Welcome, everyone, and welcome from Chicago. We're broadcasting live from the NRG-GOG meeting. So it's great to actually have one of these meetings in person for the first time in a few years. So it's great to be here. My name is Rob Coleman. I'm a gynecologic oncologist in Houston. I serve as the chief scientific officer for US Oncology Research, but really serve as the president of the IGCS. And we're so happy to be able to have this opportunity to speak with these two wonderful experts. IGCS is committed to providing meaningful opportunities to our industry colleagues, and we're so great to have this great partnership and support from Immunogen, who's brought us together to talk about this important topic today, which is on folate receptor alpha and folate receptor alpha targeting. Obviously, this is a very exciting new era for us, and today, we're going to spend a little time talking about precision medicine. What is this target? Antibody drug conjugates. What's the preliminary data? Why are we excited this time of year as we hope for the impending approval? Talk a little bit about our clinical experience so far, and we'll hit topics such as the efficacy and toxicities. And then kind of future directions. I think most of us, once we say, OK, well, that's good. What do you got for me next? And so our hope is that we'll be able to share with you where this development program is going and the space and how it's expanding for our patients, which is obviously where we want this place, where we want this field to move. So I'm going to go ahead and have my two distinguished colleagues introduce themselves. Katie, I'll start with you. Tell us a little bit about you and what you do. So thank you for having me, Rob. I'm Kathleen Moore. I am a genome oncologist. I serve as the associate director of clinical research and director of phase one clinical trials at the Stevenson Cancer Center in Oklahoma City. And I'm the GOG partner's associate director with Tom Herzog. And so that's what I do. Domain to this conversation, I'm the international PI for the Mirasol study, which evaluates mervitoximab in the platinum-resistant space. So I'm excited to talk about that. And I'm really excited to join you in New York City for IGCS in person in a few months. Absolutely, absolutely. That's great. Dave? In person. In person. Hopefully. And I was happy to hear that Chicago is a place you can get here by plane nonstop. One place out of Oklahoma City? Yes, it's one place. It is one place. Traveling these days seems to be a little bit challenging. And I can get to New York. I will get to New York, yes. My hook or my crook, I will get there. Good morning, good afternoon for our European colleagues and good evening for our Far East. Dave O'Malley, I'm from the Ohio State University, the Ohio State University in Columbus, Ohio, where I am so honored to lead the division of gynecological oncology. In GOG Partners, we have a series of advisors that are each one of our disease sites. And I have the honor of leading ovarian cancer. With regards to MIRV, I owe so much to Katie. Katie introduced me to immunogen for their first in-human trial eight years ago? Yeah, about eight. Eight years ago. In our phase one program. So Katie introduced me to immunogen. I'm proud to have enrolled in the first in-human trial and now lead the phase three trial in MIRV plus Bev and platinum-sensitive ovarian cancer, which is just launching now, as well as the PI-442, which was the trial which looked at a series of combinations of MIRV plus additional agents. So a lot about what we're talking about today from some of the things I'm bringing in really is, can we combine MIRV with other agents? Exactly. But most excited to talk about what Soraya and oh my gosh, how soon are we gonna hear about Mirasol, Katie? Quarter one. All right. Quarter one, 2023. Yeah, okay. So it's awesome. Well, I know you guys are not passionate about this field, I can tell that, but I'm hoping to raise the energy up here so we could really get this thing going. So thanks so much for both of you joining. We talked about, or we started to introduce this idea of precision medicine. It's kind of a broad term. We've used it for many years. And Dave, maybe you can start us off by maybe just giving us your thoughts of what is precision medicine to you and why is it important? I think in ovarian cancer, but we're really identifying the right treatment for the right patient at the right time, okay? The right treatment for the right patient at the right time. And how are we doing that? We're really now not just looking at the germ line, genetics, which, thanks to Katie, great work in Solo One, we identified how important that the genome, that the gene changes were, but now we're looking at the somatic or the tissue changes, knowing that those are separate. And so from when we tried to identify the agents which we need to utilize, it's not just taking lumping. Remember in the NRG, we used to lump everything, right? We're taking out the groups which are so important to identify who should get PARP, who should get hopefully new antibody drug conjugates, okay? And taking that at the right time. Now we need to figure out what the right time is in some of these agents, right? Definitely, so Katie, this idea of targeting folate, we've done for quite a bit of, number of years, right? Methotrexate, so thinking about folate metabolism, it's been, there are a lot of drugs that have gone through that. Why are we so excited about folate receptor alpha? And maybe you have a high level thinking about how that's different from the other folate transporters and such. Well, folate receptor alpha is distinct from the other folate transporters. It's really not involved with normal folate metabolism, number one, which is why you don't have to replace folate and do all the things that we do with methotrexate. It is almost, you can almost say it's ubiquitously expressed on at least high-grade serous ovarian cancer. Now the amount changes, but it's there like 80 plus percent of the time. And it's a target that internalizes what binds to it, which for antibody drug conjugates is key. If you have a tumor expressing antigen that's just on the surface and you bind to it, then you're kind of relying on ADCC sorts of mechanisms for cell death. But when you can internalize a molecule, as you can with folate receptor alpha, and not just a molecule, a big molecule, you can kind of use that like a Trojan horse to sneak in some kind of, here a payload of cytotoxic, but even other things in the future to try and deliver either more effective or more potent or both therapies to that cell. So it's a way of targeting whatever therapeutic you're using, hopefully directly to the cancer cell. And the important thing, this is true across all antibody drug conjugates for the target for the tumor expressing antigen is you want it to be either solely expressed on the tumor or so overexpressed on the tumor as compared to normal that you don't really get normal uptake of the delivered payload. Increase that therapeutic window, so to say, yeah. Yeah, and so you get that with folate receptor alpha, it kind of hits all of those tick boxes as an ideal target for ovarian cancer. We've known this for a long time. I think it's just taken us a bit to get to the agent that is gonna finally get approved. Right, so you're, we had a great opportunity at the Winter SGO meeting to talk about ADCs, a whole session built on that. And we spent a lot of time talking about what an ADC is. So for those, I just wanted to take this moment to also remember online, for those of you online in the chat or the Q&A, please send in your questions and they'll send them to me by text and I'll ask our distinguished experts here. So don't be afraid to send them in. I'll try to remind you in 20 minutes or so and then we'll try to get to those questions at the end. So at the SGO meeting, we had a fantastic session and Katie, you, I think we're charged to talk a little bit about the structure of an ADC. We know that these molecules can be used as a ligand to deliver and they can be an antibody to deliver to the tumor. So tell us a little bit about what the general structure of an ADC is. And I think, as you mentioned, we've seen an acceleration of development and we've gotten smart with the chemistry, but what is that? What are the components, ADC? And then I'll ask Dave where we've seen this to start to enter into the clinic. So ADCs are antibody drug conjugates. And so they kind of start with an antibody that's right now targeted to one target, although in the future we could potentially see bispecifics, we're already seeing some bispecifics but not conjugates yet. But right now for antibody drug conjugates, they tend to be solely one antigen, so one protein that they're going after. So you can picture them, I tell patients to picture them kind of like an arrow. And the head of the arrow is targeting, what we just talked about, the tumor-associated antigen that we've identified and there's a number of them we can talk about. Today we're talking about full receptor alpha. And then the antibodies there. And then on the feathers of the arrow, you have conjugated these highly potent molecules of chemotherapy. And so these are not, it's not Paglitaxel, it's not PLD, it's not gemcitabine. These aren't just we're sticking normal chemotherapy on the tail. These are highly, highly potent agents that are way too toxic to give as, they're real active, but they're way too toxic to give as free drug. And so, and they're active on sort of the nanomolar level. And so you can conjugate a few molecules onto the structure. And how many you put on there, you'll see something called the DAR, the drug antibody ratio. So most antibody drug conjugates have a DAR of like three to four. So you want to be kind of even in that delivery. There's newer in development antibody drug conjugates that are trying to put more molecules on and we'll see if that is more effective or more toxic. So we'll have to see. So that's the basic structure. It's targeting to a tumor-associated antigen that will internalize that molecule. It's got the payload on the feathers and they're linked. They have these linkers that are really remarkably engineered to be stable in circulation. So if this thing doesn't hit the target, you just pee it out and there's no free drug, right? So, but when you get internalized into the lysosome, then it gets broken down, the linker releases and the payload will take out that cell. It's like a smart bomb. Or Trojan horse. Yeah, or Trojan horse, yeah. And then you kill the cell, hopefully. Now the cell still has to be sensitive to that chemo. So that's the little kind of thing. It's targeted, but it's still a little empiric as to whether or not this cancer cell would be sensitive. If we can solve that question, that would be unstoppable. But it kills the cell and then some, almost all the antibody drug conjugates have some degree of bystander effect. So even if the surrounding cell maybe doesn't have as much foliar receptor alpha or didn't have a molecule bind to it, some of the, in this case, DM4, which is the cytotoxic, it's a metazanoid cytotoxic, will get into that next cell and take it out as well with really minimal release of free drug. There's little, but really minimal release of free drug into the circulation, which is why for most of these agents, you see a very differentiated safety profile as compared to other systemic chemotherapies. So Dave, there's like five components in, right? So you have the target, you have the antibody, you have the linker, the warhead, and then you have the endogenous chemosensitivity, right? So those are the things, the five components that would be a successful delivery. Yeah. And then we have the bystander effect too. Right. It's really kind of a sixth component. Now the bystander effect, we aren't completely able to predict also because of the active agent. But again, we have, in this instance, antimicrotubulin. So we have a mechanism actually well known to us like paclitaxel, right? Which is highly active within this drug antibody conjugate that we can't give as free drug because it's too toxic. So we're delivering it locally. You know, as I think of this, so antibody, linker, payload. The DARS and things like that, for most of us, we're not really worried about that. We just want to know if the drug works and how toxic it is. But it's important to understand, right? Exactly. So that's, so the, so one of those components was the, we talked about as the target. So, and you mentioned it was ubiquitously expressed. So what does that mean, Dave? And how do we know if we have it? Yeah. So, you know, we have about 80 plus percent of ovarian cancer will express folate receptor. One of the things that we learned about in FORWARD-1 is we have to have a high level of expression. Uh-huh. To have, FORWARD-1 was what? Maybe just explain, Phil, yeah. Great point. Well, I, I have the PI here. I'll let Katie explain FORWARD-1. You can explain my study. Okay. It's a general design. It's just what it was, just for the audience. So they may not be familiar with it. FORWARD-1 was the randomized phase three study that evaluated Mervituximab versus physician's choice monotherapy chemo. So it was Paclitax, weekly Paclitaxel, PLD, or Tobutican in women with tumors that were considered resistant to platinum, one to three priors, and you could or couldn't have prior PEV, it was a stratification factor. And FORWARD-1 enrolled women with tumors that were considered folate receptor alpha medium or high, and unfortunately failed to reach its primary endpoint because of some difficulties with how the tumor was forward. Right. And so that's why we went to high. But I will say, it works in medium, and someday we'll get back to it. Exactly. I was gonna say the same thing. It works in medium. This is a spectrum, right? Yeah. Exactly. You don't have to be high. It's not a bimodal. But right now you do. It's a bimodal distribution. Right. It's a continuous variable. Yeah. Right? And it works most effectively at the high. Yeah. Okay? But we see activity going back to the original trial in low, medium, and high. Now we haven't really tested those that don't express, which is less than 20%, right, 10 to 15% of patients. Yeah. It is effective in those patients who have the folate receptor alpha. It's most effective in folate receptor alpha high. Mm-hmm. So just for the audience, when we talk about this expression and stuff, how do we measure it? Is this like a, is this a next-gen sequencing? Or is this a protein test? Great question. What is it? And I'm gonna back up a little bit. Okay. Because Kate and I have, and all of us have talked about this a lot, right? Is when are we gonna test this? Mm-hmm. Okay? So currently I have a patient diagnosed with advanced ovarian cancer. Early, I don't do it. Advanced ovarian cancer. I get their genetics sent off. Mm-hmm. I have diagnosis now. You know, it used to be, well, let's wait. We don't wanna overwhelm them. No. They come in, I have them. I have the opportunity to have genetic counselors embedded right in my clinic. So I'm spoiling those ways. But now I've gotten comfortable with ordering the genetic test by myself. Okay? Then I take the biopsy, if it's laparoscopic or with regards to our interventional radiology, if I'm doing neoadjuvant, making sure I get cores on those, I send it for somatic testing. So I get my HRD test, I get my somatic testing. I sometimes order next-generation sequencing on the tumor at the beginning. Yeah. Or if I'm taking the operating room for a primary tumor-reductive surgery, okay? When am I gonna send folate receptor alpha? Or NAPI 2B? What are you sending it for? That's a... Looking at that expression. So protein expression. In the IHC, right? Protein expression. So it is an IHC. I hope we'll actually be able to do this locally. But with our commercial vendors, where I send the next-generation sequencing, that's another option. So we'll ask for, what is the folate receptor alpha positivity? At the time of diagnosis, now we're gonna have a lot of patients out there who are eligible for MIRV, right? Who we didn't know about folate receptor alpha at the time. Yeah, right, exactly. So in those patients, I'll send it upon recurrence, okay? So germline, somatic at diagnosis, and now folate receptor alpha expression. Immunohistochemistry tests that will be available through commercial vendors and maybe even locally. Right, so we can test it like estrogen receptor or something like that. So Katie, you mentioned in 4-in-1 something about the differential and expression, and that there is this continuum of response to expression. So in, how are we, now that we've kind of retooled and brought this back forward in Soraya and Mirosol, what are we? I'd look back forward. That was, oh, yeah, you like that pun? Yeah, I didn't even catch it. Okay, I'm here all week, you know that. Good to your servers. So what were we looking at? What are we looking at for eligibility? Let's, why don't we start there with Soraya and Mirosol. How do we change that eligibility? You said we went to the highs and the mediums and stuff like that. How do we, first, I guess maybe I should say, how do we know if it's high? What are the components of that? So the differences were, so it's based on immunohistochemistry. The original hundreds of patients that were evaluated in the phase one cohorts were looked at by something we call PS2, which considers both the percentage of cells that are positive plus the intensity. And that's how we determined folate receptor low, medium, and high. And the medium and high in that scoring system appeared to benefit most. And so when we moved into forward one, there was an effort to make this, what we call a companion diagnostic, or CDX, a little bit easier for the community to do. And so there was a bridging study done that appeared to show that you could just look at the percentage of cells under 10X magnification and that would be equivalent. And so that's what was done in forward one. So it wasn't that the assay changed. The assay that we're using to mark the protein was the same. It's just how it was scored. And what we discovered in forward one is that there was quite a bit of shift. So there were about a third of patients enrolled who probably were not eligible. So that dilutes your end point. Because it really doesn't work well if you don't have folate receptor alpha. And then there were quite a number of patients who were medium expression in the high group. But even so, I will say, I think you have to just remember that even with that, in that high group that was half diluted by medium, it was still, if we had done a different statistical analysis which is beyond this discussion, it was still statistically significant. I know how passionate you are about that. I know. It's not that it didn't work in that group. It actually worked. It's just how, aren't we just kind of armchair quarterback forward one all the time and it's not worth doing other than it informed how we did Mirosol. So I just want to emphasize that because I think you'll see coming forward, not back, that we will probably include women with folate receptor alpha medium expression tumors in some upcoming studies. And the reason for that, especially when you're combining it for Dave's work with other agents is that it is a biomarker for response. But for our studies, Soraya and Mirosol, for a lot of reasons, we focused just on the folate receptor alpha high by the old assessment intensity and staining. And so you have to have greater than 30% of cells staining, you know, two or three plus, to come on. And there's been a lot of training for how that is scored. Maybe we went a little too far because it was a little more precious of an end point than we expected. But both studies were completed and in record time. So that's where we are right now. And that's why the studies were redesigned just with the high or starting to include the mediums back in some additional studies. Yeah, before we get into the studies, I just wanna highlight that this, I think we talked about it in the beginning, that full receptor has been, or full receptor alpha has been on our radar for many years. We've had other agents that have targeted it directly, thinking that it was important for cellular function. And I think those, we learned through a series of trials, that's how we generate hypotheses. We develop studies to address the hypotheses. And then depending on what happens, we make an interpretation. And so we know that from the previous studies of targeting full receptor alpha through an antibody alone, didn't really impact therapy. And we spent a lot of time working in that space. So, and now there are a number of drugs that are, Mervitux being one of them. But there are a number of, this particular target as an ADC target seems to be important. And I don't wanna not mention that there are other, this is a focus for other potentially delivery systems that are out there and being studied right now. But obviously Mervitux being the most mature for this long, and we have the most data for right now. So that's exciting to talk about. So you mentioned, we've talked about two studies so far, Mirasol and SREA. We have data from SREA. Why don't we dig into that trial a little bit? And Dave, maybe I'll start with you. Tell us a little bit about what that studies, how it was set up with the eligibility or whatever. I think we need to flip. I think I need, can I just- I'm answering the questions. Wait a second, let me moderate. Hey Dave, tell me about- As you know, I'm a much better moderator. Tell me about the study that I did. Okay, why don't we do this? Why don't you tell us about your trial? So, no, I'm the moderator. I get to ask you guys the easy questions. So SREA was set up as a single arm phase three trial, which is kind of interesting terminology, to look at the efficacy in a population that Katie just mentioned, right? And our patients was one to three priors. You know, we had required that these patients had had prior exposure to Bevacizumab. Required Bev, one to three priors. One to three priors, right? And if they BRCA tumors or BRCA expression, they should have had a PARP inhibitor. So some important elements that defines that patient population. But the key was is that we were trying to learn on the expression data and the efficacy. And I think it's really important to go back to that point, that this is a continuum of response. We know this drug shrinks tumors, right? So what we were trying to do was to identify the patients that we thought would benefit the most so that we could discriminate the efficacy of the drug versus what we would normally use in that patient population, right? And, you know, which would be, we expect to be a very relatively low number, right? So it's interesting because, you know, I think we've always said, oh, it's, you know, 15, 20%, the response rates in platinum-resistant ovarian cancer. What we're finding on the contemporary treatment paradigm, which is continue to use platinum until patients become refractory or not eligible due to hypersensitivity, okay? So it, you know, this, while they recur within six months, they're not gonna go back to platinum, probably applies in the first-line setting with regards to lower response rates. But in the subsequent settings, we now are going forward. And the, you know, we have the ESGO guidelines, ESGO guidelines, and our European colleagues who just continue to utilize it. And most of us are doing that in the U.S. So when we look at the contemporary trials outside of weekly paclitaxel, outside of weekly paclitaxel, which I think is a fantastic regimen, our response rates are about 10% plus or minus 3%. 10% response rates, platinum-resistant ovarian cancer. So, you know, if we have 10% and we're setting up a trial, that lower level confidence interval, that 95% confidence interval, we really wanna be at about 25%. So when we're looking at agents, which we, you know, every day, we're not even really excited about an agent unless it has a 25% response rate, because the contemporary treatment at best is 15%. Outside of weekly paclitaxel, which is probably closer to 30%. Yeah, well, that was, you know, kind of a key component, right? Again, so we're setting up these trials to isolate a treatment effect in a population that we think that we commonly see. And so that's why this becomes a clinically relevant trial to try to do in a patient population that would inform potential future therapy. So this was deliberate. I mean, I think that's what, as trialists, you know, as part of the GOG partnership, we try to design trials that are informative, that reflect the patient populations that we hope to treat. So we have this patient population with recurrent, you know, documented platinum-resistant ovarian cancer tumors, and we're trying to see if we can do better than what we would otherwise use off the shelf. Before we get into the, maybe a little more of the details, you mentioned that 10% kind of background response rates. Is it, does it matter in folate receptor alpha-high? This is a tough, tough question. But in the folate receptor alpha-high, is that a prognostic factor that chemotherapy would work worse or better in? So this was a really important question, right? And it's a really important question on all our anti-drug conjugates. Is the marker, is the antigen a prognostic indicator? So we talked about this a lot going back to the very first trials, and there was some data that wasn't very strong that it was a negative prognostic indicator. The same thing could be true where it could be a positive and the patients are doing so much better, right? Well, I forget where you presented that, maybe an SGO or ESMO. When we looked at the chemotherapy arms in those high folate receptor alpha, and those with high folate receptor alpha actually did worse. And we now have that in prospective data. I don't think that's been published yet. In prospective data that shows high folate receptor compared to others actually has a worse prognosis. So in this instance, raising the bar even higher into the challenges we face with the low historical response rates of 10%. So it's probably closer to 7% in a high folate receptor alpha. And we have that with some data from Forward One. So that's, and you know, obviously in Serea, we were very excited to see the 32% response rate and the lower limit of the confidence being around 24%. So, I mean, that's a, for us, yeah, we had a lot of smiles when we saw that because we know that we were finally seeing what we were, you know, collectively as a result, what we were seeing in the clinic, which is that it was shrinking tumors. But everybody said the median progression of free survival was so low. Yeah, right, exactly. So, you know, when we have these patients, we know that most patients in platen-resistant ovarian cancer are gonna come off at the first or second disease assessment. So we really need to look at those curves separated beyond that, because the curves are pretty similar up to that point. You see some separation, but the true separations are those that have a response. Right, and the duration of response was meaningful, right? Katie, I mean. Yeah, it was seven months. Seven months. But I mean, I think just to go back to that point, I think we can't really comment on PFS in a single arm study. Exactly. It's just irrelevant. And so it will come to, we have to wait for Mirasol. Because I do believe it's a negative prognostic marker, and we'll prove or disprove that in Mirasol. I think we'll prove it. And then I think we'll have a benchmark for that PFS. You can't really put that PFS in full receptor alpha high up against any sort of outcome or benchmark. So I get a little annoyed when. Yeah, when people focus on it. But it's to Dave's point, right? Because when you look at a total population, you're looking at those that have the target, don't have the target. And that's true. We do see a drop off in a large, at the first assessment cycle. So it's really misleading. And it's not really reflecting the activity of the drug. So that's why we spend so much effort on duration of response. Because once those patients are demonstrating a response, and actually, if you look at, if you include the stable disease, because when you make decisions for patients, when you're looking at their CAT scan, if they're coming in for treatment, you're not saying, well, you didn't respond, I'm gonna switch your therapy. You're gonna say, we didn't progress. I'm going to continue on your treatment. So when you combine those two together, then I think you're starting to see some real benefit. And that's hard, I think, to show, because it's a fuzzy clinical trial endpoint. But Dr. Matulonis presented at ASCO this year. And so if you can look at her poster, that would be great. The spider plots for, actually it was for looking at the different dose levels and just showing that there didn't seem to be a loss of efficacy by dose level. So that was a nice part of it. But you can see, I like to look at the spider plots because you can kind of just see folks tracking along and maybe they shrink by 18%, but they sort of track along for months and months and months and months. And they never hit that response rate. So they're not counted as an end point in psoria, but they certainly would be someone that, as a clinician, I would be celebrating that response or benefit or whatever you wanna call it. So I think that's a nice, you can look at that poster, it was just presented by Dr. Matulonis and it's a really good visual, I think. Well, and that's why I brought up the PFS, because a lot of people have talked to me about, well, PFS and platinum-resistant trials like psoria. And very important point, how do you differentiate that in a single arm trial? But really, it's not, when we start quoting median progression-free survival and platinum-resistant, it's not a valid end point. Even in, I think, in phase three trials. Now, it's a nice talking point, right? Well, here's your difference. But it's really looking at the magnitude of benefit, the hazard ratio in two-arm trials or three-arm trials. When you see that differentiation between the curves, we've concentrated in median progression-free survival, because in the past, it was, maybe it was more meaningful. It's a point on the curve, that's what I always say. It's a point on the curve. It's one point on a curve, not descriptive. I mean, it is only descriptive. It doesn't really tell us the meaningful impact of the treatment. So we'll get into that when we start talking about Mirasol. But so this single-arm trial, impressive response rate. Those patients who responded had a duration response of seven months, 6.9 months old. Pretty impressive, because you think about how many CAT scans that led to. And that's just the median. So you can see the curve of the time to, you know, progression in the patients responding was pretty flat, which is nice to see, especially when we don't expect them to have a response. So, so all rosy. So what, why are we, why don't, what was our, was there any concern for the, I mean, what is the, maybe talk about the toxicity profile, because I think that's important with all drugs. Berbatoximab has a very, what we call differentiated toxicity profile. So we actually have great data on that from 4-in-1, your beautiful comparison data to chemotherapy. So no alopecia, far less neuropathy than its appropriate comparator, which would be Paclitaxel, almost negligible hematologic toxicity as compared to chemotherapy, really just like very low grade, but, you know, compare like the, I wish I could show the slide, just, you know, almost nothing versus what you just normally expect with chemotherapy. And so those are all very much in favor of merbatoximab. And when you have women, people who have been treated with multiple lines of therapy, sometimes they're, they don't wanna lose their hair anymore. They have preexisting neuropathy. Their bone marrow is kind of beat up. And so they kind of come in with these marginal, you know, ANCs of 3,000 all the time, and, you know, nine hemoglobin and platelets are 105. And you're like, well, this is, you know, it's a safe drug to use there. But it does have toxicities. It's not without toxicities. You can't trust a drug that has no toxicity. So- It's like, yeah, we didn't record anything, yeah. It's all good. So the two main things are, you can see diarrhea with merbatoximab, but it's very low grade and it's very mitigatable. I know it's not a word. With over-the-counter medications. So no one came off for that, but you should counsel patients about it because you don't want them to get caught off guard. And then the kind of bigger issue is the ocular toxicity. And we presented this at ASCO this year, a kind of, I wouldn't call it a meta-analysis, but a pooled analysis of about 460 patients who've been treated at the recommended phase two dose for over years, cumulative, and then compared it to psoria. And so you'll see ocular disturbances in about 42 to 45% of patients who receive merbatoximab. It is dry eyes, blurry vision, up to kind of keratitis. It tends to be low grade, grade one to two. It is 100% reversible. We've not seen any long-term vision effects over time. And we have patients who've been treated on some of the maintenance studies for very long periods of time. And so we use eyedrops, preservative-free lubricating eyedrops and steroid eyedrops. And if patients have symptoms, that's one of the things when you're talking to a patient who's starting it, you just say, it's pretty common. Ursula, Dr. Matulonis will tell them it's 50%. I think it's kind of a conservative, it's 50-50. If you wake up one day, cycle two, day 15, is when it happens. Exactly on that day. On that day. And you wake up and you're like- It's gonna be a Saturday morning at eight o'clock. That's when it's gonna happen. I can't read the paper. Don't panic. Just call me and don't drive in. And I'm gonna tell you what to do. And they'll get better in a few days. Like it resolves pretty quickly. And sometimes we don't even have to dose modify. But we do have to have good ophthalmologic partners. Key, patients do have to understand the risk. And they do have to take the eye drops. And so it does require some expectation setting and having a good partnership so that you can keep patient's vision safe. But I think kind of the proof in the pudding to use a colloquial term is only less than 1% of participants across all studies of myelotoximab have discontinued therapy because of the ocular toxicity. And actually, in fact, less than 7% of patients discontinue myelotoximab for any reason due to toxicity. So when you think about all of the great agents that we are developing, a 7% discontinuation because of toxicity for any reason is really low. It's very low. I mean, if you think about it, just chemotherapy in general is so much different. Right, 1% for ocular though is very low. So I don't ever want to minimize it. Oh, it's not a big deal. It is a big deal. But it's reversible, it's low-grade, we have good mitigation strategies, and I don't think it should inhibit someone from accessing the drug. Right, and you know what? With the antibiotic drug conjugates, they're now TV-approved, right? So we have the approval in the U.S., accelerated approval for cervix cancer, another antibiotic drug conjugate. But I think it's really important to differentiate. We both have eye toxicities, but the eye toxicities are different. You see a conjunctivitis with TV, and they walk in, you can see it, their eyes are red, they're irritated. This is a keratitis, so it's not conjunctivitis. And so the complaints that patients have are the blurred vision, or maybe some spots and things like that. But it's really impressive, the consistency on the onset, cycles two, cycle two, that day, 10 to 14. And it's very consistent. And that's what's nice about the education with regards to that. Now again, take some mitigation. We've learned with TV to have our optho partners that are comfortable with these new agents, and helping us negotiate when our mitigation strategies aren't as effective. We're unfortunately getting the hook here to close out. We're running out of time. But I wanted to just mention that, obviously, we talked a little bit about Mirasol, and when we expect to hear that, just maybe, Katie, just tell us what the arms of that trial were. And then Dave, just want you to give us a brief snippet of, you kind of already mentioned the development plan with some of the partners that we're looking at, but maybe we'll close out with that, and then I'll wrap this up. So tell us a little bit, just the arms of Mirasol. Mirasol. Mirasol was a global trial. So thank you to everyone on this, what are we calling this, a podcast, or a tumor board, who enrolled. Thank you, thank you, from the bottom of my heart. Mirasol was kind of a take-two, a forward one with some significant differences. It was only in full receptor alpha-high, randomized phase three, platinum-resistant tumors, one-to-one randomization, tumor vitoximab, versus physician's choice chemotherapy, pegly-liposomal doxorubicin, paclitaxel weekly, or topotekin, given however you wanted to give topotekin. And then the endpoint was progression-free survival, or is progression-free survival, as measured by the investigator this time, which is a little different than forward one. Again, all in full receptor alpha-high. And we expect it to be a little different population, because more patients are going to be PARP-exposed. You had almost 50% PARP-exposed. That's very different than forward one. So we probably expect that in Mirasol. And Bevcizumab. And Bevcizumab. So Bevcizumab was not required, so it's a little different than SORYA, but it was a stratification. So that, we closed enrollment just a week ago, and then are anticipating top-line results in quarter one of 2023. Very exciting, very exciting. And Dave, obviously, because now we're so excited about this new agent, we hope to get in our hands very soon for, in the wild. So, and what's the development plan? So, I've always said- In the public domain, of course. I've always said, my goal is to replace paclitaxel, okay? Anti-microtubulin, hair loss neuropathy. None of our patients like it. We don't like it, right? So what are we doing? Platinum-sensitive maintenance gloriosa. So patients who have received a platinum doublet, are then, with Bev, are randomized to Bev versus BevMerv, based on the combination trials that we've done in 4WR2. Which, again, looks even more impressive, okay? We also are doing a single-arm trial piccolo, which is, look, I shouldn't say we, that Angeles Alvarez-Saccord, I think, is the PI of that, is platinum-sensitive for patients who are, that you're comfortable with a single agent. So Merv in those patients. And then, hopefully, we're gonna be able to start talking about in the future, moving even to the first line. That's what I'm hoping, right? I said, I wanna replace- And in different diseases. Pat paclitaxel, and in different diseases. We won't talk about that, but we're excited about the opportunities. Yeah, absolutely. Thank you, again, for this, all the time we have today. I do wanna thank Immunogen for their support of the session that made this possible. And, again, as I'll mention, again, just because you brought it up, but please, please, please come join us in New York City, October 29th, I mean, September 29th, October 29th, we're not gonna be there. We'll be in Berlin. September 29th to October 1st at the Javits Center. Go to igcs2022.com to check the website out. It's gonna be a fantastic program. I'm so excited. We have such a great lineup. Brian and you guys have done a great job. Yeah, thank you. And Audrey Sonota. So, it's gonna be great, and I'm looking forward to seeing you both there. And so, thanks again for joining us, and I hope to see you soon, live. Thank you, guys.

gynecologic oncologist

folate receptor alpha

precision medicine

ovarian cancer treatment

clinical experience

toxicity profiles

Mervatuximab

IGCS conference