All right, perfect. My name is Tiago Fauci. I'm a biotech analyst here at Wells Fargo, joined today by the Pharvaris team. I appreciate you guys joining us today for our healthcare conference. We're going to do a fireside chat and run through some questions. Usually, I like to start by giving you some room to just do intro remarks, where the company is today, next upcoming catalyst, and then we'll dive into the more nitty-gritty questions.
Very good. Thank you, Tiago. Thanks for having us here. Pharvaris, we're a late-stage pre-commercial biotech company. We are in Phase 3 right now for two products. One is the Deucrictibant immediate release (IR), a product for the treatment of HAE attacks. The other one is the same active ingredient, Deucrictibant, but in an extended release form for the prevention. The key, it's very exciting times for us because end of the year, we'll have read out our first Phase 3 for on-demand, followed by a final in the first half of 2026. In the second half, we'll have the read out of our second Phase 3 for prophylaxis. We're very excited here to get our product to patients as soon as possible.
There you go. Easy enough. Yeah. The HAE market, I guess, let's start there, right? It seems to be very crowded, but also growing. It's a substantial market opportunity. I understand why there's continuous innovation there. What are some useful ways of trying to subsegment that market? Again, on-demand, prophy, or kind of the classical, I don't know if there's any other subsegmentations that might be helpful to think in terms of what's going to grow, what's going to expand.
Yeah. Very good. As you said, we'll start off with the basics, on-demand and prophy. We anticipate that both markets will grow independently. The on-demand market will grow particularly because of the entry of oral opportunities, oral products that will lead to hopefully more attacks being treated. We know that today about 40% of the attacks never go treated. Patients don't have their medication with them. They are reluctant because it's very painful to inject yourself with so many treatments. Sometimes there is, can you say the attack is not severe enough? Having an oral can really radically change that. We anticipate that in the next couple of years, we'll see growth in on-demand. That said, the biggest part of the market is clearly prophylaxis. Even today in the U.S., there are about 60% of the patients on prophylaxis, but they represent 80% of the value.
That comes because of the yearly cost for prophylactic treatment. The prophylactic market, we kind of look at it as a market that will ultimately evolve in a blue ocean and a red ocean. The blue ocean being the orals and the red ocean being the injectables. What I mean by that is that when you start on prophylaxis, today already, the majority of patients new to prophylaxis start Oral Already. it's kind of logical that you start on an oral in this space. For most therapeutic areas, orals are the first step into a treatment. Once you don't respond, you want to have something better, you go to an injectable. Our plan is, our ambition is to really capture the majority of those new patients once we get approved. Every year, there are between 150 or 250 new HAE patients in the U.S. They flow through to prophylaxis.
If we can capture those year -over -year, combined with a much lower dropout rate Oral Already, because we seem to have at least numerically a better efficacy level, that becomes a pancake effect whereby we build up significant share in the market. That kind of first line option with orals will ultimately lead to the orals obtaining at least 50% or probably more of the total market. Why do I call it then a blue ocean, the orals? Because there's going to be two competitors only. It's going to Oral Already and it's going to be Deucrictibant. I think if we confirm the data in the Phase 3 from our Phase 2, we are very well positioned to take a leading share in that segment. On the flip side, you've got the injectable market.
In a couple of years from now, there might be seven to eight products competing for the same patient pool. Today, there are still patients on Cinryze. They probably get still on that product until they die. There will be patients on Firazyr. There will be patients on Danazol. All these seven to eight products, there might be a winner there, but they're going to have to share some market with the others. Ultimately, it will be much more easy for us to become a leading product for prophylaxis than it will be to any of those injectables in the market.
Got it. You assume that the growth on the share for the orals are going to be mostly from patient churn and the new patient starts. Why is it so difficult perhaps to see switches at some point? To your point, there seems to be a lot of patients that are very sticky to their brands, right?
It's interesting because stickiness is driven by how satisfied are you with your therapy? And B, do we have an alternative? Right now, we know from patients, if you listen to the Harris poll that was conducted by IONIS a couple of months ago, 65% of the patients on prophylaxis are not satisfied or would like to get a better prophylactic therapy. Better can be nominated in many different ways. It can be convenience, it can be efficacy, it can be tolerability, you name it. With a profile as the Deucrictibant, where you can offer injectable-like efficacy with very good tolerability and an oral daily regimen, we think we do can switch patients. I spoke about the new patients, but by the time we launch, about 1,000 patients will have Oral Already and come off.
They are probably today on an injectable, but they've clearly shown that they were interested in an oral. Those are the patients we will go after. Thirdly, Oral Already patients that are so-called stable or sticky, they still have a significant amount of breakthrough attacks, a lot of them. We are going to go aggressively after those. Lastly, there are going to be some patients that stuck with Takhzyro or Haegarda Oral Already came to market because they didn't want to sacrifice on the efficacy. If they have an oral that has the same level of efficacy, they might make that move.
Especially for patients, as we mentioned, that have been injectable for a long time. A lot of patients and physicians notice that they've already tired of injection, but meanwhile, they don't want to sacrifice anything regarding the efficacy part, right? They're waiting for the alternative oral option that can provide injectable-like efficacy and also placebo-like safety, so they can consider to try new options. That's exactly even though we consider maybe sticking to their brand, but because patients have no option yet, these 65% of patients are waiting still for the new treatment available.
Got it. No, I think that's perfect. I get to your point, your Phase 2 data stacks up really well against the competitive landscape, right? I guess the questions that you might get all the time is like, how likely are you to actually translate that into the competitive Phase 3? A lot of nitpicking there. The first one is just related to the Phase 2 interpretation and the multi-rate attack relative to historicals and relative to typical Phase 3 trials. There are some differences there. Again, how reliable is the translation, I guess, to some of those findings?
Yeah, actually, that typically, especially for prophy trials and for HAE, it's quite standard that the trial design and all the endpoints there. Also, if we look at the past development for prophy treatments and the translation from early Phase to late Phase, it's quite consistent, we have to say. You mentioned a very interesting point, it's about that frequency of attack, right? For patients there, actually, if you look at all the prophy trials, especially for the placebo group, you can notice the patient that the attack rate is typically all around two attacks per month. Quite consistent across the trials. If we're lucky, we can get more severe patients that you know that in the pivotal trial there, actually, it will be further boost efficacy because that really our primary endpoint is the active treatment arm, the attack rate compared to the placebo group, right?
If the placebo group attack rate gets elevated and the reduction that maybe we can even achieve 90% or above 90% reduction there, that currently is regarded as a saving of the efficacy for prophylactic treatment.
Got it. No, I think that's a fair point when you're thinking about that. I guess the other question is just related to formulation, right? Again, incentive release. What drives efficacy here seems to be fairly well understood from a PK perspective, right? What was the work that you guys did to be comfortable with the bridging between the two formulations?
Yeah, that's really important for us, especially with the major difference for us from Phase 2 to Phase 3. As you said, for our Phase 3 study, we will use that once daily extended release formulation. As you mentioned, that PK and also that really the target therapeutic exposure level is very important for prophy treatment, especially the 12th level, typically was treated or regarded as a surrogate for efficacy. Therefore, compared to the 20 mg BID we use for Phase 2 and the 40 mg extended release formulation we use for our pivotal study, further boost the 12th level for our PK profile that looks like it's doubled, even more than doubled. For the C, we call it a C24, is the 12th level we expected from prophy trial.
We have even fewer hours of patients at the lower 12th level.
Exactly. We can consider, we have more buffer room to consider the variability from the Phase 3 trial, that the large patient population there. Therefore, based on currently our PK/PD modeling there, we expect that the efficacy will be at least comparable to the Phase 2 and maybe potentially can be even better.
Got it. I guess the two points of risk that are brought up in terms of the differences in baseline characteristics and also the formulation, theoretically, you guys feel like it should be the same if not better.
Right, exactly. Not only convenience, but you can say from the formulation that changing here maybe potentially can even boost efficacy and reduce the potential safety concern because the peak concentration is reduced. The PK profile gets even optimized for peak and the 12th ratio there.
Got it. I guess when you're thinking about commercially, what is the bar of differentiation? Between injectables Oral Already, you have some buffer there. Do you have to be exactly like injectables, not necessarily?
Yeah. Before we had the Phase 2 data, we assessed kind of what would good look like. Based on the input of the market, we assumed that as long as we had 75% attack reduction, we would be good. We would be able to win in the oral market. With the Phase 2 data now, our target has changed. We basically feel that we now have the duty really to make this product the leading product in prophylaxis, not just win Oral Already, but even, as I said before, to capture some of the patients from the injectables. Because injectable-like efficacy, win oral, is a huge advantage. We've seen, if you look at the uptake Oral Already, i don't think a lot of people would have predicted that based on the efficacy. They really have demonstrated, they've done a fantastic job, by the way, in commercializing.
We're going to steal and copy as much as we can from what they've been doing. They also have shown how important this oral really is for American patients. We're going to hopefully be able to build on that and, as Peng said, raise the bar and really be in the right level versus the injectable as well.
Got it. Okay. We talked about the competition. Share for new patients starts seems to be there should be a strong preference for oral. The pace of that conversion could be a little faster if you get positive data and eventually get approved. The conversion from potentially Oral Already patients or injectables, that could take a little longer, right? If they have a breakthrough, how should we think about the potential pace of uptake in those subsegments in the prophy setting?
I think the switch from injectables is facilitated by the fact that it's an oral. There is not a lot of, if we confirm everything we've seen till now, there is not a price to pay to try it. If you don't take Takhzyro, you get 85%, 90% attack reduction, but you take a needle and you have then the option to try Deucrictibant, the daily pill. We don't anticipate any GI side effects, no tolerability issues, and the efficacy is going to be similar. That's a relatively small step to try. That's partly Oral Already is successful. Oral, you don't have to do much to. I think even though it's in that whole pool of injectable patients, it might be a smaller group, but I don't think it's going to be the whole group. That switch is something that we really can induce.
We can really achieve that by bringing the arguments forward about this trifecta of efficacy, tolerability, and convenience. On Oral Already side, very similar. If you look at their real-world evidence, they show that patients still have attacks, a lot of breakthrough attacks. If 50% of the patients have more than one breakthrough attack per month or one per month, we can really target those patients and say, look, you feel you're good with what you have, but you can try the other one. That's where the confidence around IR also can come in. Patients have used it, for instance, for on-demand for rescue. They believe in the drug, see that it works. Yes, it's not going to come by itself, but I also don't think it's going to be climbing the Mount Everest to achieve that.
Has payers' influence the HAE market share substantially in the past, or how does that, could that come into play here as well or not?
Not yet, really, particularly on the prophy side. On the other hand side, there's a bit more discounting on it, but it's not really driving behavior. There are obviously prioritizations, potentially step edits, but given that most patients have already tried most products, it's easy to kind of, it's an administrative hurdle. You have to go through it, but it's not really a real hurdle. On the prophylactic side, either, at the moment there hasn't been a lot of debating going on, so we don't have a lot of preferential use of first-hand products. One of the advantages we could have there is a bradykinin-mediated angioedema label. So , Peng is actually initiating a study in acquired angioedema. We've been asked by the regulators to include normal C1 patients in our on-demand and prophy Phase 3 programs. If we can get a bradykinin-mediated angioedema label, that's different from our competition.
It's basically a broader label, and a broader label equates with potential preference from payers, as well as for some physicians.
One-stop shop. Don't have to think too much about it. Much easier.
Got it. No, that makes sense. We've spent a lot of time talking about prophy, but your next data point is actually on demand. Let's pivot to that again. Data is Q4, correct? What do you think you need to see there to differentiate versus standard of care or for the new oral that has recently gotten approved in that market? It feels like from what we know of the Phase 2, the efficacy should stack up favorably, but what's the bar for success?
Yeah, good questions. That's exactly we have a high hope for our pivotal readout from our Phase 3 study here, especially based on our Phase 2 observation there. As we know that for the response, right, you know, to the on-demand treatment, it's not as, you know, that only one part, it's several parts from how quickly that the symptom can be relieved and how quickly the patients can feel their ataxia vertigo can be reduced and how quickly people can feel they really go back to the normal life and no symptom anymore. All these perspectives is a holistic package. We expect we can see the differentiation for the Deucrictibant there. Based on our Phase 2 data, we expect, for example, the time to onset of symptom relief may be between one to two hours. Currently, our data show 1.1 hour.
That's why we set up this window for the onset of the symptom relief. Meanwhile, our data also shows that attacks can be reduced from, for example, severe to moderate or moderate to mild attack within three to four hours. You know, compare our, you know, the competitor there is significantly, maybe better there, even though it's not a head-to-head comparison. We expect that Deucrictibant can lead a median time to the complete symptom resolution within 12 hours. Hopefully, in the future, it helps our peer discussion is that we also expect over 85% attacks can be resolved with a single dose of Deucrictibant. All this, I think, is very appealing, no matter if it's compared to the past standard of care or the injectables, also compared to the new approved oral treatment.
It must mean the commercial dynamic on the on-demand side of things is a little different, right? What is a successful launch? What are some of the main drivers where you can actually gain share there?
On-demand has the advantage that you can, it's slightly easier to switch because every time a patient comes into the office to get a repeat script, you can basically be there and say, "Hey, why don't you try the other alternative?" One attack, two attacks, just go. I think our belief is that if patients really get the opportunity to try IR, they will notice the difference. I think the product, as Peng was explaining, brings a full package. It's not just fast onset. It gets you really to complete resolution as rapidly as possible, and with the confidence of doing that with one single dose. That's something, by the way, which is an argument of payers. When we shared our data with payers, they were really impressed with that because that obviously has a cost implication.
If you double the cost for an attack by needing a second dose, that can add up very quickly.
Got it. If everything goes according to plan, you're going to be on the market for on-demand. How does that actually set up the launch in prophy? Different formulations, different price points, different everything, but I'm assuming the API is the same and there's going to be the trust on the data, right?
I think the great benefit of having on-demand first is that it gives us a year or nine months, six months, whatever the difference would be, to build relationships with the community, to build trust in the compound, and actually build up pent-up demand for the time we get approval. If you wouldn't have on-demand, you can't promote obviously your product beforehand. We can't promote prophylaxis, but we'll be promoting on-demand. There will be a spillover, there will be a halo effect to that for the prophylactic approval. That is, it's a huge thing that we call it a launch pad for prophylaxis because that's ultimately, I think, where we want to focus our efforts, given also that the guidelines really clearly lay out that no patients should suffer any attack. The only way to do that is with prophylaxis.
Got it.
On-demand, the response will be very direct and straightforward. That's exactly as you mentioned, right? If the patient really gets interested immediately in response, then they indeed build up really great credits to the prophy use.
Yeah, I'm assuming the real-world experience actually builds up interest and the positive feedback to physicians on the prophy setting, so on and so forth. Okay, that makes sense. Again, the on-demand side of the business seems like it's been stable. It's not necessarily growing substantially over the last few years, and you are introducing more effective options, I would argue, over time. Is there some cannibalization here? You mentioned that you've actually thought that both sides of the business could grow over time. What are some of the dynamics between the interplay of those markets?
I think what we're going to see is in the first couple of years, we see a growth in on-demand, but then I think it will get caught up in the growth of prophylaxis. At the moment, about 60% of the patients in the U.S. are on prophylaxis, but that's growing every quarter, small, 0.1%, 0.3%, 0.5%, but that continues. That's why we anticipate that the overall prophylactic market will grow to 70%, 75%, maybe 80%. It will never be 100%. That ultimately will start taking away some of the market for on-demand. Initially, absolutely, there will be growth, we think, by more attacks being treated. The other aspect that could help growth, where we might particularly benefit from, is the acquired angioedema segment.
Patients with acquired angioedema today are only diagnosed because the doctor who's treating the underlying condition, whether it's lupus, MGUS, or lymphoma, when they realize this angioedema should be treated and send them to an allergist. The 800 patients that are more or less identified in the U.S. right now are really patients that the hematologist or the immunologist have realized they should be treated. I've been spending a lot of my career in myeloma. I spoke to a friend of mine who is a doctor in myeloma and asked him, "Have you heard about acquired angioedema?" They had no clue.
Which tells me that if we have a label for acquired angioedema and we can go and educate at ASCO, at these big conferences, that there is a solution for this condition, that it is something that should be treated, that will actually unlock a lot of patients that are today unknown. Given that we then have a label there exclusively, that would obviously help for us in building our leadership position in the market.
Let's talk more about that. Mechanistically, again, why pursue the indication? Any ways of subsegmenting the addressable market there? Biologically, why pursue that indication and why haven't others tried or have not been as successful?
Yeah, that's an excellent question. That's why we feel Deucrictibant is unique for the patients there because they compare all the approved treatments or the current under development. You know that the Deucrictibant is only the treatment targeted most downstream. Can it be too receptive there as a new prophy treatment here? All the other prophy treatments currently under development are either plasma, catecholamine, or upstream there, right? That's exactly why from MOA, magnesium part, we can really block bradykinin bind to the receptor. Regardless, the bradykinin is generated either a catecholamine pathway or catecholamine independent pathway there. That's exactly that we were being that a lot of physicians are looking forward to us because a lot of normal C1 patients, for example, if the plasma manager mutation or other mutation, they are plasma catecholamine independent. All other treatments supposedly wouldn't work for them.
That's exactly that Deucrictibant becomes the hope for these patients who have not had any approved treatment yet. That's why we were that include normal C1 patients in our pivotal trial and looking forward to provide the new treatment for this patient population.
How do you even buy our study? For like in terms of thinking about natural history and some of the baseline characteristics, is that patient that dissimilar, that adds some degree of clinical risk? Is the bar different given the lack of treatment options? How should we think about the clinical risk?
Good question there. Basically, from the symptom-wise, that normal C1 patients is quite comparable to the Type 1, Type 2 C1 deficiency patients. That's why we can include it into our trial for assessment. From the type-wise, we expect for our pivotal study that 90% patients do Type 1 and maybe 5% patients Type 2 and another 5% will be Type 3 and normal C1 patients. Therefore, we did not dedicate a power for the study, but we included it into our pivotal trial.
Therefore, you can get a free option on the label based on.
Exactly, we will include all this data, hopefully, that you know into the label there. Only the difference is acquired angioedema patients, because this patient population is not hereditary. That's why, as Wim mentioned, we have the dedicated pivotal study will be initiated by the end of this year.
We will collect the data for prophylactic data first, the on-demand data. The prophylactic part one of this trial will be parallel to the HAE prophylactic trial there. Hopefully, as mentioned, we will target that bradykinin-mediated angioedema, not only limited to HAE.
Got it.
That's also consistent with the orphan destination. We've already been granted no matter for U.S. or ex-U.S.
Okay. We haven't talked about XUS almost at all. Anything noteworthy either from a pricing, reimbursement, access, treatment paradigm? What are some of the puts and takes there? Yeah.
A very different landscape there, mainly different by pricing. Yes, completely different. Prophylaxis is still meaningful, still significant, but particularly on the demand side, it's much more challenging. That is why our focus right now is really on the U.S. We think with a very limited footprint, we can really unlock a significant, very significant opportunity. Outside of the U.S., we're looking at options, we're looking at potential partnerships that can be licensing, can be distributorships. We're doing the work, which is kind of on the clinical path. For instance, when we do KOL engagements, that is happening by default because of a very international community. We're working on health economic models, the preparation for that, but we don't deploy yet like any commercial resources in those markets.
We really want to look at what is the best way of getting the product as fast as possible to patients, because that's ultimately the most important thing that we try to achieve.
Yeah, no, fair enough. With the recent capital raise, I think the latest guidance from Pharvaris perspective is into first half of 2028, right? You get to.
Yeah, first half of 2027.
First half of 2027. I'm sorry. Thanks for the correction. Again, you get to a data point in the on-demand setting, on the prophy setting. Can you talk about launch prep, I guess? Again, you could be very imminently with a good problem to solve, right?
Until now, we have been very prudent financially with deploying big resources, but we have really focused on hiring people that have a lot of experience and relationships in HAE. HAE is a very particular therapeutic area. It's relationship-driven. You have to be engaged with the community, and community means physicians, means the patient organizations, means the payers as well. Our leadership, whether it's Sales and Marketing, Medical, Market Access, Patient Advocacy, in the U.S., they all have a long history in HAE. Peng is another one on the clinical side with our team. That is really what we're focusing on right now to build that relationship. As of next year, we're going to be starting to build out the organization further, prepare the infrastructure, hire the field force to support the launch, and then we're really going to be in the absolute launch mode.
Ready to roll?
Yes.
Perfect. All right. Feels like it's a natural stopping point. I don't know. Is there anything else that we didn't cover that might be worth highlighting? Again, I feel we could cover a lot of ground.
I don't think.
Should we do this?
I think you're pretty complete.
Fantastic. Perfect. Again, I really appreciate the time.
Thank you very much.
Thank you.
Thanks.