Morning, everyone, and welcome back to Oppenheimer's Healthcare Conference. I'm Jeff Jones, one of the analysts on the biotech team, and I'm delighted to welcome this morning, Berndt Modig, CEO of Pharvaris, as well as Maggie Beller. Thank you both very much for joining us this morning or afternoon, in Berndt's case, from Europe.
Mm-hmm. Yep, thank you. Good to be here.
Maybe just to start off at a high level, for those who are a little less familiar with the Pharvaris story.
Mm-hmm
Your focus on HAE, could you just give us a high-level background, and then I think we can dive in to the indication and the lead programs?
Mm-hmm. Yeah, sure. Pharvaris actually, and now where we are now in the phase III, late stage, so they're getting ready for commercial, started the journey actually 10 years ago. This is the 10th anniversary of setting up Pharvaris. We even go back further than that because my scientific co-founder, Jochen Knolle and myself, we worked with the company that developed icatibant at Jerini. We've seen the evolution of the HAE space over now two decades. HAE is, for those of you who don't know, it's a rare genetic condition. It's a lifelong condition that manifests itself as painful, in some cases, fatal, swelling attacks in the face, hands, feet, throat, and stomach, and genitals.
These are not necessarily painful. They could be life-threatening, and stomach attack is extremely painful, and it's a big burden for people living with HAE. Not only the attack itself, but also the anxiety and uncertainty that goes with it because it has a big impact on what you're doing in a daily life. An untreated attack takes 3-5 days to resolve, and not knowing when the next attack is gonna come, and in a moment when you don't want it, is a big stress factor for people living with HAE. Over the years now, they've developed two different paradigms to treat this.
It's either treated when the attack comes in an on-demand setting or acute, or a prophylactic treatment to prevent attacks. You would have a regular regimen of taking a therapy that will, with the aim of preventing the attacks from occurring. We set out 10 years ago because we all had seen an unmet need for people living with HAE, which is even today, not fully filled, in our opinion, a highly efficacious oral therapy option. Because for the most part, over the years, all the new therapies that have come to the space have been injectables, except for very recently.
The unmet need for a highly efficacious, at the level of the current injectables, in an oral form, has not yet been met, and that's what we are hoping to achieve with deucrictibant. What it has in common with the icatibant is the mode of action. It's a B2 receptor antagonist, it works the same way, and the beauty of that is that it is applicable to all forms of angioedema, not just HAE type one and two, but also so-called type three patients with normal C1, and also other forms of angioedema.
That's an important element of our strategy, is to develop the deucrictibant and hopefully get a label through the acceptance with the regulators to get a label for a broader indication called bradykinin-mediated angioedema. That's basically the overview. Happy to follow up questions.
Yeah, absolutely.
Yeah.
Given deucrictibant, you know, you have phase III data in the on-demand setting, and the second half or third quarter now, we're expecting phase III data in the prophylactic setting. Could you just talk a little bit about the difference in market size for the on-demand versus prophylactic setting? You know, maybe the portion of patients that are actually on prophylaxis today and how you think a better oral option could impact that.
Again, looking back, right, in the first 10 years ago, it was mostly just the approach to treat attacks when they came. With the introduction of injectables that reduced the injection frequency, primarily TAKHZYRO, that started, you could say, the prophylactic segment. Today, that is the dominant segment. I think it's about 63% of people are long-term prophylaxis, and that's a growing segment. In terms of value, it represents about 80%. These are not U.S. numbers.
In Europe, it's a little bit different, a little less, prophylactic use and a little bit not so homogeneous and a little different depending on what country you're looking at. The current clinical guidelines that really say that ideally, people living with HAE should never suffer from an attack, and that is sort of the ultimate goal here in HAE therapies. As I said, nobody has been able to achieve that yet, so, you know, 100%. The, which is to prevent attack can only be done prophylaxis. That's the starting point.
But any patient that given the fact that nothing works 100%, breakthrough attacks do occur, patients also are guided to always carry an on-demand treatment with them at all times in case of an attack, of a breakthrough attack. So you could even say that almost every HAE patient is an on-demand patient, and most of them are also on prophylaxis. The interrelationship of on-demand and prophylaxis is very important, and it's also an important part of our approach and strategy, having two products that cover both the on-demand as well as prophylaxis with the TAKHZYRO.
Excellent. In December, you reported out your pivotal results for deucrictibant in the on-demand setting. Maybe talk us through the highlights of what you reported there.
The basic design of the on-demand trial is to compare the resolution of an attack when it occurs compared to placebo. Basically, the patients, so then once they experience an attack, then they take either a drug or placebo, and then you measure how that evolves from the very beginning, minutes after the therapy is taken, and up until the complete resolution of the attack. We are really excited about the RAPIDe-3 data because it didn't just hit the primary endpoint, all the other 11 secondary endpoint in a very robust statistical approach, were mapped with statistically significant.
The onset of symptom relief was measured by something called PGIC. These, all these endpoints are patient-reported. PGIC means I feel a little better, that's called the onset of symptom relief. We showed that 1.28 hours versus 12 for placebo. Another endpoint that we had in our trial, which is unique to Pharvaris, was the end of progression as part of the protocol. That is even before, that's the point when the patient starts to feel that the attack is not getting worse and it's under control, and that was only 17 minutes. That's clinically meaningful because, as I mentioned earlier, the anxiety factor of going through an attack is quite significant.
The patient having the comfort that the drug is starting to help them is very important. That's not by far the only part or not the end of the story here, because what's really, really important for the patient is of course, to how to get rid of and have to complete the attack resolution in a reasonable time, because that's when the patient can go back to normal and go to that job interview or go to the wedding of their son or daughter, whatever, and then they happen to have an attack right at that time frame. You can think about a lot of real-life situations where the quick resolution, complete resolution, really is very meaningful for patients.
the onset of symptom relief is like you cover the 100 yards in a marathon in nine seconds. That's not gonna help you if you're not gonna get over the finishing line at the end of the day. the TAKHZYRO was showing very robust data through all these endpoints, and that makes us very, very excited, and it's even numerically faster than the standard of care, and also faster based on numbers on the recently approved oral. we think that shows a very clear differentiation that we think will possibly be noticed and appreciated by patients.
Okay. Obviously, very positive results, and there's another recently launched oral, which would put you guys second to the market here. We'll talk about that in a second. Just in terms of next steps for you, timing of your regulatory filings, and then, just remind us, is that a six-month or 12-month review? What, when would we expect, be expecting you guys to be ready for, launch here?
Yeah, I mean, we haven't provided specific guidance on that, of course, because it's all in the hands of the regulators and at the end of the day, but just following basic, what you consider, the customary timelines that we are guided, that we're gonna file for our NDA in the first half of this year. If in the regular review period, then we could then, if that works out, the launch about a year later, that would basically be the timeline. As I said, that's just based on customary timelines in this space.
Perfect. KalVista Ekterly launched this fall. Uptake is going well. I mean, as you mentioned earlier, most of the options for these patients were in the on-demand setting. All of these options, until very recently, have been injectable. Having an easy oral option is going to see a very attractive market opportunity. When we look at the Ekterly data, it's always challenging to compare things, you know, from separate trials, but where do you really see the differences for deucrictibant, you know, on these PGIC endpoints?
Just so it goes back to what I said, a few minutes ago, is really the if you think about what a patient is looking for in treating an attack is fast onset, because that makes you feel comfortable that things are starting to get under control. That is only half of the story, and then it becomes, but almost not so meaningful if you don't get really full resolution within a reasonable timeframe. You're not helped much by having a fast onset, and then you're still gonna wait 24 hours or more to have the attack go away.
I think that just based on, purely based on the numbers from the trials, and also, of course, the different trials, there's not a head-to-head.
Mm-hmm.
In our trial, we made sure that we really treated HAE attacks and so have a very robust trial design that qualified the attacks and make sure that we treated attacks related to HAE and nothing else. That provides an even higher hurdle to show a robust efficacy. I think simply based on that, and the efficacy, and then other differentiating factors that where we are different is that the redosing rate, and that's another anxiety factor or uncertainty factor for the patient. Should I take a dose?
They like to take a dose, one dose and know that that's it, I don't have to worry about or to kind of wonder, should I take a 2nd dose, or should I not take a 2nd dose, and how do I feel? Just the comfort and confidence of one dose resolution is very key here. It's also relevant from a commercial and a payer perspective to have a more attractive drug from therapy from that perspective. Lastly, but not least, is the oral part of the softgel capsule. We have a small softgel capsule, and Ekterly is that one dose is 2 300 milligram tablets, and if you need a 2nd dose, you need to take another two tablets.
You'd end up taking four tablets to treat an attack or quite a few attacks, actually, given the second dose usage. If you contrast that to a very small softgel capsule, much lower second dose usage, and that could also be a factor. I mean, sometimes people ask about laryngeal attacks and having a softgel capsule that's very tiny and easy to swallow as quickly as possible when you start to feel an attack is also an important consideration. The multiple areas we see a very strong differentiation. We do see the oral uptake on Ekterly.
That just illustrates to us, also why we started Pharvaris in the first place, because we see a big unmet need for an oral therapy option, and so today, that has not been met fully, and we hope to make meaningful to fill that need with deucrictibant.
Yeah, I think we certainly noticed in... if you look the two trials, to your point about the percentage of attacks treated with a single dose, in your phase III trial, you were at 83%. KalVista was at about, well, it was 59%. The surprising thing was the percentage of placebo patients they treated with that only took a single dose of placebo. It, it does to, as you were implying, it appears that maybe they had a less severe patient population that they evaluated.
Of course, we have the big AAAAI conference coming up this weekend, and hopefully we'll get, you know, some more, we'll be getting, more data from a lot of folks, be able to do a more thoughtful comparison of these two programs.
I think that the, I mean, the less severe attacks, it's, it might be easier to see, like, a first onset, or the differences is not so great as compared to we have 1.2, right? KalVista and Ekterly is two hours, so you can debate that at that particular endpoint, how significant that difference really is. As I said, it's really about the symptom resolution and the complete resolution where really the, where things go totally apart. I think that that's really what is meaningful for patients.
I think even having less, I mean, as I mentioned, our trial design, but due through to the qualification of the attacks, there may have been a tendency to have more severe attacks, which then of course, would be even more challenging to get complete resolution in the reasonable timeframe, right? The nuances of the early onset is one thing, but to really get the attack completely go away is something completely different. It could be. Somebody said it's like night and day. It could literally be night and day. You can have a resolution at 12 noon, or you can have to wait until the middle of the night to have a resolution of the attack in 24 hours. That's.
Okay.
Oral is a great thing for patients, we believe, and we, so I think that's very clear, and we believe that the especially the ODT market is gonna be very highly focused on an oral therapy option in the future.
Yep. All right, I think that covers us pretty well for the on-demand option. Obviously, your pivotal study for the same drug in prophylaxis, just the extended-release version, is anticipated to read out in the third Q. The on-demand market remains, I guess, dominated by injectable TAKHZYRO, I think $1.5 billion in revenue for 2024. BioCryst is doing quite well there, $600 million in revenue last year for ORLADEYO. There are certainly some I think there's more competitive room in terms of benefit versus BioCryst, based on what you've shown in your phase II. Would you mind highlighting sort of your phase II data in the prophylactic setting? We can talk about sort of the expectations and et cetera, for phase III.
Yeah. I mean, first off, I'd like to say that, I mean, what did we observe or with ORLADEYO, I mean, they came before, Actemra, but it's the same phenomenon. It's, it reflects the desire for an oral therapy. In the case of the Prophy, it's the patient decision whether to be on an injectable versus an oral or what therapy to be on is sort of a composite of many factors.
If a patient is really absolutely do not wanna have needles and wanna get away from needles, that patient may then say, "Okay, I'm willing to put up with more attacks, because I'd definitely prefer an oral." That's what you can call a patient so-called doing well on ORLADEYO, depending on how you define it. That is, in our view, is gonna change once they have, if the deucrictibant gets to market and is approved, and if the efficacy is borne out in a phase III that we saw in phase II, which is characterized as injectable-like efficacy.
We think that that would be a very logical switch for patient to make, to then finally have an oral that provides the same level of efficacy that they experienced potentially with the TAKHZYRO or any of the other injectables before. That's really a first for the oral space.
Okay. You mentioned that oral versus injectable trade-off today. What is the gap in efficacy between injectables today and orals in the prophylactic setting?
I give you, based on the data, I mean, I hand over to Maggie also an opportunity to contribute here. Maggie, you can provide that comparison.
Me too. Yep. What we're seeing from phase III data for the approved injectables is about 80%-87% attack reduction. When we compare that to the 44% attack reduction in ORLADEYO, we think that our phase II data, which read out at about 84.5% attack reduction, is much more in line with the injectables and really places deucrictibant to compete well in the prophylactic space.
Great. As you said, that's injectable-like efficacy here, without that trade-off, and you're then looking at an oral with really potent efficacy. In this case, I guess, how much risk is left in that phase III between, you know, what you've shown in phase II? Is it just a larger study size? What is it that, you know, what risk is left as we think about phase III? Obviously, you've shown positive phase III on-demand data for the same molecule. It seems to me that this should be an extremely de-risked phase III.
Yeah, I mean.
Maybe I'll-
Yeah, go ahead, Maggie.
As you said, Jeff, we, in both our RAPIDe-3 that we just read out and in our CHAPTER-3, we have expanded both of those phase III studies from the phase II. In addition to including adolescents in both of those studies, we also are including people with normal C1 inhibitor, and we are going to a broader geographic range. We also tapped into clinical sites in APAC and LATAM that we did not do in phase II. What we're really proud of is that the RAPIDe-3 data, our on-demand program, read out phase II data as even stronger than our phase II data. Even though we added in this additional risk, we were able to mitigate that with just the strength of the efficacy data.
We're hoping to see that again in our CHAPTER-3 data, because that's really about clinical execution and operational excellence. The other part of it is that in our phase III, we are switching from a BID immediate release capsule. Two times a day, people took the capsule that we're using for on-demand, and in the phase III, we're going to be switching to a once daily extended-release tablet. Instead of having these really high peaks and troughs in PK, the extended-release has a much stabler, more optimized peak to trough ratio. We think that that is optimized for the once daily extended-release, it's once daily prophylactic treatment. I don't know, Per, if there's additional stuff that you want to add to that.
No, I think that covers it. I mean, I think the robustness of the efficacy of deucrictibant in the ODT, it's the same molecule as you pointed out, the quality of the, of a more global footprint of the trial, which is sometimes a generic risk factor in phase II to phase III. I mean, that's, that was... we were happy to see that in RAPIDe-1, and hope to see the same for prophylaxis. Then, of course, importantly, also the XR formulation, which has more favorable PK profile. I think that's, that, those are things that make us optimistic.
Another factor, very small data in an investigator trial in acquired angioedema for patients. You can see that in that corporate deck. I believe it shows four patients over an 18-month period with XR formulation experiencing no attacks in that time frame. That's another indicator. As always, any trial is different and unique, and we have to see the data, which we are looking forward to very much.
Great. I guess, the, for you, what is a win here on your phase III? What, what, I guess, what is your target that you're hoping to hit, in terms of the third quarter readout?
Yeah, I think that the key here is, of course, to maintain the differentiation that we saw vis-à-vis the other, the oral therapy option, is meaningfully enough to make a difference for patients. That could be an individual decision. Of course, at the end of the day, is it 70%, is it 80%, 85%, or 90%? Injectable seems to be sort of in the mid-80s, and which is what we have seen so far with the quick demand around that range. If we can replicate what we saw in phase II, I think that would be a great outcome.
The focus, of course, is to be differentiated enough, so that we can have a very strong position in the oral segment, which we believe is a very significant segment of the therapy options, in the future, if not more than... if not the majority.
Okay. As I mentioned earlier, AAAAI is coming up this weekend. You'll have a number of posters, as will many others in the space. I guess, what should investors be paying attention to this weekend coming out of AAAAI?
We have a whole array of lots of exciting things. Maybe Maggie, you can walk us through that, starting with RAPIDe-3 and so on.
Yeah, absolutely. Yes, we have six posters at AAAAI this year. This will be the first time that we are presenting our phase III top line data to the medical community. That's really important for us, not only to have scientific exchange with prescribers and really understand what they're looking for, but to be able to speak individually to physicians about our phase III data. We will have final data from our CHAPTER-1 open-label extension, so that is the prophylactic study with the BID dosing. Those people have been on therapy for over three years, so we're gonna be able to show that the continued safety database, the efficacy that we've seen. We've done a couple of cuts of that open-label extension. The efficacy is actually bolstered in the open-label extension.
We're showing 92.3% attack reduction from randomized studied baseline. We're really proud of that. We've got some data around our extended-release formulation, as well as, some information around endpoints, our AMRA endpoint for on-demand and our biomarker study. Lots of really cool things. We're really excited to be at AAAAI. The other thing that we're really proud of is Pharvaris as a sponsor of the HAEA Foundation's 5K run walk. It's a great way for us to give back to the community that we are all serving, and of course, it's gonna be very fun to run a 5K in Philadelphia in February, or I guess it'll be March that this is occurring. Everybody bring your gloves because it's gonna be cold.
Snow boots, right? I guess just last question, as we are just about up on time, in terms of cash and runway, where are you guys today? Obviously in the midst of preparing for regulatory and commercial, just a financial update.
Yeah. So, yeah, as you pointed out, given the projected or possible timelines we discussed on launching. We're of course preparing for that. This year is the year of ramping up on the commercial build and adding to the team. That, of course, increases cash consumption to some extent. Given that with the cash on hand, we guided runway into the second half of 2027.
Sorry, first half.
Yeah. Sorry, first half of 2027. Yeah, correct. Thank you. We have, of course, meaningful milestones now in this year. We have the options to decide on the next step in our capital formation strategy.
All right. Well, thank you both very much. We are up on time, so, great update. We look forward to seeing you guys at AAAAI and seeing the updates there this weekend. Thank you very much for participating, and I hope you have some great meetings with the rest of the day.
Yeah. Yeah. Thank you. Same. Thanks for your time, and great to be here, and I look forward to that. Thanks a lot.
All right.
Thanks.
Take care, guys.