Sutro Biopharma, Inc. (STRO) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Sutro Biopharma Luvelta Forum Webcast and Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to our first speaker today, Bill Newell, Chief Executive Officer of Sutro Biopharma. Please go ahead.

Thank you, Jonathan, and welcome to everybody, who is joining us for today's Luvelta Forum. We decided to call this event a forum because for the first time, we will be presenting a comprehensive overview of the clinical and preclinical data in both solid tumors and hematologic malignancies that illustrates the broad therapeutic potential of our lead molecule luveltamab tazevibulin or as we call it, Luvelta. Today, for the first time, we will be presenting aggregated response data from approximately 100 treated ovarian cancer patients. We will also be presenting [ response ] and durability data for an aggregated 43 ovarian cancer patients, all of whom are platinum resistant. And we will be presenting response and safety data from our luveltamab-bevacizumab combination. In the course of today's presentation, we will be making forward-looking statements, and we refer you to the text of this slide, as it pertains to such statements. Joining us today are Dr. Anne Borgman, our Chief Medical Officer; Dr. Hans-Peter Gerber, our Chief Scientific Officer; Jane Chung, our President and Chief Operating Officer. Additionally, we are pleased to have Dr. Brad Monk, a leading key opinion leader joining us as well. Dr. Monk is a Professor in the Division of Gynecologic Oncology at the University of Arizona College of Medicine and Creighton University School of Medicine. He is also Vice President and Co-Director of [ GOG Partners ] . We'd like to thank him for taking time from his busy schedule to participate today. So let's get into it. We've been developing Luvelta as a therapy for multiple cancer since 2019. Luvelta is an antibody drug conjugate, targeting folate receptor alpha which is a validated cancer target. While that validation occurred initially in ovarian cancer, our data suggests the potential for Luvelta to benefit patients with other cancers that also express folate receptor alpha, including endometrial cancer, leukemia and lung cancer. Luvelta has the potential to be a pipeline in a drug. So why are we bullish on Luvelta? I think the reason that we are so excited about the potential of this drug to benefit patients is that as we will discuss today, there is a broad totality of data across multiple cancers that tells us this is a drug that can benefit patients in multiple tumor types. We see promising clinical activity in all tumor types where we have treated patients with Luvelta, both solid and hematologic malignancies. We see clinical activity in patients whose expression levels of folate receptor alpha was not simply in the highest expression profile, but also benefit in patients who are medium and low expressers as well. In fact, we believe Luvelta has the potential to more than double the number of platinum-resistant ovarian cancer patients, who will receive a targeted therapy. We've also established preclinical data that we are excited about in lung cancer. And as you'll hear, a lung cancer trial is planned for later this year. We've been an ADC innovator for over 10 years, and we're not resting on our laurels. We continue to innovate using our unique cell-free technology, which underpins not only these programs, but the programs that we have with our partners and the other programs that are proprietary to Sutro. Our Chief Scientific Officer, Dr. Gerber, will speak to our ability to create even better ADCs in the future with enhanced potency and tolerability, which we will believe will be needed to treat other solid tumors. Importantly, we've been a valued partner in the industry we've been able to generate approximately $785 million from our partnerships and allows us to innovate in a very capital-efficient way. What we want to draw attention to today is that Luvelta has the potential to treat multiple difficult-to-treat tumors. But let's start with ovarian cancer. I refer you to the panel on the left, and you will see towards the center of that panel, a thin gray arrow. This represents the only approved antibody drug conjugate for ovarian cancer, and that molecule can benefit about 35% of platinum-resistant ovarian cancer patients. What is most impressive to us about the potential of Luvelta is illustrated in the larger dark blue arrow, where we have data suggesting that Luvelta can benefit 80% or 8 in 10 women with platinum-resistant ovarian cancer. We believe we can benefit these women because Luvelta's unique design allows us to kill tumors expressing not only the highest levels of the target antigen, but those expressing at medium or lower levels. What does this mean? It means Luvelta has the ability to treat at least as many and potentially more platinum-resistant ovarian cancer patients than the approved ADC. It also means that Luvelta has a potentially broader therapeutic benefit beyond ovarian cancer. Today, you'll hear about the potential for Luvelta become the first fully receptor alpha targeted therapy for endometrial and lung cancer patients as well as pediatric leukemia patients. What makes Luvelta so special. Our proprietary technology enables precise design of this molecule with the potential for a wider therapeutic window. Dr. Gerber will expand on this. If you look at the panel on the left, this is a representation of Luvelta binding to its folate receptor alpha antigen. The molecule has been internalized into the tumor cell and the tailing agent, a cytotoxic payload called a hemiasterlin is released. Now there are many important properties of this hemiasterlin. It has high potency. It triggers immunogenic cell death or ICD, which is a signal to the immune system to become active and go after cancer cells as well, thus giving us a second tumor killing mechanism. Luvelta is a homogenous antibody drug conjugate. And what that means is that each molecule is identical and fully competent to kill cancer cells. We've positioned Luvelta to be the first antibody drug conjugate to market to treat platinum-resistant ovarian cancer patients, who have medium or lower expression of folate receptor alpha. Importantly, Luvelta been studied broadly in over 40 and over 180 patients. We see activity in all indications in which Luvelta has been studied. And we've also studied it as a combination therapy, because combination therapies are very important cancer therapies today. Luvelta combines well with bevacizumab, as you all see today, it combines well with checkpoint inhibitors as well, and that's particularly exciting for us and for patients. Dr. Borgman and Monk will soon share with you the data that underpins our decision to be in pivotal trials of Luvelta in ovarian cancer and pediatric leukemia. But before they do so, I'd like to highlight the extensive clinical work that has been undertaken to get us to this point. The gray bars are the completed Phase I studies that guided our understanding of the platinum-resistant patients most likely to benefit from Luvelta. As I said, that is 8 in 10 platinum-resistant ovarian cancer patients. It also guided our understanding of the optimal dosing strategies. And as we will share today, we have completed work that has informed our view on how best to improve the tolerability of Luvelta at the higher starting dose. Given the potential far-reaching benefit of Luvelta, we've been fully investing in it. We have initial clinical data for endometrial cancer, which has been presented at a medical conference. We have real-world data in the RAM phenotype of pediatric leukemia, which has been presented at a medical conference, and we'll share with you some of our preclinical data that has convinced us to start a trial in non-small cell lung cancer later this year. Now let's take a deeper dive into our clinical data and the registration pathway forward for Luvelta and I will hand this off to Dr. Borgman.

Thank you, Bill. As Sutro's Chief Medical Officer, I'm pleased to share clinical data today with you, highlighting Luvelta's antitumor activity in aggregate form in ovarian cancer and review data in other tumor types where Luvelta has been tested. I'll be joined later by Dr. Brad Monk, who has vast experience in gynaecology malignancies to discuss the registration for Luvelta and review new data for this molecule. Luvelta has been administered to nearly 100 women with ovarian cancer. The trials they participated in were Phase I, which means that they were very late-stage patients with limited additional therapeutic options. As Sutro think about Luvelta during this early stage of development, there was no requirements for any particular level of folate receptor alpha expression to participate in the studies. Here, the data speak for themselves on this waterfall plot. Each one of these bars represents an individual patient. The majority of whom experienced tumor shrinkage even at this late stage in their disease course. The median number of prior lines of therapy was 3, and over 70% of these women received prior bevacizumab or a PARP inhibitor. There are data really enabled Sutro to understand Luvelta's characteristics and chart a course towards further development. What did we learn about Luvelta? The optimal dose range was determined and 2 active doses are being tested in the REFRaME-O1 pivotal trial that's ongoing. An appropriate cutoff for folate receptor alpha was delineated. This cutoff is distinct from other folate receptor alpha targeting agents on the market and is really quite simple. 25% of the tumor cells need to have folate receptor alpha expression at any intensity. The safety profile of Luvelta was characterized. This consists cheaply of neutropenia, [indiscernible] and manageable safety signal. Once understood, a strategy to reduce high-grade neutropenia at the dose of 5.2 milligrams per kilogram was devised. Importantly, as combination therapy is used in cancer treatment, Luvelta plus bevacizumab was tested and showed early signs of antitumor activity as well as tolerability. Dr. Monk will share with you the first peak of those data later on today. Luvelta checked all the boxes. We [indiscernible] the safety profile, determined the biomarker, showed the ability to combine, just determine the proper dose for further study and all these support for the development. I'm sharing with you now a waterfall plot that represents a focused look at our data. And as an oncologist and seasoned drug developer, I have to say -- actually, I'm compelled to say that these data are quite compelling. These bars represent patients that fit the characteristics of our REFRaME-O1 study, which is our pivotal trial. These women have ovarian cancer that has become resistant to platinum-based therapy. These women were treated at doses of 4.3 or 5.2 milligrams per kilogram. These are represented by the green bars, respectively, and their tumors expressed folate receptor alpha at a level of at least 25%. In these women with platinum-resistant ovarian cancer, Luvelta had an overall response rate of 28%, a duration of response of 5.7 months and a progression-free survival of nearly 6 months. To put these data in context, it is important to note that for many of these women, their only other treatment option would be chemotherapy with an overall response range -- overall response rate in the range of 12% to 15% and a PFS of around 4 months or so. The safety profile of Luvelta is well described and largely internally consistent among the different indications we've studied. The main adverse event noted with Luvelta's neutropenia, which is predictable, readily detectable with a CBC, familiar to the treating physicians and patients and manageable. The other main safety signals are arthralgia or joint pain and peripheral neuropathy, some of which may be a carryover from prior taxane therapy and/or attributed to the hemiasterlin payload in Luvelta. Patients receiving Luvelta may also experience gastrointestinal adverse events. With these data in hand in an active molecule, Sutro commenced our registration-enabling trial, REFRaME-O1 in the middle of 2023. In addition, given data in pediatric AML garnered through single patient IND use or compassionate use that I'll touch upon later today, a focused registration-enabling trial in RAM phenotype CBF/GLIS AML is planned. First and foremost, the focus on pediatrics. Why? Why would we do a pediatric trial? Well, we've accumulated a data set of nearing 30 patients globally and seeing activity. There's a huge unmet need in these kids. These are infants and toddlers and this is an extremely aggressive clone. The outcome is very grim with overall survival rates in the 15% to 30% range. And this really can be a succinct focused trial due to the rarity of this disease. But how does this dovetail with ovarian cancer. This trial may actually fulfill certain regulatory requirements in the United States and Europe as well as provide access to a priority review voucher and potential patent extension. This trial, importantly, may accelerate time to market and increase readiness for the ovarian cancer submission. Speaking again of ovarian cancer, it is my pleasure to turn the presentation over to Dr. Brad Monk, who will share the status of the REFRaME-O1 pivotal trial and additional Luvelta data with you. This trial is supported globally by the Gynecologic Oncology Group and ENGOT or the European Network for Gynecological Oncological Trial. Dr. Monk?

Thank you, Dr. Borgman and Bill. But more importantly, thank you as a company. As was mentioned, my name is Brad Monk. I'm a gynecologic oncologist. My career has been focused on bringing new medicines to the clinic. I had the opportunity to cofound the GOG Partners that is participating in this trial. We've contributed to that. I'm not representing the GOG here, but I am the Vice President and Director of that organization. But thank you. These are women that are ill and quite frankly, it's very difficult for me to [indiscernible] terminal. So this trial REFRaME-O1 is strategically developed quite frankly, for one reason. Bring this medication to the clinic to allow me to help my patients. It is for platinum-resistant recurrent ovarian cancer. Platinum is very effective in ovarian cancer, but when it doesn't work, Dr. Borgman, as you mentioned, response rates to chemotherapy are low, lots of toxicity. So this is a great opportunity. 1 to 3 lines of chemotherapy or prior lines, ECOG performance status-01. And it's interesting folate receptor alpha expression greater than or equal to 25%. It's no secret that last November, actually November 2022, Mirvetuximab soravtansine, which you know is Elahere, wonderful medication with FDA approved the Phase III trial -- confirmatory trial has been published in the New England Journal another GOG study. But the issue is, is that most patients that I see in the clinic are ineligible, they're ineligible because about 65% of the patients are not PS 2-plus greater than 75%. Positivity score 2-plus or greater. And it's very disappointing because this medication is out there. The target has been validated and they can't get it because, quite frankly, it doesn't appear to be effective. So this trial is designed to expand that opportunity. The second thing that's not -- and again, I love Mirvetuximab and I helped develop it. But the dose has never been optimized. And as you know, the FDA said at the post-marketing commitment, which has not yet been fulfilled. The strategy here, again, working with Sutro and the GOG is to find the right dose. You say, well, 5.2 milligrams per kilogram for the first 2 doses with growth factors might be too much. You're right, it might be, and we're going to figure it out in a randomized fashion 25 patients versus 25 patients. But remember, these patients have cancer that's out of control. We need to get immediate symptom relief. And also it takes time to build up a level, okay? In some antibodies like in cetuximab we bolus it. Generally, we don't do it with other antibodies because patients are not symptomatic. But platinum-resistant recurred ovarian cancer is a terminal disease where patients are almost universally symptomatic and so rather than give a bolus, the intention was to give just 2 cycles of growth factors. And then ultimately, that the optimized dose will be carried forward versus physician's choice chemotherapy. There will be 4 options there, gemcitabine, liposomal doxorubicin, topotecan and weekly paclitaxel. We decided to add gemcitabine. It was not part of the MIRASOL trial. We could talk about that maybe later. And also importantly, in this sort of Phase III design, there will be a plan look at overall response rate and duration of response for accelerated approval. So as you know, with ImmunoGen's product, there were 2 separate trials, again, the strategy here dose optimization, expand the biomarker in a validated target and a seamless trial design. And that's obviously according to what the FDA wants us to do and that's called Project forerunner. So the primary endpoint will be PFS/OS with other secondary endpoints, overall response rate, duration of response. And of course, it's not about changing a CAT scan. Yes, it's about helping patients live longer but it's about the patient experience and those are patient-reported outcomes. So this trial next slide is the global trial. We think it's important to enroll patients around the world. We want sort of a real-world enrollment, not just the folate receptor highs. Remember, mirvetuximab is only approved in this country. And so many of the patients, certainly not all, but many of the patients in the U.S. will only be medium and low. But around the rest of the world, they will be a broad representative sample. We already have 5 countries active, 26 active sites. Our ultimate goal is to have 140 sites in 20 countries. Again, we have 5 countries now. So by the time we have the dose optimized, we'll be at the elbow and really enroll rapidly because it's not only the strategy, but it's the pace. For the next slide here. So we're excited, again, to be beyond the 75% positivity score 2 plus rather than use a positivity score of 2 plus the strategy here is to use the tumor positivity score, which we call as TPS. It uses the same then validated assay, but uses sort of a different scoring system, again, to expand the opportunity to help patients. And so as shown here in the figure on the lower right-hand corner, currently about 35% of the patients would be eligible for mirvetuximab. Our goal is to expand that to as many as 80% and excitingly, maybe with bevacizumab, we could even treat patients with a TPS score less than 25%, not shown in this figure. Next slide. So as a transition to that, I want to talk to you about this idea of adding G-CSF, pegylated filgastrim, on day 8, quite frankly, as part of the dose optimization strategy to really intervene early. Remember, one of the biggest reasons that medications don't work in platinum-resistant recurrent ovarian cancer besides that they're not active. But the patients progressed so rapidly that they don't get enough doses and intervention to benefit. And that's why the sort of dose intensification is very strategic. And obviously, I'm very -- a big fan of it, not my idea, by the way. Next slide. But what I did contribute to is how to do it. And generally, pegylated filgastrim, is given on the second day of chemotherapy. The nature of this, the neutropenia, if you will, happens sort of in the latter phase of the every 3-week cycle. So we delayed it to day 8. The other reason that it was delayed to day 8 is because the bone marrow pain that's a well-established side effect of pegylated filgastrim, G-CSF is mitigated. So we can get a longer effect towards the end of the 21-day cycle, and we could have less bone pain. I get it that everyone knows that G-CSF is an effective mitigation strategy for neutropenia. I think we needed to show it. And again, the strategy in working with Sutro as a partner. We did that in a subset of patients here, 16, heavily pretreated prior bevacizumab in 2/3 prior PARP inhibitor, taking patients and seeing if the utilization of growth factors could be as beneficial as we had hoped. Next slide. And it did, quite frankly, it sort of exceeded my expectations. We anticipated that it would mitigate the neutropenia, but not to this degree. I think part of it is in the strategic approach, Dr. Borgman, thank you again for your medical leadership, is that there was more than a 90% reduction in the first cycle of neutropenia. And again, it's only for 2 cycles, so that sort of translated to a 73.7% reduction in severe neutropenia in the second cycle, remember, it's only given for 2 cycles. And you can't really make firm conclusions on the activity, but I think the data speaks for itself. The tumor shrinkage in this waterfall plot is substantial. You can see in the table, again, Cohort A, 76.2% without new growth factors all the way down more than half, 37.6%. So we were, quite frankly, and humbly correct, and that's why this is utilized in the dose optimization phase of this innovative trial. Next slide. Now we generally present new data at scientific meetings and we will. But we thought that in this forum, thank you, Bill, for that name that we should share with you sort of what we're doing with bevacizumab. Bevacizumab is a great story. I had the great privilege of being the first in the world to report its activity in 2005. I can't imagine it's been almost 2 decades. But what we did with bevacizumab was we brought it to the market in later lines of therapy, just like we're doing here and then 3 New England Journal of Medicine publications later, got it approved in platinum-sensitive disease and threat line. So it sets a paradigm, and it's also a very important agent and continues to be in the ovarian cancer paradigm. Next slide. So what we wanted to do, and we're still doing it, and we'll present the full data set at the scientific meeting. We wanted to ask 3 questions with bevacizumab. Number one primarily, could these agents be combined, okay? But second, is there an opportunity to explore, as I've already sort of alluded to in the TPS less than 25% because the Phase III trial is in the greater than TPS of 25% and maybe with bevacizumab, it sort of would expand the opportunity, second goal. And the third goal is maybe we can utilize bevacizumab after bevacizumab. As you know, multiple lines of therapy, bevacizumab after bevacizumab is approved in colorectal cancer, but not in ovarian cancer. So there is 3 opportunities here in this very small trial that's still ongoing that we'll present at a scientific meeting, evaluate safety of the combination, look at the -- get in an influential way, less than 25% TPS and see if we can do what's been done in colon cancer, utilize bevacizumab after bevacizumab. So you can see a dose escalation, 3.5, 4.3, 5.2, again, still ongoing and ultimately looking at heavily pretreated group of patients, and as I already said, most of them had already had prior bevacizumab. So that is -- again, it's creating a hypothesis that ultimately will require testing. Next slide. And I'm happy to say that it is tolerable together, and it is active. This is the response data, and you can see that the response data, again, it's in a broad group. You may say, well, 35% isn't very good. Well, remember, mirvetuximab got approval with 31% in just the highs. So this is the high, medium, low and less than 25% even. And in the bevacizumab-naive patients, 50%, but even in the bevacizumab pre-treated patients, it was north of 20% small numbers, broad confidence intervals. But encouraging, and we're sharing it with you. This is new data on the bevacizumab combination because we want you to know what we're doing, because we need your continued support. And without your support, we won't be able to have long-term success. Although Bill, thank you to your leadership, we're well positioned to be successful. So tumor reduction is substantial. So activity, yes, very intriguing data in bevacizumab pre-treated and TPS less than 25%. Next slide. But here's the kicker really, is the tolerability. So at 20% sort of cut off, you can see that ocular toxicity doesn't appear on this list. And that is really, really important. And so there were no new safety signals to bevacizumab. We know what that does. We know what Luvelta does because we studied them extensively as single agents, but we have not seen across the program to the same level, again, hate to do a cross-trial comparisons. I like mirvetuximab, when I really look at Luvelta as sort of the next generation folate receptor alpha antibody drug conjugate, a potential best-in-class. This is what we do. We develop one medication and then we certainly get better, and that's what we're trying to do. There was some neutropenia, was some arthralgia, was some neuropathy, I'd point out and very transparently. There was one patient who was diabetic, had a serious foot infection. My mother died of diabetic complications. So I can relate to this, that's been 1.5 years. And so we said maybe it was probably related. There was also a patient who had a GI perforation, which is a well-established adverse reaction to bevacizumab. So I note those for you. Next slide. So I appreciate that opportunity. Dr. Borgman, I'm going to turn it back to you again, I want to reiterate my gratitude that without sponsors like you, investors like our listeners that can help my patients. And we've been successful in the past, but we have a lot more to do. So thank you for having me today.

Thank you, Dr. Monk for sharing your perspective on the Luvelta in ovarian cancer. And while ovarian cancer is the flagship program and the main focus of our efforts, Luvelta has shown activity in every tumor type we've tested, including endometrial cancer and pediatric RAM phenotype AML. Importantly, these tumor types are not necessarily high expressers of folate receptor alpha, like ovarian and may have lower or variable expression. This feature actually broadens future development possibilities for Luvelta, and one of these possibilities is lung cancer. On the far right, our data from a PDX model in lung cancer where Luvelta shows robust preclinical activity and Dr. Hans-Peter Gerber will share more data with you later today. Yet based on this data and on our prior experience with the compound, Sutro is planning to commence a clinical trial in non-small cell lung cancer later this year. So stay tuned for hopefully, intriguing data, assuming this positive trend continues. Clinical data from Luvelta in endometrial cancer were presented by Dr. [indiscernible] at ESMO late last year. We presented folate receptor alpha levels in this disease, we believe, for the first time and discovered that while this trial was in an early phase and included all comers in the patients whose tumors expressed at least 25% folate receptor alpha, there was an antitumor activity. These women are represented by the green bars. And while a small sample size, the overall response rate was 29% with a very consistent safety profile. Recurrent or relapsed endometrial cancer represent development niche for Luvelta. As with the migration of the checkpoint inhibitors to the front line, the relapsed and recurrent setting is largely served again by chemotherapy. As well as the ability to combine with a checkpoint inhibitor may allow for future frontline exploration in endometrial carcinoma. Turning now to pediatric RAM phenotype or CBF/GLIS AML. Collective data from the single patient IND experience were presented by Dr. [indiscernible] at the American Society of Hematology meeting late last year. As a pediatric oncologist, these data are encouraging to see notably the overall survival curve whose median has not yet been reached with Luvelta. The safety findings were consistent and this therapy was even able to be given to these children as an outpatient, which is really wonderful for their quality of life. While these patients are rare, fortunately, their disease course is highly aggressive and frightening to witness. I am pleased that we will commence a focused clinical trial for these kids with high unmet need in collaboration with the Children's Oncology Group this year. I'd now like to turn the presentation over to Dr. Hans-Peter Gerber, Sutro's Chief Scientific Officer.

Thank you. And it's a great pleasure to be here today to talk to you about our next-generation ADCs that we are developing at Sutro. And to get started, Luvelta is the first of our tubulin inhibitor platform ADCs that -- where we use our unique cell-free technology to design features into the molecule to address the current liabilities of first-generation tubulin inhibitor conjugates. And that's shown on the lower part of the slide. On the upper left, it's the anatomy of Luvelta and as Bill already alluded to, it's a for-loaded antibody drug conjugate, DAR4 and it consists of our proprietary hemiasterlin payload, which is a high potency tubulin inhibitor. And combined with the high-affinity antibody binding to folate receptor, we are able to target low folate receptor tumors present in ovarian cancer, low to moderate, but certainly also high folate receptor alpha tumors, inside ovarian tumors, but also outside, such as lung and endometrial. In addition to the high potency, these payload class also induce high levels of immunogenic cell death, as Bill already alluded to as well. And that's important for the combinability with checkpoint inhibitors payloads that induce high ICD combine better with checkpoint inhibitors in preclinical settings, and I'll give you an example of that, but also in the clinic. And then importantly, we have very high buy standard activity of the payload when it gets released from the antibody and why that is important that means not every tumor cell in the tumor needs to express folate receptors to be killed by the payload, because it can diffuse freely to non-antigen-expressing tumor cells, and we can see complete regression in preclinical models and on tumor cells that don't express the folate receptor alpha. And then for last but not least, the hemiasterlin was selected to be a low PGP substrate. And what that means is less pumped out by these multidrug resistant efflux pumps in tumors of the multiple chemo treatment, prior chemo treatment. And so we're less likely to see a resistance development of the multiple rounds of Luvelta treatment. So in the middle, it's the linker that we use, and this is the most commonly used linker in ADCs. In fact, it's present in over 60% of all ADCs that got approved. It's [indiscernible] linker. It is cleavable by [indiscernible]. And we, in addition, used a very stable conjugation technology known as click chemistry to conjugate and made very stable bonds between the linker payload and the antibodies such that we lose less payload outside of the tumor, and we can increase the therapeutic index of our ADCs. And on the very right side, I think that's a very important and critical feature that the Fc domain of our antibodies due to the unique technology where we express proteins is not engaging in Fc-gamma receptor binding. And that's important because this Fc-gamma receptor can be expressed on normal tissue and then internalize the ADC and induce normal tissue damage. So the fact that we don't engage with these receptors led to an improvement in the therapeutic index and further reduction of the platform toxicity. And so going to the lower part, some of the key liability of conventional tubulin inhibitor conjugates were aware of its eye toxicity, which manifests in blurred vision. And while this is a smaller frequency, maybe sometimes 5% to 10% and it increases over prolonged treatment, it can be having quite an impact on quality of life when patients can't read their emails, or cannot drive anymore. And this is associated with most tubulin inhibitors, including the class of MMAE, MMAF, DM1 and DM4 and it's now becoming clear what the reason for this toxicity is and it's the fact that corneal cells expressed these Fc-gamma receptors and thus combined on specifically to tubulin inhibitor conjugates and then take up these payloads and that can induce corneal cell damage and ultimately resulting in eye toxicity and blurred vision. And again, the fact that we do not engage with Fc-gamma receptors at our platform technologies, we have, in fact, seen no evidence of significant eye toxicity as Dr. Monk already alluded to, in all of the 180 patients that have received the Luvelta so far. On the very bottom of this slide, is neutropenia, which is the known DLT of most tubulin inhibitor, in particular, the ones that are using the VC linker, the same as we use for Luvelta. And the mechanism leading to the neutropenia is now very well understood actually since about 3 or 4 years. It is now known that there is an enzyme in the bone marrow known as LSAs that can also cleave the VC linker outside the tumor and then leads to release of the payload in the bone marrow, ablation of white blood cell and then neutropenia. So the way we address this with our technology is that we engineered highly specific sites along the antibody that reduced the cleavage by these LSAs in the bone marrow, but maintain the cleavage by cathepsin in the tumor. And so we selected a reduction of neutropenia right in about the 50% range, because that was enough that we could actually increase the dose of Luvelta and improve the antitumor efficacy while maintaining the DLT of neutropenia, which can be easily detected and managed by either dose reduction or dose delay or by the addition of G-CSF as we did in our clinical studies as well. So this really is, I think, one of the key advantages of our manufacturing technology that we can engineer the specific features to address some of the liabilities of the tubulin inhibitor ADCs. Now to give you an idea about Luvelta activity. We are -- we have seen in preclinical settings, very potent antitumor activity in ovarian cancer. I'm not going to review that data again. But I want to introduce you to the left panel here, which is in xenograft experiment where we use patient-derived non-small cell lung cancer tumors and treated these mice implanted with these tumors with 10 mg per kg of Luvelta shown in the blue line on the bottom, and we could see very prolonged and complete tumor regression in this patient derived xenograft models, but also others over 10 of those that we test, we could see very strong antitumor activity in non-small cell lung cancer tumors that express folate receptor. And we are particularly excited about this data because these PDX models have been shown in the past in various settings that they're highly predictive for clinical outcome. And as Dr. Borgman already alluded, we are going to start a Phase II trial with Luvelta in non-small cell lung in the middle of this year, mostly based on the outcome of these experiments in PDX tumors. And on the right side, it's one of the standard models used in the industry to study combination effects of checkpoint inhibitors with oncology drugs. And this model will be used Luvelta at the single dose of 10 mg per kg shown in the green line and see this partial inhibition of tumor growth and compared it to the activity of avelumab, which is a PD-L1 blocking antibody, and both induce some kind of partial tumor growth inhibition in this model. But when we combine the 2, and that's not always seen when you do that, it's actually a rare event. You could see the complete regression of these tumors in these models in the combination study. And this is really important for us because hemiasterlin is one of the tubulin inhibitors that can induce high levels of immunogenic cell that we know that they combine well with checkpoint inhibitors in preclinical studies that you see here, but also from other people's data that they do very well in the clinic. And we are super excited because this may be a key advantage that we can bring to the patients because other linker class as such the exatecan do not combine as well with checkpoint inhibitors, both in preclinical and clinical settings. Now talking about exatecan. I think we are all aware of the success of this class of ADCs and they're taking currently front and center stage in all the major oncology meeting across the globe. And we at Sutro started our own exatecan platform more than 3 years ago, again, with the idea to use and take advantage of our unique technology to introduce some features into these molecules to address the current liability of this class of compounds. And the first one that most of the listeners may be aware of is interstitial lung disease that can develop over prolonged treatment with exatecan conjugates, including in HER2 that use DXd or other exatecan conjugates. And again, only since about 2 or 3 years, it's now known because of the work at Daiichi that published these findings. This is mediated by, again, the expression of Fc-gamma receptors on alveolar macrophages that are present in the lung and in uses damage in that cell population, which ultimately results in the development of ILD. And again, since we do not engage with FC gamma effector, we have, in fact, not seen any signs of ILD in our preclinical studies in signals where we administered repeat doses of exatecan conjugate targeting ROR1, which is known as STRO-3 or also tissue factor. And up to the dose of 30 or 40 mg per kg, we haven't seen any signs of ILD where others have reported ILD findings at each dose levels in these NHPs. And the second liability, the current liabilities of first-generation exatecan conjugate is their relative low potency, which when the sum of the salty tumor antigens that are expressed on lower copy numbers of limits to these conjugates. And the way we address this at Sutro is by actually going above the currently highest level of DAR8 when you use conventional conjugates. By using our technology, we can go currently as high as 12. We're also looking at DAR16 conjugates to actually increase the potency of our ADCs and to be able to reach low copy number tumors. And on the lower left, this is actually an example of the potency that we have seen with our DAR8 exatecan platform, in xenograft experiment again, compared to Luvelta at the single dose of 5 mg per kg, again, which is a tubulin inhibitor with our next-generation folate-receptor alpha exatecan DAR8 ADC shown in the teal color. And you can see almost similar, if not better antitumor activity of the DAR8 folate receptor alpha conjugate. And on the right side, this is particularly important for ADC development. This is a PK analysis of DAR8 exatecan in mice and we compare Luvelta, which is shown in dark blue with our next-generation DAR8 exatecan on top that's STRO-3 ROR1. And in the blue, that's the folate receptor -- second generation folate receptor DAR8 exatecan. And these are very high half-life numbers in these mice that were obtained. And this is particularly exciting, because half long and prolonged half-life of ADCs in these animal models indicate the ablation of the platform talk. So I think we have come to a very good level of platform toxicity reduction with exatecan. And when we're comparing potency and safety of this conjugate, I came to the conclusion that we are at least as good or better than other exatecan platforms out there. Next slide, please. So with this, I want to conclude and I think expertise ADCs because of their unprecedented activity in clinical settings are here to stay. And so we thought, again, how can we use our unique cell-free technology to further improve the therapeutic index of these exatecan conjugates. And we're focusing on these 3 key areas shown here on the left to improve ADC potency in the middle, again to improve their ability to induce immunogenic cell death to actually be better combinable by checkpoint inhibitors. And on the very right to how can we overcome the formation of resistance that have been recently reported in preclinical, but also clinical settings. And the key term here is actually dual conjugates. And that, again, is enabled by our unique cell-free technology where we now can introduce 2 different types of nonnatural amino acids, which -- each of which we can contribute to a different class of payload and for ADC potency, if we then block 2 DNA damage response pathways we can increase a higher potency. And almost the same will apply for immunogenic cell death induction. We can combine DAR8 exatecan with DAR8 linker payloads, then induce high levels of cell immunogenic cell death to stimulate that immune response against your own tumor. And on the very right, of course, now that we know some of the molecular mechanisms that are being regulated in response to exatecan conjugate, we can block those as well, including the top of 2 Isoray markets and also by using dual conjugate technology. With that, I'd like to conclude and hand it over to our Chief Operating Officer, Jane?

Thank you, Dr. Gerber. So we have presented a lot of science and Luvelta data today. And with announcement of Sutro innovation philosophy that is by design. Now I want to thank Dr. Monk and Bill for getting to the key question of the day. Why do we care? Our aim here is to convey our excitement about Luvelta potential to benefit more patients, which is driven by the strength and consistency of these data, presented in totality for the first time today. Luvelta has demonstrated clinical antitumor activity and tolerability in all 4 of the 4 tumors in which it has been studied. We believe the clinical activity of Luvelta to date is just the tip of the iceberg, because as you can see in the heat map, folate-receptor alpha is expressed broadly across many different tumors to different degrees of expression. And what differentiates Luvelta is the way it was precisely designed as Dr. Hans-Peter Gerber eloquently described. It was designed for higher affinity and efficiency to engage with target receptors on the cancer cells. This is what we believe allows Luvelta to reach lower target expression. And that matters because the strategy of expanding the biomarker with the validated folate receptor alpha target with our lower TPS greater than equal to 25% criteria enables Luvelta to make a difference in more of these tumors and in more patients. Finally, the broader activity both within and beyond ovarian cancer and theoretically into even more tumors not even set yet, is which potentially makes Luvelta a pipeline in the drug. Now this broader clinical activity is what then translates to the broader potential commercial opportunity. The most common question we hear is how does Luvelta compare to Elahere? And I would say that it's only part of the question. or rather a small part or a piece of the pie on the left of this slide that you've seen before and what we want to emphasize again. Just under half of the Luvelta-eligible patients would be eligible for Elahere and the remainder would not where the comparison should be standard chemotherapy. Because Luvelta potentially benefits double the patient population in ovarian cancer, even if we only capture the folate receptor alpha expressing Elahere in eligible patients, there will be a market at least equal to that of Elahere and possibly more if Luvelta-bevacizumab combination data continue to support an all-comer strategy regardless of folate receptor alpha expression. Now on the right side of this slide, also distinct from Elahere is the opportunity to expand into a wide variety of other tumors like we discussed today, including endometrial, pediatric AML and lung cancers, some of which may even be bigger potential commercial opportunities than ovarian cancer. Luvelta is our exciting lead ADC therapy with a broad clinical development program, but Sutro is not just Luvelta, we have a growing pipeline, including a ROR tissue factor ADC with exatecan payloads, which are now very much in vogue, both of which are rapidly moving to the IND and the clinic. And as Bill mentioned at the outset, we also had important collaborations with backside, Merck and Astellas, where programs are already advancing in the clinic with pneumococcal vaccines, cytokine derivatives and future generation iADCs and serve as additional proof of concept of and enabled by future proprietary protein design and cell-free technology. So thank you for your time and attention. I want to leave you with a big picture for Luvelta and convey again our big ambitions for this therapy and what that future apart. But in short, we know we have a drug in Luvelta. We have a pipeline in Luvelta and the rest of the portfolio, and we have a very unique platform. So I want to bring it home with 3 important points. First, this is the first time we shared the growing body of evidence all at once, all supporting the differentiation of Luvelta's clinical promise and commercial potential from existing therapies. Second, the aggregated data analysis in ovarian cancer, it increases our confidence in our strategy to move forward fast with the registrational plans in ovarian and peds AML, positioning Luvelta as the first folate receptor alpha ADC to broaden important benefits to medium and low expressing patients and in further developing Luvelta in additional folate receptor alpha-expressing tumors. And finally, all of this is made possible by Sutro's unique express cell-free technology that enables us to discover and precisely design strong solutions to test problems and to boldly address therapeutic areas of high unmet need. So thanks again for your time, and happy New Year. I will now pass it back to our operator, Jonathan, to open it up for Q&A.

[Operator Instructions] And our first question comes from the line of Roger Song from Jefferies.

Great. Thanks a lot for this comprehensive update. A couple of questions from us. So the first one is, I think for this prophylactic use of the G-CSF, maybe just to help us understand a little bit more about the data there. So I think you have the cycle 2, you have 18.8% and overall seems to have a higher 37.5%, Grade 3 plus. So that means you may have a later development of the Grade 3 plus neutropenia? How could you kind of further reduce that overall neutropenia maybe like a longer use of the G-CSF versus just 2 cycle of the use of the G-CSF? That's my first question, and I have a few follow-ups.

Thank you, Roger. Dr. Borgman will reply.

Thank you, Roger. So in fact, the prophylactic use of G-CSF was mandated for day 8 of Cycle 1 and 2 of the high dose of 5.2. And in the REFRaME-O1 pivotal trial, patients will reduce down to 4.3 for their third cycle. So the cohort C data that you've seen today is reflective of these first 2 cycles. And to your point about potential later grade neutropenia, we haven't shown those data today. and neutropenia in general, is managed by the treating physician and can be managed by either G-CSF according to institutional or ASCO guidelines, dose reduction or dose delays. With respect to the dose reduction specifically, recall that we have activity in prolong stable disease going down to doses in the 2-ish range. So this drug has a pretty wide therapeutic index. And therefore, we feel pretty confident about the ability to manage later on to that neutropenia.

Got it. Yes. That's helpful. And then so I think you showed us the overall response rate for all the treated or TPS 25 plus the TPS 25 kind of patient, ORR is around 28%. And we understand that include some of them consider as a low and medium expression versus the high expression. So do you have any data to show us in terms of the ORR in those low medium versus the high expression level for folate receptor alpha, so we know the difference between those 2 kind of expression level? And how does that deviate from overall 28% ORR?

Thanks, Roger, for that last question. Dr. Borgman?

Thank you, Roger. We do know that information. And I will say that the data are -- we didn't choose to share that today. The data are very consistent among the highs, lows and mediums. These are very strong representation of all the different levels of the population. And a response rate of 28% importantly will well exceed the response rate for standard chemotherapy options.

And our next question comes from the line of Asthika Goonewardene from Truist

Apologies, there's a bunch of events going on today, so I jump in between a few, so I might have missed this, so I'll just be direct and ask it. What are the takeaways that we we're looking for with the cohort C data was potentially how adding the prophylactic G-CSF could improve the patient's ability to stay on therapy and therefore also improve the durability of response? I didn't see that on the slide, I might have missed it when you were talking about it. Can you please comment about what the addition of this prophylactic G-CSF regimen does to the durability of response of luveltamab in cohort C?

Thanks for asking that question. Dr. Borgman, I'll let you respond.

Sure. Thank you. The durability it's a little bit different than what we're planning for the REFRaME trial. For the REFRaME trial, the plan is to give 5.2 for 2 cycles with the G-CSF support and then drop down to 4.3, a dose that we know is tolerable for long periods of time. Neutropenia is one of the adverse events, and the other is potentially also our trough. And by, I think Dr. Monk also mentioned today in his remarks that getting a handle on tumor control and symptom control early on with a higher dose is very important for these women. And that's what we feel the 5.2 dose front-loaded will do.

Dr. Monk, did you have anything to add here?

Yes, a couple of things. I want to address both. First of all, neutropenia is a laboratory value. I know you know that. But what matters is febrile neutropenia and an 18.8% neutropenia is well within acceptable range and is unlikely to be associated with relevant febrile neutropenia. So we've sort of accomplished our goal as making this tolerable. But here's the point. If you look at MIRASOL, which is the randomized infirmatory trial, a significant portion of the patients came off mirvetuximab at the first assessment, and again, that's because it took time to build up a level. So it's not durability, it's initial tumor control. If you look at a very famous trial that I published in Lancet Oncology of avelumab plus liposomal doxorubicin, 60% of patients came off at the first assessment. So if we can't get control of the tumor early on, then the patients progress. Yes, ultimately, if they progress, they don't stay on trial and if they don't stay on trial, they don't have a prolonged time to progression. So it's -- but it's not really to make the responders durable, it's to increase the response rate, and that's why we showed you that data. It's very -- and I'm going to hand it to Sutro for thinking of that.

I was wondering if I can -- is there further plan to show more data from Cohort C that maybe talk about with longer-term follow-up with some swim lane plots or some spider plots perhaps later on?

We have a lot of data, Asthika, that's being shared here with you all today, and we're not going to subset the data on a going-forward basis. I'm sure there will be a scientific publication that will dive deeper and more broadly than we're able to do today. But right now, we're focused on moving forward with REFRaME-O1. Thanks for your question.

And our next question comes from the line of James Shin from Deutsche Bank.

I think a lot of the questions on Cohort C were taken. My question is on part 1 of REFRaME being completed first half of '24. Can you set the gating factors for the filing for approval and [indiscernible] benchmark you should look for or you're anticipating to hope to hit to get accelerated approval? And then I have a follow-up.

Thanks, James. Dr. Borgman?

I think I heard most of that. You were a little garbled. So let me know if I didn't address your question appropriately. You were asking about time lines for Part 1. So for Part 1, we're well on our way for enrolling the first 25 patients in each of those dose cohorts. We'll be analyzing those patients' data for exposure with an exposure response assessment and then discussing those data with the relevant regulatory authorities to agree upon the appropriate dose, the optimal dose to take forward. While that's happening, the REFRaME trial will continue to enroll unabated so that we don't lose any time in getting to our primary end point. We hope to be in a position to share the dose that we've selected, assuming we don't have any issues with trial integrity and releasing any data while a pivotal trial is ongoing towards the later part of the year. With respect to the accelerated approval, we do have a planned interim analysis that will support accelerated approval. And as I pointed out just a moment ago, the continuing enrollment while we wait for the dose question to be finalized, will help us to reach our enrollment goals more rapidly in support of that interim analysis.

Then more of a strategic follow-up just given some of the recent business development activity for overall iADCs. Would Sutro entertain any partnerships for Luvelta in ovarian cancer at this stage?

Thanks, James. For that last question. We've obviously partnered Luvelta in China previously. You're aware of that. And as we are proceeding with the global study, we're also anticipating what the opportunities for commercialization are going to be in Europe and the rest of the world. At this stage, I don't believe that we would be in a position to commercialize Luvelta globally. And we know there's a lot of interest in ADCs. We know there's a lot of interest in folate receptor alpha, particularly as it pertains to a ovarian answer. We don't comment on business development activity, but I can assure you that we are active in multiple discussions.

And our next question comes from the line of Jay Olson from Oppenheimer.

Thanks for providing this update and congrats on all the progress. Can you talk about the biologic rationale for the increased activity of Luvelta in ovarian cancer with folate receptor alpha levels below 25% in combination with bev. And if there's also rationale for combining Luvelta with PARP inhibitors in ovarian cancer? And then I had a follow-on, if I could.

Thanks, Jay. Dr. Gerber, do you want to start with that? And maybe...

Yes, I can provide my ideas. So I actually worked on Avastin about 20 years ago. So I'm a little bit familiar with the biology. And as you know, it's that changing Avastin per mobility, and it's possible that when you combine Avastin with Luvelta that it allows more of the ADC to go from the blood vessels out into the tumor, so you might get higher drug accumulation in the tumor. So that's my first thought on that, but I'll hand it over to...

Actually, why don't we ask Dr. Monk, probably have some views on this question as well.

Yes. I don't have much more to say. It sort of prunes the vasculature. And initially, we thought it's an anti-angiogenic, it would create tumor [ hypoxia ], it actually doesn't. It improves oxygenation improves blood flow. And the other thing is that with the local microenvironment getting more medication, the bystander effect, which this medication is platform, quite frankly, is so rationally designed for to be more substantial. So if you can get more drug in the microenvironment, then ultimately, you can get the bystander effect where every tumor doesn't have to express the target.

Thank you. Dr. Gerber, you had another thought?

Yes. The other addition to what Avastin might do with Luvelta is the fact that one of the biology that is regulated by Avastin is dendritic cell maturation. At the time when we developed the drug that was always something we added to the review, but we didn't quite understand. And what this could mean is that you prime the tumor to express more neoantigen that you have more of the CD8 T cells coming into the tumor, and this would combine well with Luvelta that also stimulates by this immunogenic cell that activation, the CD8 [indiscernible], so you might have more of that second wave, CD8 T cells coming into tumor. When you combine with Avastin, it is certainly something we're going to look into the biomarker studies in the clinic to actually check the CD8 T cells getting into the tumor.

Thanks, Jay. You had a follow-up or a second question?

Yes. And also, I guess, just any biologic rationale for combining Luvelta with PARP inhibitors in ovarian?