Okay. Welcome to this session, RNA Medicines New Targets. My name is Keay Nakae. I am the Director of Research and one of the Senior Biotech Analysts at Chardan. It is my pleasure to welcome our panelists for this session, Dr. Ram Aiyar, CEO and President of Korro, and Dr. Elisabeth Gardiner, CSO and President of Tevard. In small RNAs, we were just talking about a lot of the success has been in silencing translation of a protein, but where there is opportunities to upregulate a protein or be able to target, as I said, new targets, companies like Tevard and Korro are formed to advance the science to do these things. Korro obviously focused on ADAR, Tevard focused on transfer RNA. I think we will have an interesting discussion here.
Ram, let me start with you. I think most people are now fairly familiar with what ADAR is trying to do, RNA editing of a single base. As we talked about in the last session, an obvious choice to kind of prove out the concept clinically was to target AATD. You had a single point mutation. It was to the liver. You kind of got two birds with one stone, both correcting the mutant protein that can aggregate in the liver, plus allow production of the protein to do its protective role in the lung. What we have always thought was interesting about ADAR was the ability to create new proteins or protein-protein interactions.
Maybe to start, let us talk about your lead program 121, and why it is a good target, and what you are trying to do there for urea cycle disorders.
Well, first, thank you for having me. Second, I am going to take you everywhere, every time I go speak with investors because you did a great job talking about ADAR. Just for the folks that do not know what ADAR editing is, I will spend one minute on it. Our drug product, when people think about the word editing, people think about gene therapy and CRISPR. We are not that, right? Our drug product in this case is an oligonucleotide that is similar to an ASO from Ionis or an siRNA from Alnylam. That is the drug product. Easily manufacturable and very scalable. We use that to think about this as a landing pad for an endogenous protein, in this case, called ADAR to come and make a single alphabet change.
The good news is that at any given point in time, about 2%-3% of cells in our body convert this A to I to G change by itself, we do not have to do anything. All we do is provide the drug as a landing pad and a targeting moiety to come and make that change. As Keay mentioned, there are many uses for it. One of it is the repair of a pathogenic variant. I am an optimist on technology, so I think that the DNA editing guys will eventually get there outside of certain areas where we think we can be differentiated. But the real benefit of the technology is going after post-translational modifications, making a change in an amino acid, and giving a biological pathway and activating it.
Nobody can do that necessarily in large complex diseases where you want to activate some pathways in a very specific manner. That is really our sandbox. There are other things that we can do, but that is our focus at the current moment. That brings us to our lead program, which is KRRO-121. For KRRO-121, we do exactly what I said. We make a single amino acid codon change on a protein called glutamine synthetase. Let us just call it GS. It is a protein that is present in the liver, and it is utilized to, for lack of a better word, detoxify ammonia. It converts ammonia into glutamine, and in patients that have a genetic mutation that fall under a category of diseases called urea cycle disorders, where they cannot clear ammonia, this is the pathway that takes over.
We are able to stabilize this protein momentarily, transiently, not permanently, and we are able to clear and blunt an ammonia response in these patients that go through pretty severe scenarios. I am sure we will touch on that in a second. But 121 is, we are now in the clinic. We have started a SAD/MAD study. We have finished dosing our first cohort. We just announced that a few weeks ago. We also guided to getting into patients in the first half of next year, the data in the second half of next year. We have additional things in the pipeline I am sure we will talk about, but maybe stop there.
Well, let's start with the preclinical data for the program thus far, and what are the key observations that give you confidence as you moved it into humans?
Yeah. I think the way that we think about targets in general is we need to have a high level of confidence that it's going to work in humans. The background that we look at is what sort of genetic evidence really exists for some of the targets that we go after. So glutamine synthetase is very unique. There are case studies where much like there were case studies for PCSK9 when they were first developed, there's both a loss of function and a gain of function at the specific site or the amino acid that we're changing. We know that if you have a gain of function and you were to hyperactivate the site, you end up with creating high ammonia in patients.
In cases where you were to stabilize the site and prevent this degradation, you end up with low ammonia and a very improved systemic performance. Between those two gain of function and loss of function, we knew that biologically this is going to work. The only question that we're answering in the clinic is can we get enough drug there, and can the change that we make be sustainable? So from a preclinical standpoint, we've demonstrated making this change makes a lot of sense in stabilizing the protein. We have both OTC mouse subsets of urea cycle disorders when they're preclinical models we've looked at, if you were to challenge with an ammonium chloride, we can prevent and blunt the ammonia response, and we've shown it across multiple models. Then we've also demonstrated in monkeys that we can direct the cells to actually make the change.
That's the most unique thing about this product. Most drugs, when they're developed for urea cycle disorders, are very mutation specific. We have competitors that are looking at a subset of urea cycle disorders like OTC. Whereas this is the first time outside of nitrogen scavengers, which is a standard of care, that you have a drug that can go after across all mutations. We call that pan-UCD, which is very unique. We've been able to demonstrate now across multiple mutational models, both survival as well as blunting of the ammonia response in patients. Our hope is that in patients, because we can blunt this response, they can eat more protein. They don't necessarily need to worry about what we call as intercurrent events. So if you have an infection, the ammonia goes up. It's like hypoglycemia.
When you have Type 1 diabetes, you go to bed, you're catabolic, you forgot to eat dinner, and the next thing you know is that your ammonia levels shoot up, and you end up in the hospital. A drug like ours can provide that peace of mind for these patients. I think the pre-clinical data that we've generated builds that case for it.
Okay. That's great. Having advanced into the clinic, kind of fairly standard, SAD/MAD to start, and then we'll get into patients. Maybe beyond safety, talk about some of the key biomarkers you're assessing to determine level of target engagement and perhaps markers of potential efficacy.
Yeah. If I were to just take a step back, UCD is one of those indications which is ultra-rare. There's about, call it 6,500 patients in the U.S. Despite that small patient population, the current drug on nitrogen scavengers, just by treating 800 patients, makes about $400+ million . We think that if you can come in with a pan- UCD, a much better profile, we think a $1.5 billion market opportunity is going to be very easy for this product. The development timelines are also very rapid, which is that when nitrogen scavengers were approved, they were approved based on 40 to 50 patients in just two studies. Our path of development can be very rapid.
What we need to be able to show in the first study is that, one, we can lower ammonia or blunt the ammonia response, but more importantly, I think we need to be able to demonstrate that we can add something over and beyond what nitrogen scavengers can. What would that be? That would be the ability, much like in PKU, the ability to have more protein because these patients are on probably 20% of protein intake than a normal individual, and so even getting them up to 50% of that would be very meaningful for this patient population. I know people may not know this, but the median age of survival for UCD patients is 19.
Okay, one, nine. When you are diagnosed, late onset is if you are 18 months old. It is a very tough patient population where the mortality rate in the sub two years old is like 40%, and the mortality continues to remain very high despite them controlling the diet and otherwise. That is what we need to demonstrate early in clinical study. Obviously, we will show safety, we will show potential for ammonia reduction, but we want to try to demonstrate can these patients eat more protein? Can these patients survive on taking less scavengers? Even though we have not shared what that clinical design is, once we have approval, we will share those.
Yeah. It seems like you do have some opportunities to manage the diet portion of that to get some maybe early answers. If I am being fair in characterizing it that way.
That's right.
Great. Let's move on to AATD. About a year ago this time, you had some initial results. They weren't what people expected. At the same time, you continue on. You've redesigned. You'll be back in the clinic, but at a minimum, we all know drug discovery is hard, but there is value when you have a failure or you hit a roadblock. There's a lot of learnings there. Maybe explain to us the key learnings you have from that program and how you're able to apply them to better handicap your success going forward.
Yeah. Alpha-1, you could say it's not just what others expected, it's also not what we expected from the therapy. Just to bring everybody on the same page, our first product went into the clinic. It was KRRO-110. It was a single-stranded oligonucleotide that was encapsulated in a lipid nanoparticle. Our current generation of products don't use a lipid nanoparticle, they use a conjugate, so it's subcutaneous. The first product was IV. The reason we made those choices was because it was a first-generation product. Think of an iPhone 1 versus an iPhone 18. It's very different. We were just starting early on that technology landscape, so we decided to go and focus on clinical benefit.
When we entered the clinic, everything looked good in healthy volunteers. The safety profile for the lipid nanoparticle was what the issue was. We actually got pretty high, when you think about from across other LNP products, we got up to 1.2 mgs per kg, which is pretty high relative to other therapies. When we went into Alpha-1 patients, we ended up seeing that the stability of our product changed in patients relative to healthy volunteers. Never seen that before.
We did a recon and we took images of the product, and we found that indeed there was an issue in stability. We could have put good money behind a bad product and showed that we could get protein levels very high, and we decided not to do that. We decided to save our capital for our second product, which we have confidence in that we can show benefit. So when we think about a second-generation product, we knew that the mechanism worked. We created a repaired protein in every individual that we treated in that first study. Our goal next was, well, the bar there was 50%, now we wanted to come with something that can replace a DNA edit.
We wanted to give patients an opportunity to say, "I don't want to take a one-time edit. I would rather do something that's a repeat dose that will help a lot of these patients." So when we nominated our development candidate earlier this year, that's the profile that we shared, that for the first time, we got more than 90%, 95% editing in animal models. Very soon we'll give guidance as to when that will be in the clinic next year and when we anticipate data coming out of the program. We feel very good about that program as well. We hear stories from Alpha-1 patients that we've sort of interacted with. They are looking for therapies.
There's nothing really out there that has still driven the benefit that we can. One of the big areas where we can differentiate ourselves from the DNA editing folks is we've shown in the liver that we can be rejuvenative, whereas most DNA therapies, when they go with a lipid nanoparticle, stay away from that. So we have a space in which we can play.
Okay. Well, great. We'll look forward to you advancing that in the clinic and eventually seeing that data. Elisabeth, let's shift to what you're doing at Tevard. As we've talked about ASO success, a lot of it's silencing, but also a lot of focus of ASOs and siRNAs, it could be focused on the pre-mRNA and splicing or the mRNA and engaging with that in the cytosol. You're maybe at the far end of that trying to influence the ultimate translation of the mRNA into the protein in the ribosome. We all kind of know the role of transfer RNAs. It recognizes the codon, attaches the appropriate amino acid to build the protein. Maybe explain to us what you're trying to do with your engineered tRNAs to address situations where we have a missense codon.
Thanks so much, and appreciate everyone coming to this, and thanks for having us. And congratulations. It sounds like you guys have really made some excellent progress. Tevard Biosciences is actually focused on transfer RNAs that can fix nonsense mutations specifically. Our technology has an engineered tRNA that looks a lot like any other normal tRNA, but in this case, it recognizes very specifically the nonsense mutation, not the native stop codon, but the nonsense mutation itself. In its recognition, it then is able to deliver the correct amino acid and permit full-length read-through of the normal protein. This is fantastic because nonsense mutations actually cover about 35 million people, and this is a pathogenic mutation for them.
If you think about large structural proteins like dystrophin or, for example, titin or lamin A or filamin C, these large structural proteins are actually pretty tricky to deliver a full-length protein with a normal AAV. But in this case, we just deliver the DNA for our suppressor tRNA, and Nina did a nice job actually talking about suppressor tRNAs and tRNAs in general. But by delivering this DNA, it's a very small cargo. It's incredibly portable, and so we can actually put it into lipid nanoparticles or AAVs and really any construct. We've spent a lot of time actually focused on developing a tRNA cassette that we can drop into a variety of different vehicles for delivery.
Okay. You are able to build on a lot of technology that is out there. I guess maybe just a question I would have is using AAV to deliver, get into the endosome, we escape the endosome, and then we have to migrate over to the ribosome. But what are the engineering challenges that you had to overcome to be able to do that efficiently?
Yeah. So many engineering challenges actually on the tRNA side, and specifically creating this construct that was so portable that we can really drop into any AAV and focusing on the manufacturing side first. I think we were really trying to understand how to make the manufacturing as clean and simple as possible, largely because we needed to go into a variety of different settings, both we anticipate IV, but then potentially some sort of direct delivery to various different tissues. We were founded on the premise of going into the brain, and so we are actually utilizing AAVs that are tissue tropic in nature. Because of the portability of the construct, we're really able to work with anyone's AAVs.
And then, I guess when you say AAV, people are going to say, "Okay, talk to me about immunogenicity concerns, and how does that impact your target selection?
A great question. We are concerned about AAV immunogenicity. We're not concerned so much about tRNA immunogenicity, and that's a true advantage we have with our concept of gene therapy because we're not delivering a protein that the cell has never seen. What we're delivering, again, is this DNA for the tRNA, and so the cell makes the tRNA, it folds it knows how to interact with the ribosome because it's been folded appropriately by the cell, and then the cell's native translational machinery is actually making the full-length protein that needs to be corrected. The correction process of the nonsense mutation then allows the cell to make it natively, and so in that case, the cell is used to this native version of the protein, especially in the case of a haploinsufficiency, we don't anticipate having any immunogenicity at all.
Okay. Can you highlight some of your key preclinical observations today?
Yeah. Just in the past year, we've been able to see full length rescue of dystrophin and titin in a variety of different animal models. We've actually taken our suppressor tRNAs in a variety of different AAV contexts into monkeys. These look very safe, highly well-tolerated. We've also explored the aminoacylation piece. So can we have these suppressor tRNAs that are engineered actually aminoacylate correctly? Can they be actually involved with the ribosome correctly? Can they be part of a tRNA pool in the normal cell that isn't aberrant? So we can actually see high efficacy even with 1% of our tRNA as part of the total tRNA pool. We've actually looked at tRNA fragments. We haven't seen them. We've looked hard. We're looking at ribosome profiling.
We're doing a lot of proteomic studies to make sure that the proteins that we are making, such as dystrophin and titin, in the case of our DMD program and our dilated cardiomyopathy program, that those proteins are actually doing what they're supposed to do. Can they now, as a full-length protein that we've corrected, can they interact with the sarcoglycan protein complex? Can they actually facilitate normal motor function and repair? From the perspective of biomarkers, we've actually been able, in a very challenging animal model, to see creatine kinase drop down. We see 50% reduction in CK within 12 weeks. This is dramatic. We've never seen this before. We're also seeing some really nice data on nNOS, et cetera. We're excited to see the proteomic changes that are occurring in these animal models.[audio distortion].
I think that's given us a lot of confidence from both the safety and efficacy perspective to move forward.
Okay. What's your best guess of a timeline to enter the clinic?
I'm looking at my CFO, and he's going to tell me yeah, but we're moving forward as quickly as possible. We have, actually, an advisory committee meeting this week with the Duchenne community. We have a trial design for both titin and our DMD program, and my hope is that we will be in the clinic by either the end of 2027, the beginning of 2028. I'm pretty confident, that's me being very conservative. I think we could actually move faster.
Okay. Let me ask you a question. I know you don't need permission to answer. Another company focused on tRNA, Alltrna. How would you say you're differentiated from them?
I'm really excited about what Alltrna's doing. They have a completely different perspective than we do. They're also focused on tRNA, suppressor tRNAs. They're predominantly focused on the TGA stop codon. This is the TGA that you need to actually introduce an arginine. They're predominantly doing this in the context of lipid nanoparticle delivery, and they're focused largely on liver disorders, inborn error of metabolism. We're very interested in what they're doing, excited to see them progress. Everything that they do kind of like raises the tide for the whole field. We've taken a very different approach.
I think if you dig into both of our patent estates and really kind of think about how we've looked for tRNAs, we have taken similar approaches where we're interested in not modifying tRNAs so much that they break. Also not modifying tRNAs so much that they look aberrant to the cell, and I think we're both taking a very logical, methodical approach to our drug discovery, and I think we're pretty complementary.
Okay. Ram, let me ask you a question. Lessons learned as a CEO of a public biotech company. You're both located in Boston. You're both focused on small RNA. They're private. You've been public. You were private. Now you're public. Tell us the lessons learned that maybe you've gained that can help Elisabeth and the rest of our team as they move forward.
Nothing like putting me on the spot here. I don't think that the lessons are different in a private company and a public company. I think they pretty much hold the same. I would say the investor base now over the last few years, there's a big blend between the two. I think you have to say what you're going to do and do it irrespective of whether you're a private or a public company. I think that time is the only thing that we have, and so doing more in a short period of time, whether you're private or public, is still the same. People forget about capital efficiency sometimes when they go public, but I don't think you can ignore that whether you're private or public.
At the end of the day, I think even though I can say this in front of my folks, the biggest difference is managing people internally is challenging on the public front because you actually see an active-- They have nothing to do with it. There's an active ticker in terms of what the value is on the stock price. Outside of that, which can be demoralizing, the science is exciting. The work that they're doing is rewarding. As long as they see that, I think it's fine. So I don't know if anything is different between being a public and a private company in that context, except you have to be ready when something changes on the public markets.
All right. Well, great. Well, thank you for sharing those insights. Well, we've reached the end of this session, but thank you both so much for joining us today.
Thank you so much.
Appreciate it.