Cyclerion Therapeutics 3rd Annual Guggenheim Healthcare Innovation Conference

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.