Welcome to this fireside chat with KalVista Pharmaceuticals. I'm Joe Schwartz from the Biotech Equity Research team at SVB Leerink. It's my pleasure to be hosting Andy Crockett, CEO, Ben Palko, Chief Business Officer and Chief Financial Officer, and Chris Yea, Chief Development Officer. Thanks so much for joining us today and giving us an update. Thanks for having us, Joe. Great. Maybe we can start by just having you give us a quick overview and update of your recent progress and goals for the year. Happy to do that. Yes, we've been making a lot of progress with our franchise of small molecule plasma kallikrein inhibitors for HAE. Our lead program is KVD900, moving into a phase III clinical study for on-demand treatment of attacks of HAE. We had a very favorable meeting with FDA at the end of phase II for that program and agreed the phase III program and the requirements for NDA. That phase III program will be kicking off here very soon. We've guided that patient enrollment will begin this quarter, and so we're excited about that. Excited especially about the fact that our phase III study will look very much like our phase II study in terms of the design of the study and you know, Joe, as you know we had a very successful phase II study and from our perspective what we really want to do is carry forward some of those really positive things we saw in phase II into phase III. In our interactions with FDA we're able to agree to essentially that plan. We're looking forward to that study kicking off here very soon. For KVD824 our program for prophylaxis you know we are now in our phase II clinical study for that program. We're very excited about the opportunity for an oral program to deliver efficacy comparable with what we see from the very successful injectable therapies in the market. KVD824 was designed to do that to deliver efficacy comparable with those therapies, and we think it's a perfect complement to what we're doing with KVD900 on the on-demand side. A bit further afield is our program in Factor XIIa. We are leading the world in the discovery of oral molecules for Factor XIIa. As you're familiar with the biology of how these attacks in HAE kick off, Factor XIIa. Factor XII and Factor XIIa sit at the top of that cascade. I think it's always been understood that an intervention there would make a lot of sense, and the challenge has been the discovery of those molecules, and we've been successful now in discovering oral, potent and selective Factor XIIa inhibitors and moving that program forward, this year in IND-enabling studies and then eventually toward an IND. We're excited about our progress kind of across the board in our HAE franchise and opportunities to move that forward this year. Awesome. So, let's dive into the KVD900 phase III a little bit. Can you give us more insight into the endpoints? Is the hierarchy the same as phase II? It seems like it's been tweaked a little bit, but, you know, you basically everything, so, that's probably not an issue. Can you just give us any insight into, you know, how that works and maybe the rationale for why you selected and the FDA selected what you did? Sure. Chris, do you wanna take that one? Yeah, sure. Yeah, sure, Joe. I think as you say, you know, the endpoints are broadly speaking the same as we mentioned in the phase II, although with the-'cause you, as you intimated, yeah, we've tweaked them a little. I think going into the phase II, as you'll be aware, it was use of conventional attack medication or use of rescue, if you will, colloquially, that was our primary. We chose that for very pragmatic reasons based upon the data that we had available to us at that time. I think as you said, you know, we hit that one very comfortably with statistical significance. We'd always recognized going into that study that was unlikely to be a good endpoint to support approval, but it was great, if you will, in a sort of proof of concept setting for phase II. We'd included some other more patient-reported outcome-based endpoints, one of which was the one that we refer to as the Patient Global Impression of Change, PGIC, where patients report at set time points how do they rate their symptoms compared to when they first took their treatment. That was the endpoint that was used by Ruconest to support its approval in its phase III study, and it's actually the most recently approved product in the on-demand setting in the U.S. Again, like the primary, we hit that endpoint with a really good P value. Actually I think since then as well, talking to lots of patients, it's a really meaningful endpoint to patients. You know, patients want this first, if you will, hit of a treatment. Yes, I've taken something. I know it's working. I can kind of go and get on with my day. As Andy alluded to, we had a really good end of phase II meeting with FDA, and they've agreed with us that that is an appropriate endpoint to use to support the NDA submission. I think as you referred to it, tweaking in the sense that that endpoint now has been promoted to the primary endpoint for phase II. You know, there's precedent, there's regulatory precedent and also, perhaps more importantly, you've actually got regulatory agreement to use that endpoint in our phase III study. Mm-hmm. How are you thinking about numbers of patients and sites and, as an extension of that, the enrollment timeline? Yeah. In terms of the number of patients, as you'd be aware, we've completed 53 patients in our phase II study, got very good P values across, essentially across the board. We do need to provide obviously some more data to FDA and other regulators to support the approval. The phase III study, we'll be looking to recruit around about 100 patients. That's fairly typical for phase III studies in HAE. There are typically 80 to 100 patients. It's kind of, if you will, a very traditional size for phase III study in HAE. In terms of enrollment, we'll be looking to recruit probably 50 sites plus. This will now be worldwide. Remember the phase II study was U.S. and E.U. only. The phase III will be primarily U.S. and E.U., but we'll be introducing sites elsewhere from worldwide as well. In terms of time of recruitment, yeah, we've essentially doubled the number of sites, and we're kind of, you know, roughly doubling the number of patients. I, you know, I think if you will, that's some equivalence in there. I think as always, you know, phase III study, you know, you always hope that when you get great efficacy results like we got on our phase II, that's gonna help. It certainly helps the docs talk about your product. It certainly helps the docs talk about our study. I think that is very encouraging to patients to come into the study. You know, we'll update on recruitment. As Andy said, you know, we're looking to enroll our first patient this quarter. Once we get patients rolling into the study, then I think it would be appropriate for us to get out and give some more detailed guidance on our expectation of timelines. Mm-hmm. Okay. I guess, you know, given this is an event-driven study, and you've already done this once before in a pretty rigorous manner, you must have a sense of, you know, once it's fully enrolled, at what rate you'll be, you know, capturing observations and then wrapping up the study. What are your thoughts on that timeline? Yeah. The key to this actually, Joe, is what we describe as fully enrolled. You remember in the phase II, we actually recruited 68 patients into the study, and we completed 53. That's, if you will, because we said, "Right, we've got enough patients now. We can stop." The those patients who didn't complete the study, they weren't withdrawn from the study, but we just stopped the study before they had a chance to have their two attacks. That's a really important view if you will over-recruit the study. Do you recruit more patients than you need to complete? You have a batch of patients at the end. You're not waiting for one patient to have their one last attack. What you have is a you know a good number of patients. In that case, it was 15 patients, so we just needed one of those to have one attack. That minimizes that wait, if you will, from the last patient who's actually enrolled to the last patient to have their attack. Phase II, you know, that minimized the last patient, last visit. I should say the last patient enrolled to the attack. We finished recruiting that study in December and the results were out in February. Again, I would imagine, you know, it's gonna be a similar time period between the last patient actually being randomized into the study to the last patient having their attack. Right. Okay. That makes sense. We noticed you had some data coming up at AAAAI next week. Just wondering what that will highlight that might be new. Yeah. We're doing some further analysis on our outputs. We're looking at things like attack location. We're gonna show that, you know, like KVD900 is effective for all attack locations. I think as well, particularly what we're interested in, it's particularly probably KVD900 is showing just how fast it works and just how predictive that early event of seeing an efficacy outcome is predictive of your whole treatment outcome, if you will, over the whole attack. We've got some further analyses looking at our PGIC, our primary outcome, and then how that feeds into the other outcomes that we've measured. Just to show that, you know, that early effect that patients really like to feel is actually then predictive of a whole treatment outcome. Will the types of patients and the types of attacks be the same in phase III, do you think, or will it be broadened at all? I seem to recall that laryngeal attacks were not eligible in the phase II. Is that the same now? Yeah. We'll be including all attacks to get as broad a label as we possibly can. I think that would be the main change, Joe, obviously in the laryngeal attacks. We obviously couldn't include those in the phase II because at that point we didn't have proven efficacy. That just wouldn't have been right to include those attacks because they can be life-threatening. Obviously, in discussion with regulators, yeah, we're gonna try and include as many different attack types as we can. I think the laryngeal is the only, if you will, attack type that is new to the phase III. Okay. Cool. Well, that'll be interesting data. On a similar note, I noticed that you had your phase I data published in a peer-reviewed journal recently. Do you have a sense of when we might expect a publication for the phase II to come out? Yeah. I can't give a timeline, Joe, but it's on its way. That's all I can say. Okay. Well then that's great. Let's turn to KVD824 then. Can you tell us how this molecule and its properties compare to KVD900, you know, where you obtained it and you know what work has been done to optimize this for chronic administration? Yes. KVD824 was discovered in KalVista's own labs with our research unit. It's a KalVista discovered molecule, much the same as KVD900. In terms of how does it compare to KVD900, like KVD900, it's a potent plasma kallikrein inhibitor. It's highly selective. We moved it forward because it has some interesting properties which allow us to modulate the formulation a little more than we did for KVD900. KVD900, dare I say, is very simple. As soon as you dose KVD900, you've seen the PK profile yourself. It gets in very rapidly to very high concentrations. That's great in an acute on-demand setting. KVD824, because of the properties of the molecule, it allows us to modulate that a little. We did some phase I work, which I think we've shown, where we've been able to, if you will, broaden that exposure profile, to allow for a more, if you will, prophylactic-like profile, so a little bit broader. Where we're not interested in getting very rapid absorption to very high concentrations, we need to maintain the concentrations to have a continuous suppression of plasma kallikrein activity. That's what KVD824 allows us to do because of the properties of that molecule. Okay. I guess what's the latest status of this program? You know, what have you been able to get going and, you know, what remains to be done in order to execute this trial? Yeah, the trial's enrolling. Very pleased with the enrollment rates to date. Again, you know, I think as we will with KVD900, we will give a more fulsome update on recruitment once, you know, once we've really got that uptick in the recruitment curve. I think then we can give a lot better idea of when we think we're gonna have data from that study. Okay. Given it was on clinical hold for a while, I was wondering if you could give us any insight into how that arose and how that was resolved. Any color you can give us on that? Yeah, sure. The phase II study for KVD 824 was actually kind of unusually the IND- opening study. This was the first time that FDA had actually seen KVD 824. We'd done all of our phase I work over here in the U.K. I think, you know, it's fair to say FDA didn't get a fair amount of data that they wanted to go through. They came back to us with some questions around some of the non-clinical work we'd done. They asked us to do some reanalysis. They didn't ask for us to generate new data to run new studies. They just wanted some reanalysis of the studies that we'd already done. We provided that data back to them. As you're aware, we announced that the clinical hold was lifted. Okay. I guess what's the bar for success here? What endpoints will you be looking at? Like, in the acute setting, it seems like there's a variety of trial designs that you could employ here. Can you describe, you know, what this trial looks like and how you settled on this design? Yeah, sure. As you alluded, Joe, there is some flexibility, if I can call it that, in the on-demand setting. In the prophylactic setting, it's kind of pretty well established now with all of those recent approval on the donidalorsen prior to that. You know, this is a treatment over a period. We'll be looking at treatment over 12 weeks. Dare I say, it's a simple frequency of attacks over that 12-week period. That is the primary outcome. It's the primary outcome in our phase II. It would be the primary outcome that supports approval and did for ORLADEYO and lanadelumab. It's kind of a well-established study design to support the prophylactic treatments. Do you think that you'll be selecting for any particular types of patients, given the variety of options that are already out there? What's your view on, you know, who you're likely to enroll in the trial and whether that might influence what you see? Obviously, to have power, we need a certain minimum attack frequency. The patients have to have three attacks in eight weeks. We're doing a run-in period where the patient will use on-demand treatment only, so we establish their baseline attack frequency. Obviously you need enough attacks during that period to give you the opportunity to power to an outcome. I'm sorry, I missed a response as well to you earlier when you asked, you know, what's our hurdles for success in this. You know, I think clearly, you know, we think we get lots of KVD824 on board. We think we get very effective inhibition, and I think the work we've done on KVD900 talks to how we measure that appropriately. Our expectations for KVD824 are that over that 12 weeks of treatment, we should see lanadelumab-like efficacy. We certainly inhibit plasma kallikrein as effectively as lanadelumab. There's no reason to expect that we shouldn't be as effective. Yep. Yeah, that makes sense. I guess, you know, that segues pretty well into a question about the overall landscape and, you know, we have these various acute and chronic treatment options. You know, where do you see the gaps in treatment currently that each of these agents can help address and, you know, make patient outcomes better? Can you quantify, you know, those gaps for us in any way? Yeah, I guess I'll pick that one up, Joe. The need is essentially as it has been in the space, which is for a highly efficacious oral regimen, and whether that's in the on-demand space, absolutely, 'cause there is no other option nowadays in the on-demand space for an oral therapy. We even think that despite how the initial ORLADEYO launch has gone, we think there's probably over time gonna show to be some efficacy gap there as well that we think we can fill. With both KVD900 and KVD824, the objective here is to be a therapeutic that gives patients, you know, very rapid relief of their symptoms in the on-demand space. In the prophylactic space, as Chris said, our objective and our belief we can achieve is lanadelumab like efficacy, both with ideally favorable safety profiles. The truth is the market hasn't really evolved all that much. Focusing on KVD900 and the on-demand space, again, patients have a lot of choices nowadays. Firazyr, generic icatibant is obviously marketed and has taken over majority share in the on-demand space. It's very clear that the acute market really hasn't shrunk at all in the past several years despite all these concerns. If you look at IQVIA data, overall acute market scripts are absolutely flat since 2018. There's really There's been a lot of concern expressed about this potential shift to prophylaxis. We just don't see it in the data. I think we're confident that the on-demand space is and will continue to be attractive because patients wanna treat their attacks on demand. It's important to remember that about 40% of the-I'm sorry, the most patients in the space only have about two attacks a month. For those folks, the ability to treat on demand as opposed to prophylaxis can actually be attractive. We're confident the on-demand space is going to continue to exist. We think we'll come with the first oral therapy that'll have extraordinary efficacy for patients. We think they'll be able to take it earlier. We think it's gonna have a favorable safety profile. You know, I think we're very confident, you know, we're positioned well for success there. Yeah. What do you make of the commercial success of ORLADEYO in the chronic setting and prevention setting, both there, you know, in terms of what you might be able to achieve if your profile is better, and then, you know, do you think that will carry over, the conversion to oral treatment will carry over in the same way to acute? Or do you think that, you know, the uptake different? Yeah. ORLADEYO, if nothing else, absolutely validates what we've said for years, which is patients are desiring of an oral therapy. It has certainly had a tremendous launch out of the gate. Despite the fact that the efficacy in the phase III studies, we all know was fairly uninteresting, it has done really well in the launch. We think that's simply because it's oral, and patients are so desirous of oral that they're willing to try it to see if they can be in that group, however large that group might be, that actually get the kind of efficacy rates they wanna have. I know BioCryst has already talked about some data, and I'm not sure we're completely confident in those numbers they talk about in terms of efficacy rates. We think there's a fair amount of patient selection criteria involved there. The fact of the matter is, I think it validates, no matter what, that patients want oral. With regard to how that affects us going forward, again, Cinryze didn't destroy the on-demand market. I mean, as I've said, Cinryze didn't destroy the on-demand market. Takhzyro didn't destroy the on-demand market. I don't know that we think that ORLADEYO is gonna destroy the on-demand market as well. We'll come with KVD900 first, ideally, you know, launch into the on-demand space. We think we can do very well there, and we think that honestly, it's important to remember that even patients on prophylaxis do have breakthrough attacks. We think patients, even the ones using prophylaxis nowadays, will have the opportunity to try KVD900 and see if that works on their breakthrough attacks. The vision is that KVD824 comes along. Again, we think the efficacy can certainly be on par with the leading therapies which is primarily Takhzyro. As that occurs, we think patients will have tried KVD900. Ideally, they'll have had success with it. We think they'll make them more amenable to KVD824 regardless of their experience with ORLADEYO, if they had any. From our perspective, the opportunity to be the only company, and we think we will be the only company, that actually has this full portfolio of therapies for both sides of the marketplace, is gonna position us very strongly with patients and with payers and with docs to offer patients a complete solution to their needs to treat this disease in whatever manner they see fit best. Yeah. That's a good segue to my next question, actually. In terms of this portfolio that you're developing, can you talk some more about the Factor XIIa program and, what are the next steps for this asset to advance? Yeah. I mean, we view Factor XIIa as kind of the next generation here in therapies for HAE. You will have seen the data from CSL with garadacimab, with their antibody showing, you know, fantastic efficacy in phase II. We would expect the same from them in phase III. It makes complete sense given where it sits in the pathway and kind of validates, you know, I think what not just us, but a lot of people have thought makes a lot of sense to target. The challenge, you know, for us and for others has been in the small molecule space, there just has been, you know, nothing out there. It's a really challenging target from a medicinal chemistry perspective. We've been working on it for several years. Finally, you know, we're really pleased to cross that threshold where we now have a multiple series of potent, selective, and very orally available molecules. What it tells us is, we think there's an opportunity here for a once daily therapy that, you know, potentially you can give, you know, much lower doses and achieve the type of efficacy that, you know, we're aiming for, which, you know, as we've talked about with KVD824, with that lanadelumab-like efficacy. For us, it complements kind of what we're doing with plasma kallikrein. It makes for us, you know, obviously commercial sense to be there, and we're leading the space here in terms of, you know, being able to provide that therapy. I think what you'll see next, you know, from us here is more data on. You know, we haven't shared a lot, you know, given the competitive dynamics there, but, you know, we will start to share more data with regard to the molecules that we're moving forward and what those properties look like. And then as we approach an IND, you know, even more information about kind of our plans with clinical plans and then kind of how it fits in the portfolio for us. Okay, great. What makes this target challenging in particular? Can you talk about what you were able to overcome with your chemistry in-house? You know, is it some of the same challenges that you were able to overcome with the KVD824? Yeah, that's a good question. I mean, you know, what we're expert in is, you know, small molecule protease chemistry, right? You know, one of the basic, you know, basics in all of it is if you have some starting points, right? If there's some information in the literature, you can kind of get your feet under you from a medicinal chemistry perspective and get moving. We did have that benefit with KVD824, where we did have our own starting points, starting points from others we could work with. We're able to build out, you know, a platform of molecules that way. With Factor XIIa, that just didn't exist, right? The medicinal chemistry challenges, I think are similar to what you see with other proteases. From our perspective, you know, we had to kind of invent all this on our own, and that has been in and of itself a major challenge. Now, of course, once we've done that, it gives us a major competitive advantage, right? Because we have all of that in-house. We've been able to, as we've moved through this, really canvass the patent landscape and be able to own that ourselves. It becomes a major barrier to entry for others. Very interesting. Are there particular patient subgroups that make the most sense to use each of these agents alone or in combination? To what extent will having three different approaches allow you to capture more market share versus you know, I'm just wondering if you know, one agent, like Factor XIIa, might obviate the need for either of the others that we've already talked about at length. Yeah, that's a good question. I mean, I don't think we have any kind of magic bullet in terms of there. You know, knowing exactly which patient would benefit more from these different approaches. I think, you know, what we see always in these type of things is heterogeneity in responses for individual patients, and patients will kind of self-select into those therapies that work best for them. From a commercial perspective, what we wanna do is be able to provide patients a full suite of therapies that they can kind of self-select into. Also, of course, you know, with KVD 900, it complements what we're doing on the prophylactic side, right? 'Cause all patients are gonna have access to on-demand therapy, whether that's their primary form of treatment or whether that, you know, is, if you will, a backup to their prophylactic therapy. From our perspective, we think there's real power in providing a full suite of therapies and be able to then, you know, once a patient is working through, you know, one of our therapies, be able to use others if more appropriate. Mm-hmm. Great. The only program I think we didn't touch on was your DME franchise. Can you just give us a quick update there? Yeah. We remain very interested in DME. We've said that, you know, kind of our early heritage is there. We think the results from our phase II study with KVD001, while we didn't meet the statistical significance of those endpoints, gave us a lot of insight into kind of where we would go next. Also we've been clear that we think oral therapy in DME is it is a real opportunity with a plasma kallikrein inhibitor. We continue to kind of work on those, and we'll give further updates as we kind of make decisions on how we wanna progress that franchise. Okay, great. Well, I think we're out of time, but thanks so much for the update. We look forward to following all the continued progress. Thank you for having us. Thanks, Joe. Thanks for having us, Joe.