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

Okay. Welcome, everyone. It's my pleasure to lead this fireside chat with Pharvaris, and we're very pleased to have CEO, Berndt Modig, with us today. Thanks so much for coming here and giving us an update.

Yes. Thanks, Joe. Good to be here. Thanks for having us. Nice to be in a warm place compared to Switzerland.

Exactly. Well, super exciting time for the company. Maybe you can bring us up to date on all the recent progress and the goals for the coming year to start.

Yes. So yes, so we are now very excited about being -- have 2 Phase III studies ongoing. So we announced at the beginning of the year that we had initiated the prophylactic Phase III trial and the on-demand trial was initiated a year ago. So that is a key focus for the company. And we are really in an execution mode for 2025, also preparing for launch and also building up and looking at infrastructure and supply chain. And another exciting thing that we also announced recently is that with our intention to potentially expand the footprint of deucrictibant into other forms of bradykinin-mediated angioedema. So announced the intention to do a small study in acquired angioedema, which is a completely different indication for which there's nothing approved today. And so that is -- if approved, could be a potential label expansion of deucrictibant.

Great. So let's talk about the data that you've generated so far since that will frame the opportunity. Can you remind us of what does the profile look like? And how will this help the HAE space evolve?

Yes. So maybe just to set the stage and remind everyone about a little bit about HAE. So some people living with HAE are fundamentally looking for 3 pillars or 3 very important things. And the first one, of course, is efficacy. The second one is tolerability, safety and also tolerability in dealing with the therapy in the lifelong setting and the treatment burden and how to live with the therapy and the burden of treatment and what it means to -- what the impact is on their daily life. So those are 3 fundamental things that someone living with HAE is looking for. And today, even in spite of all the developments that we've seen in the space, I mean, I was involved in a company that developed icatibant 20 years ago. So it's been interesting to observe the different therapy options that have come to market in recent years. But even today, there's nothing that really scores fully on all these 3 parameters. And so what we are aiming for is basically the combination of all 3. And with an oral therapy, the convenience is, of course, obvious and the efficacy is paramount and also safety tolerability. So we are looking to fill an unmet need to maintain the level of efficacy that we have achieved now with some of the injectable therapies and in combination with the oral convenience.

And it's a first for a company to be able to have both treatment options in a pill for on-demand and prophylactic use. So how do you think about taking advantage of that opportunity and leveraging that unique aspect of the Pharvaris story.

Yes. So yes, that's a good point. We have the deucrictibant use of molecule. So we have -- with that molecule, it's a B2 receptor antagonist. And it's similar same mechanism as icatibant but a completely new chemical entity and new IP. And it's also different compared to icatibant and that the properties of the molecule, it makes it suitable for prophylactic development because it has a longer -- significantly longer half-life. And so with that molecule, then we have 2 distinct products, the immediate release capsule and an extend for on-demand and extended release tablet for prophylaxis. And that in combination, we see that, that could give for the treating physicians and patients the possibility of making the right decision for the patient, whether you want to be something on-demand or you want to be on prophy or maybe different phases in your life or even if you prefer the on-demand and then you have an important event in an exam or a procedure, you can then take -- move over to prophylaxis. So it gives a lot of options for patients. That's the idea. And also the early diagnosed typically in the adolescent age start out with an on-demand therapy and can then start with an immediate release capsule. And then if they do well, then decide to go to prophylaxis at some point. So we see -- as you said, we're the only company that offers both products, both for on-demand and prophylaxis.

Yes, exciting. So earlier this year, the company provided guidance for the Phase III pivotal data in the on-demand setting. I think it's expected in the first quarter of '26 that we'll get that data. Can you talk a little bit about how that trial has been progressing and what assumptions are baked into that guidance?

Yes. So as I mentioned earlier, the trial was initiated a year ago, and we are very pleased with how enrollment is going. And we noticed the difference also compared to Phase II. I think that's attributable to the data in Phase II that we saw and also bigger -- higher visibility of the program in general. The study design is -- it's only treating 2 attacks and with a crossover design. So one with drug, one with placebo. And we also allow for a certain percentage of patients to be on prophy during the trial, which is then, of course, less disruptive for patients in joining a clinical trial and they don't have to go off the therapy and makes it attractive, especially for somebody who's interested in an oral option. And so that is going well. And as I said, the current guidance is Q1 at '26.

Okay. And how has enrollment been trending in terms of like the types of patients that are in the trial? Can you talk a little bit more about that? Just given there are many different prophy options available for patients. How does that influence what the event rate might be that underlies? And what do you hope to see in terms of a treatment effect?

Yes. I think we would expect to be very similar to the Phase II. I mean, of course, that -- as always, you have to see what the actual data tells you, but we expect that to be very similar and also given the results that we did see in the Phase II. So what we also do in our trial, which is the same as in the Phase II is to make sure that we qualify attacks. So to make sure we treat so-called real attacks in the clinical setting in order to provide the data to demonstrate efficacy. So all in all, that's -- it's going good.

Okay. And can you talk a little bit more about the primary endpoint? And what did you see in Phase II? And how does the Phase III primary endpoint compare? And what is that -- so what is the powering assumptions that you're using to design -- when you design the Phase III?

Yes, Powering is -- I mean, the effect size is expected to be similar. So power -- we haven't talked in details about powering, but of course, the patient numbers and everything has also been aligned with the regulators and to satisfy the powering assumptions. We have also in the Phase II trial, we used an endpoint called VAS AMRA at 4 hours. And in the Phase III trial, we are using an endpoint called PGI-C and which is a little better. I mean the endpoints in the measurement in an on-demand trial is essentially measuring the same thing fundamentally. So it's asking the patients as an endpoint, do you feel better or you ask the patients to make a score in the case of AMRA on the scale of 1 to 100, how the severity of symptom is. And the -- then there's also another endpoint that we are including in the Phase III, which is called end of progression. And what we have seen in our data so far is that the end of progression looks like it's about 25 minutes. That's an endpoint in our protocol that is we haven't seen in any other studies. So I think that, that also is an earlier -- even earlier time point where you can have a demonstration of that the drug is acting.

Yes. Is that important for patients?

Yes, the end of progression, I mean, what we hear from clinicians is that, that is the first point that the patient experience is that the drug is doing something for them. And the -- to have that sense of security that the drug is starting to work is clinically meaningful. And so that's why we believe that that's -- in our Phase III study, that's in the secondary endpoint, but if positive, then we think that, that is also a significant differentiator potentially in our label.

Okay. Great. So staying with the on-demand for another minute or 2. The size of this market has been a bit of a debate in the investment community. I'm wondering how do you think the market will evolve? And how large do you see this market once we have a couple probably new treatment options in a pill for on-demand as well as more prophy options?

Yes. So the -- what we have -- what also I wanted to mention also in the on-demand in addition to that is the -- what is important and you mentioned icatibant earlier, which is a drug that has -- is very efficacious, but quite a few patients need a second dose. And another step in the demand segment of filling an unmet need for improving therapy is the sustainability of efficacy. And I think that's -- I encourage you to take a look at the data that we have generated so far on the -- on that particular aspect. It's not just only the onset of symptom relief, it's really the ultimate resolution of the attack. And so the -- we have seen that in the on-demand, as I mentioned earlier, there are nothing -- not much innovation has been taken place in the on-demand segment in the last 10 years. So we believe that an oral option for on-demand is something that is potentially very attractive for patients. So we believe that there definitely is a market for on-demand in the future. And in the case of the prophy segment, the market -- the competition or the sort of a lot of intensity of new therapy options tends to be in the longer-acting injectable side versus -- in the oral segment is just us in another company at the moment. And the longer acting -- we see the market fundamentally in 2 different -- 2 different patient profiles and somebody who is looking to prefer an injectable and maybe see if they can do better with the longer-acting injectable is somebody who's fundamentally okay with needles, then you have the oral segment, which is a patient profile that definitely would not want to be on needles. And I think we see that also in the recent uptake of the first prophylactic oral option that has very -- the clear unmet need for an oral option. So that we see the future of the market in those 2 segments and within which then we also think that potentially an oral is -- could be the clearly preferred option.

Right. Okay. Can we talk a little bit about your commercialization strategy? How much work have you done on that front? Where are you in terms of preparing for the launch?

Yes. So we are now -- this is one of the key activities in '25, which is an execution year for Pharvaris in -- to develop are thinking about the go-to-market strategy and develop the ideas on supply chain infrastructure, et cetera. So it's our strategy for -- certainly for the U.S. market to go it alone and to commercialize on our own. In other territories in that evaluation of the go-to-market strategy, we may -- if we think it makes sense, do work with a partner collaboration in certain markets or territories where it could make sense from a business perspective.

And can you talk a little bit about how the product will be presented to patients and packaged actually? Because again, you have -- you're in a unique situation where you have both the on-demand and the prophy options. And I know they'll be launched at different times. But once they're both available, -- is there any way that the company can take advantage of having both treatment options?

Yes. So the -- we expect it to have 2 different brands. They also need to be clearly distinguished from each other also for safety so to make sure that the patient takes the right product, prophylaxis or on-demand. And I think the whole treatment paradigm, I think, is with having the possibility to have your on-demand therapy always on hand. There is guidance that any person living with HAE should always have at least 2 on-demand acute treatments available to them any time. And so the ability to -- we haven't talked much about the details and packaging. But as you can imagine, a very small soft gel capsule is very convenient to carry with you compared to a prefilled syringe or anything else. So the idea is then to -- for the patients then to -- whether you're on prophy and then you can have -- even if you're whatever appropriate treatment you're on, also to have a small soft gel capsule that you can take any time should you need it.

Yes, it's very interesting that you have both of these options. So switching gears to prophy then. You recently initiated the Phase III Chapter 3 study. Can you start us off there by giving us an overview of that trial design? And how does the Phase III compared to the Phase II?

Yes. So the Phase III trial in terms of the protocol is looking at the reduction of attacks compared to placebo. And so it's a very straightforward trial design in 2:1 randomization and using the 40-milligram dose from the Phase II. And then in the Phase III trial compared to the Phase II, we're also moving from a BID in Phase II with the soft gel capsule to our XR extended release tablet formulation, which is then the prospective commercial formulation for prophy in Phase III.

Okay. And then how does what you saw in Phase II frame what you'd like to see in Phase III?

So yes, so we saw in the Phase II trial, we saw a very good level of efficacy around 87% reduction in attacks in the primary endpoint and even higher in the percentage of over 90% -- I think it was 93% in the -- or 96% even in the moderate to severe attacks. So in that territory, of course, it would be our ambition to also have in our Phase III trial. And I think that, that is the level that you also see now already in the current approved therapies for injectables. So I think that, as I said in the beginning, patients are looking for a high level of efficacy in combination with the lower treatment burden.

Okay. And you mentioned that an extended-release tablets being used in the Phase III. Can you talk a little bit more about what we know about how that behaves? And could that influence the results in any way relative to what you saw in Phase II?

Well, it's a different formulation. We have looked at the PK profile of that. And if you have an opportunity to take a look at our corporate presentation, you will find a slide in there that shows you the PK profile of the XR formulation compared to the XR. And the objective in here in this setting is to maintain the exposure level above the plasma concentration that's associated with therapeutic efficacy as defined in cases, EC85. And it's about 13.8 nanograms per milliliter. And what you see in the PK profile of the XR is that it maintains that exposure over a 24-hour period. And whereas in the Phase II trial, with the BID with the on-demand capsule, it's more like a yoyo effect you go up and then you go down at the 12, of course, because of the on-demand has a shorter duration and then it goes up again. So you have more -- you get closer to the trough level maybe in the BID versus with the extended release. So that gives us some confidence that the -- that would also be seen in the Phase III trial. There is another trial that also you can take a look at it in more detail in our corporate deck, and it's an investigator trial at the Amsterdam Medical Center in acquired angioedema with only 4 patients. So it's a very small trial. But in that trial, the patients took the XR formulation and have seen basically no attacks in the period, except for one attack right at the beginning, but in over 18 months, these 4 patients had 0 attacks. So that's another indication that suggests that we will -- about the outcome of the Phase III. But of course, the trial as such has to tell us what -- we'll see when we get it.

Yes. Right. Exactly. Very interesting. And I think Chapter 3 is designed to enroll around 81 patients. And given that's less than pivotal studies for several other key trials in the space, I'm just wondering if you can talk about how you're able to get alignment with the FDA on that feature? And how does that influence the powering?

Well, in fact, as you pointed out, the 81 patients in 80 sites globally. The -- is not really powered -- is primarily powered for safety and less so for efficacy because if you compare the number with the Phase II trial in the 40 milligram, we had 2 dose groups in the 40-milligram in the Phase II trial, we had something like 10 or 15 patients, and we had a p-value of 0.0008. And so now we have 80 patients in the same one dose group. So I think for purposes of powering, I think we are in a good spot there. And as I said, it's more focusing on building the number of patients to build the safety database.

That makes sense. Okay. So earlier this year, you provided us guidance that data from Chapter 3 would be out in the second half of '26. And I think there's a 24-week endpoint. And so this implies full enrollment in the first half of '26, which is a little bit over a year. Does that sound right in terms of the progression that we should expect for Chapter 3 execution?

Yes. So the -- and I think if you compare the prophy trial versus on-demand, once you have last patient in, it becomes much more predictable when you have the endpoint, of course. So the key there is enrollment. And then once it did 24 weeks after the last patient in and then you have your normal valuation of the locking databases and all that stuff. So I think that that's sort of how you should look at it. In the on-demand trials, of course, enrollment is the first step. And then the second step is the actually investigating the attacks. So then that adds another variable that you don't have in the prophy trial.

Right. And what's going on in acquired angioedema? You alluded to some of the data that you saw there. What's the company's plans to -- does the company have plans to develop?

Yes, we announced our intention to also do a study in acquired angioedema. We are currently in discussion with the regulators about the details of such a study. But what I can say is that it's expected to be quite a compact or small study and also pivotal so that if it works out and the idea would be then also in terms of timing could be similar to the hereditary angioedema program. And then if approved, then it could be an expansion of the deucrictibant label. Acquired angioedema is an indication for -- it's a form of bradykinin-mediated angioedema for which there is nothing approved today. And the -- it's estimated to be about 10% of the HAE market, and these patients are referred to HAE treating or allergists or patients treating HAE patients from other doctors because the symptoms are caused by underlying disease in autoimmune disease or lupus and other underlying disease that causes dysfunction or C1 deficiency then results in acquired angioedema. So it's basically mechanistically the same as the hereditary form. And right now, the patients are -- there's nothing approved. So patients, the most common treatment is icatibant actually for these patients.

Interesting. Is there something about the bradykinin mechanism that lends itself particularly well to this indication.

I mean some of these other bradykinin-mediated -- I mean, it's also relatively complex that there is a presumption that bradykinin inhibition could have an advantage there. It's not necessarily the case, but it could have -- there's been studies looking at other forms of angioedema or surveys, I should say, that suggest that bradykinin inhibition is a good way to deal with this.

Okay. So it seems like you'd have separate on-demand and prophy studies like you have in your current HAE program.

Yes, that -- that's something we are discussing exactly how -- what that would look like or if you have like start with one to roll over to the next and the exact design of this is that the [indiscernible] to talk more about later. But I think the point is that it's a small trial. It's expected to be pivotal. And so the number of patients in small trial also doesn't have -- it's not a huge impact on our cash usage.

Right. Okay. And then how about we talk about the commercialization strategy? And what kind of resources do you need to bring to bear in order to be impactful and be able to commercialize this?

Yes. Yes. I mean this is a space where the commercial footprint is -- can be very compact in terms of focusing on the key physicians. And so I think it's something along the lines of order of magnitude, like 50 people in the commercial organization in a market like the U.S. So it's relatively compact and certainly doable for a small company.

And how do you think about -- I know it's early, but how do you think about pricing, particularly because you have both on-demand and prophy options.

Yes, of course, as you said, it's early to talk about pricing, and we can also not give real guidance there. But of course, I mean, of course, we would -- looking at the pricing to value and the benefit for patients. Okay. So I mean, basically, expectation to this what you see currently today. So I think this is not a disease where I think you would be competing on price.

Yes, there's a lot of precedent for healthy price levels here. Okay. Great. Anything we didn't touch on that we should make sure that we mentioned before we go?

Well, I think -- I mean as the -- what we think is key is, of course, I think that the concept of 2 product that makes us a little bit different in this space. And I think also the -- to really understand what patients are looking for. It's not just sort of one particular endpoint or one particular is really the totality of the patient experience. And the patient today could say that they're doing well, but what does that really mean? It means that they're doing okay with what they have because they don't -- there's nothing better out there. And I think the one last point I'd like to make is that sometimes there's a debate whether this is a sticky market or not. And we think that it's not a sticky market. I think you see data that there is quite a bit of churn, data that suggested about 5% of the patient population is looking for switching therapies because -- presumably because they like to try something better that works better for them. And so I think the key point here is also that HAE, there is no real sustainable first-mover advantage. It's really about providing the best therapy for patients, and that will be the success for any company in the end, yes.

Yes. That makes sense. Thank you so much, Berndt. Really appreciate the update.

Yes. Thank you, Joe. Good to see you.

Thank you.