Welcome to the Global Healthcare Conference. I'm Peter Stavropoulos, biotech analyst with Cantor. With us we have KalVista. It's a company that I cover, and I'm pleased to introduce the CEO, Ben Palleiko.
Thank you.
Yeah, so let's start off with an introduction of yourself, you know, followed by a description of the company.
Ah! Thanks, Pete. Yeah, thanks for having us here. It's really nice to be back at this conference again for another year and get to talk to you all. KalVista Pharmaceuticals is a pre-commercial company. We have a product called sebetralstat, which has. We've now filed an NDA in the US and also MA in Europe to get marketing authorization to sell for treatment of HAE attacks. For those who don't know, hereditary angioedema is HAE. It's a genetically derived disease. It's very rare. It's about one in fifty thousand globally. And what happens is, patients either lack a gene or have a low-functioning gene that causes them to suffer these sporadic variable bouts of extreme swelling.
And so, for a bunch of reasons or effectively for no reason, what they will have is a cascade takes off, and it leads to typically localized swelling, commonly in the abdomen, but also peripherally. And in extreme cases, sometimes patients will actually have laryngeal swelling, and that can lead to asphyxiation, actually, if untreated. So it's a fairly small population, obviously, but it is a lifelong disease. It's obviously familial. It has a great impact on people's lives.
And so despite the fact that there's a number of treatments involved, and I'm quite sure we'll get into competitive dynamic here, the fact is there's still a very high unmet need in this population because a lot of patients treat only in on-demand way, and they only inject. The therapies nowadays are available to them are all injectable or infused, or they use prophylaxis, which there is one oral prophylaxis, but also most of those are injected or infused. But the problem is, even patients on prophylaxis still have breakthrough attacks at a fairly significant rate.
So it's a disease where there is still a severe need for more efficacious and treatments that allow patients to actually live a more normalized life, and that's where we're looking to provide here in next year, assuming FDA approval.
All right. So you just mentioned that you had an NDA filing. It's supported by the phase III CONFIDENT study presented data at AAIC.
Yep.
I'm sorry, not AAIC, AAA AI.
Yep.
Confusing Alzheimer's maybe. And you know, you also published it in the New England Journal of Medicine. Just take us through the key highlights of that study, key takeaways.
Yeah. So, so the phase III study, which we called CONFIDENT, with a K, was, a follow-on to our phase II study, obviously, which was essentially the same, the same study design. And what we did in this study was, it was a, It's an on-demand treatment, so what we did is we brought patients in, they enrolled in the study. And I'll talk more about the criteria here 'cause I think that's important in a minute. But functionally, what we did is we had two active doses of sebetralstat, three and six hundred milligrams, and we also had a placebo. And so what patients would do was come in and treat up to three attacks, one each, in a blinded manner, randomized with each of those therapies.
And then what we did is we collected the data points we collected. The primary endpoint was what's called time to initial symptom relief, using a scale called Patient Global Impression of Change, which is a seven-point categorical scale. We can talk more about that if you're interested. We had a number of secondaries as well. So the point was what we asked patients to do is when they feel an attack coming on, to take their therapy and then recorded various time frames, how they feel, compared to the time at which they took their dose. The first time point at which twice in a row they said they started to feel at least a little better was the primary that would be reached. The data was highly statistically significant.
We showed them the 300 milligram arm patients started to have initial symptom relief for about 1.6 hours. It was, you know, much, much longer than that, the placebo arm. On the secondaries, we hit all those in a statistically significant manner, well. So the data was really very positive. It completely tied together with the phase II data, which showed very similar results. Actually, equally importantly, probably, is the fact that the safety was just absolutely pristine. We've always displayed really good tolerability with this drug in all the clinical studies. We actually published in the New England Journal, as you said, the Phase III results back in the spring.
You know, a notable point, which I think our CMO is very proud of, is the fact that in the New England Journal, they actually know that the safety profile was no different than placebo, which is a pretty strong statement. I think the key thing about this study, though, which is really what matters, is, this is the most inclusive, broadest-ranging, largest study ever conducted in HAE. We enrolled the most number of patients, and we enrolled effectively everybody with HAE. We allowed them to treat all attack locations, we allowed them to treat all attack severities, from mild all the way to severe. We treated laryngeal attacks. We've now got the largest, I think, the largest database of laryngeal attacks created, treated in a clinical setting ever.
We allowed patients on prophylaxis to use this as well, and so this population, the study was really intended to look very much like the real-world population-
Mm
... of HAE in terms of all the way they treat and the attacks they treat. And I think that's what makes it particularly powerful, is we'll now, again, assuming we get approval here, be able to go off and talk about the fact that no matter who you are, what kind of attack you have, or what else you're doing to treat your disease, you know, we've shown that we can actually... you can benefit from this.
Right. You know, when we initiated on KalVista, back in 2018-
Yeah
... you know, I remember looking at the PK, PD curves, you know, and, you know, what was striking was how fast you onboarded.
Yeah.
You reached two times IC50 in a very short period of time, I think less than-
Fifteen minutes.
Less than fifteen, and then you hit a hundred times.
Yeah
... IC 50, I think in less than 30 minutes.
Yep.
Okay, and so, you know, it seems like that translated into the Phase III, but, you know, there was a little bit of a debate about requiring a second dose, and so-
Yeah.
Can you tell us about that?
No, that's a great question. So what Pete's referring to is the clinical trial protocol. You're right, and this is a point I didn't talk about. What the clinical trial protocol said was that patients should take a dose at the first you know signs of an attack, as soon as they believe they're having an attack. And then the protocol said, "And if desired..." And it, that's not quite what it said, but you know, basically, they were allowed to take a second dose if they thought the symptoms warranted, if they wanted to take a second dose. And the reason we did that is 'cause in the real world, actually, patients fairly commonly take additional doses of their drug.
You know, the re-dose rates of Firazyr, depending where you look, range between, you know, maybe 20% on the really low side, but I've seen numbers as high as probably 50% re-dose rates. So we're, again, we were trying to sort of enable patients to treat the disease in the way that they think is warranted, and so we put that in the protocol. Now, at the end of the day, what happened is, you know, actually, the poster that the KOL presented, where they talked about this, he was asked this very question, and his answer was, "Why'd they take a second dose? Because they could." Like, it was because it was the protocol. And so we did...
As part of the data release, you were very, you know, well to point out, they, we did point out the fact that patients took, you know, about 40% of patients took a second dose in the study. We honestly didn't think that much of it. That was probably our fault, but it did raise this question of, you know, is there an efficacy issue that you have to sort of solve for? And so we went back and re-looked at the data, and well, and we sort of talked later, and we said, "Well, actually, pretty much everybody got to the primary endpoint with one dose." So it wasn't really an efficacy thing. What it really more was the fact that the protocol allowed it, and it was a patient behavior thing. Since then, we've generated this open label data.
We've now treated more HAE attacks in a clinical setting than anybody ever has before. We've treated upwards of 1,600 attacks in the open label now, and what's been very interesting is we've monitored things like that, and actually, the re-dose rate in the open label is down right around 25%, which is actually the low end of those Firazyr numbers I talked about.
Mm-hmm.
You know, the use of conventional therapy, which was, I don't know, maybe 10% in the Phase III trial, is down around 5% in the open label, which is about what you see in the real world. You know, A, I don't think it was that much of an issue to begin with. Like, I think it just. I think we just didn't, maybe we didn't present it as well as we could have. B, you know, certainly to the extent that it was something people were paying attention to, the open label has really shown that everything about sebetralstat trials, that is just trending to what you see in the space generally, which really goes more to patient behavior than the drug itself.
I can see it. I mean, you know, if your throat's closing or you're starting to swell-
Well-
You want to see it come down, you know?
Or even you're going to work, right? And you think to yourself: Oh, you know, I took it, I feel good, but I want to make sure I continue to feel good. I'll take a second dose. I mean, that's. This is why when we ask people in the real world why they take a second dose, that's the kind of answer you get. "I've got to go to the store. I've got to go to work. I, you know, whatever. I just want to confirm that I'm feeling better." And so it's a lot of times that, as opposed to the drug itself.
Yeah. And I think, you know, actually, I won't get into that one, but anyways, you know, the treatment guidelines for HAE, you know, it says, attack as early, not attack, treat as-
Yep
... early and, as early as possible.
Yep.
You know, and so I guess, you know, you do see significant delays, you know, in treatment-
Mm.
- with standard of care. Just, you know, talk about that delay,
Yeah
... the reasons behind it, and again, the Phase III data and the interim OLE data, you know, that you presented at...
Yeah
... EAACI.
Yeah, yep.
That suggest, you know, Sebi can actually-
Yeah
... shift that behavior.
Yeah. So, again, everything in the on-demand space nowadays is either injected or infused, and the leading drug in the space is branded name, Firazyr. It went generic a few years ago. It's branded generic name is icatibant. It's probably, I don't know, what, three-quarters of the marketplace, you know, in total. Patients, and this isn't really our data. There's been a number of studies that have shown this. It's well known that when people are having attacks, they delay, in many cases, for several hours before they treat, and despite the fact they know they're having an attack, and there's a lot of reasons for that. It's kind of a matrix thing.
One issue is that Firazyr or Kalbitor is actually very painful to inject. It's very acidic, and so it certainly. They call it - I mean, sometimes it's kind of morbidly called Firazyr 'cause it hurts when it, as it disseminates. It also causes effectively, at a 100% rate, injection site reaction.
Yeah.
It actually yields this mast cell inflammatory response, and so patients get a pretty substantive welt when they inject themselves almost always, that can last for several hours, and so it hurts. Abdominal attacks are quite common, and so it's also... Imagine you're having an abdominal attack, and you're having to inject abdominally you know this medication. People pause because of that. People also pause because it's really awkward to carry. I mean, it's a pre-filled syringe. It's pretty big, and even if it's disassembled, which it commonly comes as, it's still a pretty good sized box. You kinda you know it's hard to carry in your pocket. You can't really leave it in your car.
I mean, it's not supposed to be sort of sitting at high temperatures and the stuff for a long time, so it's an awkward thing to carry, and again, the injection process by itself is non-trivial, and so people don't want to treat themselves, whatever, here, you know, in the office, at work, whatever, at a party, so commonly, they'll go home. The end result of all this is, and multiple surveys have shown, people unambiguously know they should treat early, but on average, they wait something like three hours or more on average to treat. In our open label study, adolescents using, and adolescents actually don't have access to Firazyr. Adolescents only have access to IV infused therapies currently, and on average, adolescents are waiting closer to eight hours before they treat.
So there's these enormous treatment delays, despite the fact you know that early treatment really matters. That leads to unnecessary suffering, right? Because attacks do generally escalate if they're untreated for, you know, for a period of time. And so it's just, and at the end of the day, you know, maybe a third to a half of attacks aren't treated at all. I mean, you do see that treatment rates vary between about 50% and 65% in the world generally. So by comparison, sebetralstat just utterly changes all of that, and we've seen this data in the open label. In our open label study, patients are treating on average within nine minutes of attack onset. Adolescents are treating on average within three minutes of attack onset.
So, these people know they're having attacks at, you know, they can tell when they're coming 'cause it's obviously a disease you have your whole life, and you're familiar with it. So they're, they unquestionably know when an attack is commencing. Now, they're able to treat it as soon as they could, and also, they're able to treat at a much higher rate of attacks. So I told you, in the real world, maybe at the high end, maybe 65% of attacks are treated. Right now in our open label study, they're treating north of 85% of attacks. And again, maybe that doesn't play through in the real world. You know, maybe it goes down to something less than that. But they unquestionably, though, they're not treating enough attacks, and they will treat more in the presence of sebetralstat.
Yeah. Firazyr, I've heard of, but bee sting is what the KOLs that I've spoken to.
I've heard more than that.
All right.
Yeah.
All right, so, you know, you did have a whole bunch of presentations at EAACI. You know, any of them that you wanna highlight?
We have put out a phenomenal... I mean, again and full credit to our medical department here for this. We've put out a phenomenal amount of data cuts on the sebetralstat development program. I mean, we've, in addition to running the biggest and the broadest and most inclusive trial ever, we certainly run the most transparent trial ever. I mean, the phase II results were published in The Lancet. The phase III results were published in The New England Journal. We did at EAACI. We had six posters. I think at AAAAI, we had something like ten posters. You know, we were just in Berlin a couple weeks ago at a different conference. We had another six posters. So the data is just, you know, at a tremendously high rate.
You know, I think, and so I think it's really hard for me to pick out any single data set that I think would be important. But I, you know, but everything we do, I think, just continues to point to the again, and you know, I can touch on so many different levels. Just the high unmet need, the fact that, again, not enough attacks are treated, and they're treated until it continues to show. The quality of life that people endure as a result of this is really impacted substantially. There'd been this commonly held myth in the space before we did our phase III, that patients on long-term prophylaxis actually had much milder attacks on average, and so they didn't require treatment generally. That was kind of this been this common refrain.
What we show in our study is actually that they have attacks that look exactly like patients on on-demand. I mean, the severity, you know, distribution is about the same, and also the impact on their quality of life is about the same. I mean, if you're a prophylaxis person, and you're having one attack on an infrequent basis, you still have the sort of challenges that are associated with that in terms of just thinking about your disease and having it feel like it's something that's omnipresent in your life.
Mm-hmm.
You know, the idea here is obviously now that that can all recede, 'cause you'll have this tablet in your pocket, your backpack, whatever, and when you feel the attack coming on, you'll take it, you'll go about your day, and you know, and overall, the impact on your overall well-being is gonna be much less. So we've highlighted those kind of topics. We've covered long, you know, we've shown all this data with regard to long-term prophylaxis patients, you know, compared to on-demand users. We've shown adolescent data, we've shown European data. I mean, the data set is. I mean, to call it rich would be, you know, is to underplay, I think, how much we've actually put out there.
Okay. All right. We're gonna pause here for a second with Sebi and ask you about a competitor program. They recently, you know, had data at the Bradykinin Symposium.
Mm.
Just want your perspective on that data.
Yeah, yeah. Yeah, there was these other folks that put out a press release, actually, right? A couple weeks ago, and a couple posters they presented this Berlin symposium I mentioned. I think it got some attention, some quarters. I think some of your competitors probably got a little enthusiastic. I think our summary is it's. There's much less to it than it appears, I guess would be the summary. The clinical development program that those folks are doing is sort of the old school clinical development program.
It's kinda, you know, Firazyr was approved in two thousand and eleven or something, and their model is sort of what that model was, which was you basically don't treat all attacks, and you don't treat them early. What you actually do is you treat a subset of attacks because you require them to wait until the attack reaches a certain level of severity. And so I think they've been very open about the fact that there's, they're not doing what we do, which is what the guidelines say, is they're not encouraging patients to treat all attacks and not encouraging them to treat them immediately. They're, and for the clinical trial purposes, they're sort of waiting till they get to this level, because what that does is kind of maximize your apparent treatment effect.
Yeah.
And so I think, and there's probably a lot of other things, but I think to summarize it would be it's just a very different clinical trial program that is serving a different purpose than I think ours. You know, I just wanna come back to what we are, which is, again, we've run the largest, the broadest, the most inclusive, you know, clinical trial ever in this space. We've treated every kind of attack you can see. Paradoxically, sometimes mild attacks are actually harder to show clinical benefit in than severe attacks, right? If you're really, really, really severe attack, you know when you've kind of peaked. It can be harder for folks who are having a mild attack to do that.
But the problem is, mild attacks can really still be debilitating.
Yeah.
I mean, you know, if your hand is a little swollen, and you can't turn the doorknob, you know, that's-
Yeah
... that's a problem, actually, and so, you know, what we're really doing is, our trial was designed to work, to show it, demonstrate this, that this drug works in everybody, and also to demonstrate that, you know, we sort of can make patients' lives better in a very real way, as opposed to just trying to show a, you know, effectively a clinical trial-based result.
Yeah, and I believe them, when they move forward, it's gonna sort of be a mirror, a little bit, of your Phase III?
Well, no. I mean, they have to use the same endpoint we did in their Phase III, 'cause the FDA made them. But other than that, the Phase III trial is actually the same as their Phase II. This whole not treating every attack and having it reach some minimum severity threshold is actually how it works.
Okay.
And so at the end of the day, again, I don't like—you know, I like to focus on us more so, but-
Yeah.
At the end of the day, I would say that what they're gonna show is that, assuming it works, assuming they have positive data, they're gonna show that they've had efficacy in essentially a kind of subset of attacks.
Mm-hmm.
Whereas we've shown that we have efficacy in every kind of attack.
Okay. Really quickly on these ones, so we can get to the market, you know,
Yes
... potential language in a label, how many doses?
I wanna keep a few things under, in our pocket.
All right.
But you know, Firazyr label is, you know, which is probably instructive in terms of how we think this works. Firazyr is labeled as up to three doses in a 24-hour period.
Mm-hmm.
So I think at the end of the day, what our label will look like is, you know, some number of doses in some time period, probably somewhat comparable to where they are.
Okay. Why not file for both doses, 300 and 600?
We thought about it. I think at the end of the day, it just ends up that the curves essentially overlaid each other. And generally, I think the question we actually had to ask ourselves was, what's the incremental benefit of having a six hundred as opposed to a three hundred?
Mm-hmm.
You know, having both, and we couldn't really identify, you know, a need to have both doses. Patients in the study showed that effectively, everybody can get to the primary endpoint with a single dose of 300. They'll always have the option to redose again, as they do nowadays. And so we, we felt like that was, that's probably a better solution. 'Cause again, a lot of this is you have to, you have to trust that patients know what their disease is and how to treat it. And so there may well be, at the end of the day, some attacks where patients need to take two doses, right? You have a really severe, you know, you feel a really severe abdominal attack coming on, so you wanna be sure. You have a laryngeal attack, maybe. I don't know.
There could be-
Yeah
...that, but there's no reason then to not let people who've lived with this disease their whole lives decide that, as opposed to us just kind of putting this dose on them.
Okay, so moving on-
Yeah
... market research.
Yeah.
What do you believe the market size is for the on-demand HAE space?
If you look at the script data nowadays, and we, you know, we put this out there. There's something over 120,000 scripts a year for on-demand medications. There's always these assertions that the market's been shrinking, but the truth is, that number has been essentially flat for the last five years at least. In fact, it's actually gone up a little bit in the last five years. Which is kinda counterintuitive, 'cause again, everything here says that prophylaxis has taken over the world. But the truth is, the reason it's very stable is because you've got two segments in the market that are very stable in their demand for on-demand therapy.
You've got people who are inherently satisfied with on-demand, for whatever reason, and they're gonna be even more satisfied in the presence of sebetralstat, and then you've got the other end of the spectrum. You've got folks who are on prophylaxis, but who still have a very high rate of breakthrough attacks, and we've actually shown that there's a population that actually has so many attacks that the average number of on-demand attacks in the prophylaxis space is actually higher than the on-demand space, so those people, despite being on prophylaxis, still have a need for a lot of on-demand therapy.
And what's interesting is, despite the fact that there's now four therapies approved, there are one more coming soon and six more behind that, by my count, the fact is, none of those actually meaningfully move the efficacy up any, to any degree. Everybody's in sort of this, in a clinical trial setting, in this kind of 85%, maybe 90%, you know, number. And so these people who are on therapy but still have breakthrough attacks, I think they're essentially gonna have breakthrough attacks no matter what therapy they're using.
Yeah.
That's why the market has stayed where it is, because these two populations are very stable, and nothing's going to disrupt those two populations. The punchline there is, in the dollar size, the market shrank the last five years, but that's purely because the Kalbitor went generic. If you put in a Kalbitor price on that, all those scripts, it would, you know, it's a number meaningfully north of $1 billion in market size even now. Our view is that the opportunity here is for us to capture a large share of that marketplace. I think patients will also treat more attacks, as they should, in an appropriate manner, and that grows. I do believe that actually, again, maybe counterintuitively, there's...
Prophylaxis has been really easy by and large, for people to get on in the last few years, 'cause it's kind of the least worst option. Takhzyro twice a month is generally dominant in terms of its combination of efficacy and treatment burden. We change that whole concept fundamentally. Sebetralstat can now become the foundational therapy in the HAE space, where you go in and talk to your doctor about treating your HAE, and actually the conversation, which now goes directly to Takhzyro on, as prophylaxis, can actually go to, "Why don't we try this on-demand therapy? Use it when you have attacks, take it early, it seems, you know, and then see how you're doing." And then, so the point is, you can actually...
You know, it's not clear to me is that, that prophylaxis sort of discussion, it continues inexorably to sort of go in the same direction. I think you can really change, again, at a very fundamental level, how you have these doctor-patient discussions. And a number of these folks on prophylaxis who went on because it offered the best option at the time, or at least worst probably option at the time, may now think this is actually an even better, less burdensome way to treat their disease.
Okay, you talked about the patient, you talked about the physician, treating physician. How about payers? Has there been a shift in terms of how the payers view prophylactic treatments?
Yeah, it's interesting. So we've started to have some payer interactions and which are, you know, kind of an early stage, right? You started having these, you know, pre-approval information exchanges, and so we've been. But we've been having conversations for the last several years. The data's powerful. I mean, again, we've shown again, because of the breadth and the scope of the trial, as I said, you walk in with data, and it's really it's uniformly effective and beneficial for patients. So that's a pretty easy conversation to have. What's actually been most interesting so far is this is not an area that payers pay an enormous amount of attention to.
I mean, the therapies are high-priced, but the population's really small, and in a total dollar share of their area of concern, it's really small.
Mm-hmm.
But what's been interesting so far is. What really happens is we go in and meet with the payers and sit down to talk, and of course, as part of this, they pull out their costs for HA therapy. And what really jumps out is they say, "Boy, we're paying a lot of money for prophylaxis right now," and on top of that, a lot of these folks are still using a lot of on-demand medications. So I think what's been interesting is, as opposed to having any challenges for us in terms of access or pricing, what we've really highlighted for them is there's a lot of spend in prophylaxis that they probably weren't as attentive to as in the past.
Okay. We got two minutes left. In terms of commercial preparedness, you know, what's the groundwork-
Yeah
... that you've been laying for the launch?
Yeah, yeah. I mean, the plan for sebetralstat is this really deserves to be a global product, and so we're a company of our size can actually do this and actually launch it globally. We intend to maintain strategic control of this product. We think it's the kind of thing that deserves our attention and focus on, so we're gonna manage this ourselves. We're obviously gonna launch it ourselves in the US. The sales force is really tight there. It's you know, maybe low thirties sales folks, just to give you a sense of what you need to really cover the market well so it's a very small number.
Mm-hmm.
We also plan to launch ourselves in Europe and Japan. We've built smaller teams in both those geographies, and then to global... For the rest of the global reach, we'll do what everybody else does. Typically, that's a lot of distributor-type arrangements and such, but-
Mm
... we've had an enormous amount of interest already. I mean, there's a couple dozen folks in different geographies that have reached out to us, looking to talk about launching in whatever, with Gulf States or, you know-
Yeah
... the South America or Eastern Europe, whatever, a lot of places. We've got a really experienced team. I mean, just to hit on this, you know, each of our Chief Commercial Officer, U.S. Head of Sales and Marketing, Head of Europe, and GM Japan have all launched multiple products in the HA space before. So we've got a really deep bench here of skill set in the area. We know how to commercialize these assets properly and I think within a few years after launch, we can have this in 10 or more countries.
All right. Actually, second to last question. Cash flow positive, how are you gonna accomplish that?
Again, the great thing about this product from our perspective, you know, besides the benefit to patients in the system generally, is that it's not a terribly expensive sales and marketing effort. I just told you, the numbers are really small in terms of the commercial infrastructure. We don't have a lot of other late-stage spend, where that's coming through the system. We have the major clinical trials that have been related to sebetralstat that are all winding down in terms of expense. So the point here is like the cash spend of the company is really focused on the launch, and as I said a minute ago, it's really not a terribly expensive launch in the scheme of things.
Given the scale and scope of the market opportunity, we do think that, you know, we'd expect this to have a fairly positive reception. As a result of just keeping our cost structure lean, which we've always been really attentive to, and generating revenues, ideally globally in the short term, we think that's what drives cash flow positivity.
All right. So last question: if we're sitting here twelve months from now, what would you like to say your key, value-creating accomplishments have been?
In a year, I'd like to be able to tell you that we've launched in the U.S. and effectively, immediately after approval, which remains the goal. I think we'll be very close to, if not launching in Europe. I think we'll be making plans to make several other launches, potentially late next year or in early 2026. So the truth is, I think what we're doing is saying, "A year ago, I sat here and told you how we had this, what we think is a terrific drug with a great efficacy and safety profile, and now we're actually achieving that by bringing this out and getting it to the patients, and you know, around the world who actually will meaningfully benefit from this.
All right. Ben, I thank you, KalVista, for attending the Cantor Global Healthcare Conference.