Okay, we're live. So, thanks for being here. My name is Liisa Bayko. I'm one of the biotech analysts here at Evercore ISI, and this is HealthCONx, day two. Today I'm up here with Maggie Beller, who's head of IR at Pharvaris. Pharvaris is working on a new oral treatment for HAE, and we're, you know, I've been covering the HAE space for some time, and there's been a ton of innovation in this field. So, you know, I think it seems to be an area that adopts a lot of new therapies. So, and your product looks pretty interesting. So, with that, why don't I turn it over to Maggie, and she can give us a just an overview of the company to start.
Yeah, awesome. Thanks so much, Liisa, for having us. Pharvaris is developing an oral small molecule called deucrictibant, which is a bradykinin B2 receptor antagonist for the treatment and prevention of HAE. We have one oral molecule that's formulated in two different ways for the two different ways that you can treat HAE. One is an extended-release tablet. This enables us to have sustained therapeutic exposure for over 24 hours, which supports a once-daily oral prevention of HAE. The other is an immediate-release capsule, which quickly reaches therapeutic exposure for us to be able to treat attacks as they happen. Both prevention and treatment of HAE attacks. We are in phase three for our on-demand program. We initiated that phase three program, which we call RAPID-3, in March of this year. We generally have seen recent phase three on-demand programs go in about 27 months.
We're hoping to beat that, but we haven't quite set formal guidance on when our readout of our phase 3 on-demand program is going to be. Our phase 3 prophylactic program is called Chapter-3 . We plan to initiate that by the end of the year, so it's December 4th now. We're still pretty confident in being able to do that, and so we're excited about that.
Great. Tell us a little bit more about the mechanism and how this is different from, say, kallikrein inhibition?
Absolutely. So, the B2 receptor is at the bottom of this whole cascade that leads to angioedema. So we feel that this could actually address all types of HAE, not just the ones that are focused in kallikrein. So that's a bit more upstream. It's unlike oncology, where you want to be further upstream in oncology. Here, we think that by plugging the stopper as it is, we may be able to address any way that bradykinin is introduced into the body.
Okay. And so, let's walk through some of the phase two data you have for both prophylaxis and treatment of attacks.
Absolutely. So starting with prophylaxis, our CHAPTER-1 phase 2 program read out in December of 2023. We were really pleased with this data. This is the first time that a bradykinin B2 receptor antagonist has shown any sort of efficacy and safety in prophylaxis. So we were thrilled with that. 84.5% attack reduction monthly, so that really brings us in line with other injectable therapies. We were once again thrilled to see that. We were happy with anything above 70%. So 84.5% in the randomized clinical trial was really exciting for us. We've continued an open-label extension. We have some participants who have been on the open-label for up to 18 months. And that data we recently announced at the Bradykinin Symposium in September of this year that showed a 93% attack reduction monthly.
So we're really pleased to see that continued treatment with deucrictibant enables continued, sustained attack reduction. Like I said, we have both the randomized clinical trial data and then also our open label extension data. Both of those are using a twice-daily BID capsule. So people took them 12 hours apart. In our phase three study, we're going to be using an extended-release tablet. So instead of sort of peaking and troughing with your PK, we're going to be able to have a sustained exposure there. And we could see that some of the phase three data drops that we've seen in HAE could be protected against it with that extended-release formulation.
Will it still be twice a day?
Nope, once daily. So our PK profile supports over 24 hours of therapeutic exposure. So we're pleased to be able to provide people with just QD dosing on that one.
And so what happens? Because we have seen as you go from phase two to phase three that sort of the reduction in attacks has softened to some extent. So why is that? And why? So why do you think this different, this new formulation might alleviate some of that?
Absolutely. So, across the board, as you go to phase 3, you're treating a larger patient population, maybe a bit more heterogeneity there. We certainly are. We're trying to be very creative with the way that we are identifying sites in our phase 3 study to be able to bring this therapy to patients as quickly as possible. We could see also that potentially some of this compliance in a BID dosing, so twice-a-day dosing could lower or soften that. As you look at the PK curves of our BID dosing, it could be that some people dropped below the therapeutic threshold for some time before they took their second dose. So that could be where they saw some breakthrough attacks.
We're hoping that with this sort of tapered PK profile that's extended and covers the full 24 hours, that people are able to remain above therapeutic exposure for that full time.
And you've done the bioequivalent studies and all of that, so you know exactly.
Yeah, we're all good with that. Very pleased with the PK profile. If you look on our corporate deck, there are some data there that shows phase one data for the actual extended-release formulation that we're going to be using in the phase three study and intend to use in commercial product.
Okay.
The data support it.
What was the baseline attack rate in the phase two?
I believe that we were a little bit under two attacks per month. Yeah.
Okay. And then you had the placebo. Then when patients were in the study on placebo, what was their attack rate?
Their attack rate went down a little bit, which is a common phenomenon within HAE. HAE attacks are stress-related. And so sometimes when people join a clinical study, even if they're on placebo, they feel the protection of, oh, it's okay, I'm taking a therapy now. And so their attacks go down a little bit, but we saw that it was pretty much in line with our placebo attack rate was in line with other phase three, phase two and phase three prophylactic programs.
So, let's talk about the design and timing of the CHAPTER study.
Absolutely. So, CHAPTER-3, we are on schedule to initiate that by the end of the year. We will be trying to enroll 81 participants in a two-to-one randomized fashion. So that is more appealing to people. They have a better chance of being on active drug. We are enrolling participants 12 and up. So we'll be opening up to adolescent patients as well, which we didn't have in our phase 2 program. And we'll be doing a global study there. So, excited to step into some new geographies, South America, APAC, Europe. We'll, of course, have U.S. participants as well. And, yeah, so, so we're excited about that. 81 participants, two-to-one randomization.
When do you think we'll have data? When are you targeting?
We haven't guided to that formally yet. We'll be able to provide much more information once we actually start the study. But, as we look at peers in this space, recent phase three studies have taken about 24 months. Like I said, we're really trying to be thoughtful and creative with the way that we're enrolling participants. So we hope to be able to beat that 24-month timeline that's been set by others. But we'll be providing more guidance, more granular guidance in coming months.
Okay. And then for the treatment of attacks, let's walk through sort of what you saw there in terms of the data and stuff.
Yeah. So our phase two study was RAPID-1. That top-line data read out in December of 2022. We saw in that study a 2.4-hour timeline to attack reduction. That was measured by AMRA 30. So, a different endpoint than what we're going to be using in our phase three study. In a post-hoc analysis of that, we also evaluated a new endpoint called end of progression. We saw with the end of progression data that our blended time to the first time that you stop being, stop having something get worse was about 25-26 minutes. So very pleased with that rapid onset of attack reduction. In our open label study that we've recently announced data on, once again, that came out at the Bradykinin Symposium, measuring with PGIC, which will be our primary endpoint, we saw a 1.1-hour time to attack reduction.
In that open label data as well, we saw that we had about 11.5 hours until complete symptom relief. That's measured by PGIS. And of that, 85% of participants were completely resolved within 24 hours. Within that 85%, 90% of people only had to take one dose. So as we really think about what the treatment landscape looks like for somebody who's treating an attack, they want it to work quickly, they want it to work completely, and they want it to work with one dose. And we think that our open label extension certainly supports that. We'll be using those same endpoints in our phase three study. And we're obviously hoping to confirm what we saw in the phase two and in our open label.
Did you have laryngeal attacks within that?
Within our open label study, we did. We didn't have it in our phase 2 because it's not really ethical to measure that until you know the drug, you know, has some efficacy.
Okay.
Yes, in our open label, we will be including laryngeal attacks in our phase 3 study. We'll be announcing more data on laryngeal attacks specifically in upcoming medical conferences in 2025.
How does the timing and resolution look with this deucrictibant as opposed to, let's say, you know, more traditional injectable therapies?
Yeah. So we are pleased that our 2.4 hours was in line with icatibant. Icatibant also utilizes the same mechanism of action as deucrictibant. In fact, our team was on the development team over at Jerini for icatibant. So please use that history and knowledge in the development of deucrictibant. And then as we look at it, when we compare the 1.1 hours of deucrictibant to standard of care, we can say that we're, you know, faster in a non-comparative, not head-to-head study, lots of, you know, legal asterisks around that. But really pleased to see that we're playing in the, this injectable-like space so that we're able to really provide the convenience of an oral therapy while not asking participants and patients to give up what they expect of their efficacy.
Is there any impact if a patient is having a little laryngeal attack and ability to swallow and that kind of stuff?
Typically, participants and patients have a bit of a prodrome before they actually have an attack. So they're able to stall their attack beforehand. This is why the end of progression endpoint is so exciting, because our 25-26 minutes that we looked at post-hoc from the phase two data was actually based off of our first timeline, or time point that we looked at data was 30 minutes. In our phase three, we're actually going to be looking at 15 minutes as our first time point. So we're hoping to get more resolution around what exactly that first end of progression time point is. Once somebody takes the oral capsule, we think that once they start to feel that it's stopping the attack, they'll. That'll, you know, build confidence in an oral therapy for laryngeal attacks.
Okay. And have you done any studies like combining, you know, someone who's on prophy with deucrictibant and then using kind of the treatment of the attack formulation? Just, is that too much of the same mechanism or do you need a different mechanism?
It's a great question, so right now, of course, we can't have them treat their deucrictibant with deucrictibant since they're both investigational, but many people, when they were taking deucrictibant, rescued with icatibant, so using the exact same mechanism of action. We've also seen the same mechanism used across other forms within HAE, so you have a kallikrein inhibitor rescued with a kallikrein inhibitor, so we don't really see that that's going to be a big hurdle for us. But of course, we're very interested in exploring that because the idea would be that if your PK ever drops below the therapeutic threshold, you could just top it off with an immediate-release capsule and bring you back within that threshold, so that for us would be really exciting.
Okay. How do you see the market opportunity? Maybe you can walk us through some of the math.
Yeah, absolutely. So, right now we have seen that obviously there there's a huge explosion in the prophylactic space. Tons of innovation has been there. Takhzyro is a great drug. It's been doing really well. Orladeyo launched a couple of years ago. They've had a phenomenal launch and clearly shows the need for an oral therapy. So very excited about how the prophylactic market looks. With that, we're really thinking about how can we bring all three aspects that a patient wants to the table, the efficacy that they want, the tolerability that they want, and the oral convenience. And so we really think that there's space for deucrictibant within the prophylactic market. So we continue to see that growing, especially as treatment guidelines recommend that nobody ever experiences an HAE attack. The only way that you can get to that state is through prophylaxis.
So we think that people will continue to be transitioning to prophylaxis. However, people sometimes do still have breakthrough attacks. So they would treat with on-demand. We think that the on-demand market, though it has been shrinking, will be able to stabilize and potentially even grow. Right now, people aren't treating as many attacks as they could because they're either waiting for the attack to get more severe to where they can say, "Oh, this is just a hand attack. I'm not going to treat it because I don't want to waste my therapy," or "I don't want to step away from this conversation that we're having to go inject myself." If you were able to have an oral therapy, we really think that treatment burden would be lowered. And so people would treat more attacks.
So we see the prophylactic space growing and we see the on-demand space either maintaining where it is or even growing as people treat more attacks. So once again, in on-demand, we think of the same thing. What do people want? They want the efficacy that they're used to, the tolerability, and the oral convenience. Deucrictibant is uniquely positioned to be able to address both of those aspects in prophylaxis and in on-demand.
How do you think, what is your pricing research adjusted? Do you think like a premium pricing is what makes sense? Do you think you want to take share by offering a lower price? Does that even make sense? How are you thinking about that?
I think at this point it's premature to comment on pricing. We're definitely going to need to wait for our phase three data because, you know, that will support any conversations that we're having with payers. But, you know, right now we don't anticipate having a major, you know, degradation of the pricing.
Okay. Okay. And then commercial plans?
Commercial plans, we are really excited about what that's going to look like. Once again, we haven't disclosed our full, you know, salesforce rollout or anything there. But one of the things we're very proud of is our Chief Commercial Officer, Wim Souverains, joined the company back in 2021. So he's really been building the relationships within the community. And we think that engagement with our partners, both with you all, with physicians, with patient advocacy organizations is going to be important so that we're making sure we're bringing the right therapy to participants, to patients, excuse me.
Okay. So just as we wrap up, maybe you can walk us through sort of where you are from a cash perspective, your cash runway, how far that gets you, and then 2025 catalyst.
Yeah, absolutely. So, as of September, we have EUR 305 million in the bank. We haven't guided to how far that cash runway is because we're thinking about a couple of different strategic options right now in terms of what our go-to-market strategy is going to be, as well as our pipeline expansion. So earlier this year, we announced intention to develop deucrictibant in acquired angioedema. So that's another bradykinin-mediated disease, similar to HAE, but people end up acquiring their angioedema due to their underlying disease that they have. So we have an intention of going there. Normal C1-INH is another really exciting bradykinin-mediated angioedema, and so those could be potential catalysts for us to announce in 2025, as well as continued open-label extension data.
Of course, we're really looking forward to upcoming phase three data in the coming years.
Okay. Good. Well, thank you very much.
Thank you so much, Liisa.