Trying to keep running on schedule here. Good afternoon, everybody. Thanks for joining us for a session with Pharvaris. My name is Jonathan Wolleben, Senior Analyst here at Citizens Life Sciences at our 2025 conference. We have Peng Lu and Wim Souverijns.
Good. Good enough.
Head of medical and head of commercial, so it's a perfect time to jump into hereditary angioedema. Cat's out of the bag, but tell us what you guys are working with because you guys have a little bit of different spin on the space and what you're targeting. You're blazing a path forward with the mechanism, and I'd love to learn more about how you guys are thinking about the differentiation. I'm not sure who would like to jump off, but maybe talk to us about deucrictibant and how you guys are different in the space.
Yeah. Actually, maybe I will start since you mentioned the mechanism part. We will start from the science and medical part, then we will go to the commercial part. As maybe everyone knows that HAE is definitely a highly competitive field, even though it's a rare disease here. So far that compared to all available treatment or currently the ongoing treatment, that all this, the new treatment here is targeted on the kallikrein-kinin system, no matter for Factor XII inhibition or prekallikrein or kallikrein there. Compare all this upstream, that target or upstream, the products there and the deucrictibant actually is a bradykinin B2 receptor antagonism. It's sort of like the compound maybe someone of you know, icatibant. It's oral treatment and the target of the B2 receptor is more downstream.
That currently from the science part, we consider that one molecule and have two different formulations. One is called immediate-release formulation. It can reach the plasma exposure level really within the 15 minutes. It will be great for the rapid onset and the oral treatment. The other is the extended-release formulation. We can cover the 24 hours exposure range with one daily treatment. Based on this, we will have the one molecule, two different formulations cover the oral, the two efficacy, safety, and convenience that all three parts in our phase II data. That's from the current available phase II results here.
In addition, I want to also highlight, because we are more downstream compared to others, we have broader patient coverage or broad indication because we are not only treat type 1, type 2 HAE patients highly depend on plasma kallikrein-kinin system, but also potentially type 3 patients is some of the genetic mutation is plasma kallikrein-independent pathway there. Therefore, the deucrictibant in addition to the three part we just mentioned, also can have broad patient population and can provide the new treatment for patients we still have high medical need there.
Can you talk about the differentiation from the plasma kallikrein inhibitors, which we have a lot of today? I think just mechanistically thinking about the efficacy, it makes sense, but we also get questions about long-term safety, and I think that might just be a function of a new mechanism and probably people who like the other stories more are saying, "Wait till something happens." Talk about what's giving you more confidence in the long-term safety of bradykinin antagonism today versus what we knew five years ago.
That's excellent question, Jonathan. Because as mentioned, icatibant as the only B2 receptor antagonism molecule there, is only on-demand treatment. As you mentioned, people always ask, how about the long-term proper use, right? Block this receptor. Compared to the five years ago, as mentioned, icatibant first had been used over 10 years, have a lot of really the clinical practice there to show that this mechanism is well-tolerated and safe, even for certain different patient population there.
The second we have to say, for the deucrictibant here, that even for our phase II result, for example, the CHAPTER-1 results that we've already accumulated the safety and the tolerability data up to two years now, and the deucrictibant is a very well tolerated, and that's direct evidence to show even though we agree still small sample size, but up to two years, deucrictibant was very well tolerated and no any treatment-related signal was observed.
Can you talk about your pre-clinical tox package and where you guys are in that development?
Yes. Far that we've already almost complete all the tox package, no matter to support on-demand or proper filing later on.
All right. That should give everybody a lot more confidence in long-term safety. We cover a few HAE companies, and no one else has both an acute and a prophylactic. Wim, you got the heavy lifting. Talk about the evolution of those two different markets and the interplay between the both. Can you tell us how has this changed and how could you guys fit in?
I think the beauty is that, as you said, we have one product, one drug that can work in the two settings. Very different in how this market really evolves. What we do see from the market and what we see from the guidance from the academic and the scientific community is that no patient should suffer no attack. The only way to do that is through prevention. We know that today already, in terms of number of patients, 62% of the market in the U.S. is prophylactic. That is even more than that. We anticipate that to grow. We anticipate that is it 70%, 75%, 80%? Who knows? We don't think that that will retract. Whatever is happening in the market, there is big expectation on all on-demands, but I don't think that will fundamentally change the dynamic, which is to go to more prevention.
I think in each setting, it's really important to offer a value proposition, to offer a profile that really can stand out. I would say there's been tremendous progress in HAE, particularly on the prevention side in the last 10 years. For me, good is the enemy of great. When you look at the market today, whether it's on-demand or prophy, patients have to make a choice. They have to make a trade-off. Either they say, "I absolutely want to have efficacy." If you want that, you have to go for an injectable. If you're willing to give up on that, you say, "I prefer the convenience of an oral. I don't want to stick myself with a needle," you have an oral option. You have no product that offers injectable-like efficacy with all the profile in convenient daily oral dosing.
That's, I think, where we make a difference, both on-demand and on prophy, where we have a package, if we confirm that obviously in our phase III, which is critical, that really stands out, and that will entice a lot of patients to make that choice. We hear very often people say, "Well, it's a sticky market." Reality is not. We know even in this market where there is not much change, 5% of patients every quarter are switching therapies.
That will increase if there are more entries. If you have alternatives in front of you can make that choice. I think I'm very confident. We're very optimistic about if we can repeat the data from the phase II and the phase III, that this will be a very competitive profile.
I agree that we see a willingness to switch and adopt new therapies, but also we do see some stickiness to like CINRYZE and HAEGARDA or some of the older drugs. What's going on there? Why aren't those going the way of the dodo?
It's frankly, we call it a dying race, but Kalbitor's the same. These are patients that have been on Kalbitor for 10 years, 15 years, and they just don't want to give up. They don't want to change anything. We'll see that's going down on the.
It's a minority.
Exactly. That's going to be. Yes.
Maybe we should dial in on acute first. Can you talk about the Phase II data you guys generated and what you saw that gets you so excited?
We definitely have very exciting data, phase II, on-demand, the treatment data there, and we show that overall that with even though it's oral molecule, as mentioned, because of fast absorption there, we show that the time to onset of the treatment relief, that there is about one hour, 1.1 hours there. Even before that, I have to say, some data we just released for end of progression, the first sign patient feel the drug being effective is only around 25 minutes. Go beyond it, deucrictibant also show dramatic good sustained effect. That means that with only single treatment there, we show the time to substantial symptom relief is around two to 2.6 hours there. The resolution, complete resolution, it shows that within 12 hours. All this, we also that people think is only the oral, right, icatibant.
To be honest, we agree that it provide convenience and show that great, that the treatment option for patients. Meanwhile, from efficacy side, compared to icatibant data, we also say it's maybe not only just the oral one, but it's a better one.
You guys have given us a lot of data, and sometimes it's hard to parse through what's important. There's time to symptom relief, time to stopping progression. What's the important thing that people should look at when they're thinking about the acute data?
I think what's really important for me.
Maybe from a clinical trial perspective, and then what do patients care about in the real world or physicians care about if those aren't the same thing?
Well, I think they align, but I think ultimately what matters for the community is the area under the symptom curve. You know from our corporate deck, we have this picture of an attack. When it happens, when you treat, how we then see end of progression, and it goes to complete resolution.
It's not enough to be very quick in the plasma and have a first stopping attack in early onset of symptom. You have to go the whole way. I think that holistic package of making sure that this area under the symptom curve, that's minimized to the maximal extent. That's really what the value is that patients and doctors are looking for. That's why they will put out the comparison with injectables because whether we like it or not, sevelamer and icatibant, they're pretty good. What Peng was describing is the data we have is indirect treatment comparisons. We can see that deucrictibant can really have an impact, not just in the beginning but over the whole course of an attack.
How important is it treating early? Do injectables work slowly or less slowly just because they are used later in an attack?
Working quickly is absolutely important. The benefit of an oral is I can sit here next to you, I feel an attack coming, and I pop a pill. It's super fast. You need to have your pill with you, but if you have that, it's super fast. Most patients on injectables don't have their medication with them. That is the first burden. The second burden is you need to find a place to inject yourself.
Do you mean like a location or a body part?
Body part is probably in kind of no doubt.
Yeah.
The location. We heard a story. We had a patient actually come to our office talking about she's on an IV. She says from the moment that she's in the car, she's at an event, she has an attack, she has to find her car. From the moment she's in the car, she has her kit. It takes an hour to infuse the drug.
That's a massive time that you lose compared to oral. Now, for a trial perspective, I think it was really critical what Peng did in terms of qualifying attack because we really demonstrated that the drug works in attack. In real life, it's completely different story, and I 100% align with KalVista. Bell's early onset treat right away.
One more thing I would like to add is also for injectable, it's because that, especially the most popular injectable, that it's very painful. The inject site pain is a big factor, actually prevents the patients even treat acute attack. Patient even evaluating which one is more painful, is my swelling or my attack here?
Interesting.
It's really the injectable pain from the treatment here, right? That's another layer of the treatment burden for patient to overcome. That's exactly with oral treatment here, this burden is much less or zero here. Hopefully it can benefit most patients here.
Remind us of your phase III trial that's ongoing, the design, how things are enrolling, endpoint, timing of data, all the good stuff?
That's a big question. Indeed, I have to say that our phase II trial for on-demand, that RAPIDe-3 study went very well. We've already made announcement that we complete the target enrollment, and we expect the top-line readout the first half of the 2026. Currently, team is closely monitor the attack because it's time to event, right? Really the attack assessment there. We maybe update more, give more update regarding the readout soon. The team still evaluate that all the study here. As mentioned, that from the primary readout, that for study is a onset of symptom relief. Meanwhile, we have a serious secondary endpoint. Just as we mentioned, is not only onset, but it's really area under the symptom curve. We will definitely show that even that repeat the symptom relief, resolution, single dose use, all these are very important factor to evaluate.
How the studies were run 10 years ago versus today are different. How should we think about what you need to show to get people excited? I think the expectation should be that the trial's going to be successful versus placebo, but it's going to be how meaningful is that result. How do you think about what's good data in this readout?
I think that we can say if the phase III data is as good as our phase II, I think it's definitely the very exciting news for patient. Compared to the past, all the patient have to drive to the center to get a treatment, to evaluate. For our phase III study right now, it's really home setting. The patient just take medication, qualify the attack by the call with the physician, and get the treatment. It's more like a real-world setting there. In addition, we have our RAPIDe-2, that open label extension is completely like the real world evidence generations that settings. All this data put together, we think we will provide a very good picture there.
What goes into adjudicating an attack? Is it just calling and talking about the symptoms, or is there a specific criteria that require the treatment?
We do. We have specific criteria. Just mentioned the patient do have to demonstrate that they have swelling there. It's not like a prodrome of the attack, for example, headache or some prodrome there. The patient will really talk with doctor to say that they have either peripheral swelling or abdominal pain, or maybe some patient have laryngeal attack there. Confirmed that the physician confirms that's an attack, then they will treat.
When we think about the on-demand acute opportunity, what does that look like? Because it was a fairly large market when FIRAZYR was a branded drug, a genericization, and then more prophylactic drugs coming. What's kind of the evolution there, and what do you think the opportunity is?
If you look at data at the moment, I think these are data from Q4 2024, about 62% of the patients are on prophy. The complement is on-demand, it's a smaller proportion of the market, the value is even lower. It's 21% of the value of HAE comes from on-demand. It's definitely not the biggest segment there is out there. We anticipate, as I mentioned before, that the prophylactic will still grow. Small, fast, we'll see, but with new entries of products coming in as well, I think there will be some push behind that. I don't anticipate a move back to on-demand. Now, that said, we also believe there is opportunity in on-demand, the reason is to what Peng was describing earlier, between 30%-40% of the attacks are not treated.
The patient has left hand swell and they're right-handed, and they know what it takes to inject themselves with the icatibant. They say, "You know what? I'm not treating." If you have a capsule, why would you not treat yourself? There is a lot of impetus from the physician community on this as well, and it's very telling. At a patient meeting, I was talking to a doctor and he told me that, "I'm really frustrated because I thought I was clear to patients that they should treat all attacks, but they don't. It's a joint effort from the whole community to really drive that further, and that will be enabled by effective oral therapies.
Do you think there's going to be pricing pressure then because of the lower prices there?
Sorry, in terms of?
In an acute setting with generic icatibant available, does that kind of limit the opportunity or does the value proposition still stick?
We actually did a payer ad board last year with about 230 million lives covered for the payers that were there. When they saw the data, they were, "Wow, if you can repeat this is a big deal." Their anticipation. There is indeed generic in U.S. market. It's not a real hurdle for uptake for better medicines. You got to obviously, if you have not the same efficacy, it's a different story.
Yep.
I think if you look at the holistic package that we bring and being oral, there's a lot of advantage associated with that. Payers will probably on an individual basis, sometimes there is abuse. I mean, I heard from one of the KOLs saying, "I limit my prescriptions to two months because I had a patient who was taking icatibant every two days. That's abuse.
Yeah.
Besides that, payers are relatively standoffish in terms of managing HAE at this stage.
Okay. I want to pivot to prophylaxis. Can you talk about the data you guys generated in phase II? You mentioned injectable-like efficacy. What is that?
In our phase II study with the placebo-controlled settings, the data showed that compared to placebo, there are 85% attack reduction for all the attacks. Meanwhile, for moderate or severe attack, this reduction up to over 92% and also over 92% attack reductions at attacks who needed that on-demand treatment. That's in our placebo-controlled trial. With the open label extension study there, that up to almost two years, the data showed a 93% attack reduction for the overall baseline attack there. That really compared to the injectable-like efficacy that they demonstrated in other treatments. We do have strong belief that even though it's oral treatment, it can reach with injectable-like efficacy as the data tell us.
Can you talk about your phase III design for prophylaxis?
Actually, for prophylaxis, all the study design that is quite comparable. It will be six months treatment, placebo-controlled, and we targeted to enroll around the 80 patients there, 81 patients, try to encourage the enrollment. Our active placebo ratio will be 2: 1. Therefore, that the patient have a higher chance to get the active treatment.
When do you think you get data from that trial?
Currently, we expect the second half of 2026.
I was thinking about this either today or yesterday. Have we ever seen a phase III prophylactic study fail?
I don't think so.
At least not-
Only type 1, 2.
Yeah, I don't think so.
Yeah.
This trial should work, and again, it becomes how does this look comparative, right? Again, do you just want to see what you did in phase II? Is there an opportunity to enrich the population to show better efficacy? Do you expect to see migration? What do we see when we go from phase II to phase III, typically?
I think you mentioned a very good point, Jonathan, that the translation from the phase II to phase III is really high for HAE, as mentioned. Also, the study design is similar from the phase II to phase III. For us, I think one thing we really want to highlight for our phase III study, we would use extended-release tablet, our to-be-marketed formulation in phase III. Compare the formulation we use in phase II. Actually, this formulation even further optimized that is a peak to trough ratio, and it provide even more that 24-hour that exposure coverage there. Therefore, that it gives a buffer that some maybe we get the questions of variability.
For phase III trial, will be higher compared to phase II, but with that really very sufficient or even better or high that C trough of the exposure coverage there. We expect the efficacy from the phase III study at least comparable, even better.
I think that's a really good point. I'd recommend people take a look at your corporate deck showing those PK curves, because usually you go to phase II, phase III, don't change anything. The change you guys made actually gives you better drug coverage for a longer period of time. I think that's a really important point to keep in mind. I'm glad you mentioned that.
Exactly. Yeah.
When we think about the prophylactic opportunity, we have TAKHZYRO, the market leader that's doing very well. ORLADEYO keeps taking share and selling well, despite efficacy not on par with injectables. How do you guys think about that dynamic for you guys? Because you're going to be an oral, and it seems like you have a wide window where there could be success.
Yes, absolutely. We were very pleased when we saw the update from BioCryst this week. I think it's testament to the need of having oral in the prophylactic setting, that's really reflected in their forecast. I think it was very interesting how they showed how the patients today have a higher preference for an oral when you ask them than a couple of years ago. It went from 35% to like 70% of patients all want to have an oral intervention. I think that bodes extremely well for us because what we can bring if we confirm our data in the phase III is on top of that, we have the injection at a different level, meaning at the level of a TAKHZYRO and HAEGARDA.
I think that really offers as a great opportunity and also means that we anticipate that in equilibrium, in the HAE prophylactic market, orals will be dominant. Is that 55%, 60%? Who knows? I mean, crystal ball. We think it will be dominant, and I think we have great cards to really be the dominant leader in the oral segment in that respect. New patients, they should go onto XR because if you can start on a drug, why would you go into an injection if you can get the same efficacy with an oral? There are a lot of patients that tried ORLADEYO. By the time we launch, around 1,000 would have done that and left ORLADEYO.
A big pool of patients. Even those patients on ORLADEYO today, they still have breakthrough attacks, and each time, that's an opportunity for us to step in and say, "You know what. Switch.
Why do you think that there was that increased preference for an oral? What changed? Do you think either I prefer it and I always preferred, or is there something that.
I think there's maybe some psychology, because I remember my grandmother when injection was given, oh, that must work. That's a serious A pill was like, "Oh, yeah. It's like.
You're doing something more, harder.
Yeah. I think that's maybe a perception that has been in people's heads, but now they see, you know what? Actually, there's a lot of peer-to-peer interaction. HAE is a really great community. Patient meeting in Baltimore in beginning of July will bring together 1,200 patients. They talk, they exchange, and so building that confidence. Some people want to take that first step, other people say, "I'm going to wait a little bit." That's probably behind that preference change.
We covered a lot of ground, and maybe just to put a button on everything, can you talk about your current cash position and then remind us just of the timing of your readouts, just to give some context for investors?
From a cash perspective, end of December 2024, we had EUR 218 million in the bank, which is important today.
For the readouts, for our on-demand, as mentioned, our pivotal readout will be Q1 2026. For prophylaxis, will be second half of 2026. Meanwhile, we also want to mention and highlight we also will initiate acquired angioedema pivotal study by the end of this year. Therefore, deucrictibant, as we mentioned earlier, our target population is not only HAE. We target a broad primary needed angioedema. That's including HAE Type 1, Type 2, even Type 3 HAE, and also acquired angioedema.
Which is differentiated again.
Absolutely. Yes.
Well, Wim, Peng, thanks so much. We're going to see you over here on Pharvaris, and we look forward to tracking the progress. It's going to be an exciting time coming soon.
Thanks so much.