Welcome, everyone. We're going to go ahead and get started. So welcome to day two of the Evercore ISI Annual Healthcare Conference. I'm Gavin Clark-Gartner, one of the senior biotech analysts here, and really happy to kick the day off with Ram Aiyar, who is the CEO of Korro Bio. Thanks for joining us, Ram.
Thanks for having us, Gavin.
Absolutely. All right, why don't you just start us off, overview of the company, where things stand today?
Yeah, so as of today, Korro Bio is a clinical stage company. Our focus is on RNA editing. We have our lead program that we have taken towards the clinic, gotten approval in Australia to start a clinical study. We anticipate dosing, as we said, in Q1 of 2025. The company is focused on RNA editing, the idea of switching a single base on RNA using an oligonucleotide, think of Inclisiran for editing. The thesis for the company was always around activation of a biological pathway, and so staying away from knockdown of proteins, staying away from knockdown of biological pathways. It's a sandbox that we play in. That may seem like a small sandbox, but hopefully we'll be able to show what the breadth is. The company was founded in 2018.
Operation started in 2019, and over the last, call it, four years, we've sort of built a pipeline around multiple programs that we'll hope to demonstrate over the next year or so. As of Q3, we have cash of about $169 million. That gives us runway into the second half of 2026, enabling us to meet multiple milestones for our lead program as well as for other pipeline programs.
Yeah, great. Maybe a good place to start then, just thinking about delivery in general. Hot area of debate, GalNAc versus LNP. What are you guys using? What are your views there?
Yeah, I think, so just taking a step back, right? RNA editing as a modality before October was pretty new, untested in humans. We didn't have a good perspective on where things are. Does the biology really work in humans? As we started out the thesis for the company, we wanted to take multiple layers of risk off the table, right, so to go into Alpha-1 was a little bit of a no-brainer. It was a pathogenic G-to-A variant, large commercial opportunity, known for investors in terms of what that opportunity is, and it has a circulating biomarker, and so the only issue with the consideration for Alpha-1 patients is two things. One is you want to get editing really high so that you get a large amount of protein. This is the fifth most concentrated protein in the body in circulation, so large amount of editing.
And then the second perspective is that you needed to get high editing. From the liver standpoint, the more cells and the more transcripts you get out of the liver, the better the outcomes from a liver perspective as well. And so when we put those two together with a novel modality, we wanted to give it the highest likelihood of success. And so that's how we picked the delivery in that context to say, let's go with the first generation using a lipid nanoparticle that's been tested in the clinic. And then from a lifecycle management standpoint, once we know that this works in humans and we understand what potency is going to look like, we can come back on board with a sub-Q more convenient therapy. And so that was the intent of picking the LNP versus the GalNAc perspective.
We'll have to see how that plays out because there's a regulatory perspective that's moving in terms of all the competitive landscape. And so that was the third reason that we picked an LNP because we wanted to get as close to normal as possible in these patients. I'll stop there. I can continue. The choice of LNP versus GalNAc is an interesting one because it's not an either/or. It's a question of where the technology is and where you can see it in humans and how do you show benefit for patients. And so that was really the choice. As an example, our second program, which we haven't disclosed the target and we haven't disclosed the indication, is a GalNAc conjugate, which will be sub-Q. And for that patient population, that makes a lot of sense.
Yeah, that preempted my next question. That makes perfect sense. All right, so let's turn over to your lead indication, AATD, and go in a little more detail. Maybe one place to start, and this is more of a relevant question going back a couple of months, but I think it's still relevant, which is AATD is a very logical indication from an ADAR editing perspective. But as you said, very high editing efficiency is needed just given how abundant the protein is. What do you see as kind of the main barriers to editing in AATD, and why did you choose this as your lead indication?
Yeah, so Korro is not my first rodeo from a biotech perspective. And so I think your lead program success and showing a novel mechanism working in humans is actually very, very important. And so when you think about delivery, multiple ways to get to the liver, when you think about the indication itself and the unmet need, and you think about looking at target engagement and potential activity in humans, it sort of checked all of the boxes in terms of this is a good indication, i.e., single point mutation that's pathogenic, delivery to the liver with multiple modalities, biomarker in blood that can be quickly detected. And so within 100 days and within 100 patients, you will know if you have a drug that works or not.
Thinking about the disease manifestation, how important do you think it is to address both the liver and the lung phenotype at the same time?
I think that's a critical component, right? So that's where the elegance is rather than fixing just on the DNA or otherwise, and so the elegance here is by correcting or repairing the protein, you actually push out these polymerized crystals that are in the hepatocytes that cause the issue out and correct them, and then you also have enough in circulation. The third component is that this is not. We're not putting an exogenous amount of protein that is dependent on PK or otherwise. When the body needs more, it's going to transcriptionally regulate and we have enough oligonucleotide to support a need for more protein when it's needed, and so all of those pieces fit in a very elegant solution, and that was really the thesis behind it.
Yeah, and not to jump too far ahead, but I think it's worth kind of having a view of the end goal, which is thinking about the regulatory perspective. Do you have any early indication whether you may pursue more of the lung approach using serum AAT as a potential accelerated or maybe more of the liver approach, which may require a placebo-controlled trial? Any early thoughts there?
My experience in multiple companies has been we can have those conversations with the regulators. It's best to show up with data and have tangible inputs in terms of what could be meaningful for patients, and so that's a discussion we'd like to continue as soon as we have human data. It's hard to predict because each modality is slightly different, right? Because in our case, we're making a very specific edit. We're returning the protein back to normal. If we can return it back to normal levels in humans, there are a lot of things that are working for us in terms of having that conversation, but best to have data before we have that conversation.
Yeah, I think that's very fair. And I think the next question ties into that one, which is essentially when you're thinking about your proof of concept data as it does emerge, what is your target level as you're thinking about steady trough on serum AAT?
Yeah, it's hard to answer that without actually seeing data in humans. What I would say is that the work that we've done between the mouse in the transgenic PiZ mouse, the surrogate information that we've got from the mouse plus the monkeys, and then now an inkling of data from one of our competitors, I think that we are well set to get to threshold levels as close to normal as we can. But we'll need to find out in the clinic as to how much we can dose. There are some considerations around lipid nanoparticle where there is going to be acute impacts that we're going to have to see and manage. We believe that we have a large therapeutic index based off all our preclinical studies. And so I think it's going to be dependent on what we see in humans.
Yeah, and historically, some other players in the space have indicated 11 micromolar based on the IV augmentation therapy, maybe a reasonable precedent. Personally, I think the field is moving more towards a 20 micromolar level with inhibitors and other approaches. And I think the SPARTA trial might be an interesting one reading out in 2026, maybe informative. We will see. What do you guys think about the, I guess, that shifting paradigm?
Yeah, the next two years are going to be very interesting. I think there is definitely information out there in terms of what regulators could approve versus not approve. Again, I think that it's hard for me to say what that path is going to be and what that threshold is going to be. What we do know from clinicians is that more is better. What we do know is that if you edit more, the liver gets better, right? And so if you get a threshold level of 11 micromolar, let's say the peak of 11 micromolar, that's somewhere between 10%-15% editing based off of allele frequency and genetics. And so if you want to get much, much higher, which is MZ is 50%, we have a long way to go to be able to get there.
I think that that's, like I said, we need to come back with data and answer that question. Your point is valid, though. I mean, there is a double-dose study from Takeda that's going on. That's a SPARTA study for 20 micromolar. Inhibrx has said something around the context of at least from a PK standpoint of 20 micromolar. But they are different modalities, right? Having that discussion is going to be important.
Yeah, I think that's well said. Maybe you could just recap your preclinical data. Don't want to go into too much detail, but editing efficiency, where that puts you as you look to enter the clinic.
Yeah, so we've done, I mean, so just taking one step back, so the way we designed our compound is entirely in human iPSC-derived human hepatocyte-like cells, okay? So human ADAR with the human Z allele. We then tested it in MZ hepatocytes. So if we look at one in 23 individuals, Caucasians are actually MZ phenotype. So you can get those hepatocytes and test them out. So we know that we have a dose curve in that patient population. And then we've done the monkey studies to understand what we see in the rodents. Does that correlate from an allometric scaling body surface analysis? And we've sort of checked that box as well.
So all that said, I think the data that people pay most attention to is a study that we did in PiZ mice, which is the NSG immunocompromised mice where we did dosing once every two weeks at 2 mg per kg. And we demonstrated that even with a single dose, we could get to median levels seven days post the first dose because from an LNP standpoint, you see efficacy in the one to two days first and then sort of tapers down. So we see median levels of 50% editing and then AUC levels as we continue to dose by week nine. And then week 13, we hit a steady state where we see north of 60% editing one week post the last dose.
Just thinking about the PiZZ mouse model, it hasn't always translated very well with other approaches, specifically correctors. I don't know if part of that is the relatively rapid loss of transgene expression or something else. Do you have any initial thoughts on that?
Which is why we didn't do only that, right? We did. There is a C57BL/6 model that was generated by Teckman, or at least he holds it, Jeff Teckman, who's a KOL leader, one of our SAB members, so we took mice from him. It was a more robust liver-based model, and so it has a different set of copies, different background, and so we demonstrated in that as well from a % editing standpoint, even though the copy numbers are different, we get to the similar levels.
That makes sense. And do you have any view on how much accumulation you'll see over time as you move from single to repeat dosing?
Oh, that's a really tough question to answer. I mean, what I would say is that we have modeling that's done that demonstrates that we can provide some durable impact in patients. Just as an example, when we did, so we created a surrogate. I keep referring to the surrogate. The surrogate is, we identified a target adenosine that's seven to nine amino acids away from the E342K site. We chemically similar to our initial compound and showed that what we see in mice, something around 25% editing at day four, we see about 50% editing in the monkeys at day five and seems to last longer. And so when you look at stability of these compounds, oligonucleotides in general are, the mice are harsher, monkeys are less harsh, humans are less harsh.
We know we can achieve greater than two-week, three-week dosing in monkeys. In humans, depending on the dose, we think that we could get to once a month dosing subject to how high we can go. When you sort of play that out, I think we're in the range of what could be meaningful for patients, which current therapy is once a week infusion, right? The balance, of course, in people's minds is, well, how does that correlate with a GalNAc therapy versus something that would be an LNP? The question, of course, is how high is the protein level for a once a week, once a month IV versus a subq dose that we'll have to see where it gets to.
Yeah, that's fair. And it's probably worthwhile, just given the relevance of Wave's update, to make some initial comments. What do you think? And obviously, we haven't seen the full data, so there's still a lot to be determined. But any initial thoughts on that?
It's not our data. So I don't know if it's appropriate for me to talk about it. What I did or what we were excited about, and I think investors were excited about, is that this mechanism works in humans. And that's a great place to be because then now you can start to think about what else you can do. And it's a question of an engineering problem of potency, right? Because you have different mechanisms to deliver to different tissue types and ensuring that we can get potency to where SIs and ASOs are.
Are we able to make any rough cross-trial comparisons with your preclinical data, their preclinical data to mix and match?
We have internally, but we haven't shared it publicly. That's what gives us the confidence that as we get to the clinics, the levels that we're looking at, we'll be able to identify a dose that's very meaningful. That's actually just a segue into the clinical study that we're currently planned. We file in Australia. Part of the reason why we file in Australia is the speed at which we can go and start those clinical studies. The requirements in Australia are no different than the requirements elsewhere from a rigor perspective, from a submission standpoint, and so the way that the study is set up is a two-part study. The first part is the SAD. The SAD includes up to 64 patients, sorry, 64 participants, a mix of healthy volunteers as well as PiZ individuals.
We haven't really said how many yet, but the idea is to get to a dose that's therapeutically meaningful and start to treat PiZZ individuals and see what the impact is. That's the fastest way without losing patients and also getting data in a very meaningful range. Then we'll do a MAD portion and a multiple ascending dose setting. We'll test out a couple of different dosing regimens. But once we identify what the data looks like at the end of next year, we should be able to get into the MAD pretty rapidly. The one additional point is that Australia is where we're starting. Our intent is to be in multiple jurisdictions by the time the MAD study ends.
Okay, by the time it ends, you're planning to do the whole MAD portion in Australia as well?
No, TBD. I think that we want to make sure that we get in multiple jurisdictions before the study ends.
Okay, that makes sense. In the MAD portion, that's only going to be in patients?
It's only going to be in patients.
So then for the SAD portion, how exactly does the mix of healthy volunteers versus patients work? Do you have to start like a cohort or dose in healthies to clear that before going to patients? Or why couldn't you start right in patients?
We could. I think for a novel therapy to start in patients at sub-chronic doses, it's borderline unethical to bring patients and give them a drug that you know is not going to work, and so part of that reason is to start in healthy normal volunteers.
What are your current plans for data disclosure for the trial? Whether you're going to show some earlier looks in the SAD, later looks in SAD, wait for MAD?
It's a placebo-controlled study, double-blind. So I think the ideal scenario would be to wait till the SAD portion completes, walk through all the dose cohorts, ideally show a dose response in PiZZ individuals. But it just depends on how things go from a recruitment standpoint. We're confident that we can get there. And so ideally, that's the data that we'd like to share. So as time progresses, we'll give more updates in terms of what that data looks like.
All right, that's fair. Thinking about the rest of the pipeline, you noted one of the rare metabolic liver programs earlier. Roughly when should we expect disclosure? Is that going to be associated with any type of company event, et cetera? What are the plans there?
We haven't publicly disclosed when we would do that. I think the intent there for us is to, because if you remember, one of the strategies for the company was Alpha-1 from showing the mechanism works as we discussed was ideal. But beyond that, the power of the technology is creating these novel variants and variants of proteins that are overactive or activate a biological pathway. And so that second program is specifically in that area. It's in the liver because we know ADAR works in the liver, so why go somewhere else? And I think we hope to show data next year in terms of what's the preclinical evidence and hopefully share what the indication is and what the data is.
Awesome. And I'll squeeze in one last question since we're just over time. Maybe you could quickly touch on your CNS delivery capabilities, quickly highlight the Novo partnership or anything else we didn't really get to discuss.
Yeah. So CNS delivery is a little bit early. We'll hopefully start sharing data in terms of the biology over the next months, upcoming months. I would say we entered into a partnership with Novo to really expand getting into large patient populations. So Novo is not interested in an IV delivery from an LNP standpoint. When you go to millions of patients, you want a sub-Q therapy. So that's what we're working with them on. We have a cash balance of $169 million as of Q3. So we have enough runway to get into the second half of 2026 where we should be able to read out not just for Alpha-1, but also preclinical data and multiple milestones for some of the pipeline programs that we anticipate. The Novo collaboration is a very interesting one.
I mean, there is great excitement on both sides in terms of where this modality can get to. And they are very well aligned in terms of the activation of the biological pathway that we're interested in. And so hopefully we can share data from that collaboration over the next upcoming months.
Sounds great. Well, look forward to speaking again soon. Thanks for being.