At Biotech in the U.S. It is my pleasure to have the fireside chat with our next company, Sutro Biopharma CEO, Jane. Welcome.
Thank you. Thank you, Greg. Thank you. It's great to be here.
Awesome. Yes. I know lots going on, happening at Sutro lately. More important is kind of a strategic reprioritization, and then to focus on the real value of your very unique platform. Maybe we'll start from there. With this recent change, and then how you think you can maximize the value of this unique platform, which I always will be a fan, but seems that's take a bit longer than I expected to maximize, to realize the value. Maybe as a new CEO, and then how you think about the strategy from here.
Yeah. Roger, thank you for the question, and appreciate the opportunity to be here to tell the new Sutro story. I know you're familiar with our technology, and we've made significant improvements in the product design and manufacturing. One of the things that we think about in terms of our technology is its uniqueness and the power in being able to optimize every part of the ADC, from antibody to linker to payload, and all at the same time. There are some companies that will focus on one or maybe two of those features. We can actually do big changes and big optimization to actually deliver differentiated products. I think that's really the goal here. For us, first off, we've improved our beta glucuronidase linker strategy. It's not an off-the-shelf sort of beta glucuronidase.
It is a proprietary beta glucuronidase linker that's further stabilized with our non-natural amino acid in the cell-free system that will cleave more in the tumor and less outside the tumor. We should avoid some of the toxicities that would be in the bone marrow and so forth, and avoid neutropenia we've seen in other products. In addition, like other companies, we've upgraded our payload system to an exotic platform. While we have some products that are near-term on a DAR8 format, we actually have made a DAR16 exotic without compromising PK. That's really significant because when you dial up the DAR, you can destabilize the antibody and the ADC. That runs into some problems there.
In addition to that, for payloads, we actually have multiple payloads, whether it be combining with another cytotoxic payload, like an exatecan plus an MTI or microtubule inhibitor, or a PARP inhibitor, or an immunostimulatory agent. The ability to actually combine with other modalities in different ratios is something we call internally as protein engineering on steroids, right? Like how do you do this well? That is further differentiating for the platform. From the very beginning, our antibodies have been expressed and made in the cell-free system. They're not glycosylated, so they don't engage in the FC gamma receptors that are located in the lung or the eye. We can avoid certain toxicities like ILD that is associated with Exatecan-based ADCs, actually further driving the safety and tolerability of our ADCs.
With this platform, this is why we believe we have one of the most powerful ADC platforms. You're not optimizing just one feature, but actually optimizing the whole thing. Our go-forward strategy is really not to make what other companies can do in a conventional ADC manufacturing system. It's really to do what other companies can't do well. That is, for our single payload ADCs, going after harder-to-reach complex biology targets. This ensures our commercial viability and competitiveness moving forward. We're especially excited about the dual payload ADCs. Really, the opportunity there is to overcome resistance from single payload ADCs. When you eventually move these therapies to earlier lines and go head-to-head against single agent ADCs, you can actually show best-in-class potentials with a supercharged sort of payload system. This is really exciting and very innovative.
This is why we believe that this is the right strategy to move forward to drive shareholder value. We have committed to delivering three INDs over the next three years. That does not include any of the programs with our strategic collaborations, which could be double that. You will see we are going to execute a lot of programs getting into the clinic over the next three years and way more than we have in the past 10. My background is in strategy, operations, and execution. You are going to see a lot of execution from Sutro moving forward.
Excellent. Yeah, I think that's a good kind of refresh of the strategy. You laid it out very clear that the platform is really differentiated. You try to deliver the value to address all the men within the ADC, maybe start from the top one exotic platform, but you can also expand to dual payload even beyond.
Exactly.
OK. All right, so that's a platform and then strategy, and then talk about the delivery, right? You have the background for the operational side. What are the key programs? You say you have three and then three IND next three years. What are those, the lead pipeline you have? What are the target and the rough timeline sequence? We can drill down for each one a little bit.
Yeah. The three programs we have heading into the clinic are our tissue factor program. It is a DAR8 exatecan program. We also have an integrin beta 6 program, also a DAR8 exatecan-based program, as well as our dual payload ADCs.
OK, very good. All right. It seems the tissue factor is the lead, all four, right? So that's the closest to the clinic. What's the timeline look like? Then based on the preclinical data, what are the key evidence to support your notion, say, they are differentiated from the tissue factor because we have approved the drug already, right? A couple other pipelines.
Excited to talk to you about the tissue factor program. Again, it's a tissue factor DAR8 exatecan with a beta glucuronidase linker and a site-specific conjugation, whereas the approved ADC in the market is actually a vcMMAE DAR4. I think one thing to note here is we're seeing very encouraging preclinical data here, probably the strongest data package we've seen in terms of differentiation. With our program, we've actually benchmarked it against the approved agent. We're seeing a 50-fold increase in exposure, as well as we've actually been able to achieve an HNSTD of 50 mg per kg, which is the highest dose we've actually seen in NHP. We're really pushing the science.
Kiddle highs.
We're pushing the science very high here. I think we have to remember the approved ADC is HNSTD of 3 milligrams per kilogram. This is a really big delta, a markedly differential delta between the two programs. That's why we believe this should show clinical differentiation by the time we get into clinic. The one thing to remember about the tissue factor program is that it is also expressed in the normal tissue as well as in cancer cells. You really want to make sure that you're getting to cancer cells without interfering with the tissue factor biology, right? It is expressed in the eye, in skin, as well as involved in bleeding events.
In our preclinical study, despite the fact that we're able to dial up the exposure by 50% higher, we're not seeing any of these liabilities, which is definitely something to speak to the safety of this potential product. In addition to that, in our PDX models, we're seeing strong activity compared to the approved tissue factor program. We're seeing activity not only in cervical, but also beyond cervical in other solid tumors that express tissue factor, inclusive of head and neck, lung, esophageal. This really sort of redefines the potential for tissue factor as a much bigger commercial opportunity moving forward.
That's very interesting. Maybe just one thing, how all four is sparing the normal tissue in terms of the tissue factor?
Yeah. So again, tissue factor is expressed in the eye. Actually, we've seen some market research data that upwards of 50% of patients don't actually receive the approved tissue factor ADC because of the eye tox. Our antibodies are not glycosylated. They don't engage with FC gamma receptors that are also in the eye. We can avoid some of those liabilities from just not engaging or being FC silent, if you will. In addition to that, the exatecan payload itself is less damaging to the eye.
Ok, interesting, because the glycosylation seems to be one of the features of your platform. Now you turn this into advantage now.
Exactly.
You engage the eye. Okay, got it. And the exatecan payload does not typically cause eye.
The beta glucuronidase linker actually cleaves in the tumor and less outside the tumor.
Got it. Okay, very good. All right. And then in terms of the timeline sequence event, IND phase one.
We're on track. We're on track for IND second half of this year and look forward to seeing what this program can do in the clinic.
OK. Do you have any guidance on when we're going to see initial data and then what we'll be able to see, what kind of data we're going to see?
Yeah. As soon as we're able to achieve the IND, we're headed into the clinic. I think we are looking forward to having some data next year.
OK, awesome. All right, that's good. Because you mentioned the PDX model, it's not just cervical and then many other indications. What's the thinking about the indication given we have approved the drug, but seems not that well tolerated? You can still do that. Also, maybe the bigger opportunity is outside of the indication.
Yeah. If you look closer to the tissue factor approved program, their dosing strategy in their phase one went up to about 2.2, but then had to back down to 1.8. If you're able to dial up the exposure and the dosing so that you can deliver a tolerable medicine, but also do it in also delivering the potency, it's going to be important. We haven't disclosed specifics on the phase one program as of yet, but we know that the tissue factor target is validated and that it is already approved with an approved agent in cervical and also shows early data in head and neck. We are going to take a very inclusive approach in our basket trial of solid tumors, looking at in cervical for the patients that have actually been treated with the approved ADC or naive.
I think it'll be interesting to see the clinical differentiation in cervical because tissue factor is expressed very highly in cervical, but then really focused on expanding the opportunity to beyond cervical into the other tumor types.
Awesome. In your PDX model, do you see the activity difference among different indications and why cervical is one of the lead indication for other tissue factor? Maybe you don't need to use cervical as the lead indication.
Yeah, we are seeing. That's why we're taking a broad and inclusive approach in our phase I program, not just cervical, but more of the solid tumors that express tissue factor, inclusive of, as I mentioned earlier, the head and neck, the lung, esophageal, pancreatic, and colorectal, all possibilities here in terms of potential.
Yeah, yeah. A couple others is absolutely even higher MNE than a bigger population, right?
Agreed.
Yeah. Oay, good. Let's move on to because you have a couple and we want to make sure we cover all of them. And then the Integrin beta six . So we just coming off from the ethical, we see some very interesting data from update from Pfizer. We saved that for a moment, but maybe why did you choose that as your second indication using the similar platform? And then what attracted you? And then what pre-current data to support your differentiation given we have other options there, pipeline there?
Historically, Integrin beta six has been a challenging, complex target. It is a target that's included in the integrin beta family of adhesion proteins. It's a heterodimer between the alpha V and beta six receptors and proteins within that protein family. You don't want to interfere with the biology of the integrin beta family because it's involved in autoimmune and GI effects. This target actually exists in multiple conformations from a closed-open structure. It's not an easy target to go after. Because of the capabilities of our platform and the fact that we have such an extensive library of antibodies that we can really select the optimal antibody to go after just this alpha V beta 6 heterodimer, we are confident that we can actually show that we can be differentiated here.
In our preclinical work, we actually show strong activity benchmarked against the lead candidate for Pfizer. Yeah, for Pfizer.
Major Pfizer name.
Benchmarked against their program. We have a DAR8 Exatecan beta glucuronidase design, whereas their design is a vcMMAE DAR4. Again, we're seeing very strong activity. I want to make the point with clinically relevant doses. We're not dosing up to 10 or 20 mg per kg in the PDX models. We're actually going after clinically relevant doses that should reflect the potential and the same ability to replicate in the human trials. We're seeing activity in three different tumor types in head and neck, lung, and bladder that's stronger than the lead candidate.
Okay, got it. Ok. All right, now we have to comment some of your competitor or the pipeline, the data. We just saw that data. It's interesting, right? It is learned. And then in certain populations, seems to be working. The profile certainly can be improved. What are the key aspects you want to be better in terms of the efficacy and durability, maybe on the safety side?
Yeah. In looking at the Pfizer Seagen program, we're seeing some liabilities with respect to the profile. There is on-target side effects around stomatitis, as well as off-target for peripheral neuropathy, neuropathy, and neutropenia. I think for our program for STRO-006, it's all about how do we, again, dial up the exposure in a safe way. Mind you, our PK that we're establishing benchmarked against many of these conventional ADCs are two- to three-fold higher. If we can dial up the exposure in a safe way and actually show better safety and efficacy, it will be very differentiated. The side effect that is, I think, really of more importance in lung cancer is this ILD that is associated with Exatecan-based ADCs. You do not want to actually introduce lung tox to lung cancer, right?
If we're able to really avoid that side effect moving forward into the clinic, then that's a really good value proposition. In addition to that, I think if we can actually show that we're more effective. At the end of the day, if both products make it to lung cancer, lung cancer is quite a big commercial opportunity that you can actually share the upside.
Yeah. Also, how do you think about the monotherapy activity versus the combination? Because they are already moving to the Pembrol combo. It seems also the activity more coming from the PD1 high population versus the low. What's your expectation from what you hope for to do at the monotherapy versus the combo? What are the population you think for combo?
Yeah, it's a really good question, especially in lung cancer. While integrin beta 6 is expressed in multiple tumors, it is really focused on lung. I think we have seen the data that supports both chemo combination plus or minus PDL1 as sort of the standard of care. If you're going to enter into lung cancer, you want to do both a monotherapy sort of study as well as in combination with PDL1 or immunotherapy. I think we would have a good ability to actually combine, given the greater exposure we have from a safety and tolerability standpoint, to actually combine with other agents as well.
OK, good. All right, so that's another program. What's the timeline for that program?
Yes, so we're getting to IND in 2026 and then into the clinic.
OK. Before the IND, would you be able to give us some updates in terms of preclinical, maybe IND data?
Yes, we will definitely have more preclinical work to establish sort of the highest non-severe toxic dose, all of which to inform our strategy moving forward.
Excellent. Okay, great. All right, so and then we spend a little bit more time on the other pipeline as well. You have a dual payload. And you are absolutely in the center of the ADC world because the top one, we see more and more and more top one kind of a platform. But also people start to talk about the dual payload platform. You may be one of the first companies that is really focusing on this because you also have some partnership. So tell us about the dual payload. And then more biologically or scientifically, what's the pros and cons for dual payload? What are the key things? Why do you think that makes sense? And then what are the key risks when you try to do the dual payload?
Yeah. Before jumping into dual payloads, let's talk about the progress being made on the single payload ADC front. I think we have made some very good progress, but more can be done. Just like I think eventually we will see resistance happening to single payload ADCs. When you think about what ADCs really are, they are delivery of chemotherapy in a targeted way. We have seen single agent chemo lead to resistance and tumor progression. We also see that combination of different Chemos with different modalities can be synergistic to overcome resistance of single payload or single agent chemotherapy. Also, when going up head to head against single agent chemo, they can actually be best in class. Combination chemotherapy is the standard of care in most cancer therapeutic areas.
The ability to actually design two payloads in one product requires sophisticated protein engineering and design capabilities.
That's your expertise.
This is what, yeah, we believe that fundamentally this is what our technology was really made for, not only to include multiple modalities of payloads, but also the ratio. It's not necessarily an eight plus two or eight plus four or eight plus eight. The ability to kind of customize this so that you can get to the safe therapeutic window is really important. This is very differentiating for us at Sutro. We believe that this is the next wave of innovation for the future of the field. I think this is really compelling. You asked what are obviously this is the excitement and the pros of it. In terms of the cons, it's really the risk is really around safety, right? There is a challenge today in terms of combining ADCs with systemic chemotherapy because of the toxicity.
In addition, there's a challenge of combining two ADCs that may have different targets and different payloads. Because again, the toxicity can be something that needs to be managed well. To be able to design this in one product and establish the sweet spot of the performance therapeutic window is really something that would give us a competitive edge. Right now we're working on resistant models. This is going to be exciting for the field moving forward. Now that you have so many of these exotic ADCs coming to market, eventually patients will lead to tumor resistance or will progress. What's next? We're actually looking at tumor models today that either have been treated or are resistant to a topo one or a microtubule inhibitor or an inheritor specifically.
Now we're seeing the dual payload ADCs actually show activity in those models. That to me is really exciting. How many other companies out there can actually say that they can actually build a better inheritue? Not many. I think that's really bold and really the upside in terms of the dual payload opportunity.
Got it, got it. Yeah, that's a very elegant way to say this. Basically, you are trying to deliver a targeted chemo combo, right? To me, it's a little bit complicated because the dosing of the chemo is basically that's how you're going to do that. Then how to realize this in the ADC format versus you just doing two injections or the IV for the different dosing of the chemo. That's something you are trying to figure out in the protein engineering perspective.
Yes.
OK. You just mentioned for the model-wise, you see some activity post those chemo resistance. Any other preclinical model or data you have generated and then can share with us?
Yeah. We have an exciting collaboration with Stellus right now on an IADC program. It is a proof of concept for the dual payload ADC programs in that they combine a cytotoxic agent and an immunostimulatory agent. That is really exciting. Really, they are going after addressing real big unmet needs, right? This is an ability to go to cold tumors and treat cold tumors or tumors that are unresponsive to immunotherapy. Despite the advances we have made with immunotherapy and oncology, there are lots of patients that are unresponsive to immunotherapy and do not have a good option. I think this is going to be a very exciting program for Stellus and for us.
Okay, good. That is one of the models you are doing. In terms of the timeline for the dual payload, how should we think about that?
Yeah, currently we've guided to an IND in 2027 for our internal program. I can't guide to the Stellus program. You'll have to ask them.
OK, keep progressing. In terms of the because this is still early, right? You're going to select the target. You're going to select the payload. Target-wise, you're really indication dependent. Payload-wise, probably will be the exatecan as one of them. Based on the current thinking, what are the key partnering payload makes more sense for the exatecan?
I think for Sutro, we are really excited about the combination of two cytotoxic payloads, right? With the Exatecan and the MTI payloads, lots of proof of concept that combination of chemotherapy works. How do you actually deliver that in a targeted way? What's really exciting about this, the upside and the beauty of the dual payloads is that you can now, you're not restricted to hard-to-reach complex biology targets. You can actually open up and go for any target. Should we want to be bold enough to go after Integrin, we can. Would we want to do that? Maybe not. Don't know. We'll think about that. This makes all the old targets that have been established and validated back on the table as new targets for dual payload delivery.
I think one thing to really acknowledge here is that we're getting to higher levels of DAR in a safe way. The dual payloads, if we are able to combine an eight by two or eight by four, we'll get into a lot higher DAR and a lot higher potency than we've ever seen before.
Got it. Sorry, I missed maybe in terms of the payload class, outside Exatecan top one, and what the other class you're using?
It's the microtubule inhibitor. Yeah.
Got it. Okay, good. All right, so I've been covering Sutro maybe more than, I think, six, seven, eight years. The lead program used to be Levelta. And then where this program right now, you have a lot of the promising data, but also the landscape is evolving. It seems you are doing some strategic consideration for that program.
Yes, so thanks for the question on Levelta. This was a hard decision for the company. It was not a decision based on data or safety around the program. That would have been an easy choice. Given the capital we had, we had a hard choice to make between, we talked about all the improvements we have made on the technology, on the product design front, and the next generation of assets. How do we sort of invest in the future? What is going to be the biggest driver of value for shareholders? We had to make the hard decision that maybe our next generation, third-generation products are going to be better than potentially our first-generation product. Every company goes through this in terms of reprioritization of their portfolio at some point. This is the decision we have made.
Hopefully people can better understand why we're so excited about a lot of the improvements we've made and the optimization. With regards to Levelta, we have communicated that we are deprioritizing the program. We are still in discussions around the program because it is a late-stage program and many companies are interested in it in late-stage programs. We hope to continue to seek a partner and find a partner that can fulfill the potential of the drug.
Yeah, I do see this is still very helpful for a lot of patients can benefit from that. Okay, good. Maybe we can talk a little bit because you signed a lot of partnership with different pharma and the biopharma. How much you can tell us about the progress there? This is definitely going to help your runway. That's my last question.
Okay. We have ongoing strategic collaborations with both Ipsen and Stellus that provide upwards of $2 billion in potential milestones and royalties. For Stellus, we have two research and development programs ongoing, one of which just initiated an IND enabling study, which we received a milestone payment for. I think with these strategic collaborations, they're very important for us, dually. One for the value creation for the future in terms of potential validation of our platform and the programs, but also the increasing relevancy of the need for these specialized ADCs to benefit and to bring bigger benefits in the future for patients. We are very much excited to continue these programs. We've been very successful on the BD front given sort of the excitement in our portfolio and on our platform. We'll continue to do that.
For cash, at the end of Q1, we had about $250 million. That now further extends our runway into early 2027. This does not include any of the additional anticipated milestones from our strategic collaborators, which could further extend the runway and get us more time to get to real data.
Excellent. Thank you, Jane, for being with us this morning. Thank you, everyone, for listening.
OK.