Good morning. We should be live now. Welcome to Guggenheim's 3rd Annual Healthcare Innovation Conference. My name is Yatin Suneja, one of the biotech analysts here. I'm joined here by my colleague, Delma Caiati. Our next presenting company is Korsana Biosciences. From the company, we have Jonathan Violin, who's the President and Chief Executive Officer. Jonathan, why don't you make some opening comments? Korsana is a relatively new story. I don't think many investors are up to speed or know the story. It would be good to 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, Yatin, thank you for having us here. Thank you to the Guggenheim team. Pleasure to be here today. Korsana 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, Kisunla and Leqembi, are starting 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 trontinemab program.
So we have, in phase III with trontinemab, the next generation, but we firmly believe that is not the end of the road. There is more to do 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. 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 is driving this interest in this brain shuttle? Like, what have we seen? What are the challenges 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. 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. A lot of credit goes to the team at Roche who developed trontinemab, which showed, I think, some striking findings in its phase I/II study. First, plenty of drug gets in the brain, far more than unshuttled antibody. That allows much faster and deeper clearance of amyloid plaques than we've seen with unshuttled antibodies. Just getting more drug in the brain is allowing much quicker activity. Then, maybe surprising at first, it's not just that there's faster plaque clearance, but the rates of ARIA, amyloid-related imaging abnormalities, microhemorrhage, microedema, are far lower with trontinemab than the unshuttled antibodies.
That's because of how this class of drug gets in the brain. That sort of opened the door for how we can generate a better therapeutic index. But when we look at trontinemab, it's dosed intravenously, it has a high rate of infusion-related reactions that require pretreatment with steroids, and it also acutely destroys reticulocytes and has a low rate of anemia in the clinical trial. That means, as much as we think trontinemab is going to be a great entrant to the market, there's still room to improve to deliver a true best-in-class therapeutic.
And maybe following up to that point in particular. Can you give us more color on the specific features of your lead asset, KRSA-028? How is it differentiating in terms of the epitope you're targeting, and why specifically that epitope to start with?
Yeah. KRSA-028 is our lead program. It is a shuttled anti-amyloid antibody, and it differs from trontinemab and other entrants in a number of ways. First, it binds to the pyroglutamate-modified forms of amyloid. Those are enriched in plaques, so you can think of this as more plaque-selective. It's like donanemab and remternetug, two Lilly 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 trontinemab shuttle. A lot of the differentiation is in the Fc engineering that we've employed. 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.
That's the mechanism by which the approved products clear plaque once the antibody gets to the plaques and binds to them. But we hypothesize that CDC and ADCC, two other effector functions, could be responsible for some of the less promising effects of trontinemab, 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 the field right now. So, the approved products have full effector function. They're IgG1, so maximum effector function. trontinemab does as well. On the other end of the spectrum, there are products like ABBV-1758 that they acquired from Aliada, that has no effector function at all, and is thought to potentially eliminate plaques via a 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 right Fc 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. Another important differentiation point for your program is also that you are starting with a subcutaneous formulation from the get-go. So, what are the preclinical data that allow you to target that? I think you are aiming to a monthly dosing. So, what do you need to see then in phase I? We will talk about that more later, but if you can give us an overview of what gives you confidence about the formulation and the dosing.
Sure. 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 subcu 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 controllability. This program was designed from scratch. We weren't trying to fix some old antibody. This was a new antibody designed from scratch. So, we screened, along with our partners at Paragon Therapeutics, where we had 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 subcu 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 donanemab, even Leqembi or trontinemab, they are able to very effectively clear the plaque, right? So, what additional benefit do you get with that additional exposure? Does it translate into sort of lower dose? Just talk about that, and then I'll ask you the second one later.
Sure. Important to note that trontinemab 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. 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 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 trontinemab 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. With regard to anemia, you mentioned the Roche program has that sort of liability. Why you don't have, how quickly you can see that? Is there preclinical model that are sort of predictable that you're not going to have it?
Yeah. 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. The trontinemab shuttle, for example, doesn't disrupt transferrin signaling, so it doesn't disrupt the normal iron homeostasis. We do still see, compared to the first generation of shuttles, it's far, far better. Again, we do see this 10% or 20% rate of anemia that we would love to avoid if we can. One of the observations from trontinemab is this acute destruction of reticulocytes, the progenitors of red blood cells, and that's something we can measure in non-human primates. In fact, the selective effector function modulation was designed specifically to avoid that acute reticulocyte depletion. At least in non-human primates, head-to-head against trontinemab, we are strongly differentiated.
Got it. With regard to the phase I 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?
We've designed a phase I/II study that we hope can be phase III enabling, and it's comprised of three parts. Part one, single ascending dose in healthy volunteers. For that, we're planning 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. I'll explain what we expect in each of these parts momentarily. From the multiple ascending 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 III. 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 I/II.
CTA for that SAD by the end of the year, and then IND early next year to allow the multiple ascending dose, because we think most of our patients will enroll from the U.S. for that part of the study.
Got it. With regard to the sort of 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. The key things we'll learn from healthy volunteers, right? This is single dose.
Yeah.
First, again, this is via subq route, so as long as we see exposures, we'll know that we've got a subq 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.
Okay.
Now, levels in the CSF are not the same as levels in the parenchyma, so is more an indicator of, is the shuttle getting more drug into the brain? We can look at Roche's data for trontinemab compared to its parent molecule, gantenerumab, for precedent there. We will learn a lot, and that data will be in the middle of next year. But we will 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 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.
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? 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.
Yes.
We have not seen that data yet. That acquisition was about two years ago now. We do know that AbbVie started a multiple ascending dose in patients this summer, so we are certainly excited to see that data in due course.
Yeah. I mean, that's what I was trying to get to, that even SAD is important read, given what we saw with Aliada. I mean, obviously MAD is better.
And maybe proceeding on that topic. When we think about initial efficacy data, what's the bar there? And we will have trontinemab data in 2028. So what will be the possible read-through for your program?
Yeah. This is one of the things that I think is remarkable in how the field has evolved in the last 10 or 20 years. We can measure plaque clearance with PET tracers with high precision. Even five or 10 patients per dose, you'll see very robust data. Honestly, if you look at the trontinemab phase I/II, or for example, Lilly's remternetug, it's some of the prettiest dose response data I've ever seen. And this is for plaque clearance in Alzheimer's disease patients. So that's a very strong measure of activity, and now there have been enough molecules in phase III 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 trontinemab, that we can achieve trontinemab-like plaque clearance, we'll have high confidence in having activity at least as good as trontinemab as well.
Got it. 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. Where do you differentiate from other programs, and how should we think about the market as a whole?
Sure. In terms of analogies, Alzheimer's disease looks a little bit like multiple sclerosis a generation ago. A couple approved products. In this case, the two approved Alzheimer's products are annualizing over $1 billion 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.
Better safety, better tolerability, better convenience. We see this as potentially the next truly gargantuan market opportunity, which means that there should be multiple winners in this space. We think we've got a great shot at a best-in-class molecule with KRSA-028. We should expect that there will be other successful products as well. That means what we need to do, and we are designed for this is our lead program, this is our focus, so our job is to move our program forward as fast as we can with the best possible data. Again, that's what we're here to do.
Maybe just moving back to the program itself. Another little detail we didn't touch is about the population you're recruiting. Are you including also the APOE4 homozygotes there, and how should we think about the ARIA risk with the shuttles in that population?
Yeah. The APOE4 status does confer increased risk of ARIA, but we are bringing all comers for APOE4, just as trontinemab did. In fact, our patient population is very similar to the trontinemab population, so early Alzheimer's disease. That is because that is where we know that this class works. It also is going to enable, as best you can read across trials, that will allow us to understand how well we stack up against trontinemab, which, of course, I think investors want to know as well. The APOE4 status is something that we will track, but we will not recruit for any kind of bias. We will take all comers.
Got it. Maybe thinking forward, let's say one year from now, and after your MAD results. 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. Again, we have great precedent that we can point to. There are plenty of examples of integrated SAD and MAD. Roche with trontinemab did a MAD with expansion cohorts. The only difference is that we are putting all three together. What we would like to see, obviously, we need standard safety and tolerability. This is all going to be done via the subq route. As long as we can see plaque clearance measured with these PET tracers that is trontinemab-like or better, and we would expect ARIA to be in the single-digit percentage, right? That is where trontinemab is. As we go through the SAD, we learn about PK, the brain penetration, early safety, and then in the MAD, we will understand how active the molecule is. We will start to understand the ARIA risk.
Again, we expect low single-digit percentage because even placebo patients in this population have a couple percent.
Then 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 III.
Okay. With regard to the ARIA, is there a particular consideration for monitoring, especially for the shuttle technology? 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. 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 first six months. We agree, that's a burden. It's expensive for payers. It's annoying for patients. Patients hate MRIs, right? It's annoying for prescribers as well. Reducing that burden is going to require data, right? 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. It's just too early to know.
Okay. But the initial protocol should be similar to other companies, at least on the monitoring front?
Correct.
Got it.
In terms of the commercial opportunity, I know you are not guiding for potential peak sales, but when we think about the addressable population, there will be most likely trontinemab already there, so how should we think about that?
Yeah. I think multiple sclerosis is probably a good example, right? We should expect there to be waves of entrants with incremental improvements until we get to a molecule that is really hard to beat. We think something that is an auto-injector 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. When you think about multiple sclerosis and how that market evolved, the biggest difference is that there is something like six or seven times more Alzheimer's patients. The opportunity truly is huge.
Got it.
Got it.
Okay. Maybe, in these last few minutes, what do you think is the most underappreciated by investors of your company and different programs?
We are new to the public markets. We have an incredibly strong core shareholder group that have supported us so far. As we talk to new investors, I think they understand the scale of the opportunity, that we are built to win in this space. The biggest thing for us is honestly socializing our story, and it is 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 target. Just love to hear from you, either your view on the tau side, like how you are thinking about other sort of molecules as you progress.
Right. 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 are laser-focused on product development. We think that's where the most value can be created. We're focused on KRSA-028 and amyloid clearance, but we're not here just to deliver a best-in-class amyloid drug, right? We really want to win in Alzheimer's. Certainly we're paying attention to tau and other targets in the Alzheimer's space. There is opportunity in other neurodegenerative disorders as well. 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.
Very good, Jonathan. Thank you.
Thank you.
Thank you very much.