Morning. My name is Jason Zemansky. I'm one of the SMID Cap Biotech analysts here at BofA . Thank you for joining us on this, our second day of the 2024 healthcare conference here in Las Vegas. I'm pleased to welcome to this particular meeting Ram Aiyar, CEO of Korro Bio. Ram, thank you so much for joining us.
Thanks for having us, Jason.
Well, perfect. Maybe just start broadly, especially for those who may be newer to the story. Can you briefly describe the platform? What is RNA editing, and how does OPERA work?
Oh, thank you for that question. It's always interesting when you use the word "editing" in RNA; it gets a little bit more complicated. So, you know, when you follow central dogma, the idea of going from DNA to RNA to protein, over the last, call it, five years or a little over five years, you've seen a lot of companies that have taken DNA editing technologies, where they edit specific genomic material, co-opt a bacterial system to go and make a change, and then impact biology. The reason why they did that is because you have these rare Mendelian diseases, where you know the root cause for the disease. You know if you fix that, you're going to have good outcomes over time.
Most of those Mendelian diseases have really bad outcomes, i.e., they don't survive more than two years of their lifestyle, or they have very progressive disease further on in life. So it makes a lot of sense to go and fix the DNA where you know that's the problem. But human beings are more complicated than that, and so as you move down central dogma, there are mechanisms that exist to alter gene expression, i.e., read your code and make the protein. Systems like RISC that antisense oligonucleotides use, systems like Argonaute that siRNA is used to silence genes. And so one of those mechanisms, or one of those proteins that are in the human system, is called ADAR. ADAR is adenosine deaminase, acting on RNA. And this specific enzyme makes a single base change, that converts an adenosine, one of the alphabets, into inosine, which is a universal base.
What we do at Korro is co-opt that enzyme, ADAR, to make a single change on RNA, and that's what we term RNA editing.
Interesting. I guess the natural question here is: are there certain indications where RNA editing, as you would have it, is more helpful or useful than kind of DNA editing for, you know, those Mendelian traits that are, you know, potentially deleterious?
Yeah, unfortunately, both in B school as well as in R&D, the answer is usually it depends. So it's almost as simple as asking, you know, which one of your children do you like better? You know, they're sort of different. They bring different characteristics, and they're more, you know, one could be good at climbing, the other one good at art. And so that's how I view RNA versus DNA. There are indications where DNA editing, as I mentioned, rare Mendelian diseases where you know the root cause of the disease, and you know for sure you don't need to look at outcomes. Spinraza is a great example. You know, going after a rare Mendelian disease where you knock out a certain gene makes a lot of sense. RNA editing is a little bit more interesting.
So when you start thinking about complex diseases, chronic complex diseases, there are areas where you don't want to touch your genomic material, right? Because you don't know what the outcomes are going to be over time. There's not a fixed reason for the root cause of that disease. Moreover, you could have a broad severity of that disease. So you could have mild patients all the way to very severe patients. So that root cause of the genomic mutation is a risk factor rather than something very causal. So Alpha-1 antitrypsin deficiency is a perfect example, right? You can go in and fix the gene, but you could have a healthy 20-year-old with no symptoms. You could have a healthy 60-year-old with no symptoms. So how do you pick and choose?
And so that's where something like RNA editing is ideal, because you can come in, RNA in its nature is transient, so you bring a drug-like modality to make an edit, and if you take that drug away, you come back to normal, and so you don't have any of the potential deleterious effects you could have long-term by fixing something. So that's a perfect example where, you know, you have a disease that's Mendelian, broad severity, you want something that's irreversible, you can come on and do RNA editing. There's a whole slew of other indications where you can't do it any other way, okay? I'll give you one example. Let's say you have pain, all right? You go through ACL surgery, you go through spinal fusion surgery. Opioids are out there, problematic. People have been trying to develop non-addictive pain medications for a really long time.
Well, we can learn from genetics. There are certain ion channels, which are the drivers of pain, where we can make structural changes to the ion channels that reduce the current that goes through that ion channel, and therefore you sense pain. You don't want to do that permanently, because you won't feel pain at all, and that leads to other issues. And so this is an opportunity to say you have spinal fusion, you come on board with something like a nerve block-ish that is transient, you know that you can still feel pain without being entirely numb, all based on genetics, and again, once the drug is out of the system, you're back to normal. So it's things like that where you leverage genetics as well as pharmacology that you can't do with DNA editing is where our focus is.
Got it. You know, beyond repairing single pathogenic point mutations, you also have the capability to produce de novo proteins. What are some of the applications of this part of the technology?
Yeah, so the example I gave. It's a perfect segue. The example I gave of the pain is learning from genetics, okay? So the good news in that case is that you know there are certain individuals that have that variant, and you can learn from it and move forward. We've actually shown that you can also have an impact, as you said, on creating de novo variants, which means that, you know, if you have 20% of this protein that has a different amino acid change. So let me take one step back. The way that we create de novo proteins is we can make an adenosine to an inosine change. That inosine on RNA gets read as a guanosine through the translation machinery. So we have the ability to swap out 12 amino acid sequences, which then become the part of the protein that are the building blocks.
By doing that, we create variants that we can add characteristics that you can't do otherwise, okay? As an example, we've shown that we have created an amino acid change in a very hard-to-target transcription factor that prevents its binding to another large protein. By doing that, we've increased the level of this transcription factor. You can't do that any other way, right? You can block it. That doesn't work. You can block the negative regulator. That doesn't work. People have tried. They try to increase gene expression. They find that all sorts of crap happens down the line, so you can't do it very specifically. This is where the specificity is so good that we can say, okay, this portion of the protein binds to its negative regulator, and we're going to change it.
By just changing that one small portion, we can increase the half-life of that protein. This particular protein is like one of those, you know, protector proteins, if you want to call it. It's there in all cells, and if you upregulate it, it protects every cell possible. People who think about longevity and things like that have been trying to do this for an extremely long period of time.
Well, great. Cameron from the team had a few questions. Cameron?
Yes. So your first candidate, KRRO-110, is advancing for Alpha-1 antitrypsin deficiency. Can you provide a little bit of background on AATD? You know, how common is it? Where do we stand with treatments today? And then kind of, if you can classify what the unmet need looks like.
Oh, thank you for that question. So, as you're aware, alpha-1 antitrypsin deficiency is a rare Mendelian disease that has a large spectrum of the disease. You have patients that are on the extreme end that need to do double transplantation, both the lung as well as the liver. And earlier on, you have patients who end up in the NICU because they have this manifestation, and everything in the middle. It's caused by a single G-to-A variant in a gene called SERPINA1, primarily produced in the liver, okay? And so this specific mutation, this G-to-A mutation, causes in normal human beings, the protein is fine, is active. As you get an injury or an inflammation, the protein goes up and has a protective phenotype, systemically, okay? But when you have this mutation, this protein aggregates. Now, because it aggregates, it gets stuck in the liver cells.
And because it gets stuck in the liver cells, slowly the cells start to die. It's like calcium plaque, you know, that would be a very good analogy. The problem is that this protein is actually needed in circulation. That's where it does most of its job. So if it's stuck within the liver, it can never get out, okay? So by fixing this protein, or changing this, or repairing this pathogenic variant, we can get enough of it out so that it functions well. So that's the premise. So this is, again, one of the only ways where you can target the liver cells, fix the disease in the liver because of cirrhosis, but also have it out in the systemic domain so that it prevents the lung injury, okay? So it provides a benefit on both sides. So with KRRO-110, we've been able to show a best-in-class profile.
So 110 is an IV product that encapsulates an oligonucleotide. The IV product, the encapsulation, was licensed with Genevant because they had clinical precedent. And we've been able to show a best-in-class profile where we show close to 3x the amount of protein that is needed, normal protein that's needed in circulation. And we believe that we can get this to the clinic in the latter half of this year and generate data in the second half of next year.
Yeah, I think that's a great question and to a great segue into my next question. So you've guided to a regulatory filing in the second half. How quickly do you anticipate initiating a clinical study?
Yeah, I got this question. Is it July 4th or Christmas in terms of when we do a regulatory filing? I would say it's somewhere in the middle. I think, depending on the, we haven't guided to which jurisdiction we would actually file. So depending on the jurisdiction, we have an ability to start either this year or early next year.
To the extent that you can, how have your engagements with FDA been going, and how comfortable has the agency been, given, you know, the mechanism is somewhat novel?
Yeah, great question, and thank you for it. So it's a novel mechanism in terms of using ADAR for editing, but the FDA is going to be primarily concerned, or is primarily concerned, around safety, right? So you want to make sure that you start safe. The second component is that it's a mechanism that already exists in the body. So even if we don't do anything, 2%-3% of cells already undergo this process. So in that context, it's not an issue. So when you take those two things into consideration, we don't foresee any challenges because the Genevant lipid has been in the clinic, and oligonucleotide with the chemistries that we show has been in the clinic. It's a transient therapy from an infusion standpoint. So if worst-case scenario, you can take the drug away.
And so we don't foresee any challenges in terms of getting into the U.S. to file and start a first-in-human study. The question is going to be when.
Maybe in the time we have left, I'd kind of want to take a higher-level question here. Looking at the pipeline, you're pursuing a number of, you know, preclinical targets and diseases that have had little success over the years, like Parkinson's and ALS, and one where there's, in contrast, been more commercial challenges, as you mentioned before, with pain. Can you discuss the puts and takes here involved in the decisions to invest in more established targets with maybe, you know, a novel approach as a means of getting your foot in the door versus something a little bit more less well-established where, you know, maybe if it doesn't go as well, the negative read-throughs to the mechanism?
Yeah. Jason, I'm an engineer by training, so we're taught to take one variable at a time from a risk standpoint, right? So the first compound that we take to the clinic, we've taken the delivery risk off the table, we've taken the chemistry risk off the table. The only thing we're going to see is will the mechanism work, and will the mechanism work enough to provide benefit for those patients? The natural second step would be is we know we can deliver to the liver. So we did it IV. We would do it IV for the first product. So can we do it sub-Q for the second product? And do we take a little bit more risk on the biology standpoint? So creating a de novo variant in the liver with a sub-Q delivery is likely going to be our second product.
It's not listed in our pipeline for nuances around how we had to deal with the SEC and the process we did to go through a reverse merger. So very likely, we'll be nominating our second program in the liver that will be sub-Q with a de novo protein. It will be a target that will be very well-known. It will be a target that people have a sense of. It'll be in a market that people have a good understanding of the risk that you'll be taking forward. So again, just one step at a time. And then, you know, as you talk about, the things in the pipeline are really to showcase why we are differentiated, right? So TDP-43 and ALS is a great example. What we're trying to do, you cannot do with any other modality.
Well, perfect. Makes complete sense, and looking forward to some very exciting readouts in the near future. Ram, thank you so much for joining us.
Thank you for having us.