Hi everyone, good morning. Thank you all for joining us today. My name is Henry Jiang. I'm with the banking team here at JP Morgan, and it's my pleasure to be introducing Korro Bio today. Joining us on stage and presenting will be Ram Aiyar, President and CEO of Korro Bio. Just a quick note, we'll have some time after the presentation for questions, so please wait until then. But without further ado, I'll pass it over to you, Ram.
Thanks, Henry. Also, thank you for the JP Morgan healthcare team for giving us the opportunity to present here today. It's great to see this amazing crowd here, so thank you for being here. Really appreciate it. Hopefully, we'll tell you a little bit about what we do at Korro. Here are my customary forward-looking statements. You can always go to the SEC to find our most recent filings. So what do we do at Korro? At Korro, our vision is to develop transformative medicines for both rare as well as highly prevalent indications. And so we do that primarily by activating biological pathways. It's a very hard thing to do. Most modalities are focused on knocking down proteins or knocking down certain areas. Gene therapy is the only one where you can add another protein or activate signals.
In this case, we use a simple chemically modified oligonucleotide or RNA to go and affect the change. So we do that to make a single base change from an adenosine to an inosine by editing RNA, not touching DNA at all, to really impact the protein structure and sequence. We have an ability to deliver very modularly, so based on cell types, based on tissue types, we can conjugate with different chemical entities to really be very precise and target the right cell type. And then lastly, here's where I think that this takes a lot from gene therapy, where we learn with the genetics and are able to influence the similar sort of outcomes that you could see, but in a very transient fashion and nothing permanent. And so knowing that you can have predictable outcomes or biological impact, I think that's going to be important.
Just wanted to set the stage so that we're all on the same page in terms of what the technology is, what we're trying to do, and what the base case assumption is. So today, I want to leave you with three things. The first thing is that I don't believe that RNA editing as a modality has really been articulated in a way that people understand where its benefits are. So today, with our pipeline, which is very focused, we'll be able to share with you how we can alter biology in very meaningful ways. So that's the first thing. The second thing I want to leave you with is we have a program called Korro 121. It will be in the clinic in the latter half of this year. It is a very unique program that highlights where the benefit of RNA editing is going to be.
I will give you a snippet of information in terms of what that looks like. We'll have a larger analyst day or an education session on January 27. Watch out for that, and you'll learn a lot more about both the patient need, how we're going to approach it from a market perspective, what the clinical development considerations are, and with even a caregiver of a patient being there, talking to us a little bit about that indication, and then finally, 2025 was an amazing year for us. It epitomized what biotech is all about. It was the first time we took a clinical program with an RNA editing compound within two years into the clinic and generated data within about a nine-month period.
The flip side to the biotech roller coaster is that the data that came out was not as anticipated, did not meet our expectations, so we pivoted, and so we'll give you a little bit of learnings that we have from that program, how we have incorporated it into our other programs moving forward. And hopefully, you'll be able to see that we've removed the question of, can RNA editing get to close to 100% or not, so bear with me, I'll walk you through all three of them. OPERA is the platform that we use. It was built on four different pillars. When you think about understanding how ADAR works and how you can leverage it, that is the first pillar of our knowledge base that has helped to build this platform.
The second pillar, when you think about oligonucleotides, it's all about chemistry, whether it's novel chemistry or whether it's fit for purpose or it's utilizing the existing chemistry that we have that has been applied to other oligonucleotide therapies. We leverage all of those. The key is around how we design these constructs. You can't talk about all of those without talking about delivery, so that's our third sort of pillar. We leverage existing delivery. And as these therapies get better, we would get more and more access to clinically validated technologies that can take us to different tissue types. And finally, since 2021, we have been using machine learning to both design and identify targets within the organization. So those are the four pillars that make up our platform, Opera. Again, just to set the stage, so where can you apply them?
When you think about the ability to change a single alphabet, in this case, an adenosine to an inosine, we can do that in multiple ways. We can go in the pre-mRNA stage, post-DNA transcription, and actually affect a change where you can change gene expression, either up or down. That's not our current focus. Or the other place you can have an impact is really thinking about changing protein structure by altering amino acids. And I'll tell you a little bit about what we mean by that. So on the left-hand side is how we utilize this technology to repair a protein that is a pathogenic variant. So if you have a disease, let's just take Alpha-1 as an example, Alpha-1 antitrypsin deficiency. There's a single G to A pathogenic variant in a gene called SERPINA1.
That's in DNA that gets transcribed into RNA, and that creates a pathogenic variant. We can step in the RNA and make that change and correct that protein. So we can convert that A back to a G, and therefore returning the amino acid that was not a mutant, that is a wild type, and therefore repairing a protein. So that's the example of what you can do with the repair. That is not where we think the main primary focus of this platform is. There are many ways to go after those pathogenic variants. You can alter DNA. You can alter the protein. Even though we have a single program in that space, our primary focus moving forward is on the right-hand side.
This is where it gets very exciting in terms of all the things you can do with biology that haven't been able to be done before. For example, what do I mean by that? On the right-hand side, we have the ability to modulate proteins and therefore activate biological pathways. And again, as I said, we do this by creating a single adenosine modification to a guanosine. And therefore, we can change 12 amino acids in the final protein. So there are many ways we can go after biology where just a single change can really activate a pathway. So that's what our pipeline is really focused on. As you can see, our lead program right now with Korro 121, we're focused on stabilizing an intracellular protein. It is a Gal-conjugated liver-focused program, primarily indicated for reducing ammonia in multiple indications.
I'll tell you a little bit about it very shortly. We anticipate a regulatory filing in the second half of this year and then entering the clinic and data very shortly. As I mentioned, we have a teaching session on the 27th. If you're available, please do make it. It will be two hours of scintillating conversation around why ammonia is bad and what the patients go through and how we think we have a best-in-class compound to help the patients. The second program here, as I said, we repair a pathogenic variant in Alpha-1. I'm going to use that as a test case to show that we can get close to 100% editing, which has never been shown before. We anticipate getting to a development candidate in the first half of this year and entering the clinic, and we'll give you guidance as we move forward.
The last two programs are, again, a very solid indicator of how we are approaching biology. And I'm going to give you later in the talk small snippets of data where people have tried to go after both of these proteins for these indications and have not been successful, and we've been able to show that. You don't see Korro 110 on this pipeline. It was our lead program last year. Based off of the evidence that we have and the information I'm going to share, we're terminating the study. We have a lot of learnings here. We've kept the patient community up to date in terms of what we're doing. They're excited about our next-generation program that we're bringing forward, but we are not progressing with Korro 110 moving forward. All right, so let's take a step back now.
That was part one of what I wanted to share with you in terms of where RNA editing is best suited. As you saw, it is not in genetic diseases necessarily, but it's slowly moving towards more prevalent indications. So today, I'll start with 121, which is our first step into going into prevalent indications where gene therapy cannot really be applied, and you need a transient way to go after it. So every time we eat, we generate waste. And so one of those waste products is ammonia. And when ammonia increases in serum, typically, it gets cleared by clearance mechanisms both in muscle as well as in the liver, but primarily through the liver because that's your master regulator and metabolic stabilizer. When you have no issues, ammonia gets secreted out or excreted out.
When you do have liver failure, cirrhosis, mutations in this urea cycle processing mechanism across all of the eight enzymes, you end up with an increased level of ammonia. That increased level of ammonia causes many different things. It causes neurological and cognitive challenges, causes frequent hospitalizations, causes you to not eat and have a highly restricted diet. Pizza is out of the question. Steak's out of the question. We're talking about very, very minimal protein consumption. It also increases your risk of infection, and so they all compound into you showing up in the hospital more often and with a very high mortality, depending on the indication.
And so having a modality that's transient, that is an injectable that's subcu that has the potential to go once a month, is pretty amazing for the current patient population where either they have no opportunity in one of these indications, and in another indication, you're fighting against a three-times-a-day oral therapy. So what's our solution? Our solution is a Gal-conjugated oligonucleotide going after the specific RNA where we are changing an amino acid and therefore changing the actual function of the protein. You may have heard of molecular glues. You may have heard of E3 ligase as molecular degraders. Well, what we're doing is removing the substrate where E3 ligase can actually bind that. So by removing a lysine and converting it in an arginine, you can't degrade this protein. And so it's more stable, sticks it out intracellularly longer, and has a higher capacity to clear ammonia.
It is not in the urea cycle pathway, so it can actually go after and treat patients across all urea cycle disorders, so when you think about the market, not just focus on specific genetic mutations or specific subsets of urea cycle disorders, we're actually going after all of them, and so in the U.S., there's a prevalence of about 4,500 patients across all of the mutations. There is an equal number in Europe and the U.K. These patients, liver transplants, the only way they can get out of it early in life. If they are detected late onset, they actually have tremendous malnutrition, and so providing a way to help these patients is actually going to be very, very meaningful by providing a subcu therapy that they can inject, and the caregivers don't need to worry about these patients.
Similarly, for patients with hepatic encephalopathy, again, not a small patient population. Just in the U.S., we're talking about 80,000 or so individuals that have high ammonia as well as hepatic encephalopathy. There is no therapy that has been proven to work except for a nitrogen scavenger to reduce the ammonia and therefore improve its benefit. So in both of these patient populations, we think that we have enough genetic evidence to suggest that we can have a benefit as well as clinical evidence to suggest that we are going to be successful in doing this. Again, not small patient numbers and not small market opportunities. So again, I just want to recap. 121, we're not correcting a mutation. We're creating a de novo variant of a protein that's more stabilized. It's a very unique way of using RNA editing from a modality standpoint.
We intend to treat patients across multiple indications that have elevated ammonia. They are both large unmet medical needs. In clinical studies, in the first clinical study, we will know whether you can reduce ammonia or not in a very rapid fashion in both of those patient populations, and as I mentioned, we'll have a workshop on the 27th to give you a little bit more insight. We anticipate filing from a regulatory standpoint in the second half of this year. That, to me, is exciting, never been done before, and so there are many other such protein modifications we can make, and hopefully, we'll have the opportunity to take you through each one of them. The last piece I wanted to connect with you on is what we have learned in Alpha-1 antitrypsin deficiency, our experience through Korro 110, and what we have generated moving forward.
To set the stage, Korro 110, we started a REWRITE study. RERITE was a two-part study, a single ascending dose part that had both healthy volunteers as well as Alpha-1 patients, and a part two that was a multi-dose study to do once in three weeks or once in four weeks. We stopped after the first part. We took the drug in a single dose into patients. Dose escalated up to 1.2 mg per kg, which is very high for 110, which is a lipid nanoparticle encapsulating a single-stranded oligonucleotide. The only issue we saw, which was resolved within 10 hours, was an infusion reaction in two of those individuals that were treated with ibuprofen. We think that the profile was really good when we took it into humans and healthy participants. When we went into patients, we saw two things.
The first thing was the seven patients that we treated that had Alpha-1 antitrypsin deficiency. Every single one of them had an increase in M protein. They went from not having any protein at all to seeing a level of protein in circulation, and that happened very rapidly, so we know that when the oligo gets into the system, it can go and edit. The unfortunate situation is that we did not see the M protein at levels that we thought would be competitive moving forward. The reason we didn't see that is we saw differences in pK in the healthy volunteers versus Alpha-1, and then when we dug in a little bit deeper in terms of root cause analysis, we saw that the structural integrity of the Korro 110 as a product changed. We did Cryo-EM. We saw that these products were spherical in healthy volunteer serum.
They looked like a football, not the European kind, the U.S. kind, in serum ex vivo from patients. And so we don't exactly understand the mechanism, but we know that the morphology has changed that changed the pK, and we believe that that has changed the exposure for these patients. That's one reason to terminate and not move forward with 110. The other reason why we decided not to do that is that we made a ton of progress on our next-generation Alpha-1 product. I don't think till date anybody has shown greater than 90% editing in an in vivo model for a target that is meaningful. From a potency standpoint, this is almost three logs more than 110 in and of itself. And we've been able to achieve this in about six months.
So the platform has evolved significantly for us to learn from what we've done in the past to get to a very potent compound in a very short period of time. We have now the ability to provide an option for these patients that's going to be as good as gene replacement in a transient fashion, which has never been done before. So we are pretty excited about this, and it gives us a lot of optionality in terms of moving forward. As I said, we're close to a development candidate. Over the next couple of months or a few months, we'll be able to nominate that, and we have guided towards a first-half development candidate nomination. As you see on the slide, on the left-hand side, you see it's in two different animal models. We're achieving similar levels of editing, which is very exciting.
All right, I'm going to leave you with two targets that have been close to us and have taken a little bit of time, but we really have made a ton of progress. AMPK gamma-1 is an isoform-specific energy pathway modulator. It's involved in lipogenesis. I think Merck, Pfizer, Lilly, and others have been trying to use a small molecule activator for, I want to say, three decades, and they have not been very successful in terms of showing a compound with high selectivity, high specificity, and low toxicity. The biggest issue for this compound or this target is that when you activate it systemically, you end up with cardiotox because the isoform specificity doesn't exist. So we've been able to create a highly selective gamma-1 isoform-specific activator just targeting the liver that removes some of the toxicity profile that can be seen. So what does that look like?
As we develop this program, it's one of the first steps towards longevity. If you've seen a target that has been implicated in longevity through metabolic stabilization. So on the left, we took this compound with a Gal-conjugated oligo to target AMPK gamma-1 to activate it in a diet-induced obese model. On the left-hand side, we show that we have normalized the liver health. We only show AST-ALT here, but if you look at all the other parameters, you will see such a normalization occur. On the right-hand side, we show that within a week, we're able to see a differential between body weight. It's not tremendous. It's not intended to be that way, but the food intake that's being taken is very similar in these mice.
So if you put those three pieces together where you see normalization of the liver, reduction in body weight despite food intake, now you can start to see where this program can come in specifically in the spectrum of MASH. And again, as we progress this asset later this year, we'll give you more insight into where it will fit on that spectrum relative to the approved therapies that will be out there. The biggest thing here is we only need 20% editing. We don't need more than that, which is a huge advantage as we think about moving forward. Knowing that we can achieve 100+% editing or close to 100% editing with Alpha-1, we feel very confident that we can get here in a very rapid fashion.
Again, very unique way to go after a target that has been traditionally undruggable and to provide a subcu therapy with infrequent dosing in a patient population that people have been trying to go after. And the last one I'll leave you with is our program in ALS, which is restoring function. TDP-43 is a protein that has been very, very hard to go after as it has three different pathologies implicated. You need to have signaling that is lost in ALS because of aggregation of this protein. You have aggregation of this protein in the cytoplasm that leads to cell death. And then you have a mislocalization of this protein that enables both of those functions. And so you need a therapy that can bring everything together, keep the protein inside, keep it functional, and prevent the aggregation.
We presented this poster very recently in December that we can do all three of those things. Never been done before. You can only do one or two of any one of those things. So on the left-hand side, we induced iPSC motor neurons with a chemical stress inducer that pushed the protein outside the nucleus into the cytoplasm and created aggregates. We then, when we treated with an oligonucleotide to edit a specific site, we were able to not only keep the protein inside the nucleus, but on the right-hand side, we can show that we continued signaling in two different downstream signaling pathways, Stathmin-2 at the bottom, POLDIP3 at the top. Both of those, again, very hard to do by themselves, to do both of them by themselves.
And so we're demonstrating here that in a very unique way, we're using RNA editing where no other gene therapy can be utilized. So recapping everything that I just said, the three things that I wanted to leave you with. Hopefully, I've laid out for you what RNA editing can do in very unique fashion. It's like going to the moon or going to Mars, baby steps to sort of get there, and we're starting to take those steps. So that's the first one. The second one, hopefully, I gave you an indication of where Korro 121 is going to be and the milestones that we anticipate in 2026 and how exciting that product is going to be for these patients.
Then the last one, hopefully, you have seen the learnings that we have at Korro 110 and how we've translated that by moving away from a lipid nanoparticle, focusing on a gal-construct for all of our pipeline programs targeting the liver, and then expanding from the liver into the CNS. We have a cash runway into the second half of 2027. We believe that we can achieve a lot of these milestones in a very rapid fashion. And it's going to be an exciting year for us, and hopefully, we can share that with you. And happy to take any questions.
I'll repeat the question. Thank you. The first question is that what is the general safety problem of RNA editing comparing to DNA editing?
So RNA editing is the enzyme itself that makes the single edit is very specific. When you think about window size from gene editing to RNA editing using ADAR, it's a single base. So the likelihood of off-targets is very, very low. We didn't see anything in Korro 110. When we even went into humans, we didn't see anything that we saw in the preclinical studies, ex vivo in human cells. So the specificity of making that edit is actually very, very high. We, in fact, looked for 110. We looked across the transcriptome and didn't see any other place where it could actually have an impact. So that's on the RNA side. On the protein side, we go after targets that have been genetically validated. So you know that what the mechanism exists, whether when we create a novel protein, we know what it's going to likely do.
And we have ways to test it out in vitro as well as in silico. And so in this case, when you go after intracellular proteins, you have a little bit more privilege in terms of making these changes that are not going to have an impact on the immune response. And so when you add all of that together using a Gal-conjugate that has been now in approved products, we feel very confident that the safety profile is going to be very, very good for these products.
Okay, thank you. The second question is about the Gal-conjugate. When you conjugate Gal-conjugate with the ASO, are you decreasing the dosage of it?
Let's just make sure I understand the question. Increase the dosage relative to our LNP product? Is that the question? I think we have to see in humans what that actually looks like. Traditional ASOs have been able to show somewhere between 200 and 400 mg fixed dose. You can have tremendous impact. SiRNAs and ASOs have taken about 15 years to sort of get potency up. With the construct that we showed for Alpha-1, that is a sub-nanomolar EC50, which has never been shown before. It's very close to an ASO benchmark. That's why we feel very confident that we can get to both durability as well as dosing and achieving close to 100% editing for those constructs.
I have a question, Ram. So you've obviously demonstrated that RNA editing can achieve similar profiles as DNA editing. To what extent do you think that it's possible to achieve this with targets other than AATD?
Yeah, I think that we have spent a long time on Alpha-1, and we have understood both what the structure of the RNA is and what chemical modifications are needed to make those changes. When we started with Alpha-1 for 110, it took us two years to get to a development candidate because it was novel biology. When we did 121, it took us 12 months to sort of get there from a potency standpoint. For this asset, it's going to take us close to seven months to get to that context. So I think that whether we can achieve it or not, that's not the question. We can definitely achieve it. The question is how long would it take to get there? And we've built out our platform such that we have enough diversity of targets and chemistry that we can actually get there pretty rapidly.
So proof is in the pudding. We have to get to humans and show that this works at a high level. And so that's been really our focus.
Thank you.
Hi, Ram. So thank you very much for the presentation and congratulations for all this progress in the early pipeline. So I'm just curious, what are the sort of principles of disease that you are selecting for this RNA editing that your platform is uniquely advantaged compared to directly delivering an mRNA gene editing or AAV-based therapies?
I'll use 121 as a perfect example, or even AMPK gamma-1 as a perfect example. You don't want to constitutively upregulate these pathways because they are energy management. They utilize and burn and create more mitochondria. If you make that edit, it's going to leave a permanent challenge in terms of having that pathway always on. That's problematic. But when you...
mRNA is not permanent.
Yeah, but our dosing frequency is going to be much, much longer. So when you think about a chronic indication with an mRNA, I don't think you want to do once a week. Even when you take an OTC, we're talking about once a month, once in three months, depending on the potency of the construct. And so the goal for us has always been, as I said, in prevalent indications. And so the safety bar increases tremendously as you go higher in population.
Thank you very much.
Great. Well, I think that concludes our session today. Thank you so much for being here, Ram, and thank you all for joining us.
Thank you.