All right, thanks very much. It's my pleasure to be moderating this panel with Ben Palle, CEO of KalVista. Sure most folks know the company well, but maybe we can have Ben just kind of give a quick snapshot of where things are at with respect to the NDA filing, launch prep, for sebetralstat, and then we can do a lot of, lot of Q&A and get into all the debate. So thank you, Ben. Please take it away. Yeah. Nice to be here, Paul. Thank you for inviting us today, as always. Sure, so I'll skip over most of the background on KalVista, but you know we're developing sebetralstat, which will be the first oral on-demand therapy, ever for hereditary angioedema. We reported, very positive phase III data back in the wintertime, and as you noted, we're working towards the NDA filing, in the U.S., which we expect to be next month. To be followed in relatively short order by filing in, Europe, and then, in Japan later this year, with the expectation of a commercial launch in 2025. Great. So as it relates to the NDA filing itself, maybe talk a little about your sort of alignment and discussions with the regulators, you know, more recently or over the years, and kinda your level of comfort, right, that you've checked all the key boxes. Yeah. So we've already had our pre-NDA meeting. In fact, we had it before the phase III trial even wrapped up, so it was late last year. It was... The pre-NDA meeting was pretty short and pretty administrative because we'd really settled everything with them well in advance. And during our end-of-phase II meeting in preparation for the phase III, we really went through in great detail all the key elements here we had to solve for the trial. So, as you know, everyone always wants to talk about the primary endpoint. We spent a lot of time working on the primary endpoint with them, confirming with them that they agreed that that endpoint was the appropriate one to use, and as well, the measurement on the scale we used, and the PGA scale, was the proper one to go for. And as part of that, we actually conducted, for their benefit, a series of patient interviews that actually confirmed that that endpoint made the most sense to patients, and that's why I picked it as the primary. And then the secondaries, we can talk a little bit about as well. They were also obviously quite well thought through, and, in particular, one of them was quite aggressive. But we'll get to that in a minute. So the endpoints were all settled well in advance. The size of the trial we had to conduct was settled well in advance. The safety database was settled well in advance. So we really rolled into this trial with an exceptionally good understanding of what we had to do to be able to file, and we've checked every box. There is nothing they asked for that we didn't do. There's nothing they said we shouldn't do that we did. There's you know no important questions we left unasked or unanswered. So I think as we roll into the NDA filing, we feel really comfortable that on the trial data itself and on the other ancillary elements, things like the size of the safety database and all, that we're firmly on the side of having addressed their comments. And other things, the right things, what trips you up a lot of times, things like CMC and such, we've actually settled that years ago. So the phase III study and the open-label used a final formulation tablet in all respects, and so, there's really no outstanding items on that that we haven't solved for in that case a long time ago. Great. Maybe on the safety side, right, you wanna talk about, you know, total exposures, total doses, and I think specifically the interesting question with an on-demand therapy like this, if I'm a regulator, is, you know, trying to not just have a certain number of doses you wanna see, but also a certain number of doses within, like, a period of time. Like, what happens if a patient takes two doses or three doses in a given day? You know, what's the max number of treatments per month that you see? Is there gonna be a cap on that on the label? So just as it relates to kind of the other angles with which we can think about safety that may ultimately be relevant to how people use this in the real world, to what degree have you thoroughly interrogated all of those kinds of questions? I think to a really, really high degree. I mean, it's important to start off by pointing out that the safety profile of sebetralstat through the entire clinical development program has been pristine. I mean, there's been no drug-related SAEs ever. There's in the Phase III study you saw, I mean, it was really completely the same as placebo, right? I mean, the highest rates of adverse events you saw in the study were, you know, dyspepsia, things like that. I mean, it was... There's really been no safety signals of any sort through the study. That includes both the 300 and the 600 milligram doses, and as you know, we're gonna file on the 300 milligram dose. The open-label extension actually, which allows patients to treat for up to several years, has actually dosed at the 600 level, so we've been dosing patients at a higher level, and we have patients who've treated upwards of 40 attacks. I mean, you know, multiple dozens of attacks. Multiple dozens of patients have now treated multiple dozens of attacks with this drug over a long period of time. So there's... We have blown far past the size of the safety database in terms of exposures that the FDA was looking for, and again, these are patients who've taken this drug, you know, in for many instances over a long period of time. Again, if you look back at some of the early studies in terms of the, you know, the max dosing, I mean, we've dosed in some prior studies, MTD type studies. I mean, we've gone up to multiples of where we are on the dose level, with again no real dose-limiting toxicities noted. So we're quite comfortable the safety profile here is going to be is going to continue to be pristine, because there's literally never been any indication of anything here. ... Yeah. Okay, okay. From a commercial perspective, right, I'm sure you hear this ad nauseam, right? The investor concern about, you know, many companies in the HAE space is, "Oh, my gosh, it's so, it's so competitive," right? How do you think about navigating that from both the perspective of you launching the drug and also, you know, over time, sort of preparing for a future where the treatment landscape in this area might, you know, continuously evolve? Well, again, yeah, you're right, the space looks quite competitive for a lot of interesting reasons. But what's important to note is that most of that competition actually is in the sphere of prophylaxis. I mean, if this market is really unique in that people view it as one sort of big space, but really, it's kind of two, it's really two fairly distinct markets that really haven't shown a lot of sign of flowing into each other. The on-demand portion in the U.S. is right around a third, you know, maybe 35% of patients. It's been remarkably stable over the past five years. There's been very little indication of any meaningful shift to prophylaxis, despite the fact that for a decade or more, there's been high-quality prophylaxis therapies out there, and so we haven't really seen that world shifting towards prophylaxis, despite the fact that this is what the prophylaxis players say. The scripts remain rock solid, very, very stable, I mean, essentially unchanged from, you know, since 2019. And that's because at the fundamental level, a lot of these patients want to actually treat their disease on demand. I mean, they value the ability to not take a chronic dosage of whatever form that is, and really, you hear from a lot of them that they like to feel like they're controlling the disease, not the disease controlling them. So that market, for a lot of reasons, seems really stable. Clearly in that space, though, everything is injectable. Obviously, Firazyr generic icatibant is far and away the market leader. That's subcutaneous. It's well known to be a painful injection. It's well known it has actually a mast cell inflammation, you know, event that it almost universally causes. So basically, 100% of people using icatibant have injection site reactions. So the point is, we're gonna come into that market with a drug that's at least as efficacious as everything out there, and it's just got a far more benign usage profile, and so we think that's the marketplace that we'll, you know, we can fairly quickly dominate and, you know, to a very high degree, on the basis of really offering them a better therapy. The reason that matters is because what everyone talks about all the time is prophylaxis. Everybody else other than us is working in the prophylaxis space. The perception is that the world is shifting toward prophylaxis, but the problem really has become that the data doesn't support that. I mean, there's four therapies approved. There's another one on the way very shortly. There's at least five, if not six more, in development. So what you've really got is just a lot of people out there pursuing a marketplace that doesn't seem to us to be growing at any substantial degree, and is going to become intensely competitive over the next few years as those players come to marketplace. And I will honestly say that I don't, when we look at them, I don't think we think that any of them are actually gonna dominate. I mean, there's no one there that's gonna come on board and be such a, such a dramatic change in the way that Takhzyro was. And so our, you know, our view of the HAE space is that prophylaxis becomes increasingly competitive with a bunch of much smaller products, in a market that's not gonna grow all that much. And by contrast, in the on-demand space, we're the only player there for at least the next several years. We have a meaningfully differentiated offering, offering that we think is substantially better in all dimensions. There's nothing coming. Even if anything else does come, it's gonna be better than that in any direction. And so, you know, I truly think that the, the next largest product in the, in the, in this marketplace after Takhzyro is going to be sebetralstat. Makes sense. On the payer side, what do you... What, what's your expectation for how access may look like and whether a patient might have to step through generic icatibant, and if they did have to step through it, you know, what could that actually look like, given that, you know, generic icatibant, when used correctly, does work? Right. This is, at a baseline, we expect our access to be excellent. We've, we've started having interactions with payers. We've done some, you know, we've done a fair bit of qualitative work. We started off some quantitative work. We think the pricing can be, can be quite attractive, certainly on par with, with branded peers here, if not at a, at a premium, and we think the access is going to be, really strong, just driven by the, the value proposition we have of the product. I mean, when you start talking to payers and, and you talk about the shortcomings of the existing therapies, and you talk about the fact that patients don't treat enough attacks, I mean, it's well known that maybe less than two-thirds of all attacks are treated on average. And when you talk about the fact that even the attacks that are treated, patients commonly wait too long to treat them. I mean, we've shown in our own studies that, you know, patients commonly wait 3 or more hours, at which point the attack has really blossomed much more meaningfully. When you so when you talk to payers about what patients are actually getting nowadays in terms of value for the, for the drug, it's a pretty challenged environment. I mean, they're so payers are paying a lot of money for therapies that aren't giving the kind of benefit they really should be. And so my point is, as we've started to educate them on that, using all this data we've gathered, most of which we've published, you know, we have 10 abstracts. You saw this, this weekend at EAACI, which will have a lot more of, of this information that we've been talking to them about. The conversations on pricing access become a lot more straightforward. And so we, you know, we really don't anticipate any substantial roadblocks in the way of, in the way of access, certainly nothing unusual in the space. Everybody has a prior auth that's just kind of par for the course, so we'll, we'll work through that. Step edits, we don't really expect that to be a substantial issue in the space, and to your point, even if it is, arithmetically, most patients are on icatibant anyway, so they're already gonna be using it. So moving them from icatibant to sebetralstat isn't gonna be a heavy lift. You know, there's a lot of ways we can, we can address that. So we think we're in a really strong position, and our access should be really favorable. Yeah. Yeah, okay. So I guess what could that look like tangibly, right? Like, let's say at launch or 6, 6 months after the launch, I mean, you know, maybe not on day one, but 6 months after launch, a patient or a physician writes a prescription. Yeah. Do you think it's just verifying simply that the patient has HAE, or do you think it's more complicated than that, from what the insurer might ask for? Certainly in the minimum that you're gonna, you're gonna need to confirm diagnosis of HAE, but all these people are gonna have one. Of course. You know, could there be some circumstances where you're attesting that a patient doesn't tolerate needles or, you know, a patient isn't getting the benefit or patient's having a negative reaction right again to icatibant? Let's come back to this ISR rate, which is effective. I mean, if you look at the phase three for, you know, for Firazyr, it's essentially 100%. So patients having, you know, negative, adverse, you know, having adverse reactions to Firazyr, that would be an easy one. So there's a lot of pathways you can go through to the extent you have to provide more than a diagnosis of HAE. Again, common in all rare diseases, you have these patient support services networks, that this is their mission in life, is to work through these processes between the patient, the physician, and the payer. And so this is the kind of thing. We'll have a full team in place that will actually be working on all these activities to make sure that every payer is able to support this, the prescriptions that are written. Yep. Yep. Okay. So where are you right now in terms of, I mean, you're assuming you're not hiring sales reps, but in terms of just kind of building out, you know, the groundwork for launching this drug? We've obviously hired a chief commercial officer last year, so she's been building out the team. We've hired all the key roles in the U.S., so market access, head of sales, BAI, those are all in place and actually have been for a while. We've also got a head of Europe who's built out a small team there, so a market access you know, a little bit of market access folks and kind of similar roles. We've actually got a general manager in Japan who's been doing the same thing. Japan has slightly different regulatory requirements, so he's been working on that as well. The key roles have all been filled. Where we are now is we're starting to hire down the second next tier, which basically becomes the heads of all the groups you'll hire. So your maybe, you know, your national sales director type levels, your head of patient support services. Again, these, you know, these kind of positions that start to build out the leadership of the various field forces you'll put in place. So that's all, that's all starting to get done. And then to your point, you really don't, as you know, you really don't start to hire the sales reps till much further along. But we're getting the base, the really key, not the most senior people, but probably that next tier in place now, and you know, we'll be filling those over the next few months on the commercial side. On the medical side, actually, we've already fully built out the entire medical team to the extent we need it. So we've got a full network of MSLs in the U.S., as of this year, Europe as well, and we even have some MSLs in Japan. So medical has actually been very active, been exceedingly active, and they're already working on physician education activities and a lot of physician outreach, with a very well-defined strategy and set of activities to work through with them. Yep, yep. Okay, very good. You know, in the prophy space, we've seen a great willingness to switch, right? I mean, you can look at the launch of Orladeyo or Takhzyro, and the Orladeyo launch, I think, is really- Yeah ... interesting, right? Given the relative efficacy data and the fact that it's also oral. In the on-demand space, is there any reason to think that, you know, patients and physicians might be more conservative? Because when attack is actually happening, right, like, the bar to switch to something that's, that's newer is higher. Like, I don't know, maybe tell me if I'm reaching here, but I guess as you think about the kinetics of launch, what have, what have you heard from clinicians- Yeah ... as it relates to sort of the sense of urgency that patients by which will want to get this drug? In summary, I would say it's been, there's been overwhelming enthusiasm. Everybody's—I mean, there's been really no pushback from the physician front at all. I mean, you, you always have questions, you have to talk through, things you have to explain, but there's, there's nobody who doesn't think this represents a substantial advance in, in the therapy, in the space. I mean, just, just period, full stop. Everybody knows that icatibant, you know, works reasonably well when, when dosed and when dosed properly, but everybody now knows that those latter two things aren't true. When we started on this a couple of years ago, really starting to interact with physicians, what was, what was really... One of the early things we discovered, because we'd been doing patient interviews before this, was there was a fairly wide gulf between how physicians perceived their patients to be doing on their HAE therapies and how patients actually described it. We found this on both with on-demand-only patients and with patients using prophylaxis. 'Cause, I mean, a key, not always obvious point to mention, is that almost all patients on prophylaxis still use on-demand therapy. Everybody's, I mean, our view, you know, it's true to say that basically every patient's an on-demand patient, is just some of them also use prophylaxis.... So what we learned early on was that physicians really thought that patients' disease was well-controlled, and they were fine with using, you know, their existing therapies, and they weren't having breakthrough attacks, and that they were taking it when they should, and they were carrying it all the time, and that they were following all the guidelines. And fairly quickly, you know, we had discovered, and we started to educate them on the fact that virtually none of that is actually true. I mean, what you find is that patients on prophylaxis aren't attack-free to the extent that has been kinda commonly asserted, and that when either patients... That patients on, and we showed this in our phase three study, patients on prophylaxis, when they have attacks, look exactly like on-demand patients. The attacks aren't any less severe. The attacks, I mean, are virtually identical. I mean, we've actually published that data already from the phase three study. So we showed that the attacks are actually no different for patients on prophylaxis. We showed that patients on prophylaxis and on-demand delay their treatment too long. We showed that they really don't appreciate the injectable therapies, and that they don't carry them, for a lot of reasons: 'cause they don't like using them, 'cause they prefer to treat at home, because they're really bulky. So the point is, we've already gone through that process with the physicians, you know, a year or two ago. So when the data came out, and it was as positive as it was, there was really unbridled enthusiasm among the physician world that we've talked to for this. And so I guess we don't really expect any pushback. And in terms of patients, I mean, based on the folks in the open-label extension, they love this drug. I mean, there... You know, there's people using it appropriately, but, you know, people are using it, people are staying on the study. People are getting the benefit we expect them to do. They're taking it early, which is exactly what they should do. I mean, in the phase III, we all know they took, you know, on average, patients dosed right around 40 minutes after the onset of an attack. Now, that's in a phase three study, and it, there's a lot of issues with the packaging and the recording of data. In the phase, in the open-label extension, they're dosing within nine minutes of attack onset, and the first quartile is right around three minutes. So- Wow! ... so patients are actually doing this the way they should, and as a result, they're getting the benefit they actually should have gotten from these other therapies, but they never did. So I think we feel really confident that physicians are gonna be supportive of this in a way they probably weren't with Orladeyo early on, and that patients are gonna clamor for this in the way they did for Orladeyo early on, except we think we have a really good drug, and the patients are gonna want to stick with it over time. Yeah. Yep, okay. All right, makes sense. So as you think about KalVista and sort of building a company, you know, for the mid to long term, right? You decided to... Is deprioritize the right word, your earlier stage, work with the, with the next gen product that could have been positioned in HAE and look at bigger indications? You know, what was sort of the thought process there? Well, it's a couple things. I mean, Factor XII is a really hard target to work on, and so it's taken us longer than I think we might have liked to get something that would be clinic-ready. We're still a ways off from that. The second thing is, the more I looked into Factor XII, coming back to your point on the marketplace, at the moment, you've got, you know, you have the potential to have 10 therapies in HAE, I mean, in prophylaxis, in the next 5 years. And as I said earlier, that market looks to us like something that's gonna get chopped up into small pieces. There are none, very, really none of them are meaningfully differentiated from the other, to be perfectly honest. And so, you know, we don't really see any clear winner in that space. And so and 2 of them, Orladeyo and potentially the other one that may come later, would be oral. And so we'd be several years behind all the other oral therapies in a market that's gonna be a bunch of, you know, much closer to, you know, $200 million products than $2 billion products. And so when you start to think about the challenge of doing trials in HAE nowadays, I mean, again, just running a phase 3 trial in HAE is a real, real challenge. I mean, all the... Imagine all those therapies out there in a pretty small patient base that's getting fairly well exhausted by all these studies- Right ... and it doesn't see a whole lot of difference in most of these therapies. The logistics of it, the market, you know, the end game of where you're getting to seems challenging to us, and the logistics of getting there seem really challenging to us. So barring some unusual development in HAE that would make prophylaxis HAE look more favorable to us, it just doesn't look to us like a tremendous use of corporate resources. The nice thing about Factor XII, and one of the reasons we got into it early on was, though, it also offers places to go outside of HAE, and there's much bigger indications that potentially could be advanced there. Now, those are the kind of things that are too big for a company like us to do, but they're, you know, they're interesting and large market opportunities if it did work. And so we have, you know, we decided to sort of pull back from our, you know, a massive level of investment we were planning to make in Factor XII, much of which was going to be directed toward moving toward HAE, and really start to, you know, to think more about other indications we might go and proof-of-concept type activities we might pursue. Things that might allow us to sort of engage knowledgeably with partners down the road, to move it forward in an interesting indication that probably isn't as, you know, overwhelmingly competitive and, as HAE is, as prophylaxis HAE is going to become in the near future. Yeah. Yep, okay. Makes sense. For HAE and sebetralstat and KalVista watching this independently, do you wanna talk about, like, the path to profitability? And I know you conveyed that, you conveyed confidence that there is one, but- Yeah ... any other sort of color you can kinda give on that, and why you're confident, I think would be, would be interesting. Yeah. What's great about HAE is it's a very straightforward sales call from a commercial standpoint, and it's a very tight marketplace. So, you know, you got 7,000 patients in America, you got basically 1,000 docs that write scripts. Half of those are written by probably a couple hundred docs, and 80% are written by 600 or 800 docs, 700 or 800 docs. So it's a really tight sales call. The point here being that in the U.S., most of the other folks in the space have on order of maybe 25, 30 sales reps, and so the economics of the thing really work for a biotech company. You don't need an enormous army of people. The physician call points are tight. It's a very limited number. The pricing is obviously good. The, you know, the net pricing is also really good, and so a company can generate meaningful, we think, meaningful cash flow on the basis of these sales, based upon the way, the kind of operation and the cost of goods and everything else that goes into it. Europe is a much lower price market, but probably in terms of volume, I mean, overall, Europe's probably about the same in volume as the U.S., and so the dollar net is small or much smaller. But again, commensurately, though, the effort you need to put into it is also small, and it takes longer to build. You don't, you don't need as many reps even in, in Europe, because unlike the U.S., you- most of these patients are treated in actually these kind of large catchment centers. So, you know, a good-sized doc in the U.S. is gonna have 10 patients, probably less. A reasonable-sized catchment center in Europe might have 200 patients, and so it's a much, it's a much easier, more straightforward- Right -to go to. So the point is, Europe, Europe, the economics also makes sense for slightly different reasons. And then Japan's a small market, but, but again, it's a straightforward call. It's tremendous unmet need. We think there's opportunities for growth there 'cause there really haven't been a lot of therapies approved, and it's just been treated somewhat differently. So the point is, all these markets, actually, from our view, are worthy strategic investments. And as long as you control the level of expense across the company, which we've always done carefully and will continue to, you know, we think within a few years of launch, you can be reasonably cash flow positive. Yeah. Yep, okay. That's great. You know, I think, trying to think of the other sort of key, key questions here, right? I mean, I feel like we've talked about the category, we've talked about the payer questions, right? You talked about the opportunity with the attacks that go untreated. I feel like the only other piece, right, and I think that in part this is because, you know, your data sort of speaks for itself, and the investing community largely expects you to obtain approval. I think the only other piece is competition within acute, specifically as it relates to the data from Pharvaris, and I feel like that's always one of the trickier questions to answer because I feel like the two trials are just hard to compare. But I guess, look, you have a lead to market, but beyond that, when you look at their data, it looks pretty good. So how do you kind of think about the durability of your market opportunity, especially in a hypothetical world where maybe the compound from Pharvaris were to have the optionality of being used in, in prophylaxis as well? Yeah. Again, I don't know if there's any linkage here between having a prophylaxis therapy and having an on-demand therapy. So I- Yeah, I saw that. No, I mean, it isn't like you're gonna, you know, give a package with one of each or something. I, it just, it just doesn't, it just doesn't- Mm ... doesn't make seem apparent to us. I mean, Takhzyro being instructional, I mean, Takeda being instructional, right? Having Takhzyro and then, and then Firazyr. So it's just, that doesn't seem like anything to us. In terms of the data set, I mean, you know, there's a lot of things get thrown around. I guess the summary is we've generated the most robust and positive data set ever, ever shown in, in on-demand therapies, period, full stop. You know, that means both efficacy and, safety. Nothing they've shown has shown certainly any better and probably arguably even comparable to our data set, and so we don't... You know, and they all have some different endpoints, and there's conversations that sometimes go on, people trying to make more out of other things than need be. But we see no pathway for them to generate clinical data that shows any kind of superiority, and so, on any dimension. And so, you know, the truth is we'll be at least, you know, ideally, you know, probably 2 years plus to marketplace. I think we have plans for a very aggressive launch. I think patients are going to like this. In fact, I think we're very comfortable with that. So I think, you know, if anybody else comes along, we'll be pretty well-established by then. And so, Yeah ... so, you know, I sometimes hear about markets being split and such, and I see no examples in history of that ever happening, and I don't think this is gonna be the first one. Yeah, okay. All right. So maybe last question, Ben, just, you know, let's just talk a little about, you know, launch. You know, remind people the expected timing of approval and timing of when you launch thereafter. And then, as you think about the first few quarters of the launch, you know, have you socialized internally yet what types of metrics you might provide or sort of- Yeah ... benchmarks you might give us to help understand how things are going? Yeah. So the filing is expected to be in June. That ideally, obviously, get to a, you know, on a standard review cycle that gets you a June of 2025 approval. We'll be ready to launch immediately on approval. There's a potential for priority review, I'd obviously ask for it, but I don't think we'd guide to that. There's a lot of therapies in HA. I think that might be a little bit of a challenge. So we'd expect to be launching roughly this time next year. Again, we'll be ready to launch immediately on approval and start moving. In terms of the metrics to talk about on the street, we're in the process right now of starting to talk about the internal metrics that we're going to look to gather and analyze. I think after that conversation is when you get to the things we think would be most useful for investors to start to track. So we're probably a little early on that front, but later this year, early next year, you know, is a good time for us to start talking that through with people. Yep, yep. Okay, great! Well, thank you, Ben. We covered a lot. I appreciate you taking the time. Always good talking to you, Paul. Thanks again. All right. Thanks.