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

All right. Good morning, everyone. 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. Love to take a couple of minutes of our discussion here 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?

Yes. 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 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 attack but also for the prophylactic or the prevention of attacks. And we do that by developing 2 formulations. There's a soft gel capsule that very quickly gets absorbed and allows to mitigate symptoms. And 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 allow us 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. And 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 breakthrough with FIRAZYR, or icatibant, as a B2 receptor antagonist, were launched -- developed and launched by Jerini first in Europe and then sold through Shire/Takeda. We begin 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 their condition. And then '17 and '18, 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 write innovation and the value to the community here is that all of these therapies are forcing patients to make trade-offs between efficacy, tolerability, convenience and 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 is a little -- looks a little different. Would you mind commenting on sort of how the 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 of 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're in Latin America, Asia Pacific, on-demand 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 to 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 if bringing 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 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-label extension data and where you are in moving that through your ongoing pivotal study.

Yes, 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 in 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 and on-demand. But I think on the flip side, HAE has shown time over again that it's not the first product necessary that becomes the market leader. At the end of the day, there is a lot of influence from the patients 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 the 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 1 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.

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 how you're -- what time lines look like as you look to your Phase III?

Yes. So maybe I can speak about data and the positioning first and then let Peng talk about the trial time lines. We kind of captured our results from the Phase II in the open-label session as offering injectable-like efficacy with an oral product. I think that was really -- we were really amazed. 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% sac 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 with TAKHZYRO. And 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. And 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 an injection if you can achieve the same efficacy with an oral? And 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's stuck with injections because they didn't want to compromise on the efficacy. And if you then come with something that has similar efficacy, that might be an attractive alternative. So I think we are 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 we can probably get into that. One is we've seen really significant uptake from Orladeyo as the first oral approved in a prophylactic setting. Maybe surprised -- somewhat surprising due to the lower efficacy, substantially lower efficacy than TAKHZYRO. And so with you coming forward with TAKHZYRO-like efficacy within 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?

Yes, maybe Peng?

Yes. Maybe I can start to share what we observed from our Phase II and also open-label extension data and hope to pave the way. Wim, you can show, right, our value and our position for deucrictibant. So as we know from our Phase II is double-blinded, right, a placebo-controlled trial. That's exactly as Wim mentioned. We have to set 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 of 85% around that range, that for attack reduction and also for moderate, severe attack or required rescue medication, deucrictibant even achieved over 90% to 93% reduction. That pretty much means that if patients take deucrictibant as a prophylactic treatment, that's 1 attack per year, still needs the rescue medication there. So that's really a very good efficacy result from prophylaxis part. Meanwhile, that from the open-label extension data we shared the last year, also the patient will treat up to 18 months. Maybe in the coming quarter, we will share more data there, that we can see that the patient, 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 6 months, attack is medium tag is 0. That's really compared to just, as you mentioned, in the open-label extension data is still around 1 attack per month here. So that showed dramatic difference. And also all the data show no matter the patients who have frequent attack, for example, more than 2 attacks per month or less 1 attack per month, deucrictibant showed very equally that a reduction, 80%, 90% reduction protection there. The last but not least I want to mention is that sometimes that all the physicians always ask how about the compliance, right, of the treatment or treatment compare injectables? From the open-label extension data, I think that we are very happy to see the compliance went very well, does reflect really to see that the efficacy data, safety data and also the quality of life data, that 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.

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. As you rightly point out, having this ease of administration with an oral and have this injectable-like efficacy 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% to 40% of the attacks today are not treated simply because: A, patients don't have the 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.

Yes. 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. But that program -- 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 and the -- as well as the prophylaxis programs, the CHAPTER-3 and RAPIDe-3 programs. Anything you can share in terms of study time lines and sort of expectations there? When might investors be anticipating updates on those programs and what could that look like?

Yes, Jeff. As Wim has already initiated this topic that we introduced a program there. So basically, for both our on-demand and prophylaxis studies in the Phase III, right? For on-demand, as I 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 an oral treatment is very well received by the community and by the patients. Therefore, I'm very happy to say that our Phase III, that RAPIDe-3 on-demand the pivotal study, the recruitment went very well. It's consistent, very consistent with our expectation. That's why that we just announced our time line. Even though the detailed time line is very hard to manage because the 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, this means 2026. For the prophy part that we also achieved a significant progress for our Phase III study, as public announced, we've already initiated our CHAPTER-3 study for our pivotal Phase III prophylactic study. And we've already started the screening of the patients. And we would expect that this global trial will be wound as well as our on-demand that RAPIDe-3 study because we've already received very good feedback from the sites and from the patients there. Therefore, we would expect, even though that we have 2 or even 3 some other Phase III studies, we just announced that for AAE study there ongoing in parallel, but we would expect the prophy top line readout also can be achieved around second half 2026.

Okay, great. And I'm assuming but I don't know that you could have patients and -- would you have patients potentially enrolled in both studies for the on-demand as well as prophy, assuming patients enroll in both studies?

Yes. We cannot release details to the public, but indeed, there is option we provide the patients. After they complete the on-demand treatment, they can be considered for our prophy 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 time lines?

Yes. So as of September '24, it's the last time we made our announcements public, we had EUR 305 million in the bank. And that, 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 1 for long-term prophylaxis yet.

Okay, all right. Now as we look at these studies, and I guess beyond the sort of the pivotal readouts in '26 and maybe recruitment updates, are there other updates we should be looking for in 2025 from you guys?

Yes. Actually for 2025, that's indeed a big strategic and execution year for ours, for all the team here. As we mentioned here, even though that post 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 for on-demand. We also wrap up the CHAPTER-1, our Phase II extension study there. So that we know that in the next few major conference, we will gradually release more data regarding no matter for on-demand and prophy long term, no matter, efficacy, safety, quality of life data. Meanwhile, as also we just discussed, the team is very actively prepared for another pivotal study, acquired angioedema study, for deucrictibant. That's a new indication that really address a high unmet 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 finalized here.

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.

Go ahead, Wim, yes.

Yes. I mean, 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 were dependent on referral of these patients from the physicians that treat their underlying condition to the allergists. 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 is a trauma, a similar bradykinin-mediated angioedema attack can happen as in HAE. So physiologically exactly the same as HAE but the source or 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 is deucrictibant works there and we can 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 to 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.

Yes. Maybe I think a different way that Wim said definitely, they're a great opportunity, but from the other side, when we talk about the patients in the community, that's definitely a lot of requests. They are exactly why we put the limited resources, I have to say, on this part. As I mentioned, a lot of doctors and physicians, they have no access to treatment because there is no approved. Maybe some patients can be used for the off-label HAE treatment. However, some work, some doesn't work because as we 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 how to address their needs. 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 such kind disease, such kind of indication. That's exactly that, as we mentioned, based on really the unique mechanism for deucrictibant, we are the only ones that target downstream B2 receptor, we can cover more broad the bradykinin and the disease indication there. Therefore, in addition to type 1, type 2 HAE, as a team, why we think about it, whether other patients, just like we discussed acquired angioedema patients or normal C1 patients, we have no any treatment but maybe potentially we can bring that novel treatment for this patient population.

Okay. And is the study, given deucrictibant is 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, we just seen, as the type 1, 2 HAE patients, we would consider providing both options for patients, including both on-demand and prophylactic treatment.

And for the study that you guys are getting ready to conduct, so would that be an on-demand study or a prophylaxis study?

We do 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 here.

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 is still in discussion so speculating a bit here.

Yes. I think that's a very reasonable speculation. Meanwhile, all this, we need to get that discussion with the agency. As mentioned, there is no any approved treatment. There is no past or present example, right, we can refer to. That's why we really work dedicatedly with the agency to think about it how we can address the need there, yes.

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?

Yes. Actually, Jeff, that's a really great question. 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, we have strong desire to do a clinical trial. That's quite unique for this patient population. As I mentioned, there's indeed a high unmet medical need. Meanwhile, there is no available treatment and with the first AAE trial can provide to this patient population. Therefore, 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, Wim. And really wish you the best of luck with your continued meetings during the conference. Thank you very much for taking your time.

Thank you, Jeff.

Thank you.