Hi everyone, my name is Maury Raycroft, and I'm one of the Biotech Analysts at Jefferies, and I'd like to welcome our guest today, Ben Palleiko, the CEO of KalVista. Thanks so much for joining us today, Ben.
Yeah, Maury, nice to see you. Thank you for inviting us. Thank you to Jefferies for all the invitations and all the other things you do. So happy to be here.
And we're going to do fireside chat format. So maybe for those who are new to the KalVista story, provide a brief intro.
Okay. Yeah, sure. Brief summary. KalVista Pharmaceuticals, we are currently in the process. We're a pre-commercial company nowadays, which has been a little bit of a change to my presentation, that is developing a product called sebetralstat, which is currently under FDA review and with some other regulatory agencies to be considered for approval for the treatment of HAE attacks. And HAE is hereditary angioedema. It's a genetically derived disease whereby people lack a functional gene that creates what's called C1 inhibitor, and it leads to these episodes of what can be severe swelling in certain parts of the body. Abdominal attacks are very common, but also peripheral or occasional laryngeal. And they can be, they're obviously very disturbing and have high impact on people's lives. They can also obviously be fatal if the airway gets closed.
And like I said, we've generated a really robust data set here behind this product candidate. We've conducted the largest clinical trial program I think that's ever been conducted in HAE at this point in terms of the number of attacks we've treated and certainly the breadth of the patient population we've treated that we'll talk about. We have a PDUFA date of June 17th, 2025, and we expect to launch in the U.S. soon afterwards. And as I said, we've got filings in five other territories now and one more to come this year. So there could be multiple launches next year and globally.
Got it. Yeah, it's a great intro. And so this would be the first oral drug for on-demand HAE. Maybe for the audience, as a reminder, if you could just walk through some of the key data and takeaways from your phase III programs?
So. Right. Right. So we've conducted really two very robust studies, both of which I think were actually the largest ones ever done in HAE before. We had a phase II that we announced data on in 2021, and then the phase III that you were referencing in 2024. And they both showed about the same thing. The phase III primary endpoint, which was our priority secondary in the phase II, is what's called time to initial symptom relief. And basically what happens with HAE attacks is they initiate, and then by and large, they will kind of just escalate over time if they're untreated. And they have this kind of natural course, kind of a sine wave, and they may peak in 12 hours, 18 hours in terms of the severity, but then it takes a long time for them to sort of come off afterwards.
The swelling, once you have swelling in your body, that's obviously just a biological process to get rid of it. And so untreated HAE attacks can go on for days. And so the point here is initial symptom relief is really important to people because what that shows them is that the trajectory of the attack has now changed. And so they're going to start the process of feeling better. And so when we conducted the phase III, before actually selecting this endpoint, we analyzed a whole lot of other options because there's been a number of trials in the space, all of which use different endpoints. And this turns out to be the most meaningfully important to people and the most clinically indicative of an improvement that's going to come to people. So the phase III endpoint, we hit in a very robust statistical fashion.
We ran two doses, and the dose we've moved forward with the FDA, we had initial symptom relief in right around 1.6 hours from dosing. That compares, it's at least on par, if not better than the existing therapies out there, all of which, as you noted, are currently injectable or infused. We also had a number of other secondary endpoints that we hit in a statistically significant fashion as well. Probably equally significant and very important in a space like this is the safety profile, which has been absolutely pristine throughout, was very clean in the phase III study. If you look at it, actually, numerically, there were more events on the placebo arm than there were on the active arms. So a drug that really shows good tolerability to date. Again, we think that's been a consistent theme.
Got it. And it's a robust data set too from the phase III, and you're running open l abel extension. Maybe just talk about the total number of patients and the total number of attacks that you've treated to date.
Yeah. As I said, I think this has become now the largest clinical development program ever conducted in HAE. We've now, in our open label extension, treated as of the last data cut, which was early fall, to support the 120-day safety update to FDA, we treated 1,706 attacks in the OLE. We're treating something like 10 attacks a week. So the number has really gone up. And that means in total, we've treated something over 2,000 attacks nowadays with sebetralstat. And importantly, this has been, again, just in terms of the breadth of the way the patient population we've treated, I mean, there's effectively nobody we haven't looked at. It's important to note that our phase III study, in addition to being in adults, included adolescents, which is a population with particularly high unmet need.
In the open label, again, so we've continued to treat adolescents as well as adults. So this data set now includes people, everybody 12 and up. It includes people using all forms of prophylaxis, approved prophylaxis, as well as people using on-demand only. It includes all attack severi ties ranging from mild to severe, which is really important because mild attacks, despite the fact that they are described as mild, can actually really have an impact on people's lives. It includes all attack locations. Again, probably the majority of attacks are abdominal, but we've treated all the other peripherals as well. We've treated now something like roughly three dozen or more laryngeal attacks. Again, they're pretty small as a percentage of attacks. You can tell 36 out of 1,700. Again, they're the ones everybody worries about.
What's been really nice on that is prior to all this data being generated, we had normal concerns about can people swallow it, will they be able to retain it, all those kinds of things. We've never had any of those problems arise. The data set really is quite rich. As we go out, hopefully next year to people, and we're starting to talk more about sebetralstat trials, what we really like is we're going to be able to tell people that no matter who you are, what kind of attack you have, what location, what severity, anything, we've generated data that shows this can actually work for you.
Got it. Yeah, and since you had the top-line data, you've done a lot of post-hoc analyses, presented those at medical conferences. Maybe talk about some of the key highlights from some of those.
Yeah. I mean, we do put out just an astonishing volume of data here. And there's going to be more coming early next year based on some of these cuts from the 1,706 attacks from the open label extension. I mean, a lot of these things we've put out have been more in the nature of actually addressing questions or views that have persisted in the space for a long time, but turned out to maybe be not quite accurate. Again, there's been this perception that people don't necessarily wait too long to treat attacks. And we've shown in multiple data sets that actually that's just not the case.
I mean, on average, in a number of these analyses we've shown or other data sets we've generated, people are waiting on average nowadays, certainly two to three hours is very common, and you find a fair number of people who are waiting longer than that. And again, coming back to the natural escalation of an attack in its course, waiting is just undesirable. You should really not do that. In fact, the treatment guidelines, to point out, call for people to consider treating all attacks regardless of severity at the time of the attack, but also they call for when people do treat attacks to treat them early. So these are really important elements. So we've shown they wait too late. We've shown that they don't treat enough attacks. The general consensus in the industry is more or less around two-thirds of attacks are treated.
That's not because these other ones don't need it. That's because actually the alternatives they face are equally undesirable. In a lot of cases, it's people asking themselves a trade-off between having an attack and having to suffer through that versus taking the medication, which can be equally challenging in a lot of cases. So that's some data we've generated. We've again shown, well, again, some of this is things I probably can't talk too much about until we actually present the posters, but we've generated data showing laryngeal attacks. We have the same efficacy in laryngeal attacks in terms of time to initial symptom relief. We've generated data showing that one of the great challenges of prophylaxis, which gets a lot of discussion nowadays, is the fact that adherence to prophylaxis really has an impact on how well it works.
And so something we'll start to talk more about next year is the fact that even though a lot of these prophylaxis therapies and clinical trials show these very high rates of attack rate reduction, when you get in the real world, it turns out adherence is really challenging. And so as a result, half or fewer of people are actually fully adherent to their prophylaxis regimen. That goes to the ongoing need for on-demand.
So there's just a very rich data set.
I mean, I'm sure you see this every conference. We have six or eight posters just going through all these.
And so these will add to the value proposition of the drug. How do you plan to leverage those commercially? And maybe just talk a little bit more about the unmet need. You mentioned how patients wait two to three hours because they don't want to take their injectable treatment. Maybe talk about some of the issues with the injectables?
Yeah. Yeah. I mean, all these are designed in an analytical way that I think hasn't previously been done, demonstrate largely, in this case, to physicians, the fact that you do have this unmet need. Because when we started talking to people a few years ago, we would commonly get these answers that all my patients are well controlled on prophylaxis. They're not having attacks. When they have attacks, they're not severe. Right? All this kind of anecdotal information and just time after time, we've just generated through this trial and the other work we've done that those things just aren't the case. We've shown that people on prophylaxis have breakthrough attacks. We actually showed in our phase III trial, when they have breakthrough attacks, they look exactly the same as the attacks in people who only use on-demand. I mean, severity, location, everything is identical.
It was commonly asserted that when people on prophylaxis have breakthroughs, they tend to be mild, and again, we just showed in our study that's just not the case, so it's really intended to just really give a much richer and again, more data-driven view of the world that I think supports people understanding that there is still significant unmet need in the space. Prophylaxis doesn't solve all the problems, and therefore on-demand is a critical element here, which brings me back to, yeah, where you said, talk about the unmet need and on-demand, and that's really what drives it. The fact of the matter is there's a number of folks in the patient population who prefer to treat their attacks on-demand, and so they're still looking for a better oral option.
And then what we've also found is even in prophylaxis, like I said, maybe half of people on prophy are reasonably well controlled, very low breakthrough attack rates, but the other half aren't. And some of them have astonishingly high levels of attacks. And so for that group, there's a really high unmet need. In fact, that's probably the highest unmet need of everybody next to adolescents because they're now having to deal much more frequently. And by the way, I'm talking about 10, 20, up to as many, believe it or not, the largest number we've ever seen is 120 breakthrough attacks a year. These people are dealing with very high volumes of attacks that lead to just really significant trade-offs they have to make between treating those attacks and just suffering through them effectively constantly.
Yeah. And there's a competitor in the space, which we hear about, Pharvaris, which ran a phase II study. They've got an oral drug for on-demand HAE as well. Maybe talk about some of the data that they've shown and some of the compare and contrast how that data compares with your data.
Yeah. I mean, it's actually a little hard to look at their data because the phase II was done on a different model, which is basically the way all these other trials were done in the space. And actually, their ongoing phase III is the same thing. And so the data, and that's the only placebo-controlled trial they've actually run is this phase II. So it's a little bit apples to oranges. They use different primary endpoints, which are the primary endpoints that were used in older trials. Until we ran our phase II and our phase III, the last trial conducted in on-demand space had been over 10 years ago. So they kind of ran it according to that model. They had a different primary endpoint. They used a VAS scale, which people have moved beyond.
So their phase II data set wasn't easy to compare against ours, and I think that's been a little bit of a struggle. That said, I don't think there's been really any differentiation shown. They did have this open label data they put out recently. I think that's probably even harder to compare because just some of the statistical analysis techniques probably aren't acceptable to FDA. So I think we probably hesitated to read too much into that. I mean, the headline number was fine, but I think the way they got the headline number probably leaves us less confident that that's how an FDA-supported data set would read.
Got it. Yeah. And there were some differences with how they ran their study too, which I think we'll see through.
Yeah. Yeah. Well, again, the old format of trials, every other trial ever done in the space except for ours, what they require people to do is have an attack start and then allow it to escalate to a certain level of severity before you treat it. And what that boils down to is the reason people are doing that is because it allows you to more significantly demonstrate a treatment effect. Right? If you're treating further up the curve, the symptoms are more noticeable. It generally brings all of your response times in. It makes them shorter because obviously more severe attacks, it's easier to tell if they're getting better, faster. So there's a little bit of a clinical trial artifact in those studies.
The problem is what that's doing is causing people to treat the way they're not supposed to because what they're doing is they're treating attacks that are becoming more severe, not where they're still in the early phase. And they're also delaying, obviously by definition, treatment of those attacks, which allows them to get more severe. So just because it's in the front of my head, like the Pharvaris phase II and the phase III, the attacks had to basically escalate over a period of time to be at least moderate in severity to moderate-to-severe level to be eligible for treatment. And again, it's driven by this clinical trial objective. Our study, by contrast, was the first and it remains the only study ever designed to allow people to treat the way the guidelines say they should treat.
So what we said is, as soon as you feel an attack, come on, take your dose. And regardless of what the attack severity is, the time. And so what the result is, we treated a lot of mild attacks because almost half of all attacks are mild. So we end up with a lot more mild attacks in our database. That tends to make obviously the response times look a little longer sometimes because milder attacks, it's harder to tell if they're kind of improving. So it doesn't work in our favor from a clinical trial standpoint. But coming back to what I said a while ago, mild attacks can really still have a severe impact on your life. If your hand is swelling up, even if it's a mild attack, it makes it hard to pick up a drink or answer the phone or do anything.
So we think this is the right way to do it. And then also having them treat early is obviously one of the ways to enable that. And as a result in our phase III, we had people treating within 40 minutes of attack onset, which compares against that couple of hours that I talked about before. And that's in a clinical trial where there's packaging and there's diaries and there's a lot of friction. In the open label, which is much closer to real-world use, we've actually got people treating within nine minutes of attack onset, which is remarkable first, and also exactly what should happen. Treat the attacks. They don't escalate. You go about your day. This is really changing in a more fundamental way than I think is sometimes appreciated, the treatment dynamics in the space.
Got it. And I know you can't say a whole lot about the label in that I think you've mentioned that it's probably going to look more similar to icatibant, the injectable. But for how you ran this study and being able to treat a broader range of attacks, the attacks in different regions like the laryngeal attacks too, maybe just talk about what are some of the key things that you think are going to be in the label.
Yeah. Yeah. What's interesting is because again, we did all this. We've done all this work and showed in all these populations, we'd obviously seek to be able to treat a wide variety of attacks, including laryngeals. Right? We'll obviously have adolescents in the label. It's worth pointing out there's only one approved therapy for adolescents right now, and that's an IV. So certainly adolescents would be in the label. The FIRAZYR, to your point, is a good comparison. They have multiple doses over 24 hours in the label. We'd expect something like that. But because everybody else did those studies and there was really nothing else available in those times, their labels are pretty broad in terms of attack treatment. I think the only one that has any differentiation really is Pharming for RUCONEST. They don't have laryngeal attacks in their label because they didn't study them.
But the labels are pretty broad. I guess our label will be pretty broad too. I think that what's interesting to me at least is what does it mean for the future though? Because when we've gone forth and we've studied all these attack types and we've done mild attacks and we've done everything, I think the question then becomes, what do future labels look like that haven't done that? And is there some differentiation going forward?
Got it. All makes sense. And let's move on to just regulatory. So you filed for approval. You've got the PDUFA date scheduled for June 17th, 2025. Maybe talk about whether you've gotten questions from FDA, what kind of questions you're getting from them, and just how the dialogue with FDA has been generally.
Yeah. Again, once you file, you're having almost constant back and forth. Probably once a week, there's something going back and forth with the FDA. I described it all as normal course. I mean, there's been no real significant issues that have come up to date. It's just been, I don't know how to describe it, kind of administrative almost in nature type things. We did provide the 120-day safety update last month. Again, that data set looked really good. The safety still looked great. The efficacy, if anything, was even improving. So I think on that front, we don't really expect anything. We do have a mid-cycle review coming up. Again, no indications that anything meaningful will come out of that based on our interactions to date. So I don't think we have a lot of expectations there.
I think where it starts to get more interactive, and you know this anyway, is once you get to the labeling conversations, which are more of a Q1 next year kind of timeframe. I think there's inherently some back and forth on that. But again, as I sit here today, I don't think we have any expectations of anything dramatic. I just think that's when you start to go, there's just a little more interaction with the FDA to talk it through.
Got it. Okay. And based on your market research, what are the key data and info that investors should know on just the current HAE market dynamics and where the market's going?
Yeah. I mean, there's a lot of noise in the market nowadays. I mean, I think it's interesting. And certainly, it's really all on the prophylaxis side. But on-demand is kind of the quiet neighborhood here. I mean, a little bit. Right? There are three major therapies out there. They've all been out there for a long time. They're all IV or injected. Most of them aren't even all that actively detailed. I mean, Takeda doesn't put a lot of energy into FIRAZYR and CSL, not so much to BERINERT and Pharming less so. So there's not a lot of real competitive dynamics going on in the on-demand space nowadays. Prophylaxis is definitely obviously the kind of noisy part of the city. There are four therapies approved. There's, I think, something like six more that could come over the next few years.
And you're talking about a market that's basically 7,000 people in America, right, and an equal number in Europe. And so I think the competitive intensity over there is poised to really get a lot higher. From our perspective though, it really doesn't impact us in any meaningful way. All those folks, if you look at their clinical data, it all looks roughly the same. No one's really breaking out. They all have these quite apparently high attack rate reductions in their clinical trials. But again, none of them really differentiate all that much. What they really are differentiating on is dosing profiles. And so I think our vision of that space is over time, to the extent the market starts to kind of fragment, I think it probably does on dosing. You want once a month, I want once a quarter, somebody else wants an oral.
I think that's how it's going to kind of shake out for those folks going forward. But from my perspective, none of that has any impact on us. The on-demand scripts, again, TAKHZYRO was launched in 2019. ORLADEYO was launched in 2021. Since 2018, which is as far back as we've gone, on-demand scripts have been absolutely steady. I mean, if anything, they've gone up slightly. None of these are reducing the need for on-demand for two reasons. One of which is there's an on-demand-only population that's pretty well satisfied, and in the presence of sebetralstat, that will be even more satisfied. And the second of which is there's this population out there that for whatever reason, disease severity, maybe it's adherence challenges, whatever the reasons are, and it's probably a matrix, need to use a lot of on-demand.
They will continue to use that on-demand as well because nothing that's coming down the horizon, ex maybe the gene therapies, which are kind of a whole different thing, is going to change that. And if anything, what we expect really is sebetralstat that creates opportunities here that don't exist. And I do think this is disruptive in a way that's maybe not completely appreciated sometimes because in the presence of this, and we've seen this in the open label, attack rate, treatment of attacks, that rate will go up. Right? Maybe now it's whatever, mid-60s. In our open label, they're treating right around 85% of all attacks. And you don't have to be heroic. You don't have to say it's going to go all the way there in the real world. But if they go to 80% of attacks, that's still 20% more than they treat nowadays.
We think that goes up. We do think also there's a population that nowadays maybe moved to ORLADEYO because they like to oral or maybe have less severe disease and their injection rates maybe are higher than they want them to be. Right? Because nowadays, the only two choices in the world fundamentally are TAKHZYRO or ORLADEYO. We think some of those folks over time may think that sebetralstat is a better option. I mean, the low treatment burden is not to be underappreciated here.
If you don't have a lot of attacks or if you just don't like the fact you're taking 30 tablets a month or two injections a month, the fact you have a pill you can keep in your pocket when you feel an attack coming on, you can take it and you know because of the data set we've generated that whatever it is kind of attack you're having, we're going to have efficacy. I think that really is going to change people's mindsets in a way that, like I said, I'm not sure it's completely appreciated nowadays.
So some prophy patients would come over and just use on-demand treatment to manage their disease.
I think there's an opportunity there. Again, I do think this disrupts the treatment paradigm fairly substantially.
And so maybe briefly talk about just pricing and your conversations with payers. But also one of the questions I think a lot of people are interested in is just how to think about the launch and what that could look like. With BioCryst, ORLADEYO, I think it's a really interesting proxy. It's in the prophy setting, but it's an oral drug. And so you learn a lot of information about how patients switch and also how well they're doing commercially too. So maybe just talk about launch expectations.
Yeah. So real quick on pricing. Current branded pricing is right around $11,000 for branded FIRAZYR. And actually, on an attack basis, is more like in the mid to high teens for the other therapies out there because they tend to use more for an attack. We expect our pricing to be somewhere on par with branded pricing. And in the payer conversations we've had, we haven't really had any pushback on that to date. Now, again, there's more to come on that. But the value proposition is high and we don't really anticipate that there's going to be substantial challenges to that. So I think we feel pretty comfortable about pricing. On the launch, yeah. I mean, without getting too far into that because it's probably a little early and some of the stuff we'll start to talk about next year, I do think ORLADEYO is instructive.
I mean, the efficacy in the trial, as you know, was probably not unlike the others. The safety had a little bit of challenges. But yet, the launch went really, really well driven by all this patient demand. So what I think ORLADEYO does validate is patients want an oral therapy to a very high degree, and that's going to play through for us. I think the fact that we have this efficacy we've demonstrated and this terrific safety profile is going to only enhance that attractiveness. Whether the numbers go the same as ORLADEYO or not, we're not in a position to forecast that just yet. But I do think it goes to the fact that this market's looking for a better alternative, and I think sebetralstat can offer that.
Got it. It's been a great conversation. A lot of things we didn't get to, but maybe in closing out, if you want to just highlight the financing and the cash position that you have and just anything else you want to.
Yeah. We recently did a royalty financing. It was a pretty, I think, viewed as very attractively, and we did a small equity deal on top of that. We're funded a long way out. I mean, somewhere in 2027's kind of time range, depending on how the trajectory goes. So we're really stable. We really are just focused now on putting our heads down and getting ready for the launch and giving this product the opportunity it deserves.
Great. Thank you very much, Ben.
Thanks.