KalVista Pharmaceuticals, Inc. (KALV) Earnings Call Transcript & Summary

Everyone, welcome to this fireside chat with KalVista Pharmaceuticals. I'm Joe Schwartz from biotech research team at SVB Leerink. It's my pleasure to be hosting Andy Crockett, CEO; Ben Palleiko, 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. So 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. So yes, we're just 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 we -- Joe, as you know, we have 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. and interaction with -- in our interactions with FDA, we're able to agree to essentially that plan. So we're looking forward to that study kicking off here very soon. For KVD824, our program for prophylaxis. 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. And so 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 if 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. So I think it's always been understood that our 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 discovery and oral, potent and selective Factor XIIa inhibitors and moving that program forward this year in IND-enabling studies and then eventually towards an IND. So 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. And can you give us some more insight into the endpoints? Is the hierarchy the same as Phase II? It seems like it's been tweaked a little bit, but basically everything. So that's probably not an issue. Can you just give us any insight into how that works and maybe the rationale for why you selected and the FDA selected what you did?

Sure. Chris, do you want to take that one?

Yes, sure. Yes, sure, Joe. I think as you say, the endpoints are broadly speaking, the same as we mentioned in the Phase II, although because as you intimated, yes, we tweaked a little bit. I think going into 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 a very pragmatic reasons based upon the data that we had available to us at that time. And I think as you said, we hit that one very comfortably with statistical significance. We'd always recognize going into that study that, 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 included some other more patient-reported outcome-based endpoints, one of which was the one that we referred to as a patient global impression of change, PGI-C; replacements report at set time point, 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 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. And actually, I think since then as well talking to lots of patients, it's a really meaningful endpoint to patients. Patients want this first, you will hit of a treatment. Yes, I've taken something. I know it's working. I'm kind of going 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 NDA submission. So I think as you referred to it, tweaking in the sense of that endpoint now has been promoted to the primary endpoint for Phase II. This precedent -- the regulatory precedent and also perhaps more importantly, you've actually got regulatory agreement to use that endpoint in our Phase III study.

And how are you thinking about numbers of patients and sites as an extension of that, the enrollment time line?

Yes. So in terms of number of patients, as you'll 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. So the Phase III study will be looking to recruit right about 100 patients. That's fairly typical for Phase III studies in HAE. There are typically 80 to 100 patients. So 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 EU only. This will -- the Phase III will be primarily U.S. and EU, but we'll be introducing sites elsewhere from worldwide as well. In terms of time to recruitment, we've essentially doubled the number of sites, and we're kind of roughly doubling the number of patients. So I think if you will, there are some equivalents in there. But I think, as always, a Phase III study, you always hope that when you get great efficacy results like we've got on our Phase II, that's going to help. It certainly helps the docs talk about your product. The docs talk about our study, and I think that is very encouraging to patients to come into the study. So we'll update on recruitment. As Andy said, 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 expectations of time lines.

Okay. And I guess, 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 what the -- once it's fully enrolled, at what rate you'll be capturing observations and then wrapping up the study. What are your thoughts on that time line?

Yes. The key to this, actually, Joe, is what we described is fully enrolled. You remember in the Phase II, we actually recruited 68 patients into the study, and we completed 53. And that's, if you will, because we said, right, we've got enough patients now, we can stop. So the -- those patients didn't complete the study, they weren't withdrawn from the study, but we just stopped the study before they had chance to have their 2 attacks. That's a really important view. If you were to over-recruit the study, you recruit more patients, you need to complete. So you have a batch of patients at the end. You're not waiting for one patient to have the one last attack, what you have is a good number of patients, in that case, it was 15 patients. So we just needed one of those to add one attack. So that minimizes that weight, if you will, from the last patient who's actually enrolled to the last patients to have their attack. So the Phase II, that minimized the last patient, last visit to -- I should say, the last patient enrolled to the attack, so we finished recruiting that study in December and results right in February. Again, I would imagine it's going to 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. And then we noticed you had some data coming up at AAAAI next week. Just wondering what that will highlight that might be new.

Yes. So we're doing some further analysis on our outputs. We're looking at things like attack location. So we're going to show that KVD900 is effective for all attack locations. I think as well, particularly what we're interested in, and it's probably what KVD900 showed just how fast it works and just how predictive that early event of seeing an efficacy outcome is predictive of your home treatment outcome, if you will, over the old attack. So we've got some further analysis looking at our PGI-C, our primary outcome and then how that feeds into the other outcomes that we've measured. Just to show that, that early effect that patients really like to feel is actually then predictive of a whole treatment outcome.

And 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?

Yes. So we'll be including all attacks that goes broader label as we possibly can. And I think that's probably the main -- that will be the main change, Joe, obviously, in laryngeal attacks. We obviously couldn't include those in the Phase II because at that point, we didn't have proven efficacy. So just that we just wouldn't have been right to include those attacks because they can be live for any. But obviously, in discussions with regulators, yes, we're not trying to include as many different attack types as we can. I think the range is the only, if you will, attack type that is new to the Phase III?

Okay. Cool. Well, that will be interesting data. And 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?

Yes. I can't give you a time line, Joe, but it's on its way. That's all I can say.

Okay. Well, that's great. Let's turn to 824 then. And can you tell us how this molecule in its properties compared to 900 and where you obtained it and what work has been done to optimize this for chronic administration?

Yes. KVD824 was discovered in our KalVista labs with our research unit. So it's a KalVista-discovered molecule, much the same as KVD900. In terms of having it compared to 900, like 900, it's a potent plasma kallikrein inhibitors, it's highly selective. We moved it forward because that's some interesting properties, which are allowing us to modulate the formulation a little more than we did for KVD900. KVD900, I'd say, is very simple. As soon as you dose KVD900, you've seen the PK profile yourself that gets in very rapidly to very high concentrations. So that's great in an acute on-demand setting. KVD824, because of the property as a molecule allows it to modulate that a little. So 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 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 concentrations to have a continuous suppression of plasma kallikrein activity. So that's what KVD824 allows us to do because of the properties of that molecule.

Okay. And I guess what's the latest status of this program? What have you been able to get going and what remains to be done in order to execute this trial?

Yes, the trial is enrolling. Very pleased with the enrollment rates to date. Again, I think as we were with KVD900, we will give a more fulsome update on recruitment once we've really got that uptick in the recruitment curve. And I think that we can give a lot better idea of when we think we have data from that study.

Okay. And then 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?

Yes, sure. So the Phase II study for KVD824 was actually kind of unusually the IND opening study. This was the first time that FDA had actually seen KVD824. We've done all of our Phase I work over here in the U.K. So I think it's fair to say, FDA don't get a fair amount of data they wanted to go through. They came back to us with some questions around some of the nonclinical work we've done. They asked us to do some reanalysis. They didn't ask you for us to generate new data to run new studies. They just wanted some reanalysis of the studies that we've already done. So we provided that data back to them. And as you're aware, we announced the clinical hold was lifted.

Okay. And I guess what's the bar for success here? And what endpoints will you be looking at? Like in the acute setting, it seems like there's some -- there's a variety of trial designs that you could employ here. So can you describe what this trial looks like and how you settled on this design?

Yes, sure. As you alluded to, 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 and we're going that prior to that. This is a treatment over a period. We'll be looking at treatment over 12 weeks. And it's -- their effects are simple. Frequency of attacks over that -- over that 12-week period, that is the primary outcome. The primary outcome in our Phase II, it would be the primary outcome that supports approval and did for ORLADEYO and lanadelumab. So it's kind of a well-established study design to support the prophylactic treatments.

Do you think that you will be selecting for any particular types of patients given the variety of options that are already out there? What's your view on who you're likely to enroll in the trial and whether that might influence what you see?

We need obviously to have the power and we need a certain minimum attack frequency. So the patients have to have 3 attacks in 8 weeks. So we're doing a run-in period where the patient we use on-demand treatment only. So we established no baseline attack frequency. So 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 earlier to you when you asked what's our hurdle for success in this. I think clearly, 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. So our expectations for KVD824 that over that 12 weeks of treatment, we should see lanadelumab-like efficacy. We certainly inhibit plasma kallikrein as effectively as lanadelumab. So there's no reason to expect that we shouldn't be as effective.

Yes. Yes, that makes sense. So I guess, that segues pretty well into a question about the overall landscape. And we have these various acute and chronic treatment options. Where do you see the gaps in treatment currently that each of these agents can help address and make patient outcomes better. Can you quantify those gaps for us in any way?

Yes. 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 because there is no other option nowadays in the on-demand space for an oral therapy. We even think that despite how ORLADEYO, the initial ORLADEYO launch has gone, we think there's probably over time going to show to be some efficacy gap there as well that we think we can ensue. And so with both KVD900 and KVD824, the objective here is to be a therapeutic that gives patients very rapid -- in the on-demand space, very rapid relief of their symptoms. And in the prophylaxis space, as Chris said, our objective and our belief we can achieve is lanadelumab-like efficacy, both with very -- with ideally favorable safety profiles. So the truth is the market hasn't really evolved all that much. Focusing on 900 and the on-demand space, again, patients have a lot of choices nowadays. First, generic icatibant is obviously marketed and has taken over a majority of share in the on-demand space. But 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. And so I think we're confident that the on-demand space is and will continue to be attractive because patients want to treat their attacks on demand. It's important to remember that about 40% of -- I'm sorry, the most patients in the space only have about 2 attacks a month. And so for those folks, the ability to treat on demand as opposed to prophylaxis can actually be attractive. So we're confident the on-demand space is going to continue to exist. We think we'll come with the first oral therapy they'll have extraordinary efficacy for patients. We think they'll be able to take it earlier. We think it's going to have a favorable safety profile. So I think we're very confident that we're positioned well for success there.

Yes. And what do you make of the commercial success of ORLADEYO in the clinic setting and prevention setting, both there in terms of what you might be able to achieve if your profile is better. And then 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 the uptake...

Yes. So ORLADEYO, if nothing else, absolutely validates what we've said for years that just patients are desiring of an oral therapy. It has certainly had a tremendous launch out of the gate. And despite the fact that the efficacy in the Phase III study, as we all know, was fairly uninteresting, it has done really, really well in the launch, and 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 want to have. And so I know BioCryst has started talking 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. But the fact of the matter is, I think it validates no matter what the patients want oral. With regard to how that affects us going forward, again, CINRYZE didn't -- I mean, as I've said, CINRYZE didn't destroy the on-demand market. TAKHZYRO destroyed the on-demand market. I don't know that we think that ORLADEYO kind of destroy the on-demand market as well. We'll come with KVD900 first ideally, launching 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 to have breakthrough attacks. And so we think patients even the ones using prophylaxis nowadays, we'll have the opportunity to try KVD900 and see if that works on the breakthrough attacks. Then the vision is that 824 comes along. Again, we think the efficacy can certainly be on par with the leading therapies, which is primarily TAKHZYRO. And as that occurs, we think patients with 900, ideally they've had success with it. We think they'll make them more amenable to 824 regardless of their experience with ORLADEYO, if they had any. And then 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 it's going to 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 and whatever may or they see best.

Yes. 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?

Yes. I mean, so we view Factor XIIa is kind of the next generation here in therapies for HAE. You will have seen the data from CSL with garadacimab with their antibody showing fantastic efficacy in Phase II. We would expect the same from them in Phase III. Makes complete sense given where it sits in the pathway and kind of validates I think what not just us, but a lot of people have thought makes a lot of sense to target. The challenge for us and for others, has been in the small molecule space where it just has been nothing out there. It's a really challenging target from additional chemistry perspective, and we've been working on it for several years. And finally, we're really pleased kind of across that threshold where we now have 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 potentially you can give much lower doses and achieve the type of efficacy that we're aiming for, which as we've talked about with KVD824 with lanadelumab like efficacy. So for us, it complements kind of what we're doing with plasma kallikrein, it makes for us obviously, commercial sense to be there. And we're leading the space here in terms of being able to provide that therapy. So I think what you'll see next from us here is more data on -- we haven't shared a lot given the competitive dynamics there. But 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 even in more information about kind of our plans with clinical plans and then kind of how it fits in the portfolio for us.

Okay. Great. And then what makes this target challenging in particular? Can you talk about what you were able to overcome with your chemistry in-house? And does that -- is it some of the same challenges that you were able to overcome with the 900 and 824?

Yes, it's a good question. I mean what we're expert in is small molecule protease chemistry, right? And one of the basic basics and all of this 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 an additional chemistry perspective and get moving. And we did have that benefit with KVD900 and 824, where we did have our own starting points, starting points from others we could work with, and we're able to build out a platform of a molecule that way. With Factor XIIa that just didn't exist, right? And the medicinal chemistry challenges, I think, are similar to what you see with other proteases. But from our perspective, we had to kind of event all of this on our own, and that has been in and of itself a major challenge. But 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 canvas the patent landscape and be able to own that ourselves. And so it becomes a major barrier for others.

Very interesting. And are there -- are there are particular patient subgroups that make the most sense to use each of these agents alone or in combination? To what extent will having 3 different approaches allow you to capture more market share versus -- I'm just wondering if one agent like the XIIa might obviate the need for either of those that we've already talked about at length.

Yes, that's a good question. I don't think we have any kind of magic bullet in terms of their -- knowing exactly which patient would be -- would benefit more from these different approaches. I think what we see always in these hypothesis heterogeneity in responses for individual patients and patients will kind of self-select into those therapies that we request for them. From a commercial perspective, what we want to do is be able to provide patients a full suite of therapies that they can kind of self-select into. And also, of course, with KVD900, it complements what we're doing on the prophylactic side, right? Because all patients are going to have access to on-demand therapy, whether that's their primary form of treatment or whether that is, if you will, a backup to their prophylactic therapy. So from our perspective, we think there's real power in providing a full suite of therapies and be able to then -- once the patient is working through one of our therapies be able to use it, if more appropriate.

Great. And the only program I think we didn't touch on was your DME franchise. So can you just give us a quick update there?

Yes. We remain very interested in DME. We've said that kind of our early heritage is there. We think the results from our Phase II stated, 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. And also, we've been clear that we think oral therapy in DME is a real opportunity with plasma kallikrein inhibitors. So we continue to kind of work on those, and we'll give further updates as we kind of make decisions on how we want to progress that franchise.

Okay. Great. Well, I think we're out of time, but thanks so much for the update, and we look forward to following all the continued progress.

Thanks, Joe, for having us.

Thanks, Joe.

Thanks for having us, Joe.

Thank you.