All right, we're gonna get started. Hi, everyone. My name is Tara Bancroft. I'm one of the senior biotech analysts here at TD Cowen. Thank you so much for joining us at TD Cowen's 46th Annual Healthcare Conference. The next session here, we have a presentation, followed by some Q&A with Sutro. From Sutro, we have the CEO, Jane Chung. Jane, it is so wonderful to have you here. It's such a privilege. You can get started on your presentation-
Awesome.
Whenever you're ready, and I'll join you back up here for Q&A after.
Great. Thank you, Tara. Thank you for the opportunity. It's a pleasure to be here at the TD Cowen Conference, and share the new Sutro story with all of you. I've been the CEO now since March of last year, and this past year we've done a lot of work to transform the Sutro business. Actually, we've right-sized the team, we've extended our runway several times, and we've accelerated our programs. We're now, after the strategic pivot, we're back into the clinic six months afterwards, with our first ADC, tissue factor ADC, and also focused on getting into the clinic with two or three additional programs this and next year. A lot of catalyst on the way. How do I do the clicker? I will be making forward-looking statements as outlined here.
The new Sutro team is excited to deliver on the mission of delivering the next generation ADC therapeutics to deliver value now, as well as to shape the future of the ADC field. We have a very unique ADC technology that is differentiated by design. This ultra design capabilities enable us to make highly differentiated medicines that can actually address significant clinical opportunities. We have also developed, in a very short amount of time, a very exciting pipeline, where we have committed to three INDs over the next three years. Actually, we're on track to deliver three INDs over the next two years, which is really amazing to see. We have extended our runway now 4x with our recent raise.
We're now have runway into the Q2 of 2028, which does not include all of our partner milestones. What makes Sutro's platform especially unique is the ability to optimize every component of an ADC. If you're familiar with the makings of an ADC, there's the antibody, the linker, the payload, sites of conjugations, and many other companies can focus on one or maybe two of those areas, but actually, Sutro's technology enables us to look at all of those areas. We have done this to incorporate all the advantages of the cell-free platform into the design of our next-generation pipeline. We've optimized our payload system to a DAR 8 exatecan payload. We've even gone as high as DAR 16 without compromising PK, and that's not an easy thing to do.
We can incorporate multiple payloads in the process, and that allows us to deliver even greater potency to these programs. In addition, we've optimized the linker. We have a β-glucuronidase linker that's further stabilized with our non-natural amino acids, in the cell-free system with click chemistry, which really stabilizes the linker payload. If you look at our PK profiles of all of our pro-programs, you'll see rock-solid PK, meaning that there is very limited free payload distributed, which also then enhances the safety profile of our programs. In addition, we have updated our antibodies in the way that we make it in cell-free is Fc-silent. Most conventional ADCs are companies are trying to make them Fc-silent.
They don't engage with Fc gamma receptors in normal tissues, we can avoid liabilities like pneumonitis, ILD, and ocular tox, and other associated liabilities. All of these design features really enable us to drive what we see in our preclinical work, a ADC, we were able to increase ADC drug exposure two to threefold higher than conventional ADCs, which then would lead you to think that we can actually drive greater safety as well as greater efficacy in our programs. Our pipeline consists of both single payload and dual payload ADCs. The single payloads are meant to really validate this new linker payload system and the sites of conjugation we have optimized and really move quickly to dual payloads, which very few companies out there can do well with the protein engineering required to do them well.
We're already in the clinic with STRO-004. It's our tissue factor ADC program. Because of our optimized linker strategy as well as the profile, the best-in-class profile that we're seeing, we're looking to expand the benefit of tissue factor ADC across many tumors beyond just cervical cancer in which the approved tissue factor program is indicated. We also announced that we will be getting to top-line data middle of this year, and we're very excited about the fact that our safety window looks so good with a dose at 50 milligram HNSTD of 50 milligrams per kilogram, which is one of the highest we've seen with an ADC. In addition, STRO-006 is our integrin beta-6 program, which is also a target that's validated in lung cancer.
Not an easy target to make, but we feel very good about what we've made here for this target, and we're also seeing a high safety window with doses tolerated at 30 milligrams per kilogram in NHPs. Our dual payload programs we've announced recently is our PTK7 dual payload program. This is a DAR 10. DAR 10, 8 exatecans, 2 MMAEs, and going after, in this program, we've accelerated from, like, the second half of 2027 into later this year. This is great to see and noteworthy to note the HNSTD or the doses tolerated here at 25 milligrams per kilogram. Tissue factor is a target that's expressed in multiple in a broad set of tumors. Here we've done an extensive PDX work to understand where the activity may be seen.
Here we have a PDX model where we're looking at 1 single dose of STRO-004 at 5 milligrams per kilogram, which is a clinically relevant dose. We're looking at models here for head and neck, lung, pancreatic, and colorectal, and you'll see partial responses seen across the board, and best response is 73%. We believe that this is going to be the best in class tissue factor ADC. We're in the clinic already. We are in dose level 3, which we're moving very quickly into this program. We're looking at a basket of tumors that express tissue factor, and we look forward to sharing some top-line data middle of this year.
Moving quickly into the dual payloads, this is an area where we know that resistance from ADCs is actually being driven not by the target but by the payload itself. Even recently, there's been some emerging real-world data that shows that exatecan ADC followed by exatecan ADC does not actually do as well as chemotherapy. We know that resistance will happen, and this is a strategy to overcome resistance to any single payload ADC. Sutro's technology is well-positioned to be very competitive versus what's out there because of three reasons. One, we're well ahead in terms of the number of modality payloads that we have. We've got the topo, the tubulins, the DDRi, ATRi, PARP inhibitors, as well as the immunostimulatory agents.
What's even more important is this ability to control the ratios of these different payloads. This is what really allows you to get to a nice safety window in delivering a dual payload ADC. Already we're seeing doses as high as 25 milligrams per kilogram being tolerated at an NHP, and that is comparable to what you would find with a single payload DAR 8 exatecan. We've also achieved proof of concept for dual payloads overcoming resistance to single payload ADCs.
You can see here on the right a HER2 tumor model that we have actually treated to progression and to resistance first within HER2 on a weekly basis, and then followed by an MTI payload on a weekly basis, and then these double-resistant or dual-resistant tumors are now responding to a dual payload ADC, which is the next big innovation for the ADC field. In addition, on your right, my left would be a colorectal tumor model, which is traditionally and classically known to be resistant to MTI tubulin payload ADCs. You can see that here with the black line on the vehicle and the green line being the MMAE ADC payload. You see limited response there.
In the light blue, you see the DAR 8 exatecan payload driving a bit more response, but the dual payload in the dark blue actually showing more response in these tumor models. We feel that this is gonna be really exciting for the field. We announced PTK7 as our first target for the dual payload. This target has already been validated by the Pfizer program, but can be improved upon from a safety and an efficacy standpoint. Here you'll see that our dual payload program in purple shows a marked response in this breast xenograft model. All right. That's what I have to share for our presentation.
All right. We can go. Let's get comfy over here, and we can get into Q&A. I wanna remind everyone here if you have questions, don't let me hog it. Just raise your hand, jump up and down, shout at me, whatever you'd like. Make sure you get heard. Thanks for that great overview. It's super helpful to see, even for me, having known the story for years. I think obviously the biggest focus this year imminently for investors is STRO-004. Maybe you could give us a little bit more history with the target and, you know, with Tivdak, what certain aspects of it are you trying to overcome? In the preclinical data that you have, what is it that gives you the most confidence that you can beat it?
Just to provide a little bit of background on tissue factor and as a target, we like the target because it's definitely expressed in a broad set of tumors. Now Tivdak is approved for cervical cancer. It also has shown some early signs of activity in head and neck, and I think other tissue factor programs have even shown some promise in pancreatic as well. It is a target that's well expressed. Tivdak, their HNSTD for that program is 3 milligrams per kilogram, and if you look closely at their phase I trial, they couldn't get over the 2 milligram per kilogram dose on without running into more toxicity. Here we have an H in comparison to the STRO-004 program, we've actually changed a lot of things with STRO-004. It's a DAR 8 exatecan.
Tivdak was a DAR 4 MMAE. We've changed the platform payload. We've optimized the linker, the β-glucuronidase linker. We have an HNSTD of 50 milligrams per kilogram, so remarkable distance between the 3 milligram per kilogram. Not that we would need to have to dose that high, but even at those high doses, we're not seeing the tissue factor liabilities like ocular skin and bleeding risk. We're really trying to achieve a safe, clean profile for the STRO-004 program. Anything to add? I also wanted to introduce Jonathan Fawcett, our head of clinical development.
Yeah. Oh, thanks. Do you mind if this is on?
Yep.
Thanks, Jane. I mean, we acknowledge that the tisotumab vedotin molecule worked, but it was, you know, cruelled by its tolerability issues. You know, we set out to make it better. You know, Jane's addressed all those issues. On top of which, you know, we also anticipate the questions being asked about ILD because of the exatecan payload, and we've come back to some of the point that Jane made that we Sutro antibodies are intrinsically Fc-silent, and Fc gamma receptor engagement is, you know, felt to be a main driver towards the development of ILD. We think, you know, we've examined carefully where TV fell down and, you know, worked on making it better, because we think it is a great target.
Okay, great. As you said, the phase I data midyear, it's the first time we'll see data from this. Maybe, you can set the stage for us what to expect in terms of number of patients. I know you already talked about number of cohorts, but even by then could we see more than that? Just what can we expect from its profile and that initial update?
Yeah. We haven't got into specific numbers just yet, right? I think we have to acknowledge that we're moving really fast in this program. We started the program in early November, and now we're into dose level three and committing to data six-eight months afterwards. I think really the aim of any phase I program is to confirm the tolerability profile. We wanna make sure that what we're seeing in the cyno at the HNSTD of 50 mg/kg and no ocular and skin or bleeding risks are kinda translated into the human trials as well. And, you know, we will look to get some human PK as well as looking for a signal in other tumors, in addition to cervical. We'll be looking at a lot of things. Yeah.
Okay, great. For safety specifically, can you give us some numbers as benchmarks for... You know, I know you mentioned ILD and various other things, maybe just some benchmarks for thresholds that you want to overcome in various events.
Yeah, I can take that. Well, first of all, for ILD, you know, you've got to be in low single digits for ILD to have a drug, especially if you have ambitions to take it into frontline therapy. You know, to be honest, we think the potential of STRO-004 could lead us there, you know, down the track. We need to be right down there. We need really no clinically significant bleeding risk, and ideally, we'd have no iTox. We have good reasons to believe the iTox will be mitigated with our design. The payload is intrinsically less injurious to corneal epithelial cells. A lot of the Tivdak iTox is driven by the really by the target 'cause TF is expressed in conjunctival epithelial cells.
We postulate that the Fc, the active Fc of TV may be driving the engagement of inflammatory cells with conjunctival epithelial cells to come back. The Sutro antibodies have no Fc receptor activity. We, you know, we think what the iTox is gonna be right down there at clinically not non-important levels. Obviously, we're collecting the data, and we're collecting the data with the intention of proving that there's no problem. By mid-year, you asked about the N, I think, Tara.
I have.
The N. Yes. Well, this isn't a 3 + 3 design, so it won't be. You know, we're not gonna be turning up with 12 patients in mid-year. With a MTPI Bayesian type design, we have some flexibility over enrollment, and we have disclosed that we are doing some backfill cohorts per FDA guidance, where they advise seeking tolerability in patient, you know, in patient populations where you might go on to develop further. It won't be a dozen patients, but it won't be 100, and you can choose a number somewhere in the middle of that for mid-year.
It's a nice range.
Yeah. Pretty reasonable. Okay. Oh, yes, Len.
Yeah.
Do you wanna sit?
This question wasn't a plant, but as you're probably aware, Tara wrote one of the finest reports on the ADC technology with her staff, over, you know, several months ago. One of the things that I got out of it was that, you know... Like other technologies, like monoclonal antibodies that got discovered now 41 years ago, it took time to get to where they became well-used.
Mm-hmm.
One of the issues here, I guess, was the initial toxicities of the payloads were quite high. We're moving down from those level of toxicities. I was wondering if you could go through as we look out, 'cause I try to look out five-10 years, what do you think the payloads will look like? Will they be reduced toxicity? Will it be where we are now? What could make ADCs much more widely adopted?
Yeah. It's a great question. Listen, in any therapeutic area modality, it takes time for it to come to fruition. I mean, I previously worked on immunotherapy, and nobody believed that that could even happen, and worked in the PD-L1 space, so there you go. It takes an evolution and effort to kind of really understand the human body and how it reacts to medicines. I think for ADCs, you know, the rate limiting or the still the unmet need for ADCs is toxicity. You wanna deliver something targeted so that it is actually beneficial and better tolerated than standard chemotherapy.
Having just attended the lung session this morning, I was actually quite surprised to hear that, you know, some physicians still believe that chemotherapy, systemic chemotherapy is actually better tolerated than ADCs when actually ADCs are trying to deliver that. They're trying to, like other targeted TKIs and other agents, they're trying to deliver targeted therapies in a way that is impactful and offer a better patient experience. I think in the ADC field, we've seen different payloads. We see the first MMAE tubulin class payloads now getting evolved to a Topo1-based payload. Many of these companies are trying to attenuate the payload to some extent, getting to a weaker version of that payload in order so you could dial up the highest non-severe toxic dose.
At the same time, when you do that, you actually compromise on the efficacy as well, right? The antitumor activity. You want to try to get to a highly safe dose, but at the same time, you want a potent dose. How do you best get there? I think this is where the Sutro technology is really unique in that way. Tissue factor as an example, the fact that we can get to 50 milligrams per kilogram HNSTD, so that's a really high ceiling for safety, but we're actually seeing antitumor activity as low as 1 milligram per kilogram. This means that you don't have to dose these things all the way up to, like, 10 or 11. You don't have to.
Patients can actually you could dose it much more modestly, and then patients can actually take the medicines for a lot longer, and that translates into more durability and more delayed disease progression. I think, you know, whether it's. We actually did not attenuate the payload. The payload that were chosen for our platform is actually a very potent exatecan. We're not attenuating payloads. We're trying to design these things in a way that through a stabilization of the linker, the better performing site conjugation, as well as potent payloads going after the whole design as opposed to one or two components of these things that'll help you improve the therapeutic safety window and widen that therapeutic safety window. We've seen it with every single program in our pipeline.
STRO-006, we see antitumor activity as low as 0.5 milligrams, but then their HNSTD is 30 milligrams per kilogram, and we're doing the same for the dual payloads. When you combine these payloads, it's even more important that you get to a more tolerable sort of combination as well. I mean, I think, you know, just so much is still being worked on to actually improve the safety window. We have to do that in order for the standard of care to really adopt ADCs, you know, for the long haul. Would you have anything to add there?
Yeah. I mean, I think that's it, Jane. I mean, the key thing is we first of all have to solve the delivery issue so that we don't get the, you know, the drug ends up where it should, and you don't get the off, the, the off-target deconjugation. For instance, our β-glucuronidase has really no neutrophil elastase-driven deconjugation, so bone marrow release of payload is so that's an example. We also now have to recognize that some payload will always be delivered to normal tissue, some. That, I think, effectively rules out the pyrrolobenzodiazepines, the PBDs, really having a future because that, those targets affect, you know, normal tissues, non-dividing tissues. I think we're gonna hone down our choice of payloads.
The other thing is that just the lesson of combination chemotherapy was partly to address resistance, but partly also to reduce exposure and reduce toxicity by, you know, having two drugs at lower dose rather than one drug hammering at a big dose. I think the dual payload piece will be something we learn a lot about, and I think it will establish its place definitely. I think in some ways, it'll be down to dialing down dosing and also understanding ratios. Again, that is one of our strengths, is that we can tune ADCs, you know, absolutely precisely just by the number of non-naturals we incorporate. I think, you know, I think the dual payload piece will be a very important part. There will be new payloads, I think.
Yeah. Yeah.
There will be new. In fact, we have a bunch. The scientists can't help themselves.
Wonderful question and discussion on that. Thank you for that. you know, I guess we have time for one more thought question from each of you. What do you think is the most underappreciated about Sutro? Jane?
Yeah. Sutro's not a new company. We've been around for quite some time. We have a brand-new team. I think people who followed Sutro know how powerful the technology can be. We even had a company that spun out of Sutro called Vaxcyte, and it's enabled a whole vaccine discovery and development. The technology is well known. I think the fact that, you know, we have transformed the business, we have a new management team, a new strategy for differentiating our platform technology and our science, and the focus we have on execution and the discipline we are going to have to run a business is something that's new, and hopefully more people will learn more about our story. Yeah.
I agree. John, do you have an answer?
Well, of course, I have to, would have to call out Jane here for you know, basically refreshing the whole leadership team and sort of moving us into, you know, into making us into a very joined up company where we know we directly connect the work of discovery, the work of process, you know, process and manufacturing development, and clinical development into a coherent sort of, you know, a coherent organization that puts things through the discovery development process as efficiently as we can. I just, you know, I think, I think the world's beginning to catch on to that it's been a huge turnaround, you know, driven by Jane's appointment to CEO. I, you know, I mean that absolutely genuinely.
You know, I think people will, in time, will also come to appreciate the huge flexibility of the platform to absolutely tweak the antibodies to their most effective forms and able to do it quickly. I mean, we can generate a new antibody in a matter of, you know, a whole ADC construct in a matter of a few months, you know, almost ready, clinic ready. I think that's gonna be good for us in the future.
All right. Fantastic. Thank you both so much for all of your insights. Thanks everyone for listening.