Good morning and welcome to the Pharvaris event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Pharvaris website following the conclusion of the event. I'd now like to turn the call over to Maggie Beller, Head of Corporate and Investor Communications at Pharvaris. Please go ahead, Maggie. Thank you, Tara. Good morning, and thank you for joining us today for Pharvaris' first virtual R&D call. My name is Maggie Beller, Head of Corporate and Investor Communications. Our presentation today will include forward-looking statements, including but not limited to statements regarding deucrictibant and its potential, as well as our preclinical and clinical studies, regulatory interactions, and future plans. 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 in the future, we specifically disclaim any obligation to do so unless required by law. During this call, we will hear from members of the Pharvaris executive team who will explore the potential expansion of treatment applications for deucrictibant in people living with bradykinin-mediated angioedema beyond hereditary angioedema types 1 and 2. Pharvaris' Chief Executive Officer, Berndt Modig, will review the status of our two late-stage programs evaluating deucrictibant in the prophylactic and on-demand treatment settings for HAE. Anne Lesage, Pharvaris' Chief Early Development Officer, will share recently presented exploratory biomarker data and discuss the potential applications of this assay in the identification of people with bradykinin-mediated angioedema beyond HAE types 1 and 2. Peng Lu, Pharvaris' Chief Medical Officer, will review the development strategy for deucrictibant in bradykinin-mediated angioedema beyond types 1 and 2, including proof-of-concept data and our proposed clinical design for a phase III pivotal clinical study of deucrictibant for the prevention and treatment of acquired angioedema due to C1 inhibitor deficiency. Professor Danny M. Cohn, Internist and Medical Specialist in the Department of Vascular Medicine at the Amsterdam University Medical Center, an accredited ACARE site, has provided remarks about the pathophysiology and prevalence of bradykinin-mediated angioedema, including HAE types 1 and 2, HAE with normal C1 inhibitor, and acquired angioedema due to C1 inhibitor deficiency, the current treatment paradigm for those living with these bradykinin-mediated angioedemas, and the unmet need of those people. Thank you, Professor Cohn. Hello. My name is Danny Cohn, and I'm an internist specialized in vascular medicine, and I work at the Amsterdam University Medical Center in Amsterdam, which is an accredited center of excellence of the global ACARE Angioedema Network. In the next minutes, I will provide a brief overview and an introduction to bradykinin-mediated angioedema, its definition, an overview of types of angioedema that are currently classified as bradykinin-mediated, and the main unmet medical needs in current management of hereditary angioedema with bradykinin in real-world clinical practice. Both current ACARE/WAO guidelines and the more recent DANCE classification identify and group together multiple types of recurrent angioedema as bradykinin-mediated angioedema. What all these types have in common per definition is the bradykinin-mediated activation of the bradykinin B2 receptor, which ultimately leads to similar clinical manifestations, which include recurrent and unpredictable painful swellings of various body parts following local vasodilation and increased vasopermeability to fluids into the subcutaneous or submucosal space. The types are also different between each other, and they are different from disease characteristics. Some are genetically determined with hereditary transmission, and others are acquired during life. Some are due to a deficiency of a protein called C1 inhibitor, versus others are associated with normal levels and functions of this C1 inhibitor. All these mechanisms lead ultimately to excessive bradykinin formation. It is important to accurately classify and diagnose bradykinin-mediated angioedema because this will inform the development of tailored treatment and management decisions in clinical practice to eventually achieve most favorable outcomes for people with these conditions. The current unmet medical needs exist in management of bradykinin-mediated angioedema with regard both to diagnosis and treatment, and we will briefly discuss them in a few minutes. Some are general and common to all types of bradykinin-mediated angioedema, and then there are other additional unmet medical needs specific to certain types of bradykinin-mediated angioedema. The most common and best characterized known forms of bradykinin-mediated angioedema is hereditary angioedema due to C1 inhibitor deficiency, or type 1 and type 2. This occurs due to mutations in the relevant gene, and people living with hereditary angioedema type 1 and 2 make too little C1 inhibitor or make a non-functional version of this C1 inhibitor, respectively, which leads to uncontrolled overproduction of bradykinin, including which induced vasodilation, vasopermeability, and clinically evident swelling. The incidence is estimated approximately 1 in 50,000 people worldwide, with no evident difference between ethnicities or geographies. About 75% of cases are inherited from their parents, and about 25% of the cases are due to new mutations which have not been already present in the previous generations. There are also non-inherited acquired forms of C1 inhibitor deficiency. Similar to hereditary angioedema type 1 and 2, this deficiency of C1 inhibitor also leads to uncontrolled production of bradykinin and similar clinical manifestations. Acquired forms of C1 inhibitor deficiency are also different from hereditary angioedema type 1 and 2 because this form is not due to genetic causes but secondary usually to underlying other conditions such as lymphomas, monoclonal gammopathies, or autoimmune disorders, which leads to consumption or neutralization of C1 inhibitor, which would otherwise be normally functioning. The incidence is much rarer and approximately 1 in 500,000 people. Finally, other types of angioedema without C1 inhibitor deficiency are defined as bradykinin-mediated with normal C1 inhibitor. This is also much rarer, approximately 1 in 500,000 or so, and it's further differentiated between other forms associated with known mutations in gene encoding for other elements of the bradykinin-forming cascade, different than C1 inhibitor, and forms without identified mutations or unknown forms. The hereditary forms with normal C1 inhibitor and known genetic mutations include factor XII, plasminogen, and kininogen. There are hundreds of families known with factor XII hereditary angioedema, which is the most common form, and it's very rare, for instance, in the kininogen manifestation, where only a handful of families have been reported. All these manifestations are driven by excessive production of bradykinin. Interestingly, in some cases, bradykinin is produced through different and plasma kallikrein-independent pathways, which are different from hereditary angioedema type 1 and 2. There are also other forms with normal C1 inhibitor and no identifiable genetic mutations, which are defined as unknown and further divided into hereditary manifestations with a family history or acquired without a family history. The prevalence of these manifestations has not been fully estimated yet, but they appear as a majority of angioedema, the bradykinin-mediated angioedema with normal C1 inhibitor in some geographies, including the United States, Canada, and Northern European countries. The mechanism has not been fully clarified yet, leading to how this leads to increased bradykinin signaling, but anticipating that we will discuss shortly about the unmet needs, especially also regarding the diagnosis, because these are the most challenging forms to accurately diagnose because of the lack of measurable markers, and this represents an area of major unmet need and scientific and clinical interest. To summarize for this part, bradykinin-mediated angioedema includes multiple types mediated all by bradykinin and may come from different sources, in some types through plasma kallikrein-independent pathways, but eventually converges toward the bradykinin B2 receptor. The multiple bradykinin-mediated angioedema types require multiple and tailored diagnostic and treatment approaches for which current unmet medical needs exist. Let us now focus on the unmet needs in bradykinin-mediated angioedema. Some, as I already mentioned, are general needs which are common to across all types of bradykinin-mediated angioedema, and then there are specific unmet needs in certain forms. The common unmet needs include improved education, especially among other specialists who are not being angioedema experts to timely and accurately diagnose bradykinin-mediated angioedema, including the most rare types. Then also, we have an unmet need for wider and easier access to well-established diagnostics for hereditary and acquired types of C1 inhibitor deficiency, and wider access to treatment and additional treatment options to further personalize the management of bradykinin-mediated angioedema, meeting individual needs for efficacy, tolerability, and minimized treatment burden with regards to handling, portability, and administration. Let me now focus on additional needs for specific forms of bradykinin-mediated angioedema. There is a need to go beyond type 1 and 2 with regards to the development of diagnostic instruments as well as generating clinical evidence in controlled setting, also for other forms of bradykinin-mediated angioedema, such as acquired C1 inhibitor deficiency and bradykinin-mediated angioedema with normal C1 inhibitor. Regarding acquired angioedema with a C1 inhibitor deficiency, we need to improve recognition as well as access to diagnostic assessments. More importantly, there is an absence, and we have a need to have data from controlled clinical trials and licensed treatment because the current off-label treatments that are being used now have very low responses and outcomes. For bradykinin-mediated angioedema with normal C1, in the absence of other measurable biomarkers, especially for types without identifiable mutations, the development of diagnostic tools to measure activation and products of bradykinin-forming pathways is needed to enable us to objectively diagnose bradykinin-mediated angioedema by relying on objective measurable markers identifying bradykinin-mediated angioedema versus the sole and largely subjective and reported clinical information and diagnostics by exclusion of other causes of recurrent angioedema. Furthermore, we need to identify forms with activation of and contribution by bradykinin signaling among not further defined cases of recurrent angioedema to differentiate between other forms associated with or are driven by activity of other mediators. An accurate diagnosis would also allow more reliable identification of populations for clinical trials of treatment of bradykinin-mediated angioedema with normal C1 inhibitor, thereby de-risking development. Lastly, treatment with evidence from controlled trials includes populations with correctly diagnosed bradykinin-mediated angioedema with normal C1 inhibitor, possibly targeting common steps of pathways leading to bradykinin-mediated signaling. Thank you very much for your attention. We are appreciative of Professor Cohn for taking the time to provide this expert perspective. With that overview of the current landscape of bradykinin-mediated angioedema, I'd now like to turn the call over to Pharvaris' Chief Executive Officer, Berndt Modig. Berndt? Thank you, Maggie. We want to thank Professor Cohn for his insightful comments and contribution to today's event. We're grateful to partner with the broad HAE community, including experts like Professor Cohn, as well as the patient organizations HAEA and HAEI, to better understand the unmet needs of those living with bradykinin-mediated angioedema. As we collaborate, we potentially address those needs. Pharvaris is uniquely positioned as, to our knowledge, we're the only company that is developing an oral therapy that addresses both the prophylactic and on-demand treatment paradigms of those living with bradykinin-mediated angioedema. Our investigational therapy, deucrictibant, has the potential to offer injectable-like efficacy, placebo-like tolerability with the convenience of oral therapies. We're currently evaluating the efficacy and safety profile of deucrictibant in two ongoing pivotal phase III studies, one for prophylaxis and the other one for on-demand treatment of HAE attacks you can see here on the slide. The important aspects of both our CHAPTER-3 and RAPIDe-3 study designs is the treatment of HAE beyond types 1 and 2, including people with hereditary angioedema with normal C1 inhibitor. As Professor Cohn mentioned, people living with HAE with normal C1 inhibitor, which represent potentially an additional 15%-25% of patients on top of the, in addition to the HAE type 1 and 2 population, are underserved. Now, I'd like to welcome Dr. Anne Lesage, one of Pharvaris' founders and our Chief Early Development Officer, to share the recently presented data of a biomarker tool that can identify people with bradykinin-mediated angioedema. Over to you, Anne. Thank you again to Professor Cohn for his in-depth presentation of the unmet needs of those living with bradykinin-mediated angioedema. As one of the company's scientific founders, I'm proud to see the coming to fruition of almost 10 years of hard work as we develop deucrictibant in partnership with the HAE community. The next step in this journey is the potential expansion of deucrictibant's treatable bradykinin-mediated angioedema population beyond HAE types 1 and 2. Angioedema is defined as recurrent, localized, and self-limiting swelling of the subcutaneous or submucosal tissue due to transient increase in vascular permeability. Angioedema is a heterogeneous condition mediated by either mast cells, bradykinin, or unknown mediators, and bradykinin-mediated subtypes of angioedema are classified based on the role of C1 inhibitor and then further classified based on whether the angioedema is inherited or acquired. We aspire to develop deucrictibant for bradykinin-mediated angioedema. This includes HAE due to C1 inhibitor deficiency. This is type one and two, acquired angioedema due to C1 inhibitor deficiency, HAE with normal C1 inhibitor, and people living with HAE unknown and angioedema unknown. Importantly, when angioedema is caused by excess bradykinin, it's associated with an enhanced risk of morbidity and mortality. Early recognition and proper diagnosis are therefore essential towards adequate management of disease. Diagnosis of HAE due to C1 inhibitor deficiency type one and two is well established based on clinical presentation and lab tests of C1 inhibitor and complement factor C4. The diagnosis of acquired angioedema due to C1 inhibitor deficiency is also straightforward based on lab values and the recognition of underlying disease. The diagnosis of HAE with normal C1 inhibitor levels is generally more challenging. Today, it's mainly based on clinical presentation of disease, family history, and in some cases, genetic information and response to available treatment. Unlike HAE due to C1 inhibitor deficiency, there's no confirmatory blood-based laboratory tests. All lab measures seem normal. The same is true for HAE unknown and angioedema unknown, for which the underlying genetic mutation or pathomechanism are unknown. These challenges associated with the diagnosis of bradykinin-mediated angioedema have inspired us to develop a novel biomarker assay to help identify bradykinin-mediated angioedema. We developed a biochemical assay for the quantification of bradykinin and its breakdown peptides in human plasma using liquid chromatography- tandem mass spectrometry. We succeeded to bring this assay to a high level of standardization, reproducibility, sensitivity, qualification, and validation. We then applied this analytical method to assess the sensitivity of the bradykinin-forming cascades. In this novel approach, we submit human plasma in vitro to cold temperature. Cold reduces C1 inhibitor function, thereby removing what can be thought of as the brake from the bradykinin-forming cascades. In the plasma of healthy subjects, this will not lead to bradykinin production. However, in plasma from people living with bradykinin-mediated angioedema, this disinhibition will expose the sensitized bradykinin-forming pathway, leading to the activation of the cascades, resulting in uncontrolled excessive production of bradykinin. I will share our recent data using this novel biomarker assay. This slide shows the clinical validation of the cold activation biomarker assay. We used plasma samples from HAE due to C1 inhibitor deficiency type 1 and 2 angioedema. It has been well established that signs and symptoms of angioedema in these people are mediated by bradykinin and the bradykinin B2 receptor. Cold incubation was applied for 24 hours to healthy volunteer plasma, showing no activation of bradykinin production, whereas in HAE type 1 and 2 plasma, cold activation leads to increased production of bradykinin. This confirmed our hypothesis that cold activation can identify individuals with bradykinin-mediated angioedema. Acquired angioedema due to low C1 inhibitor levels is another recognized bradykinin-mediated angioedema. Plasma from these patients showed the same signal. The bradykinin-forming cascades are significantly activated by cold. Now we come to HAE with normal C1 inhibitor levels. Here, the diagnosis of bradykinin-mediated angioedema is more challenging as lab values, especially C1 inhibitor levels or activity, are indistinguishable from healthy volunteers. We have so far analyzed plasma from individuals with HAE due to factor XII and plasminogen mutations. The samples show increased activation of their bradykinin-forming cascades following the cold trigger. We're taking away the break in healthy volunteers does not lead to high bradykinin production. It does so in these two types of HAE with normal C1 inhibitor, indicating that their bradykinin-forming cascades are unstable and sensitive to activation. In essence, these data confirm that HAE due to factor XII and plasminogen mutations are mediated by bradykinin in line with their classification. Importantly, the assay not only works for the contact system and KKS pathway involving plasma kallikrein and factor XII, but also works for mutant plasmin, which is known to produce bradykinin independent of or bypassing plasma kallikrein and the contact system. Last but not least, using our clinically validated assay, we set out to characterize the role of bradykinin in HAE unknown and angioedema unknown. These are patients with normal C1 inhibitor levels and function without known genetic mutations or without known underlying pathophysiological mechanism, whether hereditary or non-hereditary. The diagnosis of bradykinin-mediated angioedema in these people will be of great help for the management of their disease. We submitted six samples to cold activation and see four responders, indicating that angioedema attacks in these patients are expected to be mediated by bradykinin and to respond to bradykinin B2 receptor antagonism. Now, from time to time, we see non-responders in our assay. Non-response to cold activation is either correlated to absence of attack, ever, the patient is asymptomatic, or it is a result of prophylactic angioedema treatment. In this experiment, we have actually no explanation for non-response in one subject. It remains to be seen whether this is because we do not have the full clinical history of the patient or whether this is indicative of another mediator or pathogenesis. In conclusion, based on these early data, we are confident to use this novel cold activation biomarker assay as a tool to identify bradykinin-mediated angioedema. This will greatly help the diagnosis and disease management of people with bradykinin-mediated angioedema, especially for those with normal C1 inhibitor with and without known mutations. I'll now turn over the call to Pharvaris' Chief Medical Officer, Dr. Peng Lu, to discuss how we have leveraged our bradykinin B2 receptor expertise to better inform the development strategy of deucrictibant. Thanks. Thanks, Anne. With a unique mechanism of action for the deucrictibant, Pharvaris has always stood for its scientific rigor in testing the hypotheses that emerged from our deep understanding of the bradykinin pathway. The bradykinin challenge study, a foundational in vivo experiment to determine the therapeutic threshold of the deucrictibant, was a first example of this philosophy. Today, Anne just showed another example of how the novel biomarker research enables us to further develop the deucrictibant for the bradykinin-mediated angioedema beyond type 1 to HAE. As Berndt had already highlighted, the pivotal trial to evaluate the efficacy and the safety for on-demand and prophylaxis to deucrictibant in type 1 and 2 HAE patients is ongoing. We are expecting the top-line results of both phase III studies within the coming 18 months. How about the type 3 hereditary angioedema patients with normal C1? In the introduction by Dr. Cohn, like hereditary angioedema due to C1 inhibitor deficiency, HAE with normal C1 inhibitor patients are also at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE with normal C1 inhibitor patients with appropriate diagnosis is critically important. In 2023, HAE International and HAEA convened a global symposium of experts to synthesize all current knowledge. Early this year, they updated the consensus paper in this area. In addition to the clinical signs, symptoms, and family history, the latest diagnostic algorithm for HAE with normal C1 inhibitor patients also includes lab testing, C1, C1q, C4, Anti-C1 antibodies, genetic screening up to eight potential genes, and importantly, medication responses. For example, lack of response to mast cell-mediated medication and durable response to a bradykinin B2 receptor antagonist. In addition, a novel marker showing the increased formation of bradykinin, as Anne just presented, could further support the diagnosis of HAE with normal C1 inhibitor. Consistent with the unmet medical need for diagnosis, information on the effectiveness of the treatment of HAE normal C1 remains very limited. So far, only one controlled trial for plasma kallikrein inhibitor was ever conducted, but it did not show a sub-positive treatment effect in normal C1 patients. Based on the latest real-world normal C1 consensus treatment survey, the predominant prophylactic treatment for normal C1 patients is still off-label use of tranexamic acid. There is no approved therapy available yet. Therefore, there is a truly high medical need to develop effective and safe prophylactic and on-demand treatment for normal C1 patients. Such unmet medical need is also reflected in the regulatory agency's recommendations. With the advice and suggestions from FDA and EMA, we agreed with both U.S. and EU agencies. Beyond type one or type two HAE patients, HAE normal C1 patients are also added into the ongoing phase III RAPIDe-3 and CHAPTER-3 studies. This new data will be very helpful to assess the efficacy and safety of either prophylactic or on-demand treatment effects of the deucrictibant in type three or HAE normal C1 patients. Now let's continue with acquired angioedema due to C1 deficiency. As Professor Cohn illustrated, the occurrence of angioedema attacks in acquired C1 patients are mainly due to either neutralization or increased consumption of C1 inhibitor, resulting in locally increased vascular permeability and tissue swelling. These symptoms usually manifest in patients who are over 30 or 40 years old and often associated with underlying disease, for example, lymphoma, MGUS, or autoimmune disease. Currently, treatment guidelines for acquired angioedema due to C1 deficiency are still under drafting. The evidence for off-label use of hereditary angioedema treatments is still limited to mainly small non-controlled studies. C1 inhibitor concentrates are generally considered less effective in the acquired C1 patients due to increased clearance. In addition to the compiling phase II data of the deucrictibant in both the prophylactic and on-demand treatment of HAE, data from an investigator-initiated study, ONCE-AID, led by Professor Danny Cohn, was also presented at the C1 inhibitor workshop last week. The randomized portion of the study called POP-AID has previously been published. POP-AID demonstrates acute treatment with the deucrictibant reduced attack severity when taken as an on-demand treatment. During eight weeks of prophylaxis treatment with 20 mg of deucrictibant twice-daily regimen, a complete reduction in attack rates was shown for all three patients. The second part of the study, named ONCE-AID, targeted to assess long-term efficacy and safety of once-daily administration of 40 mg of deucrictibant extended-release tablets as a prophylaxis for acquired angioedema due to C1 inhibitor deficiency. This is the same dose regimen used in the CHAPTER-3 phase III prophylaxis study with the to-be-market formulation. As presented in the C1 workshop, altogether, four acquired C1 inhibitor patients, three from the POP-AID, and one new patient participated in this study. The baseline attack rates for these four patients were 4.1, 0.5, 3.2, and 2.3 attacks per month, as shown in the figure. During the study period with the deucrictibant, patients one, two, and three were attack-free. No attacks reported up to 20 months during the study. For patient four, one mild abdominal attack occurred two days after the start of the drug administration, with rapid symptom resolution by icatibant. After that, this patient was also attack-free during the rest of the study. Professor Cohn commented that he's very happy to see no birth actually show up for the birth on the wire plot. Throughout the study, the deucrictibant extended-release tablets show a consistent adequate exposure above therapeutic levels, with a mean concentration of the deucrictibant around 50 ng per mL. During both the POP-AID and the ONCE-AID part of the study, the deucrictibant was very well tolerated. A total of 29 adverse events were observed in the ONCE-AID study, and the majority of them were mild. None of the adverse events were related to the study drug or led to the treatment discontinuations. Also, no clinically significant changes in the vital sign, ECG, or lab parameters were observed. With a strong desire for effective treatments for those with acquired C1 patients and highly encouraging POP-AID and ONCE-AID data, we are currently initiating a randomized placebo-controlled phase III CREAATE study to assess the efficacy and safety of the deucrictibant prophylaxis and on-demand treatment in the acquired C1 patients. In the part one prophylaxis assessment, patients will receive either 40 mg once-daily deucrictibant treatment or placebo. The primary endpoint is the investigator-confirmed number of attacks. Part two of this study applies crossover design to assess on-demand treatment of the deucrictibant. Each patient will treat two attacks, one with 20 mg of deucrictibant and the other with placebo. The primary endpoint for on-demand evaluation is time to symptom relief as sustained within 12 hours post-treatment. Part three of this study will focus on the long-term safety and efficacy assessment for the deucrictibant on-demand treatment. Hopefully, the outcomes of the CREAATE study, plus POP-AID and ONCE-AID results, can turn deucrictibant into the first approved medication to help acquired C1 inhibitor deficiency patients. Currently, the study design and key elements of the CREAATE study have been aligned with the regulatory agencies. The study will be initiated this year and conducted in parallel with the RAPIDe-3 and the CHAPTER-3 studies. As shown in the graph, all approved therapies and ongoing investigational developments for HAE focus exclusively on the kallikrein pathway. Deucrictibant stands out as the only treatment targeting the bradykinin B2 receptor, allowing it to address both kallikrein-dependent and independent pathways. As a result, deucrictibant has the potential to benefit a broader range of bradykinin-mediated angioedema patients beyond type 1 or 2 HAE. With a unique mechanism of action and encouraging data, deucrictibant is the only treatment granted by U.S. and EU regulatory authorities for off-and-drug destination as a treatment of bradykinin-mediated angioedema. Eventually, the outcomes of all ongoing phase III studies will support the regulatory filing of deucrictibant for the treatment of bradykinin-mediated angioedema and help address the significant unmet medical need in this patient population. That concludes the formal portion of our presentation. Anne Lesage, Peng Lu, and Berndt Modig are available for questions, and we're also joined by Wim Severans, Chief Commercial Officer of Pharvaris. With that, I'll now open the call up to Q&A. Great. Thank you, Maggie. Yes, at this time, we'll be conducting a question-and-answer session with our speakers. To our analysts joining us live, please use the raise hand feature to indicate you have a question. Please hold for a brief moment. Our first question comes from Max Skor at Morgan Stanley. Please go ahead, Max. Great. Thank you very much for hosting this informative event. I was wondering if you can elaborate a bit on just disease severity in these patients beyond HAE type one and two, specifically are attack rates comparable across subtypes. Does the biomarker assay offer any insights into the potential severity or frequency of attacks? Finally, do you anticipate any challenges with enrolling the CREATE trial? Thank you very much. Yeah, thanks, Maggie. Thanks for joining the call. This is Ferrand. I'll hand over that question to Peng. Yes. Thanks, Max. Excellent question. As I mentioned, that I'm introduced by Dr. Cohn, actually for bradykinin-mediated angioedema, no matter if it's HAE type one, two, normal C1, or acquired angioedema, fundamentally, their clinical symptoms are very similar and comparable. Also, we do observe that patients that have the wild severity from the mild, severe, or even very severe HAE attacks. For some subtype of the angioedema, for example, acquired patients, there are more facial attacks reported compared to that HAE. Overall, the symptoms and clinical observations are very comparable. The second question, I will turn over to Anne regarding the biomarker risk. Yep, yep. I heard the question about whether there is a correlation between the frequency and severity of attacks and the biomarker signals, right? I've mentioned that there's an exception. We have non-responders plasma in this biomarker assay, which basically are due to the patient being attack-free or asymptomatic. With that exception, it seems that we do not have enough data to further answer the question whether there is a straight correlation between the frequency of attacks or the severity of attacks and the biomarker signal. We are collecting further and additional data to better answer that question. Yeah, regarding the third question about the enrollment for the CREATE study, you know, Max, as I mentioned, this is the first and the only acquired angioedema study currently planned and will be conducted. As mentioned, while we talk with the community, there is a strong desire for the effective treatment for acquired angioedema patients. We talked across the community, and even though this is an ultra-rare disease, we do not expect too much challenge for the patient enrollment. Meanwhile, we just want to highlight, as we are still at the initiation stage for this study, we will keep everyone posted once the study moves forward. Great. Thank you. Thanks for the questions, Max. Our next question comes from Jeff Jones at Oppenheimer. Please go ahead, Jeff. Jeff, you may be on mute. Can you hear me now? Yes, we can. Okay. I'm sorry about that. Number one, really appreciate you hosting the event, and it has really helped us understand these other indications. I may have missed it, but did you speak at all to the number of patients that you are anticipating recruiting in the trial? And Peng, you mentioned a little bit the community that is involved in these alternate forms of HAE. Could you speak a little bit to how that helps you in identifying these patients beyond the biomarker profiles you were discussing? Is there essentially a previously identified community and what the size of that community is and how that helps you enroll the study? Yeah. Thanks, Jeff. It's great to get in. Also, good. Thanks for joining. I think you asked about the number of normal C1 in the—what was the question again? Can you maybe repeat the first question? The number of patients in the acquired angioedema. Okay. Yeah. We haven't really talked about that detail yet, so if Peng can also comment further. Aligned with agency because it's an ultra-rare disease. Also because we mainly evaluate the treatment effect that they're driving by the efficacy part. Therefore, we expect this will be a very small study, especially compared for HAE study. We will release the exact number of sample size once the study initiates. Okay. Thank you very much. Great. Thanks, Jeff. Our next question comes from Joe Schwartz at Leerink. Please go ahead, Joe. Great. Thanks so much for taking my questions. I have one on the CREAATE study and then one on the biomarker. I guess, do you require a certain attack rate to enter the CREAATE study in acquired C1 inhibitor deficiency patients? How long do you expect this trial to take? It seems like if the deucrictibant works really well in part one, then part two could take a long time to generate data. What are your expectations there? On the biomarker, I was just wondering if you could talk a little bit about the practical and logistical implications of rolling this out in the marketplace. Have you run any pilot programs, and what's the yield been on your efforts there? Can you just talk about the practical implications of implementing it? Thanks again for taking the questions. Yeah. Hi, Joe. Thanks for joining. Yeah, as Peng said, we provide more details as we get the study up and running, also particularly the timelines. Of course, the objective here, if we're aiming for, subject to the usual things about setting up a trial and all that, is to synchronize as much as possible with the deucrictibant filing for HAE type one and two. We will provide more updates as we get further along in terms of specific timelines on the AAE study. The second question for Peng, yeah. Yeah. Thanks, Berndt. Regarding the CHAPTER-3 study, you're right. Actually, for the part one prophylaxis assessment, we do require attack frequency is at least two attacks per two months, basically one attack per month that are qualified to join part one study. Regarding the on-demand part, we do have the relatively less attack frequency requirement, which is about one attack per three months. Therefore, once the patients that have more frequent attack, they will join the part one. After finishing part one, they can go to part two. However, if some patients have less frequent attack, they are also open to join part two study directly. As Berndt mentioned, we did not give the detailed timeline regarding this study yet. Once we get more information and this study starts, we will provide more updates. Regarding the practical implications, I'm happy to answer that question. We are not intending to use this assay as a formal diagnostic tool. We would rather use it as a facilitator to identify the bradykinin-mediated angioedema. We do not want to use it as a companion diagnostic, purely for exploratory research purpose. We want to use it to guide us, pointing to the role of bradykinin in the various pathophysiological variants of angioedema. In essence, we're not planning to develop our assay to a diagnostic level, but we're happy to support the community and clinical research. Great. Thanks for the questions, Joe. Our next question comes from Jon Wolleben at Citizens JMP. Please go ahead, John. Hey, thanks for taking the question. I had a couple on the normal C1 inhibitor opportunity. Can you talk a little bit about how you're identifying these patients in ongoing studies, and is there some limit to them, or is this you notice these patients once they're enrolled in the study? Do you think that this will need a separate development program, or is this something that if you have a sufficient number of patients, you could get the data included in a label for a broader HAE? Hi, Jon. Thanks for joining. I'll hand over straight to Peng on that one. Go ahead, Peng. Sure. Yes. Thanks, John. Great question. As we present during the talk there, because currently, there is a latest consent paper about normal C1 just published. Actually, our inclusion criteria for normal C1 are very consistent with the new consent guideline there. Pretty much, the patients will be identified based on clinical symptoms, family history, and genetic testing, and also biomarker testing, as I mentioned there. Also, most important, as I mentioned, integrate the medical response. These patients' lack of the response to mast-mediated medication, but have a durable response to bradykinin B2 receptor antagonist. Also, for some patients without genetic mutation, and as I mentioned, the bradykinin formation I see and all the biomarker data there will help support the diagnosis, but it will be optional. Maybe you can—Will you know—Will you know when you report data, how many patients you had in the studies with normal C1 inhibitor? Yeah. Actually, as I mentioned, the idea that the normal C1 patients in our current RAPID-3 and the CHAPTER-3 study are actually recommended by regulatory agency from both U.S. and in EU, basically EMA there. There is no specific number required to include in this study. We do not expect a lot of patients due to the ultra-rare of the normal C1 patients. Similar as the type two HAE patients in the study, we expect less than 5% patients within the study. All this data will be very helpful to support the label discussion. Got it. All right. Thanks, Peng. Thank you for the questions, John. Our next question comes from Steve Seedhouse at Cantor Fitzgerald. Please go ahead, Steve. Yeah. Thank you so much. Thanks for taking the question and for hosting the event. I wanted to first ask just on technical question on the assay. Is it sort of standardized or centralized, or is this being done at each individual site? Just how challenging is it really to sort of get the sample and retain sample quality and actually execute the assay technically? Then along the same line, just so I'm understanding sort of the nuances of the assay, if you run this cold assay in the same patient today, tomorrow, next week, next month, is it pretty consistent for a patient, or does it wax and wane just depending on maybe unknowns or waxing and waning of the disease itself? Yeah. Hi, Steve. Thanks. Over to you, Ben, on this one. Thank you, Berndt. Yes. Yes, it is standardized, obviously. It's straightforward. The analytical part is the tricky part because of what we know about bradykinin. The cascade can be activated ex vivo. It can be broken down by all the proteases. We have that under control and by standardization of the assay. We have basically achieved the very reproducible assay. For the cold activation formats, we've done this longitudinal exploration of plasma from the same patient over different time points, and it's very reproducible. Basically, we are very confident that we can reproducibly, very sensitively measure bradykinin at either absolute levels or cold activation levels. Okay. Just the outlook here for the angioedema types beyond HAE type one and two, how do you think the adoption or interest or excitement in prophylaxis versus on-demand therapy will ultimately compare to sort of what we see currently with approved options for HAE? Do you think there'll be a skew that's different for on-demand or prophylaxis than HAE currently, or do you think it'll sort of shake out the same ultimately if you have a broad label and availability for both? Yeah. Steven, I just wanted to—I think Peng can also add to this, but I think some of the same factors that come into the decision of a patient in type one and two, whether to do prophylactic or on-demand, which is sort of based on preference, attack profile, anxiety level, and personal circumstances, I think we also would apply in the acquired angioedema setting. That is also what we would expect to be very similar. Maybe Peng has also something to add to that as well. Yeah. Thanks, Berndt and Sarah. I would definitely agree with your comments here. As I mentioned, currently, there is no approved treatment, no matter for HAE normal C1 or acquired, right, that C1 deficiency patients. There are indeed off-label use of the current hereditary HAE treatment for these patients. As I mentioned, because of the iCADMB there, certain that off-label use for on-demand treatment of iCADMB can help these patients. However, from prophylaxis side, we do feel there is even more strong desire because there is no prophylactic B2 antagonist available. Especially for the normal C1 patient, it seems from the mechanism of action from pathway side that especially for the patients, the mechanism is the calcarein-independent mediated. It's only the B2 antagonism that has the potential to benefit these patients. Thank you. Great. Thanks for the question, Steve. Our next question comes from Sushila Hernandez at Kempen. Please go ahead, Sushila. Sushila, you may be on mute. Hello. Can you hear me now? Yes, we can. Okay. Great. Thank you for taking my questions. For these patients beyond type one and two, are they already met and followed by the same treating physicians as HAE type one and two? Or do you expect to also put in effort to identify these patients? A second question, what is the treatment goal for these patients beyond HAE type one and two? Can we envision these patients remaining attack-free with the treatment gone? Thank you. Hi, Sushila. Thank you for your question. Please repeat the first one because I didn't get that perfectly. Yes. For these patients beyond type one and two, are they already met and followed by the same treating physicians, or do you have to put in effort to identify these patients? They are treated by the same physicians that treat HAE one and two. They are brought to these physicians by referral. Wim must have something to add there. Yeah. Maybe to add that that's actually the interesting thing here by the acquired angioedema, whether it's due to C1 inhibitor deficiency or not, because it's maybe the tip of the iceberg. Because at the moment, the only patients that we know of are the ones that are being referred by the doctor treating the underlying condition. If the doctor doesn't realize that there is an angioedema that can be managed, can be treated, they don't refer. This is something that we hear quite frequently. One of the care wells told us recently that he had a patient referred to him who for five years had been having angioedema attacks, but it's only after five years that he was sent to the allergist. That means that with a label in our hands, hopefully in the future, it gives us an opportunity to actually actively educate some physician segment specialties that today are not really aware of this. Indeed, that could potentially increase the number of patients that are actually running around with this type of angioedema that could benefit from treatment. Okay. That's clear. What is the treatment, what is the realistic treatment goal for these patients beyond HAE type one and two? I mean, I think the treatment goal will be similar or the same as the goal you have for somebody living with type one and two. Basically, reduce or minimize or eliminate if possible the burden of attacks. Basically, the clinical manifestations are the same, and the treatment goals, I think, are also the same. Yeah. Okay. We can envision these patients also to remain attack-free with treatment. Yeah. I mean, that's, of course, a very nice goal to aspire to. Okay. Great. Thank you. Great. Thanks for the question, Sushila. Our next question comes from Jacob Mekhael at KBC Securities. Please go ahead, Jacob. Hi there. Good morning and good afternoon to you all. Thanks for taking my question. I had a few, if I may. My first one is on for type one and type two HAE, there are multiple products approved, and the reimbursement situation is relatively clear. On the other hand, in acquired angioedema, there is nothing approved, as you mentioned earlier. My question is, how do you look at the potential for reimbursement in this setting, and do you have any insights from payers that you can share with us? That's first. I have a question about the assay that we discussed earlier. Could you maybe explain why cold activation appears to lead to different bradykinin responses between healthy subjects and those with angioedema? If the assay works really well, why not develop it as a diagnostic? Wim found the first. Yeah. Thank you, Jacob. Thank you for the question. You're right. At the moment, patients with HAE are being covered, being reimbursed. Acquired angioedema, that's not the case. We anticipate, obviously, if we demonstrate the same efficacy and safety as we've seen in our phase II program and the phase III, that we definitely would be able to get reimbursement for those patients with payers and get coverage there. The benefit also potentially from a payer perspective is having a broader label, which is probably more relevant in the US than outside the US. That could help us to potentially have a preferential treatment there from payers as well. It is very similar or anticipated for type one, type two, given that we have an extra indication on top of that that might be a positive from a competitive perspective. Does that answer the question? Yeah. Very well. Thanks. Yeah. Perhaps you can comment on the question about the mechanism behind the cold activation. Good question. Cold activation is a technology, a concept that has been understood or to a certain extent since 2021, and we apply it here for bradykinin formation. Basically, the cold, we know, reduces the function of C1 inhibitor. Thereby, it disinhibits the bradykinin-forming cascade. Now, in healthy volunteers which have a healthy bradykinin-forming cascade, nothing will happen. This disinhibition, this taking away the brake from the cascade, will not lead to excessive production of bradykinin. However, in bradykinin-mediated angioedema patients, that cascade is sensitized, is unstable, either because of mutations such as in the normal C1 inhibitor or any other pathophysiological mechanism. When taking the brake away from those individuals, that actually will expose the cascade to spontaneous activation. We actually detect with this assay the sensitivity of the cascade or the instability of the cascade in these subjects. Where in normal C1 and healthy volunteers, they both have the same levels of normal C1 inhibitor or C1 inhibitor levels or activity, in healthy volunteers, nothing will happen. In angioedema patients, the cascade will be activated. That's the mechanism. The second question was, if it works as well, why not develop it as a diagnostic? Yes, the assay really works well. We are very confident. We're very happy with the sensitivity, with the reproducibility. We've standardized it. It really does respond to all of our expectations of a qualified and validated assay. We do not intend to develop it as a diagnostic because we are not a diagnostic company. We just want to use it for exploratory research purpose and to do and help our clinical trials and to learn about which of these various pathophysiological variants are bradykinin-mediated. Okay. That's very clear. Thank you. Thank you for the questions, Jacob. Our next question comes from Deban jana Chatterjee at Jones Research. Please go ahead, Deban jana. Hi. Thanks for taking my question. And very interesting presentation. I know that you haven't decided yet the trial size for the acquired angioedema indication, but could you provide any preliminary guidance on the overall cost range you're anticipating? Or if any of the startup activities is already embedded in your current cash runway guidance? Yeah. As we said, we can provide more details further along on the trial. I think we already said that it's a limited patient number. We expect it to be relatively compact in terms of both from a financial perspective and a patient perspective. We have included that in our current runway guidance. That's embedded in the current guidance. There's no incremental spend that hasn't been guided to previously. Sure. Okay. Thanks for confirming. A quick follow-up. To what extent do you view this indication as an opportunity to expand deucrictibant's commercial potential beyond HAE, if I'm thinking in terms of revenue potential? Yeah. I can take that question. It clearly is an interesting opportunity for us because from a mechanistic perspective, it's something where we potentially are uniquely placed there, but also in terms of numbers. There was a recent paper published or in publication as we speak, sponsored by the American HAEA, the patient organization. Based on the claims analysis, they showed that there are about 9,500 patients in the US taking therapies for HAE. After expert review, that was brought down to about 7,600 HAE patients. That means there are more patients taking actually HAE therapies than there truly are HAE patients. Our assumption at the moment is that probably between 700 and 1,000 patients in the US, we use 800 that are being treated as we speak that are known. As I mentioned before, the opportunity really here is to see what is the real population, i.e., are there patients out there treated by hematologists, by immunologists that really do not think about referring them to the allergist? If you just think about increasing that by one, two, threefold, then that becomes a very significant incremental opportunity. Obviously, without a label, you cannot really activate those patients because you cannot really promote this. If and when we would be able to have this in our label, that really would enable us to kind of go after those patients as well. But at the moment, I can't give you a perfect answer, but we believe that there is significant opportunity there. Does that make sense? Yes. Absolutely. Thank you so much. Great. Thank you for the questions, Deban jana. Our last question comes from Tazeen Ahmad at Bank of America. Please go ahead, Tazeen. Tazeen, you may be on mute. Thank you so much for joining us. That concludes the Q&A portion of this call. Berndt, would you like to have a closing remark, and then we will complete the call? Yep. Thanks, everybody, for joining this R&D session of ours and also for the great questions. We are, of course, very excited about the potential that we see here and to serve additional unmet needs for people living with bradykinin-mediated angioedema. Stay tuned for more updates in the future. Thank you for joining.