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

Thank you, Nadia. Welcome to the top-line data announcement of RAPIDe-1, a Phase II clinical study of PHVS416 for the on-demand treatment of hereditary angioedema. My name is Maryann Cimino, Director of Corporate Relations at Pharvaris. Please note that today's webcast is being recorded, and the slides will be uploaded onto the Investors section of our corporate website immediately following this call. Please note that the statements of our guests today are their own and not those of Pharvaris. While the company believes these statements to be reliable as of the date of this presentation, it has not independently verified and makes no representation as to the adequacy, fairness, accuracy or completeness of the information in their comments. In addition, our presentation today will include forward-looking statements, including, but not limited to, statements regarding our future plans, product candidates and clinical studies. Such forward-looking statements are subject to certain risks and uncertainties that could cause actual results to differ materially from those projected. For additional information regarding the various factors that could cause such differences, please see the section entitled Risk Factors in our annual report on Form 20-F and our other filings available on the SEC's website. In addition, any forward-looking statements represent the company's expectations only as of today. While we may elect to update these forward-looking statements, we specifically disclaim any obligation to do so unless required by law. During our call, Pharvaris' Chief Executive Officer, Berndt Modig will speak to our mission and vision to improve the standard of care for people living with HAE. Next, Pharvaris' Chief Medical Officer, Dr. Peng Lu, will go through the top line efficacy and safety findings from RAPIDe-1. We are also joined by Professor Marcus Maurer, the principal investigator in the RAPIDe-1 clinical study, who will share his perspective as a treating physician on these data. Thank you, Professor Maurer for joining us. Additionally, Pharvaris' Chief Community Engagement and Commercial Officer, Wim Souverijns, and Chief Business Officer, Morgan Conn, are available for the Q&A portion of the call. I will now turn it over to Berndt.

Thank you, Maryann, and thank you all for joining our call. Today marks an important milestone for Pharvaris, as we will be sharing for the first time clinical data in people living with HAE from our Phase II on-demand RAPIDe-1 study. In the last 2 decades, substantial progress has been made in treating HAE attacks. However, despite this progress, people living -- people with HAE have significant unmet need. Today, the Standard of Care for on-demand treatment requires a painful injection, which often requires redosing and can be very burdensome. Therefore, many attacks go untreated or treatment is delayed counter to the international clinical guideline recommendations for treating all attacks early. When we ask patients what they expected from a new therapy to treat their HAE attacks, they were crystal clear. They are looking for a treatment that provides rapid onset of symptom relief and attack resolution with one single dose and in the form of an oral medicine. Targeting bradykinin, the ultimate cause of the signs and symptoms of HAE attacks has the potential to deliver on their hopes. At Pharvaris, we discovered and developed the first orally bioavailable bradykinin B2 receptor antagonist. The dose and exposure level as determined through the bradykinin challenge in healthy volunteers provided the foundation for the design of our RAPIDe-1 trial that we will look at in a few minutes. I will now hand it over to our Chief Medical Officer, Dr. Lu to walk through the RAPIDe-1 data. Peng?

Thank you, Berndt. I'm very happy to share the top-line results of the RAPIDe-1 study today. RAPIDe-1 is a Phase II study to assess the efficacy and safety of 416 for the on-demand treatment of HAE attack. The RAPIDe-1 study has 2 parts: In Part 1, all the patients are randomized receive a single dose of 416, either 10, 20 or 30 milligrams for PK and the safety assessment; in Part 2, patients treated 3 attacks at home citing, 2 with active and one with placebo. Altogether, in RAPIDe-1 study, 74 patients were enrolled from 13 countries. The primary endpoint of RAPIDe-1 study was a change in composite of VAS-3 score from treatment from pretreatment to 4 hour post-treatment. Five key secondary endpoints were planned to assess time to onset of symptom relief and the symptom resolution. In this primary analysis for either primary or key secondary endpoints, multiple placebo-controlled procedure was applied in testing the medium and high doses. In addition, safety, PK and use of rescue medication data will also be shared today. In the primary analysis of RAPIDe-1 study, 156 attacks were included for safety assessment. 147 attacks were included in the efficacy analysis. Demographics and baseline features of patients in this study are generally well-balanced. Female to male patient ratio is about 2:1 among the patients. There are around 90% Type 1 HAE patients and 10% Type 2 patients. Here are the PK profile from subset of HAE patients in RAPIDe-1 study, consistent with observations in healthy volunteers. This PK data showed that all 3 doses of 416 achieved a therapeutic level within 30 minutes. The plasma concentration are maintained above EC85 for approximately 8 hours for the 10 and 20-milligram dose, and for more than 10 hours for the 30-milligram -- for the 30-milligram dose level. All these data indicate all 3 doses would be effective to treat HAE attacks. For the primary endpoint, all 3 doses of 416 significantly reduced attack symptoms by VAS-3 at 4 hours post-treatment. Compared to placebo, the dotted gray line, the treatment of the effect of active doses can be noted after about 1.5 hours. The difference in the treatment effect reached about 15 to 13 points at 4 hours and sustained through 24 hours. For the key secondary endpoint, all 3 doses of 416 significantly shorten time to onset of symptom relief, defined by 30% reduction in VAS-3. The median time to onset of symptom relief about 2.5 hours for active doses compared to about 8 hours for placebo. Consistently, 416 also significantly reduced time to 50% reduction in VAS-3, the medium time to 50% reduction in VAS-3 score was about 4 hours for active doses compared to 23 hours for placebo. Regarding to the almost complete or complete symptom relief is defined that all individual VAS-3 score less than 10. From the data and graph we can tell that 416 significantly reduced time to symptom resolution. Medium time is about 7.5 hours for 416 compared to about 42 hours for placebo. For the efficacy analysis, RAPIDe-1 study also includes MSCS and TOS assessment. MSCS mean symptom complex severity is a patient reported outcome measure for HAE patients to capture symptom severity of attacks. As for our post dose, the severity score was greatly reduced for all 3 doses. The MSCS reduction for 416 is about minus 0.9 compared to minus 0.29 for placebo group. TOS, treatment outcome score is a measure of the symptom response to HAE treatment. As shown in the graph, 416 significantly improved response scores compared to the flatline of placebo. The treatment effect start to be onset from 1 hour as a mean difference between 416 and the placebo reached over 6 days at 4 hours post dose. In addition to the symptom and the response evaluation, another important secondary endpoint is to assess the use of the rescue medication. As shown in the graph and the bar chart, within 12 hours post treatment, about 61 placebo patients used the rescue medication, while only 19% for 10-milligram, 11% for 20-milligram and 6.5% for 30-milligram patients in active arm used rescue medication. This data demonstrate 416 substantially reduced the rescue medication use in a dose-dependent manner, which is consistent with the effective exposure duration across the 3 dose levels represented by PK profiles. The 61 rescue medication use for placebo patients is also consistent with a real-world acute treatment rate for HAE attacks. While using cost to assess the response to HAE treatment, it captured the symptoms of HAE attacks in 5 complex internal, external head, neck, cutaneous, GI and genital/buttocks. At each time point, the symptom change from treatment is reported by patients with 5 [ scales ] as shown in the slides. Waiting 48 hours assessment. Approximately 90% attacks treated with 416 achieved a little better for all 5 symptom complex. The median time to achieving a little better is about 2 hours, for active doses compared about 8 hours for placebo. Over 80% attacks achieved a lot better or resolved for all 5 symptom complex the median time to a lot better or resolved is about 5 hours for 416 compared to 23 hours for placebo. Time to symptom relief by TOS PRO further demonstrate consistent efficacy across all doses. From the safety perspective, 416 is also well tolerated across all 3 doses. No treatment-related serious adverse events or severe events were reported. No adverse events led to treatment discontinuation, no treatment-related abnormalities were observed for lab, vital signs or ECGs. There are few treatment-related AEs reported within 48 hours after drug administration. From the table, we can tell in the non-attack visit, 1 nausea and 1 headache were reported for 10-milligram and 20-milligram cohort. During the home citing period for 1 attack treated with 30-milligram, vomiting, nausea and fatigue for 1 attack were reported. For 1 attack treated with placebo plus 1 [ place ] or events were observed. Overall, we are very pleased to report for RAPIDe-1 study, it met all primary and secondary endpoints. 416 showed consistent and clear efficacy across all endpoints. Together with its well-tolerated safety profile, it positions 416 well for the next step in our clinical development program. Thank you all. Now Dr. Maurer, I will hand it over to you.

Thank you very much. Hi. This is Marcus Maurer, joining you live from Berlin. I'm a dermatologist, allergist and running angioedema clinic here in Berlin, one of the biggest in the country. And I was involved from the very beginning with this program, and I'm very happy to say that this is a great day for us as the angioedema treating community and a wonderful day for HAE patients everywhere. Look, a lot of things have been said, but I think a couple of them need to be said really loud. And again, hereditary angioedema is an unpredictable disease. You always have to be ready for the worst and that's an attack that could lead to suffocation or extreme pain. This is so for patients who do not have treatment. This is so for patients who are on prophylactic treatment, wherever they are. So it is essential that all patients with hereditary angioedema have on-demand treatment. Okay, so we have on-demand treatment that [Technical Difficulty] is best applied in all settings of attacks, meaning we should have patients treat their attack that occurs as early as possible. Any burden, any hurdle to fast treatment is a hurdle to fast response. So the best thing that we can advise our patients to do is to take a pill and stop the attack as early as possible within the first 10 minutes in the first half hour. Is that possible today? No, it is not. Patients need to find a quiet place to do an IV infusions or subcu injection. This is not very comfortable or possible in many places. So we need see that the convenience that an oral on-demand treatment will provide will also result in better clinical responses, less burden and less impact of attacks in routine clinical life. I think from the data presented, there's no doubt that this works. It's a very effective, very fast treatment, and it's safe. So it is a milestone in the development of novel solutions for patients with hereditary angioedema, no question. And I'll tell you what was most convincing to me when I saw the data. These people, people with angioedema in this clinical trial, they didn't know whether they were getting the real drug or placebo. And to see these dramatic differences in the use of rescue medication in a setting where you do not know is this the real drug or not is super convincing. You saw that there's a dose response. You saw that there's a huge difference in the rate of patients on the real treatment groups versus placebo when it comes to the use of rescue medication. When it comes to thinking this is not working. This is not getting better or at least it's not getting worse. So that shows to me that patients do know that this treatment helps them that they do refrain from taking other medication, rescue medication that this is something that they will use and like in real life. So well done. Congratulations. And I'm very much looking forward to be working with this drug in my clinical practice. Thank you.

Thank you, Professor Maurer for your kind words and great insights from a treatment perspective of HAE. We're excited with the data that we shared today. RAPIDe-1 has met its primary as well as its -- all its secondary endpoints, providing the foundation for the further development of PHVS416 as a potential on-demand treatment of HAE attacks. As some of you may recall, our product strategy is to develop 2 formulations with this same active ingredient, the dose and exposure levels as determined through the bradykinin challenge in healthy volunteers provided the foundation for the design of our RAPIDe-1 trial. We apply the same principle to the design of our proof-of-concept prophylactic study, Chapter 1, which we anticipate announcing top-line data from in the second half of 2023. Back over to you, Maryann.

Thank you, Berndt. And now Nadia, if we can please open this up for the Q&A as this concludes our presentation section.

[Operator Instructions] And the first question comes from the line of Joseph Schwartz from SVB Securities.

Congrats on the data. I was wondering if you noticed any differences in baseline characteristics or response for patients in RAPIDe-1 who were enrolled outside the U.S. versus inside the U.S.? And how do the patients outside of the U.S. who are enrolled in Chapter 1 compared to those in the U.S.? And if they follow the same pattern as what you saw in RAPIDe-1, how would that be expected to influence the results in Chapter 1, if you need to rely on just enrolling patients outside the U.S. for that trial?

Yes. Thanks, Joe, and thanks for joining the call. We don't believe that there are any differences here that we have in our -- the structure of our patients, but I'll also let Peng Lu, our Chief Medical Officer, comment here.

Thanks, Berndt. Thanks for the question. Indeed, in RAPIDe-1 study, we include both U.S. patients and -- U.S. patients. So far, we only present the top line data. We did not go to the details to compare the patient features across different regions. But in the future, we would expect to share more information.

Okay. If I could just ask one more. I saw that you had your Type A meeting with the FDA. Are there any features in particular, which are more or less clearly an alignment on that you're waiting for the minutes to confirm? And how do you feel about the likelihood of gaining alignment after the one meeting that you had versus requiring more interactions? And kind of related to that, how is it going securing the necessary resources required to undertake an additional TOS study, assuming you gain alignment with the FDA, how quickly can you get that up and running?

Yes. So yes, we said we had a Type A meeting with the FDA, and we will provide a little bit more fulsome update on that once we have received the formal minutes. So it's hard to comment on that right at this moment. But once we have the formal minutes, we will be able to provide you more information on that. And in terms of resources, I did -- as you have seen, the FDA has requested of us to do nonclinical study in rats and that is, of course, costs money, but it's not significantly material in terms of the cost. It's the time of course, the more important aspect of that. And as I said, we will provide more information once we have the formal minutes.

[Operator Instructions] And the next question comes from the line of Jon Wolleben from JMP Securities.

Congrats on the data. A couple from me. Just wondering when we're looking at the primary endpoint graph, is anything going on with the placebo patients at 4 hours that they seem to be pretty steady, but then they started having to slide downwards similar to drug at that time point? And did you see anything as far as baseline characteristics, whether it's severity of attack that showed better responses on drug?

Yes, I'll hand over to Peng to answer the question.

Yes. Thanks for the great question. Actually, we just want to just give a little bit more detail regarding the study design for the RAPIDe-1 because before that waiting 4 hours post treatment, we recommend the patients that don't use the rescue medication, if possible. And from 4 hours, if the patients need a rescue medication, typically the patients in the study will start using rescue medication. As we showed in the slide deck for rescue medication part, around 50% to 60% placebo patients used rescue medication within 12 hours. All these patient data has been censored and removed from the top line graph. Therefore, all the data showed that the post 4 hours here is maybe that potentially is more mild attack or attack who don't need a rescue medication. So far, we don't have more detailed data, but in the future, we will do further analysis. Therefore, we expect the drop of the line there is highly possible is due to the natural resolution of the attack. But as mentioned, we will do further analysis in the future.

And was there anything that in the baseline characteristics that portended a better response on 416?

That's also excellent question. As I mentioned, so far, we only have top line data. But we indeed, in the future, will include that analysis based on the baseline severity for the attacks, and we will provide more analysis in the future conference.

And one more, if I may, before I jump back in the queue. What is FDA's current thinking on primary endpoint for a registrational trial for acute treatment? Is it -- you think sticking with the VAS-3 4 hours? Or is there a different end point? Obviously, you have good data across all the endpoints here. But how are you thinking about the path forward? And I'll jump back in the queue.

That's excellent question. I will start first, maybe I will hand it off to Dr. Maurer. In the RAPIDe-1 study, we used that composite of VAS-3 and MSCS, TOS because they were recommended by FDA [ companion ] published in June 2021. I think all these endpoints are acknowledged by the agency. But for the future, that is the Phase III trial, we will further work with agency and consider more about our data than to make the final decision about our future pivotal study. So Dr. Maurer, would you like to comment for this question?

Sure, Peng. To me, these are 17 ways of looking at the same thing, either the drug works or it doesn't. So whether you look at a total composite score, a single score, the dominant symptom, the time to response, the use -- you could go through the entire list of outcomes that have been used as primary or secondary in all the previous on-demand trials. And in the end, you will see whether a drug works or not. So I'm very happy to see so many outcomes being looked at in this trial, including a little better, which I like a lot because in my clinical practice, the first thing that I want to hear from a patient using on-demand treatment is it's not getting worse. Because that's when I know that I can expect the patient to survive in case of a laryngeal attack and to get a little better because it never gets a little better and then worse again. There's a dynamic to think. And to see that this occurs so early here, I think is very meaningful. But that's not to take away from the other outcomes that were measured, including, as I said, for me, most importantly, the use of rescue medication.

[Operator Instructions] And the next question comes from the line of Jacob [ Mikkel ] from Van Lanschot Kempen.

And also congrats on these results. My first one is, we can see that the biggest buck improvement was seen in the 10-milligram dose and also on the time to almost complete onset of symptom relief, it was also shown the best at the 10-milligram dose. Are you able to comment on that? Are there any reasons for that? And also, perhaps maybe if you can tell us what dose would you go with in a future trial? And one other question that I had is, with the business at now in hand, what are the next steps for the program in the underline setting? Is there a plan to progress for the Phase III outside of the U.S. first? And then add U.S. later on? Or do you want to resolve the hold issue and start with a global trial straightaway?

Yes. Thanks, Jacob. So I'll hand over to Peng here to say that the -- in all 3 doses, we reached above the therapeutic exposure levels very quickly in all doses and the differentiation between the dose is really in the duration of effect. But I'll let Peng also comment further on that.

I have to say great questions. Thanks for the questions here. I would answer maybe one by one here. And regarding for the 10 milligram, this is mainly due to that for this study that as a prespecified multiple test procedures. We have the testing for the Type 1 error for the 20 and the 30-milligram and it is supported by nominal statistical analysis for 10-milligram. But from all the graph and from the data, it demonstrated 10-milligram is also effective. It's from our prespecified multiple test scheme there. The second question regarding for the time to the almost complete or complete resolution. We think that may be mainly due to the 2 factors. First factor is that currently, we also do further analysis, to see the location of attacks across the different dose groups because each dose group we only have limited attack. Therefore, we try to see whether data for the 10 milligram, whether maybe potentially more abdominal attacks than periphery attacks or such kind of data. So far, since we only have top line results, it's not available yet. Second, we also acknowledge that for this trial, the design is mainly to assess the time to onset of the symptom relief. Therefore, we have more intense assessment up to 6 hours and a very smart sample collected post 6 hours. For example, we only have 8 hour, 24 hours and 48 hours, try to reduce the patient burden. Therefore, in the future, we will try to optimize the sample collection and maybe it's more accurately captured the time to almost complete and complete the resolution. But even with the smart data here, we can tell that the time to complete or almost complete the resolution for active dose is much more shortened compared to placebo. If we put all attacks treated here together with a larger pool here, we can tell that the time is about 7 to 8 hours for active doses.

And also Jacob, this is Berndt on the question on plan going forward. So you mentioned, we had the FDA meeting and Type A meeting. And in that meeting, we discussed and proposed path forward and to resolve the hold and that's also included proposals for the demand indication and the prophylactic indication. So as I said earlier, once we have the minutes from that meeting, we'll provide more updates and more clarity on the next step in our development for 416.

[Operator Instructions] And the next question comes from the line of [indiscernible] from Oppenheimer.

Congrats on the data. I have 2 questions. The first one is with the reserves currently available, does the team have a strong sense of what they anticipate would constitute the late-stage design of on-demand trial with 416, including any direct comparison to currently available on demanded therapies? And my second question is, can you talk a little bit on the expectations for timing of data from Chapter 1 whether these are influenced by the ongoing efforts to remove the FDA creates a hold?

So thanks for those questions. I'll start with the second one, and then I'll hand over to Peng. So we have, as we've seen guided now for readout on Chapter 1 in second half of next year. And as we said before, I mean, to date, no regulatory agency outside of the U.S. has put the hold on any of our sites outside the U.S. So this Chapter 1 study continues to enroll patients. And so based on that, we've updated our guidance to second half of next year.

Thanks, Berndt. Regarding for your first question, that currently, we are indeed very dedicatedly working on the study design for the pivotal study and also based on the exciting data here. Regarding for your question to compare the current Standard of Care on demand treatment, it will be challenged to have head-to-head comparison because of the current Standard of Care treatment is injection -- by injection. Therefore, it's almost impossible to blind the trial. Therefore, we expect it will be still placebo-controlled trial.

[Operator Instructions] And the next question comes from the line of Avikal Malik from Bank of America.

This is Avikal. Congratulations on the data. I think most of my questions are already answered, but maybe if you can comment on how do we think about this data in comparison to Firazyr? Because I think if they had shown time to 50% symptom relief of 2 hours, and I understand that there's a convenience involved here, which also plays a role. And then -- but like if you have to talk about the unmet need and like if you do some comparison like how do we interpret that? And maybe also like a follow-up to your plan to meet with the FDA if you are able to share anything about your strategy there now that you have this data in hand like how you're planning to have discussions with them? What do you plan to discuss?

Yes. So I'll answer again the second question first, and then I hand it over to Peng. I said earlier, we had our Type A meeting, and we proposed plans to resolve the hold and also for on-demand and prophylaxis separately. So as I said earlier, we have to wait for the minutes and then we can provide more information about the plan. The data that we're seeing today, of course, is also important in that context. So that's all I can say right now, but we look forward to providing more information once we have the minutes.

Yes. Thanks, Berndt. For the first question, I will try to address and then I will hand it over to Dr. Maurer to share -- for him to share the experience. So basically that for the comparison, it's very hard to compare to icatibant head to head because the trial sizing is completely different. When that Firazyr outcome icatibant was conducted 10 years ago is in the clinical setting. Around that time, the baseline severity of attacks is much higher than the RAPIDe-1 trial. Therefore, around that time, there's a 50% that VAS reduction is around from 40 to 20 there, but with the current citing, you can tell for RAPIDe-1, the baseline severity attack is only around 25 to 27. A lot of patients, if we still apply 50% VAS reduction for the onset of symptom relief is already falling under 10%. It's almost complete of the attack resolution. Therefore, after discussing with Dr. Maurer and other [indiscernible], we feel it's more appropriate to use 30% of VAS reduction as a definition to define the onset of symptom relief. Therefore, we can -- from the data, we can tell time to onset of symptom relief is about 2 hours with a VAS-3 30% reduction. So Dr. Maurer, would you mind to share yourself?

Absolutely, Peng, you're right. Speed of onset is important and also -- and that's equally important, but features into the how fast patients can treat. So Firazyr is a great drug, it made a huge difference when we got it for our patients because they could use it much faster than an IV infusion, which was Standard of Care then. And yet we see that it still takes time for patients to give themselves the subcu injection, not because they don't know that this is an attack simply because of practical reasons. No finding time and space in order to give yourself that injection. And mind you, most of my patients anyway have their injection with them because that's what they use today. Sometimes they forget, and then they're stuck, but that's not the fault of the syringe. And so what we expect will happen with drug that is biologically very similar to Firazyr, don't forget these are both -- don't forget, they both act on the same target, bradykinin-2 receptor, and both have very similar kinetics in their biological functions. So it will make a huge difference or probably the biggest difference, how fast people can use, a tablet versus a subcu injection. And that, in turn, will have a huge impact on the time that patients will have an attack, time to complete resolution, time to response because, again, the earlier you hit in a check the more effective you're going to be in every minute counts. So that's why I have hope that the practicability of having oral medication that is basically oral Firazyr, if you want, oral icatibant will play out in higher efficacy and lower burden of patients who experience an attack.

Got it. Maybe a quick follow-up on the FDA part. So you had your Type A meeting. Do you have any update? I know like you will share your update after you get your minutes, but like what is the timing of that? You've got like 30 days, right? So do you think we do hear something back in January or like this month, what is the estimated time?

Yes, we haven't talked publicly about the exact date when we had the meeting, but you're correct that the FDA typically have it. There's a 30-day period there. So I can give you some indication. But we haven't specified the date. But we'll be coming up soon, as I said. So we look forward to providing that update when it comes here.

[Operator Instructions] Dear speakers, there are no further questions at this time. I would now like to hand the conference over to our main speaker today Maryann Cimino for closing remarks.

Thank you, Nadia, and thank you, everyone, for joining our call. Have a great day.