Good afternoon, everyone. Sam Rollenhagen here, Associate Biotech Analyst under Tara Bancroft. Thank you very much for joining TD Cowen's 45th Annual Healthcare Conference. For our next session, we have a hybrid presentation and Q&A with Sutro Biopharma, and it is my pleasure to introduce Hans-Peter Gerber, the Chief Scientific Officer. Hans-Peter, it's a privilege to have you here. Thank you very much for joining me. Feel free to get started on the presentation whenever you're ready.
All right. Thank you for the introduction. It's a great pleasure to be here today to present on behalf of Sutro. These are my forward-looking statements. I want to start here with the overview on what we're currently doing at Sutro. Just from the get-go, what we do different from others is not just incrementally different in the ADC space. It's fundamentally different because we manufacture in cell-free extracts as opposed to CHO cells. This allows us to do things other ADC developers cannot do. I walk you through the slides where that is different and where there is added benefit to ADCs based on that cell-free manufacturing method. One of the products of this method, the cell-free manufacturing methods that we started actually 20 years ago, is Luvelta. It's our lead ADC currently in registrational trials.
It has the potential for best-in-class tubulin inhibitor ADC in the ovarian space. We then will advance later this year our first next-generation ADC that's a Topo1-based ADC. Luvelta is a tubulin-based ADC. We are filing an IND by the second half of this year and will be followed by two additional ADCs with overall goal to advance three ADCs to INDs over the next three years. Behind that, and I'll give you a little bit of an insight, we have developed a unique platform that allows us to advance dual payload ADCs towards the clinic. We heard a little bit from Mersana why this is critical and strategically important currently for ADC development. I'll give you a little bit of an insight where we are there. We do have multiple partnerships and collaboration across this platform. I'll give you a little bit of an insight.
We have two ongoing collaborations on our Topo1 platform, one with Astellas, which is on the dual payload platform, and one with Ipsen, which is a Topo1 ADC. Those two companies actually validate our next-gen ADC platform already because we're collaborating with them. Just as a reminder here, we have significant near and long-term opportunities with the pipeline. On the left, our registrational program, Luvelta. We're currently in the phase III trial with REFRαME-O1. We're also looking at combination with Avastin in ovarian cancer patients, PROC, as well as PSOC. We are looking at additional opportunities for this folate receptor alpha tubulin ADC, including a small fraction of AML patients that have the target upregulated that respond very well. That is a registrational trial already on the way, as well as we're exploring other indications.
We've done preclinical exploration of non-small cell lung carcinoma with PDX model, but also endometrial trial. We're looking at expansion options. Again, on the bottom here in that green color, this is all powered by our cell-free platform, which is unique. I would say 95% of all the ADC of the other ADC developers use CHO. We use cell-free, and we have recently announced the industry's largest ever cell-free manufacturing run of ADCs with collaboration with Boehringer Ingelheim, a 4,000-liter run. That really is kind of an example of our fully outsourced manufacturing capabilities that we did work on over the last 20 years. We can now manufacture entirely outside of our facility. The next-generation ADCs is shown on the right. Again, the goal is to advance three novel ADCs to an IND in the next three years. The first one is STRO-004.
I'll give you some of the fundamental preclinical data that makes us believe there's going to be the industry best Topo1 in that space. We then follow up with dual payload ADCs. I think recently we've been nominated and identified as the industry leader in the dual payload space by Beacon or Hanson Wade, which is one of the leading databases for ADCs. I'll give you a little bit of insight where we are. Lastly, a reminder, we have that Astellas collaboration, which is essentially a dual payload where we combine Topo1 payloads with our platform with immune activator compounds. This program is going very well. There are two targets that we are working together and they're progressing up to the timelines, if not faster.
Overall, we have by the end of the last year, we had $388 million cash available and also over the last 20 years generated about $975 million in funding with these various collaborators that actually are listed below and more. This is kind of in our DNA. When we have new technology, we like to partner with a pharma or biotech, just as in the case for Astellas, where we combine immune activators with topo1 and explore this together in the clinic. If something works, we can rapidly copy-paste that modality onto our ADC program and move forward. This is the overview on our pipeline. Again, Luvelta is all the way on top. Multiple clinical trials going on in ovarian cancer, AML, but we also started the non-small cell cancer trial. We expect some early data during this year, later this year.
Moving on with STRO-004 tissue factor, the first topo1 ADC that we're developing, and then followed on by dual payload conjugate. In the meantime, you can see in the bottom, we had several collaborations with other companies. We had a spin-out company known as Vaxcyte. It's very successful in the generation of vaccines using our cell-free manufacturing platform. Also, the two programs that we partnered, STRO-003, which is an ROR1, DAR 8, topo1 ADC with Ipsen, as well as the collaboration with Astellas. The last two did very deep due diligence on our platform, decided to go forward. We look at this as an external validation of our topo1 platform. Really empowered by this green area here, we advanced the next topo1 ADC to the clinic.
The green area is something I've been working on since 25 years at Genentech, Pfizer, but also Seattle Genetics. I advanced personally over 15 ADCs to IND and was involved in BLA filing of two ADCs while I was at Pfizer. I was leading the ADC program and the group at Pfizer, now leading the ADC program and group in Sutro. The green area, this is known as therapeutic index. The goal is to make this larger and larger because the larger your therapeutic index is, or TI, the better your chance to get to success in the clinic. What you can do to expand this TI is shown on this slide on the left. You can either move down the minimal efficacious dose, and that is basically when you make ADCs more potent.
We've been doing this with our cell-free extract methods, and that's shown there in the green box by either going to high DAR, that means a lot of linker payloads on an ADC. The conventional CHO cell approaches are limited by DAR of eight because there are eight cysteines you can conjugate to. We can go now to DAR 16 because we are having these non-natural amino acids that we can build into the antibody and then conjugate to those. In addition, actually, we can conjugate with click chemistry. The others with cysteines can't do that. Click chemistry is the most stable bond you can form between an antibody and the linker payload. We have much better stability and exposure in animals and patients when we actually use this click chemistry.
The green space we covered, and I'll give you more examples of how we can make these ADCs even more potent in combination, for example, when we have a topo1 and a tubulin. We have two payloads, and that actually is an advantage in overcoming that resistance that is currently reported in major clinical meetings. Resistance to topo1, but resistance to tubulin inhibitors is also described. When you switch the payloads or you have two payloads on one ADC, you're less likely to see that early. That's the green area. If the people that are familiar with ADC know that when you inject an ADC into a patient, it's about 1% of the ADC that ends up in the tumor, and it's where the potency matters in the green box.
The other 99% of the ADC is outside the tumor and in that blue box. What is that? That is the safety corner. The other way to expand the TI is to make ADCs more safe. If you wonder why ADCs are all of a sudden back en vogue when five years ago they were rather in the dark house, it is because of that improvement in the bloom space. The exatecans, for example, do much better when the ADC is outside the tumor, when the 99% that are in the circulation are less toxic. Why is that an advantage? You can dose up, and with a higher dose, you get more drug into the tumor, so you get better anti-tumor activity.
Here, it turns out that cell-free manufacturing method turns to be uniquely positioned to provide better benefit in the blue box. Some of the tools that we have at hand that others don't have as easily, we have a unique linker that only we have. It's a beta-glucuronide linker not the VC linker. So we don't get the DLT of neutropenia 2.6 mg per kg that you see with all the vcMMAEs . So we can dose up. We use that click chemistry I mentioned that leads to very high stability of the ADC. Then we have site-specific conjugation. So we can actually position the linker payload in places of the antibody that maximizes the TI. When you have eight cysteines, you have no choice. You take what's there. Nature was not made.
These cysteines in the IgG were not designed by nature to make ADCs. They are likely not optimal. We actually can actually show that we can improve the exposure when we go to other sites on the cysteine. Of course, we have unique strength in antibody engineering. This means that when we screen our leads, we can screen about 100 to 1,000 constructs per week because we can manufacture in cell-free. We just add DNA, wait overnight, a little bit more complicated. Then we have our protein that we can test for the rest of the week and then start the design cycle. We can find better solutions faster with our cell-free manufacturing method. This is just a lineup of the toolbox that we are enabled by using cell-free manufacturing.
It's not that others couldn't use it, but all of those in a row, much easily integrated into an ADC, I think makes us very differentiated compared to other competitors in the field. I mentioned to you already that the beta glue linker, the high DARs that we can do, and we're getting to the ADC dual payload. We're also making these immune activators that are IADCs. We can do site-specific. FC silent is one thing in an antibody. We do not engage with FC gamma receptors because our antibodies are not glycosylated, because we make them in these cell-free extracts. If you don't engage in these FC gamma receptors, they are expressed on normal cells and can mediate toxicity, such as the ILD, for example, or eye tox.
We do not see that for any of our ADCs with a topo1 or tubulin inhibitors because we do not bind to these receptors. Not by design. It just came with that decision that we are going to manufacture in cell-free extracts. Here is now the example for STRO-004. If you line up all these benefits that I showed you, the toolbox, you end up with safer ADCs. How do you recognize a safer ADC? It is the exposure you can achieve. Here, in this case, not yet in the patients, but in cells. What we did on the right side, we compared the publicly available data for the already approved tissue factor ADC. This STRO-004 is a tissue factor ADC. There are two Tisotumab Vedotin and tubulin inhibitors already approved. The data is published.
We looked at the Cmax, the maximum concentration you can get with an ADC in cell. We found this number is gone now, but it's about 17-fold higher maximum concentration we can get in cell and still don't see toxicity. Exposure is really the number that translates into efficacy. We get 50-fold higher exposure with a topo1 ADC compared to Tisotumab Vedotin. These are numbers I haven't seen, and I've been 25 years in ADC drug development. The tissue factors express in multiple cancer types shown on the right. This is a multi-indication opportunity. Actually, the reason why there is not a lot of competitor out there, it's very difficult to get the right antibody binding to tissue factor that still internalizes, but doesn't interfere with key biological function of the target. We were able to succeed.
I'll give you the numbers and the data to support that claim. The other part of there here, we're going to the blue box again, making ADCs more potent. You see here two different tumor types where we could get complete regression of tumors at about 1 mg per kg. You see this data all the time. The finesse here is when you look for topo1 ADCs, usually you need more, higher dose to get regressions. Tubulin inhibitors, for example, the Tisotumab, they need about 1 mg per kg too. This is an unusual potency or activity of an ADC with a topo1 that you actually get to regression at 1 mg per kg. You can see about equal potency on different tumor types, but much higher safety window. You can already see there's a massive improvement.
I don't want to give you the numbers because they can be done in different ways, but it's a massive TI improvement over the existing Tisotumab Vedotin. The reason why I really like this, we actually used these numbers and calculated the predicted efficacious dose in the clinic because it's what you do when you file an IND. You talk to the FDA and you explain what you did. We came up with a number. At the lowest dose, we're going to start here and there. We overlaid where we expected clinical activity based on this kind of data and PDX data. To my surprise, we already realized in the lowest dose we're going to start, we're already above the expected clinical efficacious dose. During my 25 years of ADC development at Pfizer, Seagen, and Genentech, I've not seen a situation like that.
When you start with your lowest dose, you're already into the clinical efficacious dose. We are super excited about this ADC. I think it will be a massive benefit for cancer patients to have this safety window present here that is not there with the already approved ADC. One of the issues with Tisotumab is eye toxicity. We knew that. The reason for that is the target is also expressed not only in the tumor, but also in the eye on these cells that are known as corneal epithelial cells. After our cytotoxins were reduced at 50 mg per kg and the DAR 4 at 100 mg per kg for a topo1, you will not find anything similar in the literature. This is, I think, the highest dose you could ever test in a cell. We did not see any eye toxicity.
Of course, you can look at the eye. That's an easy one. We looked at the eye, and there was no ITOX. We asked, why would that be? Why do we not have ITOX? With a tubulin inhibitor, you have ITOX when the target is expressed in the eye. We grow these corneal cells in vitro, that's shown in left, and compared to Tisotumab in orange with our ADC in blue. You can see that split in toxicity. It turns out, even though both ADC recognize these cells and damage them, the topo1, I think it's the payload and the linker to this payload, doesn't damage these cells as much. The other toxicity of the Tisotumab is the skin toxicity, keratinocyte. We did the same experiment in vitro and found the same outcome.
Now we understand why we have that massive safety window with a topo1 compared to the others. Here to the last part of my presentation, this is where we start combining different payloads shown on the left side and look at how we can improve the potency. Now we're working on the blue box again. How can we overcome resistance, for example, towards one or the other? Can we overcome resistance when we approach this? The benefit of this is shown here on the right, reduced toxicity. We just heard from Mersana that the DAR trial where they combined the topo1 ADC with a tubulin ADC in the clinic could actually provide that activity benefit. They went from 50% to 70% ORR, but the toxicity of the two ADC really was multiplied.
There was maybe not so much of a benefit, even though the ORR looked good. Having the two on our system with a click chemistry and a beta-glute linker, I think we can overcome that toxicity disadvantage. Reduced clinical complexity. Of course, if you run a trial with two ADC versus one ADC, you end up with four arms for the two ADC combined versus a two-arm comparison versus standard of care with a dual payload. On top of that, if you want to combine your ADC with a checkpoint inhibitor, it's much more easy to do that when you already have the two payloads on one ADC. In particular, because the tubulins so far have shown to be better combineable in the clinic with checkpoint inhibitors.
Actually, Pfizer really has engaged fully into this pathway to combine all the VCMME with a checkpoint inhibitor, such as that VEGF PD1 bispecifics, because it is known now that tubulin inhibitors do much better with checkpoint inhibitor. Combining a topo1 with a tubulin will combine the best of both worlds and hopefully now make also these tubulin inhibitors actually respond to checkpoint inhibitors. Overcoming resistance mechanisms by having both on board, I think this is a strategic, a very important asset because we already heard from Mersana, doctors do not like to treat a patient that relapses from a topo1 with a second topo1 across four different indications, including ovarian and others. When you actually change the payload, they respond again like they have not seen another ADC before.
The goal would be here with these ADCs, with the dual payload, you start at the end. If they do not respond to any ADC, you go in with this, but ultimately go upfront because they will be sensitive to two payloads, and you would expect a more deep and a more prolonged anti-tumor response. Actually, this is kind of the preclinical data that supports that claim. This is a model that is sensitive to both payloads. This is not resistant to one payload. We are actually running these trials now. This is like when you go upfront with your dual payload and you compare to the single payloads. The dual payload is a tubulin, a DAR 4 tubulin combined with a DAR 8 exatecan.
Just to give you the point here, we tend to forget that when people do that, they have a massive drop in PK. If you go over DAR 8, you go to DAR 12, PK drops. We didn't see any impact in PK. We actually saw an improvement in PK when we added the tubulins to the DAR 8. You can see what it is, the same data looked at survival or tumor quadrupling. There's like a PFS endpoint or an OS endpoint in the middle. Every time the dual payload wins and the single payload, such as the single tubulin in light blue, as well as the pink DAR 8 topo1 ADC, have been moderate in their anti-tumor activity. Here is the second platform we're working on where we combine a topo1 with PARP inhibitors. That's a biologically relevant combination.
We get the same outcome on the left on in vitro activity and on the right on in vivo activity. The last slide here is that Astellas collaboration where we combine the topo1 with an immune activator. You can maybe have heard about that. You kind of debulk the tumor with the topo1 payload, the chemotherapy, and then you stimulate the innate and the adaptive immune system with the immune activator. You actually ask your own immune system to get rid of the remaining tumor. As we all know, if you get this right with PD1, you can have very durable responses. We are kind of combining the two modalities in one ADC.
Astellas has been very forthcoming to actually take on the risk of developing these in the clinic because of all that benefit of a dual payload ADC, as we call them, shown in the left compared to other modalities that try to harness that benefit of CD8 T cell activation of the innate immune system shown in this checkmark. Just a little bit of a heads up, we have Mersana. They had this experience with their ISAC. We think we have sufficient differentiation on our molecule not to run in the same toxicity problem because first of all, we have this click chemistry. We actually do not lose payload over 21 days in serum. And there's no drop in any of these payloads, either the topo1 or the IO in cell over 60 days. It's a rock solid peak.
We do not lose that IO compound, so we do not get systemic toxicity. We are very bullish about that. Just a reminder again on our team, very experienced team, lots many years of ADC development and clinical development. We are looking forward to the upcoming years to further develop these novel payloads and also work with Luvelta. You may be familiar with. We are working very actively on partnering with Luvelta to actually free up capability to advance our next gen ADC platform. That I would like to conclude and move on to the discussion.
Great. Thank you very much, Hans-Peter, for the detailed presentation. Before I get into the Q&A, anyone in the audience, feel free to jump in or raise your hand with any questions. First, just maybe briefly discussing Luvelta, if possible. You reported the dose escalation data in December.
Just wondering if you could either review or discuss this briefly, how it might change expectations for the results of the ongoing pivotal trial, and if we might expect to see those later this year at a medical conference or some other forum.
Yeah, I have to do that. Can you hear me? Is it on? Oh, now it's on. Yeah. Happy to answer that question. Yeah, as you said, we did report the top line data from the Luvelta trial earlier this year. We're very encouraged because we have confirmed the previous data. We see very good anti-tumor activity, no change there. Also actually reported improved safety by adding G-CSF on day eight, not as on day one as we did previously, but we moved the G-CSF administration to day eight and could significantly reduce the neutropenia. We lowered those levels.
We think we have a very promising profile, a very promising TI. Actually, we position ourselves as industry best tubulin inhibitor in ovarian carcinoma, in particular in PROC. This may become important. As you know, there's a lot of topo1 being developed in PROC. If patients become resistant to topo1, if they relapse, they will all be looking for a tubulin inhibitor. That Luvelta molecule can actually go to more patients. We can go with an IHC cut of 25%. The already approved tubulin inhibitor has to go with an IHC cut of 75%. We reach about 80% of all the patients that will relapse from a topo1 inhibitor versus 25% by the competitive molecule.
Got it. Great. Thank you.
I think you just discussed that and potentially how sequencing and selection might go for folate receptor alpha. I guess with part two ongoing now, curious if there's an update there either on enrollment or sites, and when the next update with that could be and the eventual timeline for submitting for accelerated approval.
Yeah, yeah. So far, we don't have any reason to change any of the guidance that we gave previously on the milestone and the speed of enrollment and the potential BLA target date.
Can you remind us because some folks are not as familiar with the story?
Yeah. I would say I think the target BLA filing would be in 2027. Yeah. The enrollment is as predicted. We are on track to achieve that goal in the manufacturing space. We're doing fine as well.
What is the primary endpoint?
Primary endpoint, it depends on whether we go for accelerated approval. That will be ORR, or the overall approval will be based on PFS.
Can you get accelerated approval with the other drug already approved?
We could because we are going into the unmet medical need where the approved drug cannot go. We can go there for accelerated approval. We have this option open depending on the evolving data to do actually that and then go later on for the full approval for the PFS.
Got it. The accelerated approval would be based on the 25-50%?
Exactly.
Okay.
The full could actually include all depending on what we do between in the 75 and above.
Got it. Okay. Yeah. Thank you. Great.
I guess just lastly on the pipeline outside of Luvelta, so there's three INDs in three years. Just wondering if you could briefly discuss what each of these INDs were for. I mean, you went into STRO-004, but potentially also highlighting what the other two could be as well.
Yeah, happy to do that. Super enthusiastic about these programs. The first two, you may have realized the STRO-004 is a DAR 8 exotican. The reason why we're advancing this is there's two competitors out there, but we think we have significant differentiation to be competitive, if not better. We're also starting around the same time. We're not behind. We're not like Luvelta where we're already behind when we started. We tried to avoid that mistake. With the next one, is it going to be another DAR 8 exotican?
There is currently, when I look at competitor, nobody out there with a topo1. It's a very well-validated target in the tubulin space, but people have a hard time to develop the antibody because it's a very complex target biology. You have to be careful where you bind your antibody not to interfere with certain aspects of biology. This is the strength of our engineering group, same for tissue factor. Our next target, we are rather unique in our ability to make these antibodies. That's why we go with a DAR 8 topotecan. The follow-on ones, that dual payloads, the target space opened again. We're going to go for big targets, big indications because we want more patients to benefit from dual payload, especially once they relapse. They will all be looking for an alternative payload.
We can be there for them with our dual payload and ultimately go all the way up to first line or ahead of the other ADCs to actually provide hopefully double, if not more, of the benefit than each single ADC can provide combined. If you think about cancer development history, it's very clear chemotherapy is not administered as single chemo. It's a combination. The reason for that is the resistance formation towards one payload targeting one target will be much faster than when you have two targets targeting two different pathways. It takes double as long to develop resistance. That's where we're super bullish for the benefit of the patient and just for the more durable and longer anti-tumor responses of the dual payload.
Got it. No, thank you very much. Very exciting.
I think we just have a minute left, so we'll just close out with, Hans-Peter, what do you think is potentially the most underappreciated aspect of the Sutro story currently?
Yeah, so I had looked at all, like I was at Pfizer, I was at Seagen. Again, most of the time I worked on making ADCs more potent, like the rest of the field. I realized when I joined Sutro, that unique way of manufacturing opens both ends of the TI for dramatic improvements. If you see what our exposure is for DAR 8 exotican in cells, it's about one and a half to twofold compared to the Enhertus of the world, compared to all the successful drugs already approved. Actually, you had to very carefully look at the data to figure that out.
Now we're starting to understand where these benefits are and really use that learning for the dual payload class, which I think is the next big thing in ADC development.
Can you remind us of your cash run rate?
Yes, I think we had, as I had on the slide, it was about $388 million by the end of the last year.
And you were spending your burn rate?
Our burn rate? Yeah. It is somewhere between $20 million-$30 million.
Great. Thanks. With that, Hans-Peter, thank you for your time. Thank you to the audience for attending and participation. Have a great afternoon, everyone.
Thank you.