Everyone, welcome to our chat with Pharvaris. I'm Joseph Schwartz from the Biopharma Equity Research team at Leerink Partners. It's my great pleasure to host Berndt Modig, CEO, and Maggie Beller, Director of Investor Relations. Thanks so much for being here to give us an update. Yeah, thanks. Thanks, Joe. Good to see you, and thanks for having us. Look forward to the conversation. That would be making forward-looking statements. Also refer to our SEC filings, including the risk factors available on our website. Okay. Great. Well, maybe one of you could start us off with a brief overview of the company's recent progress and your priorities for this year. It's another exciting year at Pharvaris. We said that almost every year since we started ten years ago, but particularly this year is exciting because of looking to file our first drug in acute based on the strong data that we saw in December last year. Focusing on the completion and execution of the ongoing prophy trial to have top line readout in Q3, and continue to enroll in a small pivotal trial for acquired angioedema. Last but not least, preparing for commercial launch and ramping up the organization, so the company is firing on all cylinders. Great. Maybe if you could continue on the point about the on-demand results and recap those for us and help us appreciate. Mm-hmm ... how that positions you in the treatment landscape there. Yeah. Yeah. I'll take that one. Thanks, Joe. We read out our RAPIDe-3 data in December of last year. We were really pleased with the data because we hit our primary endpoint and 11 key secondary endpoints, all with statistical significance in a hierarchical fashion. Had we missed statistical significance in one, we wouldn't have been able to hit it for the rest of them. It was a bit of a risk taking on that statistical plan, but we were thrilled to see that the efficacy of deucrictibant was demonstrated through that, through those endpoints. Our primary endpoint was PGIC a little better. That's how you measure the time to initial symptom relief. Deucrictibant demonstrated that it was able to relieve symptoms in about 1.28 hours versus over 12 hours for a placebo. Other key endpoints that we talked about include a brand-new endpoint that we developed called End of Progression. That's the first time that people stop feeling worse. It's a really important psychological endpoint for both patients and physicians because they know that the medicine is working. HAE tends to be a stress-induced, the attacks tend to be stress-induced, and so having the knowledge that your medicine is working is really important. Our endpoint for that was in about 17.5 minutes. Another key endpoint was the time to complete symptom resolution. Deucrictibant was able to completely treat all symptoms in less than 12 hours, and that's really important because that also outperforms standard of care and we think that that's a really important thing for both patients and physicians. It means you could take deucrictibant at night when you start to feel symptoms and wake up in the morning symptom-free. Amazing. I think your current guidance is for an NDA submission in the first half of the year. Mm-hmm. Can you talk a bit about how those preparations are going? Yeah, that's going well. There's a team is working hard on that, and so pulling it all together. What we also are able to do is to also get a head start on the potential prophy filing. Because there's a lot of synergies and a lot of things that the two filings have in common, of course. There's also actually already a prophy filing team that's started to do work. That's on track to file in the first half of this year. Great. Sounds good. I guess, are you planning to have a Pre-NDA meeting? What do you think the focus of your interactions there would be? Are there any outstanding questions that need to be addressed? We already have that behind us. We've had a Pre-NDA meeting and then to work on to get a complete filing. Okay The regulators. Mm-hmm. All right. Is your base case that you'll get a standard review given there's other on-demand treatment options available? That would you- Yeah, I think that is our base case, the standard review so that they could then, if approved, then could potentially launch again in the first half of next year. Okay. How are you approaching your launch preparations? You can even say that the launch preparations started already some years ago, and I think building the visibility of Pharvaris in the community, healthcare practitioners and the patient organizations which have this, the disease awareness campaign called Deflate HAE, which has been very appreciated, and also in medical affairs team. Now of course, this year then can start to ramp up the organization. We already have a core team. We're experienced with HAE and expecting to ramp up also particularly in the second half with the sales reps and so on. The HR departments are busy, things are, there's a lot happening. What kind of things have they been emphasizing as part of Deflate HAE, and how will that evolve when deucrictibant is available commercially? I mean, it did. We of course were very careful and focused not to kind of do promotion in something that hasn't been approved yet. We really want to stay within that. The campaign is a bit more general in about the disease awareness. It's not focused so much on deucrictibant, but of course, as we get closer and are able to talk more, when we have approval, that can continue and be able to also be part of the whole promotional setup for ours. Right. It's an evolving thing. To create the awareness that also that in the patient community, there's still a big unmet need and patients are still looking for better ways to treat. There's a lot, although there have been so many drugs approved in the last 10 years, it's still a lot to do and there's still big unmet need. I think that's where we see the great potential for deucrictibant. Yeah. I think one of our key campaigns with Deflate HAE is deflate your HAE without deflating your expectations, right? Mm. You shouldn't have to give up on certain aspects of your treatment just because you need to treat or prevent an attack in HAE. That means that there could be a situation in which you are able to have an effective, tolerable, and convenient therapy. Right now, we think that there's still unmet need there. Just having the communication and conversation around not deflating your expectations as you're thinking about deflating your HAE. I like it. Thank you. Very interesting. The marketers are good. Well, people have been waiting for oral on-demand and prophylactic options for a long time. Mm-hmm It is exciting. We've seen another company launch an on-demand treatment option that's oral recently with some really good reception in the marketplace. Mm-hmm. What does that tell you about the opportunity for deucrictibant? Yeah, I mean, that makes us very positive about deucrictibant, because, I mean, that clearly shows the need for an oral. I think in particular in the on-demand segment, it makes a lot of sense intuitively to have an oral therapy, because of the portability of an oral compared to some of the injectables. So we think that really shows the strength of that segment. I think ultimately they would be clearly dominated by oral therapy in the on-demand. It's a very viable market segment, we think. With the profile that we just talked about a minute ago, with the data that we showed for deucrictibant, we think that we would be in a strong position in that market space. How does that data compare? Are there other attributes that you think position you favorably given you'll be launching after them? I mean, fundamentally, it's if you think about what somebody who has an attack really needs and what they're looking for is. This is where the oral part comes in. It starts with knowing that I have my therapy on hand, that the confidence that I can take it anywhere, anytime. That's a big advantage with oral. I can take it quickly. Of course, it's a big burden to go through an attack. It's a lot of anxiety. The company that you mentioned also has addressed that the anxiety is a hurdle to treat for injectables. Having the confidence that you have something in your pocket that's gonna help you and really take you through the attack, ideally with only one dose. You don't have to sort of worry about should I take a second dose or should I take or should I not take it, and how is my attack. The onset is important, because the onset is the point when you feel that things are, you know, the drug is doing something. At the end of the day, it's all about resolving the attack. A fast onset is less meaningful if in 24 hours, you're still struggling with the attack. The complete resolution, basically from start to finish to the complete resolution of the attack, I think is key here. I think that's where particularly what we're seeing the strong data of deucrictibant that will we think will make a difference. That makes sense. There used to be some debate about the size of the on-demand market. Some of that might have gone away with the strong recent launch. You know, we're hearing the docs have really good projections about the ultimate position of on-demand treatment options. Mm-hmm. What do you think will determine whether patients will ultimately swap out their existing on-demand treatment options, and maybe patients who don't use on-demand treatment options as much as they should will use more of them going forward? What are you watching? Mm. Mm Mm in order to see. Yeah, I think that. if the on-demand treatment options- Mm-hmm ... including deucrictibant, will convert the whole market and penetrate more of the market than currently? Yeah, as I said, I mean, the on-demand segment is clearly viable. I think it will grow in the future also because more attacks will be treated. That's what the oral feature really makes more attacks being treated, we think. So today there is a hesitancy or somewhat of a hurdle to treat some instances because you have a painful injection, you have to find a place to take it, et cetera. The speed and convenience of an oral, we think will lead to more attacks being treated, and I think that would be a growth factor for that segment. You may see patients kind of be able to go from prophy to on-demand, so the treatment modality can be based on what fits best for that person or that patient in their life or wherever they are. There could be phases where patients feel like right do on-demand and then other phases where they think it's better with prophy. I think that's also one of the key benefits potentially with the deucrictibant that we are able to offer that choice with the same compound. I think in particular for the deucrictibant, the potential advantage is that as we know today most attacks are treated with icatibant. The confidence of that that's been established over a decade in patients with that mechanism, et cetera. I think it's also could help patients feel comfortable to say now you have an oral icatibant, a better icatibant and even better than standard of care, that could also be for us an advantage in the space. Yeah. Could change the overall market, because if we're able to switch people from generic icatibant back to branded deucrictibant pricing, that could grow the U.S. market as well. Right. Yeah. That makes sense. Mm-hmm. Can we talk a little bit about as we segue into discussing the prophylactic opportunity what having the same API in two different formulations for on-demand and prophy means for you that will certainly be unique. You'll be the only company able to offer that kind of a solution. Mm-hmm. How do you take advantage of that fully, strategically? Yeah, I think it's a choice. I mean, as you said, it's a choice, so patients can decide how they wanna treat within the same drug, and also starting off with, let's say, with on-demand and then transfer over to prophy. To have that concept if I take prophylaxis for example, and then I can have the on-demand in my pocket in this scenario that I might have a breakthrough attack, then that whole concept of controlling your disease I think is an important aspect. I think also another differentiation also for deucrictibant is the broader label that we are aiming for with other forms of angioedema, so acquired angioedema, normal C1. We have data in our normals, in our Phase III trial for normal C1, where the mechanism is should have better efficacy just because of at the end of the cascade. That's so that whole concept and the whole package you could call it really has a lot of advantages and makes life easier for prescribing physicians, for patients, and also potentially for payers. That we see that as you said, a very unique position that we have. Mm-hmm. One of the things that we heard prior to our strategy was that the mechanism plus mechanism in prophy and on-demand was a concern. We're really happy to see that people who are on Takhzyro and having or ORLADEYO and having breakthrough attacks with a kallikrein inhibitor are being treated there on-demand with a kallikrein inhibitor. That supports the mechanism plus mechanism. As Berndt said, if we have a broader label, we may also be a one-stop shop, like a Humira of HAE. Mm-hmm. Which is pretty cool. What does the normal one, C1 inhibitor market or how does that compare to HAE? Mm have been, you know, historically thinking about it? Yeah, I think that's currently, I think it's estimated to be about 20% patients with normal the C1 and other mutations, and that there are more discovered. Right now it's about 20%. That is just mechanistically because the bradykinin expression or production it goes through a different pathway. It doesn't go through the kallikrein pathway. Right Being at the end of the cascade then, with the B2 receptor antagonist, really is what you need to have efficacy, real efficacy in those patients. Right. You'd have a lot less competition there. Yeah. None. Yeah. Great. Shifting to the prophy opportunity, how is the CHAPTER-3 pivotal trial progressing? Mm When will you be in a position to report that data to us? Yeah, that's progressing on track, and also as we said earlier, guided to read out in Q3. That's all on track. Okay. I guess you're working on an extended-release formulation. Mm-hmm. How will that development look alongside the development of the current formulation? For on-demand, we have the softgel capsule. As for the IR for immediate release. It has its PK profile. It is very fast uptake and then sufficient exposure to treat an attack. We also have for the Phase III trial in prophy the XR, the extended release. That's being used in the Phase III trial, and that has a PK profile as the word says is extended. It has a more favorable trough to peak to trough ratio and maintains a more stable over longer duration exposure over the therapeutic efficacy level. That's a slower uptake, so it wouldn't really function well as an on-demand, so they're not interchangeable. It's a distinct formulation and that it actually where the absorption starts in your small GI tract and also even in colonic absorption. The properties of the drug makes it suitable for that formulation. Mm-hmm. That, that's why we're having a Phase III trial and we have seen, I mean, at EAACI, we show some PK data for that oral formulation, and you can find that on the website. Also, there have been an investigator trial in acquired angioedema, which is only four patients that have used the extended release formulation that's basically showed zero attacks over an 18-month period in these patients. Okay. You're pretty comfortable that it'll work at least as well. Yeah, we had to as comfortable as you can be. Yeah. Yeah. In our CHAPTER-1 study, our primary endpoint was% attack reduction. Mm. We got 84.5% in that Phase II study, and that was using the immediate release twice a day. As Berndt said, with a more optimized peak to trough ratio, we may be able to defend that efficacy, and that's kind of our goal for the Phase III, is to be able to repeat the Phase II data. We believe around the 85% attack reduction would put us not only in at dominating the oral market, but also in strong competition with approved injectables. Makes sense. Mm-hmm. Are there any other differences in Phase III relative to Phase II, or is it pretty comparable? The differences are, as I mentioned, the formulation, the XR. It's also a more global footprint and more sites. I mean, same as we had in on-demand, and we're happy to see that the execution was done well in the on-demand trial. That gives us some comfort about the execution on the prophy side. But that's sort of typical Phase II, Phase III different. We also include normal C1 patients in the prophylactic trial at the request of the regulator, because they encourage us to include normal C1 to at least generate data there so that then potentially we can have a broader label and fill that unmet medical need as well, and then also including adolescent patients. Okay. Mm-hmm. Very helpful. Mm-hmm. BioCryst has done really well with their oral ORLADEYO. Mm In prophy HAE, despite efficacy that seems like it can be improved upon, you know, judging by your data so far, and maybe some tolerability issues. What do you think the opportunity is for deucrictibant extended release in prophy relative to that? Some patients seem to do well. Maybe they might not switch. How many patients do you think could switch? Do you think you could expand the market further? There's obviously other. Mm-hmm many other things coming to market in prophy as well. How do you see the treatment landscape and role for deucrictibant- Mm-hmm Given all the above? Yeah, I think, I mean, it's as we have seen also in the last 20 years even of development of therapies, it's always been the stepwise improvement and to meet unmet need and efficacy and the treatment modalities, et cetera. I think that continues, and I think, especially in the oral segment, there's still the same phenomenon as we just talked about a minute ago with Dr. Earley, that there's a huge demand and need for an oral therapy option. So I think that is really driving the uptake, and I think the Yeah There is still a significant drop off ratio for ORLADEYO. I mean, I think we estimate about 1,000 patients that would have dropped off by the time we potentially get to market. The concept of doing well is also. It also depends on what the choices are and what your preferences are. If somebody definitely wants to stay on an oral and is willing to compromise some efficacy, then 'cause there's no other choice if I want an oral and it's only today the only available option. If that changes and you have an oral that provides a better efficacy profile, then switching to that is very easy. I think that's why we're also in the prophylactic segment. We see that the strength of the oral overall, so that's the same as in on-demand and with the profile, if we can replicate that data in our Phase III, and then we would also be in a very strong position. I think overall the HAE landscape has gone, especially in the last year, that whole, you've seen the elevated switching dynamics overall in the market with the other therapies coming in, and that really shows that it's not a stagnant or static space. It's very dynamic and patients are looking for better ways, options to treat. For what works for them. For what works for them, yeah. Yeah. Do you have a sense of how many options patients do or will cycle through before they find the optimal option for them and which patients in particular might stop at deucrictibant? Well, I mean, I think that again, the oral segment we think was gonna be the dominant segment. We think that there's also a place for longer acting injectables for some patients. It's really a per-person individual preference. But we believe that the oral market really will be the dominant market segment. I think also first line therapy, we think that the oral will be in a very strong position because it's a very logical thing to start out and to try to you know to train and to start this new therapy. The oral I think will be. Again, it depends. I mean, it also of course and assumes that they really are able to offer the efficacy that really somebody would expect. I think the injectable segment is people are trying and to sort of reducing injection burden and I think the injectable segment is more or less marginally differentiated among the different therapies. I mean, the debate how painful is the injection if you do it once a month or every two months, etcetera, but it's not much differentiation in that segment. Right. What about the new injectables from CSL and Ionis? Is there anything you're watching as a barometer to see how well they're adopted or where they're adopted and what that means for Pharvaris? I mean, I think they have net gains of patients and also taking, you know, patients from also naive patients. I think it just said it illustrates this elevated switching environment that we've seen. I think that paves the way for us, I think 'cause it really shows that there's still a need to find better therapies. We have some claims data from the third quarter. Mm. that shows that there are almost 150 patients in the U.S. who started on either ADZYNMA or DAWNZERA. Mm. which is especially compelling 'cause that's within their first quarter. Already you're getting a portion of the population that's looking and seeking for, once again, these better treatments. Mm. Really interesting switch dynamics there. Yeah, for sure. Okay. Can we talk about how you envision packaging deucrictibant? Have you thought about the potential of, you know, combining a combo of the on-demand and the prophy in like a single package? Is there any advantage to doing that, and having the same, you know, now that you have the same API for both settings? I'm just trying to get a sense of? Um- -like how you- Yeah. The packaging is, I mean, that's also still looking at a couple of options there. I think the key point here is that we're also aiming to have two brands. The two distinct brand, one for prophy, one for on-demand. They can, I mean, be prescribed together and then a patient can carry them to- Okay ...to together. I think the key point is that the combination feature really relies on sort of having that you take your once daily with the oral prophylaxis and then the portability of the on-demand is you can have that on you all the time. That's the idea. From that perspective, it might be separate brands and separate products. I think it also gives us the flexibility here, right? Mm. Where we hope to have really compelling Phase III prophy data as well. The ability for us to be able to speak not only to payers, but to regulators about the opportunity to have them either grouped together or separately, that also can determine our pricing around both of these. We're in a really unique and great position to be able to have those leverage points. Yeah. That was actually my next question on pricing. I know, you know, it might be a little bit early because you haven't launched anything yet, but is this purely a price takers market or do you have flexibility for, you know, going higher or lower, and how does the company Um- -think about- Yeah, I think there's sort of less competition based on price here for the branded products. I think on the on-demand side, the single doses usage and then not so needing a second dose, if you compare to Takhzyro, that's a higher second dose usage, and you have to actually take four tablets in some cases if you have to take every dose. That makes pricing complicated, and providing us potentially with some sort of space to maneuver there strategically. As you said, it's premature to talk about that in detail, it gives us some flexibility potentially, yeah. Yeah, there could be value in that. Mm. Yeah. Interesting. From a business model perspective, can you just give us a sense of how you're organizing the company in order to execute in this market where you clearly you're gonna have some advantages, but it's somewhat competitive, and there isn't that much of a pipeline behind your key initiatives? Mm. How do you foresee the business model going forward? Do you have an eye on profitability? Mm-hmm In the foreseeable future? What are your thoughts there? Yeah, I think I mean getting the first product to market as a small company is of course a big first step. I can describe it as breaking the sound barrier. Then, of course, looking at what comes next is important, and we're looking at some ideas of potential product extensions of the deucrictibant if they're commercially compatible. I have some thoughts there. Also building the pipeline with other follow-on molecules, and then, of course, which would be much earlier in that case. To maintain the pipeline then also in the middle, so to speak, of the pipeline, then potentially also looking at once you get sort of real commercial traction to add to the pipeline and with some assets from the outside to sort of build the company further, sort of. Yeah That's our vision. Okay. Very helpful. Thanks. Mm-hmm. Just to end on the cash balance and runway that you have. Yeah. Yeah. Cash was EUR 380 million in Q3, the most recent reporting date, and we have guided runway to the first half of 2027. Fantastic. Mm-hmm. Well, thanks so much for the update. Yeah. Thanks y'all too. Thanks, Jeff. Yeah. Great. Thank you.