Pharvaris N.V. ($PHVS)

[Audio Gap] biotech analyst at the firm. It's my pleasure to have with us our next presenting company, Pharvaris. Up on stage with me are 2 members from Pharvaris. Thanks for making the trip guys. We've got David Nassif, who is Chief Financial Officer; as well as Maggie Beller, who is Head of Corporate and Investor Communications. Thanks, guys, again for flying over from Boston. So maybe we can start off with an overview of the company before we go into some specifics about updating on catalysts.

Sure. Well, first of all, thanks for inviting us. We really appreciate it and also the opportunity to have a chat with you. Before we get into the overview, maybe for those of you that don't know, this week, we priced a $132 million underwritten offering, which takes our cash runway into 2028. So now both launches, both ODT and Prophy are fully funded. Any overhang on the stock completely lifted. So we're looking forward to future data and approvals. As to the pipeline, I guess there are basically 3 updates. On ODT, we are on track for the first half of 2026 filing of the NDA on -- as it pertains to prophy, we are still on track for top line readout by Q3 2026. And then on AAE, the enrollment is progressing well. So if you wanted to talk about differentiation of the products, basically, our story is we are a portfolio strategy at this point, where patients, payers professionals know they can use our products for a vast array -- or will be able to a vast array of indications. We have a single molecule supporting 2 formulations. We have once-daily dosing, we think, for the vast majority of cases. And so far, we've shown superior efficacy in ODT.

Okay. Great. So maybe we can go into a little bit more detail on some of these items that you just mentioned. So on demand, can you just remind us what the takeaways from the top line data were for the RAPIDe-3 study?

Yes. Thanks so much, Tazeen. So we read out our RAPIDe-3 top line data in December of last year. Out of that, we were pleased to hit our primary endpoint and all 11 key secondary endpoints with statistical significance in a hierarchical fashion. So that from our bio stats colleagues is very hard to do because if you miss the stat sig on one, you don't get it for any of the subsequent ones. What we are really proud of is that across the entire attack trajectory, we were able to show rapid onset of symptom relief, complete symptom resolution and single-dose durability. So there are some key endpoints within our 12 that I just talked about, including end of progression, which is the first time somebody stops feeling worse. It's a really important psychological moment for a patient because they know their drug is working. HAE is a stress-induced disease. And so if you're able to relieve some of the stress and anxiety, that could help you come to attack resolution faster. We were able to put end of progression at 17.5 minutes. We are the first and only group to have done that in a prespecified manner. So depending on how our discussions go with the FDA, that could, in fact, be included on our label. Next is our primary endpoint. That is time to symptom relief as measured by PGI-C a little better. We were able to show that deucrictibant works at -- in about 1.28 hours for that primary endpoint. Next is substantial symptom relief. This, once again, is when people are able to kind of get back to their normal life, whether that's you're able to go to the grocery store, you're able to get your haircut, you're able to just get back to living. We showed across 2 different endpoints about 2.5 hours for that. And then lastly is complete symptom resolution. So that is when you are no longer experiencing any symptoms. Deucrictibant was able to do that in less than 12 hours. That's really important because that means that somebody, if they feel an attack coming on at 7:00 p.m. at night, they could take a single dose of deucrictibant and be completely symptom-free by the time they wake up in the morning. You can get on a plane and feel better within 12 hours, right? That is just really impactful for patients, for physicians. So we think across the board, those are really key endpoints. And lastly is our single-dose durability. 83% of people were able to achieve these efficacy findings with a single dose of 20 mg deucrictibant. So all of those things, I know there's a lot of data, but we think that, that really across the board differentiates us not only from standard of care, which is deucrictibant, but also from a recently approved oral.

Okay. So maybe can you just talk us through what the demand in on-demand is just given that the prophy market continues to grow. There's continuingly new launches you expect to be one of them over time. But maybe can you talk to us about the latest market data that you have on TAM and some important metrics like what are the average number of breakthrough attacks patients having even if they're on a prophylactic drug?

Yes, that's a great question. So as we look at the on-demand market, I think we can say holistically, we think that the entry of an oral should actually grow the number of attacks that are treated because the treatment barrier is so much lower when you have an oral. Before there was this recently approved oral, people would need to excuse themselves, inject themselves, it's very painful. There's all sorts of stigma associated with injections. And we believe by removing the challenges around discretion, around portability and oral should allow people to treat more attacks. So before the summer of last year, about 70% of attacks were treated. That leaves 30% that are untreated. So we think that there could be more attacks treated. However, as you said, there have been recent oral -- recent entries in the LTP space that are really putting up great efficacy numbers. You've got 80% to 90% attack reduction. Based off of our open-label extension data, we think that deucrictibant could have less than 1 breakthrough attack a year. So there could be a bit of an increase and then a decrease as you think about more attacks treated. In 2025, there are about 87,000 doses given. And that's an important distinction because some people require multiple doses to be able to completely address their attacks. So some standard of care takes 2 to 3 vials. We know that the oral takes -- about 38% of people have to take a second dose. So we believe that the total attacks treated is probably a little bit less than the number of doses taken. But once again, that's a flexing number right now as we think that there could be more attacks treated in the future.

Okay. Now can you talk about the heterogeneity of HAE and the type of attacks patients have? If they tend to have one type of attack, is that what they tend to get most of the time? Or can it be any variety of parts of the body that are impacted by an attack?

It's a great question. So when we think about an HAE patient, a person can have changes in their HAE throughout their lifetime, right? It tends to be stress-induced, as I said, hormonal changes can cause either more frequent attacks or more severe attacks. So somebody who -- even for me, you can have one attack that is a mild attack, maybe it's a peripheral hand swell. And then the very next attack could be a laryngeal attack, which is potentially life-threatening. So as you go throughout your life, that can change over time. That's one of the benefits of deucrictibant is this ability to be able to address attacks depending on how a person and their physician decide to treat their HAE. At some point, there may be a situation where people don't want to be on long-term prophy all the time. And so you're able to quickly come off of deucrictibant XR and switch to maybe just treating on demand. Also important for women of child-bearing age or who are breast feeding, you shouldn't be on an HAE medication if you're pregnant or breast feeding. And so the ability to come on and off therapy is a unique selling point of deucrictibant's.

Okay. And then in terms of types of attacks, are there ones that patients feel like I don't need anything for this so if my pinky is swollen, I can deal with it. And if that's their current way of thinking, do you think that having an option like deucri could change their mind?

That's a great point is that we -- in fact, our goal right now is to change treatment expectations. Right now, somebody may, as you said, get a peripheral hand swell, it could be their left hand, I'm right-handed. You know what, I'm just going to deal with this because I'd rather save my medication for my next attack, which could be an abdominal attack, which is super painful, laryngeal attack or something that impacts my life more. As we said, with the decrease in treatment burden of an oral therapy, we believe that those decisions that people have to make when they forego treatment could be lessened if you're able to have something that's discrete, that's portable, that's easy to take, easy to swallow. And like I said, what we believe outperforms standard of care, though no head-to-head studies have been conducted.

Okay. So you do have a comp in the market, a recently launched comp of an oral for on-demand I'm sure you guys have been following that. What are you learning from that? And where do you think deucri can potentially perform better?

Great question. We believe EKTERLY's launch has gone really well. It confirms what we and the sponsor of EKTERLY had said beforehand, which is that there is a severe unmet need for oral therapies in on-demand. We think that they've done a great job being able to capture that market. For us, we view the on-demand commercial opportunity in 3 main segments. One is the people who are on icatibant right now, deucrictibant and icatibant utilize the same mechanism of action. However, deucrictibant is more potent than icatibant. That means -- and it has a longer half-life. That means that, as I was saying before, some people who take 2 to 3 vials of icatibant to fully treat their attack could now do that with just a single pill. So if people have been using icatibant since it was launched in the U.S. in 2011, they've built a trust in the mechanism. And now we can go to them and say, this is the same mechanism. It works for you because this is at the bottom of the HAE cascade. However, it works in a single pill and it's oral. So that's sort of that first segment that we think we can go after. The second segment is people who are on a C1 replacement right now. The way that people are utilizing C1 replacement is to address patients with normal C1. So mechanistically, this shouldn't work, right? If you have normal C1, you add more C1, doesn't really work. However, that is an infusion that's done with a health care practitioner. So if there is a risk of an attack progressing to a laryngeal attack, which could cause association, at least there's a health care provider on site. We believe that with the mechanism of deucrictibant, our data in normal C1, which showed equivalent efficacy from normal C1 to type 1 and type 2 that, that whole 20% of the HAE market that's currently unserved could work well with deucrictibant. And then lastly, as you said, EKTERLY is the oral that's on the market right now. We believe that although not head-to-head studies, we believe we have a differentiated profile there. We approach that market in providing people with a risk-free trial of treating their on-demand attack either with deucrictibant or if they're using EKTERLY, you can just say, try it once and see how your attack progresses. We've heard anecdotally that for physicians and patients who participated in both the Phase III study for confident and our Phase III study, RAPIDe-3, that there is a marked difference between these 2 drugs. We want people to experience the -- the 17.5 and the progression, the less than 12 hours complete symptom resolution, the single dose durability. And we think that with this differentiated profile that, that's how we're going to capture those oral switches as well.

Okay. So the 3 subgroups that you just mentioned to me, which are the ones that you think will be the fastest to onboard?

Based off of the mechanism, we believe that the icatibant switches and the RUCONEST switches are going to be the fastest. It will take more effort to be able to get in front of people who have already tried EKTERLY. That's probably the largest opportunity, but also maybe the more difficult to switch.

Okay. Got it. Now as you think about what type of commercial organization you'll need, assuming that it will be -- this launch is first and then prophy after, how big of a footprint do you think you're going to be needing?

So I'll take that one. We believe that by the end of this year, we'll have 70 people in commercial, ready to launch on demand sometime in '27. And then we think that we're going to need another 20 by the end of '27 to fully address the prophy market. So 90 people ultimately over the course of 2 years.

Right. And have you started the process of identifying people? And...

Oh, yes.

And then when would you start to hire people?

Yes, the sales force will come, call it, Q3, Q4. Some of the more senior people, we probably already hired 3 or 4 this year, and there are another 3 or 4 in the mix. So it's happening.

Okay, got it. And then from the time you get approved, let's say, your PDUFA is on a Tuesday, would you be able to launch on the Wednesday?

Well, the goal is to launch as soon as possible thereafter, which is why we want to make sure -- everyone's been hired and trained and product is available and we're ready to go. So we're hoping that it's virtually instantaneous.

Good. So maybe let's move on to prophylaxis. So maybe give us an update on the timing for the top line data that you're expecting to show us. Is it this summer?

Third quarter.

Third quarter. Remind us the design of the study and what would be good data or clinically meaningful data rather?

Absolutely. So our Phase III study is a global study. We enrolled approximately 81 people in a 2:1 fashion. So that helped us with approaching people that there was a higher likelihood that they would be on active drug. Our global footprint included the U.S., Europe, APAC, LatAm we included type 1, type 2 and normal C1 participants as well as adolescents, so 12 and up. The -- like I said, guided towards data in the third quarter. Now leading into our CHAPTER-1, our Phase II study, we had done some market research of what would be a meaningful efficacy number for us to be able to own the oral segment. Our market research indicated that we would need to put up at least 70% efficacy for percentage of attacks reduction monthly. When we flipped over the CHAPTER-1 data, we were happy to see 85%. That put us squarely within the other injectables in this space. Right now, those injectable numbers are between 80% and 90%. Our goal would be to replicate that Phase II data. So if we could be between 80% and 85%, we think that, that not only significantly gives us ownership of the oral segment, but also enables us to compete with injectables. And then I can sort of talk about maybe our 4 segments that we have in the LTP space as well. So we know that 80% of physicians will start naive patients on an oral therapy, if all things are equivalent, efficacy, safety. So in the U.S., there are about 200 to 250 new HAE patients each year. If we're able to capture 80% of that, 200 and keep them on therapy, then each year, that's 200 stacking on top of one another. Now of course, we're not going to keep 100% of every new patient. But unlike another approved oral, which has about a 60% retention rate, we think we can be closer to 90% if we're able to put up our 80% to 85% efficacy. So that ends up just being a pancake effect over time. The next segment is people who have tried an oral but come off of it. Based off of those retention numbers I was just stating, if 40% of people each year drop out, we believe by the time we could potentially get to market, there are 1,000 people who have tried an oral and come back off of it. So that's 1,000 people who have indicated they want an oral, but for whatever reason, efficacy, tolerability, they've moved back to their injectable. If we're able to go to those people and present an equivalent efficacy and tolerability profile, we believe that we could capture some of that market. The third segment is people who are on the oral right now, who maybe are foregoing efficacy and tolerability because they prefer their oral so much, whether it's they don't like injection or there's some sort of antidrug antibody with other therapies, they're foregoing their efficacy. So if we're able to say, you like your daily oral at 44% attack reduction, here's an 80% to 85% daily oral, we may be able to switch those patients there. We know from data that's put out by another sponsor that those orals are still having about 1 to 2 breakthrough attacks a month. As I mentioned earlier, our open-label extension data indicates that we could be at less than 1 attack a year. So we're really excited about that opportunity to provide a potentially better efficacy and tolerability oral for people. And then the last segment is people who are staying on injectables right now because they don't want to forgo their efficacy and tolerability. We had done some market research questioning people on when they would prefer a daily oral to a long-acting injectable at the different injection rates right now. So once every 2 weeks, 4 weeks, 2 months, 3 months and then 6 months. It's only when we get to daily oral versus once every 6 months that people tend to prefer about 50-50. So let's assume that another sponsor can put up a 6-month injectable that once again has the same efficacy and tolerability that we're seeing with these others. That prophy market, which is about a $4.7 billion market right now, splits evenly between 50% orals, 50% injectables. We believe with an efficacy profile that we could dominate orals. And then within the injection space, that tends to be a little bit of a crowded market, right? You've got about 9 injectables that are all going to be competing for that other 50%. So although we don't believe that 100% of the market will go to orals, we do think that we can have a strong market leadership for the prophylactic space.

Okay. So -- and also the split between on-demand versus prophylaxis, right? So you're going to further be differentiated in that you're going to offer patients in both segments' treatment. So what's your concern about cannibalization if you have a really strong prophylactic oral as you described with the outcome that you're hopeful for with the 80% plus reduction in attacks, kind of how do you think about what the on-demand opportunity would be for that same product?

Yes. So right now, 38% of the U.S. market is on on-demand only. We believe that, that will get smaller over time as more people add on prophylaxis to their treatment regimen. However, every HAE patient is an on-demand patient because you should still carry rescue medication with you in case you get breakthrough attacks. Now for us, we believe that we can really address both aspects of that, right? So it's not -- we're not as concerned of, oh, well, what happens if 80% of the market becomes prophy, Okay, we're good with that. We have a prophy. Well, what happens if on-demand takes over? Okay. We also believe that we have a dominant profile there. And one of the things that we're working towards building a high level of data around is what if somebody was on deucrictibant XR? And then if and when they had a breakthrough attack, they could treat with deucrictibant IR. So we've pulled together some initial efficacy findings around mechanism on mechanism. So people from chapter 1 who had breakthrough attacks treated with icatibant, same mechanism of deucrictibant and had equivalent efficacy findings as people from placebo who treated with icatibant. We most recently put out some interesting safety margin data around people if somebody was -- who was modeled around if somebody was on XR daily and then they treated not only with IR tablet, but a second IR tablet right away, those safety margins were well within what we would expect of NOL. So we're thrilled with that.

Okay. Okay. So as you think about time lines for the data readout, what should we expect to see in 3Q when you top line the data?

We will be, of course, showing numbers around our percentage attack reduction, safety profile as well. I think one of the things that we've been seeing from other people and what is shifting in expectations on prophy is some data around either number of days that are attack-free, percentage of patients that are attack-free, right? Like the bar is being raised as these efficacy -- as the efficacy improves from all of our peers. And so I think the attack-free percentage and numbers will be important for us as well.

Okay. Now that 80% plus that you have the goal of achieving, as you expand from a Phase I/II to a pivotal study, the population is quite heterogeneous. So how do you get comfortable that with more patients enrolled in this pivotal study that you could do a similar number to what you had in that impressive smaller study?

Yes. Thank you. So one of our -- one of the items that we've implemented in the Phase III to be able to protect against this Phase II to Phase III efficacy degradation is we are switching our formulation from a twice daily immediate release capsule. -- so that has a very swift uptake of therapeutic exposure and then it sort of drifts until about hour 12 and then you take a second one. Now at around hour 12 and 24 in our CHAPTER-1 study, we believe that some patients could have been vulnerable to breakthrough attacks because there's an opportunity to drop below that therapeutic threshold of EC85, about 13.8 nanograms. We have modeled our PK around the XR formulation, which is the formulation we're using in CHAPTER-3 as well as our intended commercial formulation and put out recent PK variability data, which indicates that even from patient to patient, the PK and therapeutic exposure is about 2 to 4x higher than that minimum EC85, where you're blocking 85% of the B2 receptor. Because the PK profile is much softer and you're not having these drastic peaks and troughs. We believe that, that is an optimized formulation for a once-daily prophylactic.

Okay. Got it. So if you want to go back to comparing versus Orladeyo, which would be your oral competitor in the space. Historically, the HAE market has tended to be sticky, which means if something is working for you, whatever it might be, even CINRYZE, which is an old drug, some people are still on it, you tend to stay on it. If it's not working for you, our feedback from physicians is that you tend to switch to something else pretty quickly. So what portion of the population are you really looking to have patients switch from? Because it's our understanding that for ORLADEYO, if it's not working for you, you've already moved on to something else. So would it be from the injectable population, at least initially that you would expect to see most of your uptake?

We believe -- I think we're in complete agreement. There is some brand loyalty that people have. However, I think that your point is very well taken, which is if it's working for you, they will stay on it. As I mentioned before, people in Orladeyo are still experiencing 1 to 2 breakthrough attacks a month. Based off of what we're seeing from the other injectables, that actually isn't working well for them, right? Like that is not the expectation that patients have when they take an injectable. So we believe that people are accepting a lower efficacy because they prefer an oral so much. So we actually really do think that good is not good enough, right? Just because you are on an oral right now and putting up with breakthrough attacks doesn't mean that that's what you should be experiencing. So they -- Orladeyo was able to capture about 25% of the market in 5 years with the maybe not as compelling profile. So as much as people say that it's a sticky market, it's not that sticky if they're able to get 25% of the market in 5 years. We believe that people will switch to the better product for them.

Okay. And then maybe one more question about your point on switching. So it is true that if it's not that different, it's hard to get patients to switch unless they feel like something is really different. So going from an injectable to an oral would be one of those things where, hey, this is different enough, I want to try it. But what about the flip side of injectables? There's now a bunch of [Audio Gap]

To dominate 100% of the market. There are -- each patient and physician has the opportunity to choose what's best for them. There are benefits to being on a long-acting injectable and then there are trade-offs as well, right? We see that at the end of those long injection frequencies, there tend to be more breakthrough attacks as sometimes triggered by stress, right? You know that your next injection is coming up. The longer people have in between injections, the more likelihood that you're going to miss an injection, right? You can't remember if you took it in the first week of July or the second week of July. And then lastly, the control that you forgo by just taking an injection and then having to wait for your next injection could actually be quite a deterrent for people. If somebody -- for example, like I said, for people who want to get pregnant, if you are on a 6-month injection, that means that you need to start family planning multiple half-lives before that. So you start to family plan 1.5 years to 2 years before you can actually begin that process. So we believe that the control around being able to say, each day, I wake up and I'm able to control my HAE by taking a daily oral is going to be really appealing to people as well. Like I said, not 100% of the market. There are going to be people who prefer to just get an injection every 6 months and not worry about it. That's okay. We're trying to provide patient choice.

Okay. All right. So when the top line comes out, assuming that is positive, what are the next steps with FDA?

Yes. So in addition to having our efficacy and safety from the randomized clinical trial portion, there's an open-label extension that's running where we need to be able to have enough people who were on deucrictibant for a full year. So we need to pull together that safety database. And then the other thing, as David mentioned, is our ongoing CREATE study. This is an acquired angioedema. Part 1 of that study is a 12-week prophylactic study that if the timing allows with the setup of 24 patients in that group, we could actually take the efficacy and safety from AAE, add it on to CHAPTER-3 plus the CHAPTER-4 safety database and submit that for a broader a broader submission on AEBK, which is bradykinin-mediated angioedema.

Okay. And when would that happen, do you think?

We haven't guided towards when that data is going to be. But once we get enough visibility into that, we'll provide a disclosure on it.

Okay. Perfect.

It's also true, I think, given that there are no approved AAE therapies that if we are able to put the 2 together in filing that we could get priority review.

Okay. Perfect. Well, with that, we're out of time. So thank you, guys, for spending the last 30 minutes with me. Thanks, everyone, for joining as well.

Thank you.

Yes, thanks. Thanks, Tazeen.