Hello, welcome to this fireside chat with Pharvaris. I'm Joseph 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.
Mm-hmm. Yeah. Yeah. Great. Thanks, Joe, and thanks for having us today. Pharvaris, we our key focus is developing oral therapy for hereditary angioedema, which is a great unmet need in that patient community. Patients are looking for better ways to treat and manage their condition. 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. We address the HAE focusing on the B2 receptor antagonism. 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 is also seen with icatibant and Firazyr, with over decades of experience as the most common way to treat HAE attacks in the last decade. In fact, our Chief Scientific Officer is an inventor of icatibant in the old days. So that's the one common connector there, the mechanism. We're excited about our ongoing trials and look forward to the data readout when that comes.
Great. Maybe we could dive into the rationale behind the mechanism for PHA121 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 tried to develop an oral bradykinin B2 receptor antagonist.
It 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 enabled us to come up with that molecule. The challenge has been to find something that's specific to the receptor, but at the same time is orally available. That's sort of the thread the needle there that's been the challenge. We're excited that we've been able to come up with such a molecule. Morgan being the chemist from our side here, maybe you could add some color to that.
Yeah. I mean, the challenge is that the bradykinin receptor is a GPCR, has a fairly long channel where peptides bind. Bradykinin itself is a nine-mer peptide. The challenge is finding, and that our team was able to do, was to find a small molecule that was small enough to have potency to bind into that pocket. We found a core that had that potency with extra interactions that allowed us to stay small enough as we elaborated, so that we retained orally available properties. That's really been the stumbling block before.
Yeah. Okay. That's helpful. Thanks. Can you just quickly remind us, you know, what did you see pre-clinically? You know, how does that combine with the exposures that you saw be well tolerated in healthy volunteers? What questions does 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 far, and then we'll get into the ongoing programs.
I mean, in our pre-clinical work also done the dosing at very high level and also with very good margins. We also have in our phase I studies dosing up to 50 milligrams in our MAD study. So far the profile there has been clean.
The activity of the molecule has also been seen in an experiment that we call bradykinin challenge, where, in healthy volunteers, we administer bradykinin on an hourly basis, and then when you do that, we observe the hemodynamic effects of the bradykinin that lowers your blood pressure and increases your heart rate. We did that preclinically in the monkeys and also in our part of our phase I work in healthy volunteers. That both have experiments, both in monkeys and in humans, show the activity of the molecule that it indeed did observe the inhibition of the bradykinin, clinical signs of the effects of bradykinin.
This was a surrogate assessment to help us develop the dosing and getting insights into the PK/PD profile, to model that to help us determine the dose for the clinical studies. That was also an experiment that was done with Icatibant back in the day. It also, Giorgini did that in phase I work with Icatibant. 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 provided very good basis for our compare that to our data that we show in our molecule.
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 that?
I think what we've seen, the properties of our molecule is that it appears to have a very fast onset and exceed EC85 levels, EC85 in about 15 minutes, and also both in the fed and fasted state. It looks like this is totally independent of 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. The potential for longer duration of effect, which also in an on-demand setting, and it's much more potent. It's like 25x more potent than icatibant.
In that modeling in the bradykinin challenge, we saw that to model the PD effect that the single dose of our molecule could appear to have the same effect as two injections of icatibant that are six hours apart.
Mm-hmm.
I don't know, Morgan, also if you have something to add there.
No, I think you covered. I think that we were able to do icatibant head-to-head in our preclinical model, where we saw that our onset was faster than icatibant. Our orally dosed 121 was faster onset than a subQ injected icatibant. That gave us a lot of confidence there. I think that it's worth noting that we're the only folks who can do an in-human assessment of efficacy. This is, you know, actually measuring the mechanism of our compound in a human being. We think that it gives us a lot of confidence in the conclusions we draw from that.
Mm-hmm. Mm-hmm. You have a unique opportunity to test the same agent in both acute and chronic settings too. Maybe it's a good time to have you describe the development plan, and you know how that will dovetail with the development ultimately of two separate agents, but based on the same underlying molecule.
Yeah. As you pointed out, we have the same molecule, the same API, which we then have two separate products. It's for our PHVS416 optimized for on-demand and in softgel capsule formulation. Then we have PHVS719 extended-release tablet formulation optimized for prophylactic. We have offering these and looking at preclinical data and data packages between the two products. It also potentially have synergies in further clinical development.
Right now, the phase II study that we have ongoing in both on-demand and prophylactic actually use the PHVS416, the on-demand and softgel capsule. We do it in a prophylactic study. We do that BID to get the first insights into efficacy and to determine dosing and to get further safety data. Then in parallel, we also about to finish our study, PK study for the PHVS719, the prophylactic formulation, extended release.
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 further development on the prophylactic side. We also have some potential synergies in our phase II studies between the two with using the same. The patients also can roll over from our on-demand study directly into our prophylactic study if they're eligible and willing and like what they experienced in the CHAPTER-1 study.
Okay.
Is that their goal is to have patients really have the ability to have a full spectrum of choosing between on-demand and prophylactic. Because we think 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. 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 two is important.
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 then to have the ability then to migrate patients or provide the full spectrum of treatment options for these patients starting with prophylactic, on-demand and maybe moving into prophylactic as depending on how the disease progresses.
That's interesting. I guess you said that PHVS416 is a softgel capsule, and PHVS719 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? You know, how
PHVS416, the on-demand of course is first coming from a PK/PD profile is optimized for in an acute setting, so fast onset and a correct duration to cover an attack. It's also very small. The capsule is very small, easy to take, easy to swallow. That's, and that we feel that's also important for patients. I mean, that is the oral is not just, the oral is not like any oral. You have to be able to take it conveniently. Having a small tablet, a small capsule we think is a potential benefit for the patient to be able to do that.
On the prophylactic side, the tablet formulation is then optimized for the longer duration and maintaining the plasma level that's needed for protecting against HAE attacks over a longer time period ideally than, of course, QD. But ultimately, the patients on the prophylactic side primarily are looking for efficacy. That's our sense. But if you can combine a very high level of efficacy with the QD, then that's, I think, ultimately what patients are looking for.
Okay.
Mm-hmm.
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?
Yeah. You said it already. It is event-driven, so that puts out an additional element of uncertainty in terms of predicting exactly the timing. In our assessment, as I said, we guided Q4 of this year. The enrollment is ongoing, study is ongoing. The first patient was dosed about a year ago, and it's moving along according to our expectations. Having said that, as you pointed out, it is event-driven, so that makes it, that's additional dimension of uncertainty. To our best assessment, as I said, it's Q4 is the data read.
I also should say that the trial is done in a home setting, or it's not in the site. If a patient, for example, is not able to treat an attack with a study drug because they are on the job and they can't really take the four hours time out 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.
That's an additional element then with the call, some kind of, not delay, but it was sort of you have to get through all the attacks, but there might be attacks in between that for those practical reasons are not really part of the study.
Yeah. There's always some residual uncertainty, it sounds like.
Right. Mm-hmm.
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 sites and how often they get attacks? Are they doing a blinded crossover like KalVista did? Can you just describe the-
Mm-hmm.
the underlying rubric so we can appreciate
Mm-hmm.
You know, how you get to Q4?
Yeah. I mean, the total size of the study in RAPIDe-1 is 72 patients, or I should say up to 72 patients. Each patient is to treat three attacks. There's like two on study drug and one on placebo. That's the basic design. I think that's where Morgan can jump in there. I think we have about 33 sites or something like that and activated.
Yeah. Each patient will get only a single dose.
Mm-hmm.
There'll be three doses in the study. Patients don't cross over to change doses.
Mm-hmm.
Okay. 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, I mean, the difference is, we have a different endpoint. We have the VAS at the observation at four hours, which is different from KalVista. We might also look at rescue medication. That would be one comparator. I think what we expect to be looking at it, that would be on par with the icatibant data. There's a difference between the study, the icatibant study and our study in that it's sort of they got treatment. The paradigms have changed a little bit, so patients tend to treat earlier. In our study in the home setting, the patients have to have a certain severity of attacks.
Once they get an attack, they consult with the site and to qualify that the attack is eligible for treatment. The attacks in general tend to be treated early, whereas in the icatibant study, the patients had to go into the clinic. The attacks was more progressed once they did the treatment. That’s one difference. Overall, I think we would be looked at in the light of the icatibant trial and anticipate to be on par with icatibant. Yeah.
Yeah. 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, you know, different treatment approaches?
Yeah, it's hard to say. As I said, I think the state it's, there is a certain level of severity before you treat. I think it should be able to see the difference there. I think also asking a bit more energy also comments on how that I think the maybe of course, taking that into account and when we look at thing and that there is potential. There's a difference between how the studies were set up between the icatibant study and our study.
Yeah. I think you may see sort of, there is maybe a smaller absolute difference between attack and placebo. Because if you're going on drug or starting to measure earlier, you may have a less advanced attack, and that 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.
Yeah.
Mm-hmm. Right. Yeah, that makes sense.
Mm-hmm.
Okay. Great. 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?
Mm-hmm. Yeah. It's a similar story in terms of assessing the progression and the completion and the data readouts are there also for Q4 of this year. That's also actively recruiting and enrolling. That's ongoing. It's been going according to our expectations so far. That's similar types of uncertainties. The one difference being, of course, that the prophylactic trial, once you have completed everybody in the study, the last patient in, then it's easier to really predict because it's a fixed period. It's a 12-week study. Then you have the readout and the evaluation phase.
Once you have everybody in, it's easier to really make a clear prediction. In our assessment that we've done, we also assess Q4 for the CHAPTER-1 study.
Mm-hmm. Is there less uncertainty with this because you're not beholden on the number of attacks, which you're, you know, treating independently. You know, you're treating each attack, and you're just capturing the attacks while on-
Yeah. Of course, you don't have the element of event-based. In that sense, there's one kind of variable less compared to the on-demand trial. The CHAPTER-1 trial is smaller. As I think I mentioned, it's only 30 patients as compared to the RAPIDe-1 trial. It started later than the RAPIDe-1 trial. As I said, so far it's been going according to our expectation. We're not commenting specifically where we are in terms of enrollment, other than to say that we're actively recruiting and enrolling right now.
The answer is when the last patients or the patients are gonna be when you're gonna have it, is the study complete, of course.
Right.
We have-
Primarily dependent on enrollment.
also fair to say that, as I'm sure you know, there are several studies out there in HAE. It is a competitive environment. I think we have a lot of good things to offer in our opinion. We're working very hard with the KOLs and the sites, and that, of course, is a very strong focus in the company to progress both of these trials.
Considering you're using the softgel capsule formulation in CHAPTER-1, and then you've got the upcoming PK/PD data with PHVS719, the formulation, can you remind us, you know, what you're looking for in each study and how you'll ultimately analyze these things together to determine the right dose for chronic administration?
First one is PHVS719. That's in healthy volunteers. It's a one dose where we look at PK profile and the world, I mean, or bioavailability of the formulation. Looking at the coverage of maintaining the plasma concentration at EC85 over 12 and 24 hours to assess that and assess the potential for QD. That's the data that we will have in this quarter. Then we will do an additional multi-dosing also using that tablet.
We have a couple of different XR one and XR two different types of formulations or recipes you could say, in the 20 milligram and the 40 milligram that we were assessing. We will do based on the data that we get now in Q1, further multiple dosing. Together with the data from the CHAPTER-1 study and the insights on those to steer that, putting all that together will help us put together the right dosing for the pivotal phase III studies for prophylaxis.
Yeah. I know that this study, Chapter 1 is smaller than RAPIDe-1. Can you remind us what you're looking for in terms of PK/PD and, you know, is there just a critical threshold you have to exceed? I'm just wondering because of the relatively smaller size, you know, if there could be some variability across people naturally based on how they metabolize the compound and, you know, whether that might influence how it interacts with the target. You know, 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 now for the data on the 719, the extended-release?
Yeah. Exactly.
And so-
You've got a couple recipes, as you said, you know, so-
Yes. You're looking at, I mean, the
What you're looking for.
The test efficacy level, the plasma, the concentration, I think it's 13 ng/mL 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. That's what we will be looking for in that data when it comes out and how we are able to maintain that plasma concentration over 12 and 24 hours, also taking into account fed and fasted to see that in this study. That will then you know as I said help us then to determine the further path forward.
Yeah. I might just chime in here. The CHAPTER-1 study, we're using 10 patients per dose arm.
Mm-hmm.
Which is consistent with the field in terms of studies that have been done in proof of concept efficacy studies. I think it's very much in line with what we've seen before. We think that gives you an assessment of the dose response that you might see. You can, as Berndt said, correlate that back to the exposures we're seeing with the tablet.
Mm-hmm. Yep. Okay, cool. That's very helpful.
I'll just sort of mention a reminder, because we're inhibiting the receptor mechanistically, right? Different from the kallikrein inhibitor. I think that's where our doses could be very different and much, much smaller than what we've seen with other oral agents.
Mm-hmm. Very helpful.
Yeah.
Thanks. 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 our 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 is part of the expertise that we have in Pharvaris. We are looking at other molecules as the sort of follow on molecules or new molecules that we have in the works to also look into other indications where the B2 receptor mechanism is relevant. We're looking at from a scientific rationale, unmet need, commercial opportunity and maybe ability to differentiate.
That we are working on that. It's premature to really name specific indications right now where we have some ideas. 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. When we have a little bit more solid progress there in terms of ideas and also IP and on new molecules and things like that. That is, we're 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, let me chime in that because of our mechanism, we can access other causes of HAEs. Normal C1 inhibitor-
Mm-hmm.
is also a potential application of PHVS719 or PHVS416, and acquired angioedema I think is another possibility, sort of non-genetic, but other ways patients develop angioedema chronically.
Yeah, 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 one and type two HAE with it, might be that they will work in normal C1 as well. So that's very different from kallikrein inhibition that we can treat all forms of angioedema.
Mm-hmm. What would that mean in terms of the patient population?
Well, I think that there's thoughts that the number of patients with, you know, normal C1 inhibitor could be a quarter, up to a quarter, third of patients with HAE in general, nationwide.
Mm-hmm.
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 it.
Yeah. Right. Interesting. Okay. Well, thanks so much for the update, and we look forward to following the continued progress.
Great. Yeah. Thanks, Joe. Good to see you.
Thank you, Joe.
Thanks again.