Nasdaq under the ticker KRRO. The floor is yours.
Thank you, Daniel, and thank you for the H.C. Wainwright team for having us here. I'm Ram Aiyar, President and CEO of Korro Bio. Welcome, everybody here. Today I'm gonna tell you a little bit about the company, what to anticipate over the next few months, and how we've been doing so far. Customary disclaimers, forward-looking statements. If there's three things I'd like you to take away from today, it's the following. First one is, we are based on a technology platform that co-opts an enzyme that's within every cell in the body, and we use it and recruit it to make a single alphabet change in RNA, and that's what we call RNA editing, and the platform is called OPERA.
Platforms are great, but, you know, without a drug and a application, they don't mean anything. So our lead indication that we're going after is alpha-1 antitrypsin disease. This is a single point pathogenic variant that is primarily driven by liver-mediated secreted protein. So I will share with you that we have a potential best-in-class compound that we will likely take into the clinic over the next coming months with data anticipated in the second half of next year. Lastly, I would say that we have a strong team and a strong balance sheet that will give us runway into the second half of 2026, by which point in time we would have already demonstrated or completed our phase I/II study for alpha-1, but also would have progressed additional pipeline programs into the clinic. So what was the genesis of the company?
We started the idea or the concept of RNA editing not to be another me-too-like therapy. So the idea was: how do we expand the genetic medicine toolkit that really exists so far? There are many ways to knock down a protein, there are many ways to bind antibodies, but there really wasn't a way to have a pathway to activate biology in a meaningful manner, with very, very high specificity. So RNA editing was developed to bring forward a transient and reversible way to edit a specific alphabet, in this case, an A to an I edit on RNA. And we do it with an endogenous editor, as I mentioned. The idea, again, is to activate a biological pathway, so we don't think about knockdown of a certain protein or knockdown of a biological pathway.
It's always in the intent of moving something and upregulating something. We've built out this platform through key discoveries that we've done internally, i.e., we have not in-licensed any programs. And really, the idea is to develop multiple drug candidates through this platform that we've built, both from an intellectual property and otherwise. And as we think about the company build, we think about it in the context of reducing risk, which is, we want to go into areas where there is precedented delivery, there is precedented chemistry. And so one of the major pillars for us is start removing layers of risk as we move forward, which is why we started with alpha-1, and then we build from there beyond that. Our initial focus is gonna be in rare liver diseases, and then we'll slowly expand into other tissue types, such as the CNS.
So if you want to take a giant step back, you know, when people think about genetic medicines, they always think about rare Mendelian diseases, where the outcomes are pretty severe, you have either point mutations or deletions, and really impact a pathology in very meaningful ways. But what over the last two decades or so, what people have identified is that single nucleotide missense variants also cause chronic conditions and are implicated in chronic diseases, and that was the genesis in terms of how, you know, Korro has been built. I'll spend a brief moment on the technology in itself. RNA editing is a mechanism much like Argonaute-mediated or Dicer-mediated or RNase H-mediated silencing. It's an endogenous mechanism that exists.
At any given point in time, 2%-3% of our cells undergo what we term editing, i.e., an adenosine to an inosine conversion. And so all we're doing is co-opting this mechanism and redirecting this enzyme, ADAR, to go and make a change. We do that because of. We identify the target site and the sequence, and we deliver and design a synthetic oligonucleotide that can go and bind that target site on RNA. And we design the oligo such that we can only affect a single adenosine at that location. And that process is very, very specific because the enzyme that we use can only convert a single base. And so we have very high specificity and very high efficiency through this process by delivering this single oligonucleotide.
The way that this change occurs from an adenosine to an inosine, when the pre-mRNA gets translated, that inosine gets translated as a guanosine, so it is an endogenous way on RNA to make an A to G edit. So why do we care about that A to G edit? Well, it turns out that we can have broad applicability of this technology. So when you think about central dogma or what we have learned in textbooks, you start from RNA. There is a pre-mRNA stage, after which processing occurs. A messenger RNA is formed that eventually will get translated to proteins. There's lots of mechanisms that happen in the middle. ADAR-mediated editing is one such mechanism.
And so where we think about redirecting this ADAR, we can actually make a change in pre-mRNA in non-coding regions that can change the expression of the gene, and therefore have more or less of protein in circulation. That's one way to apply this technology. The other way to apply this technology is to do one of two things: actually change the protein that's created. So in cases such as alpha-1, or in the case of Parkinson's disease, where you have a pathogenic point mutation, that is a G to A variant, we can convert that adenosine back to guanosine, so we can repair the protein. But the more interesting way, and where we've focused our pipeline on, is really about making a single change, changing the amino acid sequence, and therefore the function of the protein.
And by just changing an adenosine to an inosine, we can make twelve amino acid changes to twelve others, and therefore, the, the vastness of the biology that we can go after is pretty, pretty broad. So as an example, on our pipeline, our first two indications are going up. First two rows, both for alpha-1 as well as for Parkinson's, is repairing a pathogenic variant. These are both G to A variants at specific locations in the genome. But beyond that, when we think about an indication like ALS, where we are targeting TDP-43, we're actually making a single variant that can provide both a gain of function by continuing signaling, but also prevent loss of function by preventing aggregation of TDP-43. No other modality can do that by providing two functions at the same time. We're not gonna focus on the rest of the pipeline today.
We're not gonna focus on the platform today. I will take you more towards alpha-1, 'cause at the end of the day, it's, you know, we have to show the proof in the platform, which is where our lead indication is. I'm gonna skip a few. So alpha-1 antitrypsin deficiency is a rare Mendelian disease. As I mentioned, it's caused by a single missense variant, a G to A mutation, in a gene called SERPINA1. SERPINA1 is expressed primarily in the liver, and under normal condition, almost all of us have the MM genotype, i.e., we produce this protein at a normal level, and it's secreted by the liver and present in circulation.
In circulation, it's the fifth most concentrated protein in the body, and the reason for that is, from a function standpoint, if you get a wound, if you get an injury, and you have an influx of neutrophils, the neutrophils start eating up bacteria, starting repairing, the tissue. But if you let them loose, they start eating away healthy tissue, and so you need a stop signal, and that's where alpha-1 comes in. In the normal level, you have a stop signal that says, you know, "Neutrophil, stop, don't eat the rest of the body." So under a normal phenotype, which is the MM, you have both normal liver function as well as lung function. When you have this point mutation, it causes a misfolding of the protein. This point mutation occurs at an E342K location.
It is referred to as a Z allele, and so if you have two copies of the Z allele, you end up with a protein that misfolds, crystallizes, and aggregates in the hepatocytes, and because that happens, you start to get inflammation, and due to that inflammation, you get destruction and apoptosis of the cell, finally leading to fibrosis, but that's not where this alpha-1 protein actually works. It works in the rest of the body, so if it's not in circulation and stuck in the liver where it's needed, the neutrophils, when you get a wound, starts eating away tissue, and where it's most manifested is in the lung. Think about a bacterial infection, think about tuberculosis, think about RSV. When you have an over-exacerbation of neutrophils, you start eating lung tissue, and so the manifestation of this disease occurs both in the liver as well as the lung.
It's also a perfect indication to test out the technology, because most of the protein is actually in circulation. You know if you have corrected the protein, corrected the mutation or not. So when you look at this graph here, on the top, you see the ranges of alpha-1 protein in circulation. On the left-hand side, moving from an MM phenotype, all the way to the right in the gray to a ZZ phenotype. You can see that you start at about 35 micromolars of protein in circulation in normal, all the way to five at baseline in the ZZ homozygous individual. What does that mean? When you look at the table below, the risk of getting both COPD as well as liver is about eightfold higher than when you are a normal individual.
Not only that, when you are an MZ heterozygous individual, which is you have a single allele, your lung risk is almost reduced to none, but your liver risk still exists at a low level, but it's still very close to normal, with an odds ratio of 1.5. The idea for us, or the goal for us to hit, is to get those ZZ homozygous individuals as close to normal as possible. The way we know how to do that is if we edit 50% of the transcripts, it will get us to an MZ phenotype, and that would put us in the light blue range, having a protein level between 11 micromolar all the way to, like, 35 to 40 micromolar, with a median of 20. That's our goal from a therapeutic standpoint. KRRO-110 is our lead candidate.
It is a single-stranded oligonucleotide that we call OPERA, that is encapsulated in a lipid nanoparticle. It is delivered IV. The lipid nanoparticle, we've in-licensed from Genevant. This lipid has already been in the clinic. We've already demonstrated a large therapeutic index in terms of what we can do, both in mice as well as in monkeys. And once we deliver this KRRO-110 through an intravenous infusion, we deliver it to the liver, where most of the gene expression exists, and then we convert the Z allele to the M allele, and that manifests itself in protein in circulation. It's a chronic therapy. Our estimation is that we could get somewhere between Q3W, much like Onpattro or beyond, in terms of a dosing frequency. The goal for us is to get to as close to normal protein circulation as possible.
So how do we know this is gonna work? Well, we've tested. On the left-hand side, we've tested it in iPSCs, that are human hepatocyte-like cells that have the human Z allele, or two copies of the Z allele. We know that we can edit as close to 80% or above in this in vitro human model. On the right-hand side, turns out one in 23 individuals, one in 23 Caucasians, are MZ phenotypes, so we've been able to secure MZ liver cells and deliver 110 and show editing at a high level. We've also shown that this editing occurs without any off-target effects or bystander effects or halo effects. What I mean by that is, in a transcript, you have 25% of the transcript is covered by an adenosine.
This demonstrates how specific our compound is to go and target the single adenosine that we intend to change to a guanosine. We see no off-target effects from a cis standpoint in MZ hepatocytes. We've then demonstrated PK/PD in a transgenic mouse model that others have used as well. In this instance, or in this experiment, we've looked at once every two-week IV dosing, and looked at seven days post the last dose, both at week one as well as in week 13. If you look at the graph on the right-hand side, it demonstrates that we achieve greater than 50% editing, even as early as week one. With oligonucleotides, you see an accumulation of them because of the stability of the oligonucleotides.
So you see that by week 13, we see about 60% editing at one week post-dose, and that translates on this graph, on the left-hand side, to achieving greater than 60 micromolar of total protein in circulation. I don't think anybody has demonstrated this either in animal models. There are multiple transgenic mouse models, and nobody has shown this level of protein in circulation. Not only is that the case, they've also not shown the amount of M protein in circulation, which is, in this case, a ratio of about 75% or more of the total protein in circulation. I'd like to finally end in the context of okay, mice. We've caused and solved a lot of cancers and diseases in mice. Does this really mean it's gonna work in monkeys and in humans?
Turns out that the human ADAR and the monkey ADAR are greater than 99% homology. So if we see that it works in monkeys, the likelihood that it's gonna work in humans is actually very high. So in this case, given that monkeys don't have this protein or don't have the alpha -1 mutation at the E342K location, we generated a de novo variant. So we took an adenosine somewhere between six and seven amino acid sequences away from the target adenosine on the monkey SERPINA1 gene, targeted that and converted that adenosine to an inosine. By making that change, we changed the amino acid sequence on the protein, and therefore we can actually detect it in circulation as a different variant.
We then tested it in both the transgenic mice that I shared data with on the left-hand side, as well as, in the non-human primates on the right-hand side. And so you can see on the left-hand side, even with a single dose, we get about 25% editing at this location. We didn't spend time optimizing it. We wanted to find the correlation between what we see in mice and what we see in monkeys. And so just with a single dose at 2 mg per kg, we see in monkeys achieving greater than 40% editing at day five and lasting for 15 days after a single dose. And we know that in monkeys with repeat dose, we're going to get an accumulation over time.
So this de-risks the technology, showing that what we see from an editing standpoint is conserved between species, but also what is known about oligonucleotides and its stability in higher species, shows that we can achieve the dosing frequency that we need to get to with Q3W and beyond. So why did I say that 110 has the potential for a best-in-class profile? So we show with efficacy, at least in preclinical models, that we've achieved dose levels and protein levels that nobody else has been able to show so far. We've been able to show that we can clear. It's not presented on these slides, but we've shown histopath resolution of the liver disease, at least in this transgenic mice. From a safety standpoint, we see no off-target effects.
We see that from a dosing standpoint, it's well tolerated, both in non-GLP and GLP studies, in the dose levels that we need to be in humans. And lastly, we're the only ones that did the translation to higher species in the context of can we look at human cells, mouse in vivo, and monkey in vivo, and build that correlation between in vitro and in vivo? We're the only ones that have been able to do that. So this preclinical package supports our goal to submit a regulatory filing in Q4, in the second half of 2024, with data in the second half of 2025. I'd like to highlight just two things before we end. We recently hired Kemi as our Chief Medical Officer. She comes from Ultragenyx and Ionis.
She's done many, many translational studies, at least in this early translational phase, as well as all the way through approval. And the second individual that we just recently hired is Jeff Cerio from Atomwise. Prior to that, he was at Moderna and took the company public. So we have a very, very strong team with a strong drug development background. I believe we have somewhere between 25 INDs filed between the few of us, and have taken more than 10 therapies from an approval standpoint. From a board perspective, we just recently brought on Kate Knobil. Kate completes our board in the context of having clinical experience at the board. Most recently, she was CMO of Agilent, and prior to that, she was Chief Medical Officer of GSK.
With that, I'd like to end, and happy to take any questions.