Pharvaris N.V. (PHVS) Earnings Call Transcript & Summary

Hi, good morning. Happy Monday. Welcome to our Needham's 21st Annual Healthcare Conference. I'm Serge Belanger, one of the health care analysts at Needham. And 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. And they'll tell us a little bit more about Pharvaris. And for those listening in, there is a Q&A portal where you can submit your questions. We'll do Q&A after the presentation. So 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 hopefully we'll have some time for Q&A. So next slide then. Here's an overview, and we'll talk about some of these things in more detail in the deck. And by the way, the presentation that we're going to go through is also available on our website. So Pharvaris, we -- our key focus is the development of a new oral therapy of hereditary angioedema. And also part of our platform is also to look into other bradykinin-mediated diseases down the road. But first and foremost, HAE is a large -- HAE market is a rare disease market with over $2 billion in sales. And it continues to be very dynamic with predicted growth of around 9% over the next 5 years. There's still an unmet need for these patients and reducing treatment burden. There is a larger undiagnosed population still globally in HAE. And we addressed this market with an orally available small molecule, which is addressing the same target as in other HAE therapy, icatibant. It's a validated target. It's a B2 receptor pathway and bradykinin inhibition. And 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 will have shown clinical proof of mechanism, and you'll see that also in some more detail in the deck. And 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, it's patent granted in the U.S., pending in other territories. We recently got FDA orphan drug designation. And Pharvaris, as a company, we're basically based in 3 locations in the Netherlands, 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. And we have an experienced team in -- with experience in development all the way to approval in HAE. I don't see that here on this page. I'm Berndt Modig, the CEO. And 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. And Jochen is an inventor of icatibant and the Firazyr, and which became -- after it was launched in the U.S. in 2011, became 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. So in our team, we have a deep experience in the development for HAE. On the next slide, then 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 see some pictures here on these slides. And it's a potentially life-threatening condition, with patients ending up having laryngeal attacks of swelling in the larynx that could be fatal and lead to suffocation if left untreated. Most attacks are not painful. They're uncomfortable and big burden on these patients. Nevertheless, the abdominal attack that you see here on the right is -- on the other hand, is extremely painful. And it's a global disease. It's, as I mentioned in the beginning, 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 also in Europe. On the next slide then, you'll see the mechanism behind what causes the selling attacks in HAE, and it's ultimately caused by excess levels of bradykinin which is released in the pathway due to a genetic defect in 1 -- mutation and the gene that codes for protein C1, that results in uncontrolled release of bradykinin. Bradykinin binds on the beta receptor and causes the extravasation of fluid into the tissue and it causes the signs and symptoms associated with hereditary angioedema attacks. We believe that bradykinin inhibition and 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 as these are same target. Another advantage of bradykinin inhibition is it also makes it possible to treat other forms of angioedema that are not related to C1 deficiency. So the other forms of angioedema with normal C1, you see here on the left, different types of mutations, can also be treated with bradykinin inhibition in contrast to other approaches further up in the cascade. So therefore, we believe that there are advantages in addressing this with bradykinin inhibition. On the next slide then, 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. So 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 an 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 to 24 attacks per year. And there are patients with many more attacks and also patients with 0 attacks and that is a key driver of determining whether a patient will be treating prophylactically versus treating when the attack comes and what we call on-demand treatment. And on the next slide then, you'll see the overview of the key element that really patients are looking for, basically 3 things, that HAE patients are concerned about in managing their condition. Efficacy is the prime concern, that's very clear. But also safety, tolerability, of course, are important. And this is the factor that pushes patients also to explore alternatives because to date, even though there are several products that have come through the HAE community, none of them are perfect so far. And also convenience is a key factor. This is a lifelong disease, and that's also driving patient preference. And we believe that an oral therapy option for HAE patients is the ultimate inconvenience. And our targeting here is to provide all 3 elements of what patients are looking for with our program. On the next slide then, you'll see an overview of the current market. In this circle diagram here, the right part is, these 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. And in the last years that have been -- you would have seen an increase in the use of prophylactic products and primarily driven by improved convenience in the injectables. So everything that you see here on this slide, except for Orladeyo, the yellow slice at the bottom, are injectables and the growth in the prophylactic segment recently has been driven primarily by the relative reduction in injection frequency. But 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. So as I mentioned in the beginning, we have PHA121, that's our basic molecule, a new chemical entity, that's -- on which we have IP. And with that molecule, we developed 2 separate products, PHVS416, to the left, optimized for on-demand treatment to -- that's designed to provide fast, easy and reliable symptom relief for the attack when it happens. And 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. And we have seen in that formulation of softgel capsule formulation, the fast onset and also a longer duration than icatibant. On the right, you see PHVS719, that's our extended-release tablet formulation for angioedema and that is designed to maintain compound exposure to prevent attacks and that with the once daily providing easy and effective way to live with HAE. The red line on both curve, you see this target plasma level, that is the trough level of the plasma concentration that is associated with therapeutic efficacy. So you need to have -- be above this line in terms of exposure. We're using the same API with these 2 products, that's an important thing to remember. On our pipeline on this slide, we have 2 Phase II studies ongoing, RAPIDe-1, which is our on-demand trial using the 416 softgel capsule. And we also are running a Phase II trial for prophylactic. And in this study, we are using 406, 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. But the product strategy, I mentioned, is really -- for the prophylactic is ultimately to go with 719 for prophylactic. So 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 will talk about in a minute, and the data shows that it's suitable for the daily dosing -- once daily dosing. And the plan with 719 is to do the Phase III study for prophylactic using the 719, so that is expected to be the final commercial product for prophylactic use. So 2 products, 416 for on-demand and 719 for prophylactic. So 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. So as Berndt mentioned, we've taken PHA121 through Phase I studies, a single ascending dose and multiple ascending dose studies. And 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 is about 3x as long as icatibant. As Berndt mentioned, this is a key advance over icatibant in addition to the oral dosing. And so 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 of other key things that we learned in that Phase I really sets up our product strategy. So on the left here, you're seeing the first hour after dosing with the solution of 22 milligrams underfed and 2 different -- sorry, 2 different fed conditions and fasted as well. And the really important lesson there is the EC85 line, we've mentioned earlier, is the target level that comes out of a bradykinin challenge that I'll tell you about in a couple of slides. So that EC85 is what we see as the target for suppressing the effects of a surge bradykinin. And you can see that in all 3 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. And so that really enables us to use that softgel capsule with the solution in it as a treatment for an attack once it's occurred. And then on the other side, on the right-hand side, you see a food effect for the longer-term exposure. So here over the longer term fed, either 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 and the inset is the result from our multiple ascending dose study where we gave healthy volunteers twice a day dosing with food. And we see that in the 3 doses that we're looking at in this graph, well above the EC85 at the trough on the last day. So the food effect both gave us the confidence about being able to do an extended release technically as well as giving us a tool to get faster into the prophylactic study with the compound. So I've shown you a couple of 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 -- in their 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. So in the case of icatibant study, of course, that was used as a subcu injection. You do a single dose and then administer bradykinin. And as you do that periodically, bradykinin administration through the day, the effect of icatibant wears off as this PK progresses. And so you can get a pharmacokinetic, pharmacodynamic correlation and allows you to set and establish effective concentrations for ameliorating this bradykinin effect as well as duration of that effect. So 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. So we were inspired by that experiment, and we've done it ourselves now. And this is the result of that work. And so you see here on the left-hand side, our dosing schedules that we see here, 5 doses of bradykinin administered over the course of 24 hours following a single administration of either placebo or 121. And you can see with real-time blood pressure monitoring in these healthy volunteers, the dip when bradykinin is administered before treatment and the flat but noisy line afterwards. So all of that is modeled across the group of volunteers and it allows you to pull out from that effective concentration, 50 and 85, and you see the blue boxes on the right-hand side. Those numbers are fourfold more potent than icatibant. So that reflected back through all the preclinical data that we had as well. So there's a consistent correlation between our preclinical and clinical observations. And then also from that model then, we're able to pull out the 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. And on the bottom box, you see that a single administration of the 22-milligram dose lasts as long as 2 doses of icatibant. And so that gives us our sort of our central tenet of not being just a more convenient icatibant, but better icatibant. And I'll also point out that this bradykinin challenge can only be done with compounds that are bradykinin 2 receptor antagonist. So we're the only folks in this field who can do a human-based assessment of clinical dose selection. And so having done that and using that really as our guiding star for dose selection, we'll tell you about the product strategy around 416 and 719. And so here with 416 in on-demand with a RAPID study, we're doing a 3-dose, 3-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. So we'll be looking at that at the 4-hour time point following dose. We're happy to say that we have reached the enrollment target and so 72 patients are enrolled at this point across multiple sites in U.S. and internationally. And 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 3 attacks to get the full selection of the 2 doses of compound and 1 dose in placebo. And so because these attacks are unpredictable and an attack here has to, of course, be a qualified attack, there is some unpredictability in terms of the timing of the end point by the end of the trial, I should say. So moving from that to our prophylactic program. As Berndt had mentioned, our goal here is to use the efficacy data we get from a POC -- proof-of-concept study using 416, combining it with the PK data that we get from our tablet and moving that together to go into pivotal studies using the tablet approach. And so that study, we call CHAPTER, is a 2-dose study observing patients for 12 weeks with placebo control, looking at the number of attacks confirmed by investigators. So a very standard design compared to the other folks in this field. And that trial aims to enroll 30 patients across U.S., Canada and Europe. And we expect to have top line data there by the end of the year as well. And then as Berndt mentioned, we've done a PK study. So this was a single-dose PK study, our first study using our extended release. What we saw in that, and this was a crossover experiment where we did a couple of different release profiles with extended release as well as 416 for the single dose rapid release. We continue to show good tolerability for both of these forms, extended release and the rapid release. And we show, as we've been alluding to confirm that, that oral softgel capsule releases just as fast as the solution by itself and that we've been able to show, very importantly, with our extended release, a 24-hour exposure above our EC85 line. And very conveniently, the dose we're using here, the 40-milligram dose, provides the similar overall AUC as the 20 mg twice a day with food that we're using in CHAPTER-1. And so here, we see in the graph for this, the blue line is our softgel capsule, the rapid release, that lasts 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 the attacks occurred. And then the green lines, you see both fed and fasted exposures of this extended release where you see very characteristically for a compound that is -- can be absorbed by the colon and release matrix that we're using, where you do not get exposure at stomach. So there's a delay at the beginning, but then the compound releases from matrix once the tablet starts transiting through the colon. And so when we see a good exposure well above that line over the course of a full day. So we're very encouraged by this and what it means for our ability to have to -- a differentiated profile for the 2 products. We'll be taking this on -- into multi-dose studies as we prepare to move that to Phase III. So I'll turn it back to Berndt.

Yes. Thank you, Morgan. So -- again, so -- here's the overview and the summary. So 416, our on-demand product, soft capsule, easy to take, easy to swallow, a very tiny softgel capsule, currently in our Phase II study, RAPIDe-1, with top line data anticipated in Q4. And on the prophylactic side, our 719, extended-release tablet, again, same active ingredient. And as we just saw, the favorable PK curve suitable for prophylactic in once daily potential. And in the prophylactic Phase II study ongoing with the CHAPTER-1, with top line data anticipated in Q4 2022. And financially strong, EUR 209 million in cash, provides us a run rate to Q1 2024 to execute on these programs. Thank you very much. And now we can have some time left over for some questions.

Thank you for the great presentation. Obviously, an important year for the company with some really important derisking data readouts at the end of the year. I want to start off with a broad question, I guess for Berndt, since you're, I guess, a veteran of the HAE space. How has the market changed since the Jerini days and maybe how has clinical development for HAE treatments changed since those days?

Yes, on the market, it's been an amazing journey and also for the HAE patients who have been benefited from a lot of products in the last decade. I recall that during the Jerini days, we're discussing with our investors back then, what's the market size for HAE and it turned out much, much bigger. And so the market has had a tremendous development, and it's been really good for HAE patients. And then 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 the -- in recent years, of course, prophylactic treatment become -- more products coming to the prophylactic space. And I think there the development path is well established. And I think also for on-demand, it's some variations and different types of end points. VAS is an endpoint that's been used in the icatibant study and the one we also have here for our study. And another feature we didn't mention in the development in our particular study in RAPIDe-1 is that it's done in a home setting, whereas the icatibant study was done in the clinics. So the patients in our study can treat it at home and close contact with the site by telephone. 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, like most -- 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 on board?

That's an excellent question because as I mentioned during our presentation, we think that the 1 key driver for the growth of the prophylactic segment is related to the relative reduction in treatment burden in the injectable space. So the TAKHZYRO, for example, has a lower injection frequency than other treatments in prophylaxis. So that -- we think that's been a key driver, I think, both in combination with good efficacy, but the treatment -- the relative reduction in treatment burden in 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 the initial uptake of Orladeyo. It's an oral, I think, 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. And I think that's also, in the on-demand segment will, 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 on-demand market is by no means obsolete or will go away. I think on the contrary, there's a 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. And I think our product strategy is really set up to provide the patients the choice with the same active ingredient with 2 products on-demand and prophylactic to have a very seamless transition. And I think another data point that we did not mention in our molecule is that in the prophylactic setting is a very -- you get to steady state quickly. So it also potentially enables patients to switch between the 2 and have what we call intermittent prophylaxis as an additional benefit for patients to have more flexibility how they are treated.

Okay. And 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 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?

Yes, there are 2 points there that you touched on. One is the bradykinin inhibition of B2 receptor as a mechanism for prophylactic has not been used in icatibant, and that's for 2 very simple reasons. Number 1 is the shorter half-life of icatibant, so you can't really use it prophylactically. Number 2 is the injection site reactions that we have for some patients is uncomfortable. So that makes icatibant, as a molecule -- as a compound, unsuitable for prophylactic. But our molecule, as you've seen from the data, as a B2 receptor antagonist and also makes it suitable for prophylactic development. And that the -- what we think is a potential advantage with having the same active ingredient in the 2 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 an adolescent age when -- it's the age when diagnosis is typically done, HAE patients tend to be on an on-demand therapy. And as they get older, the disease further progresses, and their attack history that they tend to become more towards the prophylactic. So having a product that starts patients off with on-demand and it gives them the opportunity and 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.

If I could just add there, I think as Berndt said, we're hugely enthusiastic about the potential of replacing the favored treatment for an attack, which is, as he said, a painful abdominal injection with a single small softgel capsule. We think that gives us opportunities for patients who we know when HAE actively switch to products they prefer. And as Berndt mentioned, an opportunity to get into a younger population, something that's really easy to take. I think there's a lot of potential there.

And then just talking about maybe expectations for the upcoming readouts later this year. So 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 416 and obviously 719 down the road to be more in line with what we see with the injectables? Or I guess, is that the goal for that?

Of course, not having seen the data, of course, it's hard to really pin down a number. But the -- what we think is that there's room for improvement, I think, in the current therapy options for oral prophylactic. So that said, I think we have the potential to provide that improvement. How much of an improvement, the data will show. I think it's also -- I mean it's clear that the patient decides whether to do -- take an injectable with a very high level of efficacy or do I take the oral with the obvious convenience with -- based on the data and the lower efficacy. That's a very individual choice where patients then draw the line there was a tipping point. And I think also whether that -- what works for that individual patient in totality. And other factor is, of course, in the oral prophylactic is when you have to take a pill every day, it's a lifelong treatment. So the tolerability is also an important aspect here in the overall benefit for the patient. So 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 the side effect profile. So I think that it's hard to pin an exact number on it, but we think we have a potential to show -- provide an improvement for patients.

And 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, we think we expect to be comparable to icatibant. That's, of course, something that we will be looking at and -- when we look at the data. Again, the data will show that, of course. And the -- in our case, also the fast onset is as fast -- at least as fast as or potentially even faster than icatibant as seen from the PK data. And also, our molecule has a longer half-life, so it maintains the therapeutic efficacy levels that we have -- that we talked about before with EC85 over potentially longer period. So that does look favorable or encouraging. And so -- overall, I think for the RAPIDe-1 study to be comparable to icatibant. And I think also 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 segment.

Sure. Well, we're coming up on our time here. So I want to thank both of you for spending time with us this morning. Appreciate it.

Yes. Thanks, Serge, and appreciate it as well. And thanks, everybody, for listening and watching.

Thanks, Serge.

All right. Bye.