All right, good afternoon and welcome to our, I think the final session of the conference. It is my pleasure to introduce Maggie Beller, the Head of IR for Pharvaris. Maggie, welcome. I know this is the first time I'm hosting you here and before I go to the Q and A, let me just turn it to you for a quick introduction of the company and maybe a brief overview about what is ahead and some of the catalysts and timing for that.
Absolutely. Thanks so much for having us. So far, Pharvaris is a publicly traded company. We are focused in hereditary angioedema, which is a disease in which people suffer from swelling attacks that can be unpredictable, really painful in your hands, your face, your stomach and your throat. If you have a throat attack, you can end up asphyxiating and it can be fatal. We are really focused on the development of an oral bradykinin B2 receptor antagonist called Deucrictibant. We have that in Phase 3 for both our on-demand program and also our prophylactic program. We are reading out top-line Phase 3 data for on-demand in the first quarter of 2026 and for the second half for the prophylactic program.
Fantastic. Obviously for HAE, it's a quite competitive market. There's a lot of different mod. You have even the gene therapy being developed there. Maybe walk us through the indication in terms of how you guys are looking at the unmet need and where you think you can fit in.
Absolutely. One of the things that we really focus on is the ability to provide the next step in treatment. Right. There are approved therapies out there. But are patients getting the efficacy that they want, the tolerability that they need with the convenience that's best for them? Those three things can mean different things to different people. As you said, there are some interesting long-acting injectables that are in development right now. There are injectables that are approved once every two weeks. TAKHZYRO is the most widely used prophylactic therapy. Right now there's an oral on the market for prophylaxis. People can also decide to treat their attacks if and when they have it. Right now there are only injectables approved on that side. What we're trying to do is develop a product in both settings.
Both on demand and prophylaxis that achieves the goals that patients want. They want injectable-like efficacy, placebo-like tolerability, and convenience as that means to them. For us, we think that a daily oral pill for prophylaxis could be that convenience.
I see. Got it. In terms of when you look across the competitive landscape, the convenience is one factor where you differentiate. Does it have to differentiate on efficacy as well? Have to be the best in class efficacy?
Yeah, no question about it. We hear from both patients and physicians that efficacy is key. However, we've seen a really great launch from Orladeyo that isn't as competitive with the injectables on the efficacy side, but they've had a really great launch. Although on the surface it sounds like efficacy is key, we think that this convenience plays a larger part in it as well. Having a drug that could be the convenience of an oral like Orladeyo, but with the injectable-like efficacy of a TAKHZYRO or some of these newer entries, Garadacimab, donidalorsen, I think that could be really competitive in this space.
I see. Got it. Obviously you guys have a Phase 3 enrolling before we get there. Maybe just, if you do not mind, just walk through the Phase 2 data and maybe discuss the highlights from that and what is making you guys excited.
Absolutely. On the prophylactic side, I'll start there and then we can touch on demand. Our Phase 2 data readout, in December of 2023, we saw from our CHAPTER-3 study that with the 40 mg per day dose we were able to achieve 85% attack reduction compared to placebo. Once again, that's in line with some of the other approved injectables. Right now we have open-label extension data from that study as well, and we saw that that attack reduction was maintained and even improved upon. Our open-label data shows 93% attack reduction. In addition to that, we have some really compelling quality of life assessments that we're including in our Phase 2, our open-label, and our phase three study. Very excited to see that top-line data second half of 2026.
Fantastic. What's giving you confidence that you can reproduce these Phase 2, these impressive Phase 2 results into Phase 3
HAE?
Is really interesting because there is some good reproducibility from Phase 2 to phase three. One of the things that we're doing, of course we're going to have a broader study. We're targeting enrollment of 81 participants. Our Phase 2 was about 30 participants. We're going to expand that patient population and we are switching from in the Phase 2, we had BID dosing of the immediate release capsule. We did that twice a day. We're going to be using our extended release formulation in the Phase 3 study that has a much leveler PK profile compared to the dips and troughs that come with an immediate release capsule.
We think that that protection could bolster any sort of degradation that you see in typical Phase 2 to phase three shifts and maybe even improve upon it with a QD dosing as opposed to a BID dosing. We think that that PK profile is really compelling for once daily treatment.
Right, I see. Got it. In the Phase 3 design, you also included adolescent and there is the expanding to global sites and then have a two-to-one randomization maybe. How do these changes, like how do you think they will affect the Phase 3 results?
One of the things that we're thoughtful of is the fact that in prophylaxis there are competitive Phase 3 studies enrolling right now. We wanted to design a study that would be compelling for people to participate in. That's why we have this two to one randomization. We wanted to increase the likelihood that somebody would be on active drug as opposed to placebo. We're including adolescents because that's a really important patient population for us. People tend to have increased HAE attacks as they go through puberty. We want to make sure that we can include those people in our study. Additionally, other HAE sponsors haven't penetrated into other regions, such as APAC, some European countries that we didn't include in our Phase 2, and LATAM. We think that there's high unmet need in these regions and we want to be able to enroll competitively.
Inclusion of those people and those regions are going to be able to hopefully bolster our enrollment there.
Right, got it. As you think about the phase three result and what you need to achieve to be competitive in the commercial market, what do you think is the bar that you need to achieve? I mean, just looking at your primary endpoint, what level of like the monthly attack reduction compared to placebo you would need to achieve in order to have that competitive profile?
Absolutely. Prior to our Phase 2 data, we were really looking at our profile and saying we can be competitive in the oral space if we're able to achieve 70% attack reduction. Our 85% attack reduction that we saw in the Phase 2 clearly knocks that out of the park and puts us in the playing field with the other injectables. Our commercial penetration strategy has switched from just owning the oral market to being able to have a competitive foothold not only in oral, but also with the injectables if we're able to reproduce the 85% attack reduction that we saw in Phase 2 and like I said, maybe even improve upon that with the extended release formulation, we think that that gives us a real competitive edge for the prophylactic market.
I see. Got it. Then you're also looking at several other key secondary endpoints. Which one of these are meaningful to doctors in terms of how they would choose the medication, and what are your bar for these other secondary endpoints?
Absolutely. You can't get more than 100% attack reduction. At some point when you're playing between 92%, 93%, is that really gonna move the needle? The other key secondary endpoints that we're looking at are use of rescue medication for when you have a breakthrough attack. Are people needing to treat their attacks with an on-demand therapy or is the reduction in severity sufficient enough to be able to improve upon the profile? That's one thing. Number of days that people are attack free. Treatment guidelines state that no person should ever experience an HAE attack. That is the goal that we're all aiming towards. If we're able to have really compelling attack-free data, I think that really bolsters our profile. Lastly, we're thinking about quality of life.
HAE is a lifelong condition and so the ability to be able to have meaningful impact and improvements in quality of life is something that we think both patients and prescribers are going to care deeply about in the Phase 3.
I see. Got it. Okay. When you think about sort of the commercial, how things are playing out commercially, you have the oral, which adds a lot of convenience to it, and then you have the injectable, which is sort of like perceived as a maximum or maximum efficacy. There is this balance between the two. What do you think is the most valued by patients? Are there different patients who look at convenience over efficacy or efficacy over convenience?
Certainly we've seen with the launch of Orladeyo that some people are comfortable foregoing efficacy in preference for convenience. We think that if we're able to provide both, that's obviously a major selling point for us. When we think about the prophylactic market, we really think about our penetration in four steps. Number one, an effective tolerable oral therapy should be the first line of therapy for any new, any new patient who is switching to profi. So that's one area that we're targeting. Number two, there are a number of people who have tried the other oral and have come off of it for whatever reason, either the efficacy doesn't meet their standards, their GI or tolerability impacts, or it just doesn't, you know, doesn't fit in their schedule.
By our math, we should have, with a 60% retention that BioCryst has reported, there should be 1,000 patients by the time we launch that will have tried Orladeyo and come off of it. These are people who clearly are wanting an oral but were not satisfied with the experience that they had. That is a target for us. The third is people who are currently on the oral therapy but may not be as well protected as they could be. These are people who may have gone from four attacks per month and now are experiencing one to two attacks per month. Maybe they are milder, maybe they are peripheral attacks, but they are still experiencing an attack. Good is not good enough for us. That is another segment.
The last segment is people who are on the injectable who didn't want to make that concession of efficacy for the convenience. However, with the entry of a therapy that could be equally, if not more effective than the injectable that they're on, plus the convenience of an oral, we really think that that changes the paradigm for those people.
Right, right. And based on Orladeyo's launch, there are certain patients who are more biased toward that. In terms of these patients have less number of attacks, maybe not as severe. So therefore they're more ideal for the oral, less efficacious therapy compared to like. Is there just curious if you found, if you found something in your market research studies or you've been hearing from clinicians of how they're using it or biasing patients to one versus the other.
We think that based off of the Orladeyo launch that there's clearly an unmet need in orals. However, we don't think that you should have to have either less severe attacks or have to experience an attack at all. We think that there shouldn't be that bias, though there may be right now.
I see. Okay. Let's switch gears and talk about the on-demand use. Can you give us a quick overview about the profile for on-demand for these acute treatment of attacks based on the Phase 2 and also the open-label extension study?
Absolutely. Our RAPIDe-1 data readout in December of 2022. With that, we used an endpoint called VAS or AMRA, which is a visual analog scale. The AMRA is, once you put it onto a smart device like a phone, no longer an analog scale. We saw in that data that the time to attack symptom reduction was in 2.4. That, along with the fivefold decrease in rescue medication use as well as the 25-26 minute end of progression timeline, made us really excited about the Phase 3. It makes us very competitive with standard of care icatibant. In our open-label study, we also evaluated other endpoints, PGIC a little better, PGIS, which is a symptom score. These are all patient-reported outcomes that enabled us, though not head-to-head studies, to have a comparison to KalVista's drug sebetralstat.
We saw PGIC a little better. That's our primary endpoint. In the Phase 3, time to onset of symptom relief was in 1.1 hours. We saw that complete symptom resolution was in an 11 and a half hour and that 86% of people were able to treat their attack with just a single dose of Deucrictibant. This open label data makes us really excited to achieve what patients want from their on-demand therapy. Therapy that works quickly, that works completely and works with a single dose.
I see. Okay. Let's talk about your pivotal Phase 3 study. Has it completed enrollment? This is an event-based trial, so we're still waiting for the database to fill and these events to occur. Can you talk about the change in the primary endpoint that you used from Phase 2 to Phase 3 and also why you made that change?
Absolutely. With Deucrictibant, we knew in the Phase 2 that we were going to need to justify some sort of comparison to standard of care. Standard of care, the most widely used on-demand therapy, is icatibant, which also used the VAS AMRA time point. That is why we used that as our primary endpoint in the Phase 2. As our discussions with regulators have changed and continued, they really wanted to see PGIC a little better. In the Phase 3, of course in alignment with regulators, we have our primary endpoint as PGIC a little better. We did a mixed methods study which took people just taking standard of care and they measured their attack resolution across all of these patient-reported outcomes: AMRA, PGIC, PGIS.
We found that based off of those just standard of care results, PGIC a little better was achieved 0.8 hours sooner than the AMRA 30 that we used in our primary endpoint for Phase 2. Because this is technically a lower bar to achieve, we think that that provides us confidence in the phase three and our ability to hit the primary endpoint. As we look at it though, we're thinking about not only this primary endpoint, but the whole totality of an attack. It's not just how quickly your symptoms are resolved, but also how completely they're resolved. If you're able to do that with a single dose, that's why our secondary endpoints are really important to us as well.
Sure, got it. What is giving you confidence that by sort of the change in these different endpoints and that your Phase 2 data could translate to what could be reproduced to Phase 3? Also, what is that bar that you guys are looking for that you believe will be competitive in the commercial setting?
Absolutely. Once again we're looking at a not head to head comparison. Right now we're looking at sebetralstat, another oral, which has a PDUFA next week. We anticipate they're going to get approval in the endpoint that they had in their randomized phase three compared to our open label Phase 2. Once again, not head to head studies. Our data showed 1.1 hours to PGIC, a little better. That's the first symptom relief that you have. Theirs is 1.6. When we look at that half an hour, is that really something that's gonna be competitive in the landscape? We don't think so. Or it can be, but that's not enough to really switch people. We look at the rest of those endpoints and say, what is the time to the first time you're starting to feel better?
Our data shows PGIS 1 point better of 2.6 hours compared to about 7.7-9.3 for sebetralstat. We then look at complete symptom resolution at 11 and a half hours for us and over 24 hours for sebetralstat. That for us is really where we start to potentially have the leg up. Now it's going to be really important for us to once again confirm these findings in a phase three. We're excited to see our data readout in 1Q 2026.
Got it. Okay. In the commercial market, when you look at these two different settings, the prophylaxis and also the on demand market, how are you thinking about, you know, in these two different settings, how would you compete? Where do you think you would have a better advantage over the other? How do you see sort of like your, you know, like where's the most potential from a sales perspective?
Absolutely. Prophylaxis is the larger market, hands down. Treatment guidelines align with the shift that we're seeing towards the growth in prophylaxis. However, there are many efficacious therapies in prophylaxis. What we look at when we look at the prophy market is what will be the split between orals and injectables, because inherently there will be people who prefer a long acting injectable. What that split is going to be, it's really going to be determined by the Phase 3 data between our product. As you said, you've got a gene therapy, you've got some long acting injectables in the work. We will see what that looks like. Is it 50-50, is it 60-40 oral? We've heard some people say 70-30 oral, we will see. Once again, that's going to be driven by the efficacy that we have there in the on demand setting.
We think that orals take over. We can't see a situation in which somebody selects to have an injectable if you have an oral effective therapy for on demand. I think our unique selling point as Pharvaris is that we're agnostic to how the market breaks down either way because we're the only company that has a product potentially for both settings. The prophy market can grow as you get more people on prophylaxis. We think the entry of an oral into the on demand market also grows that market because people treat more attacks since the barrier to treatment is lower. We're happy to be in either space, in both spaces.
Right, got it. So when you think about these two spaces, how do you, like, have you been starting the commercial, like, thinking or preparation around that or is it still too early? Like, how are you guys, have you guys started building the commercial infrastructure and thinking about. Because there's such a big commercial play here, right? Because you're talking about you're coming in a little later than a lot of the therapies out there. Would that be, will you be competing for new patients or are you trying to switch patients off their therapy and switch to yours? How are you guys thinking about all these different commercial strategies?
Absolutely. I think there are two parts to that question. Number one, we've definitely started building out our commercial team. Our Chief Commercial Officer, Wim Souverijns, actually joined the company in 2021. As we think about the community engagement with HAE, allergists historically have been very relationship driven. It is important for us to continue to build those relationships. We've been making sure that we not only have our commercial infrastructure, but also the medical support on that side to be able to engage with physicians, make sure they're up to speed on our data, make sure they have everything that we need, that they need for them to make the prescribing decision. That's number one. I think number two is what is our strategy for penetrating the market. For profi we think about it once again in the four ways.
New patients, people who have tried orals and then come back off of it. The third is people who are potentially unhappy with their orals. The fourth is people who would switch from an injectable. Combination of new patients and switch patients.
I see. Okay, so we have a couple more minutes left. Why don't we switch gears and talk about the expansion beyond just the HAE. You do have a looking to expand into the C1 inhibitor level, people with normal C1 inhibitor levels, and then other bradykinin-mediated angioedemas. Maybe talk to us about the rationale for those and why and how do you guys—what evidence is supporting you guys expanding into those two populations?
Sure. Most other HAE companies are focused on type 1 and type 2, which is people with either deficient or no C1 inhibitor. That is easy. Not easy, but there are diagnostic tools to be able to determine those people. However, there is a whole other segment, people with normal C1, which means that they have excess bradykinin. It is not through this kallikrein system that most other HAE therapies work on. Our opportunity there is to treat this severe unmet medical need in normal patients. HAE with normal C1, excuse me, as well. That represents about 15%-25% of the population on top of HAE types 1 and types 2. Additionally, there are people with acquired angioedema, which means that they have some sort of underlying disease, whether it is lymphoma, MGUS, myeloma, lupus, where the disease actually consumes the C1 inhibitor.
They end up with excess bradykinin and experience angioedema attacks following that. That's about 10% on top of HAE types one and types two. If we're able to build on the treatable population of Deucrictibant, we think that's a really compelling commercial opportunity for us and it meets an unmet medical need right now and could be compelling from a regulatory standpoint since we have orphan drug designation for bradykinin-mediated angioedema in both the U.S. and the EU.
I see. Got it. You also recently hosted a KOL day and then presented some data supporting the use in the acquired angioedema, AAE. Maybe walk us through that and how you guys are thinking about advancing that to a Phase 3 study.
Yep. In an investigator-initiated trial, Professor Danny Cohn out of Amsterdam Medical Center has run a study of Deucrictibant in AAE patients. He's done that in both the on-demand setting, in which case people saw, this person saw, then increased and improved treatment satisfaction and time to treatment resolution in the Deucrictibant arm as compared to placebo. They also rolled over to the prophylactic over 20 months in four patients using the extended-release formulation that we're using in our Phase 3. There was one attack on day two in one patient. All other patients have been attack free for over 20 months. We think that that's really compelling not only for the AAE program, but also could be used as a proxy for what we could see as potential efficacy in the CHAPTER-3 program.
I see. Okay. You guys are also developing a bradykinin-mediated angioedema assay. How are you gonna use this assay? Is it gonna be part of that overall development program and the overall launch of the drug? What are any risks associated with you guys developing this assay yourself?
Absolutely. This assay is used to identify people with bradykinin-mediated angioedema. As I said before, there are current diagnostic tools that measure C1, the amount of C1 and the activity of C1 in patients. For those people who have HAE with normal C1, there isn't a diagnostic tool for them because Deucrictibant acts at the bottom of this cascade. There are many other ways that excess bradykinin can get into the system. This assay enables us to identify those people right now. It is not our intention, or Pharvaris's intention, to develop this as a diagnostic tool. We are not a diagnostic company, but we are open to partnering with other diagnostic experts if that's something that's appealing to them.
I see. Would this assay be needed for commercialization, like for part of the launch? How are you guys thinking about that?
We don't view it as a diagnostic partner for our program. We are including people with normal C1 in our Phase 3 program. There are other diagnostic tools for HAE, type 1 and type 2 and AAE that are commercially available right now.
I see.
Okay.
Got it. Can you remind us about the current cash runway? What is included in that guidance and what is not included in the guidance?
Absolutely. At the end of the first quarter we had EUR 236 million in the bank that provides us with cash runway through the into the third quarter of 2026. As a reminder our Phase 3 on-demand data is going to read out in first quater 2026. Our Phase 3 profi is in the second half. That provides us cash past on-demand but not quite to prophylaxis. Included in that is this acquired angioedema study that we intend to initiate in 2025.
I see, got it. What is the long term aspiration for Pharvaris? Also, as you think about it, you have a lot of these data coming out and also considering that the market is competitive, why is now a good time for investors to think about investing?
Pharvaris has the intention to commercialize in the United States. We have an active BD program and we're in communications with other partners about potentially partnering off compelling regions, Europe, Japan to the right partner there. We want to make sure that Deucrictibant can be provided, access can be provided to everybody who needs it. That's our intention is absolutely hold on to U.S. rights and think about creative partnership opportunities if and when they would arise for us. I think when we think about the investment profile of Pharvaris right now, we think about the fact that we have an experienced management team that has launched drugs in HAE before. We have a very strong IP portfolio. We have two data readouts in the next 18 months and we feel that there's a differentiated profile of Deucrictibant in this space.
He is a known market and really has upside potential here. It has the great combination of being a competitive market while also having the rare disease that's appealing to us.
Fantastic. I think we're almost out of time. So Maggie, thank you so much for being here. It's been a pleasure to host you. I'm going to turn it to you for final remarks and any concluding remarks.
Thank you. Just want to thank everybody. Thanks for having us. We really appreciate it. Like I said, we think that Deucrictibant and the Pharvaris profile is quite differentiated within the space and we think that, you know, the past six months have been challenging and that we're undervalued right now. Really think that there's an interesting and compelling opportunity here with milestones in the near term that people can have the opportunity to capitalize on.
Fantastic.
Thank you.