Hi, good morning. Happy Monday. Welcome to our 21st Annual Needham Virtual Healthcare Conference. I'm Serge Belanger, one of the Healthcare Analysts at Needham. This morning to kick off our conference, happy to welcome the Pharvaris team. We have Berndt Modig, the President and CEO, as well as Morgan Conn, the Chief Business Officer of the company. They'll tell us a little bit more about Pharvaris. For those listening in, there is a Q&A portal where you can submit your questions. We'll do Q&A after the presentation. Gentlemen, the floor is yours.
Great. Thanks, Serge. Hi, everyone. Good morning, and thanks for joining us here today. For the next 30 minutes we'll talk about Pharvaris, and I hope we'll have some time for Q&A. Next slide then. Here's the overview, and then we'll talk about some of these things in more detail in the deck. By the way, the presentation that we're gonna go through is also available on our website. Pharvaris, our key focus is the development of a new oral therapy for Hereditary Angioedema. Also part of our platform is also to look into other bradykinin-mediated diseases down the road. First and foremost, HAE is a large HAE market. It's a rare disease market with over $2 billion in sales.
It continues to be very dynamic, with the predicted growth around 9% over the next five years. There's still unmet needs for these patients in reducing treatment burden. There is a larger undiagnosed population still globally in HAE. We address this market with an orally available small molecule, which is addressing the same target as another HAE therapy, Icatibant. It's a validated target. It's a B2 receptor pathway and bradykinin inhibition. We're proud to say that our molecule is called PHA121. It's to our knowledge the only orally available B2 receptor antagonist so far. We'll have our own clinical proof of mechanism. You'll see that also in some more detail in the deck.
Due to the properties of this new chemical entity, small molecule, it also makes it suitable for development in both on-demand and prophylactic treatment of the Hereditary Angioedema. That's an important element of our product strategy. We have IP on this molecule. Its patent granted in the U.S. and pending in other territories. We recently got FDA Orphan Drug Designation. Pharvaris as a company, we're basically based in three locations, the Netherlands, the U.S. and Switzerland. We have a strong financial position with the cash runway into Q1 2024. We started this year with EUR 209 million in cash. We have an experienced team with experience in development all the way through approval in HAE. We'll see that here on this page.
I'm Berndt Modig, the CEO. The connection to HAE also give you a bit of a background of where the company is coming from is I used to work at Jerini, which is a company that developed Icatibant. That's together with our CSO, Jochen Knolle, bottom left on this slide. Jochen is an inventor of Icatibant and Firazyr, which became after it was launched in the U.S. in 2011, the most successful product for the acute treatment of Hereditary Angioedema with the same mechanism as we are pursuing now with our small molecule. Also in our R&D leadership, our Chief Medical Officer was the global program lead for the development of Takhzyro, another leading HAE product for prophylactic treatment.
In our team, we have a deep experience in the development for HAE. On the next slide, you'll see a brief overview. I think many of you are probably familiar with Hereditary Angioedema, so I'll be brief here. It's a rare, lifelong condition characterized by attacks of swelling. You'll see some pictures here on these slides. It's a potentially life-threatening condition. Patients ending up having laryngeal attacks, the swelling in the larynx can be fatal and lead to suffocation if left untreated. Most attacks are not painful. They're uncomfortable and a big burden on these patients. Nevertheless, an abdominal attack that you see here on the right, on the other hand, is extremely painful.
It's a global disease. It's, as I mentioned in the beginning, it continues to be underdiagnosed and undertreated on a global basis. There are around 6,600 patients in the U.S. Some reports say up to 10,000 and around 8,900 people living with HAE diagnosed in Europe. On the next slide, you'll see the mechanism behind what causes the swelling attacks in HAE. It's ultimately caused by excess levels of bradykinin, which is released in the pathway due to a genetic defect, a mutation in the gene that codes for protein C1. That results in the uncontrolled release of bradykinin.
Bradykinin binds on the B2 receptor and causes the extravasation of fluid into the tissue and the signs and symptoms associated with Hereditary Angioedema attacks. We believe that the bradykinin inhibition in addressing this at the B2 receptor is an optimal way to deal with HAE, as has been shown with over decades of clinical experience, therapeutic experience with Icatibant that has these same target. Another advantage of bradykinin inhibition, indeed, it also makes it possible to treat other forms of angioedema that are not related to C1 deficiency. Other forms of angioedema with normal C1 you see here on the left.
There are different types of mutations can also be treated with bradykinin inhibition, in contrast to other approaches further up in the cascade. Therefore, we believe that there are a lot of advantages in addressing this with bradykinin inhibition. On the next slide, you'll see the overview of the attack frequency for patients. It's important to note that the attacks are unpredictable in frequency, also location and timing and severity. Patients, it's not just the experience of the attack that's a burden for these patients. It's really living with the fear of the unpredictability of when the next attack is going to come. Most patients, as you see from the histogram to the right here, have around 12-24 attacks per year.
There are patients with many more attacks and also patients with zero attacks. That is a key driver determining whether patients will be treating prophylactically versus treating when the attack comes, and what we call on-demand treatment. On the next slide, you'll see the overview of the key element that really patients are looking for. The basically three things that HAE patients are concerned about in managing their condition. Efficacy is the prime concern. That is very clear. Also safety, tolerability of course, are important. This is the factor that pushes patients also to explore alternatives because to date, even though there are several products that have come to the HAE community, that none of them are perfect so far.
Also convenience is a key factor. This is a lifelong disease and that's also driving patient preference. We believe that an oral therapy option for HAE patients is the ultimate in convenience. Our targeting here is to provide all three elements of what patients are looking for with our program. On the next slide you'll see an overview of the current market. In this circle diagram here, the right part are the products that are used prophylactically, and to the left are the on-demand products. Estimated total sales globally for 2021 was $2.4 billion.
In the last years, we have seen an increase in the use of prophylactic products, primarily driven by improved convenience in the injectables. Everything that you see here on this slide, except for Orladeyo, the yellow slice at the bottom, are injectables. The growth in the prophylactic segment recently, which has been driven primarily by the relative reduction in injection frequency. The big unmet need in our view is for these patients to go with the therapeutic option to manage both prophylactically and on demand. Now a word about our product strategy. As I mentioned in the beginning, we have PHA121. That's our basic molecule, the new chemical entity, that's on which we have IP.
With that molecule, we developed two separate products, PHVS416 to the left, optimized for on-demand treatment. That's designed to provide fast, easy, and reliable symptom relief for the attack when it happens. The curve that you see here, the PK curve that you see is actually real data. You'll see more of that later in the deck in more detail. We have seen in that formulation of softgel capsule formulation, the fast onset and also a longer duration than the Icatibant. On the right you see PHVS719. That's our extended-release tablet formulation for Hereditary Angioedema. That is designed to maintain compound exposure to prevent attacks. Then with the once daily, providing an easy and effective way to live with the HAE.
The red line on both curves, you see the target plasma level. That is the trough level of the plasma concentration that is associated with therapeutic efficacy. You need to be above this line in terms of exposure. We're using the same API with these two products. That's an important thing to remember. On our pipeline on this slide, we have two phase II studies ongoing. RAPIDe-1, which is our on-demand trial using the PHVS416 softgel capsule. We also are running a phase II trial for prophylactic.
In this study, we are using 416, which is the on-demand product and BID dosing regimen in order to get more efficacy data, safety data, and also to provide insights into further dosing. The product strategy I mentioned is really for the prophylactic is ultimately to go with 719 for prophylactic. We have just completed a few weeks ago a phase I PK study for the extended release tablet formulation. We'll have some more details here in the deck and that we'll talk about in a minute. The data shows that it's suitable for the daily dosing, once daily dosing.
The plan with the 719 is to do the phase III study for prophylactic using the 719. That is expected to be the final commercial product for prophylactic use. Two products, 416 for on-demand and 719 for prophylactic. With that, I'd like to hand it over to Morgan to take you through some more detail also about the molecule as such.
Thank you, Berndt. As Berndt mentioned, we've taken PHA121 through phase I studies, a single ascending dose and multiple ascending dose studies. What we learned there was first of all, we were happy to see a very well-tolerated compound with no clinically significant changes or serious adverse events, and really no difference between active or placebo groups on that. Also we saw a dose proportional PK. You see here, on the graph, multiple doses that we tried and a half-life that's about three times as long as Icatibant. As Berndt had mentioned, this is a key advance over Icatibant in addition to the oral dosing.
We've done this study using an oral solution with a particular formulation in order to make it easy for us to go through the dose ascending schedule. A couple other key things that we learned in that phase I really sets up our product strategy. On the left here, you're seeing the first hour after dosing with the solution of 22 milligrams under two different fed conditions and fasted as well. The really important lesson there is the EC85 line that we've mentioned earlier as the target level that comes out of a bradykinin challenge that I'll tell you about in a couple of slides. That EC85 is what we see as the target for suppressing the effects of a surge bradykinin.
You can see that in all three situations, we've exceeded that line within 15 minutes with this solution. We'll also show you that using the softgel capsule, which has the solution in a softgel, we get the same speed of exposure. That really enables us to use that softgel capsule with the solution in it as a treatment for an attack once it's occurred. On the other side, on the right-hand side, you see a food effect for the longer term exposure. Here over the longer term fed, either a standard or high-fat meal prolonged the exposure, and that's what's allowed us to use the softgel capsule in our first proof of concept prophylactic study through twice-a-day dosing.
You see it lasts longer. At the inset is a result from our multiple ascending dose study where we gave healthy volunteers, twice a day dosing, with food. We're gonna see that, in the three doses, that we're looking at in this graph, well above the EC85 at the trough on the last day. The food effect both gave us the confidence about being able to do an extended release, technically, as well as then giving us a tool to get faster into the prophylactic study, with the compound. I've shown you a couple times this EC85 line, and that comes from a study done in humans called the bradykinin challenge.
This was first done with Icatibant in their phase I clinical development program with phase I, where you rely on the dosing in a healthy volunteer of bradykinin that causes changes in blood pressure and heart rate. Very short-lived, less than a minute, and that blood pressure, heart rate effect can be blunted by administration of a bradykinin receptor antagonist. In the case of the Icatibant study, of course, that was used as a subcu injection. You do a single dose and then administer bradykinin. As you do that periodically, bradykinin administration through the day, the effect of Icatibant wears off, you know, as its PK progresses.
You can get a pharmacokinetic pharmacodynamic correlation that allows you to set, and establish effective concentrations for ameliorating this bradykinin effect as well as duration of that effect. That was used for Icatibant very successfully. FDA reviewed it, set the dose that's been used in the clinic now for over a decade, with a very high resolution of attacks, based on the dose setting. We were inspired by that experiment, and we've done it ourselves now. This is the result of that work. You see here on the left-hand side are dosing schedules. We see here five doses of bradykinin administered over the course of 24 hours following a single administration of either placebo or PHA121.
You can see the real-time blood pressure monitoring in these healthy volunteers. The dip when bradykinin is administered before treatment and the flat but noisy line afterwards. All of that is modeled across the group of volunteers, and it allows you to pull out from that effective concentration 50 and 85. You see the blue boxes on the right-hand side, those numbers are fourfold more potent than Icatibant. That reflected back through all the preclinical data that we had as well. There's a consistent correlation between our preclinical and clinical observations. From that model, we're able to pull out a duration of effect, and you see that in the graphs on the lower right-hand side. The top box shows you the PK.
Because we're more potent, we don't need to be as high concentration. On the bottom box you see that our single administration of the 22 milligram dose lasts as long as two doses of Icatibant. That gives us our sort of central tenet of not being just a more convenient Icatibant, but a better Icatibant. I'll also point out that this bradykinin challenge can only be done with compounds that are bradykinin B2 receptor antagonist. We're the only folks in this field who can do a human-based assessment of a clinical dose selection. Having done that and using that really as our guiding star for dose selection, we'll tell you about the product strategy around PHVS416 and PHVS719.
Here with PHVS416 in on-demand with the RAPIDe-1 study, we're doing a three-dose, three-attack experiment looking for the assessment of the VAS, change in VAS score, which is the endpoint used for the Icatibant development program. It's an objective endpoint of swelling and pain in the patients. We're looking at that at the four-hour time point following dose. We're happy to say that we've reached the enrollment target, and 72 patients are enrolled at this point across multiple sites in Europe and internationally. We maintain that our expectation that we'll be able to have top-line data for that by the end of the year.
This is an event-based study, meaning each patient has to have three attacks to get the full selection of the two doses of compound or one dose of placebo. Because these attacks are unpredictable, any attack here has to, of course, be a qualified attack. There is some unpredictability in terms of the timing of the endpoint. The end of the trial, I should say. Moving from that to our prophylactic program. As Berndt had mentioned, our goal here is to use the efficacy data we get from a previous proof of concept study using PHVS416, combining it with the PK data we get from our tablet, and moving that together to go into pivotal studies using the tablet approach.
That study we call CHAPTER-1 is a two-dose study observing patients for 12 weeks with placebo control looking at the number of attacks and confirmed by investigators. A very standard design compared to the other folks in this field. That trial aims to enroll 30 patients across U.S., Canada, and Europe. We expect to have top-line data there by the end of the year as well. Then as Berndt mentioned, we've done a PK study. This was a single-dose PK study, our first study using our extended release.
What we saw in that, this was a crossover experiment where we did a couple of different release profiles with extended release, as well as the PHVS416 for the single dose rapid release. We continued to show good tolerability for both of these forms, the extended release and the rapid release. We show, as we've been alluding to, confirm that that oral softgel capsule release is just as fast as the solution by itself. That we've been able to show very importantly, with our extended release, a 24-hour exposure above our EC85 line.
Very conveniently, the dose we're using here, the 40 mg dose, provides the similar overall AUC as the 20 mg twice a day with food that we're using in CHAPTER- 1. Here we see in the graph for this, the blue line is our softgel capsule, the rapid release, that lasts as you see, staying above EC85 for 12 hours. Again, that much longer exposure relative to Icatibant and a profile that's well suited to providing relief once an attack has occurred. In the green lines you see both fed and fasted exposures of this extended release, where you see very characteristically for S-compound that can be absorbed by the colon and a release matrix that we're using where you do not get exposure in the stomach.
There's a delay at the beginning, but then the compound releases from matrix once the tablet starts transiting through the colon. When we see a good exposure well above that line over the course of a full day. We're very encouraged by this and what it means for our ability to have a differentiated profile for the two products. We'll be taking this on into multi-dose studies as we prepare to move that to phase III.
I'll turn it back to Berndt.
Thank you, Morgan. Here's the overview and the summary. 416 is our on-demand product. Soft capsule, easy to take, easy to swallow. A very tiny soft gel capsule, currently in our phase II study, RAPIDe-1, with topline data anticipated in Q4. On the prophylactic side, our seven-one-nine extended-release tablet. Again, same active ingredient. As we just saw, the favorable PK curve, suitable for prophylactic and once daily potential. In the prophylactic phase II study ongoing with CHAPTER-1, with topline data anticipated in Q4 2022. Financially strong, EUR 209 million in cash provides us the runway into Q1 2024 to execute on these programs.
Thank you very much. Now we can have some time left over for some questions.
Well, thank you for the great presentation. Obviously, an important year for the company with some really important de-risking data readouts at the end of the year. Wanna start off with a broad question, I guess, for Berndt, since you're a veteran of the HAE space. How has the market changed since the Jerini days? Maybe how has clinical development for HAE treatments changed since those days?
Yeah. On the market, that's been an amazing journey and also for the HAE patients who've benefited from a lot of products in the last decade. I recall that during the Jerini days, we were discussing with our investors back then, what's the market size for HAE and it turned out much bigger. So the market has had a tremendous development and it's been really good for HAE patients and we are of course looking to further improve on this with our product in terms of reducing treatment burden and providing efficacy in combination with efficacy. The development programs have not changed by comparison as much as the market.
I think in recent years of course prophylactic treatments become more products are now coming to the prophylactic space and I think there the development path is well established. I think also for on-demand it's some variations and different types of endpoints. VAS is a endpoint that's been used in the Icatibant study, and number two, and we also have here for our study. Another feature we didn't mention in the development in our particular study in RAPIDe-1 is the study in the home setting, whereas the Icatibant study was done in the clinic.
The patients in our study can treat at home in close contact with the site by telephone, so they don't have to go to the hospital or to the clinic to do the treatment.
I guess just drilling down a little bit more on the acute HAE market. I think like you mentioned, most of the attention recently has been on the prophylactic side. I think that's where the growth in the HAE market has been. How do you think about what happens to the acute market from here on out, especially with your product and potential other oral products coming onto the market?
Yeah, that's an excellent question because as I mentioned during our presentation, we think that one key driver for the growth of the prophylactic segment is related to the relative reduction in treatment burden in the injectable space. The Takhzyro example has lower injection frequency than other treatments in prophylactic. We think that's been a key driver, of course, in combination with good efficacy. The relative reduction in treatment in the injectable space has been the driver, and I think that continues to be a driver for HAE. I think that's also been seen in initial uptake of Orladeyo as an oral.
I think to us that validates the unmet need for an oral and we are excited about that because I think we are targeting also to provide a good level of efficacy, of course. I think that's also in the on-demand segment, in our view, could potentially have a paradigm shift once you have a more effective oral in on-demand. That is certainly in our view that our on-demand market is by no means obsolete or will go away. I think on the contrary, there's potential for also growth in the on-demand segment once there is an effective oral therapy option also for those patients who prefer to treat on-demand.
I think, you know, our product strategy is really set up to provide the patients the choice with the same active ingredient, with the two products on-demand and prophylactic to have a very seamless transition. I think another data point that we did not mention in our molecule is that in the prophylactic setting you get to steady state very quickly. So that also potentially enables patients to switch between the two and have what we call intermittent prophylaxis as a way, as an additional benefit for patients to have more flexibility how they treat.
Okay. I guess just to drill down on that. Historically, the acute HAE treatments have been bradykinin antagonists, and Firazyr was the dominant player in that segment, while plasma kallikrein inhibitors were, you know, the dominant mechanism of action on the prophylactic side. Having that seamless treatment paradigm, is that something that physicians have discussed as something that is attractive? Same thing with patients, is that something they are looking for?
I mean, there are two points there that you touch on. One is the bradykinin inhibition of B2 receptor as a mechanism for prophylactic has not been used in Icatibant, and that's for two very simple reasons. Number one is the shorter half-life of Icatibant, so you can't really use it prophylactically. Number two is the injection site reactions that you have for some patients is uncomfortable, so that makes Icatibant as a molecule or as a compound unsuitable for prophylactic. Our molecule, as you've seen from the data, as a B2 receptor antagonist and also makes it suitable for prophylactic development.
What we think is a potential advantage with having the same active ingredient in the two products is that also in our product strategy focus on the younger population in HAE is sort of the emerging HAE patients in the future. Because typically in adolescent age, when it's the age when diagnosis is typically done, HAE patients tend to be on an on-demand therapy. As they get older, this disease further progresses in their attack history, then they tend to become more towards the prophylactic.
Having a product that starts patients off with an on-demand, and it gives them the opportunity then, if they feel comfortable and that works for them, to have a very seamless transition over to a prophylactic choice, we think is a potential advantage and also a differentiating factor that we have.
Okay.
Yeah. If I could just add there. I think, you know, as Berndt said, we're hugely enthusiastic about the potential replacing the favored treatment for an attack, which is, as you said, a painful abdominal injection with a single small softgel capsule. We think that gives us opportunities for patients who we know in HAE actively switch to products they prefer. Berndt mentioned, the opportunity to get into a younger population for something that's really easy to take.
Okay.
I think there's a lot of potential there.
Just talking about maybe expectations for the upcoming readouts later this year. The CHAPTER-1 study, I think on the prophylactic side, the pathway to development is very well established. There's been a few products that have been approved in the last few years. Do you expect efficacy for PHVS416 and obviously PHVS719 down the road to be more in line with what we see with the injectables? Or I guess, is that the goal for that program?
Yeah, of course, not having seen the data, of course, it's hard to really pin down a number. What we think is that there's room for improvement, I think, in the current therapy options for oral prophylactic. That's, I think, we have the potential to provide that improvement, how much improvement the data will show. I think it's also, I mean, it's clear that the patient decides whether to take a injectable with a very high level of efficacy or do I take the oral with the obvious convenience, at least on this trial, the data and the lower efficacy.
That's a very individual choice, where patients then draw the line there, where the tipping point is. I think also whether that what works for that individual patient in totality. Another factor is of course in the oral prophylactic is that you have to take a pill every day. You know, it's a lifelong treatment, so the tolerability is also an important aspect here and the overall benefit for the patient. It's a combination of get as good as you can get on efficacy, the obvious convenience of an oral, and also minimize any discomfort with taking you know the side effect profile. I think that it's hard to pin an exact number on it.
Sure
We think we have a potential to show providing improvement for patients.
For the acute study, focus is really on the rapid onset and resolution of the symptoms and severity of the pain.
Yes. On the RAPIDe-1 study, again, it's also, I think that given the mechanism, what we've seen so far, I think we really expect to be comparable to Icatibant. That's of course something that we would be looking at it when we look at the data. Again, the data will show that of course. In our case also the fast onset is as fast or at least as fast as potentially even faster than Icatibant, as you've seen from the PK data. And also our molecule has a longer half-life, and so it maintains the therapeutic efficacy levels that we talked about before with EC85 over potentially longer periods.
That does look favorable or encouraging. Overall, I think for the RAPIDe-1 study it'd be comparable to Icatibant. I think also the very obvious convenience of taking a softgel capsule anywhere, anytime very easily compared to injecting yourself. It also would have a big impact on the on-demand setting.
Okay. Well, we're coming up on our time here.
Mm-hmm.
I want to thank both of you for spending time with us this morning. Appreciate it.
Yeah. Thanks, Serge .
Thank you, Serge.
I appreciate it as well. Thanks everybody for listening and watching.