My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler. Before I begin, I'm required to point out certain disclosures regarding the relationship between Piper Sandler and Sutro that are posted at the back of the room and also at the registration desk. Sutro is developing next-gen antibodies with its XpressCF cell-free platform, including Folate Receptor Alpha ADC, luveltamab tazevibulin, or Luvelta for short, as I usually use and said, in both ovarian and endometrial cancers, as well as some others. Sutro plans to file three INDs over the next three years, including a tissue factor ADC, STRO-004, and a high-DAR ADC, and also the first dual payload ADC, which we'll be sure to spend some time to talk about all those. They recently partnered ROR1 ADC with Ipsen and also are working with Astellas for immunostimulatory ADCs, which is another really cool construct.
Here from Sutro is CEO Bill Newell, also Chief Scientific Officer Hans-Peter Gerber. Thanks both for being with us.
Hi, Ted. Great to be here. Thanks for the invitation.
So I want to start out. AbbVie acquired ImmunoGen for $10 billion and Elahere off to a pretty decent, respectable launch, I think $331 million year to date, really just launching. So how does Luvelta compare to mirvetuximab? And maybe you can remind us of the phase one dose expansion data that you guys reported in folate receptor positive ovarian cancer.
Yeah, thanks, Ted. I think it's exciting for women who have ovarian cancer to have a new agent after really a great wasteland of no new therapies for women with platinum-resistant ovarian cancer. Interestingly, because of the design of Elahere as a medicine, it really benefits about a third of women who are platinum-resistant in terms of their disease progression. We designed Luvelta to actually have some improved properties that would allow for a wider therapeutic window and more in the way of patient benefit, better responses, more women being able to respond to it, and less in the way of toxicity.
And so the rational design approach that we have undertaken has caused us to really demonstrate in the early clinical development that Luvelta could be indicated for eight out of 10 women who have platinum-resistant ovarian cancer, a distinct advantage over the three out of 10 who are presently on label for Elahere. Importantly, we also wanted to assure that we had a different toxicity profile because these are women with late-stage cancer, and things like losing your vision or having interstitial lung disease, both of which are black box warnings for Elahere, are not really optimal for this patient. And so we designed a molecule that has as a predominant liability asymptomatic neutropenia. It is a lab value, and the women who experience it, by and large, don't have any awareness that there's anything going on.
Their physicians can monitor the neutropenia, and we've come up with some development strategies that allow us to really abrogate some of the risk that high-grade neutropenia can present to the patient. So that was a great breakthrough for us. Really, we're planning on being the first approved therapy for medium and low expressors of folate receptor alpha, the same target that Elahere goes after. And by being that first approved therapy, we think we're going to be significantly better than chemotherapy, which is what we're compared against in our ongoing pivotal trial. And we believe that we're going to have a good duration of response based on the prior data sets that we have. So I'm happy to talk more about the trial, but we really think a safer molecule with broader efficacy potential is really going to be a winner for women who have late-stage ovarian cancer.
So let's go into some of the detail on that because you mentioned some of the strategies where you're really trying to optimize that Luvelta dose and even using Neulasta and things like that to limit the neutropenia. Remind us of the phase 2/3 REFRaME trial design and tell us sort of where you are in terms of selecting that final dose.
Yeah, that's an important question, so as you're well aware, the FDA has a new initiative called Project Optimus. It's come to the forefront over the last couple of years, and really, what they're trying to force companies to do is to find the lowest effective dose. Thinking behind that is that sometimes we may overdose cancer therapeutics and not get enough additional benefit for the additional toxicity that you get because the general rule of cancer therapy has been more is better, and in this case, they want to make certain that we're actually getting bang for the buck, and so while we did dose optimization during our dose expansion phase, the FDA required us to do a phase two dose optimization study as part of our pivotal trial, so we have two doses based on our prior data sets that we are studying.
The top dose, and they're very similar, the top dose is 5.2 mg/kg of Luvelta given once every three weeks. For the first two cycles of that dosing cohort, you receive prophylactic G-CSF on day eight because we previously demonstrated that that really reduces dramatically the risk of high-grade neutropenia in patients who start at that dose. After those two cycles, they drop down to 4.3 mg/kg, and G-CSF is at physician discretion at that point in time. The alternative dose is a 4.3 mg/kg dose with no prescribed prophylactic G-CSF. Those are the two doses that we are comparing in part one. We enrolled a little over 50 patients. We completed enrollment in the April timeframe. We've followed the women as required by FDA for a prescribed period of time. We've worked up an exposure response analysis, provided some additional information on PK and other things that are required.
We are in the process of engaging with FDA on identifying and agreeing on what the optimized dose is going to be. We expect to conclude that process in the not too distant future. I've been saying sometime around year-end, we should be in a position to talk about what the optimized dose is. I hope to be able to talk about some of the data that underlies that decision with FDA, but we want to make certain that we're not running afoul of FDA concerns about clinical trial integrity because this is all one trial. Really, what happened was after we completed the enrollment of the patients for the dose optimization phase, FDA allowed us to start enrollment of the pivotal trial phase. In doing so, they said, you don't have to wait till you've selected the optimized dose.
You can do the 5.3, 5.2 mg/kg dose that I discussed, 4.3, and then the third cohort initially is investigators' choice of four different types of chemotherapy. When we and you have agreed on the optimized dose, the other arm of Luvelta, the one that is not optimized, gets dropped, and those patients get followed for safety. So since May, we've been actually in the pivotal trial portion of this study. The recruitment is going as expected at this early phase of development. And I hope that next year I'll be in a position to give some guidance as to when we think the pivotal trial portion of the study will be concluded.
Remind us how large the trial is and sort of what the primary endpoints and what you're really evaluating on there?
Yeah, this is a new trial design that FDA encouraged us to do. It's basically a three-in-one trial, right? You've got the dose optimization phase. That's kind of a traditional phase two study. You've got the study that is ongoing for which you have an opportunity for accelerated approval in a subset of patients that is less than the entirety of the population. For the entirety of the population, we're going to have about 516 patients split evenly between the chosen dose of Luvelta and chemotherapy. And for accelerated approval, though, we would be looking at a subset of those patients. It would be a response rate endpoint with duration of response and obviously safety and a few other things being looked at. But primarily, you're looking to see better responses and more durable responses than chemotherapy.
Chemotherapy historically has been in the low teens in terms of response rates and durability in the three-ish month range. We hope to be able to better that based on our earlier data. We think that is a bar that we should be able to meet with Luvelta. Again, this is for eight and 10 women who have platinum-resistant ovarian cancer. Those women give us an opportunity to file for accelerated approval. While that data set is being analyzed and FDA is acting on that data set, we will still be recruiting more patients until we get to the total of 516. The endpoints for that part of the trial are PFS and OS. We want to see progression-free survival, and we at least want to see trends in overall survival that are positive in favor of Luvelta over chemotherapy.
That's where we're going with our study.
I think you kind of got into this a little bit in your introductory remarks just because of the breadth of women you'd be able to treat with Luvelta versus Elahere. How do you envision competing with AbbVie as kind of an entrenched player?
Sure. I think it's going to really play to the strengths of Luvelta that we've seen in the data to date and that we believe will be replicated in the pivotal trial, which is more women who come to you with platinum-resistant ovarian cancer are going to be eligible for treatment with this therapy. You have to ask yourself if it works on women with low and medium expression of the target because that's the unmet need population. It should work fine in the Elahere population and just easier to default to the more broadly labeled molecule. The other thing is, Ted, and I think this is interesting, anecdotally in this part one, we've certainly seen a number of women who would be eligible for Elahere therapy, but instead of receiving Elahere, they and their physician have chosen to participate in our study.
So I think we have an opportunity based on the different tolerability profiles to really have a more meaningful therapy for those women. As we look forward, let me add one more thought.
Yeah, please.
We've done some work looking at the combination of Luvelta and bevacizumab, and we presented some data at ESMO on that, and we saw a 35% response rate in that combination with no new toxicities other than might be expected of the two drugs, and that 35% response rate is irrespective of what you see in terms of target expression. You could have 5% target expression, and you're still within that 35% number. Additionally, it doesn't matter whether you had bevacizumab before or not, so we think an opportunity to move the molecule earlier in lines of therapy can be presented, and in a maintenance therapy, you really want something that is well tolerated by the patient, and so I think Luvelta can be an ideal maintenance therapy as a follow-on for lifecycle planning of this new medicine.
Now, you're also evaluating Luvelta in non-small cell lung, and I think we could get maybe data on that early next year. Tell us about that study and that opportunity.
Yeah, I'm going to let HP talk about why we're excited about the lung opportunity and some of the preclinical data, and then I'll get to your question.
Yeah, so the base for this non-small cell lung cancer trial that we started was really an observation we made preclinically. And the way we study these activities preclinically is using patient-derived xenograft models. So these are tumors directly from the patient. And what it now turns out in the last 10 years and that evolved these ADCs, Pfizer, Seagen, and Genentech, we use those models. If you use them right, you can pretty much predict what's going to happen in the clinic for ADCs, not other modalities, not all modalities, but in particular ADCs.
And so what we did here, and I wanted to make sure we're doing it right and not just like overdose and then show responses in non-small cell lung, so we anchored the dose that we use for those preclinical trials, as they are called now, in the dose that induced the same anti-tumor activity for Luvelta as we have seen in the clinic. So we stopped at 5 mg/kg every week, and we get about 30%-40% ORR in these PROC models, which are the patient indication we are currently in our registrational trial. And we used that dose for these non-small cell lung models. And we looked at EGFR pathway mutations.
We looked at folate receptor alpha expression, and we figured out that when you use those lung models that have folate receptor alpha expression, that's somewhere between 40%-60% at the level where they actually responded to Luvelta, actually in a way better than what we've seen in PROC. So that was kind of a surprise because you don't expect these things to do all these tricks. Even if somewhat the folate receptor is lower, the response was as good as in PROC, maybe because they may have been less pretreated or so. But that really, that kind of anchoring that dose in these preclinical models gave us some confidence to at least try in non-small cell lung and to find those patients that respond very well.
As you may know, in non-small cell lung, there is a trend that when you have an EGFR pathway mutation, then your exatecan payloads work better, but in the wild type, it's the tubulins that do better. Wild type is about 80%. We think there may be a unique possibility for tubulin inhibitor ADCs to be successful in lung based on the genomic alteration of these cancer patients.
So it was on that basis, Ted, to get to your question that we started this phase two study of Luvelta in non-small cell lung cancer patients. And it's now open for enrollment. I expect we will have an initial assessment in the first half of next year, but it'll probably be a relatively small number of patients because we are mandating that patients have a tumor proportion score similar to what we use for purposes of defining eligibility for Luvelta, which is 25% and higher. I think as the year goes on and we've had more patients on study, we'll have more rich and mature data. But I think it's fair to say that we look for an early signal in the first half of next year.
Awesome. Looking forward to that. Very briefly, I just want to touch on REFRaME-P1 where you're developing Luvelta in this CBF/GLIS AML, which is a very rare and aggressive phenotype in children. Tell us about that trial. I think you guys just started it. Again, we don't need to spend too, too much time there because I know it's an orphan indication, but at least let's put that on the table.
It's a really important orphan indication. The disease is ultra rare for certain. We've treated over 40 of these kids on a compassionate use basis, and we've seen some remarkable results in terms of complete remissions and a lot of MRD negativity. This was some work that was identified by an investigator up at Fred Hutch. Through the compassionate use opportunity, we've come to understand that this can be an important therapy for these kids. We have rare pediatric disease designation, which means that we have an opportunity for a priority review voucher. We need about 20 of these kids in order to be able to file for regulatory approval for Luvelta to seek a priority review voucher at that point in time, and then to begin to build all the commercial infrastructure that will fast forward a launch in ovarian cancer. The trial is open.
We are waiting these patients to come. Unfortunately, the disease manifests itself and then progresses quite quickly. So we are watching some of these children's condition deteriorate. And when it hits the threshold that the FDA required for them to be treated with Luvelta, we will enroll them in our study. So it's an important trial, and it has some important financial and strategic advantages for us. And most importantly, it's the right thing to do for these patients.
It could be a priority review voucher that you're rewarded. All right, in the time we have left, Hans-Peter, you're on. All right, we're going to go through these kind of fast, but you guys really had a great R&D day recently. I think it's still online and goes through kind of the next three INDs you guys have planned, first one being STRO-004 for tissue factor. Tell us about this target and this molecule.
Right. So tissue factor is a validated target. That means there's an ADC ahead of us that already is approved with an MMAE payload, the tubulin class of inhibitors. And as you look around in the community, there's a lot of ADCs where the targets got validated have been refurbished with an exatecan. So that's part of our strategy there. For tissue f actor, it's very important that you have a good antibody because you also interfere with thrombogenic events in the vasculature. You have to make sure you avoid that. So we have a very talented protein engineering group. We got an antibody that has all the right attributes, cross-reactivity with cynos that you can assess safety. And so once we've seen that, we decided to go forward with our exatecan platform.
The reason why we're very excited about that was in the R&D forum because when you go for DAR8 exatecan and we dose cynos, the safety profile of these ADCs are about twofold. You can dose about twofold higher than you can with other ADC platform, Topo I platform that report the data. And there's like 15 out there. So it's a large number of data we can compare. And we all scored about twofold higher than the competitors. And why that is important is the higher you can dose in oncology, the more efficacy you can drive. And so then we actually then benchmarked against the tubulin inhibitor, and we got that number. I checked this morning again. I got it right. It's 55-fold higher exposure compared to the approved ADC. And efficacy-wise, we're about equal dose, equal efficacy in our PDX model.
So we looked at cervical, we looked at head and neck, and we see equal efficacy in vivo, but we can dose 50-fold higher exposure levels. Our HNSTD is 50 mg/kg in cynos. For the tisotumab vedotin, it's 5 mg/kg, so 10-fold higher non-severely toxic dose. So if all this translates into clinic, we should be in good shape.
Really good profile.
And so the next one that we advanced is based on the same attribute. We can make antibodies others cannot quickly. So it's going to be a bigger target, a more complex antibody. We have found that right antibody that took a couple of years, by the way. It's not like you do that overnight. So there's a long-term planning to lead us to the position where we can advance another DAR8 Exatecan into the clinic.
But then I think, and this is important maybe for this kind of meeting, the window of opportunity for these exatecan Topo I ADCs is closing rapidly because of that recent report on major meetings, ASCO, AACR, that once you have a patient relapsing from an exatecan, if you come in with a second exatecan ADC, maybe with a different target, it doesn't matter, the second one will not work because you develop resistance against the linker payload class. And so this will happen to all these 20 major targets. And what we then move in, our third ADC internally will be a dual payload ADC. That means like even if you had a prior ADC, even tubulin or exatecan, you will not be resistant to one of the two payloads. We published on that. We're doing that with tubulin inhibitor exatecans.
And I think we're the leading company in that space because nobody has three programs that we already announced going forward in that space. And not only do we try tubulin inhibitor exatecan, we try. We published PARP inhibitors and then two more combinations, which we haven't disclosed yet. But it's good reason to believe that we can be at the forefront of these dual payloads, which will be very much in demand, I would say, in two years from now when everybody starts realizing those exatecan alone cannot be redosed. And so we're looking very much forward to advancing this dual payload class because we are the company that is in the clinic with a tubulin and will be in the clinic with an exatecan. So we should be the first one actually to combine the two of them.
That's fantastic. What a great overview. You guys did partner the ROR1 ADC with Ipsen, really nice deal. Bill, maybe you can remind us about the terms of that.
Yeah, the opportunity to partner an asset at a preclinical basis and get the sort of economics that we did is really relatively unprecedented. So in upfront payment and stock purchase, originally we got $75 million, and we have an additional amount that will be due as the molecule moves into the clinic. We have double-digit royalties on that molecule. And we also have a substantial milestone opportunity. I think it's in the order of $900 million for that program. So really robust economics from a great partner. Ipsen is going to take care of development on a global basis. We've had a good working relationship with them as we transition the program into their hands. And I'm excited for patients who express ROR1 to have this new ADC. It's a DAR8 exatecan as well.
Again, this is something that can be very exciting for many patients living with solid tumor cancer.
Very cool. And then last, with the time we have left, you guys ended the third quarter with, I think, around $388 million in cash. And I think Ed sold all of the Vaxcyte shares, which has been just a fantastic source of capital for you guys. How long does this fund the company and what's it enable you to accomplish?
Yeah, Ted, in the near term, we have a lot of things that we're going to be putting that capital to, whether it's the continued progression of Luvelta towards regulatory approval, the entry into the clinic of the new STRO-004 asset, and other things that we're doing in-house that we don't get into much detail about. We are not guiding at this stage on capital duration because we have so many moving piece parts. As you know, we've made it no secret that if there is interest in a partnership with Luvelta of some sort, we would be open to dialogue about that. And we have a number of conversations that are ongoing there. So suffice it to say that we feel confident in our ability to carry all of the assets forward we have today.
And I look forward to updating you on some of the other things we'll do over the course of the next year that really ensure our viability from a financial standpoint. But I like starting the beginning of the fourth quarter with almost $400 million in cash.
Yep. Great. Well, thank you very much, Bill. Pleasure.
Ted, thank you so much.
Hans-Peter, thank you so very much.
Really appreciate it.