Good day, everyone. Thank you for joining the 23rd annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Korro Bio. Joining us today from the company is CEO Ram Aiyar. For those of you joining on the webcast, if you want to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. With that, we'll get started. I'll turn it over to Ram for the presentation.
Thank you, Joey, for having me here, and thank you for Needham for giving us the opportunity to present here. It's my pleasure. I'm Ram Aiyar, CEO and President of Korro Bio. If we leave with anything today, there are three things I want you to leave with, okay? The first thing is that Korro Bio is a genetic medicines company that is focused on treating large patient populations using a modular mechanism of effecting a change on RNA without touching DNA, such that we can create a very specific transient and a redosable event. So that's the first thing. The second thing I want to talk to you about is our platform that we called OPERA. It's oligonucleotide-promoted editing of RNA. And this platform was built using oligonucleotides that are synthetically modified RNAs to effect that specific base change.
I'm then going to talk to you about, well, where is that going to be applied the most, and how it's differentiated from DNA-based editing and its application. The third thing and the last thing I'm going to spend a lot of time on today, which is going to be the majority of this conversation, is going to be our lead indication and our lead program, which is in alpha-1 antitrypsin deficiency. It is a genetically mediated Mendelian disease that's caused due to a single point mutation, where we've nominated, as of last year in December, our development candidate 110, which is the first candidate for us as a company, where we show data or I will share data with you that shows a potentially best-in-class compound for this patient population.
Specifically, that can provide a differentiated therapeutic modality to benefit both the liver manifestations of this disease as well as the lung manifestations of this disease. So those are the three things I'm going to talk to you about, and I'll walk you through how Korro Bio is building a wholly-owned pipeline to address this broad range of indications, both in rare as well as common diseases. As I mentioned, we have a strong balance sheet. We have cash runway into 2026, and we have a regulatory filing in the second half of this year, which is the second half of 2024, with clinical data in alpha-1 reading out in the second half of 2025. So very exciting time, both for this patient population as well as for the company as we move forward.
This idea of using genetics to go after target validation and identifying what are the root causes of some of these diseases is very easily done when you have Mendelian diseases, i.e., you have one cause for the genetic defect. It manifests itself profoundly in individuals early in life, and you can actually see that manifestation very easily and therefore the causal link to that specific gene. Over the last two decades or so, this same sort of understanding, specifically around variants or alphabet changes in DNA, has started to come to bear. And this is very important because now you have large patient populations like diseases such as Parkinson's, ALS, cardiometabolic, and others where single alphabet changes have a profound impact on disease.
We don't really have a way in which you have such a heterogeneous implication for a disease to go and make a change and impact the disease. And so that's where RNA editing sort of comes to bear. The way we define RNA editing is affecting a base change or one of the alphabet changes from an adenosine, which is an A, to an inosine, which is an I. And this process of an A to I change is actually an endogenous process that occurs in the human body. This is a mechanism that's carried out by an enzyme called ADAR. This enzyme is present in every cell, and this enzyme's function is to actually make this A to I change on RNA. The way it does it, it does it by recognizing certain three-dimensional structures inside a cell as to what these RNAs take because it becomes a hairpin.
And once it identifies these specific structures, it actually goes to that specific site, converts that adenosine to an inosine. And so much like other RNA modalities where you co-opt an endogenous mechanism, we do the same thing. We deliver a synthetic oligonucleotide. We create a similar three-dimensional structure that ADAR recognizes, and we recruited or co-opted to that specific site to go and make the change from an A to I. So this process of A to I is typically this inosine during the translation process is read as a guanosine. So we term this as an A to G edit that the adenosine is changed on RNA, but the guanosine is what shows up on the protein. The second thing, as I said, I want to talk to you a little bit about our platform, which is OPERA.
One of the things that I have learned and the team has learned over the last two decades being in drug development is you need to have a solid understanding of the mechanism, how it's implicated in a certain disease, how you can deliver the drug to a certain place, and how you can gather all the information you need to solve a particular indication. And so our platform is based on those four pillars. First, a deep understanding of ADAR biology so that we know the business end of the deal is there and functioning at the right place at the right time. We leverage the second pillar, which is the chemistry. Synthetic oligonucleotides over the last two decades have developed a large toolbox of modifications that can be made to RNA to make them more stable, to improve the potency, and give it drug-like compound effects.
So that is our second pillar, where we leverage both novel as well as known chemistries to design these compounds. The third component is delivery. You can't talk about modified RNA without talking about delivery. So we choose our delivery that is precedented, has been tested in man, but we tailor it, or as we say, fit for purpose, for a certain indication. I will talk to you about that a little bit later in the presentation. So we look at the indication, we look at what the patient need is, how much editing we need to effect to create a protein change, and we pick the delivery to match with it.
Finally, this is not a we don't talk about this a whole lot, but computational tools are inherent for us in the context of both designing these compounds as well as applicability in animal species as well as in humans. So our fourth pillar is the computational aspect that comes to bear for this platform. The combination of the four is what leads to our IP portfolio, and we have an ever-growing portfolio that gives us the freedom to operate, to develop these compounds, and get it into humans. Our first generation of compounds that have come out of this platform, we like to call CHORDs, a little play on music. They have been shown. It's an antisense oligonucleotide. It's a single strand with known chemistries. We have shown that it could have high target efficiency from an editing perspective.
It is highly specific, and I'll walk you through some examples, or at least one example in our case for alpha-1. In that case, we leverage chemistries and delivery that's known to man. So as you go into humans, to show the validity of this platform and this modality, we take the least risk possible as we get into the clinic. There are many places we can play in terms of application. So it has a very broad and versatile way of applying this technology. So when you take central dogma and you go from DNA that we don't touch all the way to before becoming a protein, there are many aspects in which we can intervene to make a change. One way of making the change to create a single A to I edit, we can modify gene expression either up or down.
That's at the pre-mRNA stage before it becomes fully messenger RNA. Or we can take an impact further once you have messenger RNA in the exons to actually make an A to I change. And in that context, when you make that change, you have an impact on the amino acid codon that comes out the other end. And therefore, by changing that amino acid codon, you can actually impact the structure of the protein and therefore augment the protein's function, okay? That's where our focus is. That's where our pipeline is initially focused. That's a place where we can control what the activity of the protein is because we have an understanding of its structure. We can view it through experimental models, and that's really what our pipeline is built on.
As you can imagine, as you take a novel technology forward, you want to take the lowest amount of risk. And that's where our lead indication with Korro 110 is focused on alpha-1 antitrypsin deficiency. This is a single point mutation where we are repairing the G to A mutation back to a G to repair the protein and therefore its function. And that's going to be in the liver. Beyond that, in the CNS, one of our lead programs is focused on repairing, in Parkinson's disease, a mutation that occurs in an enzyme called LRRK2 or a kinase called LRRK2. Again, it's a pathogenic G to A variation, and we're swapping the adenosine back to a guanosine. In both cases, what we hope to achieve is delivery and the efficiency which we need for the rest of the program.
For every other pipeline program down the line, we're focused on creating a de novo change in the amino acid sequence and therefore a de novo protein that can have unique features that are not present during the disease. We won't have time to talk about those today, and I'm happy to share over the next coming 12-18 months what the data is in those indications. For 110, we will have a regulatory filing in the second half of 2024. We haven't set the jurisdictions, and we hope and expect to present data in the second half of 2025. Our cash runway through our strong balance sheet gets us into 2026, enabling multiple milestones, not just on the first program, but also on the other programs over the next two years. Let's spend some time on alpha-1, which is the majority of the presentation.
Again, our goal, and based on the preclinical data, is to deliver a potential best-in-class candidate, walk you through both the indication, the data that we have, as well as what the next steps are. So as I mentioned, alpha-1 is a Mendelian disease. It's caused by a single missense mutation that is a guanosine to adenosine change in DNA. This change occurs in a gene called SERPINA1 that is primarily present in the liver. Under a normal scenario, which is the genotype for this protein, you have M-AAT secreted. And that protein that is secreted primarily from the liver is present in circulation at a very, very high concentration. And that protein acts as a stop signal for neutrophils or one of the white blood cells to prevent further destruction of tissue as it is implicated in and during a wound healing process.
When you do have a mutation in this gene or a single letter change, you end up in the homozygous scenario where you have two alleles, and those two alleles are called the Z alleles. That allele leads to a misfolding of the protein. So because the amino acid codon has now changed, you have a structure of the protein that starts to aggregate within the liver, and that aggregation causes accumulation of this aggregated protein in the hepatocytes and over time leads to the destruction of the liver cells and then eventually leads to cirrhosis. That's where you see the manifestation of the liver disease because of this mutation. Now, the function of this protein, unfortunately, is in the rest of the body.
So when you have a wound or when you have an event in your lung where you have an inflammatory process and you need this protein to say stop to neutrophils, this protein's actually not present. And because the protein's not present or a mutated form of the protein is present, the neutrophils start eating up the tissue, in this case, specifically around lung tissue. And when that happens, you start losing lung function. And so a single point mutation leads to a destruction of two organs at the same time over time. This is a rare disease as defined by the U.S. FDA. We are talking about close to 100,000 individuals here in the US and over 100,000 individuals in the rest of the world, leading to a pretty large market opportunity for this indication. When you look at the levels of protein, that's one indication.
So in this graph, I show you on the left-hand side the normal individuals, the diamond denoting the median levels of protein across the three different genotypes. So being normal, MZ being one allele of M versus one allele of the Z protein, and then finally the ZZ homozygous patient population, which will be the primary focus of this drug. As you can see, there's a very linear correlation in terms of the level of protein, even though the error bars, even though the interquartile distance is high, it's a pretty wide range. The normal median range for a normal individual is around 35 micromolar, and a normal in a Z patient is about 4-6 micromolar in circulation. Under that graph, you see the odds ratio and the likelihood to get either COPD or cirrhosis.
This data was collected from UK Biobank, and you can see that with the ZZ homozygous patients, there's about an eightfold increase or likelihood of both COPD as well as cirrhosis. So our goal, which has been when we started to build the target product profile, is to get to most of the patients, if not all of them, to at least the MZ phenotype, which correlates to 50% editing, and depending on the dose, as close to normal as possible in this patient population. And normal, when you talk to KOLs and you talk to the patients, that's a safe range to be for this patient population in terms of the benefit that we can have both from a liver standpoint as well as the lung standpoint.
So Korro-110 is a, as I said, it's a CORD, a single-stranded oligonucleotide, very similar in weight, molecular weight to an siRNA. It is encapsulated in a lipid nanoparticle. That lipid nanoparticle has been in-licensed from Genevant. When we started this endeavor and made the choice to go down the LNP path, we investigated multiple partners to look at which will be the right fit for this cargo, and we picked Genevant to be the leaders in the space. So what I'll share with you over the next few slides is the data that we've generated. This is in vitro data. On the left-hand side is human ADAR plus human Z alleles. These are cells that have been derived from pluripotent stem cells and differentiated to be hepatocyte-like cells with the Z alleles.
We can show that our compounds are active in this system of human ADAR plus the human mutation. On the right-hand side, if you remember, I showed MZ individuals. The right-hand side includes cells from MZ individuals where we show 110 has a pretty good level of editing in vitro. You see that because their levels start close to 45%-50% from an editing standpoint, we just go up from there. And so in both of these systems, you have human ADAR and human Z alleles. On the left-hand side, two copies. On the right-hand side, one copy. And you can see that 110 works very well in both of those systems.
The second thing from an outside of the activity, the second thing we want to look at is off-target because this is an area where, as you think about both from a regulatory standpoint as well as showing the activity of this protein, we need to be very, very specific. The benefit of using an oligonucleotide is that we can create chemistries that lead to very specific edits. We can choose where to edit and where not to edit. And so it provides a very, very modular and tunable system as we design these compounds. So what I show here is in those MZ hepatocytes with 110, we have zero off-target editing. So what we're looking at is 100 base pairs to the left of the edit site on the SERPINA1 gene as well as on the right side of the SERPINA1 gene.
You can see that at very high doses, you are able to see very specific edits made to that E342K site and zero edits or at least below the lower level of detection at every other site next to it, which is very exciting as you think about both the activity of this protein in normal individuals as well as from a regulatory standpoint to give the confidence that we have a very, very specific drug. Then we wanted to establish pharmacokinetic and pharmacodynamic activity, i.e., what does the level of concentration of the drug in circulation correlate with the amount of protein that's made? So one of the ways that we've done this is to show in a mouse model that has the human gene knocked in and is used by others as well. It's called the NSG-PiZ mouse.
We've dosed 110 every other week at 2 mg/kg. We're able to demonstrate that even every other week, we're able to achieve greater than 50% editing just 1 week after dosing, both at week 1 as well as after 5 doses, 1 week after dosing. Not only do we see editing, we also see an accumulation of the editing and a slight increase, almost up to 60% at the midpoint. So again, very exciting because in the context of editing efficiencies, these are pretty high levels that you see. We hope that this translates well into humans, so much so that in my studies, from a toxicity standpoint, they're very well tolerated up to 5 mg/kg as well. That's how high we went up to in some of these studies. How does that editing translate to protein?
On the left-hand side, in the same experiment, you can see that that level of editing, even with a single dose, led to almost 50 micromolar of functional A1AT. Let me just repeat that, 50 micromolar of functional alpha-1. It's the first time that anybody has been able to show this level. And these levels just within one week and within one dose of treatment, that's what's exciting for us. So on the left-hand side, serum was collected from that experiment, from controls that have the Z alleles, as well as treated at 2 mg/kg, both one week and 9 weeks later. And you can see that there is an increase in total protein. There is an increase in the normal M-AAT.
There's also a decrease of the Z protein because what you don't see here is in the histology, there is a reduction in the amount of Z aggregates that's present within the liver. So just to put that in context, with a single dose, we see 35 micromolar of M protein relative to 50 micromolars of total protein. That's more than 60% of the protein in circulation is normal protein. On the right-hand side, we show activity. You can see that at both of these time points, the protein that's generated with treatment is active. Each of these assays are slightly different that are utilized by different companies. So what you need to focus on is what is a change from baseline and whether that change from baseline is active across the nine weeks or not, which makes it very exciting.
One of the things that we've spent a lot of time internally with Korro that differentiates us is we've solved a lot of mice issues over the two decades or longer in drug development. One of the things with novel technologies is how does this translate from lower species to higher species? And we wanted to take our time to investigate does that work or not. So to do that, because normal monkeys don't have this Z allele in them. And so if we were to put in 110 in a non-human primate, we wouldn't see any editing because that Z allele is not there. We designed an oligo with an overlap to that location that's homologous with humans to see what does the editing in the mouse that we just dosed look like in non-human primates.
This was a way to say, can we edit at a high level, and can we edit endogenously as in a larger species, and can we edit all the cells that we need? 1494 is a separate, different surrogate CORD encapsulated in the Genevant LNP, targeting a site on non-human primate or monkey SERPINA1. We tested it both in the PiZ mice because of homology as well as in the non-human primates. The left-hand side highlights the editing in mice with a single dose, and the right-hand side showcases editing in monkeys with a single dose. As you can see, the surrogate edits at very good levels in both species. You can see in the mice, in the C57BL/6 PiZ mice, you can see something that edits about 25%, edits at the same dose level, about 40% in monkeys.
You also see that there is more durability in the monkeys relative to the mice. We believe that that's primarily driven by the stability of the oligo as a function of time. This has also been observed with other oligonucleotides, irrespective of the delivery mechanism that has been utilized in both approved products as well as products that are being developed. This is very exciting for us because this gives us a lot of sense that as we go into humans at appropriate doses, we're able to see the benefit and the editing efficiency, hopefully as early as a single dose, but definitely over the course of a multi-dose situation. What is also exciting is that that's 2 mg/kg in monkeys. We don't see any increases in LFTs. They're within the normal range.
That also makes it very exciting that we know as we go to humans, we have a therapeutic index that we can go after. So that's the program. As I said, we've shown efficacy endpoints both from a level of protein as well as function as well as a reduction of aggregates. I haven't shown the slide here, but we have shown histology that we can see reduction of the Z aggregates in liver cells. We've shared a little bit of safety in terms of off-target effects. We have shared before that we have seen no impact of our oligo to change endogenous ADAR activity, at least in the sites that we've looked at. And finally, both in non-GLP studies in both species of mice and non-human primates, we believe that we have a reasonable therapeutic index to go after into the first-in-human clinical study later this year.
That's what makes it exciting. So hopefully, again, just touching on the three things that I wanted to focus on to finish this presentation. First one is that Korro is focused on getting transient RNA editing into large patient populations. And hopefully, this data shows that we can actually get to large patient populations in a relatively small period of time. The second thing I wanted to highlight is the OPERA platform. And through the Alpha-1 data, hopefully, I can highlight the specificity, safety, transient nature, as well as the efficiency with which we can bring the editing into larger species. And then finally, I hope you agree with me that at least based on preclinical data, 110 has the potential for a best-in-class therapeutic for this patient population that we believe will really benefit from a drug like this.
I'd like to end by saying this is a team effort. We've spent a lot of time thinking about designing these compounds, making sure that we can get it to humans. Alpha-1 is the first foray. Hopefully, as we showed this mechanism can be utilized in humans, we can share with you the breadth of the pipeline that we can build using this technology. Thank you for your time.
Thank you so much, Ram, for that presentation. Excuse me. We have a couple of questions coming in from the webcast. The first one is, in terms of differentiation from your approach, how does this differ from the GSK WAVE program that uses the GalNAc technology?
Yeah. Thanks for the question, Joey, and for the person asking the question. So 110 is a single-strand oligonucleotide encapsulated in a Genevant lipid. So it is delivered IV with that LNP technology. My understanding is that the GSK WAVE compound is a sub-Q GalNAc conjugated compound and is, I believe, in the clinic, at least in the Healthy Volunteer study. For this patient population, I think our goal was to hit a greater than 50% editing, which leads to a larger than 50% protein in circulation. I believe that we can achieve that within a week. We've shared data that just at least based on the preclinical models, that we can achieve that with a single dose. I think with a GalNAc compound, it takes almost 13 weeks to show a lower protein level than we have shown relative to the GSK WAVE compound.
That's all I know from a public domain, Joey. All I can talk about is our compound. I think that given the totality of the information we have, as well as the non-human primate data that we've shared, we believe that we have a great compound moving forward.
Got it. Fair enough. And then a follow-up question, more technical. Do you need to give interferon for transduction here, Ram?
We do not. So we do not give interferon in any of the animal studies that we've done, either in mice or in monkeys. I think what you're referring to is interferon in the context of one of the in vitro studies that we've done. It's an iPSC-derived, stem cell-derived hepatocyte-like cell. When you look at although it's a human ADAR Z allele system, I think we wanted to make sure that through transfection, we're able to design our compound in that system. And so that's why you see interferon in that context. But in humans, that is not going to be the scenario.
Great. Well, thank you so much, Ram, for the presentation. Very helpful overview and good discussion here. We're close to time for this session. So thanks, everyone, for joining on the webcast, and have a good day.