Pharvaris NV Aktie

Great. Thank you very much, everyone, for attending. I'm Max Skor, a biotech analyst with Morgan Stanley. And before we get started, for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

And with that, I'm very happy to have the Pharvaris team with me today, Berndt Modig, CEO; and Maggie Beller, Head of IR. Thank you very much for joining us.

Thank you, Max. And good to be here.

Great. So maybe we start off. I think this is the third year in a row you've attended. We've sat here at the fireside chat. This is a momentous time in the story of Pharvaris. If you can just maybe step back and give us a brief overview of just how you got here and what are the key steps going forward?

Sure. So actually, our journey or my personal journey in HAE started 23 years ago with -- not with Pharvaris, but with the company that developed icatibant and I worked there together with Jochen Knolle, who is an inventor of icatibant. And then as we all know, Shire took over in 2008, and it then became -- still is the most widely used acute therapy for subcutaneous injection. But already back then, we knew that there was patients were looking for better treatments and already then, we were just starting to think about the vision for an oral therapy.

And then latest couple of years later in 2015, starting operations in 2016, then Jochen and I started Pharvaris and with the idea to develop an orally available B2 receptor antagonist really from chemistry square one, really from scratch. And we're really excited to what we see today with what came out of that is deucrictibant. And the properties of that molecule, it makes it very different from icatibant. It's a B2 receptor antagonist, but it's to our knowledge, the first and only orally available B2 receptor antagonist.

And it also has the properties that make it half-life and so on that make it suitable for prophylactic development like deucrictibant. So looking at the therapeutic area over the -- more than 2 decades, you see the big unmet need for an efficacious oral therapy option and there's still nothing approved out there. And we are, of course, hoping that deucrictibant is going to be the first orally available B2 receptor antagonist in oral therapy with a high level of efficacy for people living with HAE.

Great. Thank you very much for that introduction. So when we think about the HAE market, we have the on-demand market, which you also have a formulation for of deucrictibant and then the prophylactic. Let's start with the prophylactic because you just reported impressive Phase 3 CHAPTER-3 data. Maybe give us a high-level overview of the overall efficacy profile, and then we can dive into specifics.

Yes. So you saw the data, we had a remarkable 87% efficacy in the Type 1, Type 2 population of hereditary angioedema. And also the study included it's also part of the protocol patients with normal C1 mutations, other mutations that -- and so the primary endpoint included a small number of such patients and that total primary endpoint and efficacy -- the attack reduction was 83%. So that really means that we are in the area of what we can call injectable-like efficacy.

And if you look at the other injectables in the prophylactic space therapies out there, there are all seems to be almost like a ceiling, [indiscernible] more or less maybe not coincidence, but there seems to be like there is a maximum level of efficacy at around 87% and we're very happy to see that with deucrictibant and it really puts us in a very differentiated position vis-a-vis the others because as I said, we see a huge unmet need for a different oral therapy that really provides that level of efficacy.

And maybe if we can dive into the key secondary endpoints. Maybe you can talk about the baseline characteristics and how that compares to competitors in the space. Specifically, I imagine everyone is looking at ORLADEYO and how that Phase 3 lined up versus CHAPTER-3?

Yes, the baseline characteristics are very similar to other therapies. I mean they're all in terms of attack frequency, they range from, I think, the lowest is the TAKHZYRO with 1.7 and the highest is ORLADEYO and we were a little over 2.1, I think it was in our case. And it's -- so it's all very, very, very similar. And...

These are fairly severe patients.

Yes. Yes. So I think that's very comparable.

I'll add on that our -- those were our placebo rates in the full 24-week study. For the baseline characteristics leading into the study, our average attack rate was about 3.6. So that is a more severe patient population. So we were incredibly impressed to see the 87% attack reduction given the severity of the patients that we were treating.

And then I guess, after the results came out, there were some questions around the safety profile. We actually hosted a KOL a couple of days later. The KOL was comfortable with the enzyme elevations given the compounding or confounding factors such as androgen exposure, fatty liver. But could you comment on those?

Yes, happy to. In our study, we did see 2 Grade 3 Level 2 liver enzyme elevations. As you mentioned, Max, one of those patients did have fatty liver disease. That was also a normal C1 patient. So that person ended up discontinuing the study drug, but stayed on the study. So we were able to continue their lab assessments. The second patient had previously used androgens. They actually stayed on study and completed the study and then rolled over on to the open-label extension. Both of those patients neither were symptomatic and neither saw elevated bilirubin. So we were pleased to see that.

Okay. That's very helpful. And then there was one patient, I believe, laryngeal attack any commentary around that?

Absolutely. So that was our Grade 4 finding, which is the same as the serious adverse event in the safety table. This was, once again, a person with normal C1. They had a plasminogen mutation. This person, unfortunately, leading into the study had experienced severe laryngeal attacks. So as many as 19 laryngeal attacks in the 3 months leading up to the study. These attacks required constant intubation. So this was somebody who had been intubated multiple times. Upon start of the study, this person experienced a 90% decrease in their attack frequency. So really impressive efficacy findings there.

At one point, they had a laryngeal dyskinesia, which just means that they had difficulty breathing that resulted in them being hospitalized and being intubated. While intubated, they were scoped and it was confirmed that this was not -- there was no angioedema associated. So this was not a laryngeal attack. It was just a result of the frequent intubation prior to the study start.

This person stayed on study drug. They completed the study. In fact, afterwards, we reached out to the PI just to see that how the person is feeling. They had reported that they were happy with their deucrictibant treatment and actually were able to go back to work. So not only did they experience the improved efficacy, but also improved quality of life. So we view that as a real success story with deucrictibant.

That's great.

Yes. Maybe I should also add to that. I mean it's hard to imagine for any of us here, what it's like to have 19 laryngeal attacks and suffer through that. And so this is, as I said, that is a normal C1 patient. And so part of our approach here and also as we designed the study was to include, as I mentioned, normal C1 patients. And this is not an insignificant portion of the patient population and also because of the -- remind everybody, because of the mechanism of B2 receptor antagonist, that is really the only mechanism that has real efficacy for this patient population.

Can you talk about that opportunity?

Yes. So it's estimated now that approximately 20% of the HAE population is the normal C1 mutations. So that follows a different pathway, it doesn't go through the kallikrein pathway. So at the bottom of the B2 receptor level, then you can really most effectively treat that condition.

They do get therapy today with the existing therapies that, that is because the more generalized label for those indications, hereditary angioedema because the normal C1 is sometimes called Type 3. It's one form of hereditary angioedema. But with our data now, we hope to have to get that also included in our label and also finally a really efficacious therapy for these type of patients.

And are these patients generally managed with on-demand or prophylactic treatment?

I think for the most part, it's on-demand today. Many use icatibant. They also use [ Trid ] the other drugs that do get the other drugs of prophylactic prescribe. But not with some modest efficacy or very low efficacy.

And then maybe just going back to the safety profile. How does it compare to ORLADEYO? I think on the ORLADEYO label, something called out at higher doses, cardiac implications. Any commentary around how deucrictibant compares to that?

Yes. Thanks for the question. That is something that we're really proud of. We didn't see any additional cardiovascular signs. And in fact, we saw one of the major pushbacks that we get for the other approved oral is GI side effects. We did not see an increase in GI risk with deucrictibant treatment and the placebo and deucrictibant arms are balanced with respect to GI as well. So not only do we have a thorough QT waiver, we put out a lot of cardio safety data, and we were happy to see in clinical studies that there's no additional cardio risk with deucrictibant.

Okay. Now going down the path of potential approval in prophylactic, we'll touch on-demand in a bit. But what have you learned from the ORLADEYO experience so far? How are you going to approach marketing, talking to physicians? How should we think about the launch curve?

Yes. So on the ORLADEYO, as you know, had been a pretty strong uptake. I think -- which is not a surprise to us, because it reflects the fundamental unmet need for an oral therapy. So patients are desire to get away from injections. And I think what we have seen now since the launch of ORLADEYO is that there is a very high churn rate. It's very -- many patients drop off after trying it. And I think also in the call, you mentioned -- in the call mentioned that you also wrote about it is up -- said that 50% of the patients discontinue ORLADEYO after within 6 months. And that is -- then go back to the injectables, and that's really simply because of the lower efficacy.

So that patient segment, patients who have tried ORLADEYO. The reason for trying it is, of course, the desire for an oral and then they go back to the injectables because it didn't do so well for them. With deucrictibant now, they have the opportunity then to try again. So I think that the propensity for that type of patient to try deucrictibant will be very high. And so that's a very clear segment.

We estimated some numbers. I think BioCryst has also mentioned numbers ranging from up to 1,900 patients that have tried ORLADEYO and dropped off. So that's very clear. Then there is a patient population that, of course, are aware of that. They're still waiting for an oral, but they don't want to make that -- take that risk of starting to having attacks again. So they stay on the injectable and they're waiting for deucrictibant, you can say. So that's a very -- that's another segment that's very logical for us to approach.

And then the first-line population, newly diagnosed, it's very logical to start with an oral as a first-line therapy. So -- and that are 150 to 250 patients every year that come into the mix and that kind of accumulates over time. And what we hope to see, of course, is that when somebody starts with deucrictibant that they would be satisfied and then the search is over and there's no need to switch. So then with that building patient population also from the new patients, it again accumulates over time. And Chief Commercial Officer like to describe as a pancake effect, but it is basically accumulation of patients coming in and newly diagnosed.

So maybe that leads into the on-demand opportunity. But stepping back and thinking about the prophylactic first on-demand, having dual formulations of the same drug, how are you thinking about the market opportunities for each and then on-demand launching first? How does that help you define the prophylactic market going forward?

Yes. I think -- I mean, we do think that the on-demand market is a viable market also in the future. There are certain patients that prefer to treat when the attack happens. And especially if you have something that's very reliable and simple and again, also in the on-demand segment same phenomenon. There is an oral therapy but not the optimal efficacy. So I think similar to the prophylactic setting, we hope and expect that deucrictibant will also take over a lot of those patients.

And also there are patient population still on icatibant. And I think that's 65% or something more patients that really are still on icatibant and what they like icatibant is the reliability, the efficacy they trusted in the mechanism. But if you have an oral that works as good or even potentially better, then that's a very logical switch from that patient population as well. So it's very similar dynamics. And I think there is a segment of people living with that they want to stay on-demand. So we think that's also we're happy that we have both options for patients.

And so in regards to the actual segment breakdown, do you see prophylactic growing or on-demand growing? How does that look?

There are different growth factors. I mean, overall, the prophylactic segment continues to grow. I think that you've seen that is clearly the trend. I think that's also in the treatment guidelines that patients really should be on prophylaxis not to have attacks. So I think that's clearly the trend. I mean I think we've seen that over the years, and I think that continues. But as I said, I think there's still a remaining segment that also where the on-demand therapy option also could make sense. And I think also patients that are able to sort of maybe switch back and forth are also -- they're relevant.

Yes. It sounds as based on our conversations with KOLs, it sounds like all prophylactic patients also have an on-demand that they carry with them for breakthrough attacks. How does having 2 formulations of the same drug potentially address that issue?

Yes. So that refers to, I think you can describe as potential combo use. And I think that it's -- the treatment modalities in HAE is in angioedema is really exposure driven. So it's all about maintaining a certain therapeutic exposure. And so unlike some other diseases where you have to approach it from a different side. So a breakthrough attack typically occurs when that exposure and the efficacy is not there. So you're basically topping up with the same drug, which is -- the combo use from a medical perspective, from mechanistically is fine, and we see that as also a potential for deucrictibant.

Okay.

I'll also add that right now, in clinical practice, people use the same mechanism to rescue their attacks, when they have breakthrough attacks. So right now, if you're on TAKHZYRO or ORLADEYO, which are kallikrein inhibitors and you have a breakthrough attack, you treat with EKTERLY, which is also a kallikrein inhibitor, that is a well-understood additive process. So for us, we're using that same philosophy of mechanism plus mechanism.

Do you have any -- I'm going to ask you to put some numbers or percentages around that based on what we've learned from the EKTERLY launch or what you've learned from talking to KOLs?

I think right now, we're seeing that people on ORLADEYO tend to have about 6 to 12 breakthrough attacks a year. So those are treated in a number of different fashions. Many of them are with EKTERLY. And then for TAKHZYRO, we're seeing that although you see in the clinic, there's 87% attack reduction as people have been moving from the 2-week treatment regimen to the 4-week treatment regimen, there may be more breakthrough attacks there. We haven't seen exact numbers around how many EKTERLY treated attacks are prophylactic breakthroughs versus individual patients who are just treating attacks as they happen and aren't on background prophylaxis.

Okay. Okay. Maybe we can pivot over to the on-demand opportunity here. You have a PDUFA date coming up. Maybe just stepping back, give us a quick overview of the efforts that you've already accomplished and what's still ahead.

Yes. So the launch preparations are full underway and fully on track and the team is growing. There's a tremendous growth in the organization with Wim coming on board and building the commercial team. We're also very happy that a lot of the good talented people that we have prior experience with HAE and come from companies that have other therapies in HAE and work on those therapies. Our Head of Patient Services launched FIRAZYR, for example. I think it's almost 40%, a little bit more of our team members building from the top down have prior experience in the area. So that's very strong.

And also, there's a lot of excitement about Pharvaris, also from other areas and skilled talent from other rare disease companies have joining us. So that's going really well and fully on track. And then getting closer to the remaining phase in building the sales force and then to get ready for the launch.

How should we think about the sales force?

Yes, it's relatively compact compared to many other therapeutic areas. I mean I think that what we are building is very similar to what others have as well. I mean to have like 35 people in the field. And then the overall commercialization, I think, is around -- it's going to be around 70 and then adding a few more, maybe a total of about 90 people by the time we launch prophy. So it's -- which is also -- is an area that's also suitable for a smaller company like us to commercialize on their own and achieve forward integration and to continue to build.

And which -- so in regards leading up to the April 2027 PDUFA date, what interactions do you expect to have with regulators? How is everything going getting commercial supply up and running? And then we can potentially talk about expected label, price, economics?

Yes. So that's -- the review is ongoing, and then it will be coming soon also mid-review meetings. And so that's underway. And we also -- on the CMC and drug supply, that's also getting ready for the launch. So also on track.

And then on pricing, that's something we're evaluating now. I think that fundamentally, we'll be looking to price for value. I think that what we've also seen in other launches in HAE, there hasn't been any disruptive pricing strategies by anyone. And I think with the profile of deucrictibant, I think we have the potential to really illustrate that value that can provide an attractive pricing.

I think the key point also on on-demand is and -- our data in on-demand is significantly differentiated when it comes to a single-dose attack resolution, which is a very important aspect clinically and also in real life for patients, trusting that what they take is going to help them and they don't have to worry about should take a second dose or not and to get the resolution complete symptom resolution. I think that's a clear differentiator versus EKTERLY.

And then another point is also the -- an endpoint and data point that we have in our protocol, which is at the beginning of the whole attack process is the so-called End of Progression. And that is also a clinically meaningful endpoint. And so subject to agreement with the regulators, we may be able to get that into the label as well. And that shows that the End of Progression means that this is when the patient really feels that things are under control, it's not going to get worse. And we see that in 17 minutes [indiscernible] events.

I'll highlight that we had 12 endpoints in our study, all of which hit statistical significance in a hierarchical fashion. So I'm not sure we're going to be able to get all 12 into the label. That would be a very large package insert. But as Berndt highlighted, the key differentiating factors are the rapid onset of action, the complete symptom resolution and the single-dose durability. If we're able to have a label that's appropriately demonstrating those 3 factors, I think our commercial team will have a successful launch.

Okay. And so since we have an oral in on-demand, we have an oral in prophylactic. Specifically in on-demand, how should we think about the launch curve? Are people going -- I imagine people are going to immediately comp it to icatibant in early stages. How are you thinking about that?

Yes. So I think the level of awareness in the community that deucrictibant is coming is very high. And so that speaks in our favor. I think also what we -- it's a part of our strategy is also to the extent within compliance guardrails see to identify patients that could be interested in deucrictibant on the launch. And we have this so-called opt-in program where patient consent to receive information. And we are already, I think, up to like almost 2,000 patients target almost 3,000 patients by the time we get to launch. So I think that, that puts us in a strong position.

And that kind of accelerates further as we then progress further to the prophylactic launch because then we already have a good patient population as a basis that could potentially also then migrate over to the prophylactic version of the deucrictibant it comes. So I think that gives us a very unique advantage in the real high-value launch, which is the prophylactic as a new market entrant because you have this sort of stepping stone with the on-demand launch. It's all very integrated in our strategy.

And then in regards to the opportunity in Europe, how are you sequencing the potential launches? I believe the European package is under review now. Any commentary around that?

Yes. So that's under evaluation. And so I think that there are also other factors that play a role in the assessment of the European opportunity. I mean we like to -- I mean, fundamentally, we would like to see deucrictibant serve the patient needs on a global scale and that many patients participated in our trials globally, and we'd like to see what to do whatever we can do to achieve that.

I think the ex U.S. has its own different challenges. I think also especially in HAE, the commercial opportunities, the difference between the U.S. market and the Rest of the World is for most therapies pretty significant, but in HAE, you see even more so because of the pricing structure for historical reasons and because a lot of the therapies, the first therapies in HAE started in Europe.

So that's something we are evaluating and more to come on that. But it's -- I think it's fair to say that there's definitely opportunities there and also not only in Europe, I mean, in Japan and potentially in China and other territories could also have significant patient.

Should we start thinking about contributions coming ex U.S. in '27 or '28? How should we think about that?

That's a little bit too early to guide on. So we'll provide more guidance on that once we have...

Okay. Is there a U.S. expanded access program? Any color on that and how that's going?

Yes, that's in the sort of the medical area, that's something that we set up and there's a lot of interest for that. So that's also underway.

And is it -- are you getting any feedback from physicians? I imagine this is a good example for physicians who maybe weren't involved in the clinical trials to get some experience with deucrictibant.

Yes, that's sort of still early stages there to really has get some meaningful feedback there. But as I said, the program has a lot of interest, and we're really happy about that to be able to provide that.

Okay.

We're careful on giving guidance around that because it could be considered pre-approval promotion since it's a medically driven program. We'll say that, as Berndt said, we obviously opened it based off of interest that we received from physicians and KOLs. All of that is reactive in response to access challenges that people have. So that does give people the ability to treat their on-demand attacks with deucrictibant prior to us getting a formal approval, but it's medically driven program.

Okay. And then maybe we have about 6 minutes left. Let's touch on -- you have another clinical trial, CREAATE currently ongoing. How is that going? When can we expect data? And what does that opportunity look like?

Yes. So that's the CREAATE trial, just to remind that is for an indication called acquired angioedema. So that is another form of angioedema that's because due to underlying disease, so basically called the C1 deficiency in -- with the same angioedema symptoms that you see in hereditary angioedema. So basically follows the same pathway. That's about 10% of the patient population right now. We -- there's nothing approved for that. And in our discussions with the FDA, we have received encouragement to pursue that patient population.

And we see the potential for underdiagnosed situation there because as I said, because of underlying disease, and these are patients that are referred by the other treating physicians when they're able to figure out what's going on with these attacks that these patients have. So with the potential then with an approved approval in that indication, then that could uncover the broader opportunity.

And our plan with that trial, which is ongoing and also on track, and we guided the readout -- the top line readout in Q1 next year. And our plan is then to combine the data of that study with the NDA filing for prophy. And with that, we then may have a potential upside subject to regulatory agreement and concurrence for priority review, that we're going to receive. But the fundamental goal is to -- with that data together with the other data to get the broad label for bradykinin-mediated angioedema, not just HAE 1 and 2 and 3.

And that would be differentiated from any other.

That's another way of differentiated makes good benefits for prescribers that makes life easier, good benefits on the payer side and basically have a therapy that covers all forms of angioedema. That makes us -- there's no other company that really has that different approach.

Okay. Two more questions. First, cash runway. Can you talk about your financials? Yes, I'll leave it there.

Yes. So the guidance on cash is mid-'28 -- that is -- relates to what we referred to as the base case and the key core focus of the company, which is to launch deucrictibant in the U.S., both in prophy and on-demand. And we are now, of course, looking at other different points of potential other capital raises, and we haven't made any decisions there yet. We take sort of an opportunistic view when it comes to the potential equity. We also have other forms of financings available to us as we get closer to the commercial profile. And with the financing that we did a couple of months ago, that gave us that financial flexibility. So we have a lot of options to take the next step in our capital formation strategy too.

Okay. Then maybe in the last 2 minutes, over the next 6 to 12 months, what are we going to hear from Pharvaris outside of potential approval, launch expectations? Should we expect more data? We talked about the CREAATE study, longer-term data, LOE, et cetera.

We've submitted a -- or we plan to submit a late-breaker abstract for the college meeting, that's ACAAI. That's in the first week of November, where that will be our first opportunity to present our CHAPTER-3 data to the medical community. So we're excited about that. Our manuscript is shelled out and has data starting to be dropped in it right now. We will -- we hope to publish that for CHAPTER-3 in the first quarter of next year.

Also, as Berndt mentioned, as part of our NDA package, we'll be cutting our open-label extension data. So when that data cut occurs, we'll either be including that as a poster or a manuscript. So we'll decide on how we're going to disclose that open-label extension data. Berndt spoke about CREAATE Part 1 data. We have hopefully an approval with a PDUFA target date of April 23. And then, of course, any sort of feedback that we get from the FDA regarding our NDA submission for prophylaxis.

Okay. And mid-cycle for the on-demand, should we expect an update around that?

Yes. We're probably not going to give incremental updates on our ongoing interactions with regulators. But for -- as we've disclosed, conversations are happening, questions are being addressed. So things are going along as planned.

Okay. Great. Well, it sounds like everything is on track, and thank you very much for attending today. Really appreciate it.

Yes. Thank you, Max. Great to be here.

Thanks, Max.

Thank you.

Good day, everyone, and thank you for standing by. Welcome to the CHAPTER-3 Topline Data webcast. [Operator Instructions]. I would now like to turn the conference over to your speaker host Maggie, please go ahead.

I would now like to hand the conference over to your speaker host, Maggie, please go ahead.

Thank you, and welcome to the top line data announcement of CHAPTER-3, a Phase III clinical study of deucrictibant extended-release tablet for the prophylaxis 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 the call. Please note that 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 insight 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 as of today. While we may elect to update these forward-looking statements, we specifically disclaim any obligation to do so unless required by law. We are joined today by Dr. Marc Riedl, Professor of Medicine at the University of California, San Diego, principal investigator in the CHAPTER-3 study and a globally recognized expert treating physician, who will share his perspective on the CHAPTER-3 data and on their relevance for clinical practice.

Thank you, Dr. Riedl, for joining us. During our call, Pharvaris' Chief Executive Officer, Berndt Modig, will speak to Pharvaris' continued commitment to provide medicines that can further advance the management of bradykinin-mediated angioedema. Pharvaris' President, Dr. Peng Lu, will go through the top line efficacy and safety findings from the CHAPTER-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, good afternoon, everybody. Pharvaris prides itself on being a trusted partner to all stakeholders in the HAE community. I'm proud to once again speak to you as we execute another key milestone for our company. Starting with the on-demand program, positive Phase II data were followed by positive Phase III results in December 2025. Most recently, the FDA accepted our NDA submission, bringing us one step closer to making the deucrictibant IR available for on-demand treatment of HAE attacks.

The next catalyst for the on-demand program is the potential approval in April 27 of deucrictibant IR, which may represent a new standard of care for on-demand HAE attack treatment. Now turning to long-term prophylaxis. We have similarly built a strong foundation. Positive Phase II data were announced in December 2023. Today, we build on those with positive Phase III results, which support deucrictibant XR as a potential long-term prophylaxis therapy. Looking forward, we continue to generate additional evidence for deucrictibant in acquired angioedema through the CREAATE Phase III study, which results from the prophylaxis part of the study anticipated in the first quarter of 2027.

We expect to submit our U.S. NDA in prophylaxis during the first half of 2027. So now when you step back and take a look at the entire time line, what's exciting is that we have already crossed several major value inflection points and the upcoming milestones have the potential to transform Pharvaris into a commercial leader in bradykinin-mediated angioedema. I'd now like to hand over the call to Pharvaris President, Dr. Peng Lu, to present the CHAPTER-3 data. Peng?

Thanks, Bernd. Before reading the data, I would like to take this opportunity to sincerely thank the HAE community, especially study participants, their families, the investigators and the site staff, our study partners and all Pharvaris for their invaluable contribution to clinical research, especially the CHAPTER-3 study. CHAPTER-3 was a randomized, double-blind, placebo-controlled Phase III study of oral administered deucrictibant extended-release tablet, 40 milligram once daily for the prophylaxis of hereditary angioedema attacks. Eligible participants were aged 12 and older with HAE type 1, type 2 or HAE with normal C1 inhibitor. Participants were randomized in a 2:1 ratio, which was stratified by age and baseline attack rate. In total, 85 participants were enrolled with 55 into the deucrictibant group and 30 with placebo. Baseline demographics and HAE disease characteristics were generally balanced between 2 groups and consistent with the overall HAE population.

The mean age was about 39 years old and 4 adolescents were enrolled in each group. Most of the participants had HAE type 1 or 2. A total of 5 participants with HAE normal C1 inhibitor were enrolled. The baseline attack rate was comparable between 2 groups with a mean rate approximately 3 to 4 attacks per month. After years of dedicated effort, we are proud to announce the CHAPTER-3 study successfully met its primary endpoint, demonstrating a highly statistical significant and clinical meaningful reduction in HAE attack rate. Participants treated with deucrictibant XR experienced substantially fewer HAE attacks during the entire 24-week treatment period with an estimated attack rate of 0.35 attacks per month with deucrictibant versus 2.06 attacks per month with placebo.

This represents an 83% reduction in attack rate versus placebo, which was highly statistical significant. Of note, CHAPTER-3 is the first and only pivotal Phase III study to enroll patients across the full spectrum of HAE, including participants with HAE with normal C1 inhibitor. In contrast, all other pivotal HAE studies have exclusively enrolled patients with HAE type 1 or 2. Among the 80 participants with HAE type 1 or 2 in CHAPTER-3, deucrictibant XR achieved 87% reduction in monthly attack rate versus placebo.

Taken together, these findings demonstrate deucrictibant XR provides injectable-like efficacy with the convenience of oral therapy. This slide highlights one of the most important attributes of deucrictibant XR as a prophylaxis therapy. It's early onset of protection combined with durable effect over time. Consistent with its pharmacokinetics profile, deucrictibant XR reaches therapeutic exposure within the first day of dosing and achieved steady state within 2 to 3 days. Correspondingly, CHAPTER-3 shows that the protection of deucrictibant was maximized within the first week of the treatment and maintained throughout the study duration. Moving on to some of the key secondary endpoints. Deucrictibant XR demonstrates robust and highly consistent treatment benefit in reducing moderate to severe attacks and attacks treated with on-demand medication.

In the responder analysis, all but 1 participants receiving deucrictibant XR achieved at least 50% attack reduction from the baseline. With the most stringent threshold, almost all and 2/3 of participants achieved at least 70% and 90% reduction, respectively. Nearly half of the participants treated with deucrictibant XR remained attack-free throughout the entire 24-week treatment period. These results demonstrate meaningful attack control and reinforce the robust efficacy of deucrictibant XR across multiple clinical relevant measures.

Beyond the reduced attacks, we also observed meaningful improvements in how participants felt and functioned in their daily life. As shown in this slide, participants receiving deucrictibant XR experienced substantial improvements across all domains of angioedema quality of life questionnaire, including functioning, fatigue and the mood, fears and shame and also nutrition. Across every domain, reductions in AE-QoL scores from baseline to week 24 were consistently greater with deucrictibant XR compared to placebo. These results demonstrate the benefits of deucrictibant XR extends beyond attack prevention alone, translating into broader impact of the treatment on the meaningful improvements on patients' day-to-day quality of life. From the safety side, deucrictibant was well tolerated with most events being mild or moderate in severity.

The most common adverse events across both groups were upper respiratory tract infection, nasopharyngitis and headache. The one treatment-emergent serious adverse event also reported in this table as a Grade 4 event was laryngeal dyskinesia in a patient with a prior history of repeated laryngeal intubation, which was considered not related to study drug by the investigator.

The 3 participants with Grade 3 adverse events included tooth infection and the 2 people with Level 2 liver enzyme elevation. One of them discontinued study drug, the other remained on treatment and complete the study. The discontinuation in the placebo arm was due to urticaria. There was no evidence of increased risk of gastrointestinal side effects. GI treatment-emergent adverse events were evenly balanced between deucrictibant and the placebo groups. All of them are mild or moderate. As we have shown today, deucrictibant XR demonstrated meaningful and sustained attack prevention starting from week 1.

CHAPTER-3 study met its efficacy and patient reported outcomes endpoints with 83% reduction versus placebo in the overall HAE population and 87% reduction for the type 1 or 2 HAE participants.

Deucrictibant XR was very well tolerated. Now I would like to introduce Dr. Marc Riedl, a world-leading HAE expert to speak about the existing treatment landscape in the long-term prophylaxis of HAE, the unmet medical need in prevention of HAE attacks, his opinion on the clinical profile of deucrictibant XR and the potential of deucrictibant as an oral medicine. Marc, please.

Thanks very much, Peng, and good morning to everyone. I appreciate the invitation to join the call and give me the opportunity to just make a few brief comments. I think as the data you've seen they relate to clinical practice. So for a very brief background, I've been working in the HAE space as a specialist for about 25 years now, managing a large group of patients over that time and also conducting research and clinical and translational research in the condition. And so I would just mention, as people on the call likely know, we've really seen tremendous progress over those years with advances in therapeutics for HAE and understanding the condition.

And that's occurred both for on-demand treatment of treating attacks, but very importantly, for the prevention of attacks. And I would say in clinical practice, there's been an increasing emphasis on preventing HAE attacks because we do think that's the way to reach the goal of really normalizing people's lives and looking carefully at quality of life, as you just saw, was incorporated into this trial. So -- as people know, patients do have increased treatment options. We have achieved a lot over the years. But we've not entirely reached that goal of sort of normalizing life for all patients.

And I think that's why we continue to see the work that we're seeing in the clinical trials. That's why patients continue to enroll in these studies, and they continue to be completed because we do have unmet needs yet. We do have room for improvement in terms of managing this condition, which, as you know, is a lifelong -- at this point, a lifelong chronic condition. So just a few comments on what we still need in HAE and how the data you've seen on deucrictibant might help us achieve or meet those needs.

I would first say that the burden of treatment is a real thing for patients having to take their medicine, the route, the dosing, the schedule, this is a real issue, and it's something we spend a lot of time talking to patients about. The burden of treatment does affect quality of life. And so in my experience, many patients are very interested in the oral route, the oral medications as a more tenable, a more acceptable and tolerable way to take their chronic treatment due to portability and all the things that we know can be advantages of oral treatment. The oral medications for prophylaxis and HAE have had some limitations to this point.

That includes reduced efficacy compared to the parenteral medications or limitations due to certain side effects. And so I think the data that you've just seen is really encouraging. We're seeing the benefits of oral treatments now with efficacy that looks quite similar to the subcutaneous administered medications. And I think this will be very appealing to clinicians and to our patients as an oral medicine that can really achieve a strong efficacy in preventing attacks and appears to be very tolerable in terms of side effect profile.

The second thing I would say is that we really do work to individualize care to optimize outcomes. And by that, I mean, we do see variable efficacy and tolerability for any and all of the medications that are out there. So having treatment options are very important. I think this will be -- if it comes to the clinic, will be a very important treatment option. And I'd point out that this is a unique mechanism of action for preventative treatment, the B2 receptor antagonists . That unique mechanism of action makes it a novel treatment option where we might, in fact, see this improving outcomes for patients who to date have not seen the efficacy or the tolerability that we really aim for. And the last thing I would comment on is this group of HAE with normal C1 inhibitor. As you heard, this is a study that enrolled a small group of those patients.

And this is a condition that's been very challenging to treat in part because we understand it has a bit of a variable pathophysiology, but we strongly believe that most, if not all, of these patients have a bradykinin-mediated angioedema. So -- this is, again, a mechanism blocking that bradykinin receptor that may give us real advantages in preventing attacks for this group of patients, the HAE normal C1 inhibitor patients and really allow us to better manage these patients regardless of the reason, the pathway that there's bradykinin dysregulation.

So I think in totality, the study data that you've seen today really are encouraging that if approved for use in clinical practice, the deucrictibant will be a very important and a very useful addition to the tools, the options that we have to manage HAE. And so with that, I'll turn it back over to the Pharvaris team for the next part of the program. Thank you.

Yes. Thank you, Dr. Riedl and Peng for your insights on the CHAPTER-3 data presented today. I would like to reiterate my appreciation of the people around the world who have collaborated to generate these data. And let me take a step back to share our long-term vision. Our aspired path to bradykinin-mediated angioedema leadership has 3 steps. First, win on-demand treatment by combining effective attack control, a well-tolerated profile, oral convenience and reduced treatment burden. And second, expand into long-term prophylaxis with the ambition of offering injectable-like efficacy and a well-tolerated profile with a convenient oral administration, as we just heard. Third, leverage the B2 receptor platform beyond HAE, expanding into other bradykinin-mediated diseases and building a differentiated franchise. The opportunity is therefore much bigger than a single product or indication. Building on one foundational mechanism, we aspire to redefine disease management across the spectrum of bradykinin-mediated angioedema and beyond.

The upcoming year should be incredibly impactful for Pharvaris. Our PDUFA for deucrictibant in the on-demand setting is in April. We plan to submit our NDA for deucrictibant in the prophylaxis setting in the first half of next year, and we plan to announce top line data from the CREAATE Part 1 Phase III study in the first quarter of next year. In closing, Pharvaris is steadfast in our mission to improve the standard of care for people living with bradykinin-mediated angioedema.

[Operator Instructions]

Our first question coming from the line of Maxwell Skor with Morgan Stanley.

Congratulations team on the update. So now with 2 relatively near-term launches, can you talk about just the commercial build for both on-demand and prophylactic -- how deucrictibant in both formulations are uniquely positioned -- does the dual profile actually change payer conversations or simplify them? And then if I can, just one more follow-up. On CREAATE read-through, how should we think about the relevant comparator from CHAPTER-3, either type 1, 2 patients or what have we learned from the normal C1 inhibitor patients?

Thanks, Max, for that great set of questions. And we also start off by saying that Pharvaris has the vision of commercializing deucrictibant. We have already early on invested in getting ready for a potential launch and also handing over to Wim Souverijns, Chief Commercial Officer, who actually joined over 5 years ago, and we are well underway in building a very strong team with great experience in this therapeutic space. So over to you, Wim.

Thank you, Bernd, and thanks, Max, for the question. I hope I can answer all of you because there were quite a few in that question. I think, first of all, let me say that we're super excited on the commercial side with the data. As you remember, when CHAPTER-1 came out, we were blown away by this very high level attack reduction, as we call it injectable-like efficacy, and that's now confirmed in the Phase III. So I think together with RAPIDe-3, we are in a fantastic position with a drug that in both treatment paradigms, on-demand and prophylaxis saw really exceptional data. In terms of our commercial preparation, we are well underway. We know that the target audience in the U.S. is around 2,000 physicians, core physicians.

And what we've done is we're building a commercial infrastructure that really is going to match that market. By the end of the year, we anticipate to have about 95% of our people in place. Our aim is to really go for an organization that portrays the value of the company, the partnership, the collaboration, people with deep experience in HAE and/or rare disease. And based on the interest we get for job openings at the moment, we feel the excitement within the community of employees as well for the exciting challenge that we have ahead.

So we are very well poised to succeed that. In terms of the payer question you asked, the benefit to have an ODT and LTP, that absolutely comes true. And it's actually not a benefit just for the payer. It's actually fundamentally doctors and also patient and caregivers will tell you having one active drug, 1 molecule in 2 formulations that really cover all your needs in HAE is a super advantage. And we're going to be leveraging that. We're going to be working on that to make that a real benefit also in the market.

But from a payer perspective, specifically, yes, that is something that can become an advantage over time. We will obviously launch first with on demand. But once we have the prophylactic option approved, that would be adding to that armamentarium. Did I cover all your questions, Max?

Yes, I believe so. And then just finally, just on the CREAATE read-through, as we're thinking about that trial coming up, anything we've learned from CHAPTER-3? Thank you very much for the commercial side.

Yes. Great question, Max. As mentioned, our CREAATE study, the pivotal -- the Phase III study for acquired angioedema due to C1 deficiency is well on track. I think definitely that the CHAPTER-3 data is very encouraging and give us more confidence to see the prophylactic treatment effect for Part 1 of the CREAATE study. Meanwhile, Dr. Riedl, maybe I hand it over to you and also maybe introduce more about acquired angioedema patients.

Sure. Yes. I mean I think for the most part, acquired C1 inhibitor deficiency behaves clinically very much like type 1 and type 2 HAE. I mean it is C1 inhibitor deficiency. Of course, the underlying cause is quite different due to consumption rather than a genetic deficiency in acquired C1 inhibitor deficiency. But clinically speaking, when we manage those patients, the acquired C1 inhibitor deficiency patients, we use really all the same principles. And in fact, the same medications, they're off-label at least in most regions of the world. But point being that we would expect that success in type 1 and type 2 HAE would predict similar results in acquired C1 inhibitor deficiency. So of course, we have to do the study to prove that, but that would be the anticipated outcome.

Our next question in queue coming from the line of Joe Schwartz with Leerink Partners.

Congrats on the results. I have one for the company and one for Dr. Riedl. I think the release notes an increase in the percentage of attack-free participants, but it doesn't quantify it. So I was wondering if you could give us any insight into the proportion of patients on deucrictibant who were attack-free over the 24 weeks and how that compared to placebo. And then thank you for your perspective, Dr. Riedl. In your clinic, when patients evaluate a prophylactic therapy, what do they anchor on? Is it the percent attack reduction, those that are attack-free?

Or is it the route and frequency of administration? And when there's a once-daily pill, how do you think it will setup in the considerations that patients consider when there's monthly or every other month injections in that trade-off?

Yes. Thanks so much for the great question that within the CHAPTER-3 study altogether that we enrolled 5 HAE patients with normal C1 inhibitor. Among these 5 patients, actually 3 patients received the active treatment deucrictibant XR. As Dr. Riedl highlighted that for the normal C1 patients due to the different -- the genetic mutation or underlying that different pathophysiology pathways, the response rate relatively higher, that higher variability compared to the type 1 to HAE patients. Therefore, within these 3 patients, we observed that 1 patient with less than 50% reduction, 1 patient get a 90% reduction and 1 patient attack-free. Hopefully, we address your question.

Yes, that's super helpful. And Dr. Riedl, how do you think that a once-daily pill will set up relative to some of the less frequently administered injections that are available?

Yes. Thanks for the question. I really like your question because this is the complexity of what goes on in the clinic, and it's, it's a little bit hard to answer, meaning your question, what do patients anchor on? What are they most interested in? I think it's a combination of things. And I sort of always joke, I'm notoriously bad at predicting what specific treatment an individual will choose because these conversations are complex with a lot of factors. But I will tell you, this is just my experience, I think efficacy almost always carries the day, meaning that it's got to work.

And I think we spend a lot of time talking about efficacy. We do discuss from the pivotal trials, the average reduction in attack, percent reduction in attack rate as kind of an important endpoint. I will say that patients are also increasingly interested in this attack-free outcome that I think you mentioned. What are the chances from the study that I won't have attacks at all for long stretches of time. But I think closely behind efficacy, and you touched on it, is the route or the -- I call it the schedule, right?

What do I have to do to get the benefits of the medicine? And my experience is that patients are very, very interested in oral medications. Generally, patients don't like injections or infusions. Of course, as you said, as these become less frequent, it might become more palatable. But we've seen tremendous interest in the oral agents that have been available to date, whether those are prophy or on demand, and I see that continuing.

So I do think that there is sort of an advantage to the oral route for most patients, perhaps not all, and that that's something that they can picture themselves adhering to over time, a daily pill, it's portable. It's easy to take with them when they travel, and it becomes part of their routine. So I do think that, that is attractive to patients.

Is this drug going to be for everyone? No, that's why it's nice to have options. But I do think we're going to have a lot of conversations if and when this is in the clinic, a lot of conversations, people will be asking about this because of the considerable interest in the oral routes overall.

And our next question in queue coming from the line of Steve Seedhouse with Cantor Fitzgerald.

Congratulations on the results. First question I had is, I was just hoping you could expand on the safety profile you saw in the study. I saw there is -- I think there is a few Grade 3 events, one Grade 4 event that I think you said was a laryngeal HAE attack, which seems fine. And then there was one HAE as well. So would you mind just expanding on those AEs and the overall safety profile observed in the study?

Yes. Thanks, Steve. I appreciate the question. But as illustrated in the presentation, we do observe one that serious adverse events. It's a laryngeal dyskinesia. Actually, for this is actually a normal C1 patient. And before joining the CHAPTER-3 study, this patient reported 19 oral laryngeal attack during the screening period. That's why due to the long-time laryngeal attack and also multiple times intubation, these patients actually have the vocal cord disorder. That's why during this study, actually, this patient achieved a 90% attack reduction. And one time, the patient due to the vocal cord recorder and hospitalized.

And during the assessment, there is no swelling during the laryngeal microscopy there and the patient consider it is not -- the PI consider is not treatment related. Actually, during the follow-up with AE, the PI told us the patient are very happy once they join the study even back to work. We really feel proud that deucrictibant can help our patients here.

Okay. Super helpful. I was hoping also you could comment on prior prophylactic use by patients entering the study, like what proportion had been on prior prophylaxis versus treatment naive? And did you have representation from prior Takhzyro and Orladeyo use specifically?

Yes. Excellent question. I believe during our demographic slide deck, we show around maybe between 20 to 30 patients on prophylaxis prior to the study. Yes, that actually these patients have the Orladeyo use has the lanadelumab use and also C1 inhibitors that use there.

Okay. And then, Bernd, you mentioned in the press release and in your closing comments that this encourages the company to develop novel therapies or maybe even deucrictibant for bradykinin-mediated diseases beyond angioedema -- and of course, you recently published this review sort of summarizing a bunch of indications where B2R may be involved. So I was hoping you could expand on your plans going forward in that regard.

Yes, sure. So we are, as you also pointed out, evaluating, looking at bradykinin-mediated diseases that could potentially be product extensions of deucrictibant. So that is in the sort of final stages of evaluation, and we plan to make some decisions on potential starting some clinical development and to generate data for these other indications. We have not publicly disclosed or define exactly what that is yet. But in due course, we will provide more information about that. And so stay tuned.

Okay. Great. And just last one quickly. Can you say what proportion of the 85 patients enrolled and are continuing in the CHAPTER-4 open-label extension? And I guess, what's the plan for data disclosure from that going forward?

Yes, excellent question. As I mentioned, the 83 patients continue the study out of 83, 80 patients roll over to the CHAPTER-4 study. Currently, the study is ongoing, and we will continue to monitor long time efficacy and safety with the CHAPTER-4 study.

Our next question coming from the line of John Wolleben with Citizens Bank.

Congrats on the day.

Two for me. Just wondering if you could give us some sense of the most common AEs on deucrictibant, whether it's more than 5% or 10% of the incidence rates. And then for Dr. Riedl, if deucrictibant becomes available in both the on-demand and prophylactic setting, can you walk us through how you think about shared decision-making and introducing this option to patients when they come in or patients thinking about switching to a new therapy?

Yes. As presented for the safety section, the most common adverse events upper respiratory infection, nasopharyngitis and also headache as showed here. And overall, it's a balance between that placebo and active group.

Marc.

I believe second question for Dr. Riedl. Do you have any follow-up safety question?

No, that was helpful.

Yes, related to the -- if and when this is available in the clinic. I mean, I think the general practice at our center is as new medications come to market to discuss those with patients just as you noted. I think I don't know the future, but the on-demand treatments or the on-demand indication for deucrictibant looks like it would arrive first. And so I think we've we -- as people know, we have some experience with oral on-demand medication already. I think this is not the focus of this discussion, but the on-demand treatment data for deucrictibant looks extremely strong. And so I think this mechanism of action, the B2 receptor antagonism is something we have a lot of experience with icatibant over the years.

And so I think that will appeal to patients as an oral route with that mechanism of action to treat attacks. As I already alluded to, I think the long-term prophylactic indication, given the efficacy we're seeing, the tolerability in an oral route will really be an important discussion. And I think I think patients will be very interested in that. Those that are either not on -- sorry, not on long-term prophylaxis at this point because they haven't liked the options or those that actually are on LTP already. Again, the parenteral drugs having some burden of treatment, I think we will see people considering this as a potential switch candidate. And then as mentioned earlier, I think the appeal of having an oral treatment for both on-demand and long-term prophylaxis is something that could, in some ways, simplify what we're doing.

Of course, we haven't done that yet, but I think that's sort of having one source, if you will, for both types of medications is there's some logistical advantages to that as a clinician, a sort of one-stop shop, if you will, for these a little bit complicated treatment plans we develop for individual patients. So anyway, those are just some of my thoughts about what we might see in the clinical space if and when we're able to prescribe deucrictibant.

Our next question coming from the line of Tazeen Ahmad with Bank of America.

Congratulations on the positive data. So as you think about the world where you will have the options of both on-demand and prophylaxis available, how should we be thinking about a couple of things? First, about the initial ramp for on-demand? And based on that initial ramp, should we assume, based on the evidence presented to date, that the appeal of having both prophy and on-demand options once the prophylaxis indication launches would also accelerate the on-demand? And then I have a follow-up.

Yes. Thanks for that question. And I'll hand it over to Wim in a minute. I think basically, as you know, from our launch sequence of on-demand and prophy that the launch of the on-demand indication basically is have finder or paving the way for the -- to support the prophylactic launch that follows afterwards. So they're very much integrated. And the opportunity for patients to try first the deucrictibant with the on-demand, we think assuming that, that will be a positive experience for patients that they would have a very strong interest in also trying the prophylactic formulation. But please add to that.

Yes. Thanks, Bernd. And I would absolutely echo that. I think it's a huge advantage of having these 2 options. We -- for us, the on-demand launch is critically important because the better we do there, the better we think we can accelerate the prophylactic launch. We basically get a head start on prophylaxis just by getting experience with the therapy. And given that deucrictibant has the same mechanism like icatibant, which is still the standard of care today across the world, that bodes very well, we believe, to kind of convince patients on demand, whether they're on prophylaxis or only use on-demand therapy to switch to deucrictibant. Once the prophylactic then gets approved, that becomes an amplifier potentially for the on-demand segment too, but we definitely feel this is a huge advantage to have both in our armamentarium. And as I said before, this is a feedback we're not getting just from doctors. We're getting this from patient care. We're getting this from payers. So I think this is a real advantage that we can bring to this market here.

Yes. Maybe also add to that particularly as a new entrant into the market then to find the patients and to be able to address the patients once we have an approved therapy that the on-demand launch then would generate that information for us to fully then also support and as Wim said, amplify or put an extra boost into the subsequent prophylactic launch.

Okay. And then as a follow-up, how long do you think it would take to negotiate with payers once prophy is eventually approved in order to potentially position yourself as a preferred option having both the on-demand and the prophylaxis options available?

So actually, Tazeen, it's a great question. We are very active already. Our plan is to -- by the time of on-demand approval, if approved, to have more than 90% live covered conversations with payers, PBM, states, et cetera. So we are very active already kind of educating the payer community on the data. And whenever we speak about the data, we obviously bring forward the Phase III data for on-demand with RAPIDe-3. But in the same vein, we're also talking about already our CHAPTER-1 data, which is the Phase II for prophylactic, giving those payers already an insight that there is more coming. And obviously, that will be accelerating now, now we have the Phase III data. So I think we're going to be in a very good spot. And as I said before, this is a little bit of the advantage of having the on-demand before the prophylactic launch because as you know, building a relationship with payer is thing that takes time.

And so the bigger opportunity ultimately will be the prophylactic market, and we're going to have this time with on-demand to really establish ourselves as a preferred partner in care. So I'm very positive, very optimistic that we can accelerate normally, if you want to have only on the prophylactic launch, it would probably take more time to get on to the formulary and getting the status that we would aim for. Does that answer your question?

Our next question coming from the line of Debjit from Guggenheim Securities.

I have one for Dr. Riedl first and then one for the company. Dr. Riedl, if you have patients on Orladeyo, would you switch them over to deucrictibant given what we have seen from the data today? And then to the company, could you sort of clarify the 2 patients with liver enzyme elevations were these Grade 3 events? Or how should we understand it? It wasn't particularly clear to us.

Yes. Thanks for the question. So certainly, we do have patients on Orladeyo. As people know, that's been a very useful oral preventative drug. The responses are variable to Orladeyo, and that's true for a lot of medicines. But certainly, for instance, the responder analysis that was done in the Orladeyo Phase III trial showed much more variability than we've seen in some other Phase III studies. And so to answer your question, there are patients who are doing extremely well on Orladeyo, and I think they would probably have a little motivation to switch, but there are certainly a substantial number of patients who are getting benefit from Orladeyo, but not seeing quite the efficacy that we'd like. And so I do think that there's a subset of patients that are all about the oral route. That's their preferred way to go, and that's why they're on Orladeyo, but they would like to see better preventative effects.

And so I think these are conversations we'll have with them and humans being humans, some will stick with what they know and -- but a significant number, I think, will say, yes, I like the idea of an oral medicine that may give me better prevention. And so I think that's certainly a group that I think this would be a very useful medication for.

And as I mentioned before, there may be also certainly be patients on parenteral drugs who would -- who like the efficacy of those drugs, but would prefer the oral route. So I do think these are going to be really important conversations because we do continue to see patients switching from one medicine to another given as data comes out.

And I think we'll continue to see that as these new medicines come to market.

Yes. Maybe I will take over the second question. Appreciate the question, Debjit. Indeed, within the CHAPTER study, we have the 2 patients was observed, as mentioned, Level 2 enzyme elevation that is pretty much slightly above fivefold increase from the upper top line limit. And for both patients actually asymptomatic and no elevation of bilirubin was observed. And both patients have confounding factors with either long-term androgen use or the fatty liver there. So one, actually, investigator decided to discontinue the patient from the treatment. As we mentioned, there is one that deucrictibant patient discontinued from the study earlier and another actually continued the treatment and the patients remain on the treatment and complete the study.

Our next question in queue coming from the line of Laura Chico with Wedbush.

A couple for Dr. Riedl and then a couple for Pharvaris. Dr. Riedl, how many patients -- of all your currently managed HAE patients, what proportion are actually on an oral prophy regimen today? And I'm curious where you think that might go in a couple of years from now once deucrictibant XR reaches the market. And then with respect to switching, switches from Orladeyo makes sense. But I guess, over time, would you anticipate more switches from Takhzyro or Orladeyo?

I'm just kind of curious where you think the bulk of the switches would originate from. And then with respect to Pharvaris on pricing, just following up on your earlier commentary, how should we think about the pricing relative to other prophy therapies? I guess I'm trying to understand kind of the view of the value delivery here relative to other treatments.

So yes, for my part of it, ballpark of patients on the current oral prophy that's out there. I mean we probably have in our big center probably maybe about 20% of our patients on the oral prophylaxis on berotralstat. And so like I said, a lot of patients have been very interested in the oral route, but we have seen some moved to other things because of efficacy concerns and probably a smaller number due to some of the side effects that occur commonly. So there's that group. Your question about switches is a very good one, and it's a hard one to answer. I think that we certainly have seen slowly over time, some of the lanadelumab or Takhzyro patients moving to other things.

And I do think that's a population that -- because most of our patients are on every 2-week dosing with that medication. And while that's -- people will certainly do it, it is something we hear about that becomes a little bit onerous over time. Some of those patients have switched to the less frequently dosed subcutaneous options that have come along. And so we've already seen a little bit of migration there. But I do -- to answer your question, I do suspect there are some Takhzyro patients that, as this data gets disseminated, have kind of been waiting for oral treatment that might have similar efficacy. And so I think we may see some switches there.

I think, as already mentioned, I would anticipate some switches from Orladeyo for -- because those patients are really focused on oral medicine, but would prefer something that might be somewhat more effective for them. So a long way of saying, I think we will see some -- potentially some migration from both of those groups just based on either the tolerability profile or the efficacy profile. And -- but the final caveat is always difficult to predict what individuals or human beings will decide. So those will be really, I think, kind of fascinating conversations to have with our patients.

Yes. Then on the question on pricing. So what we haven't seen in this therapeutic area and any of the entrant is any disruptive strategies when it comes to pricing. It has to be based on value and patient benefit. And so we haven't talked in detail about our pricing strategy yet, but maybe you can also add something to that.

No, I think you're absolutely right, Bernd. I think what the beauty of this data is that it puts us, as we said before, it gives injectable-like efficacy with oral convenience therapy. And that provides us all the options. So what we'll be doing, we're looking at payer dynamics, we're looking at receptivity on the clinical value, and that will then drive our pricing decision ultimately, but we're in a very good position. So I think we can leverage really the data that we have here.

Our next question in queue coming from the line of Tehila Hernandez with BMO Capital Markets..

This is Romi on for Tehila. I have 2. First for the Pharvaris team. Just a follow-up on the safety. In relation to the liver enzyme elevation. I was wondering if you expect this to be a potential concern for the label. And then the next for Dr. Riedl, could you share your experience with enrolling patients in the trial, especially those switching from other therapies?

Yes. Maybe I can take over the first question to -- as we explained, we do observe that there is a level 2 liver enzyme elevation for the deucrictibant that we would expect that from the label part, it may be quite comparable to the others that HAE prophylaxis treatment. So maybe potentially, there is one section in the label about liver abnormalities to illustrate the liver enzyme elevation here.

Yes. And just to enrollment in the study itself, I mean we -- as people might know, enrolling in clinical trials, at least in the U.S. has become a little more challenging. As I mentioned in my comments, we're still seeing patients enroll because they do recognize there's room for improvement. And so while it's a little bit slower, a little less brisk than it used to be a decade ago, we're still able to enroll. And I think for this trial, it's going to sound repetitive, but I think the real draw was this once-a-day oral pill that at least based on the Phase II data we had looked very promising in terms of efficacy. And so that was for our patients that enrolled, that was the draw. I could take a pill once a day. And potentially get the effect that has been seen previously only really with injected medicines. So again, I think that speaks to the advance that this may represent and how that may roll out in the clinic is something that's appealing. That's what drew our patients to the study to begin with.

Our next question in queue coming from the line of Fanyi Zhong with Oppenheimer.

This is Fanyi on for Jeff Jones. A couple from us. What are the key gating items ahead of your NDA submission? Any strategic plan you could share for ex U.S. markets going forward? Also questions to Dr. Riedl. What kind of patients do you see being the first to adopt deucrictibant, most like new patients or patients currently using Orladeyo or patients on injectables?

Maybe you repeat that question because it was a little hard breaking up in the middle of it.

Sure. What are the key gating items ahead of your NDA submission? And any strategic plan you could share for ex U.S. markets going forward?

Yes. So the NDA submission is also as we also -- for prophylaxis, as we have also mentioned earlier, is the looking to generate data in acquired angioedema and potentially include that in the filing. But that's not really viewed as a gating item. We will determine the filing date based on the appropriate timing when we have the file ready, and then we will see where we stand with the acquired angioedema data. What we also need in order to complete the package for the filing is also the totality of the safety database with the CHAPTER-4 study. So that is -- which is still ongoing.

Yes. As Bernd mentioned, altogether for NDA submission regarding the prophylaxis, we integrate CHAPTER-3 and also safety package, as I mentioned, 1-year safety data from the CHAPTER-4 and also hopefully the acquired angioedema data from Part one clinical results. Then we will put all together for the prophylactic filing for bradykinin-mediated angioedema.

And your question regarding the ex U.S. strategy. So as you've probably seen, we've filed a validated by the EMA recently. So we have submitted for European approval there as well. Our focus clearly is on the U.S., but we're doing already kind of the critical path activities in preparation for Europe, looking at our value doses as you probably know, ex-U.S. payer interactions are very different. So that's the key focus. And then we'll look at how we execute on this. We still have options to decide how we want to progress with that.

Thank you.

Yes. And then I think there was a question for me for my part of it. I think the candidates for deucrictibant, first and foremost, any new patients newly diagnosed or new to prophylaxis, -- my experience is that given choices, the vast majority of patients will opt for an oral medicine before an injected medicine. I just -- I don't see too many patients signing up for injections if there's an oral medicine that will accomplish the same thing. So I think that's, that's certainly been our experience that, that would be so-called early adopters of this.

I think there is -- as we've talked about, there is a subgroup of patients that really oral medicine is what they're on or what they're going to tolerate the best. And so there is a subset of patients on current oral therapies that aren't doing as well as we'd like. And so those would be, I think, prime candidates to switch to an oral medicine with perhaps a better efficacy profile or tolerability profile.

And then lastly, I think there's a subset of patients on parenteral drugs who have gone there because of the efficacy of those agents and some of them are doing really well and we'll stay on that. But there's also a subset of those patients who tolerate those injections because it works for them. It's effective. But given the option, they would rather not have to keep that schedule of injections. And so -- so again, it's -- I think you sort of see borrowing from these different groups, it becomes a fairly substantial number of people who are going to take a close look at this. But that's kind of how I would see it rolling out those kind of groups in that order.

Thank you so much to everybody who joined our conference call. This has concluded the Q&A portion of the call. I understand there are still more questions in the queue. I'll be reaching out to those people directly.

And once again, thank you very much. We're thrilled with these data, and we look forward to continuing to progress new potential treatment options for people living with bradykinin-mediated angioedema. Thank you.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation, and you may now disconnect.

[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.