Great! Welcome, everyone. I'm Max Skor, a biotech analyst with Morgan Stanley. Before we get started, I'm gonna read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Great, I would like to welcome Berndt Modig, CEO, and Peng Lu, Chief Medical Officer and Head of R&D from Pharvaris. Thank you very much for joining us today. It's been an exciting year for Pharvaris, capped off by yesterday's encouraging long-term extension data, which will be presented at the Bradykinin Symposium. Before jumping into that, could you please set the stage with a brief description of deucrictibant and your vision for how it fits into the HAE landscape?
Yeah, thanks, and nice to be here, and good morning, everybody. Yeah, having been involved in the HAE space also for even before Pharvaris, and a part of the development of, of icatibant, eight years ago, we set out with the mission to develop a best-in-class therapy option for people living with hereditary angioedema. And, because we see and recognize, we see there's an unmet need there, and it continues to be even today. All- everything is not meant for people living with HAE, who are fundamentally looking for basically three things: efficacy, of course, it's a lifelong disease, and tolerability, and the treatment burden.
We set out with the mission to develop a therapy that really scores on all three, and that's how we came up with deucrictibant, which is a small molecule B2 receptor antagonist. It is the same mode of action as icatibant, which is an established mechanism in the approach of treating HAE, and in our view, also the optimal approach for various reasons. deucrictibant is much more than just an oral form of icatibant. It is a completely new chemical entity, and it has characteristics that also make it suitable for prevention, for prophylactic development. In our product strategy, we have actually two products for hereditary angioedema.
We have deucrictibant IR and deucrictibant for acute treatment, and then deucrictibant XR for prevention, with the same active ingredient. That differentiates us also in the space, the only company that really can serve both needs in terms of treating or preventing HAE. As Max said, yesterday, announced more data building on the phase II data that we presented at the end of 2022 for on-demand, and then end of 2023 for prophylaxis. We are really excited about that long-term extension data because it really further enhances our belief that the potential of deucrictibant to become a best-in-class therapy.
Great. Before diving into the data stepping back for a second, you included in the slide deck yesterday, a few slides in your presentation around the U.S. market opportunity. Can you just walk us through, you commented on how it's a dynamic market. Even though there may be new drugs coming in, patients are switching. Any additional color would be great there.
Yeah, so that's, as somebody looking at the therapeutic space, initially, not really so, as a first impression, then it's a very competitive and crowded market. I would say it's a developing, very dynamic market, and I think what you've seen, if you look at the, I think the slide you're referring to, is also the, see the market entrants in the last 10 years or more, and you see the sales uptake. I think what you can see from that is that it's not about being first to market, it's about having the best therapy.
What we've always seen, even 10, more than 10 years ago, when the icatibant was launched, which was also other therapies that were ahead, it's always the therapy that improves in any of these three parameters that really takes the leadership. There's a lot of until recently, everything was injectables, and for some patients, that is a burden in the treatment. People living with HAE continue to look for better therapies. We're not there yet, but with deucrictibant, we hope we can get to a state where we really can fulfill all the needs on all three parameters.
I think what we see also is that people living with HAE, HAE, in that search for better therapies, there is a high propensity to switch. I would not characterize the market as a sticky market. It's really, you see that also from data that we have seen, that patients are the opportunity to find something that works better for them, they're very open to try that. Also in an oral form, when somebody who's newly diagnosed with HAE, young adolescent or in early, early stage, then the natural thing would be, to argue, to start out with an oral. If that works, then the patient will presumably stay with that. We see that there are multiple advantages with an oral approach.
As you stated previously, you have two formulations, one to address prophylactic or preventive, and then another to address on-demand. How do you see these markets evolving over the next five to 10 years? Do you see prophylactic growing and being more valuable? Also, I'd like to touch on just the patient journey. Do patients, are they prescribed both prophylactic and on-demand treatments? Any insight around that would be great.
Yeah. I mean, in the current guidelines or the only patient community, there is this clear message that somebody who's living with HAE should not have any attacks. That is the goal to put. Therefore, the prevention and prophylaxis is really the sort of the optimal treatment paradigm, and it's also in the view of the patient community. That's also what we've seen in terms of new innovation in the last years. The patient journey is also. I mean, the one thing that's good about all these new therapies in HAE is that the awareness of the disease has increased dramatically compared to 10 or more years ago.
It is a bit of a patient journey. That starts with getting the right diagnosis, and you start having attacks, and you do not know what it is. Once you have the diagnosis, usually in a sort of an adolescent or even earlier, it could be an option also to start out with something with on-demand, which might be easier to handle in an oral form and for somebody at a young age. Then see how that patient journey continues in terms of the attack profile and then moving on to a prophylaxis. We also see that as one of the synergies with our two products that you have. You can start with on-demand, and then you can go over to prophylaxis, or you can go directly to prophylaxis.
That's interesting. There would be continuity in the patient journey.
Yes.
If they were initially diagnosed, it wasn't potentially as severe, they'd start on the on-demand, and if it did progress, then you'd have the prophylactic option there.
Yeah.
Same mechanism of action. Great. Okay, let's dive into a bit of the data. I think it would be great to start with the prophylactic update and the long-term extension data. Could you please just set the stage, the clinical trial design, how many patients were enrolled in the long-term extension, and some key takeaways?
Yeah, fine.
Thanks. Actually, we are very pleased to really announce the extension data yesterday. Before we jump to the extension data, we just want to briefly catch up regarding our phase II, because we announced our part one of CHAPTER-1 study. It's a double-blinded phase of the prophylactic study. During that study, actually, altogether, we enrolled about 30 patients in that study. We really show that the protection of prophylaxis is really fast, you know, onset there, because we reach steady state within two to three days, and we show really attack per, you know, reduction around 85%. It's injectable-like efficacy there, as Berndt has already mentioned, and over 90% really moderate, severe, and also that attacks who need rescue medication.
Later on, you know, we also yesterday announced up to 18 months extension data for both efficacy and the safety part, and all the 30 patients that completed the CHAPTER-1, part A study, go over to extension study. We are very glad to say that the strong and significant attack reduction was very well maintained up to 18 months there. The attack rate even further continues improvement compared to the part one, that the attack rate is only about half from the data we shared. Compared to the baseline, 93% attack reduction was observed and also consistent with the overall attack rate. We also see very low instance for moderate, severe attack. On average, even only less than one attack per year, that attack really need the rescue or on-demand medication there.
All the patients pretty much report medium attack rate is a zero for every month, up to 18 months there, and 99% of times, the patient report symptom-free. Therefore, we think this, the data, is really encouraging and also from the safety side, that all the patients were very tolerated up to 18 months there. There is only one treatment related adverse, adverse event observed. There is no any events, actually, I mean, that adverse events leading to the discontinuation.
In regards to that, I believe it was tooth discoloration was the treatment-emergent adverse event. Any reason to be concerned about that in the future? Any color around that?
Yeah, that's a really good question. We have no rationale to think about it, what's really treatment related. Meanwhile, as mentioned, because the patient is on the active treatment, it's openly about potential study that's evaluated by the investigator, because obviously he cannot find that obvious alternative reason for it. That may be that he thinks it's possibly related to treatment. From our side, we just report whatever the investigator reported here. From, you know, from mechanism, from the drug itself, currently, we have no rationale to explain it.
No, cardiovascular issues, those were clean on all parameters, correct?
Exactly. Also, that we have press release yesterday. We have the poster and the presentation regarding this topic in the Bradykinin Symposium. We closely monitor ECG hemodynamic parameters in both non-clinical and clinical studies. We did not observe that any impact from all the long-term prophylactic treatment with deucrictibant.
Okay, that's helpful. Diving in a bit more to the patient profile, and I guess thinking about how it compares to, let's say, ORLADEYO, which would be the oral option from BioCryst for the prophylactic treatment of HAE. How did the baseline characteristics compare across trials? I know I don't wanna push too hard on that, but just, high level, comparing the patient profiles and then the overall efficacy data.
Yeah, and if it, the patient profile in terms of baseline is also very, very similar, and also similar to what we've seen in other therapies. From that perspective, there is a comparison there. I think that overall the very similar patient profile to everything else in the ORLADEYO.
Yeah, typically for all the prophylactic clinical trials, for HAE field is quite mature and standard. Typically, we will enroll the patient with a baseline attack, you know, at least one attack per month into the pivotal trial or into the HAE trial. We will be consistent using the same criteria for our pivotal study.
In regards to the use of rescue medication for this trial, is there any insight into that or the need for rescue medication in the prophylactic setting?
Yeah, I think that there was only, the use of rescue also was reduced even further in the long-term extension. I think as Peng said, I think about one attack maybe in a year's timeframe that would be needed rescues from what we saw. Also, as we said, the median attack rate reduction was zero, so attack free.
Yep. Okay.
Drastic, drastic reduction in the use of rescue.
Very helpful. And then, one last question, just because I've... There is another competitor in the space in regards to developing a subcutaneous formulation, Astria, and I believe they have additional phase I-B/II data coming in the fourth quarter. Any insight, granted, it's a different, route of administration Any thoughts on their initial data?
No, I mean, that data also looks encouraging, and I think it's a different, it's a different approach. When we look at the HAE development and therapies under development, is the attempt to further lowering, lowering the injection frequency of injectable therapies. I think that's where you see a lot going on, so to speak, in the space and the oral side, it's less, less competitive, you could say. I think also in the longer-acting injectable, fundamentally, what that is about is the reduction of the treatment burden further.
If you take somebody who's on Takhzyro, which is an injectable, interested in trying out something with a longer or lower injection frequency, fundamentally, that patient is looking to reduce the treatment burden. I think the reason that there might be some hesitation to try out the oral option is that there's nothing out there today that really provides the same reassurance and equivalent level of efficacy. The willingness to compromise on efficacy, we see as what this is what patients absolutely do not want.
Therefore, the patient that is interested in trying a longer-term injectable, we believe, is also very open or could be open to trying out the oral alternative. I think that also, that's a very, we see as a further differentiation, with the Pharvaris approach, with an oral, with injectable-like efficacy, that we can then serve the full spectrum of patients, so that they fundamentally want efficacy and low treatment burden.
And a clean safety profile.
Yeah, yeah
... to date so far. Okay, great. Maybe we can move on a bit to where you're at in regards to the phase III trial, commercial formulation. Anything, any updates around that would be great.
Yeah, so, things are on track for the initiation of the phase III in prophylaxis, we also announced yesterday. There are no specific gating items, so we're always all about execution now, preparing sites and all that. We also, as we announced four weeks ago in our Q2 release, have alignment on the regulatory side for the phase III trial for prophylaxis. The formulation is the commercial form, is ready and available for the trial. We're looking forward to the initiation.
The regulatory agencies, based on feedback after the phase II, they're comfortable with the commercial formulation, no food effect. Any feedback regarding that?
No, no specific issues, no. They're, they're comfortable. We have alignment with the protocol.
Could you talk about the clinical trial design? Any insights into the timeline, when we can expect data, interim analysis?
Yeah.
Yeah, as far mentioned, is that we also make the announcement. We announced that our study design and also sample size and overall efficacy and the safety database with the FDA, EMA, and also PMDA. We are happy. Actually, we also aligned with the PMDA, the minimal data package we would need for filing in Japan, because Japan have really strong data motivation to join the global, you know, study here. We all align with them from the overall study design, actually same as others, the pivotal, that the prophylactic study in HAE field is quite standard. We targeted the six months treatment, and altogether, we, you know, consider around 80 patients enrolled in this six months prophylactic single trial here.
We also take advantage here that because we only, you know, select the one dose regimen, unlike the other, right, HAE trial, that for the pivotal study. Therefore, we target the two to one ratio for these 80 patients. That pretty much po ten tially can help us boost the enrollment, encourage the patients to join the clinical study.
Timelines? Without getting into hard timelines, when we could expect initial data.
I mean, on time, we haven't guided specifically yet on, on, on timelines, other than to say that, based on similar trials in the past it's sort of 18 to 24 month timeframe.
Okay
... for the duration of the trial.
That's helpful. Then last question on prophylactic: Would you expect to have a similar label to ORLADEYO, or any insights around that?
I think from label side, we would expect that the similar indication, I mean, that long-term prophylactic treatment for both adolescents and adults. From the other side, we do expect the more favorable efficacy and the safety labeling that for the icatibant.
Okay.
Yeah.
That's great.
Also, to add to that, as we yesterday also announced the expansion, that our in ten tion to expand icatibant into other forms of angioedema, the acquired angioedema. We will update more about the concrete details on our thinking and plans there, but there is the po ten tial also to have that in the same label. That would be another differentiating factor that the icatibant can be treated, used for all forms of angioedema, not just HAE.
This is based on a prior investigator-initiated study and data. It was a smaller study, but there was an encouraging sign in regards to acquired angioedema, correct?
Yeah.
And when can we expect that trial to be initiated, or more insight into timing around that?
Yeah, coming up, we have, as I said, we did announce yesterday the in ten tion to do that, and we will then be looking at the our design and plan and exactly how we do that. Stay tuned. There'll be more to talk about there.
Are these patients treated with icatibant currently? I know there's no approved- therapy for angioedema, but how, what does that patient journey look like?
Yeah, that, that's correct. I mean, the, the, from what we've seen, the most, common, treatment today, then off-label in that case, would be, icatibant. And, that, and that seems to be an advantage, due to the mechanism, because of the, in the acquired angioedema, there are also other pathways of bradykinin, and that, that's where the direct inhibition of bradykinin, could, could be a potential advantage, and, which would be then the further differentiation for the, for the icatibant.
Great.
Yeah, maybe I can add one more there, that, here, as mentioned, for HAE currently, really, that we were most asked by the community for the really the effect treatment for patients because they only use icatibant off-label, as there is no any approved treatment yet. Meanwhile, that as Berndt mentioned, and also you mentioned, despite that a very small sample size for the investigator study, but we are also very happy to see, no matter double-blind it,a nd also extension study, that, you know, that, our collaborators that are presented in Bradykinin Symposium yesterday to show up to one year that the efficacy and the safety data are really there. All the patients attack-free there and are very well tolerated in this patient population.
We are also encouraged that because extension data is the first time that, you know, we reported the use of the extension, you know, XR, extended release tablet for this study. In addition, as Berndt mentioned, we are confident for the PK part from our healthy volunteer study, but all this patient data for efficacy and safety data with the extended-release formulation give us more further confidence for the future pivotal studies.
Great. That's very helpful. Okay, moving on, with the time available, to the on-demand opportunity and the data you presented yesterday in regards to the RAPIDe-2 long-term extension data. If we can, sum up some of the key takeaways and highlights from this data set, that would be great to start off with.
Yeah, I think also what we... and, open label on the long-term extension and on demand is a, similar to what we saw in prophylaxis. It's a, it reinforces and then further enhances our, our view of, of a potential best-in-class therapy, also for, for an on-demand therapy option. In the, in the long-term extension, we also use the endpoint of PGIC a little better, which is the endpoint we also will be using in the phase III. There we saw a 1.1 hour time to onset of symptom relief. Also there, and moreover, on the duration of the effect and the resolution of attacks also very strong data that also further reinforces what we saw in phase II.
Yeah, indeed, that, as Berndt mentioned, that's the first time that we—
Yes. I was just gonna add.
...PGIC, right? The PGIC. Second, those, the data that we are very encouraged actually to see that it's consistent with our expectation from RAPIDe-1 study, but, you know, it's going to be confirmed. Our PGIC is only one point one hours, especially compared to standard of care data that we collected in the real world. The data we also shared yesterday in the Bradykinin Symposium is about two hours, and the substantial symptom relief there, that for the icatibant is, is only about 2.6 hours, two to 2.6 hours, compared to the standard of care is a four to 4.6 hours.
All this, and also over that 90% attack achieve the symptom, you know, complete symptom resolution within that 24 hours there with a single dose. All this data really, to tell us that, for, especially for the on-demand treatment, there is no new treatment in the past 10 years. Hopefully, that we can provide that as a new standard of care for the patients.
We'll comment on, KalVista being a competitor that is guiding to potentially launching in 2025 with an oral formulation for the treatment of on-demand. How did the data- How did these data that you presented yesterday compare to the data they've presented to date? Maybe talk about, the baseline characteristics of the patient populations.
Yeah. Actually, from the baseline that, that for the on-demand, we all recruit the patient with at least two attacks in three months. So the patient population are very comparable. Yes, KalVista presented their, you know, the extension, the long-term extension data. Their time to onset of the symptom relief with at least, you know, with a little better for two time points is 1.8 hours.
Therefore, that I think that, we, at least from number wise, it shows better. Our PGIC data is about 1.1 hours, and there is that, that a substantial symptom relief with the PGIS, that one grade or better there is about six hours, and we reported a 2.6 hour. Also, that our complete resolution, the median time, is 11.5 hours, compared to KalVista, presented about 21 or 22 hours from their extension data. We are quite confident that we can maybe potentially be the best in class, that on-demand treatment for patients.
Also to point out that in, I mean, in our phase two trial, and also the same in the long-term extension, we were careful to see that they qualify the attacks, that they have a certain level of severity before it really qualify for the treatment. Which and then, in the clinical trial setting, of course, then makes it easier to really see with them the efficacy. In the real world, in the treatment paradigm, treating as soon as possible is, of course, the guidance.
In order to really see the effect, that's even with that, the level of severity of attacks that potentially in our trial was a little higher than in others. Also, where deucrictibant differentiates on the on-demand side is the reliability and the duration of the effect and the use of, the need for a second dose, which is also very different to sebetralstat.
Yeah. If I remember correct, the use of rescue medication was higher in the placebo arm for your study versus KalVista. Could you read into that at all in regards to, maybe you're treating more severe pa, patients?
Yeah. That's an interpretation that we think is potentially correct. Because, as I said, we qualified it, making sure that the attacks have a certain severity, and,
Almost double, though.
Yeah. That's right. So then there's more obvious the need for rescue in the placebo group. If you have a very low number of rescue use in the placebo, that kind of raises maybe the question if the attack was that serious.
Okay, that's helpful. In regards to the phase III trial that's currently ongoing, could you just walk us through the design of the trial and current status?
Yeah. Actually, from the design of the trial, it's very similar to our RAPIDe-1, that, you know, that phase two study there. The only difference that, around that time for our phase II study, each patient received one placebo, treated as an attack one time with the placebo and two attacks with active. Now, in our phase III trial, we only treated two attacks. It's still cross-over design and one placebo, one active. From the sample size, because it's a pivotal study, the sample size is slightly larger. We target maybe enroll around 120 patients for phase III. For overall, we feel the study and the timing-wise may be very comparable to the phase II, the RAPIDe-1 study.
Okay. While it was initiated before the prophylactic study, when, rough estimate on when it could potentially read out the on-demand phase III?
Yes, it's similar to that, in terms of, based on similar precedents and similar trials. 18 to 24 months is what I've seen.
Okay.
As Frank said, also the design of this trial is also focusing on making it as efficient as possible with crossover design, making more attractive for patient to join. Also the only one dose, so.
Could the prophylactic study read out before the on-demand study?
No, that's not likely, no.
Not likely. Okay, and then just jumping back, I would like to ask briefly about laryngeal attacks. Any insight into that? I think you commented on the call yesterday, we're gonna see more data in the future. I know some of your competitors commented on how many laryngeal attacks were treated with their oral therapy. Any additional color would be helpful.
Actually in the, you know, presentation released in Bradykinin Symposium, that we mentioned that so far, seven laryngeal attacks has been treated in the extension study. We, we don't have all the data to release this time, but we are quite confident that laryngeal attack responds very well to the deucrictibant. And typically, if you, we look at the competitor or KalVista, the data there, laryngeal type typically responds quicker and faster than compare that attack in other, you know, that location. We would maybe expect consistent that, uh, result here, but as mentioned, that we targeted to release more data for laryngeal attack in the future conference.
Another feature of our formulation is that the dose is only 20 milligrams, and then it's a softgel capsule. It is a very small softgel capsule that's also easy to take quickly.
How does that compare to the other oral options?
Yeah, we have no clear visibility exactly what that looks like. On their side, I mean, we know that it is based on the dose difference, that it would presumably be a bigger tablet and a bigger, one or two tablets that we do not know for sure. What is clear is, in our case, with our capsule, that there is nothing smaller than that.
Based on your market research and physician feedback, do you find patients who generally suffer from laryngeal attacks, maybe it'll be a bigger lift to convince them to take an oral therapy? Or do you think they're open to it, and it will still be a potential market?
I think the, the, the... Another important feature of the oral option for on-demand is also the, the, that you can have it with you all the time. You can... The treatment time to treat is, is faster, which is important, generally in, in hereditary angioedema, but also, of course, also in a laryngeal attack. Instead of having a syringe somewhere in your bag, or you have to find a place to inject, and there is this extra time needed, whereas if you-- I could be sitting here in this panel and feel an attack coming on, and I just take a glass, a swig of water and take the capsule, and we can continue our conversation. That's a big difference.
Okay
... we think also in the case of a laryngeal attack.
Great.
Exactly. I really echo what Berndt mentioned. We encourage every patient to treat, no matter laryngeal attack, as early as possible, especially for laryngeal attack. We really regret to see the patients because there's no treatment available or treated too late because they're afraid of that pain or whatever from available treatment there, and it's too late, and the treating to the all the breathing difficulty. Therefore, that hopefully with the oral treatment, that we can carry everywhere, as Berndt mentioned, and take as early as possible to treat all attack, especially for laryngeal attack.
Okay, that's helpful. I guess two more questions from me, second to last being financials. You reported cash, cash equivalents of EUR 344 million at the end of the second quarter. How does this quarter relate to the runway? Will it fund both phase III trials, potentially the acquired angioedema? Any thoughts around the runway?
Yeah. So in our Q1 guidance, we had more than two years. We are now also in the middle of evaluating our go-to-market strategy and also looking into some areas of potentially where it could make sense to work with, from a business perspective, with a partner. That also has an impact on the investment and spending in the commercial side.
Also, with the acquired angioedema, of course, is another factor. We haven't changed our guidance at this point, but we'll be coming up with more definitive guidance in the near term. It's fair to say that, as you asked earlier about the timing of the on-demand readout versus the prophylaxis readouts, we expect the first readout to be in on-demand. Of course, have an objective there to have a runway to cover that.
To cover on-demand?
To cover on-demand, yeah.
Okay, great. Anything else, maybe I missed or you'd like to highlight that maybe investors are missing in the, in the general story?
I think generally, I mean, we speak to a lot of investors, as Alastair also mentioned even before we started the panel, there's a lot of interest in hereditary angioedema. I think it is very much a process to educate, especially the dynamics in the commercial side and what the patient community is really looking for. It is very easy to have this view, initial impression that it's very crowded and what the opportunity is. It is a growing market, and also in our view, less crowded than it might look like in the beginning.
Because when you first look at it, because it really is about being the best, and we see the future in HAE, as I said earlier, the prophylactic trend to more prophylactic. Within that segment, then oral and potentially other longer-term injectables. In that space, we see that potentially the oral could have a majority, but that's how the market will kind of evolve into the future. It will be consolidation, I think, and the best therapies that are available.
Great. Thank you very much.