Pharvaris N.V. (PHVS) Earnings Call Transcript & Summary

We mentioned, of course, we're going to make forward-looking statements, so please refer to our SEC filings for appropriate risk factors. We built Pharvaris around a heritage in a particular mechanism called the bradykinin 2 receptor pathway. Our founders have worked together at Jerini to find the first molecule that exploited that pathway, icatibant and built on that desire to come up with an improved therapy for that space. And we grew out the team with experts in orphan disease, also HAE leaders both in development and commercialization in those spaces. And so we built our work around the discovery of an innovative new molecule called now icatibant. This is the first orally available bradykinin B2 receptor antagonist. The real breakthrough here was finding a compound that had potency and actually a superior potency at the receptor to icatibant, but with the size and the properties that allowed it to be used orally. And so that opened up for us a new opportunity to address bradykinin-mediated diseases, particularly leading with hereditary angioedema. Hereditary angioedema or HAE is a rare genetic disorder. It's characterized by swelling attacks that occur randomly and at various sites around the body. It's unpredictable in its frequency and location. And those attacks are actually quite serious. They're painful. They often lead to hospitalization. And in the case of attacks that occur in the face or in the larynx can be life-threatening as well. There's actually quite a bit of medical need in HAE globally. Up to about 100,000 people live with HAE. In the case of U.S. and Europe, there are a number of products that have introduced. But outside those areas, especially, there's a great deal of underdiagnosis and undertreatment. So there's a real opportunity to bring forward into this space, a product that can be used in a variety of markets and in a variety of settings, much as we think and oral would be the way to do it. And so people who live with HAE treat their disease in 2 different ways. They either treat attacks when they happen, that's referred to as on demand. And you see the segment of that global market here in the upper left of this pie chart, or they prevent attacks with prophylactic treatment on the lower right. The prophylactic market currently is more dominant and has grown more, and that largely reflects innovation that's happened in this prophylactic disease space through new products that have introduced improving efficacy, tolerability and convenience for patients. The market itself, while it looks like there are a lot of products, is actually quite dynamic. There's quite a lot of movement between products as these factors and these qualities improve. And so as I mentioned, this is what patients are seeking. They're seeking products that work, that are safe and tolerable, but then more and more products that fit into their life and fit into how they want to live and control their condition and their disease. And so our ambition there is to come forward with products that meet all of those needs. The mechanism that we have our expertise and shown here on the right in the pathway that generates and was responsible for the HAE attacks is the production of bradykinin shown in the yellow box as it interacts with the B2 receptor. That sends off signals that leads to edema and swelling at various sites. And there's a main pathway that we've shown here, which is activated plasma kallikrein generating this bradykinin, but there are other ways to get at this. And so our mechanism at the level of the receptor intervenes regardless of how bradykinin is made. That's important because if you look to the left of this graph, hereditary angioedema has some subtypes. In blue, we show subtypes caused by missing or nonfunctional C1 inhibitor. It's a central inhibitor of that plasma kallikrein enzyme. But then in a whole category known as normal C1 HAE, there are other types of mutations. And so the dependency on the C1 may not be there. So we believe there's a universal approach by being down here at the receptor, the actual signal that sends off the angioedema. Another advantage that comes to us as a result of this mechanism is our ability to use a certain endpoint in humans to assess and predict efficacious dose. So we've used this endpoint. It was validated in the clinical experience with icatibant, the first product acting at the receptor, which is an injectable. Here, we have an oral product where we use this endpoint to assess in a healthy volunteer the effects of bradykinin and how we can blend those effects. And so we can set -- we set an efficacious dose through that, we've used that for our on-demand study, which read out this past December and saw positive results, and we're using that same approach for our prophylactic study, which will read out by the end of this year. And so with all of those factors in play, we have icatibant as a molecule with actually very versatile properties that give us the ability to create 2 different formulations addressing both the on-demand and the prophylactic segments of HAE. We're the only product in the space that can do that. And so we have, on the left, PHVS416 is our on-demand product. It's an immediate release capsule. You see in the cartoon below the release profile its actual PK data. So you're taking a soft gel capsule, immediate rapid exposure of compound above our target threshold to treat an attack once it's happened. On the right-hand side, PHVS719 is our extended release tablet. And the aim of that is to have slower release, actually no initial release, but maintain exposure above threshold to prevent attacks. So how we're using this in the clinic? 416 has completed Phase II with -- in the on-demand treatment of attacks. We're preparing for Phase III there. 719 is in Phase I, where we're preparing to actually jump that straight to Phase III because we've used as a tool the 416 capsule with twice a day dosing in food to give us long-term all-day exposure for a prophylactic experiment. So we're -- we'll be able to leapfrog 719 from Phase I into Phase III when we have the efficacy data. I'd like to mention a regulatory update. We are active in trials ongoing right now ex U.S. In the U.S., we are on a clinical hold as a result of some nonclinical evaluation by FDA. We've met with the FDA. We've -- they've requested that we conduct a repeat 26-week rodent study. That study is underway, and we anticipate submitting the data from that study to FDA by the end of this year. In the meantime, they had partially lifted the hold in our on-demand program where they allowed remaining patients from our RAPIDe-1 Phase II study to finish. And then outside the U.S., there's been no change to our regulatory status. So all countries and sites there remain active and our trials, both Phase I and Phase II studies continue. As we think about our pipeline and future possibilities around our mechanism of bradykinin activity, one of the additional indications we think about is acquired angioedema. There could be multiple causes for acquiring angioedema. In the blue, sort of most prominently is an illness related loss of C1 inhibitor. And so people who have lost C1 function will experience HAE attacks much like HAE. And so that's an area where we were thinking of expanding. It's about 10% of HAE. There's been a recent investigator-initiated study that's shown activity of icatibant in that setting, and that's an area where we will continue to evaluate and think about moving forward. So when we think about our Phase II data and on-demand, briefly, the goals here for patients because patients are seeking in an on-demand treatment, something that works quickly, something that works with a single dose and something that's convenient in an oral. And this was our aim with this study. We studied 74 patients in 13 countries. Together, 62 of them had 147 attacks, which built our database for this study. All the primary and secondary endpoints were met. We showed rapid onset activity, symptom relief and resolution of HAE attacks. We've substantially reduced the use of rescue medication and were well tolerated. So we were very happy with the consistent outcomes we saw in the study across all marks. Very briefly, showing the tolerability here, you see 2 AEs or AEs and 2 attacks. One was with placebo attack and one was a treated attack. Very happy with that profile across that 147 attacks. The PK profile met all of our expectations. You see all 3 doses exceeded our target level very rapidly. And so we wouldn't expect to see any difference between those doses and the initial and where you see differences in the long-term exposure, which would come out to reflect on the use of rescue communication. And I'll show you that slide in a bit. So here's a primary endpoint. VAS-3 endpoint. It's a patient-reported outcome. As I said, all 3 doses show at 4 hours, a significant drop in that score, which is a measure of swelling symptoms and very strong separation from the placebo or treated attacks. In rescue medication, we saw that most of the attacks treated with placebo required rescue medication tells us that those were -- the attacks that people were experiencing were significant and real. And we saw a very large drop in the use of rescue for attacks that were treated with active and you see a hint of a dose response there, which reflects the PK of increasing doses lasting longer for attack resolution. In prophylaxis, we're proceeding with Chapter 1 study. This is a multi-dose study, 2 different doses controlled against placebo, looking at a 12-week treatment period running in 30 patients or rolling, I should say, 30 patients, running in Canada, Europe, Israel and the U.K. All those regulators are up to speed on the U.S. clinical hold. And as I mentioned, everything is proceeding there. We are expecting that study to read out by the end of this year. Showing you for comparison this 416 and the 719, so you see here in blue, the 416 capsule, the immediate release by dosing that twice a day with food is how we get to the exposure that we need, but overlaid here with the 719 is where we aim to go when we go to Phase III with a tablet. Here, we're showing you a single dose with and without food exposure over full day with a single dose of the tablet. And the AUC that we see on this with the tablet actually is similar to the AUC we see with a twice-a-day capsule dose. So we were very encouraged that we'll be able to translate directly over. And so summing up very quickly then, in our on-demand program, we've seen successful data in Phase II. We are moving forward to Phase III in that program with the immediate release capsule. With going diagonally down to the bottom right with 719, we're -- we've shown single-dose activity there. We're doing the work to get ready to move that formulation into Phase III. And in the meantime, the proof-of-concept study using the capsule in the Chapter 1 study is ongoing, enrollment is going well, and we expect to announce the data by the end of the year. And so very briefly, that's the story of Pharvaris. Happy to be around to take any questions. Thank you.