Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Korro Bio as part of our 2025 Global Healthcare Conference. Representing the company here, we have Ram Aiyar, who is the Chief Executive Officer. Thanks so much for joining us. How are you doing?
Great. Thank you for having us.
Absolutely. Absolutely. Look, we have a long list of questions here, but maybe before we go into individual programs, I always like to start big picture. It would be great to just maybe just some opening remarks and maybe just walk us through some of the progress that the organization has made over the last few months and maybe what's ahead here for Korro Bio?
Thank you for the opportunity, Luca. Maybe just start at a very high level. Korro Bio, or when I joined Korro Bio, the intent was to build an organization that can bring genetic medicines to large, complex, chronic diseases. Using genetics, but leveraging pharmacology was the intent to go into it. The idea of doing that was learning from genetics, making specific amino acid changes, changing protein structure, and therefore creating a toolbox for a biological pathway activation modality that does not really exist outside of small molecules. We started to do that with using oligonucleotides and a modality called RNA editing, where we use oligonucleotides to recruit an enzyme called ADAR to make a specific adenosine to an inosine change. By doing that, we can change the amino acids. Highly specific, reversible, titratable.
You can think of all the modalities that you can use, both delivery as well as potency, that have existed over the last two decades with oligonucleotide companies, and we leverage all of those learnings to develop drugs. We started the company with a thesis around, you know, let's go in with an indication where we know within 100 days, within 100 patients, we have a drug. Alpha-1 100% efficiency sort of meets that bill. It's a point mutation, a pathogenic G-to- A variant in a gene called SERPINA1, and sort of go in and fix the adenosine back to adenosine, fix the protein, and therefore should return patients back to "normal." The trick there is that we need to get pretty high levels of editing. So anything about 50% or median levels about 50% sort of gets us from a genetic standpoint to as close to normal as possible.
Beyond that, you know, we want to think about how we showcase RNA editing in its best. Our second program is, again, is a liver-targeted program. It is a pipeline in a program where we have a rare indication as well as a larger patient population. In this case, we are changing an amino acid sequence to stabilize the protein and therefore increase its level intracellularly. Again, something that you cannot do with any other technology in a transient fashion. We find that 10%-15% editing is sufficient for us to have that benefit from a pathology standpoint. Over the next few months, we will sort of highlight indication, target, et cetera, et cetera, shortly. Lastly, you know, we laid out a three-to-one strategy in January of this year.
We want to take three candidates into the clinic across two tissue types with a single platform. Our third indication will likely be in CNS, where you know we're working on a very, very novel way to modulate this protein called TDP-43 in ALS. Again, highlighting and showcasing what this amino acid change can do for that patient population in sporadic ALS.
Sure. Super helpful overview. Maybe one more big picture question before we jump into Alpha-1 antitrypsin. What's going on at the FDA? You know, I appreciate it. Obviously, you guys are CDER and not CBER, but at the same time, I would argue that probably most investors would argue that the bar, the regulatory bar, is now higher with Makary and Prasad versus maybe before with Califf and Peter Marks. One, would you agree with that? Two, how are you thinking about broader implications for Korro given that, you know, there's a chance that there's an accelerated approval pathway potentially open for you guys? Any thoughts there?
First, we may consider a rebounding exercise of moving from editing to something else. We'll come back to that at another point in time. I think that, you know, as far as Korro is concerned, we've interacted with the FDA through various mechanisms. We got our orphan drug designation in Q1. We've had a pre-IND meeting with them last year. I think that the communication channels are open. You know, we haven't seen any disruptions. I'm on the board of another company that just dosed its first patients. You know, we've submitted IND a few, you know, post all of the announcements. We haven't seen any changes. I think it's really on a case-by-case basis, you know, we'll have to think about how it actually affects each of these programs.
I mean, one thing I am disappointed by is that the exodus of individuals with experience and talent and knowledge of these technologies, I think that leveraging that is going to be hard. That is the piece that is going to be challenging. As I think about it, you know, approvals will become more challenging. Getting ready for pivotal studies gets more challenging. We will have to see how that pans out. I want to, you know, we have been asking for a regulatory reform for a really long time, and we got it, whether we like it or not. Now the question is, you know, how does that affect us? I do not have a good sense of that yet. I would like to, you know, wait and see what happens.
Specifically for Korro, the data at the end of the day is going to drive everything. You know, let's see how it goes.
Sure. Sure. No, that's super helpful. You recently presented some preclinical data at the medical meeting not too long ago. Open-ended question. Do you want to maybe recap what you've seen there? Maybe in that context, if you can talk about big picture differentiations versus some of your competitors out there.
I mean, I highlighted what Alpha-1 and 100% efficiency is. I think the biggest learning there from genetics is that, you know, when you have this mutation or the single alphabet change and you end up with a mutation called a Z allele, if you are homozygous for that, you have an odds ratio of 9 for a liver disease and an odds ratio of 9 for lung disease, specifically emphysema, over the lifetime of that. You have patients in the entire spectrum. You have individuals that have no issues all the way to individuals that have double lung and liver transplants. When you look at heterozygous individuals, about 10% of those individuals, so one Z allele and one something else, 10% of individuals that get treated in the U.S. with augmentation therapy, which is standard of care, are a single Z allele.
Clearly some environmental factor is affecting them. If you have the odds ratio is one relative to if you're a nonsmoker. Our goal when we started off designing this compound was to end up somewhere between a heterozygous individual and a normal individual with an phenotype. For that, we needed to get protein levels that were pretty high, so somewhere between 17r- 20 micromolar. When we started designing this compound, you know, we stepped back and said, okay, how do we make sure we set up for success? KRRO- 110, which is our lead asset, is a lipid nanoparticle in-licensed from Genevant, encapsulating a single-stranded oligonucleotide that makes this specific edit, delivered specifically to deliver. It goes to some of the cell types, but distribution is not very large, primarily to deliver.
The preclinical data, we've demonstrated that at median levels, we get editing at around 60%-65% over the course of two weeks in mice. That profile looks like 80% or so editing at about day two and 35% or so at 14 days post a single dose. We've shown that that translates very well to protein in circulation in this transgenic mouse model. I think that nobody has shared data like that. Nobody has shared data that is even remotely close to that with their drug candidates. The second thing that we did is we created a surrogate so that we can show that in monkeys that translation exists. There we found that the potency that we saw in mouse doubles at the same dose in monkeys, and the stability of the compound increases, which is also seen for other oligonucleotides.
You get a longer half-life. You put all of that together, you know, I think that we can achieve a very meaningful benefit for these individuals, such that we get protein levels that are in the therapeutic range within MZ, if not higher, and can get to a once-a-month sort of dosing paradigm. That will be a home run for this patient population.
That is super helpful. Can you talk about your lipid nanoparticle? I mean, on one side, you can argue lipid nanoparticle at this point, they're relatively de-risked given what we've seen on Alnylam. However, on the other side, you can argue that we've seen some setbacks from Verve in their approach. Also, we have to keep in mind that these patients do have some liver pathology that may have implications in terms of like cellular uptake, and as well as maybe the therapeutic window could be different in those patients versus patients that don't have liver involvement. How are you thinking about your lipid nanoparticle versus others? Is the fact that you use a lipid nanoparticle in a patient population that have liver involvement keeping you up at night?
I sleep very little. So, you know, up at night is not an issue. What I would say is the following. Lot to unpack there and a couple of pieces of information just to clarify. Let's start with the patient population. Okay. So there was a paper published probably two years ago talking about the heterozygosity of individuals with ZZ mutation, what their LFT levels are with correlating with BMI, et cetera, et cetera. And so when you look at ZZ individuals, their LFTs are below the upper limit of normal. Okay. So they're somewhere between 30 and 40 units per liter, both AST and ALT. So clearly within, you know, below the upper limit of normal. They then looked at patients that have fibrosis within that patient population, and still the LFT levels are below the limits of normal.
The only time where it goes above is when you have a BMI greater than 35 and probably something else is going on in terms of fatty liver or otherwise. When you start this patient population and you can see data presented by other competitors or other people in this space, you will see that the baseline levels are pretty normal for these individuals. That is the first thing. The second thing is that the use of lipid nanoparticles in patients that have liver manifestations or fibrosis has been done in the past. In each of those cases, the dose-limiting toxicity has been infusion-site reactions, not necessarily issues around transaminase increases or LFT changes.
As an example, there's a company that has done mRNA in a lipid nanoparticle once a week, not at doses of 0.6 mg per kg, and have not seen any changes in transaminase levels. There's a company that, a large company that's done every two-week dosing of an siRNA encapsulated in a lipid nanoparticle for 36 weeks, no changes in LFTs. In fact, they actually did it in a patient population that had fibrosis and still saw no impact on liver elevations. Okay. We have a competitor that recently presented data at doses that were, say, at the same dose levels that the company you mentioned had issues with. When you think about the amount of lipids that they're providing versus how much we are providing for a mg per kg basis on a weight-to-weight basis, it's two times what we do.
That means that if you correlate, we should be good at 1.2 mg- 1.5 mg per kg. That's on the LNP. I think there's information there that's not right. If you go back to patisiran, the dose-limiting toxicity there is also infusion-site reactions, not liver changes. For whatever reason, humans deal with lipids better than animals. I'm really not keeping away because of that. What I am interested in doing is what's the lowest dose in which we can see the highest protein levels? The higher we can dose, the closer we can get to normal, and the closer we stay in normal, and the longer the duration. My expectation is that our dosing frequency is somewhere between once in three weeks to once in six weeks. We'll have to see where we get to from a dose standpoint.
I think you spoke about differentiation, we're the only ones that have shown with the drug candidate that we can achieve 80% editing in vivo in any animal model. We've achieved that with a single dose.
I know that's actually very helpful. How are you thinking about the, well, let me actually first start a question. On the upcoming data, that's probably more important. Let's talk about that. Maybe just walk us through how many patients will show us, what's the follow-up, what doses, what should we be focused on? Obviously, everybody's going to be focused on the total level in the serum as well as obviously the Z and the M, but like is there anything else that we should be focused on? Maybe just walk us through scenarios where it's slam dunk versus base case versus downside case type of setup.
I'll answer the last question first, which is, you know, as long as we beat whatever the bar is at the current moment, I'll be happy. And that's, you know, we'll have to see what the data comes out at. So maybe orient people as to what the rewrite study is. That's our phase I/II study for KRRO- 110. It's a two-part study. The first part is a single ascending dose. The second part is a multiple ascending dose. We haven't disclosed a whole lot on the MAD portion. We have disclosed a lot on the SAD portion. The SAD is across eight cohorts, six in healthy volunteers, two in ZZ individuals. The six healthy volunteer cohorts is placebo control, two is to one, six in total. And then the PIZZ portion, we've actually removed the placebo and made it open label. So four patients in each cohort.
We started the single ascending dose in healthy normal volunteers so that we can get to a dose level that's meaningful to take it into the PIZZ individuals. We are close to that dose level in terms of starting to dose individuals. That was a way in which we, one, get patient buy-in and not treat at a subclinical level for these individuals. What we will show as part of this second half data release, my intent or our intent is to show all eight cohorts at the same time. This means that we'll get safety tolerability from the single dose. From the healthy normal volunteer cohorts, our intent is to go higher than what we would in the ZZ individuals. In the ZZ patients, we want to look at both safety tolerability as well as we want to look at activity.
From an activity standpoint, I want to highlight over a course of, you know, two weeks to a month, what the peak levels are, what the profile of the drug looks like, you know, how much of it is M, how much of it is Z, how much of it is total neutrophil elastase activity ex vivo in terms of what that means. Just showing that profile over the two cohorts with the dose response, I think will answer questions around durability, translation, protein levels, safety, you know, all of that will sort of get laid out. That is our intent to show the entire comprehensive data set at one shot.
All right. That's actually helpful. What's your take on the Z protein? I mean, when you look at the Beam data, Z goes down. But I think if you do the math on the Wave data, actually Z goes up. So what's the best way to kind of rationalize that dichotomy, if you will, and what do you think is a reasonable expectation for, given your mechanism of action, what you're going to show?
I will let you speculate on what the others have shared. What I would say is that as far as I'm concerned, the genetics tells you a lot. If you have a single Z allele, MZ heterozygous individuals, the ratio of Z to M is somewhere between 20%-40%. If you look at what's in published literature in terms of how much of that gets aggregated within the cells versus not, 6%-10% of the cells have Z aggregates within that liver, even in an MZ phenotype, right? Which is why the odds ratio is 1.5 and it's not one. When I look at the total protein level, my assumption is that there's going to be 30% Z if you are editing at 50% and 70% M. Anything higher than that, you're going to see a decrease in Z.
Anything lower than that, your bet is as good as mine. I think that I would anticipate that depending on how high the level of editing is and how much protein is sort of out there and what the half-life of the protein is for Z versus M, you're going to see a range of that ratio through this treatment. Because this is a chronic therapy, we're going to fluctuate in the editing levels. You know, we'll see that in humans. It'll be a little bit more nuanced than it is in mice and monkeys or more stable, but you know, you're going to see that. I also think that you're going to see a bolus of Z come out every time you give an additional dose because it's like, it's almost like a transporter mechanism.
You get M out, you're going to pull some of the Z out, which is great from a liver perspective because if you start to look at improvement in the liver, if you can push out all of the Z, you're likely going to see that. If you don't, you're going to get stuck. That's my hope.
That's super helpful, very clear. Maybe pivoting to regulatory. You know, there's obviously a precedent out there with augmentation therapy being approved on, you know, surrogate biomarker with the serum levels. However, there's a debate on whether that's going to continue going forward or not. You know, there's a debate on whether you need to show something beyond just serum levels. You know, either FEV1 or some functional benefit or like what gives you confidence that the accelerated approval pathway here remains open? Maybe related to it, how are you thinking about a potential confirmatory trial or what are the functional endpoints that you're focused on for your therapy here?
That's a very complicated question. It depends on which therapy, you know, how you respond to that. There's not one size fits all because there are folks that are using an antibody as augmentation therapy, right? It's not really the protein. There are others who are making a variation or a mixture of proteins. That's not really a good estimate. We'll have to see based off of the data set that we generate, you know, how we have these conversations with regulators. My hope is that the accelerated path is open in the context of you show it's the M protein, you show that it's at levels that are as close to normal based on genetics. You can have a reasonable argument in terms of benefit. You can then show that it's glycosylated and performs as similarly to a protein that is during an inflammatory state or otherwise.
It is repeatable. I think if we can show that just on the protein levels, I think that we have a reasonable shot of having a discussion with regulators on accelerated approval. In addition to that, if we get editing levels above 50% at any point in time and we can show a benefit in the liver in a reasonable timeframe, that is a second shot on goal that we can achieve if we were to get editing levels above 50% even for a brief moment in time. Mining all of that composite information, I think is what we would like to take to regulators and say, hey, you know, this is what we want to do.
Very helpful.
Which is not the same for, you know, an antibody, which is not the same for a gene therapy, et cetera.
You don't think that the inhibitors, because the one way to look at it is that last time the FDA actually set a regulatory comparator is actually inhibitors. And inhibitors was actually asked to run a superiority trial versus the current standard of care where the primary point was actually, you know, a higher level of serum for one protein in the serum. Like is that not the right way to think about that's the path for an accelerated approval or?
We'll know pretty soon, right? Because they're going to present data shortly. So we'll find out.
All right. Okay. Very helpful. Very, very helpful. Maybe I do want to follow up on that one. How are you thinking about functional endpoint? What are the functional endpoint that you're focused on at this point? Again, FEV1, CT densitometry, or is there any other endpoints that you think are going to be meaningful to actually show that your therapy can drive the benefit for patients?
I think we're going to measure FEV1. We'll measure spirometry, we'll measure FVC, we'll measure all of the things that we need from a functional volume standpoint. I wouldn't want to put a hurdle on that being the primary endpoint for us to look at in the clinic. I think in our minds, the accelerated approval path exists or one with the protein levels and showing that it's functionally the same. There is data from augmentation therapy in terms of a certain threshold protein levels that have shown benefit. I think from a European standpoint, we'll have to show CT lung densitometry, which we'll, you know, we will measure. There are some things that we can work through, but again, at this point in time, it'll all be speculation until we have data from our phase I/II study and have a conversation with regulators.
When is the next conversation with the regulators? Have you disclosed that or what kind of meeting are you planning to have? What's on the agenda for that meeting? Just walk us through that part.
First we need to file an IND and get approved to start treating in the U.S. We have a jurisdiction in Europe that we have our eyes set on. We need to do that next. At some point in time after our SAD data, given the pathways we have for U.S. FDA, we can engage in a conversation. The goal would be at the end of next year to have guidance in terms of what the pivotal looks like.
Got it. Got it. Super helpful. In the last maybe 30 seconds or so, maybe just remind us your runway at this point and you know, it's a tough environment out there. How are you thinking about financing the company?
We have in our last disclosure for Q1, we said that we have a runway into 2027. Our cash on balance sheet is about $139 million. We have a collaboration with Novo where we have nominated our first target. We have not nominated our second target. The runway does not include any of the milestones or the efficiencies we get from working with a partner like Novo . You know, we will have our second asset nominated and in the clinic sometime next year. I think we can hit a bunch of milestones between now and the end of early 2027. That was really the goal.
Got it. Super helpful. I have a lot more questions, but one more time. Ram , thanks so much for joining us. Thanks everyone for joining this conversation and we'll talk soon.
Thanks again.
Thank you.
My pleasure as always.