City Therapeutics, Inc. (CTY) November 10, 2026 Conference Transcript

All right. Thanks, everybody. Super excited to be moderating this panel with Andy Orth, CEO of City Therapeutics, a next-gen SRNA company that recently went public. Maybe just given you guys are a newly public company, Andy, I'll let you kind of give a little bit of background on the company, your key programs. You have a lot of catalysts next year, and then we can go one by one through each asset and talk about the opportunity and some of the questions. Great. Go ahead.

Thank you. Thank you, Paul. Thanks for the invitation. So I'm Andy Orth. I'm the CEO of Citi Therapeutics. Citi founded about three years ago by, frankly, some of the pioneers in RNAi, John Marganori, the ex-CEO of El Milam, as well as Phil Zaymor and other scientific leaders here, to lead the next generation of RNAi medicines. We think there is a ton of runway left for this modality. Think about the antibodies on this front. And we're really pushing on two fronts here. We've gotten off to a very quick start with three programs using what we call canonical, right, or fairly well de-risked. Galnac delivered SIRNAs to the liver. Those three programs I'll talk about here in a moment. The next gen that is coming behind that, however, is a complete proprietary switch to the platform. We have novel innovation on what we call the trigger molecule, or the siRNA, or in our case, cityRNA, which stands for cleavage-inducing tiny RNA, a technology that was completely licensed out of Ohio State. And I'll talk more about that in a moment. Um, the three programs we have all clinical stage. Our first is factor 11. It's an anticoagulant. You're probably familiar with this class. That's currently in phase one, and I'm happy to say we're going to be sharing a ton of our data at ASH in December in New Orleans. The second program is RBP4. It's a, again, liver-derived target for Stardart disease. This program dosed the first healthy participant in our Phase I trial last week. We issued a press release on that this morning. I mean, we expect to share some of that data from the Phase I mid-next year, and we'll talk more about those trials and where they set up in detail. And then the third program is for anemia of chronic disease. This one will have a CTA filed by the end of this year, knowing that it's November here, and we're also doing an IIT for that program as well. So here we are, a three-year-old company. We've just completed the IPO. Three what I'll call technically and target biology de-risked programs with meaningful readouts here coming over the next year.

Awesome. So let's go one by one through these. Maybe we'll start with Stargardt. Maybe review for people sort of the biological hypothesis there and where you see the cleanest path to differentiation for city RBP4. Great, great.

So, you know, Stargardt, rare disease, roughly 30,000 patients in the United States, hits in adolescence, and a majority of these patients end up legally blind here at some point in their 20s. There is no approved treatment for this today. There is, however, a small molecule program from Beelite Biotin Larabent, which has had successful phase three data. The underlying mechanism here is this is autosomal recessive. It's a genetic disease. There's a mutation in the ABCA4 gene, and this causes the toxic buildup of a derivative of vitamin A in your eye. That buildup and these deposits are what causes the decline in vision. Those deposits, again, start in your teen years, et cetera, and then just continually build over time. It is stopping or slowing the progression of that buildup. That is the main goal here. What we've seen from the small molecule approach is they have inhibited something called RBP4 that is solely produced in the liver. RBP4 has one job and one job only. That's transporting vitamin A to your eye. So it's a very elegant target for this disease. You can choose which level you inhibit this or modulate this in order to limit that vitamin A delivery to the eye. You do not want to eliminate it completely. Your eye needs some level of vitamin A to function well. And Tin Larabent showed a 36% slowing of those lesions I was talking about on their small molecule. We, with an RNAi approach, are likely going to have a profile of a once-every-six-month subcutaneous shot, physician-administered, And we believe we'll easily be able to meet and most likely beat their efficacy level with a dramatic improvement in adherence and convenience with our dosing regimen.

So maybe talk about the preclinical data you have. Obviously, you just, you know, started the human study, but what have you seen preclinically in different animal models? And, you know, what gives you the confidence that that profile should translate into people? Right.

So, again, just to back up a little bit here on the technical risk of RNAi, if you look around the world right now, you're seeing a lot of these programs, liver-delivered RNAi molecules, siRNA, with GalNac. The people who work at Citi... are the people who invented the original galnak delivery of sRNAs at Lnylam. We know this space exceptionally well, and not all these molecules are built equally, right? You know, this is the only China bashing I'll do in this particular talk. We are screening every molecule we see come out of China, right? And these are not all good molecules. Importantly, many of them are dirty, right? They have off-target issues that are not going to make it long-term through the clinic. In our hands, the technology is highly de-risked. That means two things. We can specifically modulate the exact level of knockdown we want in order to get the achieved level of inhibition of that delivery of vitamin A to the eye. That's what we really proved in the preclinical side of the world. Again, now we're dosing humans right now, but we're able to see what you want in RNAi here is dose-dependent knockdown with very tight bands of modulation, And we're able to see that by knocking down RBP4 in the liver. You can see the level of vitamin A that's getting transported into the eye, and they're highly correlated. As a matter of fact, perfectly correlated. So what that sets us up to do is use the phase one studies to look at general safety, as always, PKBD, but really what is the level of knockdown we want to choose for the pivotals.

Yep. And how well do we understand... How biologically, like, whether greater knockdown will actually translate into better efficacy?

Yeah, it's a great question. And we have seen, right, from the BeLight data, that simply lowering, right, or increasing that level of reduction of vitamin A versus other trials that have tried, right, there's Alkaeus and others, have in fact correlated to greater efficacy. So, this is, I think, biologically completely de-risked, right? We've got clinical proof of concept. It's in the FDA right now. Our goal is to take that platform and be better on two fronts. So, a small molecule is dosed, and you have daily peak troughs, right? And Tim Larabent's dosed every day. RNAi will avoid the peak troughs. You simply clamp the protein at a certain level that you want, and it's flat, period. The two dose levels we'll explore are going to be one that, quote-unquote, is equal to their average inhibition, and we think on that alone we're going to be able to achieve greater efficacy because they still have that peak trough issue. And we're going to go with greater inhibition, right? We're going to dial that up further. They had to make a choice, and I think they made a pretty good choice on what level of inhibition to achieve with RBP4. There is an on-target. If you'll call it that safety thing called delayed dark adaptation. This is something I know we'll chat about here more. They had made a choice on their dosing level, and they achieved roughly 80% inhibition of RBP4, right, which correlates to the same level of inhibition of vitamin A delivered to the eye. We will go there, and then we'll also target 90. And we think both of them, frankly, will provide a superior efficacy metric on the DDAF than they got at 36%.

Yep. Yep. Okay, great. So that's a thesis on efficacy. You already anticipated my question on safety. I think, you know, it's interesting. Like, I think when I had, you know, talked to investors on Citi who were looking at this program, I think there was sort of like less concern around like the actual severity of these events, but more of a question on, okay, if you have this long acting drug and a patient has an adverse event, are they stuck? Like, are they, you know, are they permanently having this issue? Right? Also, I think there's a little bit of... I want to see confusion, but some physicians call this night blightness. They don't call it delayed dark adaptations. Maybe just give some context around what we know around the severity of these events, and then why shouldn't we be concerned that irreversibly knocking this down or irreversibly for six months won't make this a more problematic issue for some patients?

Great question, and I think There is some confusion, right? And that's up to us and possibly others to help educate on that front. First of all, let's talk about the Belight trial, right? Two, I think, patients discontinued this trial of the whole entire phase three. Those were not because of this delayed dark adaptation, as a matter of fact, right? So it was not an issue for them in their phase three trial. Additionally, we're continuously in dialogues with all the investigators from the Tenlariband trial, and their request to us is push it further for greater efficacy. So those individuals who are deeply involved here are clearly pro what we're doing and understanding why we want to push it on that front. We have heard in the community and other places that people are concerned about this. And just taking one step back here, for a normal individual who walks from a bright light environment into a dark environment, you're going to take roughly 20 minutes, actually, for your eyes to fully adjust. And you can see where Belight has done some work on this and actually reported this. Belight thinks their drug adds roughly five minutes on that. Is that the average? Yes. Yes. For a full adjustment. Right. So to me, in the. Grand scales of things. A genetic blinding disease versus those five minutes is a very worthwhile tradeoff. If we continue to push the efficacy, that five minutes doesn't turn into 10 and 20, right? It adds a very modest amount on top of that.

Why is that?

It's just simply the delayed dark adaptation is caused by that lack of retinol, right? That lack of vitamin A that's in the eye. We are going to reduce that yet another step.

You're talking about an incremental difference.

That's the best word to describe it is going to be incremental.

I see. And so with the readouts next year, what are the kind of key questions you'll be able to answer with initial data?

So the key questions we're going to answer with initial data is that level of knockdown, first of all, general safety, of course, and then this PKPD. What are the levels of knockdown we want for liver RBP4 and the correlating knockdowns of retinol vitamin A that's getting delivered? That is the goal of Part A and Part B that we're going to have coming out at the end of next year. A will be in healthies, single ascending dose. B will be in StarGard patients. Importantly, we're going to recruit this population to be as close as possible to the pivotal population. That Part B single ascending dose will then translate into a Part C multiple ascending dose, and critically here, that will then translate into an open-label extension study, which will have a host of efficacy, other imaging metrics, etc., And we will follow these patients until we're commercialized. So that is a source of rich, rich data coming over the next three years.

Yep. Yep. Okay. Very good. Anything else to add here? Or should we try to hit a few others in our time?

Let's go. Let's move to the others. Okay.

So maybe on factor 11, like I think, you know, people, I think there's some baseline knowledge of this space, right? Like, you know, huge potential market, validated target, also very crowded. Talk about your differentiation thesis here.

Right. So, yes, a crowded market. You have small molecules. Bayer, by the way, just got approved for secondary stroke by the FDA yesterday afternoon. So this is good news on that front. You have antibodies. Regeneron's kind of leading that front with multiple programs. And then you have a couple or a few RNAi programs here. In terms of the best modality for the target, and just a quick drop back here, right, factor XI is genetically validated and believed to be a much safer alternative to the direct oral anticoagulants, Eliquis, Xarelto, et cetera. The genetic validation is simply, it's called hemophilia C. You know, there's thousands of people walking around the planet right now who produce minimal factor XI. They're fine. Right? They don't have strokes and other PEs like the general population. This is what's got everybody so attracted to this. RNAi, in our view, is absolutely the best way to go after this. Small molecules do a good job of inhibiting it. Antibodies inhibit it in a different way. I think a good interesting proof point here is Regeneron has two antibodies, one that's strong and one that's stronger. Right? So if you can't achieve complete inhibition with one of those and you've got two, you already know there's some variation on that front. And then you have RNAi, right? And this is what we used to say at Lnylam, why use an antibody to mop up the floor when you can simply turn off the faucet, right? We will shut down production of this in the liver to the desired level we want. Right now, in our preclinical data that we've got public, we're showing wonderful dose-dependent knockdown. At ASH, we're going to show where we are with our likely therapeutic dose at 300 milligrams. The goal here... Once every six months, subcutaneous administration, 300 mg, you have 95% plus inhibition reduction in factor XI. So very attractive across a host of indications. The positioning, and we're similar to Bayer here, is do not go head-to-head with Eliquis right now. Start in a massive, many, many millions, of patients who cannot take Eliquis because of other comorbidities. So a lot of runway left in this space. We are in the midst of our phase one. Our phase two is going to be a TKA trial, which is kind of a well-trodden path for this space. We'll start that in the middle of next year and excited to do so. That's a great place to be more head-to-head.

Yep. And so what's the timing for initial data from the phase one study, and what is the end goal on, like, peak knockdown you think you can get?

So we'll share a good chunk of data at ASH, and that will help give an idea of how we're doing on this 95% targeting knockdown. And that is the floor. So we will be 95% or greater on the knockdown levels at once every six-month dosing.

Okay.

Okay.

You've talked about exploring a partnership for this program. So maybe just give us some context on when you think the right time is. One question I've asked you is, we're still going to get a bunch of other data readouts in this class over the next couple years? For strategics, how important is these external data readouts in impacting their perceived upside value of these programs?

Yeah, I think they're really important, and I think we're going to see with, I'm very excited with the Bayer and the secondary stroke indication that they just received what they're able to do with that in the next three months. We're going to have additional readouts coming out across the class in Q1 and Q2, et cetera. I think the right time for us is within the next year. If you're a partner for us, you want to see our data, right, and how that's playing out in phase one. We're going to execute the phase two TKA. We're going to do that very, very well. So likely at some point in there in mid-handoff. But I think a year from now is where this thing actually shows its dramatic increase in value.

And are you thinking, like, what's the right structure for City?

Yeah, I don't know, because we're open to more than just your typical, hey, where's a big pharma who's going to write a check, and it's a milestone and royalties type deal. If there was someone who wanted to focus solely on this and do a NUCO type spin, we would be open to that. The deal that Sirius did with CRISPR is kind of a 50-50. We might be open to that. The critical point here is capital required to do multiple phase threes, right? If you are looking at this... If you have this enormous multi-billion dollar space and you have the best in class RNAi, you want to put a lot of resources here, right? That may, in fact, inhibit what else we could do. RBP4, we have other programs, etc. So that's the big driver for a partnership, right? This is likely one with someone who could put. A significant amount of capital in it immediately.

Yep. Yep. Okay, great. Anything else to add there? Should I hit on anemia? Let's move to anemia.

Okay.

I mean, I love this target. I think it's super interesting. I think, you know, one of the, I'm going to kind of say it in sort of a half-joking way, but I think one of the interesting kind of research questions with this program is like, what is this market? You know? How would you characterize it?

So pulling it back a little bit, you know, if you've had any exposure to the anemia market in A lot of our minds go right to Epigen, Aranesp, whatever you want to call it from Amgen, where I happened to work long ago. And this is a completely different anemia, right? The anemia we're targeting is 40% of all anemias in the United States are what are called anemia of chronic disease. They're inflammation driven anemias where you have iron present, but it's just restricted. It is not allowed to be released in order to, you know, make red blood cells, erythropoiesis. So that is a very different approach on this front. Five million plus patients in the United States alone across a host of different indications. Genetically validated, right, the target we're using is knocking down liver TFR2. If you are born producing minimal or no TFR2, you are completely fine until probably, you know, mid to late life. And then you might see a little bit of iron overload.

You also might find yourself running sub-3 varicose.

You also are not going to be slow in endurance events. Yeah, because what you're doing is you're producing just an amount of superfluous iron. So you're limited by the amount of red blood cells you can make by your potent, your EPO counts. That's the real governor here. So excess iron goes into the system. You can get some deposits in some organs long, long term. But it will definitely boost you versus if you were having normal iron fluctuations.

Yep. And so you're running this investigator, I guess, IIT study in China in myelofibrosis patients who are or aren't transfusion dependent. You know, what is kind of the level of efficacy you're hoping to see in this study to basically, I think, one, you know, make you think, okay, this is potentially a real drug in MF. But two, okay, this thesis is correct, and we can now extrapolate this more broadly.

Yeah, it's a great question. So we're doing an IIT in China in parallel with what I'll call traditional phase one to Western study, right? They're going on at the same time. And the reason we're doing the IIT is to get a look at. Can we move hemoglobin in this varied patient population? They may or may not be on a JAK inhibitor, they may or may not be transfusion dependent, etc. So that is the core goal here is to jump right to an efficacy metric. Certainly, we're going to measure all the other things that go with it on that front. But we believe there's some obviously other data out there from disc medicine with an adjacent target. Both of them are modulating hemojuvalin, right, which is the end target that we're both modulating. But that's the real purpose here. So we will, mid-2027, have core efficacy data in that patient population, which, again, then opens up multiple other places to go here. The likely first place outside of myelofibrosis, which, by the way, there's a complete unmet need. There's nothing there right now for this. First place after that's likely IBD. And then after that, you start to get into a host of others, and it's making choices, right? Where's the biggest unmet need, et cetera.

Is there a is there like an effect size bar for the MF readout that you have? Like you've got transfusion dependent patients, right? Trying to get a certain percent no longer requiring a transfusion? Like, how are you not yet?

I think I think the underlying thing here is what we have to be able to show and what we're confident we can is, can we move hemoglobin? Right? And then let's see what the downstream result is of that transfusion dependence, etc. This, again, is going to be a once every six month sub q injection, right? And there's a little bit of a speed of onset with RNA As you know, right, this takes a few weeks to set in. So watching those patients over this time is going to be pretty valuable on that front.

Yep. Okay. Okay, great. Anything else you want to add on that program?

Not on TFR, too.

Maybe one question I have on it, just like when you look at the DISC experience, right, they've had, you know, some success, but I think in kidney disease, right, the FSC data wasn't as good. You've talked about wanting to pursue anemias related to inflammation. Right. How confident are you that that's like truly a common etiology? I mean, it's obviously not the same etiology, but overlapping enough where this mechanism should translate from MF to IBD or other populations.

Yeah, yeah. Again, with the underlying source being restricted iron in the system, we are highly confident that this MF trial is going to allow us to show that that is what's happening. Again, the reason we're picking some patients not on Jax and all these other things is there can be confounding things there, right? So we'll have the right patients that we want to to go after that. The important part is going to be, I think, the error, perhaps, and we like CKD as well, you have to have enough EPO in order to make red blood cells. CKD is famous for not having enough EPO. Once you get into 3, 4, and beyond, we might think about this in stage 1, too, but I think the broader inflammatory diseases are the better places to start.

Yep. Okay. You have this really interesting earlier stage platform with these CitiRNAs. When's the next event that we'll learn more there?

Yeah, so city RNAs are essentially a shorter trigger. An siRNA is 21 to 23 nucleotides, roughly. A city RNA is 15 to 17 nucleotides. This was discovered by a biologist, structural biologist at Ohio State, one of our co-founders, Kataro Naganishi. From that point to today, we have proven that these work, and by the way, just a quick on the underlying mechanism here. RNAi works through something that's called a risk mechanism. It's an argonaut protein. It's argonaut 2. City RNAs work through both argonaut 2 and argonaut 3 at the same exact time. SiRNAs run into a dead end in argonaut 3. Adalnylam, we got it to work through 2, which is mostly what nature does, so we stopped, right? Don't monkey with it. We're trying to prove a whole new class of medicines. Here, we've shown that now, strand for strand, these city RNAs are more potent. Then an siRNA, because you're able to access both of these agoproteins. We will release this at a scientific meeting in Q2 of 2027. But importantly, if you look at what's on our pipeline today, three liver programs, one ocular program, one CNS, right, two extrahepatic ones, every single program that appears in our pipeline from this point forward will be a city RNA, even if it's a liver. So it's moved very quickly, and we've now gotten to the spot that we are the only ones in the industry who will be able to use this trigger molecule. And the underlying hypothesis here is with that mechanistic difference, as delivery becomes difficult, think about CNS, trans-BBB delivery, et cetera, having something that's a third smaller and more potent is going to be dramatically impactful.

Yep. Okay. Very good. Looks like we're basically up on time. So you guys recently did a big financing. How long is your runway, Andy?

The runway is to the end of 2028. We did a financing. We've released here. It was $200 million. We did actually do the shoe on top of that. So it's 2028 at this point and a little bit more.

Okay. Great. Thank you very much. Appreciate it.