Cantor Global Healthcare 2021 Conference

Sep 27, 2021

Hello. Good morning, and welcome to the Cantor Global Healthcare Conference for 2021. My name is Charles Duncan. I'm a Managing Director and Senior Biotechnology Analyst with the firm's Equity Research Department. And this is day 1 of the Cantor Conference. And I have to say, what a year it has been since we last hosted our clients in the fall of 2020. So it's a pleasure to introduce the next, actually the first presenting speaker for me. This is Calvista Pharmaceuticals. Calvista is an interesting platform enabled drug developer, and it's a pleasure to introduce the company's CEO, Doctor. Andrew Crockett. I also have Mr. Ben Polanco, the Company's CFO and CDO with me today and Doctor. Chris Ria, the company's Chief Development Officer. Gentlemen, good morning. How are you? Hi, Chad. Thanks for having us. Good morning. Good morning. Great to see you. Yes, as I mentioned, it has been quite a year, a lot of challenges. However, some innovation in biotechnology as well. We've seen the delivery of COVID vaccine. We've also seen the I guess for you folks, how's it gone for you? How have you kept your staff together and moving forward? Yes. For us, it's been actually a really it's been a very good year at Calvista. We've made some significant progress on our lead products. The company is growing significantly. And so despite a lot of the challenges that we've been having with the pandemic and so many related items, at Calvista, we feel very fortunate that we've had a very good year. The year really started off for us with headline data from our Phase 2 study for our lead product KB-nine hundred for on demand treatment of HAE attacks where we showed some really fantastic data coming out of that study and moving forward now with that program to an end of Phase 2 meeting and Phase 3 quickly thereafter. Very good. Great to hear that it was a productive year for you and we will get into that. I would but I wanted to mention that you do have a distributed business model. I know that Chris is probably talking to us from London as an example, and you in the United States. So how has it worked for you in terms of being able to organize your processes and move forward with regard to productivity? From our perspective, at Calvista, we've always kind of had just, if you will, distributed model where we've got folks in the U. S. And the U. K. Since our inception, we've kind of been set up that way. We've tried to find expertise kind of wherever that is. And from when the pandemic began, quite frankly, we were kind of already established that way and set up that way. In many ways, the tools that we've had to operate have only improved, things like Zoom and other elements have only gotten better when more of the world had to operate in this way. So I'd say that our models has been benefited by the challenges of others. But we've been set up this way for a long time. So for us, it wasn't that much of a dynamic change. Very good. And I mentioned at the beginning that your company is an interesting platform enabled drug developer. And I'm wondering if you could just take a moment to describe that platform for protease inhibition. Why is that a difficult thing and why is it differentiated perhaps from other platforms that are out there for drug discovery? Sure. I think, as you say, we are focused in development of small molecule protease inhibitors and that field of drug discovery has been a challenge for a long time. And especially when you kind of add the small molecule element to it, you're from a chemistry perspective, you're always balancing among achieving potency, oral availability and selectivity with your molecules. And that's just a challenge in this field. The good news from our perspective is we've been doing it for a long time. We have chemists at Galvesta that have been researching these small molecule protease inhibitors for decades. And that really gives us a competitive advantage. We've worked on a number of different proteases and now through to our work in plasma calacryne and factor 12A with the molecules that we're generating, I think the really the fruit is and proof is in the pudding with what we're bringing forward. Well, we're going to talk about both targets over the course of this discussion. But why don't we first one more question on the platform. When you think about your approach in terms of medicinal chemistry, but better understanding even the biology of these targets. Do you believe that you mentioned competitive advantage, but do you believe that it generates drug candidates that are differentiated and have a profile that is emerging that could be different than past approaches by other companies? Yes. I mean, I think our approach, for example, with our the drug candidates we're moving forward in HAEs, we want to be able to bring to offer patients oral therapies that are every bit as effective as the injectable therapies that they've become accustomed to, right. And as it relates to each specific drug, that is a challenge, right. For example, in the on demand setting in HAE, to be successful there, you need an oral drug that is absorbed and reaching effective concentrations in minutes, right. And that you don't see that very often with oral drug candidates to have that type of rapid absorption to levels to which you can quell and attack where this biological process has kicked off in a significant way. What we showed with our data from KV-nine hundred is that actually we were able to deliver that. And so again, I think the platform, if you will, is the expertise to bring forward differentiated molecules, right. So KV-nine hundred is positioned for on demand. It was designed specifically to address that concern in that market. Whereas with KVDA24, we're focused in prophylaxis. That's a very different profile that's required. And from our perspective, we don't think it's really the right thing to try to, if you will force 1 molecule into 2 very different indications that require different characteristics of molecules. So I think the platform or our ability to discover differentiated drugs is really what makes us different. Very cool. So why don't we talk a little bit about the first indications or disease state that you're going after, Andy, and we can maybe set the table to talk about some of the specific candidates. With regard to hereditary angioedema or HAE, what do you see as the current, call it, unmet need and the market dynamics? It has been evolving certainly in the last year. So tell us what you think is remain to be wanting for patients and prescribers? Yes, I think really HAE has gone through a transformation really over the past 5 to 7 years, right, where patients now have access to a number of very effective drug therapies. Most of those therapies are injectable therapies, right. But still the same patients have access to those therapies. What we've been saying for quite a long time is that what patients really want is oral therapy, right? And they want oral therapy in kind of whatever way they can get it, whether that is on an on demand basis or whether that's in a prophylactic basis. Patients want that kind of next advance, which is oral therapy. We've had now the first approval of an oral prophylactic agent. But I think what kind of sets us apart as we think about both the on demand and the prophylactic setting is, the high levels of efficacy that they experience with their injectable therapies and what they want, which is oral therapy, right, for enabling the type of life and freedom that they want with their disease. So what we're looking to do with our drug therapies is not ask patients to make that choice, right? And I think we delivered on that at least in the Phase 2 clinical study with KB900 where the efficacy profile we saw was every bit as good as what we've seen with injectable therapies. And certainly, what we believe will be a the type of drug administration that patients really want in the space. Okay. Well, why don't we talk specifically about KVD-nine hundred and perhaps even bring in your colleagues, Chris and Ben. When you think about KVD-nine hundred and the data that you've presented thus far, what gives you confidence that it could be competitive and achieve the target product profile that you mentioned in terms of not having to compromise on efficacy for speed or vice versa? Charles, yes. Can you talk to that? So I think the first thing, as Andy said, is the speed with which COPD-nine hundred absorbed is really impressive. And so C MAX is typically around about 30 minutes. And perhaps more importantly, that time to reaching an effective concentration, a pharmacodynamically effective concentration is obviously prior to that. I think we've shown data that's in this kind of region of 10 minutes or so. So I think the speed with which it gets there, of course, is an acute setting is incredibly important. You need to stop the attack as soon as possible. Patients first of all, the first thing the patient wants to know is the treatment I've taken is starting to work and they say that's the most important thing to them. After that they recognize and there's a period over which the attack resolved. But I want to know when I've taken something, it's going to work and it's going to work quickly. So that's the first one. I think the second thing is, as Andy said as well, we get to very high concentrations. And what we've shown is that that completely inhibits plasmacallacron. There is essentially no plasmacallacron activity in the plasma from around about 30 minutes or so. So it gets there very quickly and when it gets there, it gets there very effectively pharmeconomically. I think as well the other thing around the target is really interesting. So plasma kallikrein, if you will, sits at the middle of the contact system. So what we know is that plasma kallikrein produces bradykinin, obviously, by cleaving kininogen. That's, if you will, that's the effect of the edema. However, the contact activation system is actually maintained and amplified by plasma kalacrine. So we know that plasma kalacrine is able to cleave pre kalacrine to produce more kalacrine. It's also able to cleave FACT12 to FACT12A, which is right at the top of the pathway. So if you will, plasma calacrine kind of sits in key position in the middle and amplifies the whole cascade. So I think not only are we stopping the downstream effector, we're stopping the whole pathway from this increasing activation. So I think that's really important. So I think when you add together that pharmacokinetic profile, the clear pharmacodynamic effect and the impact within the pathway, it's certainly if you've shot down plasma catacryne activity, clearly, you've shot down all of contact activation. Therefore, that should be as effective a treatment as you can get and it will get there very quickly as well. Very good, Chris. Great overview. Appreciate that. When you think about the data that you've presented and you consider it relative to designing the next steps in terms of clinical studies, what would you anticipate those clinical studies to be? Now I understand that you have an end of Phase 2 meeting coming up. So I'm not really talking or asking you about your FDA interactions. I just given the results that you've seen, how confident are you in being able to demonstrate that target product profile in a Phase As you can see, based on that Phase 2 data, Shaz, we're very confident. What do we expect the study to be? Our expectation is that essentially the study will be as close to the Phase 2 study, to be frank, as we can make it. We looked at several endpoints. FDA asked us prior to the Phase 2 that we look at several endpoints to educate that discussion that we will have with them, as you say, at our end of Phase 2 meeting. I think the nice thing, the comfortable position we're in is all of the key endpoints we hit. We hit our primary, which is use of rescue. I think we've said previously, we're not sure that that's something that FDA will necessarily believe in at least as a primary, but I think it's a very important endpoint nonetheless. But the other endpoints that have been used for previous studies, including the VAS scores, including what we call the PGIC, so this question transition question to how do you feel now? Do you feel better or worse than you did? Plus also we used this LICA at scale outcome, which is a very simple rate your symptoms now from none to very severe. We got very good P values on all of those endpoints. So I think without being too blase, whilst I like the PGIC outcome, we know from patients that's meaningful. If you ask a patient and actually if you ask a patient, when you take a treatment, what do you want to happen? A patient will say, I want to feel better. They won't say, I want my symptoms to be this level or I want to be this score on a 10 centimeter line. I say, I want to feel better. So I think that's a very meaningful outcome. But as I say, we have some flexibility at least because of the outcomes from the Phase 2 in each of those. So I think in general, the study will look we will propose very much the same as the study we just completed for the Phase 2, both in terms of study design, so crossover and also in terms of the endpoints that we'll be looking at. And I guess if you had to guess on a sample size, can you give a broad estimate? And then with regard to timing of being able to articulate that plan forward? Yes. I mean, again, I would estimate the study size to somewhere similar to the Phase 2. I mean, it's somewhat dependent obviously on our discussions with the agency. But I think from an efficacy point of view, again, because we got such good P values on the assumption that our assumptions going into that end of Phase 2 meeting are correct. I think it will be around about the same study sample size. And it's not an atypical sample size in the HAE setting anyway at Phase 2, Phase 3 level. So I think that's a pretty good expectation. We have everything up and ready. So we've selected sites already ready to go. We have drug products manufactured, that's all ready to go. So as soon as we can reach that finalize that agreement with FDA on exactly what they require in the Phase 3 program, we can press the button and we'll be up and running very quickly. As you'd be aware, once we can get a protocol filed in the U. S, you can get on and start initiating sites immediately after that. So we should be up and running very quickly. Okay, very good. We'll look forward to that information that those press releases here in perhaps in the near term on KVD-nine hundred with regard to acute therapy or on demand therapy. But you have a second candidate that Andy actually mentioned, 824, with regard to prophylaxis HAE. And as you spoke, there has been another oral agent, a prophylaxis agent for HAE. I guess I'm wondering if you can go back to the original conversation and say, how do you feel about the market dynamics there and the need for prophylaxis oral agent versus on demand? Ben, you want to take that one? Ben? Sure. Hey, Chas. So right, so what you're referring to is, yes, you said Orlandaio from BioCryst launched, it was approved in the last year and launched earlier this year. It has gotten a lot of attention in the market space because it's our 1st oral therapy for that's been approved and launched, as you point out, prophylaxis. The ostensibly, this seems like an attractive idea, right? I mean, prophylaxis in the U. S, focusing on the U. S. Market, we'll set the rest of the world aside. It's about probably 60%, maybe a little more even nowadays prophylaxis. So it looks like they're launching into a very large segment. And clearly the launch to date has actually seems to have gone fairly well. I mean, it's they've obviously got approval and reimbursement in a number of countries. They've shown some reasonably interesting numbers in the 1st couple of quarters. The what they really do is validate the fact that what Andy said previously is true, which is there's an overwhelming desire by patients for oral therapies. HAEs in some ways are very well served market. I mean, it's kind of remarkable to think that 20 years ago there were really no effect of modern therapies and I have a whole group of these. But the key issue, of course, remains that they're all either injected or infused and that becomes a huge liability for patients. Again, this is a lifeline disease. You're talking about people doing this for 70 something years. And so even if it's a couple of injections a month, that's highly undesirable for patients to go through in the long term. And because it's familial, they also have to think about the fact their children are having to deal with this as well in many cases. So the point on ALIDAYO is it's come out as an orally delivered therapy and the initial demand we think reflects the fact that again patients overwhelmingly want to have another option that's better. It's not just about convenience, it's the fact that this actually improves our quality of life by allowing them to have a shelf stable tablet, as opposed to having to deal with all the challenges that come with storage of antibodies and proteins and again to have something that can treat their disease and for the long time in a more attractive manner. The problem for Oladeo has been really the efficacy results in the safety profile. TAKHZYRO, HEYGARD and these other prophylaxis therapies are probably in the range of 80 plus percent reduction in clinical in attack rates. And the safety profile is pretty good. You have injection site reactions, you have the kind of standard injection items, but generally they're pretty well tolerated. Well, the day at the high doses and with some of the early studies showed very high rates of attack rate reduction probably comparable to those. The problem is a side effect profile make the drug essentially intolerable for large segments of patients. And so what they had to do was lower the dose, lowering the dose, reduce the efficacy. And so at the end of the day, what they ended up with was a drug that has about half the efficacy of TAKHZYRA, about a 44% attack rate reduction in the Phase III study and a side effect profile that's still challenging. A lot of patients experience abdominal discomfort with this and it has made patients getting on and staying on therapy a challenge. So our view on Oladeo is it's some again, in some way it shows that the demand is actually there and that the market opportunity is strong. It also, however, we think over time is going to show the corollary to that, which we've always said, which is patients are really going to settle for a lot lower efficacy. It's probably unusual in at least in my experience to have drugs perform twice as well in the real world as they do in clinical studies. So I think that's where we'll see how our whole data does. Yes. So good point on that one, Ben. So probably problem not solved yet with that particular oral agent in prophylaxis. And it may actually increase demand or risk with regard to acute therapy as well. And so I guess I'm wondering from your perspective or Chris or Andy's, your perspective on your agent, your candidate 824. What is it in the early data that you've seen with H824 that gives you confidence in terms of the pharmacokinetic and pharmacodynamic parameters that can actually solve the problem for not only acute with 900, but also for prophylaxis with 824? Yes, I mean to talk specifically Charles to the prophylaxis. Again, we've shared some pharmacokinetic and I think more importantly pharmacodynamic data. I mean, what we know for OLDDATA is in the earlier Phase 2 trials, it looked as if it was as effective as the injectables, Certainly, notwithstanding the GI side effects that they found in the Phase 2, at the higher dose levels, the peripheral attacks, it was very effective. It was as effective as lamodilumab. So I think that validates the fact that an orally delivered plasma calorcarine inhibitor will be as effective as an inject is not an agonist, no reason to think it wouldn't be. So I think that's really important. It was those GI side effects though obviously that meant they had to reduce the doses going into the Phase 3. And they've reduced them far enough to at least alleviate the majority of those side effects, those adverse events. But of course, not surprisingly, then you lose exposure, you don't inhibit the plasma chylacrine enough and therefore you end up with some breakthrough attacks and significant numbers in that Phase 3 study. So I think that what it says to us, as long as we can deliver enough of a drug, I. E, it's got to be tolerable that we can deliver the concentrations required and we have the pharmacokinetics to support that, then we should see efficacy. I think it's fair to say HAE is really challenging from the point of view of the amount of drug you have to deliver. You do need significant concentrations to suppress the contact system enough all of the time. And there's kind of 2 ways you can do that. 1 is you can have a very long half life drug and that's Oladeo, which has got something like a 3 day half life, which clearly brings other issues other issues forming clinical development. I have to say, we've kind of lowered the bar a bit. So, well, in the first instance, let's go for twice daily. That means, yes, we don't have to give such big doses to maintain that 24 hour coverage. And certainly the Phase I data that we have today shows that with the 2 doses that we're moving forward to or the 3 dose levels at twice a day into the Phase 2 study, we get very good suppression of plasmcalacrine. And I think you'll have seen our graphs, we show, in fact, for the vast majority of the 24 hours, we suppress plasmcalacrine probably more strongly than lamadelumab does. So I think from a pharmacodynamic point of view that says we have good suppression, should be efficacious. And in terms of tolerability, we've delivered those doses now for up to 14 days. And we've had no signs of any concern around tolerability. Now, if you can contrast that to Oladeo, even the first in human single dose studies, they were seeing these GI side effects. So I think if we were to be seeing these, we'd be seeing them within 14 days of repeat dosing. So I think I'm very confident that we have the concentrations and suppression of plasma color correction enough to get efficacy. And to date, as I say, the tolerability profile looks very encouraging. Now, one potential pushback I could imagine from the competitive side is that it's a twice a day compound. And so I guess I'm wondering, as you've thought about the future market dynamic, perhaps Ben or Andy can speak to this, are you concerned about compliance with a twice a day compound? And could that limit efficacy or really the perspective of efficacy in the market? It's something it's a good question. It's something we thought really carefully about as we were bringing 824 forward and Chris kind of alluded to this, this decision of this long half life and potential knock on safety effects with some of that profile versus having patients dose twice a day. I think the research that we did came back kind of overwhelmingly in support of that efficacy is the key driver here that patients more than anything want an efficacious oral therapy. And obviously that needs to be well tolerated. And so we need to be able to deliver doses and a therapy that's going to be very effective and well tolerated in 824 and the Phase 1 studies have shown that. In terms of compliance, I think sometimes when we look at kind of compliance on a macro level with twice daily dose drugs, We mix in some other indications that don't have the type of acute impact of missing a dose, if you will, like HAE does, right? So even we've talked about before migraine, right, when you know you've got that type of situation coming on, I think you're it's much different than say someone that has high cholesterol and taking medication daily. I think these patients understand the potential consequence for missing doses. So I think that tends to drive compliance pretty well. So that isn't something that's keeping us awake at night. Yes. So this is a highly symptomatic disease and yes, patients can learn if they miss one that that's not a good thing, correct? Absolutely. Yes. So Chad, just to don't forget though, this also highlights the potential of the portfolio, right, which is 824 plus 900 together. And so we're going to have the opportunity for patients to take this twice daily, but if they have a breakthrough attack, if somehow for some reason it's a dose whatever, 800, 900 would be available as well. And so realize this what your compliance point goes to the opportunity presented by the fact that we actually are the only company with oral therapies to both sides of the market. Well, and you're the only company that can deliver an oral therapy that actually has very rapid activity. And so that will give some comfort to the market. In the last few minutes that we have to speak, I wanted to come back around to the concept of the platform that I was discussing with Andy earlier. The Factor 12a candidate is really intriguing. And I guess I'm wondering when you think about that and think about where it sits relative to Calycron that Chris was mentioning, could you actually see an improvement if you're able to move forward with 12a or is it just a totally differentiated approach in terms of treating HAV? HIV? As Chris described, we think that plasma kalakarine obviously is a really the key mediator of the disease that we've seen so far, right. So, obviously, we have very effective therapies where plasmacallacrine is the target, both ours and others. We think factor 12a represents kind of another opportunity in HAE, right, as Ben is describing kind of our platform and our desire to kind of hit all points. We've seen some data from a Factor 12A antibody that was really effective. It sits at the top of the cascade, it makes sense to also look to intervene there. Who knows, some patients may experience benefits there better than with plasmacallacron. I think that remains to be seen. But we're moving forward with our molecules. We've seen we've actually had some great progress over the past few months in expanding kind of our Factor 12A program to have molecules that are orally available, selective and very potent and we're excited to kind of add that to the next clinical investigation that we do in HAE. Very good. Well, we're just about out of time. I hope that in a year, we'll be together talking at the Cantor Healthcare Conference for 2022, and we'll look forward to your progress then. Thank you very much for sharing the Calvista story with us this morning. Gentlemen, hope you have a great day. Thank you.