Thanks, everyone, for joining us here with Sutro today. CEO Jane and Jonathan, the Head of Clinical Development. I do want to spend some time getting more into the platform because I think it's really important to what you do and part of what makes you guys differentiated versus a lot of other ADCs. Maybe to start, if you could just briefly introduce the company, yourselves, and how your platform differentiates versus other ADC platforms.
First, thank you, Laura, for the opportunity to be here and share the update on Sutro. I'm Jane Chung. I've been the CEO since last March when we made a strategic pivot to our next-generation ADC pipeline. We have a very unique platform. For folks who have followed the Sutro story for some time, because our company has been around for 20 years, we have this cell-free technology that enables us to really optimize every component of an ADC. In fact, the design features are not bound by a cell membrane. That's why it's coined cell-free. But it allows us to ultra-design these things. Antibody ADCs are very complex structures that include an antibody, a linker, a payload. We actually employ non-natural amino acids on top of that.
All of these design decisions really help us really fine-tune what we think is going to make important decisions that can improve the outcomes for patients. I think what we're trying to do with our technology here is to make drugs that are not easily made with conventional ADCs. We will talk about this later, but the dual payload ADCs require us to really fine-tune not just one linker payload, but two linker payloads on the same antibody. That's not an easy thing to do because it's not just about adding more toxicity, because that can lead to more toxicity, but really just fine-tuning the ratios, the positioning of the linker payloads so that it's internalized and leads to better performance for these medicines.
We're very excited about the platform and our strategy right now since I've taken the lead of the company has been really taking our pipeline, which now consists of both single payload and dual payload ADCs. The single payloads will validate our optimized linker payload chemistry and non-natural positioning, and be able to kind of, once we're able to maintain and demonstrate lower hematology toxicity or neutropenia, then we can combine two or more linker payload systems in a safe way to be able to deliver even more potency and better outcomes for patients.
Since we are on the topic of platform, maybe getting a little bit more into the dual payload ADC approach. We, your investors, innately just think about one-to-one ratios when you talk about dual payload. Can you stress a little bit more how differentiated you guys are on this front and your ability to, I believe, with the dual payload, you will be getting an IND for in the near future—
Yes.
—scale the different cytotoxic payloads.
Yeah. So, our dual payload ADCs, our 227 program, which is targeting PTK7. It is actually not only a dual payload, but it is also a DAR10. It is like the first dual payload that is actually going higher with the DAR beyond eight exatecans. The whole premise behind dual payloads in and of itself is to overcome resistance to all the single payload ADCs that are currently in development. What is next after Topo1 resistance? We saw this field sort of emerging when we made the pivot last year, that we saw the field moving from first-generation tubulin payloads to a second-generation Topo1 payloads. We then asked the question, what is next?
Because resistance will happen. We believe that resistance happens not driven by the target, as evidenced by the fact that HER2 patients actually get treated with multiple treatments along their journey, but actually driven by the payload or chemotherapy. Combination chemotherapy has been a standard of care in many of these disease states. We know that delivering combination targeted therapy will be important. It is not just about adding to add more toxicity. It is about fine-tuning these ratios, not just a one plus one, but it could be a one plus two or one plus three. You have to be able to bake that off. The chemistry capabilities of our platform enable us to do that so that we could find the right therapeutic window that is both efficacious but also safe.
A lot of this has to do with the use of the non-natural amino acids, correct?
Yes. Thank you for pointing that out because I think it's a point that's an element that's a little less appreciated. We use non-naturals to If you think about conventional ADCs, the linker payloads are attached to or conjugated to cysteines that naturally occur on an antibody. Those are not necessarily made for conjugation, so they have a tendency for linker payloads to fall off. We use these non-naturals to actually pick the right positioning so that they're more protected within the ADCs from cleavage in the circulation, as well as stabilized our linker system to also provide more stability for the program so that it gets to the destination, which is tumor cells, and then is cleaved by the enzymes within the tumor.
As far as flexibility to use the optimal linker, use the optimal antibody, you guys seem to have a lot of flex here. You're not bound to just one type of linker, one type of antibody, one type of payload, or two specific types of payload. You can apply this to many different types of biology, correct?
Yes. I think it allows us to go after really complex targets that are really hard to do with conventional means. The flexibility gives us sort of a competitive edge. When you're trying to just bolt things onto inherent structures, it doesn't always work. But the ability to kind of have the flexibility of design is really the unique feature of the platform. Anything you'd like to add there, Jonathan?
Absolutely. I mean, absolutely, Jane. You've put it so neatly. I mean, with combination chemo, which is essentially what dual payloads are, there was a lot of optimization to get the dosing regimens right. How would that not play out in the dual payload ADC space?
Yeah.
The tunability of the platform is important. I mean, I sat through a large number of discovery seminars at Sutro where we discussed the ratios. In fact, they didn't just discuss them, they made them. I mean, there were a whole variety made. The system is extremely flexible for that.
Yeah.
We have gone into the clinic having already baked off a number of different ratios, and there will be the possibility in the future of looking at that further with every new asset.
Your first dual payload ADC is focused on two cytotoxic, or your first wholly-owned ADC is focused on two cytotoxic payloads. Is there any maybe future of moving into a cytotoxic plus maybe a targeted-type payload?
Yes. We have multiple modalities of payloads that we are thinking and developing. It is back when we made this pivot, again, we were thinking about, how do we shape the future of the ADC field? Once we optimize our linker payload for a single payload ADC, now it is about combining with other payload systems. We chose the MMAE combined with the Topo1 as our first program because it has really been validated. These two payload systems has been validated. It is not necessarily whether they are synergistic or whether they are additive. It really does not matter because a chemo combination is the same way.
We know that tumor cells are heterogeneous, and so you are killing different types of cells at the same time, which leads to better, deeper, hopefully, responses and durability in that process, in the growth process there. I think for us, we have a number of different payloads. We have got the ATRi, the PARP inhibitors, the immunostimulatory agents. Actually, we have a very important collaboration with Astellas right now, combining a STING agonist with an exatecan payload. Again, going after different distinct modalities of payloads that actually can be synergistic or additive to drive even more potency against cancer cells.
Got it. We saw initial clinical validation of your platform with a single payload tissue factor ADC. For those less familiar, can you just briefly remind what you guys presented over the summer and—
Yeah.
—where you guys are with that program?
Yes. STRO-004 is our tissue factor exatecan DAR8, exatecan ADC with a β-glucuronidase linker. The program is We provided an update back in August, and very encouraging data already. We see anti-tumor activity at several doses, 3 mg - 4 mg, in a heavily pre-treated patient population. The phase I trial is being conducted in the U.S. And then we also see a very safe, favorable safety profile emerging, where we see more, as the doses increase, you see more target-related toxicity, but we're still able to keep the cytopenia rates and the heme toxicity is fairly low.
That is by design and by intention. I think our pharmacokinetic profile, which we now have shared, our PK that shows that what we saw in the preclinical work is actually translating into the clinic, where we are seeing higher exposures of the ADC at every dose level, but still maintaining very low free payload in the circulation, which should translate into continuing the safety profile that is emerging.
So, I think it is very differentiating for us, the fact that we are dosing at three to four, possibly higher than that, and that is almost double what we see from the approved tissue factor ADC program that is approved in cervical cancer. So, I think that is very differentiating to drive more anti-tumor kill with a higher drug exposure and still maintaining and balancing out with a favorable safety profile. Anything more to add there?
Yeah. I mean, exactly. We have been very encouraged. The enrollment was very strong, and we moved up the escalation ladder quickly. I think the PK has been highly validating, really, because with the analysis we have done, even immediately pre-dose, the STRO-004 that is in circulation is still 98% conjugated. So, every time an antibody binds to a tumor cell, we know that it has got payload on it. It also means that reads through, I think, into the dual payload system, because you have to have stable PK, I think, to make those dual payloads work when you are delivering very punchy payloads. So this has been very good. We always knew that tissue factor would be a tough target, because it is so widely expressed in normal tissues.
We felt this was a very good one to sort of validate the platform on, and we are very pleased, in an odd sort of way, if you like, that you are always going to see toxicity, but you would rather that it was target-based and platform-based.
Yeah.
Because the target is the target, but the platform is under your control. We think we have designed a really very strong platform.
Yeah. As we just mentioned, the approved Tissue Factor ADC program is approved in cervical cancer, and the strategy for us has always been to drive up drug exposure and actually drive benefit to beyond cervical cancer. To see anti-tumor activity happening beyond cervical cancer in pancreatic, in lung cancer, and head and neck is actually very encouraging for the program.
What you're seeing to date as far as payload-related toxicity, how does this compare to other ADCs using a similar linker payload?
Well, I think, okay, so you have to remember there's two parts to this. One is the toxicity you see immediately, because when you do dose escalation, essentially you're concentrating on first cycle events and second cycle. It takes longer before you get the late cycle events, which is often why the cadence of dose optimization or the final stages of dose choosing, if you like, slows down, because you need to sort of build up how it looks over several cycles. But we've got off to a very strong start with very low levels, incredibly low levels actually, of cytopenias. We've had some anemia, but anemia, of course, is a very common AE in cancer patients generally, often multifactorial and often hard to attribute to drug, actually.
Also, in terms of impact on the patient, a bag of blood at the conclusion of a STRO-004 infusion just to sort of top you up is not the same as some AE which impacts your quality of life. So, we've been very pleased with the AE profile, actually. We've got a little bit of stomatitis, a little bit of eye tox, but we know the targets are expressed there. Remember, we had no mitigation, because we wanted to see what there was. Then, so we have mitigation we can pull out, or drop into the protocol, rather. So we're extremely pleased with the sort of initial few months on study.
Absolutely. I think in some of our conversations with investors, what stood out was you also had one response in very small efficacy data that you presented so far, but there was a pancreatic cancer patient who responded after a prior Topo1 chemotherapy regimen. How are you guys thinking about markets of focus? You showed a couple of responses around a couple different indications.
Yeah.
Where do you plan to maybe expand and focus more?
We didn't share actual numbers of responses in our update. We said that there were multiple responses across three different tumors, including pancreatic, head and neck, and lung cancer. These responses were happening in actually heavily pre-treated patients, some who've, in pancreatic, have seen irinotecan not just once, but twice. This is really something, because if you look at pancreatic as a specific indication, a lot of competitive programs cannot see responses after third line.
Yeah.
Right? It kind of falls off the cliff in terms of response rates. The fact that we're seeing this kind of response happening in such a later line patient population that have seen irinotecan multiple times is nothing to sneeze at.
Yeah.
And actually is very noteworthy. We're very encouraged by this, and the investigators we're working with are looking to actually see how the drug works in irinotecan-naive patients as well, also heavily pre-treated.
Yeah.
But also, I think this is what's really differentiating about our dataset, and that, so pancreatic is a hard tumor.
It's hard in the stromal to penetrate. But Tissue Factor is expressed highly in pancreatic, lung, and head and neck, so we're not surprised to see activity in these areas. So, I mean, right now what we've said is that we're looking to do backfill cohorts and continue the development around these areas where we're seeing activity, which makes sense.
Yeah.
But there are even other tumors that have shown response to the drug as well. Every dose level, we've seen activity with every dose level that we have investigated. So it's now, if you include stable disease and partial responses. So now it's about figuring out what is the optimal safety and the optimal durability and the optimal sort of dose that we go forward for these indications moving forward.
Yeah.
Yeah.
As far as pancreatic cancer as a potential place to go, do you think RAS inhibitors are going to give more of an opportunity to pick up some of these irinotecan-naive patients as RAS inhibitors move into earlier lines of therapy?
It's possible. They've had phenomenal data, and with their approval, they may be able to benefit a lot of patients with pancreatic disease. I think their approval is second line, so we'll see if it's moved earlier. Obviously, these are different modalities, and again, the whole idea, even with dual payloads, is to go after different modalities because we know that cancer is heterogeneous, and so there may be an opportunity to actually see benefit in patients who have been treated with a RAS inhibitor. Yeah.
You've guided for an update on this program in the first half of 2027. Can you elaborate a little bit on maybe what we should expect?
Yeah. I think the next update will have a more comprehensive view of efficacy as well as safety at the optimized doses. We're looking to get into irinotecan-naive patients as well as earlier line patients now that we've seen the safety emerge on the later line patient population. I'll pass it to Jonathan to—
Yes.
—add there.
I mean, there are upsides and downsides to doing an escalation study in the U.S. One is you get the whole thing, warts and all. You get in these very advanced patients. Also, on the flip side of it means it's less easy to access some of the patient populations you'd like. You'd ideally like to have patients who haven't been battered by six or seven lines of therapy. You would particularly like patients who haven't been exposed to irinotecan because the payload, resistance to the payload is then baked in because of the patient's prior exposure. In the U.S., most pancreatic cancer patients are treated with FOLFIRINOX to a much greater extent than Europe, actually, and Asia-Pac. You then have to broaden your net, really—
Yeah.
—to capture those patients, and that takes a little bit of time to sort out.
Yeah.
It's there, and we're very clearly with the TmAb-A data , there was a certain amount of response in irinotecan experience and a lot more in irinotecan-naive. We've had strong signs in patients who are irinotecan-experienced, and we think that's going to read through into even stronger signs in irinotecan-naive than previously seen.
Are you guys enriching for any specific type of solid tumor type, or is there any maybe natural enrichment happening where you expect more of a specific indication?
Well, I think we've got a lot on our plate now because we have seen, as Jane said, we've seen indications, responses in more than one indication beyond cervical. The brief was always to develop a drug, a Tissue Factor ADC that would have something to offer the patients beyond cervical cancer, other groups of patients. We feel we've already met that design brief, and now we need to sort that out further. Jane's mentioned we've had responses in lung, and lung, as you know, is a very large and very segmented patient population, which takes a lot of passing out to sort of work out where your role is going to be. So, we have a ton of work on our plate to try and sort that out and work out where we're going. This is a strong start.
Well, we'll have to wait until first half 2027 to learn more.
Yeah.
Want to now pivot to the integrin β6 ADC. You guys announced a couple weeks ago that you've gotten that into the clinic. Can you speak to your degree of conviction in the wake of what we've seen from Pfizer's similar ADC, how yours differentiates, and maybe anything that you took away from ESMO that learnings from what Pfizer has shown?
Yeah. So, very proud of the team. Our integrin β6 entering the clinic makes two programs into the clinic in less than a year, which is fantastic execution. Our integrin β6, despite the miss on the data for Pfizer, they are still moving forward with a next-generation exatecan-based ADC and a DAR8 MMAE payload as well in the bladder. They are still moving forward with their lead program, which is a DAR4 MMAE program in combination with pembro. I do not think they have lost conviction over this target, and neither have we. We know with our highly stable linker payload that we see the PK that has emerged with STRO-004. Many of the design features and decisions were carried through into STRO-006 from STRO-004, so we feel like we can potentially replicate that PK as well in STRO-006.
The stability is really important because if the linker payloads do fall off, that leads to a lot more platform tox. Again, we want to be able to clear that. I think for us, integrin β6 is a very important target that is highly expressed across all segments of lung cancer, whether it be squamous, non-squamous, wild-type lung versus EGFR mutation, or even small cell. It really gives us a wide range of tumors, even within lung cancer, to pursue, but it is also expressed in head and neck and bladder and other tumors as well. But I think there is high unmet need, even in lung cancer, in certain segments that have not really benefited from other ADCs, exatecan ADCs as well.
I think this is a really unique opportunity for us, and we have such conviction around this drug and our ability to actually benefit these patients.
Jonathan?
I mean, there has not been historically great success for microtubule inhibitors in the lung space. I think that's what, so you can, to some extent, discount—
That's a great point.
—discount the SigV results. The drug was active, but it is tough. No one's finding it easy to beat docetaxel.
Yeah.
But we think our antibody is actually fantastic. I mean, that sounds very boastful.
This isn't—
It's a very difficult.
—an easy body to generate.
Very difficult. Integrin antibodies are very difficult, and ours has a superb profile, superb internalization. We now know our linker payload system is good and very strong. I'm pretty bullish actually about STRO-006.
Yeah, so much so that we're actually starting at a higher dose in our phase I program than STRO-004. Given what we've seen in the PK profile, we feel that we have this higher therapeutic or wider therapeutic window that we can start at 1.5 mg per kilogram and actually move up from there. So we should get to the therapeutic window very quickly, in terms of seeing activity, anti-tumor activity, even in later line patient populations. So, I think it's not an easy antibody to make, and so it makes it less competitive.
Because the ITGB6 in normal pathway gets involved with tissue repair mechanisms, autoimmune mechanisms, and you really do not want to disturb those normal processes while you're going after this target on cancer cells. Yeah.
Have you guys disclosed what you're predicting the active range will be? How close you are to that, your starting dose?
You want to guess?
Well, I mean, where do we go with STRO-004? We saw responses between three and four milligrams.
Yeah. I mean, you guys kind of hit exactly where the modeling led us.
DAR8-exatecan, we've dropped into the escalation at a higher dose than we started with STRO-004. I think we'll be in the sort of target zone pretty quickly.
Should we expect, with the Tissue Factor ADC, you gave us periodic updates of, we've cleared dose level one, dose level two. Should we expect a similar cadence from you guys moving forward?
Nice. We will follow the data—
Okay.
—and make the decisions at the time. I think we have to let data mature. We don't want to dribble out data as well.
Yeah.
We want to make sure that it's impactful and it's meaningful. So we'll take that course.
Are you guiding to data at any specific time for this asset, or?
We did share that we would get to initial data second half of 2027.
Okay.
Execution still goes strong.
Looking forward to that as well. With the last couple of minutes here, coming back to the dual payload ADC, can you discuss why PTK7 was selected as your initial target there?
PTK7 is a validated target that was an older Pfizer program, cofetuzumab pelidotin, that actually had an MMAE payload that actually showed about 20%-40% response rate, but the toxicity profile was not optimal.
This is not the first example of when you are swapping out an exatecan payload for an MMAE for an important target that you can actually drive meaningful outcomes. It is the same approach here. I think there are several companies that are actually going after PTK7 with a single payload exatecan approach, and what we wanted to do was really differentiate our programs now that we validated our linker payload, our β-Glu exatecan, DAR8 exatecan on two single payloads. If we can, again, prove that we can maintain lower heme toxicity profiles, then we can then combine two modalities of payload and even dial up the DAR to a DAR10 to drive even more potency. Here we are actually looking at even overcoming resistance to some of the single payload ADCs. That is really the strategy for us.
We are excited about what this program can do.
Absolutely. With almost getting close to three programs in the clinic, IND for this by fourth—
Yes
—end of fourth quarter, correct?
IND is on track for submission later this year and program into the clinic early next year.
Okay.
Yeah.
Can you speak to cash runway and what for these three programs is baked in?
Yeah. We are very close to our quarterly update, so I cannot actually share that right now. But the Q3 update will be filed in our 10-Q very soon.
Okay. As of last quarter, what did you guys disclose as cash runway?
Oh, at least into Q2 of 2028.
Okay. This gets to be numerous catalysts for these programs.
Yes. 2027 will be a big year for Sutro, with three programs in the clinic. That leads to a lot of data cards to read out. That is really great for us.
Should we expect a medical meeting presence from you guys next year, perhaps?
We'll be looking at that, but we'll also be looking at the flexibility of actually sharing data outside of a medical meeting as well.
Great. Well, thank you so much. I appreciate you guys coming out today, and it's been a productive conversation.
This has been great. Thank you.
Yeah. Of course.
Thank you.