Okay, great. Welcome, everyone, to the next session of the Cantor Fitzgerald Global Healthcare Conference. I'm Steve Seedhouse on the biotech team here at Cantor. It really is a privilege to welcome a team less than 48 hours, I guess, or very shortly after their second phase III success within the last year. This is Pharvaris. I'm joined by many of the team members up here, and maybe I can have them introduce themselves as they make their introductory remarks. Berndt Modig, CEO, maybe I can start with you.
Yeah.
We can go down the line. Would love to just, as you've had time to reflect on the phase III prophylaxis data in HAE for deucrictibant, how are you feeling about the results and what's been the reaction?
Yeah. Obviously incredibly excited about seeing that, and also on top of the phase III result on the band that we had in December last year. It really makes us very excited about the future for deucrictibant. Rewinding a little bit, I came into this therapeutic area 23 years ago with the company that developed icatibant, and already back then we saw the potential unmet need for an oral. So 10 years and now four months ago, we set out to, basically from scratch, to develop a molecule with the same MOA as icatibant, a B2 receptor antagonist, with the vision of improving the lives of people living with hereditary angioedema. Really excited to say also, to our knowledge, deucrictibant is the only orally available B2 receptor antagonist out there.
Not only that, but because of the properties, as we know, it makes it suitable both for on-demand and prophylaxis. So with one molecule, we have two products to cover and meet all the needs of people living with HAE. So now with that data, we'll talk more about it in a minute, then we are looking forward to get launching this, and we are already well underway with our on-demand launch predicted for the 8th in April next year. Follow then after we have filed and with the review on the prophylaxis, also to launch the prophylaxis indication. We're also aiming to broaden the application of deucrictibant in not only HAE 1 and 2, but also type 3 and a condition called acquired angioedema, for which there's nothing approved today. Bradykinin-mediated angioedema is really the focus of ours.
I will bring in President Peng Lu as well, and Chief Commercial Officer Wim Souverijns, and maybe have an intro question for each of you as well. I guess, Peng, summarize, did anything surprise you or really your take on the efficacy and the safety side? In particular on the safety side, maybe you can address, we keep getting a lot of questions about LFT elevations and there was one quirky patient that had this laryngeal dyskinesia, I think. Maybe address some of that upfront, just to clarify any confusion that people might have had from that, because I think obviously holistically the data was terrific.
Sure, yeah. Thanks, Steve. Actually, as everyone see our top-line readout, we do have one serious adverse event reported that Steve has mentioned is the laryngeal dyskinesia. Actually, everyone is chasing around to see what the dyskinesia means there. Actually, it is a vocal cord disorder that once around the time when we see this case, this patient is hospitalized, we reach out to the site and to the investigator to understand more. Actually, this is a normal C1 patient. That is the first time we include normal C1 patients in this trial. Prior to joining the CHAPTER-3 study, this patient observed 19 laryngeal attacks before joining the study within the three months. This patient is almost frequent visit to the ER to get intubation, because as you know, that a vocal disorder can be triggered by the frequent intubation.
There are some factors, some triggers, that can lead into this disorder. That is why that while the patient hospitalized, that we checked disorder, there is also because patient in the trial, they did the laryngeal microscopy there. There is no any swelling. That is why it is exclude this is a laryngeal attack. Then the patients get better, and actually, the doctor shared more information with us. Since this patient joined the CHAPTER-3 study, of course, the doctor doesn't know the patient on active treatment or on the placebo. He only mentioned to us the patient reduced attack 90%, that laryngeal attack. The patient are very happy, joined the study, and even back to work. Because in the past, there are so many laryngeal attacks happens, he always have to visit the ER there. She cannot work. She is a pharmacist.
But she is so happy to join the study and start the new chapter of life. That is why make us, at least myself, feel really proud that deucrictibant really can help the patients with unmet medical need there to really get the new life for the patients.
This is a Type 3 patient, which of course-
This is a Type 3 patient.
are not even enrolled in the other studies.
Yeah.
Okay. How are we going to launch this drug, Wim?
Stellar launch it's going to be.
Okay.
The team is super excited. I joined five years ago, and to really be at the verge of really getting in the hand of the doctors and the people that need this is super rewarding. I think we got all the, I sometimes say deucrictibant is the product that keeps on giving. I think from a data perspective, on-demand and prophy, we can't ask for more. Now it's up to us to execute on this. I think we put the first seeds of our launch three years ago when we launched our disease state education campaign, Deflate HAE, which is a picture of a blue man with a big blue belly. The point of that campaign was to raise awareness for the unconscious unmet need. Because if you talk to patients, probably they will say, "I'm doing fine."
But what they don't realize is they're trading off efficacy versus tolerability and convenience. What we hope for is that if this drug gets approved, that we can offer something to the community that really doesn't force patients to make those trade-offs anymore. This year is a focus on building the organization infrastructure, the processes, systems, hiring the team, and then go full speed that's after approval, after PDUFA date.
Indeed. Just back to the trial, and I will just open this up to the group, whoever wants to take these questions. A couple of things that stood out to me. First of all, obviously, in the type 1, type 2 patients, the efficacy, 87% attack rate reduction, was even better than phase II. I think this was always in the realm of possibility given the novel formulation, extended-release formulation. Did that surprise you? Do you think that is really just attributed to that improved formulation? That is question one. The other feature of the study that I thought was interesting was the baseline attack rate was not low. It was higher even than phase II. I think it was in the mid threes, 3.8, 3.6. This was not a mild patient population, and yet you still achieved the efficacy you achieved.
It was even less mild, I think, than some of the contemporary injectable studies. Maybe if you could comment on those two points, and just what that means, and how you would be able to market to some of those details when you launch.
Yeah. Maybe I can start on the formulation part and then over to Peng .
Sure. Yeah.
In the course of the time or during the trial and before the data, we spent a lot of time addressing and thinking about and answering questions about the change in formulation from phase II to phase III, and with the BID on the IR capsule in the phase II, and going to the phase III with the new extended-release formulation. We are really excited to see that efficacy holds up or potentially even better. I think that one possible explanation is also that what we looked at before the data is that the more favorable PK profile that has a more sustained exposure over the EC85, the plasma level concentration that is needed for therapeutic efficacy. That seems to have borne out in the data that we have seen. We are happy that with that formulation change, we ended up on the right side of efficacy.
Yeah. Actually, as Berndt mentioned, is that we definitely around that time when we get a phase II result and think about the phase III, we feel that with extended-release formulation can cover more diverse patient population in phase III, as we discussed, right? From phase II to phase III, always have certain discount of efficacy because more diverse patient population. The same thing for CHAPTER-3. Compared to CHAPTER-2, our study mainly conducted in North America and Europe, but for CHAPTER-3 study, actually we enrolled the patients from the six continentals, including Asian Pacific, Latin American countries, and even South Africa there. That is why indeed it beat my expectation to see with extended-release formulation, our efficacy readout, just look at the type 1, 2, have apple to apple comparison, is better than to choose a phase II.
I think I definitely believe, as Steve mentioned, that the extended-release formulation provide more sustained protection here. Another thing is that to go back to address that baseline high attack rate, you can tell because the patients are also not only limited to Europe and the North American countries. The patients from Latin American and Asian Pacific and South Africa patients, these patients indeed have higher data baseline attack. That is one thing that you mentioned why the baseline attack rate is higher compared to phase II. Another factor I just want to introduce a little bit, if we look at the three months prior during the study, three months observation, the median attack or mean attack rate about three attack per month is lower compared to 3.6 during the running period.
It is also because the running period is shorter, is generally only the 4-8 weeks compared to 12 weeks or longer. That is another sort of little bit artificial reasons to boost a little bit baseline attack rate.
Okay.
Yeah. That's the two factors contribute to your observation there.
Yeah. Okay. Of course, the type 1, type 2 efficacy being that 87% number, but you did have, it was five patients that were randomized three and two, the drug and placebo. I think you made some comments on your data call, but I'd like to revisit that. What was the efficacy you saw in those type 3 patients, and what does that mean ultimately for sort of the label you get and the ability to market to that subpopulation once approved?
Yeah, I can take it. As mentioned, at the beginning before the CHAPTER-3 study, we indeed debate that whether we would like to include the normal C1 patients, because as you mentioned, normal C1 patients have much more complicated pathophysiology. We know that the response will be more diverse. However, I think that compared to all other approved treatments or the treatment under development, deucrictibant may be the only treatment based on MOA that are able to help these patients because we are more downstream. No matter bradykinin generated by plasma kallikrein pathway or plasma kallikrein independent pathway, deucrictibant expect to work. That's exactly when both FDA and EMA reached out to us, recommended including the type 3 patients into CHAPTER-3 study.
I have to say, we take the risk here, and we include the CHAPTER-3, the type 3 patient into study, really to think about that provides the data later on, help physician, help patients. Therefore, during look at the study, there are three normal C1 patients on the active treatment. All these three patients get improved compared to baseline. But one patient is not improved as dramatic as others. That's one patient and less than 50% reduction. But one patient we discussed a lot about the laryngeal dyskinesia case, that patient improved close to 90% attack reduction for laryngeal attack. The third patient actually achieved attack free for six months.
Nice.
That's why we are very happy to see this result. Back to your question. We believe all this data and also MOA information will be included in the label, hopefully in the future to help that commercial part and help all the physicians, the clinical practice there.
That CREAATE study, which would be an acquired angioedema, still bradykinin-mediated angioedema. Of course, everyone noted in your press release your intent to submit your filing in the first half of next year for bradykinin-mediated angioedema. Would that include the acquired angioedema data, or do you think you can get that broad label just on the basis of CHAPTER-3?
The plan is to include that data-
Yeah
in the overall filing.
Yeah. Okay.
That study is well on the way and on track, and we guided top-line readout for that trial in Q1 next year.
Can I just go? You did a great job, Peng, reviewing the patient with the laryngeal dyskinesia. Just because I keep getting the question, it is really the only thing in the data set that I think needed clarity. On the LFT elevations, did either of those patients with the grade 3 elevations have bilirubin increase? Neither.
I know there is some. No, we did not observe any bilirubin elevation there.
No.
Also both the patients have no symptom.
Yep. Okay.
Yeah.
There were some confounding factors, I think, that you mentioned on the data call. In those patients, I think you said fatty liver disease and long-term androgen treatment. Just a broader question, going back to the phase II and just going back to the molecule itself, what would you say about the hepatotoxicity risk or concern or narrative? Are you comfortable that there's no hepatotoxicity? Could there be potentially a warning in the label just because of this imbalance in events? What are background rates in the population? Just anything you can talk about with respect to contextualizing those events, I think would be helpful for folks.
Sure. Yeah. Overall, just same as the efficacy part, we are very happy to see deucrictibant is very well tolerated within this study. To come back, you specifically mentioned the hepatic enzyme elevation. Actually, this observation is not uncommon for the HAE prophylactic trial. Because for HAE patients themselves and due to the nature of the disease and due to the historical, a lot of patients have long-term use of the androgen, especially for Asian, Pacific, Latin American, and South Africa patients. They are short of the modern therapy there. Therefore, all this will contribute to the fragile liver of these patients. Any potential maybe infection or other factors can also trigger liver enzyme elevation. That is why when we see the data here, if we feel that for hepatic enzyme elevation, it happens. That is why for transparency part, we shared the data.
Meanwhile, we are very confident about the data. It is very well compared to the others, the prophy treatment. For example, no matter for lanadelumab, you mentioned, or [devol], that is also observed the liver enzyme elevation for the certain portion of the patients. For either of the treatment, it is mentioned one patient discontinued treatment due to the liver enzyme elevation. That is why we would like to provide all these details. From the other side, based on the CHAPTER-3 data, so far, we feel that the label will be similar or comparable to other HAE prophy treatment.
That is very helpful. Okay. Thank you. I guess just projecting commercially in prophylaxis, and I certainly want to cover on-demand. We do not want to forget, obviously, about that successful phase III and the expanded access program and the nearing PDUFA. We will get to that. As you project the prophylaxis market and the share of oral prophylaxis in general relative to the broader market, which includes these injectable prophylactic agents, where do you think oral can get to? Right now, I think it is closer to 20%-21% penetration in the market. Existing drug ORLADEYO, of course, has high discontinuation rates because the efficacy is not as good as the injectables. Where do you see that going? Can it get to 50%, 70%, 100%?
Yeah. It is very hard to give you a precise number, but conceptually, I think ORLADEYO has really demonstrated the huge desire for an oral. Despite the fact that they only have half the efficacy of TAKHZYRO, getting to 21% patient share, that is a pretty good job done, I would say. That tells you that intrinsically, the market is really looking for an oral. If you then bring an oral that is injectable-like efficacy, the game completely changes. We look at the market in three buckets. We basically have the new patients to LTP, new patients that get onto prophylaxis. Every year, there are between 150 and 250 new patients in HAE, and they flow through the therapy, and they ultimately ended up in prophylaxis, most of them. With the proposition we have, we become the de facto first-line therapy For LTP.
Yep.
For patients with laryngeal dyskinesia. What is important is that because we have such a good efficacy and tolerability profile, we do not anticipate to see that 40% dropout after one year that you see with ORLADEYO. So if we have, let us say 5% dropout, and you capture every year a big chunk of these new patients, you create a pancake effect, and that really is a driver engine to become ultimately leader in prophylaxis. Secondly, the whole Oral segment, we absolutely believe that we should eat that market. I think we have absolutely the profile to be leading and dominating there. Lastly, you have the Injectables. In that segment, there is still a lot of patients there that if they could have an oral that has the same efficacy as a TAKHZYRO or an ANDEMBRY, they will go there.
Simply because they do not want to sacrifice on efficacy, they did not make that move. So ultimately, I think deucrictibant XR really has the opportunity to become the leading product within the whole prophylactic setting. What that total share is of orals and deucrictibant, let us see that a couple of years down the line, but it will be significant.
Okay. Maybe we can spend a few minutes on on-demand then, since that would be the more near-term launch, I guess. What should we know about if we were to? We have this precedent of EKTERLY recently launching in that market, and I think we can all agree it went quite well. It proves that there is demand for oral therapy in that market. If you compare and contrast to what we have seen from that adoption, maybe the type of investment in sales force that Pharvaris is and will make, your plans ex-U.S., like some of the sort of, on the margins considerations and decisions you have to make there. Would love to walk through them. So pricing first, maybe investment, OpEx, sales force, and then ex-U.S., what is your strategy? Those three points.
You have to remind me all these questions.
I will. Yeah. Well, let's start with pricing.
Pricing, I think we're in a beautiful position both in on-demand and prophy, because of the quality of the data, strength of the data, to have full flexibility in how we price. Now, we will be looking at our pricing decision for on-demand in the context of also prophy. We're looking at the portfolio.
Because ultimately what we want to do is we want to make sure that we maximize the opportunity of deucrictibant across the whole portfolio. That means that we might take some decisions you wouldn't take if you would solely have an on-demand therapy. We're working on this right now. We're kind of putting all these ideas together. It's a very complex market. A lot of dynamics going on, but I think when we talk to payers on on-demand particularly, the feedback is very positive because payers see the single-dose resolution, and that for them is obviously an economic benefit.
I see.
That really gives us a lot of power or flexibility to kind of optimize.
If I'm interpreting that correctly, you could do something like price at a discount in on-demand if it meant that it would incentivize use of the prophylactic regimen, something like this?
Well, what for us is important is that we get a very good launch in on-demand. Because the more patients that are on-
Yep
IR, the more we can actually have those patients consider prophylaxis-
Yes
because they will have known the therapy, there is no change in the product. We want to drive uptake, and our pricing strategy will kind of enable us to do that.
Okay.
I also like to add indeed, we also agree that the launch of EKTERLY, what you've seen there validates the need for an oral.
Yep.
Having said that, though, there is still a, that we predict by the time we launch, a very significant number of patients that are still on icatibant. You could make the argument that due to the ease of trying out an oral, you might wonder why are these patients hesitating to take EKTERLY, that is because they are comfortable with the mechanism, they're comfortable with the icatibant. Deucrictibant then with the same mode of action builds on that legacy of icatibant, and that icatibant patients will be also a key segment of our approach when we launch deucrictibant for IR.
And then just on the sort of investment and the sales effort and what that footprint looks like, is there perfect synergy here between the two molecules and the ability to just have one call point for one salesperson and sell both products, and what do you need to do between here and launch-
Yeah
now that you know that prophylaxis was as successful as it was?
Yeah. So we've got a very experienced head of the U.S. market who has launched Firazyr many, many years ago. From the get go, we decided we're building an organization for HAE, actually for bradykinin-mediated angioedema. So we're not going to kind of go piecemeal and then add people when the prophylactic comes on board. Yes, there will be people coming in like patient care coordinators and the patient services hub because that's just linked to the number of patients you have. But the field force will be there from day one. We don't want to create disturbance. We don't want to change territories, et cetera. And this organization will be benchmarked against the other teams that are out there in the market. And as you know, this is a therapeutic area with less than 100 people, you can be very, very competitive.
Can I get your perspective, obviously an ex-U.S. domiciled company, would love your perspective on the ex-U.S. market in HAE. It has been handled in different ways by different players. There are a couple, obviously global pharma companies involved in this space. There are real markets ex-U.S. So how are you thinking about maximizing value for Pharvaris-
Yep.
outside the U.S.?
Yes. As you know that we are already doing some work on the filing side. We are kind of not ignoring these markets. Obviously these things get much more consecutively done because they are resource driven as well, and we do not want to explode our regulatory team for doing that. At the same time, we do some of the prep work that really foundation like the market access is the key driver ex-U.S. In America, in the U.S., you have a very important driver to the field force, the sales force. Why is that? Because there are about 2,000 doctors that you really want to call upon. If you go to a country like Germany, there are basically 40, 50 doctors that you need to see. So you can have much smaller organizations to really capture those.
What we are doing at the moment is really looking at our options, how we want to execute now because as you said, the margins are very different. Prices are very different. We really want to make sure that we do the right thing, but there is no point in pushing ourselves to go too fast in some of these markets and then not getting the return that we need there. Prophylaxis is the bigger opportunity we see in any of these territories anyway.
Yep. Can you walk us through what to expect? I feel like we are on the eve of the phase III prophylaxis study. You had the phase III on-demand study, but yet there is still more data coming, right? We have CREAATE, the acquired angioedema study. There would be an open label extension at some point where data would accrue, and you could have a decision as to how to update folks on that data. I know that it was fast-acting activity in CHAPTER-3, and that was durable over the course of the study. But it is still interesting to see at six months or at one year, at 18 months how that proceeds.
Can you walk us through what the next key updates are for the deucrictibant studies that are ongoing, and what data would be forthcoming that you would flag as being important and potentially adding to what you have already shown?
Mm-hmm. Yeah. We already mentioned the approval and the launch of IR, the data in acquired angioedema, that then together with the filing for prophy then has an upside potential of priority review subject to concurrence and agreement with the regulatory side. Then, of course, how the launch takes off and the performance of the launch. Then we also have not disclosed exactly details of that yet. That is coming in due course. But we are also thinking of possible product line extensions of deucrictibant in other bradykinin-mediated indications, where that could be compatible from a commercial perspective in terms of pricing structure, where there is an unmet need, and a meaningful potential incremental commercial opportunity for deucrictibant in a relatively short timeframe with a relatively efficient and capital-efficient development plan. So that is something we are looking at.
We will talk about more of that also in due course next year.
You have published. Pharvaris, I think, contributed to a publication you press released about the involvement of B2R in some of these non-angioedema indications and even mentioned something, I believe, in the press release after CHAPTER-3 that you are interested in pursuing that. Would that entail the extended-release formulation that you already have in hand?
Could be either, yeah.
Okay. We will look forward, obviously, to any updates in that regard strategically. You mentioned priority review is something that you believe is on the table for the prophylaxis regimen on filing.
Sorry, priority?
Do you believe priority review-
Oh, priority review.
Of prophylaxis filing is possible?
Yes. As I said, if you file the CREAATE data with acquired angioedema together with the prophylaxis filing, then as a potential upside, again, subject to regulatory concurrence and agreement with that could give us priority review.
Okay.
It's an upside, as I said, yeah.
Okay, terrific. Well, listen, obviously, congrats on the successful results. We're looking forward to continued updates from the company as you guys prosecute the filings and get closer to launch of the on-demand product and-
Yeah
look forward to reconnecting as those events happen.
Great.
Yeah, terrific, and thanks for being here. Thanks to everyone in the audience as well.
Yeah. Thank you so much. Yeah.
Thanks, everyone.