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

Hello. Welcome to this fireside chat with Pharvaris. I'm Joe Schwartz from the SVB Securities Equity Research team. It's my pleasure to welcome Berndt Modig, Chief Executive Officer; and Morgan Conn, Chief Business Officer, today. Thanks so much for joining us. Maybe we can start by having you give us a brief introduction to the company, its recent accomplishments and the key initiatives and catalysts that you expect to be tackling this year.

Yes. Great. And thanks, Joe, and thanks for having us today. So Pharvaris, we -- our key focus is developing an oral therapy for hereditary angioedema, which is a great unmet need in that patient community. Patients are looking for better ways to treat that and manage their condition. And we have developed a small molecule, an orally available B2 receptor antagonist that we now have in Phase II studies that are expected to have a data readout in Q4 of this year. And we addressed the HAE focusing on the B2 receptor antagonism. And Pharvaris is, to our knowledge, the only company that's ever been able to develop an orally available B2 receptor antagonist. The B2 receptor is a validated target to treat HAE, as also seen with icatibant, Firazyr with over decades of experience as the most common way to treat HAE attacks in the last decade. And in fact, our Chief Scientific Officer is an inventor of icatibant in the old days. And so that's the one common connector there, the mechanism. And we're excited about our place in ongoing trials and look forward to the data readout when that comes.

Great. Maybe we could dive into the rationale behind the mechanism for PHA-121 and hear a little bit about how you were able to overcome the challenges that I'm sure a lot of people encountered when they try to develop an oral bradykinin B2 receptor antagonist.

Yes. So it indeed has been a chemistry challenge for many years. A lot of companies have tried to develop such a molecule, and the combination of progress in chemistry and our expertise on that receptor that enabled us to come up with that molecule, that's a very -- the challenge has been to find something specific to the receptor, but at the same time, it's orally available. That's sort of the thread in the needle there. That's been the challenge. And we're excited that we've been able to come up with such a molecule. We're going to -- well, being the chemist from our side here, maybe you could add some color to that.

Yes. I mean the challenge is that the bradykinin receptor is the GPCR, has a fairly long channel where peptides bind. Bradykinin itself is a ninemer peptide. And so the challenge is finding and -- that our team was able to do was to find a molecule that was small enough, to have potency to bind into that pocket. And we found a core that had that potency with extra interactions that allowed us to stay small enough as we elaborated, so we retained orally available properties. And that's really been the stuff [ that lacked ] before.

Yes. Okay. That's helpful. Thanks. And then can you just quickly remind us, what did you see preclinically -- how does that combine with the exposures that you saw be well tolerated in healthy volunteers? What questions did that answer given what we know about the target and the ways that we can interrogate the activity of the molecule against the target? Can you just remind us what you saw? So -- and then we'll get into the ongoing programs.

Yes. So let me -- in our preclinical work, also done the dosing at a very high level and with very good margins. And the -- we also have in our Phase I studies dosing up to 50 milligrams in our MAD study. And so far, the profile there has been clean. And the activity of the molecule has also been seen in an experiment that we -- called the bradykinin challenge where we have healthy volunteers where we administer bradykinin on an hourly basis. And then we -- when you do that, we observe the hemodynamic effects of the bradykinin that lowers your blood pressure and increases your heart rate. And we did that in -- preclinically in monkeys and also in our -- part of our Phase I work in healthy volunteers and that -- both have experienced -- both the monkeys and humans show the activity of the molecule that indeed we observed the inhibition of the bradykinin, clinical signs of the effects of bradykinin. And that helped us to -- this sort of surrogate assessment to help us to develop the dosing and getting insights into the PK/PD profile to model that to help us determine the dose for the clinical studies. And that was also an experiment that was done with icatibant back in the day and also [ did ] that in the Phase I work with icatibant. And so we did not do it head-to-head with icatibant, but we compared our data with that study and -- which was also reviewed by the FDA and sort of provide a very good basis for our -- compare that to our data that we show in our molecule.

And how does it compare to icatibant? I know it's not head-to-head, but can you describe that? And maybe what does that tell you about what you might see clinically? Is there any way to extract...

I think what we've seen, the properties of our molecule is that it has -- it appears to have a very fast onset and reach EC85 levels, so EC85 in about 15 minutes and also both in the fed and fasted states. So the -- it looks like it is totally independent on whether the patient has eaten or not, which is important in an on-demand setting. The half-life of our molecule is significantly longer than icatibant, so there's the potential for a longer duration of effect, which is also in an on-demand setting, and it's much more potent, so 25x more potent than icatibant. And so in that modeling that we -- in the bradykinin challenge, we saw the -- to model the PD effect that the single dose of our molecule appears to be -- have the same effect as 2 injections of icatibant that was 6 hours apart. So I don't know, Morgan, also if you have something to add there.

No, I think you covered it. I think that the -- we were able to do icatibant head-to-head in the -- in our preclinical model where we saw that our onset was faster than icatibant. So our orally dosed 121 was faster onset than subcu injected icatibant. That gave us a lot of confidence there. And I think it's worth noting that we're the only folks who can do an in-human assessment of efficacy. So this is actually measuring the mechanism of our compound in a human being. And so we think that it gives us a lot of confidence in the conclusions we draw from that.

And you have a unique opportunity to test the same agent in both acute and chronic settings, too. So maybe it's a good time to have you describe the development plan and how that will dovetail with the development ultimately of 2 separate agents but based on the same underlying molecule.

Yes. So as you pointed out, we have the same molecule, the same API in a -- which we then have 2 separate products. So it's for our PHVS416 in -- optimized for on-demand in a softgel capsule formulation. And then we have 719 for the extended-release tablet formulation for -- optimized for prophylactic. And so that provides for some synergies also in development. And we have been [ at least ] looking at preclinical data and data packages between the 2 products. It also potentially also have synergies in further clinical development right now. We -- the Phase II study that we have ongoing in -- both in on-demand and prophylactic, actually use the 416, the on-demand softgel capsule that we do in the prophylactic study. We do, do that BID to get the first insights into efficacy and to determine dosing and to get further safety data. And then in parallel, we also -- about finishing our study -- PK study for the 719 in prophylactic formulation, extended release. And that's also data that we are looking forward to be able to talk about also already in this quarter that we're assessing the QD potential of the extended-release formulation to lay the groundwork then for the development on the prophylactic side. So we also have some potential synergies in our Phase II studies between them to -- using the same, the patients also can roll over from our on-demand study into our -- directly into our prophylactic study if they're eligible and willing, like what they experienced in the CHAPTER-1 study.

Okay.

Some -- but their goal is to have patients really have the ability to have a full spectrum on choosing between on-demand and prophylactic and because we think that, that patient choice -- especially in the future when there will be an oral therapy also for the on-demand side right now, we haven't seen the first oral on the prophylactic side, nothing yet on the on-demand side, but I think our goal is to provide both. And that might change the paradigm and the treatment dynamics between prophylactic and on-demand and to have the patient able to choose between the 2, and it's important. And also as you're looking at new patients coming into -- the younger patients that have experienced the first years of their life with HAE that typically start with on-demand and then later on, maybe go on prophylactic and to have the ability then to migrate patients, to provide the full spectrum of treatment options for these patients, starting with on-demand and maybe moving into prophylactic as depending on how the disease progresses.

Right. That's interesting. So I guess you said that 416 is a softgel capsule and 719 is an extended-release formulation. Can you describe each of these product presentations any more? Did you evaluate multiple and ultimately settle on each of these and how they...

Yes. 416, the on-demand, of course, is -- first, from a PK/PD profile, is optimized for -- in an acute setting, so fast onset, the correct duration to cover an attack. And it's also very small. The capsule is very, very small. They're easy, easy to take, easy to swallow. And so that doesn't -- we feel that that's also important for patients. I mean that's just -- oral is not just -- like any oral, we have to be able to take it conveniently. So having a small tablet, a small capsule, we think is a potential benefit for the patient to be able to do that. And on the prophylactic side, the tablet formulation is optimized for the longer duration and maintaining the plasma level that's needed for protecting against HAE attacks over a longer time period, ideally in the first QD. But ultimately, the patients also, prophylactic side, primarily are looking for efficacy. That's our sense. And -- but if you can combine a very high level of efficacy with the QD, and then that's something definitely our patients are looking for.

Okay. Great. Maybe could you provide an update on the ongoing Phase II RAPIDe-1 trial for acute treatment of HAE attacks in terms of enrollment? And given the event-driven nature of the trial, when would you expect us to see data from that?

Yes. You said it already, it is event-driven, so that puts an additional element of uncertainty in just predicting exactly the timing. In our assessment, as I said, we guided Q4 of this year, and the enrollment is ongoing, study is ongoing. We -- the first patient was dosed in -- about a year ago, and that -- it's moving along according to our expectations. And -- but having said that, as you pointed out there, it is event-driven, so that makes it -- that's an additional dimension of uncertainty. But to our best assessment, that's Q4 is the data readout. I'll push and say that the trial is done in the home setting or it's not in the site. So if a patient, for example, is not able to treat an attack with the study drug because they are on the job, and they can't really take the 4 hours timeout to -- for the observation period to do all the scoring or they get an attack in the middle of the night, then they're free to use their standard therapy, and then they will skip that attack and then they do the next one. So that's an additional element and what could cause some kind of -- not delay but also you have to get through all the attacks, but it might be attacks in between that, for those practical reasons, are not really part of the study. So...

Yes. There's always some residual uncertainty, it sounds like.

Right, right.

What -- maybe one more question, though, just so we can understand like the assumptions that underlie the expectation for Q4 data. Can you give us more color on like the number of patients and how often they -- patients and sites and how often they get attacks? And are they getting -- are they doing a blinded crossover like KalVista did? Can you just describe the underlying rubric so we can appreciate how you get to Q4?

Yes. I mean we -- the total size of the [ patient ] study in RAPIDe-1 is 72 patients -- or I should say, up to 72 patients. And it's -- there is a -- each patient is to treat 3 attacks. And there's like 2 on study drug and 1 on placebo. So that's the basic design. And I think the center -- Morgan can jump in here, I think we have about 33 sites or something like that and activating.

Yes. And each patient will get only a single dose. So there will be 3 doses in the study, but patients don't cross over to change doses.

Okay. So how do you view the bar of success here? Is it what we saw from KalVista's KVD900 in their Phase II? Or are there differences in trial design that...

Well, I think that -- I mean the difference is we have a different endpoint. We have the [ vast ] -- the observation of 4 hours, which is different from KalVista. Might also look at rescue medication. That will be one comparator. And so I think what we expect to be looking at it, that would be on the par with the icatibant data. There's a difference between the study, the icatibant study and our study in that it's sort of the kind of treatment. The paradigms have changed a little bit, so patients tend to treat earlier, and our study in the home setting then, the patients have to have a certain severity of the attacks. So once the -- when they get an attack, they consult with the site and to qualify that the attack is eligible for treatment. But the attacks, they generally tend to be treated earlier, whereas in the icatibant study, the patients have to go into the clinic. So the attacks was more progressed once they did the treatment, so that's one difference. But overall, I think we would -- we look at it in the light of the icatibant trial and anticipate it to be on par with icatibant.

Yes. So would that mean that the placebo rate is higher if patients aren't pushed as far as they used to be back in the day when icatibant was developed? Or practically speaking, what would you think the effect of different treatment approaches is?

Yes. It's hard to say. As I said, I think this state, it's -- there is a certain level of severity before you treat. So I think you should be able to see the difference there. But -- so I think also obviously, Morgan, if you have any other comments on how the -- I think the -- I mean we're, of course, taking that into account and -- when we look at things, and there is potential -- there's a difference between how the studies were set up between the icatibant study and our study.

Yes. I think you may see sort of maybe a smaller absolute difference between attack and placebo and because of the -- if you have a -- if you're going on drug or starting to measure earlier, you may have a less advanced attack and this increases the chance that you have attacks that don't manifest as very severe. We're trying to take steps in our study design with timings and scores that attacks are at least moderate before patients treat so that we can be measuring a real effect there.

Right. Yes, that makes sense. Okay. Great. And then turning to the Phase II CHAPTER-1 study, can you give us an update there in terms of enrollment and your expectations for data?

Yes. So it's a similar story in terms of assessing the progression and the completion and the data readout. So we also look for Q4 of this year, and that's also actively recruiting and enrolling. So that's ongoing. This has been going to our expectations so far. And there's similar types of uncertainty, so that -- the one difference being, of course, that the prophylactic trial is once you have completed everybody in the study, they have everybody in, the last patient in, then it's easier to really predict the -- because it's a fixed period, that's a 12-week study, and then we have the readout and the evaluation play. So once we have everybody in, it's easier to really make a clear prediction. But -- in our assessment that we've done, we also assess Q4 for the CHAPTER-1 study.

Is there less uncertainty with this because there's -- you're not beholden on the number of attacks, which you're treating independently -- you're treating each attack and you're just capturing the attacks while on...

Yes, of course, you don't have the element of event-based. So in that sense, there is one kind of variable with -- less compared to the on-demand trial. And the CHAPTER-1 trial is smaller. As I think I mentioned, it's only 30 patients compared to the RAPIDe-1 trial. It started later than the RAPIDe-1 trial. And it -- but as I said, so far, it's been going according to our expectation. But we're not commenting specifically where we are in terms of enrollment other than to say that we're actively recruiting and enrolling it right now. So the answer is when the last patients or the patients are going to be -- when you're going to have the study complete, of course. And so...

Right.

Yes. And it's also fair to say that there is a -- as I'm sure you know, there is a lot -- there are several studies out there in HAE. So it is a competitive environment. But I think we have a lot of good things to offer, in our opinion. So we're working very hard with the KOLs in the sites. And that's, of course, a very strong focus in the company to progress both of these trials.

Right. Okay. And then considering you're using the gel capsule formulation in CHAPTER-1, and then you've got the upcoming PK/PD data with 719, the new formulation, can you remind us what you're looking for in each study and how you'll analyze -- ultimately analyze these things together to determine the right dose for chronic administration?

Yes. So first on the 719, that's in healthy volunteers. It's one dose, the way we look at the PK/PD profile and the oral bioavailability of the formulation. And so looking at the coverage of the -- maintaining the plasma concentration in -- what you think, EC85 over 12 and 24 hours to assess that and assess the potential for QD. And then this is then -- that's the data then that we will be -- we will have in this quarter. And then we will then do additional multi-dosing also using that tablet. We have a couple of different -- we have XR1 and XR2, 2 different types of formulations or recipes, you could say, in the 20-milligram and the 40-milligram that we're assessing. And then we will do, based on the data that we get now in Q1, further multiple dosing. And then together with the data from the CHAPTER-1 study and the insights on those, they're putting all that together, will help us then put together the right dosing for the pivotal Phase III studies, prophylaxis.

Yes. And I know that this study, CHAPTER-1, is smaller than RAPIDe-1. But you -- can you remind us what you're looking for in terms of PK/PD? And is there just a critical threshold you have to exceed? I'm just wondering because of the relatively smaller size if there could be some variability across people naturally based on how they metabolize the compound and whether that might influence how it interacts with the target. What are you looking for in terms of specific thresholds for inhibition of kallikrein in order to be confident that you know enough to go into the next stage of development?

Do you mean for the -- now for the data on the 719, the extended release?

Yes. Exactly.

Yes. So...

You've got multiple -- you've got a couple of recipes, as you said. So...

Yes. So you're looking at -- I mean the...

What are we looking for?

That efficacy level last month, the concentration, I think it's 13 nanogram per milliliter EC85, which is the level that you need to maintain in our assessment for efficacy. To protect from attacks, you have to be above or at least at that level. And so that's what we will be looking for in that data that comes out and how we are able to maintain that plasma concentration over 12 and 24 hour, also taking into account fed and fasted and -- to see that in this study. That will then, yes, as I said, help us then to determine the further path forward.

Yes. I might just chime in here, that CHAPTER-1 study, we're using 10 patients per dose arm, which is consistent with the field in terms of studies that have been done or in proof-of-concept efficacy studies. So I think it's very much in line with what we've seen before. And so we think that gives you the assessment of the dose response that you might see so you can, as Berndt said, correlate that back to the exposures we're seeing with the tablet.

Yes. Okay. Cool. That's very helpful...

Sorry, I'll mention, [ a reminder ], because we're inhibiting the receptor mechanistically, right, different from the kallikrein inhibitor. So I think we're looking at a -- that's where our doses could be very different and much, much smaller than what we've seen with other oral agents.

Very helpful. Thanks. And then maybe lastly, in the minute or so that remains, are there any other indications that you're contemplating for potentially developing the series of agents?

We're not contemplating any at this time, any other indications for the 416 or 719 or the underlying molecule at this point. That's really dedicated to the HAE program. We have -- as you know, the understanding of the B2 receptor and the whole mechanism as a -- as part of the expertise that we have in Pharvaris. So we are looking at other molecules, the sort of follow-on molecules or new molecules that we have in the works, and also to look into other indications where the B2 receptor mechanism is relevant or looking at, from a scientific rationale, unmet need, commercial opportunity and the ability to differentiate. So those are the -- that -- we are working on that. It's premature to really name specific indications right now. We have some ideas, but I would expect that we would start to be able to talk more about that behind our Phase II data in HAE sometime next year, it's -- and when we have a little bit more solid progress there in terms of ideas and also IP on new molecules and things like that. So that -- but that is -- we are allocating some capital to that. It's not significant compared to our HAE spend, but there is -- some small portion of our budget is to develop new molecules for us to potentially broaden our portfolio in the future.

Also maybe chime in that because of our mechanism, we can access other causes of HAE, so normal C1 inhibitor is also a potential application of 719 and -- or 416. And acquired angioedema, I think, is another possibility, sort of nongenetic but ways patients develop angioedema chronically.

Yes. That's a very good point actually. I mean normal C1, we don't need a separate program or separate molecule for normal C1 because of the mechanistic approach that we have and that we are also -- if these products work in type 1 and type 2 HAE, well, they -- might be that they will work in normal C1 as well. So that's very different from [ division ] that we can treat all forms of angioedema.

And what would that mean in terms of the patient population?

Well, I think that there are thoughts that the number of patients with normal C1 inhibitor could be 1/4 -- up to 1/4, 1/3 of patients with HAE in general nationwide. So it's -- we think it's a meaningful portion of the population. Acquired angioedema is harder to get a handle of. It's smaller than that but still enough need and opportunity [ to work with yet ].

Yes. All right. Interesting. Okay. Well, thanks so much for the update, and we look forward to [ more ] continued progress.

Great. Yes. Thanks, Joe. Good to see you.

Thank you, Joe.

Thanks, guys.