Korsana Biosciences, Inc. (KRSA) - Guggenheim 3rd Annual Healthcare Innovation Conference - KORSANA BIOSCIENCES INC

Good morning. We should be live now. Welcome to Guggenheim Third Annual Healthcare Innovation Conference. My name is Yatin Suneja, one of the biotech analysts here. I'm joined here by my colleague, Delma Kayati. So our next presenting company is Corsana Biosciences. From the company we have Jonathan Whalen, who is the president and chief executive officer. Jonathan, why don't you make some opening comments? Corsana is a relatively new story. I don't think many investors are, you know, up to speed or know the story. So it would be good to sort of talk about the history, what you're doing, what are some of the milestones that we should be following or should be paying close attention to. And then Delma and I are going to moderate a session after that. Fantastic. Well, first, Yassin, thank you for having us here. Thank you to the Guggenheim team. Pleasure to be here today. So CorsANA was founded just two years ago because we believe that the treatment of Alzheimer's disease is at an inflection point. It's obviously one of the biggest unmet needs in medicine. And now we finally have two approved disease-modifying therapies that represent just the first steps in what we think is going to be an evolution in how we can treat this disease. So those approved products, Kistema and Lekembe, to show us how the biology can be targeted. We now know that shuttling these antibodies, Those are unshuttled antibodies, regular IgGs, but shuttling them into the brain, crossing the blood-brain barrier, dramatically improves the therapeutic profile. We learned that from Roche's Trontinamab program. So we have, in phase three with Trontimab, the next generation, but we firmly believe that is not the end of the road. There is more to make the best possible product in this category for patients, and that's what we're here to do. So we're off to a quick start as a young company. we've raised about 500 million dollars we just entered the public markets a few months ago and really pleased to start sharing our story with a broader audience perfect very good so what it's uh driving this interest in uh this brain shuttle like what have we seen what are the challenges uh with the currently existing sort of technology because it's not just you i think roche and other companies are also going into this sort of venture where they're trying to deliver more drug into the brain? Sure. Well, first, some background context. So getting drugs across the blood-brain barrier is one of the oldest challenges in medicine. It really is one OF the last frontiers in terms of how we access CNS targets. And a lot of credit goes to the team at Roche who developed Trontenamab, which showed, I think, some striking findings in its Phase I-II study. First, plenty of drug gets in the brain, far more than an unshuttled antibody. that allows much faster and deeper clearance of amyloid plaques than we've seen with unshuttled antibodies. So just getting more drug in the brain is allowing much quicker activity. And then maybe surprising at first, it's not just that there's faster plaque clearance, but the rates of ARIA, amyload-related imaging abnormalities, microhemorrhage, microedema, are far lower with trontinamab than the unshuddled antibodies. That's because of how this class of drug gets in the brain. So that sort of opened the door for how we can generate a better therapeutic index. But when we look at trontinamab, it's dosed intravenously. It has a high rate of infusion related reactions that require pre-treatment steroids. And it also acutely destroys reticulocytes and has a low rate of anemia in the clinical trial. So, that means as much as we think trontinumab is going to be a great entrant to the market, there's still room to improve to deliver a true best-in-class therapeutic. Maybe following up to that point in particular, so can you give us more color on the specific features of your lead asset, Corsana 028? How is it differentiating in terms of the epitope you're targeting, and why specifically that epitome to start with? Yes, so KRSA-028 is our lead program. It is a shuttled anti-amyloid antibody, and it differs from Trontinamab and other entrants in a number of ways. So first, it binds to the pyroglutamate-modified forms of amyloid. Those are enriched in plaque, so you can think of this as more plaque-selective. It's like Denanamet and Rinturnatug, two lily products in that regard, and we think that that allows the best shot at quickly clearing plaque as deeply as possible. The shuttle itself works very much like Trontimab shuttle. A lot of the differentiation is in the FC engineering that we've employed. So we wanted to achieve three things. First, we wanted to improve peripheral exposure to help get more drug into the brain. Secondly, we wanted to preserve phagocytosis. So that's the mechanism by which the approved products clear plaque once the antibody gets to the plaques and binds to them. But we hypothesized that CDC and ADCDC, two other effector functions, could be responsible for some of the less promising effects of trontinumab, specifically the reticulocyte depletion, potentially also the infusion-related reactions. So we've added half-life extension, we've preserved phagocytosis, and we've eliminated CDC and ADCC. So that profile we call selective effector function modulation, and our preclinical data suggests that it is delivering in non-human primates longer exposure, we're sparing reticulocytes, and still preserve that phagocytic capacity. And is the full effector function required for plaque clearance or not? Because we hear sometimes that. So this is one of the debates in this field right now. So the approved products have full effecter function. They're IgG1, so maximum effector functio. Trontinumab does as well. On the other end of the spectrum, there are products like AbbVie 1758 that they acquired from Aliata that has no effector function at all and is thought to potentially eliminate plaques via totally novel mechanism. That's novel. It's not yet proven in the clinic. So we thought, really, if we could find the right effector-function modulation, find the RightFC mutations to preserve phagocytosis, the proven mechanism, that gives us the best shot at maximum efficacy and really target the differentiation more on CDC and ADCC, which are not thought to have anything to do with plaque clearing itself. So we're not alone in this in trying to sort of thread this needle between preserving efficacy and reducing adverse effects. We just think that technically our approach is different. Importantly, the FC modifications that we've used are all clinically validated, so that does give us a less risky technical profile. The combination of putting them together is novel, and so we're not disclosing exactly what they are until our patents publish. Got it. And another important differentiation point for your program is also that you're starting with a subcutaneous formulation from the get-go. So what are the preclinical data that allow you to target that? And I think you are aiming to a monthly dosing. So, what do you need to see then in phase one? We will talk about that more later, but you know, if you can give us an overview of what gives you confidence about the formulation and the dosing. Sure. So to get to a subcutaneous presentation, which we think should be the goal for any biologic, and especially in this patient population, right, having to go for an IV infusion once or twice a month is not ideal, right? For these patients or their caregivers. So, to achieve a sub-Q presentation, you need to know that you can get the dose low enough, infrequent enough, and that you can concentrate the drug to a high enough concentration with low viscosity and constability. And this program was designed from scratch. We weren't trying to fix some old antibody. This is a new antibody designed from scrap. So we screened, along with our partners at Paragon Therapeutics, where we licensed this program from, we screenED extensively for developability for subcutaneous presentation. So as we get to the clinic later this year, we will be starting clinical development sub-Q injection. Got it. I have two questions. Maybe I think the comment that you made about peripheral exposure, I think if you look at the data from Donanumab, even Lecambi or Tontenumab. They are able to very effectively clear the plaque. So what additional benefit you get with that additional exposure? Does it translate into sort of lower dose? Like, just talk about that, and then I'll ask you the second one later. Sure. So important to note that trontinamab gets most patients amyloid negative in three to six months. That's very, very quick compared to a year or two for the approved products. And so we don't know if it's possible to clear plaque any faster. So when we think about the benefits of half-life extension and improving exposure, it'd be nice if we could clear a plaque even faster. Maybe that would translate to better efficacy. But fundamentally, we do not know. What we do know is that improving exposure can allow us to achieve the same exposure as trontinamab with a much lower and less frequent dose. And that's why we're confident that we can have a low-volume monthly subcutaneous injection. Got it. Then with regard to anemia, so you mentioned the Roche program has that sort of liability. Why you don't have? How quickly you can see that? Is there a preclinical model that are sort of predictable that you're not going to have it? Yeah, so this risk of anemia has plagued the transferrin receptor shuttle notion for decades now, and there have been a lot of improvements made along the way. And the Trontenumab shuttle, for example, doesn't disrupt transferrin signaling, so it doesn't just disrupt the normal iron homeostasis. But we do still see, so compared to the first generation of shuttles, it's far, far better. But again, we do see this 10% or 20% rate of anemia that we would love to avoid if we can. And so one of the observations from trontinumab is this acute destruction of reticulocytes, the progenitors of red blood cells. And that's something we can measure in non-human primates. And in fact, the selective effector function modulation was designed specifically to avoid that acute reticulocyte depletion. and at least in non-human primates, head-to-head against Trontenamab, we are strongly differentiated. So then with regard to the phase one study, where is it going to be conducted? I think you're doing, when are you going to bring the IND into the U.S.? Just walk us through the structure of the program, the dosing, what type of patient, what is a good proof of concept there? So we've designed a phase one-two study that we hope can be phase three enabling, And it's comprised of three parts. Part one, single ascending dose and healthy volunteers. For that, we're planning in Australia and New Zealand. We'll file a CTA by the end of this year. And then move directly into a multiple ascending dose in patients. And I'll explain what we expect in each of these parts momentarily. And then from the multiple ascended dose, we can pick our favored doses and move them into expansion cohorts to increase the cohort size enough to adequately characterize safety so that we hopefully can get buy-in from global regulators to go straight to phase three. And this is very much following in previous precedent. There's nothing really novel here. So we're very comfortable in this approach of a three-part phase, one, two. So CTA for that SAD by the end of the year, and then IND early next year to allow the multiple-sending dose because we think most of our patients will enroll from the U.S. for that part of the study. Got it, got it. So with regard to the proof of concept, and especially on the anemia side, is that going to be evident in this healthy volunteer? Or do you need to go into the patient? Yeah, so the key things we'll learn from healthy volunteers, right? This is a single dose. So first, again, this is via sub-Q route. So as long as we see exposures, we'll know that we've got a sub-q product. We can measure half-life. So we'll understand how well the half-Life extension is working. and that technology has a very great track record of translating from non-human primates. We'll have standard safety and tolerability that does include CBC. So we'll have a read on anemia, but I wouldn't say we'll fully characterize it. The other thing that we'll know is the CSF levels, which is now levels in the CF are not the same as levels in the parenchyma, so it's more an indicator of is the shuttle getting more drug into the brain. And we can look at Roche's data for Trontinumab compared to its parent molecule, Gantanerumab, for precedent there. So we'll learn a lot, and that data will be in the middle of next year. But we'll need to go into the multiple ascending dose to learn more, particularly about the activity. Got it. Could you remind us what we saw from Aliada before they were sort of acquired? I thought even they also have very limited disclosure, but at least it was very evident that the shuttle at least is working on their end. So their non-human primate data showed extended plasma exposure, sparing reticulocytes. The big question there is because it doesn't support phagocytosis, how active is that molecule going to be? And so when we talk to KOLs in this space, I think the big question is, will it work? And if it does, how high a dose do we need to get to? Aliada was acquired, we understand, partway through the single ascending dose in Healthy Volunteers. We've not seen that data yet. So that acquisition was about two years ago now. We do know that AbbVie started a multiple ascending dosing patients this summer. So we're certainly excited to see that data in due course. Yeah, I mean, that's what I was trying to get to, that, you know, even SAD is important read, you know, given what we saw with Aliada. I mean obviously MAD is better. And maybe proceeding on that topic, so when we think about initial efficacy data, what's the bar there? And how, you know, we will have Trantinum data in 2028. So what will be the possible read-through for your program? Yeah, so this is one of the things that I think is remarkable in how the field has evolved in the last 10 or 20 years. So we can measure plaque clearance with PET tracers with high precision. Even 5 or 10 patients per dose, you'll see very robust data. It's honestly, if you look at the trontinamab phase 1, 2, or, for example, Lili's remternizog, it's some of the prettiest dose response data I've ever seen. And this is for plaque clearance in Alzheimer's with these patients. So that's a very strong measure of activity. and now there have been enough molecules in phase three that we know there's a very strong correlation between plaque clearance and clinical benefit. So that's why even with a multiple ascending dose, we can establish our first readout will just be one or two cohorts worth. We'll call that interim proof of concept. If we clear plaque at a dose that tells us that we're on the same dose response as trontinamab, that we can achieve trontimab-like plaque clearance, we'll have high confidence in having activity at least as good as trantinamab as well. Got it. And as you said, there is a lot of excitement for blood-brain barrier shuttles, and many platforms are coming up and moving to clinical stage. So where do you differentiate from other programs, and how should we think about the market as a whole? Sure. So in terms of analogies, Alzheimer's disease looks a little bit like multiple sclerosis a generation ago, right? A couple approved products. In this case, the two approved Alzheimer's products are annualizing over a billion dollars a few years into launch. It's clear that that's just scratching the surface in terms of access. And partly what we need, just as we did in MS, is better drugs, right, better safety, better tolerability, better convenience. And so we see this as potentially the next truly gargantuan market opportunity, which means that there should be multiple winners in this space. Now, we think we've got a great shot at a best-in-class molecule with KRS-028. We should expect that there will be other successful products as well. So that means what we need to do, and we are designed for this. This is our lead program. This is OurFocus. So our job is to move our program forward as fast as we can with the best possible data. And, again, that's what we're here to do. And maybe just moving back to the program itself, another little detail we didn't touch, is about the population we are recruiting. Are you including also the APOE4 homozygous there? And how should we think about the ARIA risk with the shuttles in that population? Yeah, so the APoE4 status does confer increased risk of ARIA, but we are bringing all comers for APOe4, just as trontinamab did. In fact, our patient population is very similar to the trontanamab population, so early Alzheimer's disease. That's because that's where we know that this class works, but also is going to enable as best you can read across trials that will allow us to understand how well we stack up against Trontenamab, which of course I think investors want to know as well. And so the APOE4 status is something that we'll track, but we'll not recruit for any kind of bias. We'll take all comers. Got it. And maybe thinking forward, let's say one year from now, and after your MID results, so what will give you confidence once you have seen the initial data that you have a very strong product that you can bring it forward to the pivotal program? And how are you thinking to the regulatory strategy there? Yeah. So again, we have great precedent that we can point to. There are plenty of examples of integrated SAT and MAD. Roche with Trontinumab did a MAD with expansion cohorts. So the only difference is that we're putting all three together. What we'd like to see, obviously, we need standard safety and tolerability. This is all going to be done via the sub-Q route. So as long as we can see plaque clearance measured with these PET tracers, that's trontinamab-like or better. And we would expect ARIA to be in the single-digit percentage, right? That's where trontinumab is. And so as we go through the SAD, we learn about PK, the brain penetration, early safety. And then in the MAD, we'll understand how active the molecule is. We'll start to understand the ARIA risk again. We expect low single-digit percentage because even placebo patients in this population have a couple percent. And dann it's the expansion cohorts. In the case of Roche, they ran their top two doses up to about 75 patients per cohort to adequately characterize safety, and that's what regulators needed to see to allow them to move to phase three. With regard to the ARIA, is there a particular consideration for monitoring, especially for the shuttle technology? And the reason I ask that question is that when we talk to physicians, it's like, look, one of the issues is that you have so much requirement of these MRIs that needs to be done on a very regular basis, it creates a burden. So will it be additional there, or should be less or should be similar to currently approved drugs? Yeah, so the currently approved drugs are four or five MRIs in the first six months. Because if ARIA happens, it's going to happen in the for six months, and we agree, that's a burden. It's expensive for payers. It's annoying for patients. Patients hate MRIs, right? And it's annoying and for prescribers as well. Reducing that burden is going to require data, right. So as we generate data, if we see a low enough rate of ARIA, that's something we would love to talk to regulators about reducing that burden, which is too early to know. But the initial protocol should be similar to other companies, at least on the monitoring front. Correct. Maybe in terms of the commercial opportunity, so I know you're not guiding for potential peak sales, but when we think about the addressable population, and there will be most likely Trontinov already there, so how should we think of that? Yeah. So, again, I think multiple scores is probably a good example, right? we should expect there to be waves of entrance with incremental improvements until we get to a molecule that's really hard to beat. And we think something that's an autoinjector for at-home use, which is our goal at launch, that is very safe, that works very quickly, and has good tolerability should be widely appreciated. And so when you think about multiple sclerosis and how that market evolved, the biggest difference is that there's something like six or seven times more Alzheimer's patients. So the opportunity truly is huge. Got it. Okay, maybe so in these last few minutes, what do you think is the most underappreciated by investors of your company? So as I mentioned, we're new to the public markets. We have an incredibly strong core shareholder group that have supported us so far. And as we talk to new investors, I think they understand the scale of the opportunity that we are built to win in this space. And so the biggest thing for us is honestly socializing our story, and it's always exciting to meet new investors and share our thesis with them. Should we expect to hear more about other programs that you might be progressing? I think you and I have discussion about sort of other targets. Just love to hear from you, either your view on the Tau side, like how are you thinking about other sort of molecules as you progress? Right. So having a shuttle with KRSA 028 means we do have a platform, right? We could do more with this. Now, we're not a platform company. Don't expect us to go start a dozen programs. We're laser focused on product development. We think that's where the most value can be created. And so we're focused on KRSA028 and amyloid clearance. But we're not here just to deliver a best-in-class amyliid drug, right. We really want to win on Alzheimer's. So certainly we're paying attention to tau and other targets in the Alzheimer's space. But there is opportunity in other neurodegenerative disorders as well. So too early, just from a competitive perspective, for us to talk about other ideas. But in the next year or so, we'll have more to say. A very good Jonathan, thank you. Thank you. Thank you very much.