KalVista Pharmaceuticals, Inc. (KALV) Earnings Call Transcript & Summary

Good day, and welcome to the KalVista Investor Event. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Ryan Baker, Head of Investor Relations. Please go ahead.

Good morning. My name is Ryan Baker, and I'm the Head of Investor Relations here at KalVista Pharmaceuticals. I'd like to welcome you to today's webcast were members of KalVista's management team as well as 2 notable doctors in the field of hereditary angioedema or HAE, will provide an overview of the commercialization strategy, plans and progress for sebetralstat, the company's oral on-demand investigational treatment of HAE. During this call, we may make statements related to our business that are forward-looking statements under federal securities laws. These statements are not guarantees of future performance. They are subject to a variety of risks and uncertainties. Our actual results could differ materially from the expectations reflected in any forward-looking statements. Please refer to our SEC filings available on the SEC's website and in the Investor Relations section of our website for a discussion of the material risks and other important factors that could affect our actual results. I will now hand it over to Ben Palleiko, Chief Executive Officer of KalVista Pharmaceuticals. Ben?

Good morning, everyone, and thank you for joining this webcast. Our objectives today are to provide a better understanding of how sebetralstat, if approved, will fit into the HAE treatment landscape and how we expect it to shift the paradigm for how HAE is treated and to give all of you more details on our commercial strategy and preparations. In addition to me, today's participants from KalVista will be Dr. Paul Audhya, Chief Medical Officer; and Nicole Sweeny, Chief Commercial Officer. We also have the honor to be joined by 2 well-known thought leaders in the area of HAE, Dr. Autumn Burnette and Dr. William Lumry. They will speak to the current treatment guidelines, state of treatment for HAE as well as the continuing unmet needs for better therapeutic options for people living with HAE. Dr. William Lumry is a renowned expert in allergy, asthma and hereditary angioedema. He's a clinical professor of internal medicine, at UT Southwestern Medical School and has been in private practice in Dallas, treating both adults and children. As the Medical Director of AARA Research Center, he's conducted over 500 clinical trials and is a highly sought-after speaker and consultant on allergic diseases worldwide. Dr. Autumn Burnette is an assistant professor in the Division of Allergy and Immunology at Howard University. Dr. Burnette is a board-certified expert in both allergy, immunology and pediatrics, specializing in hereditary angioedema and other allergic disorders. She's a respected speaker, researcher and thought leader in the field, contributing to numerous publications and advisory boards. Our agenda today is as follows: I will start with a brief overview of how sebetralstat has the potential to become a truly global product by changing the existing treatment paradigm. Following that, Dr. Lumry will provide an overview of the HAE treatment guidelines, offering insights into the clinical standards that guide current patient care. Dr. Burnette will then focus on the current state of HAE treatment today discussing the advances made and where gaps still remain in providing optimal care for patients. Dr. Audhya will then discuss how we believe sebetralstat may provide people living with HAE with a substantially improved option to manage their disease and how the extensive data set we've generated shows the efficacy and safety of sebetralstat in the broadest possible setting of HAE attacks. Finally, Nicole Sweeny will tie all those discussions together to talk about how sebetralstat, if approved, can become the foundational therapy for HAE and how we intend to execute on our commercial plan to quickly bring this novel option to people living with the disease. After that, we'll open the lines for any questions from the audience. Now on with the program. Let me start by showing you the planned brand name for sebetralstat [indiscernible]. In January of this year, we launched our Coming Soon campaign, of which this is part introducing our brand name, which is based on a call to action for people living with HAE to act early when it comes to treating their HAE attacks. [indiscernible] is a product is intended to enable people with HAE to treat their disease in accordance with existing guidelines, which call for considering treatment of all attacks and for treating early before the most significant symptoms develop. [indiscernible] represents our commitment to the HAE community, demonstrating that we understand their desires and recognize their needs for an efficacious and safe oral product that has shown the ability to address all types and severities of HAE attacks, including mild attacks, whether used alone or alongside prophylaxis. With our intent to make it available initially to adolescents and adults, and eventually to pediatrics as well, [indiscernible] is poised to become the foundational therapy for HAE management. While we won't use the brand name for the rest of the day as sebetralstat is not yet approved, [indiscernible] is the future for us, and we believe for the entire HAE community worldwide. As we move towards our PDUFA date of June 17, KalVista stands in a particularly strong position for several key reasons. All of these will be discussed further throughout the presentation, but here's a summary. The market dynamics are favorable with consistent demand, low competitive intensity and expectations of broad payer access. These conditions create a prime environment for a successful introduction of the product. To address that market, we have generated what we believe is the strongest clinical profile than any on-demand therapy has or will have marked by a pristine safety profile and proven efficacy and effectively all potential subpopulations. Paul will provide a more detailed analysis of this data later. On the commercial side, we've built an extraordinary team with unparalleled HAE experience. All of our most senior leaders and many of our next level have launched multiple HAE treatments and the majority of the rest have worked extensively in rare disease. As Nicole will elaborate, our full commercial team is already in place and operating in the field, well prepared for what lies ahead. Because of its unique attributes as well as the status of the ex U.S. markets, we are confident that sebetralstat can become a truly global therapy for people with HAE. Though the focus of today is primarily on the U.S. launch, it's important to note that we have an aggressive strategy to introduce sebetralstat to multiple rest of world markets quickly, both on our own and through commercial collaborations. I'll give a little more detail on that in a bit. And finally, we are financially equipped to execute this plan with our existing cash balance. Because of our disciplined spending and a highly favorable royalty arrangement completed last year, we faced no cash constraints that will limit our ability to give sebetralstat, the commercial launch a product like this deserves. This slide shows both the vision that drives us here to develop novel therapies like sebetralstat that empower people to live better lives as well as some of the key events we expect over the course of 2025. As announced in this morning's press release, we have completed enrollment for our KONFIDENT-KID pediatric trial, a full year ahead of expectations and anticipate initial data in the fourth quarter of this year with an sNDA coming in 2026. The tremendous interest in this trial that led to this outcome continues to support our view that the level of unmet need in HAE remains high. Next on the calendar is our June PDUFA date. Followed shortly after by an anticipated EMA decision and, if approved, a German launch later this year. After that, we currently expect to launch in the U.K. and Japan in the first half of 2026, if we receive approval in those territories and potentially in other partner markets later in the year and years following. The net result of our work is that we expect sebetralstat to fundamentally transform the HAE treatment landscape. In a world dominated by injectable, painful and awkward to carry options and where treatment burden is often judged to be as challenging as disease burden, we believe sebetralstat can, over time, become the therapy of choice for people with HAE across all ages. And commercially, we see the global on-demand opportunity exceeding $1 billion, with a large part of that representing growth due specifically to the promise of sebetralstat. This slide shows why. On the left is a schematic of the current HAE treatment paradigm with the exception of one oral prophylaxis, people with HAE today only have injectable options, and so for the most part, they select for the best combination of efficacy and least number of injections, which typically leads them to prophylaxis. Even people without severe disease may rationally prefer prophylaxis because current on-demand treatments make it very difficult to treat incipient attacks in a timely manner. The result is a dominance of prophylaxis treatments despite their remaining burdens, high cost and the fact that most people using them still have breakthrough attacks and so require on-demand therapy. On the right is how we believe the future model may evolve. Here, sebetralstat becomes the foundational treatment for HAE offering people efficacy comparable to injectables as well as a robust safety profile in an oral on-demand product. In this model, many of the current challenges with on-demand therapy are eliminated and LTP becomes a secondary option rather than the default choice. We believe this model may offer substantial benefits to people with HAE as well as the medical system overall. My final slide here outlines our global launch plan. As I mentioned previously, we intend to launch in the U.S. immediately following approval, Germany later this year, and the U.K. and Japan in the first half of 2026. But beyond those launches are a series of potential markets we are currently enabling through an additional set of regulatory filings already made or that we intend to enter through commercial partners. I'm excited to say that we've recently made our initial partner selections in some of these markets, and I hope to be able to make announcements for several territories in the coming months. And over time, one of our key goals is to fill in this map with additional color as we broaden the reach of sebetralstat to become a truly global presence. With that, we'll move to the next item on the agenda. I would now like to introduce Dr. Bill Lumry to talk about the management of HAE in accordance with established guidelines.

Thank you, Ben. Good morning, everyone, and welcome to our discussion this morning about hereditary angioedema. My role is to discuss the disease date and the current treatment goals for this rare disease. With your being here, I'm going to assume that you're familiar with this disease and the disease state and some of the therapies that are available, but we'll go over that information with you in the next few minutes. Hereditary angioedema is a rare genetic disorder that affects somewhere between 1 in 10,000; 1 in 50,000 individuals. If you do the math in the United States, that accounts for around 7,000 individuals affected and around 300,000 worldwide. It's manifested by unpredictable recurring attacks of swelling that can be debilitating, involving the cutaneous tissue, so the face, the hands, the feet as shown in the pictures to your right. But it also can affect submucosal areas like the bowel wall causing swelling of the bowel, swelling of the stomach, as seen in the middle picture on the bottom and severe pain associated with that effective bowel obstruction. The most worrisome type of attack is when it affects the airway, as seen in the lower left picture. The airway is quite small. And with swelling, it can swell shut and actually lead to death in these individuals, if not properly recognized and treated effectively. The attacks progress over approximately a 24-hour period, reaching a peak. And then without treatment, will decrease over the next 2 to 5 days. So the debility associated with this swelling disorder can really affect an individual's life and lifestyle. We have some treatment guidelines and goals for these individuals. And as you can see, our goal of treatment is to achieve total control of the disease and effectively normalize patients' lives. In order to do this, we've got to be able to treat attacks when they occur. And in some individuals, provide medication that will prevent attacks from occurring at all. We recommend that everyone have access to an effective on-demand treatment, no matter how old they are and what type of attacks that they have. For individuals that are severely burdened by their swelling attacks, we consider long-term preventive therapy or long-term prophylaxis in addition to appropriate on-demand therapy. These individuals that are on long-term prophylaxis are not usually completely prevented from having attacks and need to have treatment for attacks when they do break through. This is -- these are sort of the pillars of therapy for our patients. And obviously, each patient is an individual and an individualized treatment plan needs to be developed between the patient and their physician. The first step, as mentioned previously, is access to an effective on-demand treatment that they can use at the onset of an attack and hopefully prevent the attack from becoming a severe and more debilitating. For those individuals that have significant burden associated with their disease, we consider a long-term prophylaxis option in order to prevent the attacks from occurring. But as mentioned, those individuals also need an on-demand treatment because the prophylaxis is not 100%. There are certain types of medical procedures and other events that might trigger an attack in individuals with a hereditary angioedema. Some of these are surgical events, medical events or dental procedures. And in that setting, we will give them a treatment of short-term prophylaxis to try to prevent that event from actually provoking an attack. Once a treatment plan is designed for a patient, we periodically assess or reassess the treatment to see how well it's working and then optimize that for the patient as their disease may change over time. There are guidelines for on-demand treatment. And these recommendations published just a few years ago, outline those for you. First of all, we need to consider on-demand treatment for all attacks, not just the ones that the patients may feel are most severe or most debilitating. We do this because the attacks may actually move from, say, a hand swelling to a throat swelling or a lip swelling to an abdominal attack. And because this movement can be very unpredictable and rapidly progress, we recommend that individuals treat very early in their attack. In order to treat early, obviously, you've got to have ready access to on-demand medications. And to provide this, we suggest that patients carry on-demand medication for the treatment of at least 2 attacks because the attacks can occur at any time and anywhere and sometimes attacks require a second dose for resolution. Unfortunately, as Dr. Burnette will point out in her presentation following mine, this is often difficult for patients to do. The current on-demand therapies that are available are not easily carried and often are difficult to administer, particularly if one is out in public when an attack occurs. This is a cartoon, if you will, showing sort of what happens during an attack. These attacks, again, will build over approximately a 24-hour period, and then the offset can be as long as 5 days. So from the time that the patient first feels that an attack is coming on, there's sort of a slow ramp-up period. And we have some time there that when the patient could take an on-demand treatment to shut down the attack and keep it mild, and as shown again in this cartoon, early treatment will allow the attack to essentially not get out of the very mild state where if you delay treatment, the severity of the attack will significantly increase over the next 12 to 24 hours. So again, a graphical representation of why we recommend that patients treat early at first onset of an attack to prevent the burden of the attack from being significant. When do we suggest long-term prophylaxis for patients? Well, this slide suggests 3 possibilities. There are others. But the most common ones are individuals who are having frequent or severe attacks. The number of attacks and individual patient might have -- could vary from once a week or once every 3 or 4 days, which is completely debilitating to less frequently once or twice a month or even less than that. So we look at frequency and severity of attacks is one, but not the only consideration when prescribing long-term prophylaxis. We also look at the overall burden of the disease. How disruptive is -- are these unpredictable attacks on work, on school, on family life and overall patients' quality of life. We also look at how the patient responds to on-demand therapy is the disease or the attacks controlled adequately with on-demand therapy or and if they're not, then potentially long-term prophylaxis should be considered for them. As mentioned at the outset, every patient is an individual and a treatment plan has to be put together so that the patient agrees with it, that it's reasonable from a medical provider standpoint. And we use shared decision-making in this disease as we do in many diseases to come up with the appropriate treatment plan. How does that work? We, as physicians share with the patient as well as their family, what the possible treatment options are. And obviously, that can be adjusted as new options come along. And then we explore with the patient what their preferences are, what matters most of them, what's the patient's prior experience, what other medications have been, and then to try to clarify what their goals of treatment are, what does control look like, what does satisfaction look like. And then by providing relevant treatment options describing what's available, how each medication may work, what to expect from it, what side effects there are and presenting medical evidence around that, then with that bit of information, the patient and the family and the physician can decide on an appropriate treatment plan for that patient. With that, I'd like to turn this over to Dr. Burnette to discuss what's happening in the real world in treating patients with hereditary angioedema. Thank you for your attention.

Good morning, everyone. My name is Dr. Autumn Burnette. I'm an allergy immunology physician at Howard University in Washington, D.C. Today, we'll be discussing persisting unmet need in hereditary angioedema. Some of the current on-demand treatments are efficacious, yes, but have limitations. For instance, plasma-derived recombinant C1-esterase inhibitor requires a needle administration. Not only that, it does require reconstitution, and challenges can be posed with patients in terms of getting trained in order to do this. Also, there could be portability issues, preparation time is a factor for these patients. And obviously, because it's a needle, patients are concerned about injection site pain and finding a vein. Ecallantide is a subcutaneous rescue medication for hereditary angioedema that the FDA has applied a black box warning on its label for anaphylaxis. Given the anaphylaxis warning, this medication does require health care professionals done with a home health nurse in the patient's home or it can be done if a patient takes their medication into an emergency room. However, the delay in the management of an acute attack can be a factor here because there is a delay in having to find a health care professional to deliver this medication. In addition to that, again, this is a needle and there may be some injection site reactions. Icatibant is also a subcutaneous injection for the on-demand treatment of hereditarian angioedema. This requires a needle and a syringe, which again, can pose some challenges with portability given that this does not easily fit into the pocket of a person who is carrying this. They may actually have to carry a bag, separate bag in order to transport this effectively. Also, given that it is a needle does require an injection, so there may be injection site reactions. Actually, the data for Icatibant shows that over 90% of patients who inject Icatibant do have injection site reactions, which can include pain, it can be a prolonged pain in addition to that redness and even swelling. Icatibant is an agonist for the MRGPRX2 receptor which lies on the surface of mast cells. Mast cells line the skin. And so when icatibant binds to that receptor in the skin, it can potentially lead to mast cell activation and degranulation and mast cell mediated pseudoallergic reactions in the skin. Even in this photo, you can see an icatibant reaction. At 0 minutes, you could already start to see the erythema from icatibant injection. At 30 minutes, you can see that, that erythema is more pronounced and larger. And at 145 minutes, you can even see that there's an actual wheel formation of the skin where that icatibant was injected. So there are limitations. Even though these medications are effective, the injection site reactions, the preparation time, the needle can pose challenges for patients when they need to rescue themselves. Poor compliance with on-demand treatment guidelines can be a factor as well. The HAE consensus guidelines state that HAE patients should consider on-demand treatment of all HAE attacks irrespective of location and severity. The data shows that 35% to 50% of attacks go untreated including among patients that are on long-term prophylaxis. The guidelines suggest that HAE attacks should be treated early to arrest the progression of swelling and to also shorten the duration of the overall attack. The data shows that only 20% of patients who treat their attacks do so early within less than an hour. The guidelines also suggest that patients who have ready access to their on-demand medication and to actually carry that medication on their person -- for at least the treatment of 2 separate attacks. Interestingly, the data shows that less than 40% of patients carry on-demand treatment outside of the home at all times. This, again, can lead to poor compliance with rescuing themselves when they really need to be rescued. Many HAE attacks are left untreated. That includes mild attacks, moderate attacks and even severe attacks. You can see here the distribution of over 3,700 patients -- excuse me, 3,700 attacks of treated and untreated attacks according to their severity are listed here. And what we see here is, on average, only 50% of attacks were treated with approved on-demand therapies. That still leaves 50% or greater attacks that are left untreated even when they're mild, moderate or severe. What's interesting is even in mild or moderate attacks, patients can still have pain and discomfort and limitations on their mobility and absenteeism from work in school and social isolation when an attack occurs. So being that an attack may be left untreated can still pose problems even when that attack is mild or moderate. Patients currently delay their treatment for the majority of their attacks. And we can see here in this chart of the time to treatment for adolescents, for adults, the time that it takes to even treat a potentially life-threatening attack in an airway of tongue and throat and even a very debilitating attack in the abdominal area, we can see here, overall, the mean time to attack treatment was approximately 3.8 hours. Patients treating in less than an hour was only about 19% of patients. And this is what we can see across the board, whether that be an adult or adolescent, whether that be in the airway or a debilitating area like the abdominal area. Most patients do not carry on-demand treatment when they're away from their home. Fewer than 40% of patients will actually report that they're carrying their rescue medication outside of the home at all times, every time they leave the house. Patients reported being willing to travel up to 3.5 hours away from home without taking their on-demand treatment with them. Now you may ask, are there any specific reasons as to why that may be the case? Yes, there are. The top 3 reasons why patients choose to not carry their on-demand treatment when they're outside of the home. For patients that are only on on-demand treatment, it may be that they would rather treat at home in 78% of patients. It also may be that they forget to take it with them in 52% of patients. In patients that are on long-term prophylaxis and also on on-demand treatment, 77% of them reported that they take their prophylactic treatment, so they're confident they won't have an attack. 65% of them will say, I would rather treat my attack at home, and 60% of them will say, I forgot to take my rescue medication with me outside of the home. However, what we know is that attacks can still continue for many patients receiving long-term prophylaxis. 40% to 60% of patients receiving long-term prophylaxis still experience attacks even when they were studied in randomized clinical control trials. Breakthrough attacks occur in all anatomical locations, including the laryngeal area, which could potentially be a life-threatening location. Long-term prophylaxis adherence can still be challenging for patients and refill gaps of their long-term prophylaxis can be associated with an increase in on-demand treatment claims. What we know at the bottom line is that irrespective of long-term prophylactic use, all HAE patients require an effective on-demand treatment. I thank you for listening, and please let us know if you have any additional questions for us today.

Thank you very much, Dr. Burnette. In this section, I'd like to review the data from the sebetralstat clinical trial program, which underlies what we and the scientific community sees the opportunity to fundamentally transform the HAE treatment landscape. From the outset, the overarching goal of our clinical trial program was to demonstrate that sebetralstat could empower patients to meet the on-demand treatment guidelines, to optimize their clinical outcomes and minimize morbidity of HAE attacks. As Dr. Lumry outlined previously, we wanted to show that sebetralstat would allow patients to consider the treatment of all attacks regardless of severity or location to treat those attacks in minutes and not hours and to allow for ready access to treatment by eliminating the many logistical barriers that Dr. Burnette highlighted. By fulfilling the promise of early treatment, sebetralstat would minimize the attack burden by halting attacks before symptom progression and minimizing HAE symptoms. Our Phase III trial, which we call KONFIDENT is the largest HAE trial that has ever been conducted. Importantly, and for the first time in a pivotal on-demand trial, patients were instructed to treat all their attacks as early as possible, completely aligned with guidelines. Our data published in the New England Journal of Medicine just months after trial completion, highlighted sebetralstat's efficacy across endpoints as well as its safety, which was comparable to what was observed for placebo. Sebetralstat enabled an early time to treatment, which was associated with an unprecedented 40% of attacks treated at their earliest stages before significant symptom progression. This is what we had hoped for and meets the most important recommendation regarding on-demand treatment in the guidelines. We also saw that time to beginning of symptom relief was in the same range as that observed for injectable on-demand treatments. These data underlie our belief that sebetralstat has the potential to evolve the HAE treatment paradigm. KONFIDENT, our Phase III open-label extension study actually extended our objective to demonstrate sebetralstat's ability to meet the on-demand treatment guidelines. This trial included multiple real-world elements, including portable, multi-dose treatment packs, treatment of attacks without any form of qualification and emphasize treatment as early as possible, basically mirroring what would be expected in a post-approval environment. The study is currently ongoing and is expected to conclude in mid-2026, allowing each participant to treat attacks for up to 2 years. Earlier this year, we shared data from our most recent interim analyses, and I'd like to share some of the highlights, which demonstrate sebetralstat's potential to fulfill critical unmet needs. As of September 2024, we accumulated 1,706 attacks, which is a pretty extraordinary number. It's also noteworthy that 85% of attacks were treated with sebetralstat, which is much higher than what has been observed in studies with injectable treatments. The large number of attacks has allowed us to delve into patient subgroups and attack subgroups. On the left, we can see that close to 20% of participants are adolescents, signaling the strong interest in that age group. We also see that more than 25% of participants are receiving concurrent long-term prophylaxis. The largest proportion of LTP users were receiving berotralstat followed by patients on lanadelumab. On average, patients on LTP were treating 1.7 attacks per month with Sebetralstat. On the right, we can see that about 60% of attacks were peripheral, which is a higher proportion than what we've seen in prior on-demand trials and in the real world where these attacks are often left untreated. We've also seen 32 attacks -- 32 laryngeal attacks, excuse me, which represents about 2% of total attacks. We're also pleased that about 40% of attacks are still mild when treated, which goes along with the fact that the overall time to treatment is now down to just 10 minutes. This is all very encouraging as it shows for the first time that patients can meet the on-demand guidelines if they have the right therapy. Here, we can see data from almost 400 breakthrough attacks treated with sebetralstat occurring among patients who are receiving long-term prophylaxis. First, we see that the median time to treatment was extremely rapid at 6 minutes. We also see that time to beginning of symptom relief was 1.3 hours for all attacks on LTP, which was the same for the berotralstat subgroup at 1.3 hours. Berotralstat results were especially well received by HCPs at WAO/EAACI as this represented the first large data set on an all-oral regimen for HAE, which fulfills a long-term unmet need for patients living with a condition. These data will also put to rest concerns that a plasma kallikrein inhibitor might not be effective when used for on-demand treatment among patients using the same mechanism of action for their long-term prophylaxis. The last data I'll share were presented as a late breaker occurred at [AAAAI] just last month. Here, we see that sebetralstat demonstrated consistent efficacy for attacks involving the larynx. First, it's important to note that there were no reports of difficulty swallowing in any of these attacks. That has been a theoretical concern for some. And the feedback we've had from many HCPs is that these data are very reassuring. The median time to treatment was just over 11 minutes, and we see a median time at the beginning of symptom relief was just 1.3 hours. So in the time it takes many patients to just decide whether to treat prepare and then administer an injectable on-demand treatment. Most patients with laryngeal attacks and confidence were already experiencing symptom relief. We also see a second dose rate of 12.5% and use a conventional treatment in less than 10% of attacks. This cartoon represents Sebetralstat's promise to enable early treatment and minimize attack burden. The first step is early treatment, close to the onset of an HAE attack, which is facilitated by easy portability and an oral route of administration. Sebetralstat leaves no reasons for patients to avoid treatment or delay therapy. Early treatment is followed by rapid absorption and high blood concentrations of Sebetralstat, which leads to halting the attack before progression, ideally when still mild before fluid has built up and caused the suffering and disfiguring associated with HAE attacks. Halting the attack leads to the end of attack progression, which is then followed by successive milestones in beginning of symptom relief, reduction in attack severity, leading to near complete attack resolution, which is still associated with mild symptoms. And finally, complete attack resolution, which means no symptoms. By enabling early treatment, Sebetralstat keeps the burden of the attack as low as possible, effectively preventing worsening of attack symptoms. This translates to total control for the patient as they can treat their attack anytime, anywhere and avoid most of the morbidity associated with HAE. In summary, the data from the KONFIDENT clinical program demonstrates sebetralstat's potential to evolve the current HAE treatment paradigm. Sebetralstat has been used in the treatment of well over 2,000 attacks with a safety profile comparable to placebo. We've observed a radical shift in time to treatment from hours to just minutes. And at 85%, we've seen an unprecedented proportion of attacks treated. Alongside early treatment, we see that attacks are being treated in an early stage long before fluid buildup and symptom progression. Importantly, all this happens with the time to beginning of symptom relief comparable to injections with a median time of 1.3 hours among important attack subgroups, including those involving the larynx or breakthrough attacks on LTP. If approved, Sebetralstat has the potential to fundamentally change the shared decision-making conversation between physicians and their patients regarding the management of HAE. Now I'd like to turn over to Nicole Sweeny, our Chief Commercial Officer.

Thanks, Paul. Today, I'll be providing a view into KalVista's efforts to launch Sebetralstat, the first oral on-demand therapy for HAE. I'll be touching upon 3 key areas today, the global opportunity and positioning of Sebetralstat. I'll then shift to a deep dive into the U.S. market opportunity and go-to-market plans, followed by a view into our first 3 ex-U.S. launches. As Ben touched upon earlier in the day, the global HAE market is valued at $3 billion. The U.S. remains dominant and most sales are driven by the use of prophylactic therapy. As we look ahead to the global market, that market is poised for tremendous growth exceeding $4 billion by 2030. On-demand sales will increase by 70% and this increase in on-demand sales is driven by the introduction of oral on-demand treatment. With this oral on-demand treatment, this will first increase the use of branded products as well as increase given the profile of an oral on-demand treatment, it will increase the attack treatment rate. After the discussions by both Dr. Lumry and Dr. Burnette, it's very clear that current treatment of HAE attacks is simply suboptimal. They share today several gaps between the guidelines and real-world experience. And we continue to see both the delay in attack treatment as well as denial of attack treatment. The rates for both of these have not changed in 10 years time as there has been no new innovation in on-demand to drive that change. A positive of the current situation is that physicians and patients both agree that on-demand is a critical component to every HAE management plan. From the KalVista view, the unmet need is clear. The community needs a better solution to overcome delay and denial of attack treatment. And we believe that sebetralstat can be that catalyst to drive a fundamental change to attack treatment. Sebetralstat is the first oral on-demand treatment for HAE attacks. The Sebetralstat clinical profile is highly differentiated and feedback from both patients and physicians identify a few key characteristics that are most compelling. First, easy-to-carry tablet, a tablet that is portable and discrete, allows patients to keep treatment on them and intercede as soon as symptoms of an attack present. Secondly, injection like efficacy. Paul shared results from sebetralstat Phase III study earlier in our program, which demonstrated efficacy in line with current injectable treatments. All attacks, patients are very clear that they want one on-demand treatment for use in all attacks regardless of severity and regardless of attack location. An additional key characteristic again, that is most compelling for patients and physicians is that sebetralstat has been studied in adults and adolescents. Adolescents have limited treatment options today. And as you can imagine, patients of adolescent age very much appreciate the benefits that a discrete portable tablet can offer as they attend school and engage in extracurricular activities. In summary, sebetralstat enables early treatment and treatment of all attacks, and we believe sebetralstat offers the potential to become the new standard of care and on-demand treatment. Next, I'd like to shift our focus and share a view into the U.S. market opportunity and our go-to-market plans. We're entering the market at a very robust time. We continue to see volume of on-demand therapies remain steady despite the use of modern prophylactic treatment. Patients continue to inform KalVista that they experience attacks. We estimate the patients utilizing on-demand only treatment approach, treat 12 attacks per year. And patients utilizing prophylaxis plus on-demand treatment treat an average of 18 attacks per year. This higher attack burden for prophylactic patients is validated by KalVista studies, where we see those prophylactic patients experience 1.5 attacks per month on average. This leads to a total attack burden requiring over 80,000 doses of on-demand medication being utilized annually. Most of this volume is associated with FIRAZYR icatibant, as you can see in the pie chart on the left. All of the treatments today are IV or injectable. There is no oral on-demand product in the market. As we look ahead to launching a product in the on-demand market, it's a market that certainly is very attractive. First, we see that it's a market with very high diagnosis and treatment rates. This allows KalVista to be positioned to focus all of our efforts squarely on converting the existing market as we introduce our product. I mentioned the stable volume earlier. From a payer standpoint, 70% of patients are covered by a commercial payer. This is attractive as typically speed to accesses is faster with commercial payers and gross to net impact is reduced. And lastly, there is high unmet need or high dissatisfaction with patients currently on IV and injectable treatments. As we share the sebetralstat profile with patients, the reaction is overwhelmingly positive. And I'll start by discussing reaction from the largest on-demand segment. Patients on FIRAZYR and icatibant. We see that 80% of these patients intend to adopt sebetralstat. The reasons are cited below in the quote and often relate to injection pain and reactions as well as tolerability. Now if we shift and we look at patients that are on the most prescribed prophylactic treatment, TAKHZYRO, we see over 70% of patients are likely to adopt sebetralstat. And lastly, when we look at patients who are already on an oral modern prophylactic treatment, ORLADEYO, the intent to adopt increases to 90%. The reason for this increase is that patients tell us they prefer an oral approach and would like to take an all-oral approach to their HAE treatment plan. Certainly, it's very encouraging to see this high intent to adopt across all key patient segments. Beyond intent to use, there's further evidence, which signals the adoption of Sebetralstat could be rapid. Since summer, we have seen increase in social media followership for KalVista as well as for our disease educational handle Mind the HAE Attack. What's more telling is that our patient database has grown to over 2,000 patients and caregivers. These are individuals who have opted in to hear more about KalVista's work in HAE. Over the past few months, we've been adding 200 patient sign-ups per month, signaling heightened interest in our work as we approach our June PDUFA date. We see similar interest, high interest from health care professionals. You'll see here that nearly 100% of health care professionals agree there's a significant unmet need for an oral on-demand treatment and 90% share likelihood to prescribe sebetralstat within the first 6 months of approval. And certainly, it's a very positive position to see strong interest from both patients and health care professionals, but we recognize that access to Sebetralstat is critical to launch. The HAE market is one where commercial payers are the dominant payer. 70% of patients are covered by commercial payers. Predominantly, this is connected or associated with 60 national and regional payers. They manage the vast majority of HAE lives. And as HAE branded therapies have been around for nearly 20 years, payers have some degree of understanding that HAE is a rare and life-threatening illness. It's also worth noting that Medicare is a smaller player in -- excuse me, a smaller payer in this market, which removes potential for any IRA-related price negotiations in the future. Now when we present the Sebetralstat clinical profile to payers, they appreciate the value in which sebetralstat can bring. They respond to the efficacy, tolerability and highlight the oral presentation is critical to enabling earlier treatment of attacks. With this profile, patients -- excuse me, payers expect sebetralstat to be price comparable to current branded therapies. As you can see in the third column of the slide, branded products today cost approximately $11,000 to $16,000 to treat an HAE attack. And again, payers anticipate sebetralstat will be comparable to this pricing. From the KalVista view, we anticipate sebetralstat will have parity access to branded therapies. Today, branded therapies typically are accessed via prior authorization. All on-demand treatments also have quantity limits as part of their policies. The quantity limits specify multiple units per month or 90-day time period, which offer, for the most part, flexibility for HAE patients. For sebetralstat, we expect access and quantity limits will play out similarly as branded therapies. It's also important to note that Firazyr is unique. Some plans require a step-through generic icatibant in order to receive or have access to Firazyr. We do not expect step edits for sebetralstat. If we are faced, we are confident patients could quickly step through the generic. Data in reviewing claims analysis tells us that today, 80% of patients are on or have been on generic icatibant. They meet the generic experience, which will allow them to rapidly move forward through that product. We also recognize that previous HAE launches, they tell us that access will evolve over time. Payers have indicated that they'll take 6 months to review a product for placement within the formulary. Knowing that time period, we expect the early months of launch to leverage medical exception as a primary means to access sebetralstat. My previous experience launching drugs in HAE, medical exception has been the standard. The review time for medical exception is variable. It can range from days to weeks and is different from one payer to the next. So KalVista expects variability in the review time for medical exception. As such, we plan to launch a quick start program. While our KalVista hub is working on start form to gain paid access to sebetralstat, our quick start program will allow patients to access sebetralstat free of charge to gain immediate clinical experience with our product. For the past several years, KalVista has been preparing the market for the introduction of sebetralstat. Kudos to our medical team for their substantial presence at scientific conferences, the robust publication plans as well as our MSL team that has been in the field for years. More recently, last summer, we launched our field national account team to engage with payers. They utilize pre-approval information exchange or PIE to inform payers of KalVista as well as the upcoming sebetralstat launch. The team has done a tremendous work and engaged with target payers who manage more than 75% of HAE lives. Earlier this year, we increased our field team by introducing field sales and field access. Our sales team members bring a tremendous wealth of HAE experience. All of our leaders have launched at least 1 HAE drug, some have launched 2 HAE drugs. The majority of our sales representatives also have experience in HAE. Within 3 weeks of the team engaged with health care professionals that they were able to reach health care professionals that manage over 5,000 HAE patients. We look forward to their continued engagement with these accounts. At the same time, we have our field access team members engaging and visiting these accounts to make sure that they fully bring the resources and understanding from an access standpoint to the staff of these health care professionals. They bring tremendous experience with complex rare disease launches. At approval, our focus will shift solely to driving demand of sebetralstat. Our field team will engage with 1,000 health care professionals. These 1,000 health care professionals account for 90% of HAE claims today. This is where the high concentration of patients are and where the highest unmet need lies. Our efforts will also focus on activating patients. This begins with increasing awareness of sebetralstat via social media, as well as local speaker educational programs in the top 20 markets around the country. Our goal is to ensure patients are informed about sebetralstat and what makes sebetralstat different so that they can engage in a discussion with their physician and assess if sebetralstat is right for them. In addition, we are very fortunate that a key community event is taking place a month following PDUFA. The HAEA, a world-class patient advocacy organization, which serves the U.S. HAE community is hosting their patient summit meeting. This meeting happens every 2 years and brings together patients and families to connect and learn more about developments in HAE. For KalVista, this creates an opportunity to provide an introduction to sebetralstat to over 1,200 members of the U.S. HAE community. It's a tremendous event and the HAEA is a tremendous partner. From the access side of things, I mentioned earlier, the availability of quick start immediately filing approval, we'll also be launching our dedicated KalVista Patient Support hub. We appreciate the dynamics exist that could impact launch, and we've taken a very proactive approach to managing them. We know that patients visit their health care professional 1 to 3x per year and that activating the patient to go to the office to discuss sebetralstat is important. We'll continue to build our patient database between now and PDUFA, so we can share product information directly with patients post approval. Also, I mentioned that payers typically take 6 months to set formularies. This is why we chose to engage payers early and why we'll continue to provide product education to them through approval. And lastly, we certainly respect the high unmet need in the patient community and that launching sebetralstat as quickly as possible following approval is critical. From a supply planning view and hub-readiness view, we are planning readiness for immediately following our FDA approval. As a company, we also appreciate that accurate -- an accurate and timely view into sebetralstat adoption is important, not only internally but also for our external stakeholders. And also in looking at other rare disease launches, some external sources often have delayed or incomplete data in the early days of launch. We recognize that as KalVista, we will need to share regular updates to our external stakeholders. Our updates on KPIs, our goal is to provide a view into patient health care professional and payer metrics in the days, weeks and months following approval. I'll call your attention to the immediate column on the slide, as this provides an idea of metrics that will be available in the early days following approval. As launch progresses, we will share greater insights that reflect broad adoption by all of our stakeholders. As Ben outlined, our ambition is to bring sebetralstat throughout the world. I'd like to share a view into our first 3 ex U.S. launches. We are poised to launch in Germany, Japan and U.K. in the months following our U.S. launch. Our readiness efforts are underway in all of these geographies, leveraging small, highly talented, focused teams. Our leaders, our Head of Europe and our Head of Japan, have extensive experience in HAE. Each of them have launched multiple HAE treatments in their respective markets. So we are very excited about the potential to bring a new standard of care to multiple countries in short order. As a company, we're thrilled to introduce the first oral on-demand HAE treatment. We believe there is a clear path to sebetralstat becoming standard of care. If we look at the U.S. in particular, that path involves growth in 2 phases: first, growing market share for sebetralstat. We'll do this by gaining initial use in the first 1,000 health care professionals and those patients who have communicated the highest dissatisfaction with current therapies, patients on Firazyr and icatibant. As we accelerate adoption, we'll broaden use across all 2,000 health care professionals that treat HAE and across patients from utilizing today all types of on-demand therapies. The second phase of growth relates to growing the treated attack market. As patients fully adopt sebetralstat and derive the full benefit of sebetralstat, we expect the number of treated attacks will grow. As the first oral on-demand treatment, sebetralstat is well positioned to fuel the growth in the U.S. on demand market. We are excited to establish a new standard of care, offering all HAE patients the opportunity to realize better outcomes. Thank you for your time. I'd like to pass it back to Ben.

So KalVista is fully prepared to launch sebetralstat as the first and only oral on-demand therapy for HAE and this is why we expect success. We have a market with high unmet need and favorable dynamics. We've executed an unprecedented clinical development effort in the largest trials ever conducted in this disease to demonstrate efficacy and safety in the broadest possible set of attack types, locations and severities for both adolescents and adults with HAE. No other on-demand product has or will have such a robust data set at approval. We have a commercial team with deep experience and demonstrated commitment in HAE, and our field team is already preparing for launch. We have the potential to take this product to a global audience. Both in the U.S. and around the world, people with HAE and their medical providers are actively seeking novel, high-quality treatment alternatives. And last but certainly not least, we have the financial resources to execute this effort properly. That concludes our presentation. We'd now be happy to take any questions from the audience. Operator, can you please open the queue?

[Operator Instructions] Our first question comes from Maury Raycroft with Jefferies.

Thanks for hosting this event, really helpful. I'll start off just with Slide 44. So it suggests high interest and adoption of sebetralstat, which is encouraging. I'm wondering for patients on prophylaxis, did you further ask if these patients would switch completely to manage their HAE with sebetralstat? And what can the company or the KOL say about willingness and ability to completely manage disease with sebetralstat?

Thank you for joining, and nice to hear from you. We have not actually done that sort of work. So we really don't have any data we can provide at this point. I guess I will ask, however, if Dr. Lumry or Burnette have any thoughts they want to add to that.

This is Dr. Burnette. Can you hear me? Yes. Great. I mean, I don't necessarily have anything very specific to share, but I think the expectation from a provider standpoint and in terms of how we think about managing our patients, this is truly what we would consider to be something that may actually change how we think and consider patients in terms of the ready access, the feasibility, if you will, of managing attacks in a very rapid way. There is a historically just an unfortunate habit that patients have at delaying treatment for a variety of different reasons that we mentioned before. This allows just ready access, feasibility in terms of carrying on-demand rescue, making it less cumbersome and less of a notion that patients have to delay this. And so from a provider standpoint, from a physician standpoint, this really potentially could change how we think about having a conversation with our patients about rescuing their attacks.

Got it. That's helpful. And maybe one other question just on some of the specifics of the launch for the QuickStart program. Can you talk a little bit more about that? Will that be 1, 2 or more free doses that patients are getting? And how will that work? Yes, and I'll leave it at that.

Thanks, Maury. Yes, Nicole will pick that up.

Yes, the plan for QuickStart is that we will offer a starting pack to patients. And while the patient is getting their original experience or their initial experience, utilizing sebetralstat that, as I mentioned, our patient hub will be working their case to ensure that we work as quickly as possible to gain that individual access to paid therapy. During that time frame, I can assure you that we will be working that case rapidly with a goal to ensure that patients gain access to pay therapy as soon as possible. If an additional shipment of the QuickStart is needed, certainly would provide that to ensure patients have that consistent and ongoing use of sebetralstat. But our goal certainly is focused on ensuring rapid access to paid therapy.

Our next question comes from Stacy Ku with TD Cowen.

Great. Congratulations on a really nice presentation. So our first question is to Dr. Lumry and Dr. Burnette. Really interesting sort of results you saw from the patients kind of suggests that there's going to be high patient demand from many different contingencies. So maybe first, can you talk about how will you guide patients through switching from their injectable on-demand option? Is this something that you're going to suggest to your patients? Or would you rather get some real-world experience from patients that are now seeking treatment? And then second, maybe talk about which patients do you think from your own practice would be most interested in trying it. And maybe if you could make a guess, the third question to the doctors would be what percentage of your patients do you expect with trial sebetralstat in your practice? And then I have a follow-up for Nicole.

This is Bill Lumry. Can you hear me? Okay. Good. Thank you. [indiscernible] feedback on this end. Thank you for your question because they are important ones. So what patient groups initially, I think, will be most interested? Well, first of all, we have a very large unmet need, as already pointed out in the adolescent population. The only thing that's currently approved under the age of 18 are intravenous C1 inhibitor or a subcutaneous drug that needs to be given in the presence of the health care provider. So access is a challenge. And when these kids have attacks, they either go to emergency room or fight with their parents about getting an IV started or they just don't treat their attacks. So this option is going to fill that need immediately, and we don't think we're going to have any convincing if you were able to do with that population that this is a good way to go to treat your attacks. To your other point, and I think the question behind it is will patients have a feeling that this oral agent will work as well for them as their traditional injectable or infusible agent. And it's interesting that how [ they used to ] name their trial KONFIDENT or KONFIDENT-S because it's going to take some time, and we saw this in the clinical trial data for patients to understand that this drug really does work. They don't see it going in them like a shot or an IV infusion, but they just swallow it and I guess the perception is, well, shots must work faster and better than pills. But once they've treated an attack or 2 with the oral agent, my experience has been in the clinical trial setting, they become confident and kind of intended that the drug will work for them and works for all attacks. The ability to treat early is huge. As Amber pointed out, 40% of patients don't ever treat attacks because of fear of a side effect from it. And many treat very late. When they do treat, letting the attack get much more severe in its action. So I think that the transition will be one that patients who haven't had experience in the clinical trials using these drugs will use them become -- find them effective and feel confident about using the drugs going forward. It's going to -- there's going to be a transition, and I think that's an appropriate question for people going to want 2 agents, an injectable and an oral, what about this kind of attack, what about this particular situation. But I think with time, patients will understand that this drug works very effectively and hopefully, will use it as their primary therapy.

Okay. Dr. Lumry, that's helpful. And actually, maybe can talk about the social media aspect then of HAE patients type community maybe sharing their experiences maybe on other drugs that you've seen kind of oral launches like ORLADEYO?

So what we've seen and you know is that the HAE community through the HAE is a very tight, tight, tight community. And often, the patients know a drug has been approved or something has changed about a drug even before we do. Patients will call up the day of the PDUFA and say, oh, did you hear sebetralstat was approved today, can I get it? And I think that, that's going to the question about how are we going to present this to our patients. I think that the word will get out once approval is obtained, if it is in the summer, and patients will be calling us as opposed to the other way around. Again, I think the enthusiasm is going to be huge. And then again, with the opportunity of presenting this to literally almost 1/3 of the HAE community at the Summit in July in Baltimore, the word will get around very quickly.

Okay. Understood. That's helpful. And then a question for Nicole. Obviously, our sense is that there is a very high awareness and enthusiasm for sebetralstat among academic KOLs. But maybe talk about your current progress in terms of outreach to the community commissions, which, obviously, there's a significant proportion of prescribers for other oral agents in HAE prophylaxis. So just curious, you've talked about that 1,000 top HCPs then broadening. Is that kind of the best way to think about the community doctors, especially as you think about patient demand that's going to be coming from kind of all sides?

Yes. Thank you, Stacy, for the question. And just to take a step back, as I mentioned in our presentation, we know that there are 2,000 health care professionals that currently manage HAE today, and that 1,000 of those HCPs represent 90% of the claims for HAE treatment today. So our team that's in the field currently, they are currently engaging with all 2,000 health care professionals. And the aim is that between now and our PDUFA, they may contact and have deep and repeat engagement with all 2,000 of those health care professionals. That will allow us, again, to introduce KalVista as well as to allow our team to have an understanding of that physician's current management of HAE in terms of the number of patients they manage and the frequency that those patients visit those offices. So that is certainly our focus between now and PDUFA. And then following approval, our immediate focus will be those top 1,000 accounts that I mentioned during the slide presentation. And to your point, the top 1,000 include certainly national physicians that manage several patients, regional and then also some that do manage, I would say, fewer number in terms of maybe a handful patients or even less than 10 that are all accounted for in those 1,000 physicians.

Our next question is from Stifel.

This is Emily on for Paul. We just wanted to ask a question a little bit on redosing. Kind of like what are you expecting or hoping for on the label? And then kind of on the [indiscernible] side. Do you expect there to be -- I don't know, I mean like your pushback with patients using, let's say, like 2 pills per attack?

Thanks, Emily, for the question. In terms of the label, I think the one we look at most commonly would be the Firazyr label, which provides for a max daily dosing. In their case, it's 3 doses per day with no really significant -- no time interval or anything noted in between. And so that's probably a pretty good place to start in terms of where we expect to land here. I think that we would expect there to be a maximum recommended daily dosage, but whether that sits at 2, 3, 4 tablets is to be determined. And I don't know, we feel terribly concerned about where that would sit. In terms of how patients will use the drug in the real world, yes, certainly, there will be some experimentation on the part of patients in terms of treatment. We certainly believe that for virtually all attacks, the -- a single tablet should suffice. I think the data very clearly shows that. But we know that in the real world, with all the therapies, people redose at a reasonable rate. I mean Firazyr redose rates, depending on the data source you look at, range something from low 20% as high as 40% I've seen in some studies. And so you do have a fairly common redose usage in the HAE world generally. In our open-label extension trial, we're currently seeing people redosing in the low 20% range right around now, which is certainly at the low end of those Firazyr numbers. We don't think that reflects anything with the drug, particularly that really just shows more patient behavior as a normal course of activity. And so I think if we landed somewhere in there, I think we'd be very satisfied. I think patients will be satisfied. And I don't think from a system perspective, there'd be any concerns about that at all.

Our next question comes from Joe Schwartz with Leerink Partners.

First one is for management. I was wondering if you could give us any insight into how we should think about the pace of the sebetralstat launch in the context of both initial prescriptions and then also subsequent refills based on how the product is going to be packaged and when you think patients are most likely to refill their prescription. To what extent do you think we can see a strong bolus and then maybe a bit of a gap as patients actually need to use their supply and then get a refill? And when do you think that refill is most likely to occur?

Yes, Joe. Nice to hear from you. Thanks for the questions. So with regard to the launch, sebetralstat will be packaged in a box. It will have multiple doses in the box. And so when people get a quick start, as Nicole mentioned earlier, they'll -- we will ship them immediately a box of sebetralstat of these multiple doses to use. You are right in that compared to the most recent launch, which was the prophylaxis ORLADEYO. This is a refill-driven event. And so once patients get that box, they'll have to obviously use it before they get another one. The pace of that will be certainly dependent upon people's usage. And as Nicole mentioned in her comments, you see somewhere between 15 to 18 attacks per patient per year on average. And so that suggests a box could last somebody between a month or maybe 6 or 8 weeks if on the low end, which means that certainly in the early days of the launch, there will be a little bit of a jagged shape to the adoption curve as we haven't gotten a large enough number of people to have that curve smooth out. That data really won't be out there anyway because IQVIA doesn't track QuickStart. And in fact, on the launch, we wouldn't really expect it to be an IQVIA data for a period of time at all. So I think from some perspective, it won't really be highly visible to people. We'll obviously be putting out metrics about that Nicole referenced in terms of how people are getting their initial doses, and we will shift into refill rates over time. But I don't know that you will -- it will be eminently visible to everyone in the world what the initial refill rates are going to be. So I guess the point here is that you're right, certainly, that has been our full expectation that you'll see a little bit of ups and downs in the volumes early on. But like I said, I think that will smooth out fairly quickly. And certainly, as we announce those parameters, we'll be careful to make sure that people understand that whether those numbers sit wherever they are, that it's definitely subject to how the refill rates are going. And over time, we've acknowledged, and Nicole put that in as one of the metrics that will be one of the KPIs we'll be putting out to people routinely.

Super helpful. If I could ask a question for Dr. Lumry. I was wondering if we could get your thoughts on the potential for the treatment paradigm to evolve once a simple and effective on-demand treatment option is available, how do you see on-demand treatment options such as sebetralstat being prioritized and used relative to prophy options? Do you think that prescribing and usage patterns could change in any particular ways?

I think that -- well, first of all, that -- it's a very interesting question that I think will evolve as time goes along. Our current treatment paradigm when we see a patient with a diagnosis or make a diagnosis with HAE is to first, as I mentioned, provide an on-demand therapy, something that they can use to treat an attack when they occur. We may discuss at that visit as part of the shared decision-making process, the availability of preventive or prophylactic therapy. But often, if somebody is absolutely new to therapy, they're interested in managing their attacks and not necessarily preventing attacks. Once they've had experience with the on-demand therapy, then at that point, we will discuss with them further prophylactic options and whether they're happy with their own demand or if they want to proceed with a prophylactic approach. What we've had in the past for on-demand therapy has been limited as you've heard in this presentation to infusible or injectable products. And that takes training, that takes -- it's a challenge for some patients to even do those kinds of therapies. And in those individuals, we have opted to move them to preventive or prophylactic therapies maybe earlier in their treatment journey simply because they don't tolerate or won't use their on-demand therapy. That may change as we go forward with an easier to access and easier to use on-demand therapy. And I can certainly see patients that were sort of on the cusp, if you will, of do I really need prophylaxis or can I just manage this with on-demand considering going just to an on-demand option and getting off of a routine medication. That somewhat goes against our current guideline recommendation that we achieved total control of the disease, meaning no attacks at all. And obviously, if you're just treating on-demand, you're still having attacks. But you could also consider that control means what the patient considers to be their control and what satisfies them as far as their treatment options. So we'll see. But I think your point is well made that we may well see a shift from everybody is moving towards prophylaxis at some point in their journey to a large majority of patients can be treated with an on-demand option alone.

Our next question comes from Deb Chatterjee with Jones.

So could you provide any additional color on what data the FDA would need to see to potentially allow patients to take more than 2 tablets in a 24-hour period? And do you believe that the data you have generated from KONFIDENT and KONFIDENT-S is sufficient to support such a level?

And just to be clear, Deb, first of all, thank you for the question. And maybe I'll have Paul talk to this in a second. But just to be clear, we're not suggesting that there'd be some kind of limit of 2 tablets a day. I think what we're saying is we're -- and we've been very clear about this, we're just initiating the labeling discussions now with the FDA. It is very common for all these therapies to have a max daily usage. And so we fully expect that there will be some type of max daily usage. Just simply factually, we haven't agreed yet to what that would be. And so I think when I put out 2, 3 or 4, I was just saying we expect it to be some multiple, but what that actual number is will be the subject of discussions. But again, we also don't know that we think it's terribly important either way just because of the way the therapy has clearly shown efficacy here at even a single dose rate that we're -- we don't view that as it is any really substantive challenge to us regardless of whether the number is 2 or 20. So Paul, I don't know if you have anything more you want to add?

I mean the only thing I'd add to that is our program's focus was allowing for dosing flexibility. So the KONFIDENT trial, our Phase III trial had either 1 to 2 doses of 300 milligrams or 1 to 2 doses of 600 milligrams, which effectively would be 4 pills. So in terms of the data that we have, both from KONFIDENT and KONFIDENT-S, we cover a broader range than 2 doses. So I think in terms of data, we certainly have more than adequate data from an efficacy and safety perspective to be able to support the use of 1, 2 or more doses.

Okay. I have a follow-up. So assuming that sebetralstat is approved and also another -- or your oral on-demand competitor, deucrictibant is in the market. How should investors think about positioning of both these therapies in the future?

Yes. I mean that's obviously a fairly speculative question. I think certainly, we have the PDUFA date June 17. We expect to be in the market for several years prior to any other therapies potentially coming along. I think we have obviously an extraordinary well-established clinical efficacy and safety profile. We have shown, again, the broadest set of data in all attack types, all attack locations, all tax severities. We've treated, I think, the largest number of laryngeal attacks ever treated in the clinical trial setting before. We've shown it on top of prophylaxis, we've shown it in adolescent. So I mean there is an incredibly robust package here that I think really positions us well to show that sebetralstat has efficacy and absolutely pristine safety in all these populations. I think that's a very powerful messaging to be able to go out to the patient population with. I think we expect that people will try sebetralstat and be extraordinarily satisfied on it given all those data sets we've generated. And so I don't know that we view there as being a tremendous risk of somebody coming along with something that's materially enhanced beyond that, certainly to a degree that would matter clinically or in the real-world setting and causing people in any sort of significant numbers to change their decision on whether or not to take sebetralstat versus some alternative. So I think we're extremely well positioned, and I think we'll continue to be so.

Our next question comes from Tazeen Ahmad with Bank of America.

This is [ Jerry Lyle ] on for Tazeen. Thanks for hosting this event, very informative. Maybe just a couple of quick questions from us. Just curious if you guys have shared how many pills each sebetralstat script will contain? And then what is your expectation for patient out-of-pocket costs for each dose? Just curious if there's some sort of relationship between the relative cost for each dose and whether or not a patient is -- will delay therapy.

Thank you for the question. We have not yet disclosed what the size of each box will be in terms of number of doses. To some extent, that's dependent upon the FDA labeling conversations. And so that's the very real reason is -- there may be a little flex there depending on how we come to agreement with the FDA there. With regard to patient out-of-pocket costs, this is a space where patient co-pay assistance programs are very robust. And in general, the out-of-pocket cost of patients here is 0. We expect that to be the case here as well. So there really would be no economic impact to patients, depending on what number of doses they use.

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Thank you for hosting the event, very informative. First one, Ben and team, can you just sort of remind us what proportion of patients on long-term prophylaxis have breakthrough attacks and are they well controlled? Or are there certain patients that have more attack? And for those only on on-demand, are they patients that have limited amount of attack? And the reason I ask is, as you think about these various patient populations, who do you think are likely to be the early or fastest adopters to sebe and perhaps we'll have the ease of getting a prior authorization?

Yes. No, those are great questions, Pete. I'm going to ask both -- I will ask Paul to answer the first part, and then I think Nicole can pick up on the second part with regard to adoption.

Great. Yes. Thanks for that question. The data from the randomized controlled trials for all the prophylaxis studies kind of ranges between about 40% at the kind of the best end of those patients to become attack-free. But about half the patients still have breakthrough attacks. Some of them have it at a higher rate than others. They do occur in all anatomic locations. And so that's the kind of the first part of the question. The other part is that in terms of efficacy, we also have to look at effectiveness. And so what we've also looked at is adherence and the potential for refill gaps to actually impact the number of doses taken. As been highlighted, the number of on-demand doses in terms of volume hasn't really changed over the past 5 years despite the advent of multiple novel therapies like HAEGARDA, lanadelumab that came after and even with ORLADEYO. So we're still seeing a very similar kind of use rate for on-demand therapies despite the use of LTP. So I hope that kind of answers that question.

Yes. And in terms of patient adoption in the early phase of launch, as I shared the market research earlier in our program, we see intent to adopt across patients on all types of current on-demand therapies today. Where we see the greatest urgency to adopt that lies with the Firazyr and icatibant patients. These are the individuals who consistently in our market research efforts and engagement speak to the unmet need that lies with injection site reactions, injection site pain and really suffering in terms of tolerability issues with Firazyr and generic icatibant. So again, while we see likelihood to adopt across all products, the current products, it's the Firazyr and icatibant patients that we expect will adopt most swiftly following approval.

And a question for the physicians, Dr. Burnette and Dr. Lumry. KalVista recently presented an analysis at Quad AI. This was mentioned several times during the call on laryngeal attacks and KONFIDENT-S. I just would like your perspective on how concerned you are about these attacks and the ability to swallow an oral medication? And are the number of attacks treated to date and the outcomes, did they give you enough confidence that sebe is safe and effective in this patient population?

Amber, why don't you take that first and jump in?

Actually, that's a valid question with the laryngeal attack, we can actually swallow a pill. But I think the clinical trial data shows us that, yes, they actually are able to successfully administer this medication orally. There were no issues that arose per se in terms of being able to successfully have early dosing of this medication. And given the fact that they can dose early without preparation, without finding a vein, without fear of pain. I think it's more likely that the swelling attack, whether that be laryngeal or any other location, I think it's more promising that they can actually quickly abort an attack as opposed to an attack progressing and becoming more like threatening. But for me -- it's a valid question to ask, but for me, it is actually not a concern.

I would agree with Amber's comments. Certainly, the clinical trial data to date, particularly with the KONFIDENT-S trial and the number of laryngeal attacks that have been treated, give me a good feeling that patients can treat laryngeal attacks early with the drug and not have a difficulty -- any difficulty in swallowing it. My understanding is later on, there may well be an oral disintegrating tablet formulation of this product, which would further negate the issue of swallowing a pill during an attack. The only concern, I guess, I have is if someone is having frequent laryngeal attacks, unfortunately, these are the most rare type of attacks anywhere between 0.5 and about 2% of all HAE attacks or laryngeal attacks is if for some reason, they delay. If they delay because they wake up in the middle of the night with choking sensation, will they have the confidence to use an oral agent at that point in time, will they feel more comfortable with the [ parenteral ] agent. I don't think we've seen that yet in the clinical trials, but I'd have to refer to Paul as far as what's been reported in the trials. But again, it's going to take a little time, I think, for all patients, as I mentioned earlier, to become comfortable with a pill working as well as a shot and once -- and we've certainly seen that happen both in the clinical trial when patients were taking 2 doses and when they really didn't need to the open-label extension where one does taken early is an adequate therapy. I think once patients achieved that bit of confidence about the effectiveness of the medication that a lot of our concerns will disappear.

Our next question comes from Serge Belanger with Needham.

First one, I guess, for Ben, can you just talk about your label expectations? You previously talked about dosing, but any other thing we should be looking out for on the label? And then secondly, I guess for Nicole. I forgot what slide number, but I think you talked about initially focusing on the Firazyr icatibant segment. Just curious what we should think about the other segment with Berinert and RUCONEST. Is that up for grabs? Or is it stickier than the other segment? I have another one for the physicians, but let's start with those 2.

Okay. Great. Serge, thanks for asking. So with regard to the label, again, we're just getting into the label discussions with the FDA. So there's more to come on this. But in general, I'll just point out, the data set is extraordinarily robust. It's very consistent. We've run, again, the largest clinical trial program in this disease. We've shown efficacy in effectively all possible subpopulations. I talked about the laryngeal data multiple times already. So -- and the safety, again, has been absolutely pristine throughout the entire development program. So we don't know that there's a lot of concern there on our side about how that data may be represented or how that may impact the label. Standard course again in the space is that there's always a dosing limit, which I talked about earlier today. So we fully expect it to be some maximum daily dosage. That's to be determined. And again, I don't know that we view that as a particularly critical factor here. Again, people with HAE in the space do experiment with the therapies to find the solution that works best for them. Beyond that, there's not a lot of challenges here we think could exist in the label. There's standard sort of things with regard to DDIs and SIP inhibitors and that kind of stuff. But but really nothing that we think is going to really jump out at anybody on the label or certainly have any substantial impact on usage or patient willingness to try it or anything else. So in summary, I guess, I would say our expectation is for a pretty clean label.

And to your other question, going back to the market research that I shared, I want to reiterate that we -- as we've engaged with patients, we hear a very -- or I should say, get a very strong signal from patients on all types of current on-demand treatments that they do intend to adopt sebetralstat. So that does include patients that are on Berinert, RUCONEST as well as KALBITOR. Our reason for focusing on the Firazyr and icatibant patients at the time of approval is twofold. One, as I mentioned, these are the patients who signal to us the greatest unmet need as they've been utilizing a subcu injection now for several years, some for over 10 years and continue to face for nearly all of their attacks injection site pain and injection site reactions that are debilitating. In addition to that, as I also mentioned in our presentation, when you look at the volume of on-demand units today, the vast majority of those units, 70% of them are associated with Firazyr, icatibant. So quite simply, it's the largest opportunity from the volume side of things as well as the opportunity that's most significant in terms of the greatest unmet need and urgency to try something new. So those are really the 2 key factors that are informing our focus of the Firazyr, icatibant patients at the time of launch. But I do want to be clear that we do have positive indicators from patients on all types of on-demand therapies.

Great. And then for Dr. Lumry and Dr. Burnette, just regarding the other oral on-demand treatment and development, the company supporting that development has taken a different approach. I think they're only treating a certain set of attacks seems to go against treatment guidelines that you highlighted in your presentation. So can you just talk about that Phase III design and strategy and what are the advantages?

Autumn can jump in. The design of the Phase III trials between sebetralstat and deucrictibant differed in that the sebetralstat trial, patients treated 3 attacks and were randomized to basically 3 treatment opportunities with 300 to 600 of sebetralstat or placebo, treating 3 attacks across their participation in the trial. They included patients, as mentioned earlier, to along prophylactic therapy, and they've allowed patients to treat any type of attacks that including laryngeal that didn't include shortness of breath or difficulty of breathing and choking. They did not in the sebetralstat trial require a patient to do a check in with the study site to verify an attack based on the instruction was you can, once you feel an attack coming on, treat and treat early and then begin a diary -- electronic diary to report the outcome of the treatment. In the deucrictibant trial, the design is to treat 2 attacks with either active agent or placebo. But before they can treat an attack, they need to contact the study site and basically qualify severe enough to be treated. And that's rated using a visual analog scale equivalent of skin pain, skin swelling or abdominal pain of 30 out of 100 points. And if that -- I think it's 20 out of 100 points. Once that's met, then the patient can begin therapy. So the trial is different -- are different in that way that a certain level of attack severity needed to be obtained in the deucrictibant trial compared to sebetralstat trial. The reasoning, I think, behind that was that in order to use some of the patient-reported outcomes effectively and statistically, you need to have a certain level of symptoms to be able to say, well, it got better from this point going forward. That didn't seem to be a problem getting excellent statistical results for treatment outcome in the sebetralstat trial. But again, in the deucrictibant trial, they basically mimicked what we had used in the early Firazyr trials back 10, 12 years ago, where patients had to reach a certain level of attack severity before treatment to be administered. So they do differ in their design. Whether that's going to affect the outcome or not, it's hard to know because, obviously, the deucrictibant is still a blinded and ongoing. Autumn, what did you think about the design and how that might affect how these results are interpreted?

I mean, I definitely agree with the study design that you laid out so nicely. I mean there may be subtle differences, I suppose, with having to, I guess, essentially half patients get some sort of clinically proven level of severity. However I think it may not -- at the end of the day, it may not matter too much in the sense that once an attack is defined, whether that be on the patient side subjectively. And by the way, this is a very subjective type of conditions just to begin with, particularly as it involves with the airway and a difficulty with cessation of swallowing or feeling that the throat is closed. These symptoms are extremely subjective. So the study designs do have variability, but I don't necessarily think that at the end of the day that they are drastically different enough to change in terms of my thought process in terms of how the data is validated.

And our last question comes from John Wolleben with Citizens.

Wondering if you guys look back and saw if there was an increase in on-demand volume when icatibant was first introduced or generics became available. And I guess, piggybacking off that, when you talk about 70% growth in on-demand market, have you teased out what that mix of contribution is between branded pricing and treating more attacks?

John, thanks for [ touching ] on the queue here this morning. So with regard to generic icatibant being launched, I think what we saw was effectively just a standard kind of transition off the branded Firazyr to the generic form. So I don't know that it increased usage all that much as opposed to just, in fact, if you look at the IQVIA data, in fact, it really didn't increase at all. It was the numbers stayed pretty much steady from generic introduction all the way through. So I think we view that as more of just a classic switch as opposed to some sort of increase in usage. Again, that does reflect the fact that already Firazyr had effectively dominant market share. And so the number of people who actually started using it and went generic wasn't really going to be that substantial. And then you add in the fact that there's not a lot of economic incentive because of the patient co-pay programs and all. So you can kind of see why that would be the case. With regard to the other question, Nicole, I don't know if you have any thoughts you want to sort of put in here in terms of how it affect them.

I think what we see is -- and it really goes back to the value proposition of sebetralstat that, that certainly with a product that patients can take earlier keep on them and take earlier that we do anticipate that the attack treatment rate will increase. And so that's something that we've also seen in our Phase III open-label extension study that as patients continue to use that they increase the number of attacks that they're currently treated. So I think certainly, that is a dynamic as we head into growth in the marketplace. And certainly, in conjunction with that, you can see clearly our focus on those at the earliest point to really focus on converting those patients that are in a generic icatibant. So going from a price point of a few thousand dollars for a generic icatibant to branded pricing as I shared in that range of $11,000 to $16,000 per treatment certainly will both impact and drive that growth.

Okay. And then one more maybe for Nicole. How do we think about the prior authorization period versus reauthorization and redosing in this market? Does the prior authorization cover a set period of time in that patients a year or 6 months later have to go through a reauthorization to get a redose? Just wondering is there some period of time where patients become in the reimbursement clear for a lack of a better word?

Sure. Absolutely. And I think there are 2 elements to your question. From the access standpoint, prior authorization typically enables patients to have access for a 1-year time period. There are some plans where payers require that patients reauthorized on a 6-month interval. But typically, it's 12 months. So again, that is access to treatment. Now when you think about drug supply at the patient level, that's connected with the prescription itself. And so today, if we use Firazyr as an analog, Firazyr is currently written typically for a multipack, a 3-pack for a patient. The physician will write that the patient should receive an initial pack and then that prescription also will signal refills as needed. And so it's important because for that patient over the months ahead, they have the flexibility to refill as they need to based on, I would say, the appreciation that their disease is variable from one individual to the next. So again, access will allow for that typically 12-month time period and the prescription will be in place during that comparable time period. I will tell you that we often hear from physicians that they do like to see their patients on an annual basis. And so often, that prescription will be updated during that in-person visit so that they can have a dialogue on their total HAE management plan and to check in, in terms of the patient outcome and experience.

And you'd expect a similar dynamic to have a multipack prescription for sebetralstat?

Yes. In terms of an initial fill, that would be a multipack and then refills that would also be for a multipack.

Thank you. This concludes our question-and-answer session. Thank you for your participation, and you may now disconnect. Everyone, have a great day.