All right, good morning, everyone, and welcome back to the Oppenheimer Healthcare Conference. I'm Jeff Jones, one of the biotechnology analysts here on the team, and I'm joined by the team from Pharvaris. Pharvaris is a late clinical stage company developing the novel oral bradykinin B2 receptor antagonist, deucrictibant, for the treatment of on-demand as well as prophylaxis of attacks from hereditary angioedema, or HAE. I'd love to take a couple of minutes of our discussion here, Wim, to talk about the market here. It's obviously a well-established market, but you guys are really bringing a novel solution in terms of your oral candidate that has the potential to penetrate both the on-demand and prophylactic market. So why don't we talk a little bit, give an overview of Pharvaris, and then talk about the market?
Yeah, thank you, Jeff. Maybe I'll start off. The company indeed was founded about 10 years ago based on a very deep expertise in HAE. And the purpose or the mission of the company was to bring new oral options to people living with HAE. There has been a tremendous amount of progress, but we felt we could bring even better, and oral was a real demand in the market. And that was what led to the discovery and then development in need of deucrictibant. Deucrictibant is a small molecule with a very high potency and long half-life that we developed not only for the treatment of HAE swelling attacks, but also for the prophylactic or the prevention of attacks. And we do that by developing two formulations. There's a soft gel capsule that very quickly gets absorbed and allows to mitigate symptoms.
On the flip side, we have a tablet that once daily can be given, stays above the therapeutic threshold level in the plasma for over the course of a day, and allows to really prevent attacks. We are currently, as you said, in phase III. We delivered pretty interesting, very encouraging phase II and open-label extension data in 2023 and 2024. Now our plan is really to finish off our trials, file them, and get this product to patients as soon as possible. The market in HAE has gone through quite an evolution. Twenty years ago, the only thing we had was treatment of attacks, replacement of the C1 inhibitor. There was Kalbitor, which was a kallikrein inhibitor.
And there was actually a breakthrough with Firazyr, or icatibant, as a B2 receptor antagonist developed and launched by Jerini first in Europe and then sold to Shire, to Takeda, which became the standard of care in on-demand. And on-demand was for a long time the only way that people living with HAE could manage the condition. And then 2017, 2018, that's when the world started to change and prevention became the new topic. And at the moment, if you look at the guidelines, the guidelines clearly state that no patient should suffer any attack. And the only way to achieve that is by providing prevention. And in the U.S. market, that has led to a dramatic shift in the way patients are managed. Today, around 65% of the patients in the U.S. are on prophylaxis, and the complement is on-demand.
At the moment, and the reason why we believe that we can provide innovation and the value to the community here is that a lot of these therapies are forcing patients to make trade-offs between efficacy, tolerability, convenience, and the ease of administration, and our ambition, our aspiration is with an oral option for both on-demand and prophylaxis to really change the lives of these patients.
Great. No, that's a great intro. And you spoke to the high percentage of patients in the U.S. that are on prophylaxis and then complemented by an on-demand therapy. The European market looks a little different. Would you mind commenting on sort of how the E.U. market looks on-demand versus prophylaxis?
Absolutely. Outside of the U.S., we see kind of a much slower penetration or uptake of the preventative therapies in HAE. Markets like Germany and France, they're probably getting to a level like the U.S. fairly soon. But it's kind of when you go broader, and particularly if you go into the periphery, if you go to Latin America, Asia-Pacific, on-demand use is still the most predominant use of managed or the therapeutic strategy for HAE. We see that slightly changing, as I said. So it's progressing with more and more new therapies coming into prophylaxis. The arrival of Orladeyo has helped quite a bit in that respect. And we see that Europe is catching up. And we hope, obviously, that other territories over time will do the same thing.
But one of the things which is amazing about HAE is that there are a ton of therapies on the market. There are new therapies coming in, but it's not necessarily everywhere in the world the same situation. And one of the things that we hope for is bringing in an oral is to really capture many more patients across the globe than just the U.S. and Western Europe.
Okay. And then the market dynamics are interesting here with some of the. You won't be the first oral to market, but you've showed some really outstanding phase II data. Maybe starting in the on-demand setting with an upcoming oral competitor launching probably this year, it would be great to hear from you what you saw in your phase II data, the open-l abel extension data, and where you are in moving that through your ongoing pivotal study.
Yeah, fantastic. So I think it's a great time for people living with HAE. If you see what innovation is coming at them, it's really incredible. And we're thrilled that after probably more than 10 years of non-innovation on-demand, we're finally going to have oral therapies penetrating the market there. We anticipate that sebetralstat will be very successful. There is a huge expectation in the community for orals in on-demand. But I think on the flip side, HAE has shown time over again that it's not the first product necessarily that becomes the market leader. At the end of the day, there is a lot of influence from the patient as well as from the doctor on what is the optimal therapy. And patients tend to go and tend to move towards that product that really satisfies their needs the most.
We've seen that with Firazyr when it took over from Kalbitor and C1 inhibitor. And we saw the same thing with Takhzyro when Haegarda came to market and Takhzyro with a much more less burdensome injection frequency really took the market here. So we anticipate that also in on-demand with the data that we have. And I would say particularly the totality of the package that we bring, meaning very rapid onset of symptom relief, patients very rapidly getting back to normal life, and all doing that with one single dose in 85% of the cases. That's really a very solid value proposition. And we anticipate that coming to market even as a second product, that the market will recognize that and we will see significant uptake and become a leader in on-demand.
Okay. And the on-demand market for people who aren't that familiar with it is significantly smaller than the prophylactic market. And so shifting over to the prophylactic opportunity here, again, with the same molecule, you guys have shown some really remarkable efficacy data in the on-demand setting with your oral molecule. And your open label extension data in the phase II showed deepening of responses, which is even more encouraging as you look at the longer-term study in the phase III. So would you mind highlighting what you've shown in your phase II and what timelines look like as you look to your phase III?
Yeah, so maybe I can speak about data and positioning first, and then at that point, talk about the trial timelines. We kind of captured our results from the phase II in the open label extension as offering injectable-like efficacy with an oral product. And I think that was really. We were really very, very happy with that data because before the phase II data came out, to be very honest, if we were hitting 75% attack reduction or maybe 80%, we would have been very happy because it would have shown that we as an oral could have very significant attack reduction. But in reality, what we have shown is that an oral can do similar things what an injectable today can do, Takhzyro.
Obviously, we need to repeat that in our phase III program, but we feel very confident that with this profile, we have a very attractive drug for the prophylactic setting. Our anticipation is that the prophylactic market will fall out over the longer term into a preferred oral and a preferred injectable. On the injectable side, that's most likely going to be the product that offers the best efficacy with the lowest injection frequency. I think on the oral side, we feel very confident that we have an optimal profile to really become a leader in that market. We anticipate that the oral will become the first-line therapy in prophylaxis. Why would you start on an injection if you can achieve the same efficacy with an oral?
From there, we want to grow the market not only in the oral segment, but also we believe that in the injectable segment, there are quite a few patients probably out there that stuck with injections because they didn't want to compromise on the efficacy. If you then come with something that has similar efficacy, that might be an attractive alternative. I think we're very well positioned with the data that we've shown. We have to repeat this in the phase III, and Peng is here to do that for us.
And I think, and you've touched on a couple of really relevant points here to expand on, and I think Peng can get into that. One is we've seen really significant uptake from Orladeyo as the first oral approved in a prophylactic setting, maybe somewhat surprising due to the substantially lower efficacy than Takhzyro. And so with you coming forward with Takhzyro-like efficacy with an oral, I think it positions you really well. And I guess, could you set the stage in terms of what Orladeyo has shown versus comparing what you've shown for deucrictibant in terms of efficacy, obviously, in phase II at this point? And so how you see yourselves positioned as you come to market?
Yeah, maybe Peng?
Yeah, maybe I can start to share what we observed from our phase II and also open label extension data. I hope that paves the way when you can show our value and our position for deucrictibant. So as we know that from our phase II is a double-blind, right? That placebo-controlled trial. That's exactly as we mentioned. I have to say beat almost everyone's expectation there. Surprisingly to say really deucrictibant as oral treatment can truly achieve that injectable-like efficacy. That means we reached that compared to placebo group, 85% around that range for attack reduction, and also for moderate severe attack or attack who required rescue medication, deucrictibant even achieved over 90%-93% reduction. That pretty much means that if patients take deucrictibant as a prophylactic treatment, less than one attack per year still needs the rescue medication there.
That's really very good efficacy result from prophylaxis part. Meanwhile, from the open label extension data we shared last year, also the patients treated up to 18 months. Maybe in the coming quarter, we will share more data there that we can see that the patients over the long-term treatment up to 18 months here, not only that the efficacy is really maintained quite well, pretty much we reached 93% reduction. And also that every month attack is median attack is zero. That's really compared to just as you mentioned, Orladeyo in the open label extension data is still around one attack per month here. So that's a huge dramatic difference.
And also all the data show no matter the patients who have frequent attack, for example, more than two attacks per month or less than one or two attacks per month, deucrictibant show very equally that reduction, 80%-90% reduction protection there. The last but not least I want to mention is that sometimes all the physicians always ask, how about the compliance of the treatment or treatment compared to injectables? From the open label extension data, I think that we are very happy to see the compliance went very well. That's reflect really to see that the efficacy data, safety data, and also the quality of life data that the patients really achieved significant changes from all our assessment that within the first few weeks, then last up to 18 or 20 months for a lot of patients here.
That's also the data we will gradually share with the community.
Okay. No, that's great. And I guess you mentioned earlier about 65% of the patients in the U.S. are on prophylaxis today. Do you expect with an oral with this injectable-like efficacy that penetration of prophylaxis would increase in the U.S. and gradually European populations as well?
Yes. Our anticipation indeed is there will be growth in prophylaxis. It will never be 100%. There will always be patients that will prefer just to take on-demand therapy. But something in the 70%, 75%, maybe 80% range is certainly achievable. And as you rightly point out, having this ease of administration with an oral and have these injectable-like efficacies is an extremely compelling argument for patients to do that. So we anticipate that indeed to be the case. That said, also in on-demand, we do believe there will be growth. And I think the value there comes from the orals helping patients to treat attacks earlier and more. I mean, about 20%- 40% of the attacks today are not treated simply because A, patients don't have their medication with them, and B, they dread the painful injection with icatibant.
So again, that market will grow even though it's in the shadows, I would say, from the prophylactic opportunity.
Yeah. And that could start changing in the on-demand setting, that could start changing sooner as we see the impact of the oral launch from KalVista probably late now this year.
This year.
But that program and that product has some challenges in terms of the number of patients that need redosing and things of that sort. Obviously, you guys are now in phase III for both the on-demand as well as the prophylaxis programs, the CHAPTER-3 and RAPIDe-3 programs. Anything you can share in terms of study timelines and sort of expectations there? When might investors be anticipating updates on those programs and what could that look like?
Yeah, Jeff, as Wim has already initiated this topic, that when he introduced a program there. So basically for both our on-demand and the prophylactic studies in the phase III, right? The phases here. For on-demand, as mentioned, we initiated the study last year. Even though it's a highly competitive field, I have to say our phase II data is really encouraging as we just discussed. And also as our treatment is very well received by the community and by the patients. Therefore, I'm very happy to see that our phase III, that the RAPIDe-3 , on-demand, that the pivotal studies recruitment went very well. It's very consistent with our expectation. That's why we just announced our timeline. Even though the detailed timeline is very hard to manage because that's on-demand treatment, right? It also depends on the occurrence of attack.
But we would expect that our on-demand phase III, that the top line readout can be expected early next year. That means 2026. For the prophylaxis part, that we also achieved significant progress for our phase III study. As a public announcement, we have already initiated our CHAPTER-3, the study for our pivotal phase III prophylactic study, and we have already started the screening of the patients. And we would expect that this global trial will go as well as our on-demand, that RAPIDe-3 study because we have already received very good feedback from the sites and from the patients there. Therefore, we would expect even though that we have two or even three, some other phase III studies we just announced that for AAE study they're ongoing in parallel, but we would expect the prophylaxis top line readout also can be achieved around the second half, 2026.
Okay. Great. And I'm assuming, but don't know, that you could have patients in. Would you have patients potentially enrolled in both studies for the on-demand as well as prophylaxis? The same patient enroll in both studies?
Yeah, we did not release the details to the public, but indeed there is an option we provide to the patients after they complete the on-demand treatment. They can be considered for our prophylaxis study.
Okay. All right. In terms of, so we've talked about competition a little bit and reminding us on cash and cash runway, where you sit in terms of your ability to complete these studies with those 2026 timelines?
Yeah. As of September 24, it's the last time we made an announcement public. We had EUR 305 million in the bank. We announced also that would give us a cash runway into the third quarter of 2026. That will be beyond the readout of the on-demand phase III study and probably not beyond the one for long-term prophylaxis yet.
Okay. All right. Now, as we look at these studies, and I guess beyond the sort of pivotal readouts in 2026 and maybe recruitment updates, are there other updates we should be looking for in 2025 from you guys?
Yeah. Actually, for 2025, that's indeed a big strategic and execution year for us, for all the team here. That, as we mentioned here, even though that both the top line readout we expect in 2026, but for this year, we also have several key milestones. For example, we will wrap up our phase II open label extension study, extension study for on-demand. We also wrap up the CHAPTER-1 , our phase II extension study there. So that with that in the next few major conferences, we will gradually release more data regarding no matter for on-demand and prophylaxis, long-term, no matter efficacy, safety, quality of life data. Meanwhile, as we also just discussed, the team is very actively prepared for another pivotal study, acquired angioedema study for deucrictibant. That's a new indication that really addresses high unmet medical need for the patients, for the angioedema patients there.
For the details of this study, we currently still discuss with the agency. We will release more details once that we feel that all the design and finalize here. Yeah.
And could you talk a little bit about what is the opportunity in acquired angioedema? How are these patients different than the typical HAE patients? And maybe a little bit on those patient numbers?
Yeah, maybe go ahead, Wim. Yeah.
Yeah, maybe in terms of the opportunity, at the moment, the acquired angioedema population is assessed to be about 10% on top of type 1, type 2 HAE. But that's really because these patients, or we're dependent on referral of these patients from the physicians that treat their underlying condition to the allergist. Because contrary to the HAE patients, those AAE patients, they don't have a genetic mutation in the C1 inhibitor. But the C1 inhibitor gets consumed by the underlying condition, whether that's lupus, lymphoma, MGUS, myeloma. These conditions lead to a disappearance of C1 inhibitor. And then whenever there is a stress situation, there's a trauma, a similar and bradykinin-mediated angioedema attack can happen as in HAE. So physiologically, exactly the same as HAE, but the source or the kind of the reason, the cause for the attack is slightly different.
Our anticipation is, and the reason why we are very keen on this program is that if we can demonstrate in a pivotal program that deucrictibant works there and we obtain a label, that allows us also to kind of educate communities outside of the allergy community about this condition, which then potentially lead to an inflow of more patients or recognition at least of more patients with angioedema that could be managed through an allergist by using deucrictibant. So we see it as a very not only medical high-end medical need because nothing approved, but also potentially interesting opportunity commercially over the longer term.
Yeah, maybe I think that definitely that, Wim, that definitely is a great opportunity. But from the other side, when we talk with doctors, patients in the community, there's definitely a lot of requests there. That's exactly why we put our limited resources I have to say on this part. As mentioned, a lot of doctors and physicians that they have no access to treatment because there is no approved. Maybe some patients that can use the off-label HAE treatment. However, some work, some doesn't work because as Wim mentioned, indeed sometimes, for example, because it's absorbed quickly for C1 inhibitor, if purely supplement C1 may not work very well for this patient population. Therefore, we try to work with the community to think about it, how to address their need.
Meanwhile, that indeed can help raise the awareness because a lot of patients, because they're taken care by rheumatologists, by hematologists, by other different doctors, they may be not even aware of such kind of disease, such kind of indication. That's exactly that as we mentioned, based on really the unique mechanism for deucrictibant, we have only one target that downstream that B2 receptor there. We can cover more broad that bradykinin-inducing disease indication there. Therefore, in addition to type 1, type 2 HAE, as a team-wise, we think about it, whether other patients, just like we discussed acquired angioedema patients or normal C1 patients, they have no any treatment, but maybe potentially we can bring that normal treatment for this patient population.
Okay. And is the study given deucrictibant being used both for on-demand and prophylaxis in this setting for these patients? Would this be an on-demand for an attack or would this be a prophylaxis?
Actually, just the same as the type 1, 2 HAE patients, we would consider provide both options for patients, including both on-demand and prophylactic treatments.
For the study that you guys are getting ready to conduct, so would that be an on-demand study or a prophylaxis study?
We did not release the detail as mentioned. We still discuss with the agency, but if possible, we would like to provide both. That's our goal, to really provide as many options for our patients there.
Okay. And given this is an even smaller population potentially as patients are yet to be identified in many cases, does that provide an opportunity for an even smaller regulatory study or that this study could serve for approval? And obviously, the study's still in discussion, so speculating a bit here.
Yeah, I think that's a very reasonable speculation. Meanwhile, that all this, we need to get that discussion with the agency. As mentioned, there is no any approved treatment. There is any no that past precedent example, right? We can refer to. That's why that we really work dedicatedly with the agency to think about it, how we can address the need there. Yeah.
Okay. And I'd imagine given it provides some unique challenges in terms of recruiting for a study like this, given the low level of diagnosis where these patients are seen. But that said, with nothing approved, there's a high unmet need. So how do you guys think about and manage your recruitment strategy for something like this?
Yeah. Actually, Jeff, that's a really great question. That basically, even though that I have to say that's really the rare patient population, however, from our discussion with the doctors, with the patients there, they have strong desire to join clinical trial. That's quite unique that for this patient population, as mentioned, that's indeed a high medical need. Meanwhile, there is no available treatment, and we as a first AAE trial can provide to this patient population. Therefore, that we are very quite positive and enthusiastic about initiating this study. And we think our recruitment will be challenged, but will be manageable.
Okay. Guys, we are just pretty much up on time here, so I want to thank you very much for your time this morning or afternoon.