Good day, and thank you for standing by. Welcome to the Sutro Biopharma Luvelta Forum Webcast and conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, simply press star one one again. 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'll 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 tazevibulin bevacizumab combination. In the course of today's presentation, we'll be making forward-looking statements, and we refer you to the text of this slide as it pertains to such statements.
Joining me 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're 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 as a therapy for multiple since 2019. Luvelta is a 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 expressors 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 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, allowing 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 to become the first folate 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 killing 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 homogeneous antibody drug conjugate, and what that means is that each molecule is identical and fully competent to kill cancer cells.
We 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 has been studied broadly in 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 will see today. It combines well with checkpoint inhibitors as well, and that's particularly exciting for us and for patients. Doctors Borgman and Monk will soon share with you the data that underpins our decision to begin 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 for 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 gynecologic malignancies, to discuss the registration pathway 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 we thought about Luvelta during this early stage of development, there was no requirement 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 three, and over 70% of these women received PARP bevacizumab or a PARP inhibitor. Their 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 two 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 chiefly of neutropenia, stable 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, luveltamab- Luvelta plus bevacizumab was tested and showed early signs of antitumor activity as well as tolerability. Dr. Monk will share with you the first peek of those data later on today. Luvelta checked all the boxes. We tried the safety profile, determined the biomarker, showed the ability to combine this, determined the proper dose for further study, and all these support further development. I'm sharing with you now a waterfall plot that represents a focused look at our data. 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 express 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 rate in the range of 12%-15% and a PFS of around four 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 is 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 and 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? While 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%-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 Trials. 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 co-found 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 is very difficult for me to admit are 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, it's 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. 1-3 lines of chemotherapy or prior lines, ECOG performance status 0-1. 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, was FDA approved. The Phase III trial, confirmatory trial, has been published in the New England Journal of Medicine 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+, greater than 75% positivity score, 2+ or greater.
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 it's a 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 two doses with growth factors might be too much." You're right, it might be, and we're gonna 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 if it's cetuximab, we bolus it. Generally, we don't do it with other antibodies because patients are not symptomatic. But platinum-resistant recurrent 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 two cycles of growth factors. And then ultimately, the optimized dose will be carried forward versus physician's choice chemotherapy. There will be four 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 planned look at overall response rate and duration of response for accelerated approval. So as you know, with ImmunoGen's product, there were two 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 FrontRunner. 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 a 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 high. 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, and low. But around the rest of the world, they will be, you know, a broad, representative sample. We already have 5 countries active, 26 active sites. Our ultimate goal is to have 140 sites, and 20 countries. Again, we have 5 countries now, so by the time we have the dose optimized, we'll be at the elbow and, and really, enroll rapidly because it's not only the strategy, but it's the pace. So the next slide here.
So we're excited again to be beyond the 75% positivity score, 2+. Rather than use a positivity score of 2+, the strategy here is to use a tumor proportion score, which we call a TPS. It uses the same Ventana 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, in 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 it transition to that, I wanna talk to you about this idea of adding G-CSF, pegfilgrastim, 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 progress so rapidly that they don't get enough doses and intervention to benefit. And that's why this 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, pegfilgrastim is given on the second day of chemotherapy. The nadir 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 pegfilgrastim G-CSF, is mitigated. So we could 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 two-thirds, prior PARP inhibitor.
Taking patients and seeing if the utilization of growth factors could be as beneficial as we had hoped. Next slide. 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 two cycles, so that sort of translated to a 73.7% reduction in severe neutropenia in the second cycle. Remember, it's only given for two cycles. You can't really make firm conclusions on the activity, but I think the data speak for itself. The tumor shrinkage in this waterfall plot is substantial.
You can see in the table, again, cohort A, a 76.2% without 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 two 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 three New England Journal of Medicine publications later, got it approved in platinum sensitive disease and frontline. 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 a scientific meeting. We wanted to ask three 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 if a Phase III trial is in the greater than 25% TPS, and maybe with bevacizumab, it sort of would expand the opportunity. Second goal. 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 are three 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 again, in an inferential 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 highs, mediums, lows, and less than 25% even. And in the bevacizumab naive patients, 50%, but even in the bevacizumab pretreated 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 pretreated and in TPS less than 25%. Next slide. But here's the kicker really, is the tolerability. So at the 20% sort of cutoff, 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. Bevacizumab, we know what that does.
We know what Luvelta does because we've studied them extensively as single agents. But we have not seen across the program to the same level. Again, hate to do cross-trial comparisons. I like mirvetuximab, but I really look at Luvelta as sort of a 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, some mucositis, some neuropathy. I 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 a year and a half. 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, and 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, I can't 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 Luvelta in ovarian cancer. 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 are 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 and endometrial cancer were presented by Dr. Bhavana Patel 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 at an early phase and included all comers, in the patients whose tumors expressed at least 25% folate receptor alpha, there was an anti-tumor 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 presents a potential 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, with AML. Collective data from the single patient IND experience were presented by Dr. Soheil Meshinchi 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. To get started, Luvelta is the first of our tubulin inhibitor platform ADCs, that's where we used 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 this slide. On the upper left is the anatomy of Luvelta, and as Bill already alluded to it, it's a 4-loaded antibody drug conjugate, a DAR 4, 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 bystander activity of the payload when it gets released from the antibody.
Why that is important, that means not every tumor cell in the tumor needs to express folate receptor 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 last but not least, the hemiasterlin was selected to be a low PGP substrate, and what that means, it's less pumped out by these multidrug-resistant efflux pumps in tumors after multiple chemo treatment, prior chemo treatment. And so we're less likely to see a resistance development after 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 an ADC linker. It is cleavable by basic cathepsin. We, in addition, use the very stable conjugation technology known as click chemistry to conjugate and make very stable bonds between the linked payload and the antibody, such that we lose less payload outside of the tumor, and we can increase the therapeutic index of our ADCs. On the very right side, I think that's a very important and critical feature, that the Fc domains of our antibodies, due to the unique technology where we express proteins, is not engaging in Fc gamma receptor binding. That's important because these 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 on the, of the platform toxicity. And so going to the lower part, some of the key liability of conventional tubulin inhibitor conjugates we're aware of is eye toxicity, which manifests in blurred vision. And while this is a smaller frequency, maybe sometimes 5%-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.
It's now becoming clear what the reason for this toxicity is, and it's the fact that corneal cells express these Fc gamma receptors and thus can bind non-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. Again, the fact that we do not engage with Fc gamma receptors with 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 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 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 elastase, 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 engineer highly specific sites along the antibody that reduce the cleavage by these elastase in the bone marrow, but maintain the cleavage by cathepsin in the tumor.
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 have seen in preclinical settings, very potent antitumor activity in ovarian cancer.
I'm not going to review that data again, but want to introduce you to the left panel here, which is a xenograft experiment, where we used patient-derived non-small cell lung cancer tumors and treated these mice implanted with these tumors with 10 mg/kg of Luvelta, shown in the blue line on the bottom. We could see very prolonged and complete tumor regression in these patient-derived xenograft models, but also others. Over 10 of those that we tested, we could see very strong antitumor activity in non-small cell lung cancer tumors that express folate receptors. 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. 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. On the right side is one of the standard models used in the industry to study combination effects of checkpoint inhibitors with oncology drugs. This model, we used Luvelta at a single dose of 10 mg/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. Both, you know, induce some kind of partial tumor growth inhibition in this model.
But when we combine the two, and that's not always seen when you do that, that's actually a rare event, we 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 death. We know that they combine well with checkpoint inhibitors in preclinical studies, as you see here, but also from other people's data, that they do very well in the clinic. And we're super excited because this may be a key advantage that we can bring to the patients, because other linker-payload classes, such the exatecans, do not combine as well with checkpoint inhibitors, both in preclinical and clinical settings.
Now, talking about exatecans, 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 meetings across the globe. We at Sutro started our own exatecan platform more than three 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. The first one that most of the listener 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. Again, only since about two or three 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 induces damage in that cell population, which ultimately results in the development of ILD. And again, since we do not engage with Fc gamma receptors, we have in fact not seen any signs of ILD in our preclinical studies in cynomolgus, where we administer repeat doses of, ADC exatecan conjugate, targeting ROR1, which is known as STRO-003, 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 these dose levels in these, NHP.
The second liability, the current liabilities of first-generation exatecan conjugate, is their relative low potency, which renders some of the solid tumor antigens that are expressed at lower copy numbers off limits to these conjugates. The way we address this at Sutro is by actually going above the currently highest level of DAR 8 when you use conventional conjugates. By using our technology, we can go currently as high as 12. We're also looking at DAR 16 conjugates to actually increase the potency of our ADCs and to be able to reach low copy number tumors. On the lower left is actually an example of the potency that we have seen with our DAR 8 exatecan platform.
We, in the xenograft experiments, again, we compared Luvelta at a single dose of 5 mg/kg, again, which is a tubulin inhibitor, with our next generation folate alpha, folate receptor alpha exatecan DAR 8, ADC, shown in the teal color. And you can see almost similar, if not better, antitumor activity of the DAR 8 folate receptor alpha, conjugate. And on the right side, this is particularly important for ADC development. This is a PK analysis of the DAR 8 exatecan in mice, and we compared Luvelta, which is shown in dark blue, with our next generation, DAR 8 exatecan on top. That's STRO-003 ROR1, and in the blue, that's the folate receptor, second generation folate receptor, DAR 8 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-lives of ADCs in these animal models indicate the ablation of the platform tox. 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 these conjugates, 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 exatecan 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 three key areas shown here. On the left, to improve ADC potency.
In the middle, again, to improve-prove their ability to induce immunogenic cell death, to actually be better combinatable with 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 two different types of non-natural amino acids, which each of which we can conjugate to a different class of payload. And for ADC potency, if we then block two, DNA damage response pathways, we can increase a higher potency. And almost the same will apply for immunogenic cell death induction.
We can combine DAR 8 exatecan with DAR 8 linked payload, then induce high levels of immunogenic cell death to stimulate that immune response against your own tumor. On the very right, of course, now that we know some of the molecular mechanisms that are being upregulated in response to exatecan conjugate, we can block those as well, including the topoisomerase blockers, 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 a nod to the 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's 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 anti-tumor activity and tolerability in all four of the four 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 this heat map, folate receptor alpha is expressed broadly across many different tumors to different degrees of expression.
What differentiates Luvelta is the way it was precisely designed, as Dr. Hans-Peter Gerber so eloquently described. It was designed for higher affinity and efficiency to engage the 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 ≥ 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 studied yet, is what potentially makes Luvelta a pipeline and a 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 is only part of the question, or rather, a small part or piece of the pie on the left of the slide that you've seen before, and 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- eligible patients, there will be a market at least equal to that of ELAHERE, and possibly more if Luvelta bevacizumab combination data continues 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 ROR1, tissue factor ADCs with exatecan payloads, which are now very much in vogue, both of which are rapidly moving to the IND and the clinic.
As Bill mentioned at the outset, we also have important collaborations with Vaxcyte, Merck and Astellas, where programs are already advancing in the clinic with pneumococcal vaccines, cytokine derivatives, and future generation iADC, and serve as additional proof of concept of and enabled by Sutro's proprietary protein design and cell-free technology. So thank you for your time and attention. I want to leave you with the big picture for Luvelta and convey again our big ambitions for this therapy and what sets Sutro 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 three important points.
First, this is the first time we've 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 benefit 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 Xpress cell-free technology that enables us to discover and precisely design strong solutions to tough 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.
... Certainly. Thank you. One moment for our first question. Our first question comes from the line of Roger Song from Jefferies. Your question, please.
Great. Thanks a lot for this comprehensive update. A couple questions from us. So the first one, I think, you know, for this prophylactic use of the G-CSF, maybe just to help us to understand a little bit more about the data there. So I think you have the cycle 2, you have 18.8%, and the overall seems to have a higher 37.5% grade 3 plus. So that means you may have a later development of the neutropenic grade 3 plus neutropenia. How could you kind of further reduce that overall neutropenia, maybe like a longer use of the G-CSF versus the 2-cycle use of the G-CSF? That's my first question, and I have a few follow-ups. Thank you.
Thank you, Roger. Dr. Brad Monk 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 see today is reflective of these first two 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 prolonged 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 onset neutropenia.
Got it. Yeah, that's helpful. And then so I think you showed us the overall response rate for all the treated, or TPS-25+, the TPS-25, kind of, patient, OR is around 28%, and we understand that include some of them considered as the low and the medium receptor expression versus the high expression. So do you have any data to show us in terms of the OR in those low, medium, versus the high expression level, for folate receptor alpha, so we know the difference between those two, you know, kind of FR expression level and how, how did that deviate from overall 28% OR?
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.
Perfect. Thank you.
Thank you. Thank you, Roger.
Thank you. One moment for our next question. Our next question comes from the line of Asthika Goonewardene from Truist. Your question, please.
Hi, guys. Good afternoon, and thanks for taking the question. Apologies, I saw there's a bunch of events going on today, so I was jumping between a few, so I might have missed it, so I'll just be direct and ask it. Wasn't one of the, one of the takeaways that we were 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 in the slide. I might have missed it in your, when you were talking about it. Can you please comment on about what the addition of this prophylactic G-CSF regimen does to the durability of response of Luvelta in Cohort C?
Thanks, Asthika, for that question. Dr. Brad Monk, I'll let you respond.
Sure. Thank you. The durability is 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 arthralgia. And, 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?
Yeah, 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 severe neutropenia. And an 18.8%, you know, neutropenia is well within acceptable range and is unlikely to be associated with relevant febrile neutropenia. So we've sort of accomplished our goal with making this tolerable. But here's the point, if you look at MIRASOL, which is the randomized confirmatory 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 thoughtful, and I gotta hand it to Sutro for thinking of that.
I was wondering if I can introduce, is there a further plan to show more data from cohort C that maybe talks about with longer term follow-up with some slim line plots or some spider plots, perhaps, Raymond?
Yeah, we have a lot of data, Asthika, that's being shared here with you all today. And, you know, we're not gonna 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.
Thanks, guys.
Thank you. One moment for our next question. Our next question comes from the line of James Shin from Deutsche Bank. Your question please.
Hi, happy New Year, guys. I think a lot of the questions on cohort C were taken. My question is on part one of REFRAME being completed first half of 2024. Can you set the gating factors for then filing for approval and benchmarks we should look for, or that you're anticipating the hook 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 timelines for part one. So for part one-
Yes.
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 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 endpoint. We hope to be in a position to share the dose that we've selected, assuming, you know, 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. 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 I've got a more of a strategic follow-up, you know, just given some of the recent business development activity for FRα ADC, 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 ovarian cancer. We don't comment on business development activity, but I can assure you that we are active in multiple discussions.
Thank you, guys.
Thanks.
Thank you. One moment for our next question. Our next question comes from the line of Jay Olson from Oppenheimer. Your question please.
Oh, hey, 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-up one, if I could.
Thanks, Jay. Dr. Gerber, you want to start with that and maybe-
Yeah, I can provide my ideas. So I actually worked on Avastin about 25, 20 years ago, so I'm a little bit familiar with the biology.
... As you know, it's, it's changing the vascular permeability, 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-
Well, actually, why don't we ask Dr. Monk, you probably have some views on this question as well.
Yeah, I don't have much more to say. It sort of prunes the vasculature. And, you know, initially we thought, oh, 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, this platform, quite frankly, is so rationally designed for, could 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?
Yeah. 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. So you more of that second wave, CD8 T cells coming in the tumor when you combine with Avastin. It's certainly something we're going to look into the biomarker studies into the clinic to actually check that the CD8 T cells getting into the tumor.
Thanks, Jay. You had a follow-up or a second question?
Yeah, and also, I guess just any biologic rationale for combining Luvelta with PARP inhibitors in ovarian?
Great. I'll start with Dr. Borgman, and then maybe Dr. Monk can add a few thoughts as well.
Yeah. I'm not sure whether there's a biologic rationale. As you are probably aware, the role of the PARP inhibitors in ovarian cancer is sort of evolving. That being said, PARP inhibitors can be, and have been, a mainstay of treatment for ovarian cancer. And the safety profile of Luvelta and the PARP inhibitor would allow for some combinability.
Dr. Monk, do you have any other thoughts on that as well?
Yeah, being a microtubule-active payload, probably the MOA doesn't make sense, but we need a strategy for anti-folate therapy in the front line. Certainly, if there was a topoisomerase payload, which would be a DA, DNA damaging, there would be a biologic rationale. We also have to see what happens for overall survival in the front line for PARP in the HRD test negative population, where PARP inhibitors don't work well. And so, quite frankly, it's a great question. We need to figure out how to move this medication earlier in the treatment paradigm. We will do that. Combination with PARP, combination with Bev, those are sort of the competing challenges. We'll have to see what happens to PARP. As you know, the PARP inhibitor indications have been sorely restricted.
The treatment indications, all three of them have gone away, and the platinum-sensitive maintenance indications are now only limited to BRCA. And they may even be further restricted in the front line once we see the overall survival next, I guess, this year, it's already 2024, this year in the HRD test negative, both in ATHENA-MONO, which I'm, you know, I'm heavily involved in as the first author, and PRIMA, which I'm heavily involved as the last author. So we'll see.
Super helpful.
Thank you.
If I could maybe sneak in one more. Since you mentioned immunogenic cell death, is that the rationale for combining Luvelta with PD-1 in non-small cell lung cancer? And would you consider pursuing triple-negative breast cancer since those tumor cells also express folate receptor alpha?
Dr. Gerber?
Yes. I think that is one of the ideas we have to go in this direction. In there is, of course, the class of tumors that are hot and the other ones are cold, and I think it's good to start where we already have a success with PD-1 inhibitors and then combine to Luvelta. But it's also worth exploring the cold tumors as we think about the right order of these trials going forward.
Dr. Borgman?
And I would add... Yeah, I would add that triple negative is among those tumor types that do express folate receptor alpha at a lower or variable level. And there have been some interesting data out there in the literature recently on this target in triple negative breast cancer. And of course, as a developer, I'm very excited about Luvelta because there really is no end to the different tumor types that we can explore. For now, we're focusing on ovarian, but yes, definitely a possibility to treat women with triple negative breast cancer in the future.
Thank you, Jay.
Thanks for taking all the questions.
Thank you. One moment for our next question. Our next question comes from the line of Boris Peaker from TD Cowen. Your question please.
Great, thanks. I just want to squeeze in two questions. First, on the REFRAME study, can you comment on the efficacy that needs to be met?
... for the study to stop at the interim analysis and kind of what the alpha cost associated with that is? And second, on the AML opportunity, can you comment what the commercial opportunity there is if Luvelta is approved?
I'll have Dr. Borgman address the first one.
Certainly. So the interim analysis is not designed to be a futility analysis. It's designed to be a look at overall response rate as compared with chemotherapy, and we've designed the trial and powered the trial such that we need to exceed the upper end of the confidence interval regarding historical chemo. And so there won't be a futility per se, but based on the strength of the data, the possibility of pursuing an accelerated approval in the low to medium, which is the extremely high unmet need population, as well as potentially in the high expressors, depending upon the strength of the data.
I think I'll ask our Chief Operating Officer to talk a little bit about why we're pursuing pediatric and what it means from a commercial perspective.
Yeah. So this is a very vulnerable patient population with not a lot of treatment options. And I think it's important and really compassionate, Sutro to be able to supply this trial. Commercially, it - we don't see it as a huge opportunity per se, relative to the other tumors we're investigating. There are about 100 patients per market, so it's not a big commercial one, in and of itself. I think how we are looking at this from a strategic standpoint is how pediatric AML could accelerate our opportunity to go fast and get ready for ovarian cancer. Also associated with that is the PRV as well, which could come at a face value of $100 million or so. So there's value there as well.
But it really is to benefit and synergistically work with the ovarian cancer registrational plan.
Boris, as you can probably imagine, given the small patient numbers, this is not a very expensive study for us to run, and one that we believe we can run rather quickly.
I guess my concern is just actually finding those 18 patients, if there's only 100 out there, how hard is that?
Dr. Borgman?
Yeah. So we've, interestingly, we've probably... I personally believe that most of the children in the world are at our doorstep. There's news spreads fast in this community, and I've looked at the number of single patient IND requests that we've gotten over the last three years, and it's going up exponentially. Initially, it was an unheard of entity, and someone was just trying it on a wing and a prayer. And as the data have increased and gotten out there, and as these physicians and families are close, so close-knit and talk to each other, we're really hearing about all of the children. So, oddly, even though it's a very rare tumor type, I think paradoxically, we are going to enroll it very quickly.
Boris, we've also reported on 25 patients already who've been treated with compassionate use, and I'll tell you, we're in the mid-30s in terms of kids who've been treated already. So, this is more, they find us immediately because their prognosis is so poor and the physician community knows this is a therapy that can benefit.
Yeah, they're even asking us for a drug before they've finished their front line induction because they say it doesn't work. It just doesn't work for this particular clone of leukemia.
Great. Thanks for taking my question.
Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Edward Tenthoff from Piper Sandler. Your question please.
Great. Thank you very much. I appreciate all the data and taking the question. I guess mine has to do with lung cancer. You know, just from, I'm assuming a folate receptor alpha positive patient, can you remind us how large that is? And would some of the similar combinations that you're considering in ovarian or even other combinations, like, PD-1 or whatever, make sense in lung? Thanks.
Thank you, Ted. Jane?
Yeah, thanks, Ted, for the question. I mean, lung cancer is a big opportunity always. And I think here we have some translational work that actually shows about 30% of adeno lung cancer patients express folate receptor alpha. And that is with our current folate receptor alpha Ventana assay. So, we believe there's a significant opportunity here in lung cancer, non-small cell lung cancer adeno, and why we're excited. In terms of combination, obviously, we know that PD-1 agents work in lung cancer, and so having the preclinical data both as a monotherapy, but in addition, in combination with the PD-L1 therapy is very exciting.
Thanks.
Thank you, Ted.
Thank you. One moment for our next question. Our next question comes from the line of Reni Benjamin from JMP Securities. Your question please.
Hey, good afternoon, guys. Thanks for taking the questions and, congrats on all the data. Maybe just a couple here. You know, in the combination, maybe this is for Dr. Monk, in the combination data with Bev, can you just maybe help set expectations in terms of how would, you know, Bev alone, you know, do in terms of response rates? You know, how much of an improvement is this? And in the three questions that you mentioned, right, could these agents be combined? Is there an opportunity less than 25%, and can you use, you know, this drug in patients that are refractory to Bev, should we be expecting that a Bev refractory patient would, you know, with just being exposed to Bev alone would be 0%?
Or is there, are there times when, you know, you might get some responses from being reexposed to Bev? I have a follow-up.
Thanks, Dr. Monk, would you mind handling this?
Yeah. Thank you. I don't know if we've ever studied single agent bevacizumab in bevacizumab exposed. We published in the Journal of Clinical Oncology in 2007, that as a single agent, it had a 21% response rate, again, in bevacizumab naive patients. I don't know if we've ever done that. With chemotherapy, there is activity of bevacizumab after bevacizumab, but I don't know if we ever studied it as a single agent. Good question.
Got it. Okay. And then just kind of, following up with the REFRAME study, what are the options that physicians have for investigator choice of chemo once you've progressed from platinums? And so... And, and how might, you know, I, I guess, what are the preferred kind of chemo regimens that one might use?
Dr. Monk?
Yeah. So in the study, there are four options. The same three that were in MIRASOL, the irinotecan, liposomal doxorubicin, topotecan, and a weekly paclitaxel. And in our study, we've added gemcitabine. The reason is because, you know, those agents are not gonna work after failing. We wanted to make sure that we could enroll a broad population rapidly. Weekly paclitaxel is the most active, and but we again, once you fail that, you generally don't get it again. Topotecan is the least active, maybe as low as single digits, and then liposomal doxorubicin is intermediate. I'm not sure I answered your question, but those are the options. They're universally poor.
I think if you look at the control arm of MIRASOL, which was presented at ASCO and now it's been published in the New England Journal, 41% of those patients did get weekly paclitaxel, 'cause that is sort of the preferred, but the rest of the patients probably had failed it. The other challenge with weekly paclitaxel, obviously, is the schedule, weekly. The neuropathy, obviously, and so if you have neuropathy, you shouldn't get it either, and then the universal alopecia. So it's a complicated algorithm, and you could say, "Well, maybe we should compare to one of those." It's just not realistic. Patients, you know, don't wanna lose their hair. Patients have neuropathy. Patients have failed some of those agents already, and so that's why these trials are designed like they are.
Got it. And Dr. Monk, you know, you mentioned that the patients, you know, come in and they're very symptomatic. What kind of symptoms are these patients kind of coming in with? And how does that compare with kind of the toxicities that come along with the treatment? Does one kind of replace the other so the patients don't really notice a difference? Or is there a significant decrease in the symptoms that they come in with, and the additional toxicities that you're getting are the patient actually views that as an improvement?
Yeah. That's so they're different. And most of ovarian cancer spread is intraperitoneal in the abdomen and pelvis. Most of that is associated with GI dysfunction, nausea, vomiting, constip- you know, obstipation, and then there are some effusions, ascites, effusions not only in the abdomen but in the chest. That's what had happened. So if you look at the patient-reported outcomes in these studies, they basically all show that these patients have abdominal symptoms. And, you know, that's what we're trying to lock down. And again, so if you don't give growth factors in this example, okay? If you don't give a good dose of the best dose, whatever that might be, then the patient has a bowel obstruction, progresses, and comes off study. And that's what has happened universally in 40%-60% of patients.
So that's what we're trying to prevent.
Excellent. Thank you very much.
Yeah. Thank you.
Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Bill Newell for any further remarks.
I wanna thank everyone today for listening in on our Luvelta forum. I hope this has been instructive, and we're really excited about the potential to showcase all of this data in one place, because this really is an opportunity to treat a wide array of patients with cancer. We look forward to the future development of this molecule in our registration-directed studies, REFRAME-O1 and REFRAME-P1. Thank you again for attending today. Thank you, operator. We're done.
Thank you. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.