Great. Thanks everyone for being here. My name is Yanan Zhu, and I am one of the biotech analysts here at Wells Fargo. It is my great pleasure to be joined by the management team of Pharvaris. With me on stage is Berndt Modig, CEO of the company, Peng Lu, President of the company, and Wim Souverijns, Chief Commercial Officer of the company. Thank you all for being here. Yeah. Thank you. Thank you for hosting us. Wonderful. Obviously, you just recently reported very important phase III data for the prophylactic, your product in that setting. To kick us off, could you give an overview of the company and maybe segue into the data that you presented? Mm-hmm. Yeah. Our journey actually started 10 years ago, and four months to be exact, when we set out to develop deucrictibant. Myself and also my co-founder had been in the HAE space, came in first 23 years ago with the company that developed icatibant. We had identified or saw a huge unmet need for an oral therapy option for people living with HAE. That is our vision then, to come up with such a molecule and then that is when we started. The scientific base of the company really focuses on the deeper understanding of the bradykinin pathway and the B2 receptor. We are proud to say that we, to our knowledge, really do have the first and only orally available B2 receptor antagonist, deucrictibant. The nice thing about that molecule is that as compared to icatibant, it has a significantly longer half-life, which makes it suitable both for prophylaxis and on-demand development. We set out to develop with that one, the same active ingredient, two products, one for on-demand and one for prophylaxis. Now 10 years later, yesterday actually, we saw we have the data for the prophylactic phase III study. Also, as you know, in December last year, we also had the phase III data for the on-demand formulation, which is currently under review by the FDA with the PDUFA date in April. With the data that we saw yesterday, we are incredibly excited to really see that vision that we had 10 years ago is coming closer to fruition and to be able to fill that unmet need in this therapeutic space. With the data that we saw, we are up there together with the existing therapies in the longer-acting injectables, but with the benefit of an oral option. That differentiates us from that perspective. The molecule itself also has, because of the modality and also the treatment regimen, be once daily and the flexibility of being able to start the therapy, having the activity kick in very quickly. Also of course, the relatively short washout. That means that if you discontinue the treatment or if you want to transfer over to on-demand or if you want to have a medical procedure where you cannot have drugs. That gives the concept of control is really a key factor that also differentiates us in this space. It is a high efficacy tolerability and the oral convenience and that is in our view, then provides the benefit of maximum control for somebody living with HAE condition. Great. I do think the efficacy is notable. I do not know if you yourself is even a little surprised by the efficacy, because I know you already have very high confidence about the efficacy. But still, the number is right there with the injectables, right? Can you just maybe talk about how do you see when you saw the results, what do you think about the efficacy? And maybe comment also on the placebo arm also a little bit- for our- Yeah. I mean, the efficacy, first of all, we're also very excited to see the replication or even potentially better than the phase II data that we saw in a phase III study and in spite of also the increased footprint of the study, more size, more diverse patient population, et cetera. We were extremely pleased with that level of efficacy. If you really compare with the patient population, type 1 and type 2 of hereditary angioedema, which is what is covered by the other injectables, we're right up there with 87% attack reduction. The primary endpoint in the overall study was 83%, because we also included a few patients with normal C1. The overall, which was included in the primary endpoint, but the comparison directly apples to apples to the type 1 and type 2 is 87% as we also presented. Maybe, Peng, if you want to add something on the placebo side of things. Yeah, sure. Actually, from the placebo part, maybe someone viewed that the placebo, actually, if we look at the placebo arm, the attack rate is around 2.6 attack per month compared to other HAE pivotal trial. Actually, very well, within the range between 2.3 as a pivotal trial. That's further, as Marc mentioned, that confirmed that this trial conducted very well, even though I have to say that this is the first, maybe the pivotal trial, covered all the six continentals. That we do, that have patients from not only North America and Europe, as we did for phase II, we also covered the patients from Asia Pacific, Latin American countries, and also South Africa. That's why the patient advocacy group are very excited to show really we covered a high unmet medical need globally. Great. Yeah, that is indeed quite an achievement, so congrats. on that data. There are some interest, after you presented the data, some interest in learning more about some liver enzyme elevation observations from the study. I wonder if we can take this opportunity to look more closer to those findings. Could you, maybe review what were the liver enzyme observations and what are the circumstances of those findings? Yeah. Actually, I can take over here. As we shared that in the public presentation there, within this trial, we indeed have the two patients with the level 2s, with the liver enzyme elevation. We shared both cases, the hepatic enzyme, around slightly above fivefold from the upper limit. As mentioned, for HAE patients, due to some patients, the long-term androgen use and also due to disease themselves, patient has quite a fragile liver. That is why from almost every HAE pivotal trial, there is more or less some liver enzyme elevation observed. Come to these two cases, we shared, there is no any symptoms reported within these two cases, and also there is no bilirubin elevation observed. Also, some co-funding factors, followed with these two patients, one with historic fatty liver, the other with long-term androgen use. Really that follow each individual investigator's assessment. One investigator feel that more cautious, that is why she discontinued the treatment for one patient during the study. But the other PI evaluate that, to continue the treatment for the patient, and the patient complete the study. That is pretty much these two cases. From that compared to other prophylactic, current approved prophylactic trial, we feel for the liver enzyme elevation and for the cases here are quite comparable to other trials. Got it. Yeah. Could you touch on? Should have used my key. Sorry, one second. Fixing some microphone issues here. Fixing the microphone here real quick. Excuse me. All right, yep. Okay. Yep, that would be good. Great. Yeah. You touched upon the last point, is regarding other approved therapies and how there might also be liver enzyme findings. Could you elaborate a little more on that? Yeah. Actually, as mentioned, for example, most now that is standard of care for lanadelumab, if we look at their label, there is also the lab abnormality for hepatic enzyme section shown. Also, a few cases, liver enzyme elevations are reported there. Also, one patient discontinued the treatment due to the liver enzyme elevation. Similar cases for ORLADEYO, another oral treatment, and also for donidalorsen, that is the latest approved treatment there. Got it. Yeah, very helpful. So, overall, what is your expectation of the implication for your finding in terms of whether there could incur any monitoring requirement? Also, in real world and commercial setting, whether that could cause any change in behavior? Yeah. For this one, we always want to wait that safety assessment until the filing, until approval, right? Because we integrate CHAPTER-3, CHAPTER-4, that long-term safety assessment there. But based on the current CHAPTER-3 data, we feel is quite, as mentioned, within the range for other prophylactic treatments. We do not expect medical monitoring there, and we expect the label may be very comparable to other prophylactic treatment. While we discuss with the KOL leaders, they fully understand the disease there, and they are fully aware that a potentially co-funding factor, no matter for disease itself or the long-term androgen use as we discussed. Right. Yeah, those make a lot of sense. May I follow up by asking, when might we see the combined dataset for safety and perhaps also in terms of publishing the study result? Could you comment on those timelines? Excellent question. Currently, our open label extension study, CHAPTER-4 study, is still ongoing because we just actually get the top-line readout from the CHAPTER-3, just unblinded. Then the team need to figure out how many patients the status, the treatment duration in the CHAPTER-4. Currently, we do not give the clear guidance regarding that one chapter data, that one-year safety data package will be available. But assume once available, we will maybe once we get the data cut off for one year safety, then we wrap up the package, and we will consider publishing the data, presenting the data in the medical conference. Got it. In terms of patients rolling over from the main study to the long-term follow-up, can you comment on the rate of rollover? Sure. As illustrated from the study, altogether 83 patients complete the study, and 80 out of 83 patients roll over to the CHAPTER-4 open-label extension study. Got it. Very helpful. Can we talk about a timeline for filing and what are the gating items before you file? Yeah. The guidance for filing is in the first half of next year. In addition to what Peng described on the safety package, we also are aiming to include data from the ongoing CREAATE trial in acquired angioedema. With putting that together with the filing for the HAE filing, and with the possibility of a subject to regulatory concurrence and approvals with the broader label for bradykinin-mediated angioedema. That study is ongoing, and is on track, and we have guided also the top line data from that study in Q1 of next year. Right. Yeah. Speaking of breadth of coverage, can you comment on the inclusion? Obviously, you touched on the inclusion of normal C1INH patient earlier. What's the significance of that? Yeah, I can comment, and later I will hand it over to Wim from commercial side. From the scientific part, as Berndt mentioned, is that deucrictibant is very unique because no matter approved treatment that are currently under development treatment for prophylaxis, they all target quite upstream of the pathway, either Factor XII, prekallikrein, or kallikrein. Therefore, they only can prevent attack depending on the plasma kallikrein pathway. However, for a lot of HAE patients, if it's not due to C1 deficiency, if it's normal C1 inhibitor, there is maybe currently eight known genetic mutation, and also a lot of patients with unknown genetic mutation. Bradykinin can be produced either from plasma kallikrein pathway type 1, 2. It's also maybe tissue kallikrein or plasma kallikrein-independent pathway. Therefore, all the other treatment will not be effective, cannot help these patients. Deucrictibant, because we block the most downstream, right, the interaction between bradykinin and the B2 receptor here. Therefore, no matter which pathway, deucrictibant expected to work. That's why we also include that normal C1 patients into our pivotal study, demonstrate for all the three patients, even though some variability there, it helped all three patients there. Therefore, that we are very proud. This patient population, there are still no effective treatment. We are able to help these patients. Right. Got it. I think the commercial implication of that is that we anticipate in that segment, where there's a wide range of estimates in terms of prevalence, people talk between 15% and 25% of the type 1, type 2 population. We anticipate having a disproportionately higher share of those patients because of the fact that we do work at the level of the receptor rather than in the kinin pathway. So that's important, obviously, commercially, to differentiate ourselves from other products in the market. I think combining that with the acquired angioedema part of the label, we all of a sudden have a label that's the broadest of all prophylactic therapies. So that becomes attractive for doctors, makes their life simple. It might be attractive also for payers because the drug will work in a different area. So that's a pretty big advantage commercially. Got it. This is a great opportunity to dive into the commercial opportunity. I guess, how do you see the commercial launch go, pending approval? How do you see this launch go? Obviously, there are injectables, there are ORLADEYO as an oral. Yeah These options out there. Is this going to be a new patient, new to therapy only kind of launch or a switching launch? If it's a switching type launch, where do you see the switch come from? Yeah. Well, I think we got an amazing profile to really win in the prophylactic segment, and that is because of the ability to tackle three distinct segments. First of all, we have patients new to LTP, new to prophylaxis. What we have learned from the community is that if you can deliver injectable-like efficacy, which we have now shown with the data, you become the de facto first line therapy, first line option for prophylaxis. With our efficacy and our tolerability profile, our anticipation is that the dropout rate from deucrictibant in prophylaxis will be very limited. As you probably know, ORLADEYO, the other oral, is being used widely in new patients, but about 40% of the patients on ORLADEYO drop out, either for efficacy or for tolerability challenges. We do not have that issue. What that means is that you create what I call a pancake effect. Because if you can take every year the majority or a large part of the new patients to LTP, which ranges between 150 and 250 per year, you build up share in the overall market. That will really drive our leadership in the long term. That is the first segment. Secondly, thinking about the oral segment. Yes, patients on ORLADEYO that stayed on ORLADEYO will feel better. They went from lots of attacks to much fewer attacks with ORLADEYO. But if you look at real-world evidence, those patients still have relatively high number of breakthrough attacks, talking between six to 12 per year. Therefore, for those patients who want an oral, it is actually a fairly easy switch to say, "Why do not I try another oral that can offer a better efficacy?" The beauty of deucrictibant is that because of the PK, if you take the drug in the morning, technically in the afternoon, you have enough drug in your system to prevent attacks from happening. After two, three days, you are in steady state. So patients do not take any risk and can really test that product. So that is why we strongly believe that the oral segment ultimately will be largely dominated by deucrictibant. Then the third bucket are those patients that are on injectables. While for sure there will be patients that will prefer to have an injectable, probably most likely a long-acting injectable when that will become available. But all patients on TAKHZYRO or ANDEMBRY or garadacimab today, they are on these products because they do not want to sacrifice on the efficacy. With an oral that actually showed the same level of efficacy, that becomes an argument to sway those patients to actually make the leap and go on to deucrictibant. So I think we have got a perfect profile to really appeal to all the different segments in the markets and make sure that ultimately, this product becomes a leading product in prophylaxis. Great. That's a very helpful way for us to think about the launch. Thanks for sharing that. I do want to follow up on this long-acting injectable point you raised. Yeah. Right. How do we think about when that comes to market? Or perhaps also give us a sense of how far is that kind of product from the market? Yeah. Well, as I said before, for sure there will be patients that will prefer to have something that they do once and with very few infections a year. So six months is definitely the aim there, to be kind of lost of I don't have to take a therapy. What people do forget, though, is by taking a long-acting injectable, you lose control, you lose flexibility. You basically have a drug in your system, and if you really want to wait till it's out of your body, you have to wait 18 months for a 6-month injectable. Your half-life plays a role there. That is something where what we try to offer with deucrictibant is people taking control of their lives. If you take that pill every morning or every evening on a daily basis, you know you should be protected. If you take a long-acting injectable, you kind of take a leap of faith. You inject yourself, and then you'll see at one point in time, you might run out of gas, I would say, and you might see breakthrough attacks happening. That might be before you actually hit the next injection. That's a model, that's an impact on the life of patient, which is very challenging because as you know, HAE attacks are driven by stress or can be driven by stress. That kind of thinking is something that really is not conducive to avoiding or preventing attacks, and which is different, we believe, with a daily oral. Got it. Great. I think one reason you see the high prevalence of injectables in the existing therapies is just also simply because of the challenges and difficulties of coming up with an orally available compound that is efficacious. Something that, as I said in the beginning, with deucrictibant, to our knowledge, the first and only orally available B2 receptor antagonist, but so far also the only oral therapy with the level of efficacy that is comparable to the injectables. Definitely. So, maybe can I ask you to comment on the pricing strategy for prophylactic setting? Yeah. Obviously, we're not going to disclose the price. We haven't decided on what the price will be. What you can say is that we will absolutely price deucrictibant based on the value that it offers. The pricing exercise for us will be a portfolio exercise. Because as you know, we have an on-demand product, IR, that we'll be launching before the prophylaxis. So we will be looking in our pricing for the on-demand product at the whole portfolio. How can we make sure that we strike the optimal balance to ultimately maximize the impact of that product on our portfolio? We are very gifted with the data we have on both fronts. We are not limited by anything. We have all the flexibility thanks to the quality of the data. So both in on-demand and in prophylaxis, we have stellar performance. Hence, we can really choose what type of pricing strategy we'll be following. Right. That's a great flexibility to have. Since we're on this topic, let's also touch on what is the implication of having the ability to offer both an on-demand option and also a prophylactic option. How can you leverage that to achieve best performance? Yeah of the sales? Yeah. It is very interesting because I think it was about four or five years ago, there was a congress in Budapest, a very specialized congress in HAE, the C1-inhibitor Deficiency & Angioedema Workshop. One of the doctors, we had results, I believe, from our on-demand phase II study at the time, and he got asked by his colleagues in the audience, they said, "Well, are you telling me that we would be using the same product for prophylaxis and on-demand?" He said, his answer was, "Isn't that what we were really dreaming of?" That makes life so much easier. You basically have little. There is no uncertainty. You have the same molecule, the same product that we can use in both circumstances. Because the disease is threshold driven, it is not there is an escape mechanism or so, it is simply when you are on deucrictibant prophylaxis and you have a breakthrough attack, it means you do not have enough drug, not enough deucrictibant in your system to prevent the attack, to compete with bradykinin. Basically you top it up to mitigate the symptoms. That is, for the patient, an amazing thing. They have to deal with one specialty pharmacy, one company. They do not have to. If you have one company for your prophy and another one for your DT, there are two channels there. This makes it much easier. For the doctor, it makes it much easier, and potentially for the payer. I think if you add to that on-demand prophy and the breadth of the label, we have the most complete solution for the community, which that ease, that simplicity will really help us commercially. I also want to say that as a past that I was in the Humira team that has also helped deucrictibant can also generate a similar halo effect, as Wim Souverijns just mentioned. When the treating physician consider deucrictibant, pretty much we can help the patients no matter for on-demand or prophylaxis, type 1, type 2 patients, or normal C1 patients with our treatment. That is why we pretty much can help the physicians help the patients with all the options they can consider. That is why hopefully that once that the physician knows the molecule there, they can handle the different scenario, different cases. Great. Yeah, that is a great position to be in. As you just mentioned, on-demand will get to the market first, indeed, with the PDUFA date of April 23rd. 23rd. 23rd. Right. I wanted, obviously, the review has started. I wanted to ask if you can comment on any color on the interaction with the agency so far, any potential focuses or concerns, and what could we expect to happen between now and April 23rd? Yeah. Currently, as you know, we announced that currently we get the PDUFA date. We also submit the EU and the EMA validated. Regarding with the U.S., we expect very soon we get the major cycle review meeting with the FDA. But currently that our interaction with FDA is very as expected. You know that we so far we did not see much hurdle there for the approval. As mentioned, once we have made a cycle review, we will know more from agency. Got it. Got it. Very, very helpful. In terms of label, is there anything for us to think about the label, or is it pretty much, for example, similar to icatibant's label? Excellent question. I want to highlight one thing that for the label, later on, I will hand it over to Wim why I want to highlight this point. Of course, compared to icatibant, we do feel that we have great ethics data, no matter from fast onset, right? That complete resolution time. We compare the fast onset that for the time to the minimal, that improvement there, we only have 1.28 hours compared to the icatibant is pretty much around two hours there. The complete resolution we can achieve less than 12 hours. icatibant is over 24 hours. For single dose use that we only said 17% patients need the second dose compared icatibant is close to 40%. All this is currently label covered, but the most important we want to highlight that potentially maybe we have the novel endpoint covered in the label. It's time to end up progression. That this is new endpoint the team developed and validated there. Based on the physician and the patients, that's the first sign patients can feel that they get protection, the drug works, because it prevent the attack get deteriorate. Our time to end up progression only 17 minutes. This correlate very well with the PK profile, the fast absorption of our deucrictibant that are capsule there. So this that really to show that the deucrictibant can help the patients by minutes there. That the patient can feel the attack is well controlled. Okay. Yeah. Yeah, I think, Peng, you said it well. The real differentiator. When people ask me, what is the differentiator for deucrictibant IR, there's not one differentiator. It's the holistic management of the attack. From a rapid onset to complete resolution with a single capsule. That's really what's appealing. It's very interesting, when we share this data recently with payers, they really, they're excited. They see the ability to really, you use the therapy, you're going to get to control very quickly, and you can do it with a single pill. That has an economic impact on them. That is the full value proposition. As Peng was mentioning, we have endpoints, like end of progression, we'd love to have in the label, but that will be the team's negotiation to achieve that. But we will publish around this thing. That information will be available, and it's something that the community, the physician community, is very excited about. They really recognize those outstanding results. Got it. I clearly hear the differentiation there. There are many in that. But help us understand when you come PDUFA date, and maybe I'll ask you when can you launch, right after PDUFA, or do you need some time to launch? More importantly, how sticky the market is, right? Yeah. Are we talking about you have to wait for all the new diagnosis of patients, or could there be switching? Yeah. I think I may also put the historic perspective on that. As I mentioned earlier, first came into the HAE space 23 years ago with the company that developed icatibant, and also have observed the new products that have come to this community over those two decades. What becomes very clear is that every new entrant has provided some additional benefit, be it either efficacy or mode of administration, and prophylactic segment, I think you could say was established with the entrance of TAKHZYRO with reducing the injection frequency, making it feasible to have an injection that you work with prophylactically. The therapy then that provides this incremental benefit always seems to take over. Also I think in our call that we had yesterday, Dr. Marc Riedl also commented on that there is a high level of patient involvement in the decision-making about which therapy. There's a high awareness of what's out there, what's coming, and patients are looking to improve how they treat their condition. In our view, and also what we see from data is it's not a sticky market, unlike maybe some other therapeutic areas. You look at switching, there's a constant churn of switching every quarter in the single digits. Every time there is a new product that comes to the market, it goes up to double digit because patients are eager to try the new and potentially the better product. It's a very dynamic space. The very interesting thing is everybody talks about EKTERLY, but by the time we launch, the lion's share of the patient will still be on icatibant, if they're still here. Now, those patients, they're going to see deucrictibant as a trusted, validated mechanism. It's the same they had before, but it doesn't come with the pain of the injection, which is really painful. If you look at indirect treatment comparison, we probably have better data than icatibant. So we're going to be very aggressive going after those patients, and we anticipate there will be a wholesome switch from the icatibant segment into deucrictibant because it's the natural thing to do. Then for EKTERLY patients, there will be different effects. One will be the halo effect of the impact we have on the icatibant patients. If people see that these drugs work very well, people are going to say, "Oh, why don't I try?" We will work through a free trial program, a sampling program with our quick start program to give people the opportunity to try. In on-demand, that's relatively straightforward. You can just try on the next attack and see how it works, and then you make your assessment. So I think we are in a very good position to win in this market, again, with the addition of the normal C1 benefit, mechanistically broader ability to address a broader population. So, I think we're well-armed to win there. Great. I think that's a great note to end this session on. Again, congrats on all the achievements and the great data reviewed yesterday, and thanks for your time. Yeah. Thank you. Thank you so much. Thank you for having us. Yeah.