. Maybe we can drill down just a bit on key data points. You highlighted qualitatively what you're looking for. But is there anything quantitatively we should keep in mind when the Phase III data comes out?

Well, I think as we sort of look at the whole sequence from when the attack starts until the complete resolution, as I mentioned it's important to really to look at the totality of that because that ultimately what the patient is looking for is a reliable resolution of the attack in a good time frame with ideally we only 1 dose. And so the -- in our trial, we also have a specific endpoint, one of the secondary endpoints called end of progression, which is unique to our trial, and that is even before onset of symptom relief. That's when the patient then starts to see that the attack is getting under control.

The primary endpoint on the onset of symptom relief is important, but it's only the beginning. And we also expect to see -- I mean, based on what we've seen so far, that's relatively similar in the -- compared to standard of care compared to other oral therapy and also deucrictibant is in the range of 1 to 2 hours. And -- but where we then need to look further is, of course, the reduction of severity called that [ 50 ] and also the need for a second dose. And I think there, based on the Phase II data that deucrictibant has a meaningfully lower usage of second dose and also the number of attacks within 24 hours result with only 1 dose is also very different in the data. So those are the things to look for to really see the differentiation between the other therapies.

And do you think it's appropriate or are you looking at it internally as trying to achieve injection-like efficacy or just compete against the other potential oral that is out there?

Well, I think I mean the Phase II data shows, we think, that deucrictibant has overall better data than even the standard of care today, better than icatibant. And that is also partly because we think because of the longer half-life, the lower need for a second dose. And I think that the other oral therapy does not really meet the level of the current standard of care in the injectable. It has the oral convenience, of course, but it doesn't have the -- from what we can see, the efficacy, and that's what we hope to provide that bring a meaningfully better efficacy.

Okay. That's very helpful. So how are you aligning Phase III with label relevant claims, payer expectations versus rivals? And will you pursue head-to-head or structured indirect comparisons to make differentiated claims at launch?

We're not directly planning to do any head-to-head at the moment, but it's potentially at some point in the future. I think the differentiations will be also, of course, developed by the data as such and the parameters that I mentioned. It's also that -- and for example, in on-demand, I think the key thing of importance to payers is the resolution of attack with 1 dose. And I think also from a patient perspective, we think that, that is a very significant difference because the anxiety of wondering should I take a second dose or they need a second dose or not is -- adds to the complexity. And so to have the 1 resolution with 1 dose, I think, will be also an important aspect not only for patients but also for payers.

And before we move to prophylactic, can you just touch on again what drove the acceleration in time line or moving up from the first quarter to the fourth quarter?

Yes. So when you start out this study, of course, the on-demand study is the first step is to complete the enrollment. And then after that, we collected -- I mean, we're also concurrently then collecting the database with the attacks. And then that went very quickly, a little bit faster than we had anticipated. We're excited about that. I think that also highlights the level of awareness about the program and interest in patients participating in the trial.

So we completed the enrollment in 12 months. That was faster than the Phase II. And then now based on our assessment of the database of attacks collected, et cetera, and the quality of attacks, then total assessment then provided us the comfort to update our guidance.

So I'm assuming there's going to be inevitable cross-trial comparisons. Is there anything you would call out baseline characteristics, attack frequencies, just severity of the patients overall compared to your competitors that you'd like to highlight?

I think it's very similar. I mean we have -- in our Phase III trial, we also allow for a smaller number of patients to be on a prophylactic treatment during the trial. So we may see some attacks may be milder potentially and -- but it's a minority number of patients that is controlled and limited that can be on prophy.

I think we still have the same criteria that we have in the Phase III trial in terms of attack frequency to be eligible to enroll and also to qualify the attack like we did in the Phase II that is considered in the assessment of the physician -- treating physician than the real attack and not just something else. So that all those parameters are the same as the [ Phase II ].

So no major changes from the Phase II to the Phase III?

No, I think that, that is maybe the key change. I mean, of course, the general Phase II, Phase III with more sites and all that. That's not unique to our Phase II, Phase III, that's typical for the Phase III trials that we have a broader footprint. And then we also have a very small number of patients with normal C1 included in the trial. And so we can collect data on those patients, then that could potentially support an expansion in the label of deucrictibant, which would be another differentiator.

Great. So pivoting to prophylaxis. With your pivotal chapter 3 Phase III readout expected in the second half of '26, can you recap the most important data you've shared so far that kind of frame expectations for this program?

Yes. I think I mean moving -- switching gears to prophy. It's relatively more straightforward or simple in terms of both in terms of trial design and also in endpoints. And there, it's really measuring the reduction of attack compared to placebo. And in our Phase II trial, we had about 87% attack reduction compared to placebo. And so that is clearly in the range of what we call an injectable-like efficacy. So in combination with the oral, which I think as I mentioned initially, is something a key differentiator for deucrictibant. And also, I think 49% of patients had 0 -- or were attack-free compared to placebo.

In our open-label extension, then we had an improvement of -- further improvement of attack reduction to 93%. And for attack reduction of severe attacks of 96% and the median attack rate was also 0. So again, in the Phase III trial, then we have 80 patients to be enrolled. In the Phase II trial was about over 30 patients in 3 dose groups. So now we have 80 -- in Phase III, 80 patients in the -- with 1 dose. So it's clearly powered more for collecting safety database rather than powered for efficacy. So it's well -- is very highly powered on the efficacy side.

And is there any chance we'll see this closer to the middle of the year? Or we're going to keep guidance around the second half?

I mean right now, the guidance is maintained in the second half, and we -- enrollment is on track. We had -- sometimes in some sites, especially in Europe, we see a slowdown in the summer period, but we actually we didn't see that. So we were happy about that. So things are on track. And once we -- when we get more visibility on the enrollment completion, then we may provide more precision in the guidance. But right now, it's still the second half next year.

Okay. And maybe you can talk about the potential patient profile because there are a lot of competitors in this space, different modalities that are being investigated. But is there a specific attack phenotype or patient segment you think deucrictibant would address that others won't?

Well, I think starting with newly diagnosed patients, I think we see the preference for an oral and it is very logical then to possibly start out with an oral therapy once you have your first diagnosis. We see about 150 to 300 new patients coming in every year. And if you are able to provide the level of therapeutic satisfaction to these patients, then they presumably would stay. I mean the switching that you see in the HAE space and continue to see is really driven about -- by the lack of satisfaction. The patients are still looking for something that works better. I think about 67% of patients based on a survey, they are still not satisfied with the treatment. So they're looking for something better.

So first-line oral within highly efficacious oral, I think it will be a key factor. I think also in the younger population within the on-demand, I think it's also the patient segment that can then benefit. And then I think the overall availability or affordability of a convenient oral is the many patients today that just don't carry their therapy with them and there's a lot of attacks that don't -- that still go untreated.

Okay. And then just talking more broadly, given that there are 2 oral options on the market for prophylactic and on-demand, what learnings would you take from the experience for these companies launching their drugs? And then thinking about prior authorization, the payer dynamic, pricing, I know it's too early, but anything you could provide around that would be helpful.

No. I mean I think our competition has done a very good job in launching from what we can see. And the -- I mean, I think it also highlights the really high unmet need for an oral. And so I think that in combination with the search for even -- for good efficacy also in an oral, I think, makes us excited and optimistic about deucrictibant. And I think on the payer side, there has been no real sort of drastic changes in the pricing landscape. I don't think because of the new therapies that have come seems to maintain the current structure.

I think on the on-demand side, the -- again, the best attack resolution with only a single dose, it will be a key differentiator in the eyes of the payers because we've been -- to really know what the attack if you have to treat a lot of attacks with the second dose, and you have uncertainty there and the lack of maybe control in the eyes of the payer, how the patients is using the different 1 dose or 2 doses, et cetera, adds complexity. And so I think the payers -- from a payer perspective, the attractiveness of single dose solution is important.

Okay. And then pivoting, I believe the FDA accepted the TQT waivers for both formulations. I think this is important overall based on how it differentiates you from the prophylactic option on the market. But could you speak to the advantages in regards to milestones or cost and time overall?

Milestones of...

Well, just talking about -- because we won't have to run an additional study.

I see. Okay. Yes, of course, I mean that is what enables us to have the time line guidance that we have now. So the -- and we had provided full nonclinical and clinical data and assays and modeling and all of the totality of that assessment and satisfied the FDA to give us that waiver. So we were happy about that, of course. And I think that is also another differentiator, we think, of deucrictibant.

Because Orladeyo did not...

One of the many differentiators...

Yes. Orladeyo was not granted that same waiver, correct? Because at higher doses, I believe it has some potential issues there. Okay. So moving on, maybe you can just talk about the next -- I mean, it's going to be an exciting next 6 to 12 months. But what should we keep an eye out for in regards to milestones, catalysts. How is CMC manufacturing going and any predicted regulatory interactions?

Yes. So the completion of the Phase -- top line data then in Q4 on-demand, and then we will then work hard to get the filing done as quickly as possible. So now got it in the first half of '27. And then we look forward to the data readout in the second half of next year for the prophy and then that will follow the same filing as well. We also expect to -- so we had seen based on those time line and if they work out as we anticipate then potential launches in the first half of '27 and the first half of '28 for on-demand and prophy, respectively.

And then we also have initiating a trial in acquired angioedema later this year. And that is with the aim also to get the label in -- for that indication. So if we are successful in that to get a broad label for deucrictibant in what's called bradykinin-mediated angioedema, not just type 1 and type 2. And if the timing works there, we -- together with the prophy data, then to potentially file all that together with the NDA for the prophy data. But that is, of course, subject to completion of that study in time.

Okay. I believe there's an investigator-initiated study that provided the supporting data to move into other indications. Can you talk about the data to date, what the opportunity looks like?

Yes. So you're correct. So there's an investigator study that's been conducted both in on-demand and prophy, and also using the extended-release formulation, by the way, in a small number of patients, only 4 patients. But what we -- these are patients with acquired angioedema that typically then use icatibant off-label and they investigated deucrictibant in the prophy setting with the XR tablet. And then we've seen except for one attacking in the first day or 2 with patient, all 4 patients have been attack-free now for almost 18 months.

So that's very encouraging, not just for the indication of the acquired angioedema, which follows the same pathway, and it's also production of bradykinin through the kallikrein pathway. This, of course, also gives us additional insight into how the XR formulation works in the prophylactic setting.

And just the relative market opportunity there compared to HAE.

So yes, so right now, these are patients that are referred by other physicians to HAE treating physicians because they experience these attacks. And then if they are suspected or diagnosed by the kind of mediated edema, they get the treatment. That's about 10% of the type 1 and 2 today. But these are patients that are treated by other physicians, but possibly the level of awareness is not as high. And so once there is a drug or with the label for that indication, then it enables us also to increase and work on that segment of the market to potentially increase that even further.

Great. So maybe one question for David. In regards to financials, I believe you reported around $200 million in cash, cash equivalents at the end of 2Q. You recently raised extending the runway to the first half of 2027. So how are you prioritizing capital allocation across pivotal trials, commercial build-out and thinking about potential BD opportunities?

Sure. So the guidance of cash runway into the first half of 2027 assumes the completion of the on-demand, prophy and AAV studies and of course -- and also the filing for ODT and prophy. It also assumes the build-out of our U.S. sales and marketing infrastructure. We'll probably be at around 80 people by the end of '26 and maybe 90 by the end of '27. So we're adding a few more for prophylaxis. So all that's baked into that H1 2027.

We do have an active BD effort. The guiding criterion for doing a deal is can a partner or a distributor do a better job directly outside the United States than we can. Obviously, it could also result in some upfront or milestone payments that might be helpful. But at this point, given how close we are to Phase III data approval or filing and approval, we have a whole array of nondilutive opportunities available to us from debt to royalty to other kinds of structured finance, all of which get easier and less expensive as you get closer to launch. So we're in very good shape from that perspective.

Okay. Great. So pivoting to a couple of survey questions that we've been asking our covered companies. With China's rise in biotech innovation, how are you thinking about your competitive position here? And will this influence your R&D or BD strategy?

Right now, I mean, of course, there's a lot of innovation coming from China, and we are watching that closely. But there's nothing that has a really immediate impact on us at this point in time. And so of course, for Pharvaris, it's also thinking about what could be the next product after deucrictibant. And so looking at what can be built in-house or what can be sourced outside, et cetera, in China, of course, new innovation comes there.

So that is conceivably something that we can look at, at some point. I mean in terms of our commercial opportunity in China, that's also a market for HAE that's significant. And -- but it's -- of course, as everybody knows, a complex territory and most likely for a company our size that we'll be working with the partner. But it's definitely an opportunity that we think is worthwhile exploring.

Helpful. So how are you currently leveraging AI or thinking about AI's future disruption potential?

Yes, we are -- I mean, like most other companies, I can imagine, are looking into AI. We are -- have a sort of a pilot in-house where we're looking at the use of a proprietary sort of AI platform then to our model, not meaning that it's not data that goes into the public domain. So something that's sort of in-house to use for medical writing to support data analysis, et cetera.

We have not really looked at AHI (sic) [ AI ] at this point as a way to reduce number of employees or anything like that. I think that that's -- we're looking at it as a tool to support it to supportive -- to support some processes maybe and also generate writing and things like that. So there's much more you can do with AI in the pharma setting, of course, also at the commercial stage, and we're looking into that also in the future and making projections and forecasts and things like that.

Interesting. Okay. Last question. What has been most impactful from the regulatory side? Would you say it's the FDA, MFN or tariffs?

Well, I'd say, first, I'd like to say that, I mean, everybody ask us, and I think every company gets the same question now these days, how is the interaction with the FDA. And then we have very positive interactions with the FDA. We found the people that we deal with, with the FDA to be extremely supportive and constructive. And so we have nothing but good things to say about that.

And on tariffs, we have a -- being an international company, something, obviously, we're looking into and also looking at potential mitigation strategies there. I mean, within the legal framework. And so it's something that we are not overly concerned about. I think we have some flexibilities there. And it's also something that the whole landscape that might change in the future as well.

There's a lot of things going on in that topic, as we all know. And then same is for M&F (sic) [ MFN ]. I mean that's something that -- watching that as a small company, influencing that. I think it's hard for us as a small company to do. But I think there's a lot of attention to that topic. And I think how that will shake out in the future, we will have to see.

Okay. Well, with that, I think we're up on time. Thank you very much for your time. Appreciate it.

Yes. Great. Thanks, Max. Thank you.

Thank you.

My name is Tiago Fauth. I'm a biotech analyst here at Wells Fargo, joined today by the Pharvaris team. I appreciate you guys joining us today for our healthcare conference. We're going to do a fireside chat and run through some questions. Usually, I'd like to start by giving you some room to just do intro remarks; where the company is today, next upcoming catalysts, and then we'll dive into the more nitty-gritty questions.

Very good. Well, thank you, Tiago. Thanks for having us here. Pharvaris, we're a late-stage pre-commercial biotech company. We are in Phase III right now for 2 products. One is the deucrictibant IR, immediate-release, a product for the treatment of HAE attacks. And the other one is the same active ingredient, deucrictibant, but in an extended release form for the prevention.

The key -- it's very exciting times for us because end of the year, we'll read out our first Phase III for on-demand, followed by a filing in the first half of 2026. And then in the second half, we'll have the readout of our second Phase III for prophylaxis. So we're very excited here to get our product to patients as soon as possible.

There you go. Easy enough. So the HAE market, I guess, let's start there, right? So perceived to be very crowded, but also growing, it's a substantial market opportunity. So I understand why there's continuous innovation there. What are some useful ways of trying to subsegment that market? Again, on-demand prophy are kind of the classical. I don't know if there's any other subsegmentations that might be helpful to think in terms of what's going to grow, what's going to expand.

Yes. Well, very good. So as you said, we'll start off with the basics, on-demand and prophy. Well, we anticipate that both markets will grow independently. The on-demand market will grow particularly because of the entry of oral opportunities, oral products that will lead to hopefully more attacks being treated. We know that today, about 40% of the attacks never go treated. Patients don't have the medication with them. They are reluctant because it's very painful to inject yourself with some of the treatments. And sometimes they are -- can you say the attack is not severe enough.

Having an oral can really radically change that. And so we anticipate that in the next couple of years, we'll see growth in on-demand. That said, the biggest part of the market is clearly prophylaxis. Even today, in the U.S., there are about 60% of the patients on prophylaxis, but they represent 80% of the value. And that comes because of the yearly cost for prophylactic treatment. So the prophylactic market, we kind of look at it as a market that will ultimately evolve in a blue ocean and a red ocean, the blue ocean being the orals and the red ocean being the injectables.

What I mean by that is that when you start on prophylaxis, today already, the majority of patients who are new to prophylaxis start on Orladeyo. It's kind of logical that you start on an oral in this space. For most therapeutic areas, orals are the first step into a treatment. And once you don't respond, you want to have something better, you go to an injectable.

Our plan is -- our ambition is to really capture the majority of those new patients once we get approved. Every year, there are between 150 to 250 new HAE patients in the U.S. So they flow through to prophylaxis. So if we can capture those year-over-year, combined with a much lower dropout rates than Orladeyo because we seem to have at least numerically a better efficacy level, that becomes a pancake effect, whereby we build up significant share in the market.

So that kind of first-line option with orals will ultimately lead to the orals obtaining at least 50% and probably more of the total market. And so why do I call it then a blue ocean, the orals, because there's going to be 2 competitors only. It's going to be Orladeyo and it's going to be deucrictibant. I think if you confirm the data in the Phase III from a Phase II, we are very well positioned to take a leading share in that segment.

On the flip side, you got the injectable market. In a couple of years from now, there might be 7 to 8 products competing for the same patient pool. Today, there's still patients on CINRYZE. They probably get CINRYZE until they die. There will be patients on HAEGARDA, there will be patients on TAKHZYRO. So all these 7 to 8 products, they might be a winner there, but they're going to have to share some market with the others. And ultimately, it will be much more easy for us to become a leading product for prophylaxis than it will be to any of those injectables in the market.

Got it. But then you assume that the growth on the share for the orals are going to be mostly from patient churn and the new patient starts. Like why is it so difficult perhaps to see switches at some point? So to your point, there seems to be a lot of patients that are very sticky to their brand, right?

It's interesting because stickiness is driven by how satisfied are you with your therapy and b, do you have an alternative. So right now, we know from patients, if you listen to the Harris Poll that was conducted by Ionis a couple of months ago, 65% of the patients on prophylaxis are not satisfied or would like to get a better prophylactic therapy. Better can be nominated in many different ways. It can be convenience, can be efficacy, it can be tolerability, you name it. But with a profile as deucrictibant, where you can offer injectable-like efficacy with very good tolerability and an oral daily regimen, we think we do can switch patients.

I spoke about the new patients. But by the time we launch, about 1,000 patients will have tried Orladeyo and come off. They are probably today on an injectable, but they have clearly shown that they were interested in -- so those are the patients we will go after. Thirdly, the Orladeyo patients that are so-called stable or sticky, they still have significant amount of breakthrough attacks, a lot of them. We're going to go aggressively after those.

And lastly, there are going to be some patients that are stuck with TAKHZYRO or HAEGARDA when Orladeyo came to market because they didn't want to sacrifice on the efficacy. But if they have an oral that has the same level of efficacy, they might make that move.

Especially for patients, as we mentioned, that have been injectable for a long time. A lot of patients, the physician noticed that they're already tired of injection. But meanwhile, they don't want to sacrifice anything regarding to the efficacy part, right? They're waiting for the alternative oral option can provide injectable like efficacy and also placebo-like safety there, so they can consider to try new options. That's exactly even though we consider maybe sticky to their brand, but because patients have no option yet, the 65% of patients are waiting still for the new treatment available.

Got it. No, I think that's fair. And again, to your point, your Phase II data stacks up really well against the competitive landscape, right? I guess the questions that you might get all the time is like how likely are you to actually translate that into the competitive Phase III? So lot of nitpicking there. So the first one is just related to the Phase II interpretation and monthly frequency attack relative to historicals and relative to typical Phase III trials. There are some differences there. So again, how reliable is the translation, I guess, of some of those findings?

Yes. Actually, that typically, especially for prophy trial that for HAE is quite standard that the trial design and all the endpoints there and also that if we look at the past development for prophy treatment and the translation from early phase to late phase and it's quite consistent, we have to say. And also, you mentioned a very interesting point is about that frequency attack, right, for patients there. Actually, if you look at all the prophy trial, especially for placebo group, you can notice the patient that attack rate is typically all around 2 attacks per month. So quite consistent across the trials.

And also if that we are lucky, we can get more severe patients that in the pivotal trial there, actually, it will be further boost efficacy because that really our primary endpoint is active treatment arm, the attack rate compared to placebo group, right? If the placebo group attack rate gets elevated, and a reduction that maybe we can even achieve 90% or above 90% reduction there, that currently is regarded as a ceiling of the efficacy for prophylactic treatment.

Got it. No, I think that's a fair point when you think about that. I guess the other question is just related to formulation, right? And again, [indiscernible]. What drives efficacy here seems to be fairly well understood from a PK perspective, right? So like what was the work that you guys did to be comfortable with the bridging between the 2 formulations?

Yes, that's really important for us, especially what's the major difference for us, from Phase II to Phase III. As is that for our Phase III study, we will use that once-daily extended release formulation. As you mentioned, that the PK and also that really the target therapeutic exposure level is very important for prophy treatment, especially the trough level typically was treated or regarded as a surrogate for efficacy.

Therefore, compared to the 20-milligram BID we used for Phase II and the 40-milligram extended release formulation we used for our pivotal study further boost the trough level for our -- that from our PK profile that looks like it's doubled, even more than doubled for the -- we call it C24. It's trough level we expected from Prophy trial.

So we have even fewer hours of patients at the lower trough level.

Exactly. We can consider we have more buffer room to consider the variability from the Phase III trial that a large patient population there. And therefore, based on the currently our PK/PD modeling there, we expect that the efficacy will be at least comparable to the Phase II and maybe potentially can be even better.

Got it. So I guess like the 2 points of risk that is brought up in terms of, again, the differences in baseline characteristics and also the formulation, theoretically, you guys feel like it should be the same, if not better.

Right, exactly. Not only [indiscernible], but you can see from the formulation that are changing here, maybe potential can even boost efficacy and reduce the potential safety concern because you know that the peak concentration is reduced that the PK profile gets even optimized for peak and trough ratio there.

Got it. And I guess when you're thinking about commercially, what is the bar of differentiation, right? So again, between injectables and Orladeyo, you have some buffer there. Like do you have to be exactly like injectables, not necessarily?

Yes. So before we had the Phase II data, we assessed kind of what would good look like. And based on the input of the market, we assume that as long as we had 75% attack reduction, we would be good. We would be able to win in the oral market. With the Phase II data now, our target has changed. We basically feel that we now have the duty really to make this product the leading product in prophylaxis, not just win against Orladeyo, but even, as I said before, to capture some of the patients from the injectables because injectable-like efficacy with an oral is a huge advantage.

We're seeing -- if you look at the uptake of Orladeyo, I don't think a lot of people would have predicted that based on the efficacy. They really have demonstrated. They've done a fantastic job, by the way, in commercializing. And we're going to steal and copy as much as we can from what they've been doing. But they also have shown how important this oral really is for American patients. So we're going to hopefully be able to build on that. And as Peng said, to raise the bar and really be in the right level versus the injectable as well.

Got it. Okay. And again, we talked about the competition. So again, share for new patient starts seems to be -- there should be a strong preference for oral. So again, the pace of that conversion could be a little faster if you get positive data and eventually get approved. The conversion from potentially either Orladeyo patients or injectables, that could take a little longer, right? And if you have a breakthrough, like how should we think about the potential pace of uptake in those subsegments in the prophy setting?

I think the switch from injectables is facilitated by the fact that it's an oral. So there is not a lot of -- if we -- again, if we confirm everything we've seen until now, there is now a price to pay to try it. So if you on TAKHZYRO , you get 85%, 90% attack reduction, you take a needle and you have then the option to say, try deucrictibant to daily pill, we don't anticipate any GI side effects, no tolerability issues and the efficacy is going to be similar. That's a relatively small step to try. That's partly why Orladeyo is successful. Oral, you don't have to do much.

So I think even though that it's in that whole pool of injectable patients, it might be a smaller group, I don't think it's going to be the whole group. But that switch is something that we really can induce. We can really achieve that by bringing the arguments forward about this trifecta of efficacy, tolerability and convenience. On the Orladeyo side, very similar. If you look at their real-world evidence, they show that patients still have attacks, a little breakthrough attacks.

If 50% of the patients have more than 1 breakthrough attack per month or one per month, we can really target those patients and you say, look, you have -- you feel you're good with what you have, but you can try the other one. And that's where the confidence around IR also can come in. Patients have used it, for instance, for on demand for rescue. They believe in the drug, see that it works. So yes, it's not going to come by itself, but I also don't think it's going to be climb in demand efforts to achieve that.

Has payers influence that the HAE market share substantially in the past? Or like how does that -- could that come into play here as well or not?

Not yet, really, particularly on the prophy side. On the on-demand side, there's a bit more discounting, but it's not really driving behavior. There are obviously prioritizations, potentially step edits. But given that most patients have already tried most products. It's easy to kind of -- it's a administrative hurdle, you have to go through it, but it's not a real hurdle.

On the prophylactic side, either that at the moment, there hasn't been a lot of rebating goal. So we don't -- a lot of preferential use [indiscernible] products. One of the advantage we could have there is a bradykinin-mediated angioedema label. So Peng is actually initiating a study in acquired angioedema. We've been asked by the regulators to include normal C1 patients in our on-demand and prophy Phase III programs.

If we can get a bradykinin-mediated angioedema label, that's different from our competition. It's basically a broader label and a broader label equates with potential preference from payers as well as for some physicians one-stop shop, don't have to think too much about it, much easier.

Got it. No, that makes sense. And again, we spent a lot of time talking about prophy, but your next data point is actually on demand. So let's pivot to that again. So data is Q4, correct? And again, what do you think you need to see there to differentiate versus standard of care or for like the new oral that has recently gotten approved in that market? Again, it feels like from what we know of the Phase II, the efficacy should stack up favorably, but what's the bar for success?

Yes. Good question. That's exactly we have high hope for our pivotal readout from our Phase III study here, especially based on our Phase II observation there. As we know that for the response, right, to the on-demand treatment, it's not as the only one part, it's a several part from how quickly that the symptom can be relieved and how quickly the patients can feel the attack severity can be reduced and how quickly people can feel they really go back to the normal life and no symptom anymore.

So all this perspective is a holistic package. We expect we can see the differentiation for deucrictibant there. So based on our Phase II data, we expect, for example, the time to onset of symptom relief may be between 1 to 2 hours. Currently, our data show 1.1 hour. So that's why we set up this window for the onset of the symptom relief. Meanwhile, that our data also shows that attack can be reduced from, for example, severe to moderate or moderate to mild attack within 3 to 4 hours.

Compare our -- the competitor there, it's significant, maybe better there, even though it's not a head-to-head comparison. And also, we expect that deucrictibant can lead the median time to the complete symptom resolution within 12 hours. And also, hopefully, in the future, it helps our payer discussion is that we also expect over 85% attack can be resolved with a single dose of deucrictibant. So all this, I think, is very appealing no matter if you compare the past standard of care or the injectables also compared to the new approved oral treatment.

Yes. And it must mean the commercial dynamic on the on-demand side of things is a little different, right? So what is a successful launch? What are some of the main drivers where you can actually gain share there?

So on-demand has the advantage that you can -- it's slightly easier to switch because every time a patient comes into the office to get a repeat script, you can basically be there and say, hey, why don't you try the other alternative? 1 attack, 2 attacks, just go. And I think our belief is that if patients really get the opportunity to try IR, they will notice the difference.

I think the product, as Peng was explaining, brings a full package. It's not just fast onset, it gets you really to complete resolution as rapidly as possible and with the confidence of doing that with one single dose. That's something, by the way, is arguing the payers. When we shared our data with payers, they were really impressed with that because that obviously has a cost implication. If you double the cost for an attack by needing a second dose, that can add up very quickly.

Got it. And again, if everything goes according to plan, you're going to be on the market for on-demand. How does that actually set up the launch in prophy? Like again, different formulations, different price points, different everything, but I'm assuming API is the same and there's going to be the trust on the data, right?

So I think the great benefit of having on-demand first is that it gives us a year or 9 months, 6 months, whatever the difference would be to build relationship with the community, to build trust in the compound and actually build up pent-up demand for the time we get approval. If you wouldn't have on-demand, you can't promote, obviously, your product beforehand.

We can't promote prophylaxis, but we'll be promoting on on-demand. And there will be a spillover, there will be a halo effect to that for the prophylactic approval. So that is -- it's a huge -- we call it a launch pad for prophylaxis because that's ultimately, I think, where we want to focus our efforts on, given also that the guidelines really clearly lay out that no patients suffer any attack. The only way to do that is with prophylaxis.

And also on-demand response will be very direct and straightforward. That's exactly as you mentioned, right, if the patients really get immediate response, then they indeed build up really great credit to the prophy use.

Yes. And some of the real-world experience actually builds up interest and the positive feedback to physicians on the prophy setting, so on and so forth. Okay. That makes sense. Again, the on-demand side, the business seems like it's been stable. It's not necessarily growing substantially over the last few years, and you are introducing more effective options, I would argue, over time. Is there some cannibalization here? You mentioned that you actually thought that both sides of the business could grow over time. Like what are some of the dynamics between the interplay in those markets?

So I think what we're going to see is in the first couple of years, we see a growth in on-demand, but then I think it will get caught up in the growth of prophylaxis. At the moment, there are about 60% of the patients in the U.S. on prophylaxis, but that's growing every quarter, small, 0.1%, 0.3%, 0.5%, but that continues. And that's why we anticipate that the overall prophylaxis market will grow to 70%, 75%, maybe 80%. It will never be 100%. But that ultimately will start taking away some of the market from demand. But initially, absolutely, there will be growth, we think, by more attacks being treated.

The other aspect that could help growth where we might particularly benefit from is the acquired angioedema segment. So patients with acquired angioedema, they, today, are only diagnosed because the doctor who's treating the underlying condition, whether it's lupus, MGUS or lymphoma, when they realize this angioedema should be treated and send them to an allergist. So the 800 patients that are more or less identified in the U.S. right now are really patients that the hematologists or the immunologists have realized they should be treated.

But I've been spending a lot of my career in myeloma. I spoke to a friend of mine, doctors in myeloma asked them, have you heard about quiet angioedema and they had no clue, which tells me that if we have a label for quiet angioedema and we can go and educate at ASH, ASCO at these big conferences that there is a solution for this condition, that it is something that should be treated, that will actually unlock a lot of patients that are today unknown. And given that we then have a label there exclusively, that will be obviously help for us in building our leadership position in the market.

All right. I guess let's talk more about that, like mechanistically, again, why pursue the indication? Again, any way a subsegment the addressable market there. But again, biologically, why pursue that indication? And why haven't others tried or have not been as successful?

Yes, that's an excellent question. That's why we feel deucrictibant is unique for the patients there because they compare all the approved treatments or the current under development. You know that deucrictibant is only the treatment target most downstream is bradykinin B2 receptor there as a new prophy treatment here because that all the other prophy treatment currently under development are either plasma kallikrein or upper stream there, right?

That's exactly why that from MOA mechanism part, we can really block bradykinin bunch to the receptor. Regardless, the bradykinin is generated either kallikrein pathway or kallikrein independent pathway. That's exactly that we were being -- that a lot of physicians are looking forward to us because a lot of normal C1 patients, for example, it's a [indiscernible] mutation or other mutations, they are plasma kallikrein independent.

All other treatment supposed will work for them. That's exactly that deucrictibant becomes later the hope for these patients who have no any approved treatment yet. That's why that we were -- that include normal C1 patients in our pivotal trial and looking forward to provide the new treatment for this patient population.

I guess how do you even power study in terms of thinking about natural history and some of the baseline characteristics, is that patient that dissimilar that it adds some degree of clinical risk? Is the bar different given the lack of treatment options? How should we think about the clinical risk?

Yes. Good question there. So basically, from the symptom wise that the normal C1 patients is quite comparable to the type 1, type 2 C1 deficiency patients. That's why we can include into our trial assessment. And from the type wise, we expect for our pivotal study that 90% of patients are still type 1 and maybe 5% of patients type 2 and another 5% will be type 3 in normal C1 patients. Therefore, we did not dedicate the power for the study, but we included it into our pivotal study.

Therefore, you can get a free option on the label based on deucrictibant.

Exactly. We will include all this data, hopefully, that into the label there. Only the difference is acquired angioedema patients because this patient population is not hereditary. That's why, as we mentioned, we have the dedicated pivotal study, we will be initiated by the end of this year. And then that we will collect the data that for prophylactic data first, the on-demand data. So prophylactic Part 1 of this trial will be parallel to the HAE prophylactic trial there. So hopefully, that as mentioned, we will target the bradykinin-mediated angioedema, not only limited to HAE. That's also consistent with the orphan designation. We've already been granted no matter for U.S. or ex U.S.

And we haven't talked about ex U.S. almost at all, right? Anything noteworthy either from a pricing, reimbursement access, the treatment paradigm, like what are some of the puts and takes there?

So very different landscape there, mainly driven by pricing. So completely different prophylaxis is still meaningful, still significant, but particularly on the demand side, it's much more challenging. So that's why our focus right now is really on the U.S. We think with a very limited footprint, we can really unlock a significant, very significant opportunity.

Outside of the U.S., we're looking at options. We're looking at potential partnerships that can be licensing, can be distributors shifts. We're doing the work, which is kind of on the clinical path. So for instance, when we do KOL engagements, that is happening by default because of very international community. We're working on health economic models, the preparation for that, but we don't deploy yet like any commercial resources in those markets. So we really want to look what is the best way of getting the product as fast as possible to patients because that's ultimately the most important thing that we try to achieve.

Yes. Fair enough. And again, with the recent capital raise, I think the latest guidance from a runway perspective is into first half of ' 28, right? So again, you get to...

First half '27.

First half of '27, I'm sorry. Thanks for the correction. But again, you get to a data point in the on-demand setting, on the prophy setting. And can you talk about like launch prep, I guess? Again, you could be very imminently with a good problem to solve, right?

So until now, we have been very prudent financially with deploying big resources, but we have really focused on hiring people that have a lot of experience and relationships in HAE. HAE is a very particular therapeutic area. It's relationship-driven. You have to be engaged with the community and community means physicians, means the patient organizations, means the payers as well. So our leadership, whether it's sales and marketing, medical, market access, patient advocacy in -- for the U.S., they all have a long history in HAE.

Peng has another one on the clinical side with our team. So that is really what we're focusing right now to building that relationship. And then from -- as of next year, we're going to be starting to build out the organization further, prepare the infrastructure, hire the field force to support the launch. And then we're really going to be in the absolute launch mode.

Ready to roll.

Yes. Perfect.

It feels like it's a natural stopping point. I don't know, is there anything else that we didn't cover that might be worth highlighting. But again, I feel we cover a lot of ground. We should be...

Pretty complete.

Perfect. Again, I really appreciate the time.

Thank you very much.

Thank you.

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 for 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. It's 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 2 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 second half of next year. So we're all gearing up for getting these products to patients, and I'm here together with Peng.

Yes. Thanks, Wim. Can you 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 into human until this stage. We target to really see how are 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. Yes. And that will be very interesting, obviously, to follow and exciting development for the really unaddressed populations here, bradykinin-mediated angioedema is 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.

Well, I would say that if we confirm our Phase II results and the Phase III, that 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. And I think that what we have shown until 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 their Phase II data because we hadn't anticipated that injectable-like efficacy, the ability to deliver the same efficacy seen with injectables like Siro, in particular, at that time. And so if we confirm that in our Phase III, I think it's becoming 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-a-vis Orladeyo and 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.

Yes. I think it's very interesting. If you would have run market research before the launch of Orladeyo, you would probably never predicted their success. Because if you talk to doctors, you talk to patients, the first thing that matters is efficacy, efficacy, efficacy. Reality has shown that actually a lot of patients are out there are willing to sacrifice some of the 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, a company that developed icatibant or Firazyr was at a patient meeting and spoke to patient, patient said, thanks so much to have Firazyr because it's a subcu option rather than an IV. But in the same sentence, they said, can you please make us an oral, icatibant? I mean here in the way, thinking, thinking, thinking.

If you go to 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. Yes.

Yes.

Absolutely. I just want to mention that because we target the B2 receptor, the receptor itself has a large pocket that the peptide can be potent and still stable there, but the small molecule is indeed very challenged. 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 both the compound and cric is Christoph that our chemist used very 3 steps that innovation there to generate deucrictibant is not only highly potent but also, it's druggable and have a great compound until we are today.

Fantastic. Let's put a pin in and discuss the Phase III on-demand therapy data, obviously, because that's upcoming in the 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 prophy. If we relate to the on-demand treatment specifically, Wim already mentioned, we really have high confidence. We can confirm all the observations from our Phase II trial. That means once deucrictibant can treat on-demand attack there, that it can bring that fast onset of symptom relief. We expect the patient, the first line can feel that the attack progress be halted within 15 to 30 minutes, then can view the symptom relief that between 1 and 1.5 hours. That's also the primary endpoint we will assess in our pivotal trial.

Meanwhile, the patient may be expect to see the attack severity reduction from severe to moderate, moderate to mild between 2 to 3 hours, and also eventually achieve complete that symptom resolution, no, any symptom anymore within 12 hours. So that's the profile we target to be confirmed with our pivotal trial. Also, we expect that 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 2. So the onset to symptom relief, obviously, which is the primary endpoint, as you mentioned, and would sort of be the -- maybe the predominant data that would appear in a label. Can you talk about that versus the sustainability of effect and complete resolution? And 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 will 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 the other standard of care or even act early just approved here that we've already included from time to onset the PGIC a little better, as mentioned, and also sever that attack severity, attack resolution, single-dose use in our trial design. Therefore, that we are in a very good position to include all this 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 the first line. I mentioned to show that how fast deucrictibant can work. This we also included in our key secondary endpoint, but we will be pending on the further discussion with the agency to be unique that efficacy assessment in the label.

Okay. And 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 the post-hoc analysis, we expect that it will be between 15 to 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 is it the same as what was done in Phase II in terms of assessing symptoms?

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 intense assessment in Phase III. That means we have more time points that 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 determined site staff and the patients there to ensure we get a high quality of 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 4 hours, the first time point is 15 minutes, the every 30 minutes up to 4 hours, the every hour assessment up to 12 hours, the every 2 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 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 on when you can launch this product ultimately if everything goes well?

Maybe I will start, and I will hand it over to Wim regarding the launch. Currently, we expect a top line that available Q4, then that really depends on the top line available time. We expect to file that in U.S. first and it will be the first half, the '26. Then that if no surprise, early '27, we will prepare for launch.

Yes. So we are -- have been financially very prudent. So at the moment, we have a very small team, but virtually every one of them has very long-standing relationship in HAE. So both our GM for the U.S., 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 1, starting in Tier 2 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 the Tier 3 level doctors in the U.S.

Okay. And ultimately, you mentioned 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 patients 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 levels, 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 I would love to talk about the prophylaxis opportunity as well because that's potentially larger, certainly is 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 is -- would be expected to play in your benefit is the extended release 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 question that we will use extended-release formulations at 40 milligram once daily there that in our pivotal study. And before that we use the new formulation that in our pivotal trial, actually, we conducted the 5 different pharmacokinetic profile and pharmacokinetic studies in health volunteer 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 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 4 acquired angioedema patients have been used extended-release formulation up to 2 years. For these 4 patients, all of them are frequent attack patients before that on deucrictibant treatment. And after, these 4 patients on the extended release formulation, only 1 patient reported 1 mild abdominal attack on day 2. After that, all 4 patients attack-free up to 2 years and also deucrictibant is very well tolerated.

So therefore, not only PK side, but from efficacy and the safety side, we are quite confident that extended release formulation is the most appropriate and fit for prophylactic use.

Those 4 patients are obviously a great precedent to gain confidence from. How do the bradykinin levels compare in those patients versus like any of the typical subgroups of HAE patients?

HAE patients.

Yes. Because it's a 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 the hereditary angioedema patients, especially type 1 and type 2. This is due to the SERPINE1 genetic mutation that hereditarily have either lack of the C1 inhibitor, the amount of function there.

Acquired angioedema, they have very similar symptom 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?

Yes. For the trough level, currently for extended release formulation for the 40 milligram once daily, we expect trough level is about 2 to 3x higher here. We did not guide the direct translation. But meanwhile, we just want to mention 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 been questioned how about the variable of the patient population and how about the global use global trial.

Therefore, that it give us the definite 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 I 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.

Yes. So for us, there are 4 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 a lion's share of the new patients. In the U.S., there are about 150 to 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 becoming -- 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 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 after. The second segment is the patient you mentioned. By the time we will be launching, about 1,000 patients will have tried Orladeyo and come off. David is in the audience here. If we hit 1,000 patients in the first year, we'll be very, very happy. So second segment, absolutely clear target for us because the patients have shown they want to have an oral. They weren't satisfied, we can maybe offer them something better.

Thirdly, you have the Orladeyo patients. And you're right, practice will tell you these patients are sticky. They have -- 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. You can -- 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 who will stick to Orladeyo because they've been there, they found something, but others will be willing to switch.

And lastly, I would say, in the injectable segment. If you would -- 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 you 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.

And what do you think -- 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 in 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. And that would be maybe once a month or once every other month. But that changes when you can just say, 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, 3 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 on prophy 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, 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 in on-demand, once 2 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 to what 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. On-demand is relatively easier to switch because you run -- you don't have a prescription for a whole year of drug. You got a prescription a month, 2 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. And so we anticipate that deucrictibant 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 launch first, right, that on-demand, the patient can feel really that quick response there, it also paves a good way for patients to consider later on adapt to the prophylactic use, right? It's about only 9 to 12 months apart.

Okay. 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 that ultimately that would manifest in an initial drug label, either with FDA or ex U.S. 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 and the product profile.

Yes, this is indeed a very interesting and tough question here. And ideally, we -- you can see how 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 strong to differentiate from the current indication part or other competitors. That's exactly that we currently that have 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 subtype 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 target the plasma kallikrein pathway are upper stream there, upper stream there. And deucrictibant is only one to target downstream to block bradykinin and the 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 treatment and also can bring really the benefits for the patients who are not respond to any treatment yet. That's exactly we work hard there mainly is to consider what the patient need.

Indeed. And the study you mentioned that's enroll in that broader population, that's a CREATE study in...

That's a CREATE study.

That will start later this year. Do you 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 for CREATE study, it's a smaller study that will be only driven by efficacy assessment. And meanwhile, because currently, there is no any approved treatment, no AAE trial available, therefore, the competition is much less. That's exactly if -- we also shared the study design that in the past conference here. So we will start for that trial profit first, then go to on-demand. That's exactly what we mentioned for the prophylactic indication part. We think we do have hope to target the bradykinin-mediated angioedema indication.

Okay. And 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 2 months ago, I believe, from the HAE on the U.S. epidemiology, which showed that in the U.S., there are about 9,700 patients that are using therapies for HAE. 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 is treating lymphoma, who's treating lupus has the reflection in case of an angioedema attack to send that patient to an allergist, then they get treated.

We were at an ad board in May, one of the doctors said, yesterday, got a patient in, "He had attacks for 5 years before the hematologist send him to me." So there is no -- there's very little awareness, very little knowledge amongst these different specialties about what bradykinin-mediated angioedema is in acquired and then it can be treated. So by having a development program and potentially a label, we'll be able to communicate, promote of 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, yes. 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 I would 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.

Thanks, Steve.

Terrific.

Thank you, Steve. Yes. Thanks, everyone.

All right. Good afternoon, and welcome to, I think, the final session of the conference, and it is my pleasure to introduce Maggie Beller, the Head of IR for Pharvaris.

Maggie, welcome. I know this is the first time I'm hosting you here. And before I go to the Q&A and let me just turn it to you for a quick introduction of the company and maybe a brief overview about what's exciting ahead and some of the catalysts and timing for that?

Absolutely. Thanks so much for having us. So Pharvaris is a publicly traded company. We are focused in hereditary angioedema, which is a disease in which people suffer from swelling attacks that can be unpredictable, really painful in your hands, your face, your stomach and your throat. And if you have a throat attack, you can end up fixating and it can be fatal. So we're really focused on the development of an oral bradykinin B2-receptor antagonist called deucrictibant. We have that in Phase III for both our on-demand program and also our -- to be reading out top line Phase III data for on demand in the first quarter of 2026 and for the second half for the prophylactic program.

Fantastic. And obviously, for HAE, it's a quite competitive market. There's a lot of different modalities. You have even the gene therapy being developed there.

Maybe walk us through the indication in terms of how you guys are looking at the unmet need and where you think you can fit in?

Absolutely. One of the things that we really focus on is the ability to provide the next step in treatment, right? There are approved therapies out there, but are patients getting the efficacy that they want, the tolerability that they need, with the convenience that's best for them. And those 3 things can mean different things to different people.

So as you said, there are some interesting long-acting injectables that are in development right now. There are injectables that are approved once every 2 weeks is TAKHZYRO, which is the most widely used prophylactic therapy right now. there's an oral on the market for prophylaxis.

And then people can also decide to treat their attacks if and when they have it. And right now, they are only injectables approved on that side. So what we're trying to do is develop a product in both settings, so both on-demand and prophylaxis that achieves the goals that patients want. They want injectable-like efficacy, placebo-like tolerability and convenience as that means them. So us, we think that a daily oral pill for prophylaxis could be that convenience.

I see, got it. So in terms of when you look across the competitive landscape, the convenience is one factor where you differentiate.

Does it have to differentiate on efficacy as well? Have it be the best-in-class efficacy?

Yes. No question about it. We hear from both patients and physicians, that efficacy is key. However, we've seen a really great launch from Orladeyo that doesn't achieve -- isn't as competitive with the injectables on the efficacy side, but they've had a really great launch. And so although on the surface, it sounds like efficacy is key. We think that this convenience plays a larger part in it as well.

So having a drug that could be the convenience of an oral like Orladeyo, but with the injectable like efficacy of a TAKHZYRO or some of these newer entries garadacimab, deucrictibant, I think that could be really competitive in this space.

I see. Got it. And obviously, you guys have a Phase III enrolling. Before we get there, maybe just -- if you don't mind, just walk through the Phase II data and what maybe discuss the highlights from that? And what's making you guys excited?

Absolutely. So on the prophylactic side, I'll start there and then we can go on to demand. Our Phase II data read out in December of 2023, we saw from our Chapter 1 study that with the 40-milligram per day dose we were able to achieve 85% attack reduction compared to placebo.

Once again, that's in line with some of the other approved injectables right now. We have open-label extension data from that study as well, and we saw that, that attack reduction was maintained and even improved upon. Our open label data shows 93% attack reduction. In addition to that, we have some really compelling quality of life assessments that we're including in our Phase II, our open label and our Phase III study. So very excited to see that top line data second half of '26.

Fantastic. So what's giving you confidence that you can reproduce these Phase II -- these impressive Phase II results into Phase III?

HAE is really interesting because there is some good reproducibility from Phase II to Phase III. One of the things that we're doing, of course, we're going to have a broader studies. So we're targeting enrollment of 81 participants. Our Phase II was about 30 participants, so we're going to expand that patient population. And we are switching from the -- in the Phase II, we had BID dosing of the immediate release capsule. So we did that twice a day.

We're going to be using our extended release formulation in the Phase III study. That has a much leveler PK profile compared to the dips and troughs that come with an immediate release in that capsule. And we think that, that protection could bolster any sort of degradation that you see in typical Phase II to Phase III shift and maybe even improve upon it. [indiscernible] with QD dosing as opposed to a BID dosing, and we think that, that PK profile is really compelling for once-daily treatment.

Right. I see, got it. And then in the Phase III design, you also included adolescent and there's expanding to global sites and then have a 2:1 randomization. Maybe how do these changes? Like how do you think that will affect the Phase III results?

One of the things that we're thoughtful of is the fact that in prophylaxis, there are competitive Phase III studies enrolling right now. So we wanted to design a study that would be compelling for people to participate in. That's why we have this 2:1 randomization. We wanted to increase the likelihood that somebody would be on active drug as opposed to placebo.

We're including adolescents because that's a really important patient population for us. People tend to have increased HAE attacks as they go through puberty. So we want to make sure that we can include those people in our study. Additionally, other HAE sponsors haven't penetrated into other regions such as APAC, some European countries that we didn't include in our Phase II and LATAM, we think that there's high unmet need in these regions, and we want to be able to enroll competitively.

And so inclusion of those people and those regions are going to be able to hopefully bolster our enrollment there.

Right. Got it. So as you think about the Phase III result and what you need to achieve to be competitive in the commercial market, what do you think is the bar that you need to achieve? I mean just looking at your primary endpoint, what level of like the monthly attack reduction compared to placebo, you would need to achieve in order to have the competitive profile?

Absolutely. Prior to our Phase II data, we were really looking at our profile and saying we can be competitive in the oral space and we're able to achieve 70% attack reduction. Our 85% attack reduction that we saw in the Phase II clearly knocks that out of the park and puts us in the playing field with the other injectables.

So our commercial penetration strategy has switched from just owning the oral market to being able to have a competitive foothold, not only in oral but also with the injectables. If we're able to reproduce the 85% attack reduction that we saw in Phase II. And like I said, maybe even improve upon that with the extended release formulation we think that, that gives us a real competitive edge for the prophylactic market.

I see, got it. And then you're also looking at several other key secondary end points. So which 1 of these are meaningful to doctors in terms of how they would choose the medication, and what are your bar for these other secondary endpoints?

Absolutely. You can't get more than 100% attack reduction. So at some point, when you're playing between 92%, 93%, is that really going to move the needle. The other key secondary endpoints that we're looking at are use of rescue medication for when you have a breakthrough attack.

Are people needing to treat their attacks with an on-demand therapy? Or is the reduction in severity sufficient enough to be able to improve upon the profile. So that's one thing.

A number of days that people are attack-free. Treatment guidelines state that no person should ever experience an HAE attack. And that is the goal that we're all aiming towards. If we're able to have really compelling attack-free data, I think that, that really bolsters our profile. And lastly, we're thinking about quality of life.

HAE is a lifelong condition. And so the ability to be able to have meaningful impact and improvement in quality of life is something that we think both patients and prescribers are going to care deeply about in the Phase III.

I see got it. Okay. And then so when you think about sort of the commercial -- how things are playing out commercially? you have the oral which adds a lot of convenience to it and then you have the injectable, which is sort of like perceived as a maximum -- maximum efficacy. So there's this balance between the two.

What do you think is the most valued by patients? Are there different patients who look at convenience over efficacy or efficacy over convenience?

Certainly, we've seen with the launch of Orladeyo that some people are comfortable forgoing efficacy in preference for convenience. We think that if we're able to provide both, that's obviously a major selling point for us. When we think about the prophylactic market, we really think about our penetration in 4 steps. Number one, an effective, tolerable oral therapy should be the first line of therapy for any new patient who is switching to prophy. So that's one area that we're targeting.

Number two, there are a number of people who have tried the other oral and have come off of it for whatever reason, either the efficacy doesn't meet their standards, their GI or tolerability impacts or it just doesn't fit in their schedule. So by our math, we should have with a 60% retention that BioCryst has reported, there should be 1,000 patients by the time we launch that will have tried Orladeyo and come off of it. These are people who clearly are wanting an oral but we're not satisfied with the experience that they had. So that's a target for us.

The third is people who are currently on the oral therapy but may not be as well protected as they could be. These are people who may have gone from 4 attacks per month and now are experiencing 1 to 2 attacks per month maybe they're milder, maybe their peripheral attacks, but they're still experiencing an attack. And good is not good enough for us. So that's another segment.

The last segment is people who are on the injectable who didn't want to make that concession of efficacy for the convenience. However, with the entry of a therapy that could be equally, if not more effective than the injectable that they're on, plus the convenience of an oral, we really think that, that changes the paradigm for those people.

Right, right. And based on Orladeyo's launch, are there certain patients who are more biased towards that in terms of -- these patients have less number of attacks, maybe not as severe. So therefore, there are more ideal for the oral less efficacious therapy compared to [indiscernible].

I mean just curious if you found something in your market research studies or you've been hearing from clinicians of how they're using it or biasing patients to one versus the other?

We think that based off of the Orladeyo launch that there is clearly an unmet need in orals. However, we don't think that you should have to have either less severe attacks or have to experience an attack at all.

So we think that there shouldn't be that bias, though there may be right now.

I see. Okay. And let's switch gears and talk about the on-demand use. Can you give us a quick overview about the profile for on-demand for these acute treatment of attacks? Based on the Phase II and also the open-label extension study.

Absolutely. So our repeat 1 data read out in December of 2022. With that, we were -- we use an endpoint called VAS AMRA which is a visual analog score. The AMRAs once you put it on to a smart device like a phone no longer becomes an analog scale.

We saw in that data that the time to attack reduction, symptom reduction was in 2.4 hours That, along with the fivefold decrease in rescue medication use as well as the 25 to 26 minute end of progression time line, made us really excited about the Phase III. It makes us very competitive with standards with standard of care [indiscernible], then in our open-label study, we also evaluated other end points PGI a little better, PGIS, which is a symptom score, these are all patient-reported outcomes.

That enabled us -- though not to head-to-head studies to have a comparison to KalVista's drug sebetralstat, we saw PGIC a little better. That's our primary endpoint in the Phase II time to onset of symptom relief was in 1.1 hours. We saw that complete symptom resolution was in an 11.5 hours. And that 86% of people were able to treat their attack with just a single dose of deucrictibant.

This open-label data makes us really excited to achieve what patients want from their on-demand therapy, therapy that works quickly, that works completely and works with a single dose.

I see. Okay. And let's talk about your pivotal Phase III study. So has completed enrollment. This is an event-based trial. So we're still waiting for the database of Phil and these events occur. Can you talk about the change in the primary endpoint that you use from Phase II to Phase III? And also why you made that change?

Absolutely. So with correct demand, we knew in the Phase II that we were going to need to justify some sort of comparison to standard of care. Standard of care the most widely used on-demand therapy as a [indiscernible], which also use the VAS AMRA time point.

So that's why we use that as our primary endpoint in the Phase II as there discussions with regulators have changed and continued to -- they really wanted to see PGIC a little better. So in the Phase III, of course, in alignment with regulators, we have our primary endpoint as PGIC a little better.

We did a mixed method study, which took people just taking standard of care, and they measured their attack resolution across all of these patient-reported outcomes. Amra, PGIC, PGIS, and we found that based off of those just standard of care results, PGIC a little better was achieved 0.8 hours sooner than the Amra 30 that we used in our primary endpoint for Phase II.

Because this is technically a lower bar to achieve. We think that, that provides us confidence in the Phase III in our ability to hit the primary end point, as we look at it though, we're thinking about not only this primary endpoint, but the whole totality of an attack. It's not just how quickly your symptoms are resolved, but also how completely they're resolved and if you're able to do that with a single dose. That's why our secondary end points are really important to us as well.

Sure. Got it. So what's giving you confidence that by sort of the change in these different end points and that your Phase II data could translate to what could be produced to Phase III? And also, what is that bar that you guys are looking for that you believe will be competitive in the commercial setting?

Absolutely. Once again, we're looking at a not head-to-head comparison. So right now, we're looking at [ Publtralstet ], another oral which has a PDUFA next week. We anticipate they're going to get approval. In the endpoint that they had in their randomized Phase III compared to our open label Phase II. So once again, not head-to-head studies.

Our data showed 1.1 hours to PGIC a little better. That's the first symptom relief that you have. There is 1 point -- when we look at that half an hour, is that really something that's going to be competitive in the landscape because we don't think so.

So then -- I mean, or it can be, but that's not enough to really switch people. So we look at the rest of those endpoints and say, what is the time to the first time you're starting to feel better. Our data shows PGIS, 1 point better of 2.6 hours compared to about 7.7% to 9.3 for several [indiscernible].

We then look at complete symptom resolution at 11.5 hours for us and over 24 hours for subtilstat. So that for us is really where we start to potentially have the leg up. Now it's going to be really important for us to once again confirm these findings in a Phase III. And so we're excited to see our data readout in the first quarter of '26.

Got it. Okay. So in the commercial market, when you look at these 2 different settings, the prophylaxis and also the on-demand market.

How are you thinking about -- in these 2 different settings how would you compete? Where do you think you would have a better advantage over the other? And how do you see sort of like where is the most potential from a sales perspective?

Absolutely. Prophylaxis is the larger market hands down and treatment guidelines align with the shift that we're seeing towards the growth in prophylaxis. However, there are many efficacious therapies in prophylaxis. What we look at when we look at the prophy market is what will be the split between orals and injectables because inherently, there will be people who prefer a long-acting injectable.

What that split is going to be, it's really going to be determined by the Phase III data between our product as you said, you've got a gene therapy, you've got some long in injectables in the work. So we'll see what that looks like. Is it 50-50? Is it 60-40 oral? we heard some people say 70-30 oral, we'll see. But once again, that's going to be driven by the efficacy that we have there.

In the on-demand setting, we think that oral is takeover. We can't see a situation in which somebody selects to have an injectable if you have an oral effective therapy for on-demand I think our unique selling of Pharvaris is that we're agnostic to how the market breaks down either way because we're the only company that has a product potentially for both settings.

So the prophy market can grow as you get more people on prophylaxis we think the entry of an oral into the on-demand market also grows that market because people treat more attack since the barrier to treatment is lower, and we're happy to be in either space. In both spaces.

Right. Got it. So when you think about these 2 spaces, how do you -- like have you been starting the commercial like thinking of preparation around that? Or is it still too early? Like how are you guys -- have you guys started building the commercial infrastructure and thinking about because there's such a big commercial player, right? Because you're talking about you're coming in a little later than a lot of the therapies out there?

And would that be -- will you be competing for new patients? Are you trying to switch patients after therapy and switch to yours. How do you guys think about all these different commercial strategies?

Absolutely. I think there are 2 parts to that question. Number one, we've definitely started building out our commercial team. Our Chief Commercial Officer, Wim Souverijns, actually joined the company in 2021. And -- so as we think about the community engagement with HAE allergists historically have been very relationship driven. So it's important for us to continue to build those relationships.

We've been making sure that we not only have our commercial infrastructure, but also the medical support on that side to be able to engage with physicians, make sure they're up to speed on our data, make sure they have everything that we need -- that they need for them to make the prescribing decision. So that's number one.

And then I think number 2 is what is our strategy for penetrating the market. For prophy, we think about it once again in the 4 ways, new patients, people who are who have tried orals and then come back off of it. The third is people who are potentially unhappy with their orals and then fourth is people who would switch from an injectable. So combination of new patients and switch patients.

I see. Okay. So we have a couple more minutes left. Why don't we switch gears and talk about the expansion beyond just the HAE. So you do have are looking to expand into the C1 inhibitor level -- people with normal C1 inhibitor levels, and then other bradykinin mediated NGO must.

So maybe talk to us about the rationale for those and why -- and how do you guys -- what evidence is supporting you guys expanding into those 2 populations?

Sure. Most other companies are focused on type 1 and type 2, which is people with either deficient or no C1 inhibitor. So that is easy -- not easy, but there are diagnostic tools to be able to determine those people.

However, there is a whole another segment people with normal C1, which means that they have excess bradykinin but it's not through this kallikrein system that most other HAE therapies work on. So our opportunity there is to treat the severe unmet medical need in normal patients HAE with normal C1 excuse me.

As well as -- and that represents about 15% to 25% of the population on top of HAE type 1 and type 2. Additionally, there are people with acquired bradykinin, which means that they have some sort of underlying diseases, whether it's lymphoma, AMRA, myeloma, lupus, where the disease actually consumes the C1 inhibitor.

And so then they end up with a excess bradykinin and experience angioedema. Attacks following that. that's about 10% on top of HAE type 1 and type 2. So if we're able to build on the treatable population of deucrictibant, we think that's a really compelling commercial opportunity for us. and it needs unmet medical need right now and could be compelling from a regulatory standpoint since we have orphan drug designation for bradykinin-mediated angioedema, in both the U.S. and the EU.

I see. Got it. And then you also recently hosted a KOL day and then presented some data supporting the use in the acquired angioedema AEE and maybe walk us through that and how you guys are thinking about advancing that to a Phase III study.

Yes. In an investigator-initiated trial, Professor Danny Cohen, out of Amsterdam Medical Center has run a study of deucrictibant in AAE patients. He's done that in both the on-demand setting, in which case people saw -- this person saw the increase -- an improved treatment satisfaction and time to treatment resolution. -- in the deucrictibant arm as compared to placebo. And then they also rolled over to the prophylactic over 20 months in 4 patients using the extended release formulation that we're using in our Phase III there was 1 attack on day 2 in 1 patient. So all other patients have been attack-free for over 20 months.

We think that, that's really compelling not only for the AAE program, but also could be used as a proxy for what we could see as potential efficacy in the CHAPTER-3 program.

I see. Okay. And then you guys are also developing bradykinin-mediated NGO edema assay. How are you going to use this assay is it going to be part of sort of that overall development program and the overall launch of the drug? And then how -- what are the -- any risks associated with sort of you guys keep up and assess it yourself?

Absolutely. So this assay is used to identify people with bradykinin-mediated angioedema, as I said before, there are current diagnostic tools that measure C1 -- the amount of C1 and the activity of C1 in patients.

But for those people who have HAE with normal C1, there isn't a diagnostic tool for them. Because [indiscernible] deucrictibant acts at the bottom of this cascade, there are many other ways that excess bradykinin can get into the system. And this assay enables us to identify those people right now. Now it's not our intention or for Pharvaris' intention to develop this as a diagnostic tool. We're not a diagnostic company, but we are open to partnering with other diagnostic experts if that's something that's appealing to them.

I see. And would this assay be needed for commercialization like or part of the launch, how are you guys think about?

We don't view it as a diagnostic partner for our program. We are including people with normal C1 in our Phase III program, but there are other diagnostic tools for HA type 1 and type 2 and AA that are commercially available, right?

I see. Okay. Got it. And then can you remind us about the current cash runway what is included in that guidance and what is not included in the guidance?

Absolutely. At the end of the first quarter, we had EUR 236 million in the bank. That provides us with cash runway through -- into the third quarter of 2026.

So as a reminder, our Phase III on-demand data is going to read out in the first quarter of '26. Our Phase III prophy is in the second half. So that provides us cash past on demand, but not quite to prophylaxis. Included in that is this acquired angioedema study that we intend to initiate in 2025.

I see. Got it. And then what's sort of -- what is the long-term aspiration for Pharvaris? And also, as you think about you have a lot of these data coming out and also considering that the market is competitive. Why is now a good time for investors to think about investing?

Absolutely. So Pharvaris has the intention to commercialize in the United States. We have an active BD program and we're in communications with other partners about potentially partnering off compelling regions, Europe, Japan to the right partner there. We want to make sure that deucrictibant can be provided -- access can be provided to everybody who needs it.

So that's our intention is absolutely hold on to U.S. rights and think about creative partnership opportunities if and when they would arise. For us, I think when we think about the investment profile of Pharvaris right now, we think about the fact that we have an experienced management team that has launched drugs in HAE before. We have a very strong IP portfolio.

We have 2 data readouts in the next 18 months. And we feel that there is a differentiated profile of deucrictibant in this space. A is a known market and really has upside potential here. It has a great combination of being a competitive market while also having the rare disease that's appealing to us.

Fantastic. I think we're almost out of time. So Maggie, thank you so much for being here. It's been a pleasure to host you.

I'm going to turn it to you for final remarks and any concluding remarks.

Thank you. I just want to thank everybody, thanks for having us. We really appreciate it. like I said, we think that deucrictibant in the Pharvaris profile is quite differentiated within the space, and we think that the past 6 months have been challenging and that we're undervalued right now. So I really think that there is an interesting and compelling opportunity here with milestones in the near term that people can run have the opportunity to capitalize on.

Fantastic. Thank you.