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

Good morning, and welcome to KalVista Pharmaceuticals Conference Call and Webcast. As a reminder, this webcast is being recorded. My name is Michelle from Notified conference call service, and I will be your operator today. [Operator Instructions] I would like to turn the conference over to Ryan Baker, Head of Investor Relations for KalVista. Please go ahead.

Thank you, and good morning, everyone. Earlier this morning, KalVista announced the results from the KONFIDENT Phase III clinical trial of sebetralstat as an oral on-demand therapy for hereditary angioedema, HAE. On this conference call today, members of the KalVista management team will make remarks about the KONFIDENT Phase III trial results in the accompanying slide presentation on the webcast. Today, speakers from KalVista include Andrew Crockett, Chief Executive Officer; and Dr. Christopher Yea, Chief Development Officer. We are also very pleased to be joined today by Dr. Marc Riedl, a leader in the HAE field. Dr. Riedl will provide his expert perspective on the unmet treatment needs in HAE. Also present on today's call from KalVista is Ben Palleiko, President, Chief Business Officer and Chief Financial Officer. Following today's prepared remarks, we will open the call for questions. [Operator Instructions] Slides to accompany this conference call are posted on the Investors & Media section of our website at www.kalvista.com. The audio webcast for the corresponding presentation slides is also available on the website. Before we get started, I'd like to remind everyone that some of the statements that we make on this call and information presented in the slide deck include forward-looking statements as outlined on the slide. Actual events and results could differ materially from those expressed or implied by any forward-looking statements, including as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and other future filings that we may make with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, if anyone disclaims any obligation to update such statements. I will now turn the call over to Andy Crockett.

Thank you, Ryan. Today is an exciting day for KalVista and also for people living with HAE around the world. Today, we are ushering in a new era of HAE as we have achieved significant milestone toward bringing the first oral on-demand therapy for safely and effectively treating HAE. We are thrilled with the positive top line results from the KONFIDENT Phase III clinical trial, which we reported in our press release today. We showed that both the 300-milligram and 600-milligram doses of sebetralstat met their primary endpoint, achieving the beginning of symptom relief from an HAE attack, significantly faster than attacks treated with placebo. Of note, the p-values were highly statistically significant for both doses. Additionally, both doses met the 2 key secondary endpoints of the trial and demonstrated an excellent safety and tolerability profile. KONFIDENT enrolled 136 patients from 66 clinical sites across 20 countries, making it the largest controlled clinical trial conducted in HAE. To begin our presentation, we are pleased to welcome one of the preeminent HAE researchers in the world, Dr. Marc Riedl. Dr. Riedl, Professor of Medicine; Clinical Service Chief and Training Program Director, Division of Rheumatology, Allergy, Immunology, University of California San Diego, California; Clinical Director of the US Hereditary Angioedema Association Reference Center and the co-author of US HAEA Medical Advisory Board guideline and the international WAO/EAACI guideline for the management of HAE. Dr. Riedl was also an investigator for the KONFIDENT Phase III trial. Dr. Riedl, thank you for joining us this morning.

Thank you, Andy, and good morning, everyone. I'm pleased to outline the persisting unmet need in the management of HAE and to provide some context for the KONFIDENT Phase III data. Most of you will be familiar with hereditary angioedema, or HAE, which is a rare genetic disorder that affects approximately 1 out of 50,000 people globally. As you can see in the pictures below, patients with HAE experienced attacks of swelling in many anatomical locations, including the face and the extremities, attacks that involve the upper airway and may be life-threatening if untreated. HAE is challenging to manage because the attacks are often unpredictable. These attacks can start off mild, but severity can increase quickly. They can also migrate to other anatomical locations, including the larynx. And attack symptoms can last for 1 or 2 days but may persist for up to 5 days if untreated. In order to support shared decision-making between HAE patients and their physicians regarding treatment, clinical experts, along with patient advocates have collaboratively published treatment guidelines. These have evolved over the past 20 years as the new treatments have become available. Before diving into the specifics, it's worth highlighting that the main goal of treatment in HAE is to achieve total control of the disease and to normalize the lives of patients. In order to realize that goal, there are 2 main treatment strategies. First, to ensure that all HAE patients have ready access to effective on-demand treatment; and secondly, to consider the addition of long-term prophylaxis or LTP, in appropriate patients, which means taking into account the frequency and severity of their attacks, the impact of attacks on patients' quality of life and patient preference. The global HAE treatment guidelines recommend that all HAE attacks should be considered for treatment regardless of location or severity as attacks are unpredictable. However, studies show that 25% to 40% of HAE attacks are not treated by patients, including those who have attacks while receiving long-term prophylaxis. The HAE guidelines further recommend that HAE attacks should be treated early to rapidly halt the progression of swelling caused by bradykinin generation and thereby reduce the duration of the attack. However, recent survey data shows that only 20% of patients treat their attacks in less than an hour. Lastly, guidelines recommend that patients have access and carry their on-demand medication for the treatment of at least 2 attacks. Here again, we have survey data showing that fewer than 40% of patients carry on-demand treatment outside of the home all the time, some traveling long distances without their on-demand treatment. Now currently available on-demand treatments are efficacious, but they have limitations. Much of this may be due to the fact that they need to be injected either intravenously or subcutaneously. Plasma-derived or recombinant C1 inhibitors are not easily portable and require preparation prior to administration in an attack setting. Many patients or the caregivers may have difficulty finding a vein and patients commonly experience pain at the injection site. Another treatment, ecallantide, has a significant risk of anaphylaxis and is, therefore, only approved for administration by a health care provider in a monitored setting. Finally, the most commonly used on-demand treatment globally, icatibant, is associated with injection site reactions in nearly all patients. This includes prolonged pain, redness and swelling in many patients. The picture you see here on the right shows an example of a local skin reaction caused by icatibant. We believe the reason this is so common is that this is a pseudo-allergic reaction, which is caused by icatibant binding the MRGPRX2 receptor on mast cells in the skin. Bottom line, the limitations of currently available on-demand treatments likely contribute to patients' decisions to delay or even withhold their injectable on-demand treatment. Now long-term prophylactic options have grown substantially over the past 5 or 6 years. However, it's important to note that although these LTP treatments have been shown to effectively reduce the frequency or number of attacks, a substantial proportion of patients still experience HAE attacks. As you can see here, this table summarizes findings from the randomized placebo-controlled trials of the approved LTP agents: C1 inhibitor, lanadelumab and berotralstat. Overall, more than half of the study population continue to experience HAE attacks over the full duration of these respective trials. Even among those on lanadelumab at steady state, nearly 1 in 4 patients continue to experience attacks. So it's reasonable to say that long-term prophylaxis despite excellent efficacy does not replace the need for on-demand HAE treatments. Clinical studies have consistently demonstrated that earlier treatment is associated with better outcomes, including rapidly halting the progression of swelling, early symptom relief and a reduction in the overall severity and duration of the HAE attacks. Sebetralstat is the first potential oral on-demand treatment to reach late-stage development. In Phase I studies, the 300-milligram and 600-milligram doses were found to result in near-complete plasma kallikrein inhibition within 15 minutes with persistent suppression over more than 4 hours. The 600-milligram dose was chosen for the Phase II study that was previously published in The Lancet. Sebetralstat had good safety in the trial versus placebo, and the time to beginning of symptom relief was significantly shorter with sebetralstat compared with placebo, with a median time to beginning of symptom relief of 1.6 hours versus 9.0 hours with placebo. The promising results from the Phase II trial set the foundation for KONFIDENT, a Phase III crossover trial designed to confirm the efficacy and safety of sebetralstat as an on-demand treatment for HAE in both adolescents and adult populations. KONFIDENT is now the largest controlled HAE trial conducted to date. And importantly, the first trial designed to align with the on-demand treatment guidelines we discussed earlier, early treatments of all attacks and having ready access to treatment. It's worth noting that KONFIDENT is the first on-demand trial to include patients who are receiving non-androgen long-term prophylactic agents. Lastly, KONFIDENT is the first on-demand trial powered to assess multiple patient relevant endpoints in a hierarchical fashion. The primary endpoint, time to beginning of symptom relief; the first key secondary endpoint, time to reduction in attack severity; and the second key secondary endpoint, time to complete attack resolution. Thanks for allowing me to provide some clinical context for sebetralstat and KONFIDENT. Now back to the KalVista team to take you through the study results.

Thank you, Dr. Riedl. Now I'd like to hand the call over to Dr. Chris Yea, our Chief Development Officer, to review the Phase III top line results in more detail. Chris?

Thank you, Andy, and good morning, all. The Phase III KONFIDENT trial is a well-powered, randomized, double-blind, 3-way crossover trial, evaluating the efficacy and safety of sebetralstat, the oral on-demand treatment of HAE. The trial investigated 2 doses of sebetralstat, mainly 300 milligrams and 600 milligrams. At enrollment, patients were randomized to treat 3 attacks, with each of sebetralstat 300 milligrams, 600 milligrams or placebo in a blinded, randomized sequence. During the study, patients self-administered each treatment as soon as possible after recognition of the onset of an attack. Following treatment, patients recorded response to treatment and adverse events on an electronic diary for up to 48 hours. If needed, patients were able to administer a second dose of the blinded medication, not less than 3 hours following the first. We have previously reported the results from a Phase II clinical trial for sebetralstat. While these trials are similar in design, the differences are shown on this slide. The key changes were the expansion of the population to include adolescent patients and also patients using long-term prophylaxis. Similarly, the nature of attacks eligible for treatment has also been expanded to include all locations and severities. Finally, while the Phase II trial included a single dose of treatment, the Phase III trial allows patients to use a second dose. The primary endpoint of the study was time to beginning of symptom relief. This was defined as a rating of a little better for 2 time points in a row on the Patient Global Impression of Change, or PGI-C scale. This is a 7-point scale on which patients rate their symptoms in comparison to when they first took medication. It was administered every 30 minutes for the first 4 hours then hourly to 12 hours. Two key secondary endpoints were also investigated using a Patient Global Impression of Severity, or PGI-S scale. These assessments recorded the severity of the attack at each time point to identify the first of 2 time points in a row when severity had reduced and also the time taken to reach no symptoms. It is important to recognize that this reflects a complete resolution of the attack rather than near complete as assessed in other trials. KONFIDENT randomized 136 patients to treatment. And by the time the end of the study was called, 110 of those have treated at least one attack prior to our decision to end the trial. All of those attacks are included in the analysis of efficacy. The study was well balanced across the treatment groups and discontinuation rate was low with no patients withdrawing from the trial due to an adverse event. The distribution of patients enrolled in the trial was typical of an HAE trial population and included multiple geographic regions. Of note, this is the first controlled study to recruit patients in Japan. Of the 110 patients who contributed data to the analyses, 21.8% continue to use long-term prophylaxis while on the trial. During the trial, patients dosed the blinded medication in a median time of 41 minutes following onset of the attack, a baseline 43.2% of attacks displayed abdominal symptoms. While laryngeal attacks were eligible for treatment in the KONFIDENT study, as anticipated, numbers were low with 8 attacks treated. This low number precludes any analysis of efficacy, especially given 4 of the attacks were on placebo treatment. I will talk to this a little later in the call. This slide shows the baseline severity profile of attacks, which occurred in patients using LTP compared to those in patients who treat their disease with on-demand only. The representation of all severity grade does not markedly differ between LTP and on-demand patients, including the proportion of severe and very severe attacks. I'll start the review of the safety and efficacy results while looking at the primary endpoint of time to beginning of symptom relief. The trial met its primary endpoint, showing that attacks treated with both 300 milligrams and 600 milligrams, all doses of sebetralstat achieved beginning of symptom release significantly faster than attacks treated with placebo, with p-values of less than 0.0001 and 0.0013 respectively. The median time to beginning of symptom relief was 1.6 hours with sebetralstat 300 milligrams, 1.79 hours with sebetralstat 600 milligrams and 6.72 hours for HAE attacks treated with placebo. While the trial is not powered to detect an effect versus placebo in subgroups of patients and attacks, the trend to treatment effect of sebetralstat was consistent across the groups we have assessed. As noted previously, we have expanded the population from the Phase II trial. And importantly, those new groups, including adolescent and patients on long-term prophylaxis show a very similar effect to sebetralstat treatment. The trial also shows that sebetralstat has a consistent effect regardless of attack severity. Two key secondary endpoints were tested using a fixed sequence hierarchical approach to support potential labeling discussions. This slide shows the first key secondary endpoints, time to reduction in tax severity. Attacks treated with 300 milligrams and 600 milligrams both achieved a significantly faster time to decrease the attack severity from baseline compared to placebo. Attacks treated with both doses of sebetralstat reached complete attack resolution significantly faster than placebo. Now turning to safety. This table shows the number of adverse events reported within 3 days of drug administration. Consistent with previous studies, sebetralstat was well tolerated with a safety profile indistinguishable from placebo. No related adverse events report were reported in any treatment group by more than one patient. Importantly, gastrointestinal adverse events were similar across all groups. There were no laboratory findings reported as adverse events, including liver-related measurements. Additionally, we continuously monitored all laboratory values throughout the study and saw no signals, specifically related to liver or any other parameter. While expanding the treatment population, KONFIDENT delivered similar efficacy results to the Phase II trial. Patients chose to use a second dose of medication in around 40% of attacks treated with sebetralstat in contrast to 55% of attacks treated with placebo. Use of conventional medication was similar between the trials. Our open-label extension trial continues to recruit and had enrolled more than 110 patients at the beginning of this month. To date, more than 640 attacks being treated with 600 milligrams sebetralstat with a median time of 10 minutes from attack onset. As discussed earlier and as expected, the contribution of laryngeal attacks to the KONFIDENT dataset was limited. The KONFIDENT-S trial has already significantly supplemented the number of laryngeal attacks, which will ultimately be used to support the NDA filing consistent with previous approvals in the space. In conclusion, the KONFIDENT Phase III trial was the largest controlled clinical trial in HAE. This pivotal trial met all primary and key secondary endpoints which, in combination with favorable tolerability and safety profile, position us to move forward with filing of an NDA. Sebetralstat was dosed early after attack onset and delivered rapid symptom relief and associated severity reduction and complete attack resolution at both 300 milligrams and 600-milligram dose levels. Patients administered the formulation soon after attack onset, most closely matching treatment guideline. Despite inclusion of a broad population of patients and eligible attacks, efficacy was similar to that reported in the Phase II trial. Sebetralstat safety profile is similar to placebo, and there were no safety signals of concern at either dose level. The open-label extension trial will provide a significant quantity of data, which supports the safety and efficacy of sebetralstat.

Thank you, Chris. In terms of next steps, we remain on track to file our NDA with the U.S. FDA in the first half of this year, with additional filings in the EU and Japan in the second half of 2024. In the very near term, we are planning to present more detail on our Phase III data to the medical community at the AAAAI scientific conference in Washington, D.C. as a late-breaker presentation on Sunday, February 25. We've also been building our commercial team over the last 2 years. Our commercialization activities remain on track for a 2025 launch. In closing, we believe that sebetralstat is positioned to open a new era of HAE therapy and could become the foundational treatment for people living with HAE, offering them an effective, safe and discreet way to treat HAE attacks without the challenges of injectables or the chronic burdens of long-term prophylaxis. Most importantly, I want to take a moment to thank the people living with HAE, their families and the investigator teams around the world who supported KONFIDENT and helped us complete this landmark study. Thank you for sharing our vision of the promise of sebetralstat and helping us achieve this important milestone. We look forward to providing further updates and progress sebetralstat for the benefit of people living with HAE around the world. With that, let me turn this back to the operator for any questions. Please go ahead, operator.

[Operator Instructions] And our first question is going to come from the line of Maury Raycroft with Jefferies.

This is Yao on the line for Maury. Congrats on the strong Phase III data. The data looks beautiful. Our first question is on the efficacy. So how does the efficacy look in attacks of different anatomic sites? And what are the characteristics for -- of attacks where a second dose was taken?

Yes. Thanks for the question. So the efficacy of sebetralstat was very consistent across all of those locations that we could identify. I think as one of the slides shows, we split them to date just by abdominal and peripheral and we could detect no difference in effective sebetralstat treatment. We have some further analysis to do the data to look at the severity related to location. That work is ongoing. However, I think because we've shown it's a consistent effect across all severities, a consistent effect across all locations, we certainly wouldn't anticipate any difference in efficacy regardless of the location of the attack.

Okay. Got it. That makes sense. Do we have a follow-up question? On the [ 2 core ], the open-label extension study, when do you think you could report the next data cut? And based on the data, how do you think the drug -- could this oral on-demand drug could actually change the treatment paradigm in the commercial setting based on some of the initial feedback you got from doctors?

I'll take the first part of that question. So we're currently making a cut of the 302 open-label extension study to support the NDA. Once we have that, then we'll share information regarding the data at the appropriate time.

Yes. This is Ben. I'll take the question on the commercial side. I think it's very clear based on the data you've seen that the results of the drug are just tremendous, and the flexibility of dosing and the ability to sort of use this has shown itself to be key advantages for patients in the study. And as Chris briefly mentioned that the open label looks like it's even better. I mean I think what we're really seeing is that patients are able to identify when they're having incipient attacks and they're taking the drug very quickly. And I think the benefits are on pretty full display now and only -- we'll only get enhanced as we put more of that data out on the open label. So the point is we really do believe that with the profile we've displayed so far, this is the kind of thing where patients could certainly look at this to become their baseline therapy. This could become the first -- not really the first line, but effectively, the first treatment patients will try to manage their HAE. And to the extent that they still have other challenges or high attack rates, they may consider adding prophylaxis to it. But we do believe at baseline that sebetralstat offers the opportunity to become the foundation and really to meet patient needs in a very positive and patient-friendly way.

And our next question is going to come from the line of Paul Matteis with Stifel.

Congratulations on the data. I had 2 questions, if you don't mind. On the efficacy side, as we think about redosing rates in this trial, looking that they're lower on drug versus placebo, what do you think the regulatory utility of that analysis is? Like were you guys -- are you guys thinking about that as an efficacy analysis? Or is that really just for safety? And ultimately, if you look at these data, what are the kind of implications of redosing on -- or I guess, allowing for redosing on a potential label? And then on the safety side, thanks for giving more color on the top line data here. I was curious if you can confirm in the open-label extension that this all holds true, that there's no signal on anything related to liver enzymes? And maybe just add a little bit more color on kind of what you're seeing on a frequency of use in the real world in terms of max number of doses or doses per day or things like that.

Okay, Paul. Thanks for those 2 questions. Yes. So I think what we agreed with the FDA that treatment in KONFIDENT will be up to 2 doses. So a patient is free to use up to those 2 doses. I think that's really important. We know that attacks are highly variable in the way they present anatomic locations, severity, speed with which they progress. In fact, they have it on patients' day-to-day activities. Of course, we also know the patients currently use more than 1 injection to treat an attack. So from the outset, we felt it was important for patients to be able to maintain that flexibility so that they can decide how they respond to each of those individual attacks. So I don't think from a regulatory point of view, there will be any [ tag ] that this will be seen as a treatment very similar to the current treatments. You can take a dose and currently based upon the Phase III KONFIDENT trial, patients will be able to use a second dose. So I think that -- I think it's entirely consistent with current labels, and I think, again, delivers just that flexibility. With respect to the safety, yes, I think it's right. So the 302 study I personally find fascinating. As you've seen, we've got over 640 attack. We have patients who are treating sort of 20 or 30 attacks on study already, and we're collecting attacks at a good rate. As far as the safety we're seeing in the 302, I think it's safe to say it's exactly the same as we've seen in the 301. We haven't seen anything -- the lapse of any concern whether with liver or anything else in the 302 to date. So I think the 302 is going to deliver safety and efficacy data, which is entirely consistent with the 302 -- sorry, with the 301 study.

Yes. I would just add one more thing, Paul, this is Andy. I think in terms of we've made a mention earlier of the use of sebetralstat in the real world. But I think it's indicative of what we're seeing in the 302 study with, especially that rapid time to dosing of 10 minutes. I just think that is really important, especially if you think about that in the context of what's happening in the real world of injectables. We know that on average, recent data was showing, on average, patients are waiting almost 4 hours to treat with their injectable therapy. If you compare that to 10 minutes, I think it really highlights the promise of sebetralstat and how that could change the paradigm here.

And our next question is going to come from the line of Joseph Schwartz with Leerink Partners.

Congratulations. My first question is for Dr. Riedl, and then I have a follow-up for the company. Dr. Riedl, you talked about patients don't treat their [indiscernible] early. I was wondering how [indiscernible] sebetralstat at least change this maybe from the real world? And where do you think sebetralstat gain the market share from existing on-demand agents? And how much do you think it could expand the on-demand market?

Yes. I had a little trouble hearing you. They're breaking up a little bit, but I think I got the gist of the question. So we do indeed see some hesitancy in the real world for patients to use their on-demand treatment. Certainly, patients will do what they need to ultimately to stop these attacks. But because they're either IV infusions or subcu injections, that can be quite uncomfortable and painful at some level. There is some delay in treatment. And so that's a very real phenomenon. And in fact, some patients will choose not to treat an attack if they think it might be mild, which is usually a mistake because it leads to more moderate or severe attacks that cause disability and sometimes even hospital visits. So we do, as the guidelines say, we do really encourage people to treat early and treat any attack that they anticipate will interfere with their activities. We hear from patients often that an oral medication is preferred by many of them. And so I do think that this offers the opportunity to give patients a much easier way to treat their attacks, something that's very portable, they can have with them at all times. And they don't have to find a place or a time to do these injections or infusions in the course of their everyday life. So it remains to be seen. We have to sit down and talk to patients about the data. But I do think this is going to be very attractive. It may very well make its way to the top choice for docs and for patients as an on-demand treatment. And it remains to be seen. It could affect the long-term prophylactic use. I do think there are benefits clearly to the long-term prophylaxis in terms of reducing attacks and making life more predictable. But I think the option to treat attacks early to easily treat them with an oral medication is going to be a big step forward for managing patients.

That's very helpful. And then for the company, as your focus evolves towards approval and commercialization, can you talk about your activities there? And what kind of launch prep [indiscernible]? What efforts remain? And what do you foresee your sales and marketing footprint needing to look like in order to leverage the strong clinical data?

Joe, thanks for the question. So to date, we've actually started -- we've been building for a while, actually a couple of years now, a small commercial activity that we've, over the past 6 months, really start to beef up. So we have -- we hired, as you saw, a very experienced Chief Commercial Officer last year. She had experience launching TAKHZYRO with Takeda, so she knows the world and has succeeded in this space previously. She has built around her a terrific team of folks so far. We filled up the key slots. We've got heads of sales and marketing in the U.S., in Europe and in Japan nowadays to lead those activities, and we've also started to beef up some of the key members of the team, and now we're moving down to the next tier of hires. So there's a -- the core positions have all been filled. The team has really started to put together a lot of early launch activities. We have a very highly evolved launch checklist that we've been moving through. And we've actually had commercial teams, launch teams starting to meet over the past few months, even as we get ready to launch in all those geographies. And over the course of the year now, obviously, on the back of this data, we'll start to beef that up more substantially. Switching to the question of what the footprint look like, there will be obviously more hiring to come in that space this year. But one of the terrific things about this indication, and we've said this for a long time, that it's tailor-made for a biotech company to commercialize the footprint in the U.S., as a particular example is really a fraction of which I've seen a lot of spaces. I mean it's something on the order of a few dozen sales reps and then a few dozen other people. So you're talking somewhere in the 40, 50 mark maybe for the U.S. organization, which is eminently affordable for a company our size. And the rest of the world commercialization efforts take a little longer to roll out just because of the approved launch time lines, and the numbers certainly are smaller than that even. So it's the kind of thing that we can cover all the key positions pretty effectively with a team of that size. I think the expense overall is going to be eminently controllable. And so we think we can really do this properly and take advantage of the great opportunity before us.

And it looks like our next question is going to come from the line of Charles Duncan with Cantor Fitzgerald.

Yes. And Andy and team, congratulations on a very, very nice results. I did have a question for the KOL Dr. Riedl first. And that is, Dr. Riedl, when you consider the composition of the patient sample, what is it that you are most impressed with? Is it the fact that there was nice efficacy for on-demand with long-term prophylaxis or in the adolescent patient population or severe versus very severe? What most impressed you about that sample?

It's a great question. I would say all of those things were important. But I think the adolescent population is a very important one. This is a time when in the natural history of HAE, we do see an increase in severity for a lot of patients. And at the moment, as people may know, we really only have the IV C1 inhibitors approved in the adolescent population. So it can make on-demand treatment challenging for teenagers. And so I was very happy to see their inclusion and see that those results look -- basically you can't tell any difference compared to the adults. The other thing that we -- some of that questions about and I think is an important one is, will this drug work in people that are already on a long-term prophylactic option that has the same mechanism of action? So plasma kallikrein inhibition And the answer looks like, yes, you can't really tell a difference in the efficacy for those LTP patients on kallikrein inhibitors with the use of sebetralstat compared to those who aren't on those agents either at all. So I think in my mind, those are sort of 2 very important pieces of data along with the fact that we didn't -- so far, we haven't, in the analyses, haven't seen any difference in efficacy for different anatomical sites which is, of course, very important. We hope to have more look at that as the open-label data cadence comes along. But knowing that the drug works for any and all types of attacks is, of course, really important when we're speaking with patients. So I would say that's probably the important highlights for me.

Very good. Helpful color. For the company, I had a quick question regarding the NDA in terms of gating steps, could you help us understand what kind of takes the timing? It seems like it's fairly acute. So probably not a lot standing in the way. But would you be seeking priority review in addition? And then secondarily, could you just remind us of the ODT? Is that planned for this filing or one in the future?

Yes. So thanks. So yes, so we are moving full steam ahead with our -- from our filing of the NDA in the U.S., as we said in the first half of this year. The KONFIDENT trial obviously was the major piece of that. As we've discussed a little bit here, the open-label safety trial, we'll take a cut of that data and include that in the NDA as well. But that's really it. So we're down to the work of finalizing this top line data from KONFIDENT. We have additional analyses, will perform. And then we will prepare that NDA for submission in short. As it relates to -- we will, of course, be seeking all expedited measures to accelerate FDA approval. And so more to come on that as we find out more and we look on that. I think finally your question about ODT, that will be a separate -- it will be a separate application. We've said that, that will be a life cycle extension in the U.S. and will be an sNDA that will come later. We know that there's some requiring further efficacy data, but the initial launch in the U.S. will be with the tablet formulation.

[Operator Instructions] Our next question comes from the line of Serge Belanger with Needham.

I want to offer my congratulations for the positive results. I guess first question is there doesn't seem to be a large difference between the 300 and 600 mg dose, either on efficacy or safety and tolerability. Curious if you agree with that interpretation and whether you'll still seek approval of both doses. And then secondly, for Dr. Riedl, I think you've authored some of the HAE treatment guidelines. Just curious if assuming this product does get approved, how do you think it will modify those guidelines, especially as it pertains to [ per client usage ]?

Okay. Thanks, Serge. I'll take the first part of that and then hand over to Marc. Yes, I think that's a very fair sort of, if you will, top line assessment of the data that we have to date. I think you're right from an efficacy point of view, the 2-dose levels I think for all 3 endpoints, you can see the curves and KONFIDENT's intervals around these point estimates look very similar. So I don't think we can differentiate on those. I think really great news, of course, is that we have really good safety profile at the 2-dose level. I think as Andy just mentioned, this is just the top line data. So we have the full dataset, which will be coming in due course. And we'll investigate that dataset more fully and see whether we can find an advantage for -- I think it will be the 600-milligram or the 300 milligram, if there's some data that supports doing that. Once we have that data, I think we can make a final decision and then obviously, we'll be looking to file the NDA appropriately with the dose that we -- dose or doses that we would then choose. And obviously, we'll update at the appropriate time once we've done that. Marc, can I hand over to you to answer the second part?

Sure. Happy to. So the -- as far as the evidence-based treatment guidelines, I certainly can't speak for the committees that write those, but I would say that we do try to actively update those as new treatment options become available. And certainly, based on the data we have so far, I would expect that sebetralstat will make its way into the guidelines as a listed first-line on-demand treatment option. That's certainly been the pattern as we get safe and effective treatments for HAE. So I suspect the guidelines will certainly be updated to include sebetralstat as it's approved in various parts of the world, assuming that occurs. The question about how it might affect recommendations for treatment strategies, including long-term prophylaxis, is a very interesting one. I think that I certainly don't see long-term prophylactic options going away, obviously. I think there are clearly demonstrated benefits. And I think we'll continue to see those heavily incorporated as an option in the guidelines. But I would just, I guess, reiterate that on-demand treatment is recommended for each and every patient because as we've talked about, even the LTP patients have attacks. And I think more importantly, it will be important in the clinic as we talk patients through the guidelines and have shared decision-making discussions with them, what -- how does HAE affect them? What are they most comfortable with in terms of their treatment strategy? That's where we may see those discussions being a little bit different. Not that we certainly will continue to discuss and use long-term prophylactic options, but you may see patients that are willing to do on-demand treatment only depending on their experience with this oral option and their comfort level with that. So I do think it will certainly -- it may change our discussions a little bit. Whether it will ultimately change the percentage of people that go on long-term prophylactic therapy, I don't know how that will all sort out. But I do think it's an option that will be very interesting to talk about with patients and see what their comfort level is.

And I'm showing no further questions. And I'd like to turn the conference back over to Ryan Baker for any closing remarks.

Great. Thank you all for taking the time to participate in today's call. Please follow up with us if you have additional questions. Have a great day, everybody.

This concludes today's conference call. Thank you for participating. You may now disconnect.