Good morning, everyone, and welcome to the Jefferies 2024 Global Healthcare Conference. It is my pleasure to now introduce Ram Aiyar, Chief Executive Officer at Korro Bio. Just a reminder that this will be a 20-minute presentation with five minutes of Q&A.
Thank you to the Jefferies team for the introduction and the opportunity to present here. I am Ram Aiyar, President and Chief Executive Officer of Korro Bio. Here are the traditional disclosures, so today I'm going to tell you a little bit about Korro. I'd like you to leave with three things today. The first one is we are a platform company that works on oligonucleotides to edit RNA, and we do that with a simple drug product by converting an adenosine on RNA to an inosine. I'll come back to how we actually apply this. The second thing I want to leave you with is our lead program, KRRO- 110, is an oligonucleotide for Alpha-1 Antitrypsin Deficiency. It is a program that we anticipate dosing in Q1 of next year. We're very excited about this program.
It's a way to correct the mutation on the RNA rather than on the DNA. And I'll tell you a little bit about why we think that's a best-in-class opportunity. The last thing I want to leave you with is looking ahead. RNA editing has a lot of opportunity in this space. We're starting to educate the community in what those possibilities are and to highlight that through a pipeline that we hope to develop over the next couple of years. Just some insights into how we do that was the last thing that I want to leave you with.
We have a cash runway that extends into the second half of 2026 that enables us to execute on not just the lead program all the way through conclusion in the phase I-II study that I'll talk to you a little bit about, but also on additional pipeline programs that we think about expanding beyond the lead program. Finally, we have a collaboration that we announced in Q3 of this year with Novo Nordisk. It's for up to two targets in the cardiometabolic space. It really brings together our vision of getting RNA editing and genetics into larger patient populations. And so that collaboration will give us additional capital and milestones as we take those programs into the clinic. Just wanted to highlight the team. We have a very, very strong team in the context of drug development.
These are folks that have greater than 25 INDs under our belt, up to nine products that are currently available on the market. And we bring a very diverse set of skill sets, both from an operational standpoint as well as on a strategy perspective. We have a very strong board. As you can imagine, we have folks that started companies like Intellia, have a sense of where the gene editing technologies can go. We have somebody like Rachel Meyers, who was the former CSO of Alnylam for 19 years, taking those programs all the way to the clinic. So we bring together a board that is operationally savvy in terms of the oligonucleotide space that we are in. So what are we doing with RNA editing? If you look at genetics over the last 20 years or so, we've made a lot of progress.
First, we started to look at rare medical diseases in the focus of what could be causal pathways where a single point mutation or a single gene has a huge impact on the disease. It turns out that those populations are very small. And from a prevalence standpoint, they don't necessarily have an impact from a commercial standpoint. From a therapeutic perspective, there's a big need. But really, as you think about large patient populations, there's never been a great translation outside of PCSK9 where you can think about applying some of these drugs. Over the last 10 years or so, people have started to interrogate the genome more, and they find that they know less than they used to know. And then they've started to make some correlations in terms of causal missense variants in complex diseases and how do you start intervening in that space?
siRNAs and RNAi and other gene therapies exist where you can knock down something that's pathogenic. Well, there's nothing really there in going after large heterogeneous populations to repair or fix some of these causal mutations, or in some cases, use those variants to actually drive pharmacology in a way that you've never been able to do before. And so what I'm going to show you today is that the platform that we've built, we use it just to activate a biological pathway and provides a very unique and a niche sandbox where we can play in where we don't compete with any of the others. So how does this work? Much like siRNAs and antisense oligonucleotides, there is an enzyme called ADAR, adenosine acting on RNA.
This enzyme inherently in all of us makes a specific alphabet change, so converts an adenosine to an inosine, an A to an I on RNA. At any given moment in time, 2%-3% of our cells, this is happening. So it's not a new process for the body. The way that it happens is it recognizes double-stranded structures where it finds an adenosine, stochastically looking at it, and then converts that adenosine to an inosine. The reason this enzyme exists is twofold: one, for protein diversity, and two, for recognizing self or non-self. So that's the genesis of the enzyme. So what do we do? We create those double-stranded structures by delivering a modified RNA. And so we can identify specifically the adenosine that we're going after, the secret sauce is in the design of these oligos that are very different from siRNAs and RNA interference compounds.
And we can direct that ADAR enzyme that's inherently present in all of us to go and make that specific change. So it's highly specific, highly titratable, and reversible. And so it brings together a lot of ways in which you can apply it. So where can we apply this? So when you look at central dogma going from left to right, you start with DNA being transcribed to RNA, goes through some processing, and then finally becomes the protein, which is the business end of the deal. So there are two places where we can intervene.
The first one is where we can upregulate gene expression in a way that we learn from genetics and say, "Okay, this specific adenosine here can have an impact on gene expression both up or down." So you can enter with pre-mRNA, edit that specific site, and alter the expression of a certain protein. The second way, and we think this is more exciting and more differentiated even relative to the folks in the RNA editing spaces, we can actually induce a specific adenosine to inosine change and therefore change the amino acid codon that's on the protein. By doing that, we can add additional functions that we couldn't have done before, and so think about stabilization of proteins, think about hyperactive variants. These are areas in biology that haven't been perturbed that we can learn from genetics, build novel IP, and that's how we've really built the platform.
But to get there, we need to start with showing can this technology work in humans, which is where we start with our lead program in Alpha-1 where we repair a pathogenic G2A variant. That's how we built our platform. Our platform consists of four pillars, the first one being a deep understanding of ADAR biology. Josh Rosenthal, who's one of the founders in the company, has spent his entire life studying cephalopods, in cephalopods, the activity of ADAR. The second pillar is the expertise in oligonucleotide chemistry we bring. If you look at the board as well as the team, there's over two decades of experience in oligonucleotide discovery as well as development. And finally, you can't talk about oligonucleotides without talking about delivery. Here, we're removing layers of risk off the table. And so we use delivery that's precedented. We're not reinventing the wheel.
We're leveraging delivery that already exists. So the only risk that we take as we go into the clinic is does this work or not, and does this work effectively? The last component I'm not going to talk much about today is, modified RNA is very ideal for using machine learning tools that have been developed over the last few decades, and so even our lead compounds are actually semi-supervised where a user and the machine actually designs these compounds, and at a later time, I can tell you a little bit more about it, so what does our pipeline look like? Again, when you think about building a company, it's all about removing risk. Our lead program, KRRO-110, which will be in the clinic early next year, or we anticipate it being in the clinic early next year, it's a pathogenic G2A variant.
The only thing that we're testing with that compound is can we get the M protein or the protein levels to what is clinically meaningful? And I'll walk you through that data in a second. Beyond that, we look at other areas where oligonucleotides have been delivered, so areas in the spinal cord, areas in the liver, specific tissue types where there are approved therapies. And so as we go through our pipeline, you will see that outside of Alpha-1 and outside of one other program in the CNS, all of our other pipeline programs are focused on this de novo protein variant where we can provide a benefit unlike some of the other companies. As I said, we have a collaboration with Novo Nordisk that we just announced. It's up to two targets on the cardiometabolic indications.
We haven't disclosed what those indications are and how we're actually even delivering it and what those targets are. So I'm going to skip through the platform for a second and just focus on our lead compound, which is KRRO-110. Before I do that, the one thing I wanted to touch on, because this keeps coming up often, is delivery. Delivery of oligonucleotides is very important. The reason why we say fit-for-purpose delivery is depending on the indication, depending on the protein, depending on how you need that PK/PD to play out, you want to align delivery appropriately. So what I show here on the left-hand side is a compound or a target called beta-actin that we've delivered in mouse, showing that GalNAc conjugated subQ delivery for multiple targets is very possible.
And we've demonstrated that not just with one, but with multiple targets, both in mice as well as, as you see over the next coming months, we'll show in monkeys. On the right-hand side is a similar compound being delivered using a lipid nanoparticle. And so as you see these profiles in mice, you can see that over time, the GalNAc conjugates in the liver stabilize, whereas from an LNP perspective, you get a large amount of editing or a boost that you don't see with GalNAc early in the delivery process. That is important because for certain indications, you want to get a faster onset of action, and you want to have higher levels of editing rather than convenience. And this will play in together as we think about Alpha-1 and the choice that we made of going down the lipid nanoparticle path.
Most of you probably know this indication, so please bear with me as I tell you just a few tidbits. We hope to show that with data next year, the potential for our best-in-class profile, so Alpha-1 is a very common, although it's a rare disease, it's a very common rare disease with about 100,000 or so patients in the U.S. and 100,000 or so patients in the rest of the world. Specifically, it's caused by a single-point mutation. This is, again, a guanosine to adenosine, a G2A mutation that happens on a gene called SERPINA1. Physiologically, this gene regulates a protein called Alpha-1. Alpha-1 is an acute phase response. It reacts to when you get a wound. It gets upregulated. The idea is that when you get injured, neutrophils come in, or when you get an infection, neutrophils come in and mop everything up.
Alpha-1 is a stop signal to prevent the neutrophils from eating cells. Under normal physiological regulation, it's produced primarily by the liver cells, and it flows across the body. When you have this variant, specifically the homozygous two alleles of this variant, you end up in a scenario where the protein misfolds, starts to aggregate in the liver. Think about plaque, think about crystallization of this protein in the liver cells, and starts to degrade and starts to create fibrosis. That's the toxic gain of function that you see in these liver cells. The problem with that is now you have all of this plaque or accumulation of the protein in the liver, but nothing in circulation, which is where you really need this protein to be. You only see some of the protein out in circulation.
Because you don't have enough, where it manifests is when you get an exacerbation or when you get an injury primarily in the lung or the skin, you start to see this fibrosis. You start to see deterioration of the cells within the lung because neutrophils are just eating those cells. You get the toxic loss of function of this protein in circulation that causes the lung disease. It's a very unique place where we can, if we were to correct this mutation and bring it back to normal levels, you can affect both the liver as well as the lung at the same time with a single edit. That's the elegance of Alpha-1 and using RNA editing here. Bear with me for one more moment. This graph is a little bit complicated, so I'll just walk you through it.
The top shows protein levels for the different genotypes. So starting from the left, which is the normal, you see the median levels of the protein are close to 30 - 35. And when you go all the way through the ZZ homozygous individuals, the median levels of the protein are somewhere between four and five micromolars. Remember, Alpha-1 as a protein is the 5th most concentrated protein in blood at baseline level. When you have COVID or when you have an infection and you are sustained in the ICU, these things go up to 90 micromolars in that setting. So it's regulated very, very highly. So as you can see, you can see a straight line between those median. There's a regression line you can draw and say, "Okay, if I have 100% editing, I'm in the phenotype.
If I can convert the Z to an M, both alleles from the ZZ phenotype, if I can get 50% editing, I end up with the MZ phenotype, which is one allele of M and one allele of the Z." That is important because as you look at the table underneath, it shows an odds ratio for each of those genotypes for two different diseases, both for the lung with COPD as well as for the liver with cirrhosis. And you can see if you have an MZ phenotype, you have over the lifetime of this phenotype, you end up with not much lung disease, but a slightly elevated odds ratio from a liver standpoint. So if you look at that data, the goal for us is, can we get to 50% editing?
And can we get higher than 50% editing? Is the goal for us as we go into clinic? Because that will enable us to get to a point where we can show therapeutic benefit over the lifetime for these patients. So KRRO-110, as I mentioned, is an oligonucleotide. It's encapsulated in a lipid nanoparticle. It is delivered IV. As it's delivered IV, the target organ that we want to go after is the liver. 90%+ of this LNP and the oligo ends up in the liver. The goal is to edit a certain percentage of the transcripts. And again, I'm talking about RNA, not DNA, so across the entire liver. And so you end up with a fraction of both M as well as Z protein in circulation. And our goal is to hit MZ phenotype at base and then hopefully above.
One of the things that has come up in the context of both gene editing as well as from a regulatory standpoint is, what do off-target edits look like? Here we highlight in human MZ hepatocytes. So taken from individuals, turns out that one in 23 Caucasians is an MZ individual. So we found these cells and showed that when you do edit, we get a very clean profile. And it's unique because the SERPINA1 location, the E342K location, has about seven adenosines- nine adenosines close by. And so the challenge there is that if your edit is not very precise, you end up creating mixtures of proteins that are not very good. Not very good from a regulatory standpoint, not very good from a functional activity standpoint. And so here I show that all of the edits that we make are below the lower level of detection anywhere around.
And the one that we do edit, you can see at the site that we can edit close to like 90%. So what does this look like pharmacologically? So we've tested this compound in multiple different models. Here we show one, which is the NSG- PiZ mice. This is a human transgenic mice with the ZZ allele knocked in. This mice progressively shows a decline in function. And so the goal here is to just really understand PK/PD relationships more than anything else. In this mouse model, we've achieved greater than 60% editing one week post the last dose, which is actually pretty important given the profile I shared earlier on delivery. As I said, with an LNP, you see higher amounts of editing early, i.e., early after dosing, and then it tapers over time.
So we're looking at 60% editing somewhere in the middle with an AUC above that for this mouse model. So on the right-hand side, I show that even with a single dose, we get up to 50% editing. And then over time, that accumulates getting above 60% editing over that 13-week period. The administration is once every other week for 13 weeks. So what does that look like from a protein standpoint? On the left-hand side, I show the shaded region is the Z protein. The solid region is the M protein. And you can see that over time, an increase in M protein to pretty high levels, close to 60 micromolars in circulation. And the right-hand side is just highlighting at week 13, we looked at, is this protein active? And so just showcasing that compared to the control, you do see activity over time.
I'm not going to go into the translational data, but just wanted to leave you with we filed with the regulatory agency with HREC in Australia to start the study. We hope and anticipate dosing participants as early as Q1 2025. We hope to grow these clinical sites and the number of patients over the next year so that we complete both our part one SAD in both healthy as well as Z patients, and then our part two of MAD in just Z patients. Look forward to hearing more. As we get approval, we'll share more details. The primary goal for this study is safety, but we'll also look at efficacy in the MAD portion in terms of total levels of protein and how active they are over the period of dosing. And with that, I will stop and happy to take any questions.
I'll pass the mic to Korro Bio for any questions.
Hi. Any concerns about immunogenicity from repeat dosing?
Let me break that down into two parts. From a lipid nanoparticle standpoint, where there has been known cases of immunogenicity, we don't anticipate that. The LNP that we've tested has been in humans before, and so we haven't seen it. The second component is if you're making the M protein, is it going to be immunogenic or not? We don't believe so because individuals have MZ phenotype. We don't believe that that should be a problem either.
So based on the preclinical pharmacology, what do you think is going to be the optimal dosing frequency in humans?
That's a tough question to answer. I would say we're going to generate data very soon, so stay tuned. Our anticipated expectation is that we'll get at least Q3W, if not QM, but it depends on how high we get from a protein standpoint. The preclinical data that we showed in monkeys that I did not walk you through shows that we can get Q3W at least in monkeys very easily.
In the total AATD space, 80% of the patients have no liver disease. So do you see a focus for this for liver only, or as you're expecting other things to come in to support the combination?
Can I gently disagree with you on that presumption? And I'll provide some data. So if you go to the Alpha-1 website, the Alpha-1 Foundation in the U.S., they've started to collect about 3,000 patients' worth of data. If you look at ZZ homozygous individuals, about 40% of them have incidental liver findings that weren't detected as overt clinical manifestations. And so I don't think you cannot have the liver disease without having the lung manifestation because the protein's going to aggregate. So the therapy here for us is to go after both. What I didn't show you is the histological data where we show that even within four weeks, we see histological benefits. And over the 13-week period, we see a 60% reduction in the aggregates. So we believe that there will be a benefit both in the lung as well as in the liver.