Let's do it. We don't have to hot mic that story.
Yeah, exactly.
Great. Thanks very much, everybody. It's my pleasure to be here with Ben Palleiko, CEO of KalVista Pharmaceuticals. I'm going to have Ben kick it off and give a quick update on the company and the regulatory review of sebetralstat and then we can do Q&A. So thanks so much.
Thank you, Paul. Yeah, thanks for inviting us here today for one of many times we've been here. Grateful to Steve for everything you've done for us over the years. KalVista Pharmaceuticals is a pre-commercial company nowadays we describe ourselves at. We are developing a drug currently called sebetralstat , which has been filed with the FDA and a number of other regulatory authorities for approval as an on-demand therapy for treatment of hereditary angioedema attacks. For those who don't know, HAE, it's a genetically derived disease. It's very rare. It's right around one in 50,000 is the incidence rate around the world. It's caused by lack or dysfunction of a gene that produces what's called C1-inhibitor, and that leads to these episodes of swelling that can be quite severe, and that can occur effectively any place in the body.
Most commonly, it's found in the abdomen, but peripheral attacks occur frequently and a relatively low rate of laryngeal attacks as well, which are the ones you worry about the most because they can obviously lead to asphyxiation. In June of this year, we filed our PDUFA, I mean, we filed our NDA with the FDA with a PDUFA date of next June 17, 2025. We've also filed in five other territories to date, which I think is pretty remarkable for a biotech company. We've got filings in place with the EU, with the UK, and then through what's called the Access Consortium, we've also filed in Singapore, Australia, and Switzerland, and we're currently working on the filing to make in Japan, ideally at the end of this year, and if you want me to keep going about the market opportunity, the market size.
Please.
Yeah. HAE typically is divided nowadays into prophylaxis and on-demand therapies. In the U.S., about two-thirds of people use a combination of prophylaxis plus on-demand. About the other third just are on-demand only. There's a lot of therapies under development generally across the space, but more so in prophylaxis. There's four approved and another six under development. We are, however, far and away the leader in on-demand and in the on-demand space. There are several therapies that have been approved there. There's three major ones. We'll, however, be the first oral therapy. And the key to sebetralstat really is its injectable-like efficacy in a tablet. The data set we've generated through the clinical trials, and we've run the largest clinical development program ever in HAE, shows that we have onset of initial symptom relief comparable to the injectable therapies.
Patients just do better on this, and the safety profile to date has been pristine. And again, at this point, we've treated something over 2,000 attacks. So we're pretty confident about the product. We think it has a lot of value to add to the HAE patient experience, and we're eager to launch it next year.
Any surprises in the regulatory view so far?
No, it's been very low impact. When you file with the FDA, you're going back and forth with them constantly. So probably every week, there's some level of interaction. But I guess to date, I would describe it as administrative, really. It's really been nothing of any substantive note. We filed a 120-day safety update with them last month. The mid-cycle review is this month. They've already said that there's not going to be an AdCom. We don't expect any REMS or anything like that. So the truth is, I think where it probably starts to get a little more engaged is once you get the labeling, but that's kind of normal course, and that really won't happen until next year.
Any nuances with the labeling here that we should be thinking about, either as it relates to how the use of this drug is framed or redosing or certain directives that could kind of swing the ease and attractiveness of utilization?
I think the most useful label is actually the one for Firazyr, which is the most comparable. And so that drug is basically treat, and then you have the option to retreat. You can do three doses of Firazyr within a 24-hour period. And so as a result, it's actually dispensed in three packs. Again, given the safety profile, we don't think there's really any safety-related concerns that would go to questions of redosing timeframe or max daily dosing even, because again, we've really shown a very large window here. So there'll be back and forth, right? And I'm sure there'll be some discussion about how many doses or how many times per day or that kind of thing. But I don't think I'd describe any of that as a dramatic concern for us.
Yeah, and remind us, so you're not concerned that there's going to be a cap on the number of doses, right? You've generated safety data now for some patients taking it up to even like five times in 24 hours, or maybe talk about that?
Yeah, I mean, we've dosed at very high levels. Everything has some upper limit on how many doses per day, right?
So I mean.
Like a no cap, but like.
Like a reasonable cap. But I generally don't know what that will be. Like I said, Firazyr is three times a day. Could you be somewhere in that vicinity? That wouldn't surprise me a bit, but we don't view that as anything other than just kind of a standard label.
Yeah, right. Okay, so maybe taking a step back, this is a population that has a lot of options.
Yeah.
How would you characterize the potential early adopters of your drug?
Yeah. There's two main groups we think will have the highest demand. And actually, the most high-demand group is actually probably somewhat counterintuitive. The people that actually we think have the greatest need for this and will be most interested are actually prophylaxis users who aren't very well controlled. And it turns out there's a fairly high number of them, and they actually can have a very high attack rate. And so these are people who are on prophylaxis, but for whatever reason, they're just not getting the efficacy. And so you can find these people actually using very high volumes of on-demand on top of their prophylaxis. So the truth is, that's probably the group that's going to be most attracted because right now they're giving themselves a lot of injections or they're suffering highly despite the fact they're using a prophylaxis therapy.
And they're such a big volume user that actually their overall average attack rate is actually higher than in the on-demand-only population. So we think they'll come early and they'll come sort of as volume users. And then the next group is obviously the people who are only on-demand. We think this is a very straightforward switch for them as well. And then the third group is this kind of group in the middle who are on prophylaxis who are pretty well controlled. The truth is, with them, in the long term, I think the question for them is, is their disease severity such that an on-demand-only option might be more appealing to them than prophylaxis at all? And so we think we get to all these segments, but ordinarily, it starts with the Prophy people, then the on-demand, and then the well-controlled prophylaxis.
These patients who are on Prophy but not well-controlled, I think you and I have talked about how when you're someone who follows clinical trials in this space, the existence of these patients is not obvious. Because the clinical trial data for prophy, you're talking 85% median attack reduction. Can you just who are these patients? Where are they? Maybe it sounds silly, but how do we know that they exist?
Yeah, well, we believe they exist from the claims data, and so that's how, again, we have this whole BI team that just sort of lives to dig through all these data sets, and so we find them through the claims data we pull, and that's how you sort of get these numbers. Why are they not in clinical trials? I think to a large extent, because they're dealing with enough challenges as is, and I think if you're dealing with a lot of challenges anyway, the notion of sort of getting yourself in a clinical trial situation where you could be on placebo even is probably very unappealing, so my guess is there's some kind of self-selection criteria that comes into play here, well, I guess that's kind of the angle of why you don't see them in the trials.
The other point I was going to make, though, is the other thing you had to realize is when you talk about these 85%, 90% attack rate reductions, don't forget that that's in a clinical trial setting. In the real world, oral therapies, people miss doses. It's a well-known phenomenon if you talk to docs that patients stretch out their injectables, right? So people are supposed to get every two weeks or every three weeks, right? Some of these drugs really fall off fairly precipitously if you extend the dosing schedule out. And so that's why these clinical trial data sets, I don't think in prophylaxis, really compare particularly well to what you see in the real world and why the attack rates you see in the real world are probably higher than you see in these trials.
Yeah. Okay. So how would you maybe just take a step back, size the market right now and what it looks like today in on-demand on a volume and a dollar basis? And what would it look like today if it was all at branded pricing?
Yeah, that's a good question. The on-demand market today, total dollar size is right around $900 million, and that's among basically five products if you include the generic icatibants. As a comparison, in 2018, before it went generic, branded Firazyr alone was an $800 million product. So you can get a sense of where a product size could be in the branded space. And then obviously, the pricing came down a lot in 2019. So that's kind of a modest size market. But what's interesting is when you dive into the actual script data, though, on a units basis, we see right around 120,000, 125,000 units a year being sold in the on-demand space. And that number is shockingly consistent since we've gone back as far as 2018. And the numbers have actually gone up a little bit since then, but certainly worst case, you could argue they're flat.
So the reason the dollar size is so much lower is not because the volumes have come down. It's because the pricing in generics is maybe a third of the branded, and the generics have maybe a third to half of the overall market nowadays. And so converting those folks back over to branded therapies is actually where the dollars are going to come from. So if you took that 125, whatever, call it 120,000 scripts a year, and you put a Firazyr WAC on it, which is right around $11,000 a dose, that alone is a $1.3-something billion marketplace just today. And that's with current usage patterns, current everything.
If you start to lay on top of that the fact that we think people will treat more attacks, right, the fact that some of these folks on prophy who maybe don't use a lot of on-demand might think this is an alternative, that's where the growth opportunity comes on top of that number.
Yeah. Okay. That's interesting. Do you think that to get access, patients will have to step through generic Firazyr? And what might that look like if so?
Yeah. When you talk to payers, initially, some of them will say, "Oh, steps." And it sounds kind of conceptually interesting, but then when they try to go through the process of how you'd actually step them through, it gets tricky quickly because you're talking about a different mechanism. It's obviously injectable. The notion of stepping folks through generic icatibant is pragmatically very challenged because nowadays, they're either on branded Firazyr or they're on one of the IV therapies. And so moving them through generic icatibant to go from whatever, Ruconest or Berinert or something, there's no straightforward pathway to that. So I think the pragmatics get in the way of a step when you talk to payers. The other thing is, obviously, arithmetically.
Is that actual feedback you've received from payers?
Yes. Yeah. Yeah. People don't universally mention steps. In fact, I think I would describe it as a fairly low rate of mention among payers we've talked to.
What do they usually mention?
New to market blocks, medical exception. That's actually the way they manage all these therapies nowadays.
All of them.
Everything. Everything in HAE gets managed through prior auths and medical exceptions, honestly. And so steps aren't really much of a feature. And again, the other point I was going to make is, obviously, since so many people are already on generic icatibant, stepping them through it's going to sort of be the standard case anyway.
Right. Yeah. Okay. That makes sense. So what are you doing right now, this week, this month, to prepare for the launch?
Oh, boy, so this month, the medical team is out and about doing. The MSL team has been out meeting with physicians around the country, actually even around the world, and obviously, our Pubs team is preparing all the posters and submissions for all the conferences we have coming up in the wintertime. On the commercial side, we've now built out the team all the way down to the sort of field manager level. We're actually gearing up to put out offer letters to the field force and the payer access managers who will come and join us in Q1, so that's the last bolus of folks to come on board. In the meantime, we've got a bunch of what we call thought leader liaisons who are out actually dealing with the high prescriber universe. There's about 200 docs who write 50% of the prescriptions in the whole space.
Our TLLs, we'll see every single one of them, and in many cases, they'll see them multiple times before we get into the new year. And so as the sales team comes on board and they start to get out in their territories, sebetralstat will be well known. These physicians will all have been touched. There's 2,000 docs who have ever written a prescription in this space. There's about 900 of them who write 90% of the scripts. All of those folks will have been met with multiple times before we get to the approval. So there's a lot of things cooking along under the surface here on the commercial and medical side right now.
Yeah. Okay. Do you expect a bolus, like a bolus of patients who are waiting? Is that like a weird term?
No, not at all. No. It goes to the question of what's the uptake curve going to go like, which people have started to ask.
It's interesting because in rare disease lately, I think we've actually seen more launches that have had a bolus and then an air pocket than the alternative.
Totally.
Well, and I can see that, right? Because what happens is you get these: will there be patient-driven demand for sebetralstat when it gets approved? We think yes, it'll be substantial. But the way you get started with all these folks, and this comes to your air pocket question, is you do these quick start forms, you get them some number of doses out there, and then you're kind of working through the payers, right? So that's where your air pocket hits in. I think we'd be pleased if we just had kind of a steady uptake curve that just ended up being steeper than I think people generally expect.
But no, I wouldn't be surprised if what you said happens, if there's a lot of folks who come in the door early who want to try sebetralstat, and then you start working through your next step.
So when you say that everything in this category is managed via medical exception, does that essentially mean that when you launch, you'll already, in a sense, be at payer parity with the other drugs? Because this will be medical exception, but everything else is, it's not like we have to wait nine months for this to become as easy to prescribe as everything else. Is that fair?
Yeah, I think that's probably a pretty accurate statement.
Yeah. I mean, even generic Firazyr is managed that way?
No. Generics obviously always get their own kind of level of management. But I think the point is, from a payer standpoint, we'll be working through the final reimbursement and all process with them. They will have, in general, ME set up for this drug in this category. But now, I think the only caveat I'd make to that is obviously these folks are already going to be on existing prescriptions, and so the ME is not going to be obviously in effect for those people, right, those drugs. And I should also point out, you know this, the last drug approved in HAE was 10 years ago. So it's been a long time on the on-demand space. So it's been a long time since they've had some other alternative here that they actually had to think about.
Yep. Yep. Okay. Okay. Makes sense. You want to talk a little bit about just sales reps, like the level of investment that you're going to get to, what that might look like over time?
Yeah, sure. This is a space that's made for a biotech company to commercialize. It's a small molecule, so obviously, you've got COGS and things of that sort. But again, coming back to it, you've got plus or minus 7,000 people with HAE in the United States, right, kind of on the one in 50,000 basis. I told you before, you've got 2,000 docs who've ever written a script, and you've got less than half of those folks write almost all the scripts. So it's a really tight universe, and like I said before, half the scripts are written by 200 physicians. That, when you size up the field sales team, that gets you somewhere into the low to mid-30s, which is right where we'll be.
That's pretty much where I mean, some of the folks, some of the bigger companies may go a little bigger, but there's not a lot of payoff to that. You're just compressing territories. We're going to have a very robust footprint with that number of people, and then ancillary to that, you've got these payer access managers who are the folks who do the interface between the physicians and the payers. We'll have a pretty robust number of them on board as well, but my point is that whole group all in is something like 50 people, so you can put whatever number you want on that, but I think the point is the OpEx of the commercial operation is very, very well controlled in this space in comparison to a lot of other spaces where you're calling a vastly larger universe of physicians.
Yeah. Okay. Makes sense. Have you thought about what metrics you might share with the street to help us judge how the launch is going beyond just revenues, of course?
Yeah, right. I will also say we're working through that at this time. I mean, the first thing is for us to get our own set of metrics that we have every team in the department in the commercial side is going to have KPIs that we're going to.
Is it fair to say you're going to know a lot of granular detail about how this drug is being used?
We certainly will.
Especially pharmacy distributed, it's a high-touch model. Is that fair?
Yes. Yes. We have all, like I said, all the groups within the commercial team have a large number of KPIs as they're starting to frame out. We then need to get those together and honestly work through the question of what is going to be most valuable to the street in terms of us putting out data that's useful and accurate and obviously not confounding in terms of giving the wrong impression of how the launch is going. I will also say we're not there yet. We're looking at what other people have done in the space. It's a little tricky to just comp to the prophylaxis. Obviously, the most recent launch in HAE was Orladeyo. They had a set of KPIs they did. It's not completely clear that that's the exact comparable set we're going to want to use.
What did they use?
[inaudible] approach it differently.
I don't even know if I could list it off the top of my head. There's a series of datasets, but I just don't remember them all well enough to at least talk about it here, but we're sifting through that, and our plan has always been that early next year is the appropriate time for us to start to come out and talk about those things. So I think what you'll expect to see from us in the whatever in the first quarter would be starting to frame out how we think the launch should go and exactly what metrics we think we expect to provide to people to help them understand how the launch is going.
Yeah. Okay. How should we think out three to four years in this category and what it might look like, right? I mean, I feel like the two sort of commercial barricades in this space are that there's a lot of options, Prophy drugs have become better, but then also that the bar is just going to continue to be raised by longer-acting Prophy and other oral coming into the market. What's your confidence level in the durability of the opportunity you're trying to see?
Yeah. Well, prophylaxis is obviously becoming an incredibly competitive space. I mean, you've got four therapies approved, you've got six more coming. You'll have two of those launches mid-next year when garadacimab, assuming they work through that CRL, they'll launch in mid-year, and then you're going to have donidalorsen coming right on top of it. And then beyond that, you've got a series of other potential prophylaxis coming over the next couple, three years. So prophylaxis is going to go from four approved therapies to maybe as many as 10 approved therapies in the next three to four years. That's a lot of options for a total 7,000-person universe. But what's interesting about these therapies, and I know everyone gets all excited about these attack rate reduction numbers, is actually, if you put them side by side, they don't look all that different from an efficacy standpoint.
I mean, they all claim they're sort of whatever, 85%-90% or something attack rate reduction in a clinical trial setting, but they're all kind of there. And by the way, the existing therapies all claim that they're kind of 85%-90% attack rate reduction in the clinical trial setting. So what you're actually not seeing, setting aside gene therapy, which is a whole different bag, you're really not seeing any sort of incredible step function shift here in efficacy and reduction of attacks. And that's probably driven by a bunch of things, right? Pharmacodynamics are kind of what they are. And then in the real world, again, people miss doses, people stretch out their injections, right? You've got these kind of real-world parameters that bring your efficacy lower.
So my point is, to me, when I look at the prophylaxis space, what I see is a market that's going to get chopped up into probably increasingly smaller pieces driven entirely by dosing schedules, right? I'm a chicken, I want every six months, right? You're happy with once every two-week Takhzyro, right? It's going to be kind of people moving along based upon what their dosing regimen comfort level is. Monthly, two-monthly, three to six-monthly, daily orals, that's what's going to happen. And none of these therapies are going to dominate. My point to you is, let's bring that back to the world I care about, which is on-demand. None of those things are going to change the on-demand equation, right? None of these therapies make the need for on-demand go away. None of them are fundamentally shifting it.
Probably none of them are actually so compelling as to cause people to shift to prophylaxis in the presence of sebetralstat, which is an oral therapy, because they were happy on on-demand only before, and they're even going to be happier when sebetralstat's there. So prophylaxis looks to me to be becoming ultra-competitive. And I don't know where that goes, but I don't know if it goes anywhere good. I think in our world, though, we'll be the first oral therapy ever launched. Again, it's injectable-like efficacy in a tablet. Our nearest potential competitor is several years behind us with data that isn't going to look any materially different or better. And so I think we feel like we're in probably the strongest position of anybody.
Yeah. Yeah. Makes sense. So maybe taking a step back, what is your long-term vision for KalVista? And saying what's the end game is kind of like a loaded question, but I think in biotech, right, you launch a drug, people want to see, okay, what's next in the pipeline? What's your ultimate plan here, assuming that this early launch is as successful as you hope it will be?
Yeah. Yeah. For the next 18 months, all that matters really is sebetralstat, right? I mean, that launch has to be prepared for well and executed well and show success early and consistently. We are laser-focused on that. We think this is a good drug. We are laser-focused on giving it the launch it deserves. And so that's going to drive, from an investor perspective, that's going to drive, I think, everything anyway. And behind that, so behind that, really, no one really wants to talk about anything else that's going on, and they'd probably view it as a distraction. Behind that, we do have some internal programs we continue to work on. We have the Factor XII space that we've always liked. We had to do a reset on it this year because it wasn't making the kind of progress we wanted.
We've kind of disclosed that publicly. We've dialed it back. But that continues to go on a low flame, and if we get to the point where that becomes interesting, I think that's something we think there's really interesting indications there as long as we make progress. There's some other options in the internal pipeline as well. Beyond that, we've shown now that we have a really good ability to execute clinical trials in the rare orphan space. Again, the fact that we've made six NDA filings already this year, I think, shows that from a regulatory standpoint, we can actually do this globally in a very efficient basis, and we're building a commercial capacity globally as well. That's going to position us, I think, as a really interesting player as a very effective rare orphan disease company.
And so going forward, I think that's where, to the extent we look to make investments and pursue other opportunities for growth in a smart way, that's where we'd kind of zero in on us putting those capacities to use.
Awesome. Any questions from the audience? All right. Thank you, Ben. Appreciate it.
Always nice seeing you.
Thanks again.