City Therapeutics Stifel 2026 Healthcare Conference

All right. Thanks, everybody. Super excited to be moderating this panel with Andy Orth, CEO of City Therapeutics, a next-gen siRNA company that recently went public. Maybe just given you guys are a newly public company, Andy, I will 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 Thank you. Thank you, Paul.

Thanks for the invitation. I am Andy Orth. I am the CEO of City Therapeutics. City, founded about three years ago by, frankly, some of the pioneers in RNAi, John Maraganore, the ex-CEO of Alnylam, as well as Phil Zamore 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. We are really pushing on two fronts here. We have 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 will 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 will talk more about that in a moment. The three programs we have, all clinical stage. Our first is Factor XI. It is an anticoagulant. You are probably familiar with this class. That is currently in phase I, and I am happy to say we are going to be sharing a ton of our data at ASH in December in New Orleans. The second program is RBP4. It is, again, liver-derived target for Stargardt disease. This program dosed the first healthy participant in our phase I trial last week.

We issued a press release on that this morning. We expect to share some of that data from the phase I mid-next year, and we will talk more about those trials and the way they are set up in detail. 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 is November here, and we are also doing an IIT for that program as well. Here we are, a three-year-old company. We have just completed the IPO. 3, what I will call technically and target biology de-risked programs with meaningful readouts here coming over the next year.

Awesome. Let us go one by one through these. Maybe we will start with Stargardt. Maybe review for people the biological hypothesis there, and where you see the cleanest path to differentiation for cityRBP4.

Great. Stargardt, rare disease, roughly 30,000 patients in the U.S., 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 Belite Bio, tinlarebant, which has had successful phase III data. The underlying mechanism here is, this is autosomal recessive, it is a genetic disease, there is 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 have 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 is transporting vitamin A to your eye. So it is 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. tinlarebant 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 will easily be able to meet and most likely beat their efficacy level with a dramatic improvement in adherence and convenience with our dosing regimen.

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

Right. 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 City are the people who invented the original GalNAc delivery of siRNAs at Alnylam. We know this space exceptionally well, and not all these molecules are built equally, right? 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 were 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. What that sets us up to do is use the phase I studies to look at general safety, as always, PK/PD, but really, what is the level of knockdown we want to choose for the pivotals?

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

Yeah. It's a great question. We have seen, right, from the Belite data that simply lowering, right, or increasing that level of reduction of vitamin A versus other trials that have tried, right, there's Alkeus and others, have in fact correlated to greater efficacy. This is, I think, biologically completely de-risked, right? We've got clinical proof of concept. It's in with the FDA right now. Our goal is to take that platform and be better on two fronts. A small molecule is dosed, and you have daily peak troughs, right? tinlarebant'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.