All right, let's just continue right away. Welcome. So again, as I mentioned, the next company is ADC Therapeutics. And it's my great pleasure to welcome the CEO here, Ameet. And so, ADC Therapeutics is in a unique situation where you have an ADC platform and a product approved that's on the market actually, ZYNLONTA. And so just remind us, you know, ZYNLONTA, you know, what are the sales that are sort of being generated right now? How do you think about the opportunity for the drug?
Okay. Yeah, thanks, Michael. Good to see you. Yeah, so for ZYNLONTA, we're currently approved right now in third line and third line plus DLBCL. So it's a late line product. There's about 6,000 patients in the U.S.. Last year, sales were about $70 million, and we think the peak opportunity in that late line setting is $80 million-$100 million. But we have multiple opportunities to expand into earlier lines of DLBCL and into indolent lymphomas. So the two specific ways we're doing in terms of getting into second line and second-line plus DLBCL is, one, a confirmatory study that we have called LOTIS-5. This is a 350 patient plus study, randomized study. It's a pivotal study since we got approved via accelerated approval, which will move us into second line. That triples the patient population.
We'll also expect to see longer duration of therapy. So in total, we think the total opportunity then increases to about $250 million-$300 million. That study is gonna complete enrollment this year and should read out by the end of 2025. That will take the company, at our current cost expenses, towards break-even or even profitability. The even bigger opportunity is our LOTIS-7 study, where we have a clinical collaboration right now with Roche on both of their bispecifics, so with Ro- with glofitamab and with mosunetuzumab. We're currently in a dose escalation, where we're escalating ZYNLONTA at three different doses, two arms combining with both of the bispecifics.
We can talk about the data later, but if, depending on the profile of the data, where we believe we have the chance to improve the efficacy of the bispecific, but also the CRS profile of the bispecific, we think that could take the total peak opportunity of ZYNLONTA to somewhere between $500 million-$1 billion. In addition, we have different IITs going on in indolent lymphomas. At ASH, there was data presented in an oral presentation that showed in high-risk relapsed refractory lymphoma patients an overall response rate of 96% and a CR rate of 85%, which is extraordinary, given that most of these patients were POD24 patients. That's a trial, that's a 100-patient trial that's ongoing.
Depending on if we have to go down the regulatory pathway or we could potentially go down the guideline pathway, that's another potential opportunity. And finally, we have a 50-patient marginal zone study, single agent ZYNLONTA, where data will be shared from the first set of patients in the futility analysis in the second quarter of this year, and then more mature data when the 50-patient study goes on. That, again, is an opportunity both potentially to look at registration, but also we believe there's a NCCN guideline opportunity there.
All right, so let's talk about some of those things. Maybe first on ZYNLONTA, sort of DLBCL, especially third-line DLBCL and perhaps also second line, is pretty crowded space. So there's CAR T, there's other antibodies, there's bispecifics coming in as well. So how is the drug being used right now relative to those other modalities, and how do you think that LOTIS-5 study, which is in a second-line setting, if that's positive next year, how could that change things?
Yeah, maybe I'll just start with the landscape in DLBCL because I think then the positioning of where we are today and where we're gonna go will make more sense. You know, the frontline DLBCL, there is a clear standard of care, which is either R-CHOP or Pola R-CHP. Whether you're treated in an academic center or in the community, you're gonna get the same basic therapy. But once you move beyond frontline therapy, there, the deviation between academic treatment and community treatment varies quite a bit. So in the academic centers, in second line, where you see 35% of the patients getting treated, the majority are gonna get a CAR T. So we estimate in total, you know, 20% of patients roughly are getting a CAR T. And you see that sales are starting to plateau with CAR Ts right now in DLBCL.
If you look at the sales evolution over the last year, they're basically flattening out right now. For the 65% of patients who are not getting treated in an academic center in the second line, there's a huge unmet need. Actually, R-based therapies represent the biggest portion of the share, and the, you know, the, the current response rates and efficacy that you get is not very good. So there's a clear room to improve. That's where we think LOTIS-5 can play, clearly play a role by adding ZYNLONTA plus rituximab. When you get to the third line, similarly, you see bispecifics playing a big role in the academic centers, but have made, I'd say, very limited roles, inroads into the community.
Outside of larger, more sophisticated centers that have hospitalization that could deal with CRS, especially high grades of CRS, which, although rare, can occur, that really limits the uptake in the community. And again, there's no real clear standard of care in the community. Today, we see our use kind of split between academic and community use, but we're also approved only as a single agent. Most things outside of CAR T and bispecifics, most regimens are combination regimens, and there's a big push towards moving to novel combinations that avoid systemic chemo. That's really the push, is to get into those regimens. And so with LOTIS-5, we believe we'll not only expand the second-line setting, but actually gain share in the third-line, third-line plus setting as well.
So talk a bit about the LOTIS-5 study. So that will read out next year, presumably. What, you know, what gives you confidence and, you know, success there, and what outcomes do you think would be necessary to really drive significant uptake in the marketplace?
Yeah, so I think what gives us uptake is, first of all, in the late-line setting, we saw response rates of 50% and complete response rates of 25%, and that's in late, late line DLBCL, where we had heavily pretreated patients. We had our safety run-in data from our phase III study. The first 20 patients' data was shared last year at SOHO, which showed an overall response rate of 80% and a CR rate of 50%. The standard of care right now, if you look at what's approved, is typically in the 30%-40% range. Even if I look at newer therapies like mosunetuzumab and other therapies that are coming out, they get to maybe around that 50% range.
So we're basically, the profile, if it holds with what we've seen so far, will be as competitive with as anything that's out there, plus that's gonna be out there. And it plays along with what physicians, especially in the community, like to do, which is they like to recycle rituximab-based therapies post R-CHOP between the front line and second line. That's a big. So we're playing along with where doctors like to go with an efficacy profile that's as good as anything that I've seen either approved today or that we expect to be approved in the future.
Okay, super interesting. And then, yeah, so LOTIS-7 sounds a very interesting trial as well, and I know you've talked about it a lot. The study's ongoing, so talk about the opportunity there and some of the data that we might see later this year.
Okay. Yeah, so as I mentioned, we're combining with both glofitamab and mosunetuzumab, so there's two distinct arms in the dose escalation. ZYNLONTA is a highly potent ADC. It's got a very potent payload, so our dosing that's approved as a single agent is 150 mcg per kilogram. It's very low dosing. But we actually know that the compound is active even at much lower doses. So we're testing three different dose levels of ZYNLONTA in combination with the approved regimens of glofitamab and mosunetuzumab. So we're testing the 90 mcg, the 120 mcg, and then the 150 mcg. We recently announced that we've cleared the dose escalation for the first two doses, and we're now currently in the last dose escalation.
We expect to share safety data from the dose escalation in the second quarter of this year, and then more mature efficacy data as we go into expansion in the second-line setting in DLBCL later this year. What we expect to see is, you know, ideally, a lower CRS profile, particularly in the glofitamab arm. We're dosing the ZYNLONTA a week before the step-up dosing with glofitamab. We know that glofitamab has about 70% CRS rates, including a small percentage which are Grade three and Grade four, and that keeps this, for the most part, out of the community. And that leads to, you know, most community doctors not feeling comfortable with that safety profile. So we believe, and what we've seen so far in our dose escalation, is that the majority of the patients either aren't getting CRS or they're getting Grade one CRS only.
So if that profile continues, that's gonna help bring bispecifics more into the community setting, which is where the majority of patients are treated. In addition, if you look at the third-line setting, the two most powerful agents approved right now are the bispecifics and ZYNLONTA. So we expect to see increased efficacy also over the bispecific alone. So we can improve the safety profile and improve the efficacy profile. We believe this becomes the standard of care for non-CAR T patients in the academic center and for basically all patients in the community.
And so you mentioned this 50% complete response rate bar, sort of in a second-line DLBCL setting. Is that right? So what are your expectations for the combination? It's kind of unusual to combine, I think, a bispecific antibody with an ADC. I don't think it's been done before. So what are some of the expectations there for, you know, a positive outcome, and then what would your next steps be for that?
Yeah, so I think when you get to the second-line setting, we would clearly like to see north of 50%. You know, ideally, if we get closer to 60%, I think that would be a transformative therapy. If we get to that level of efficacy, there's nothing out there that... that actually starts to approach closer to where CAR Ts are, especially if you see good durability. One of the rationales is, for doing this, is we're giving ZYNLONTA also on a very fixed duration. So we expect in LOTIS-7 as we move into expansion, it'll be fixed at six-eight cycles. So this isn't a long-term therapy, but we know that the speed of action, where you see, you see responses already in the first week of giving this drug.
By reducing the CRS, by getting, you know, tumor shrinkage and having a synergistic effect, we hope, with the bispecific and then having the durability of the bispecific, that will continue for the 12 months duration that you see in glofitamab, we think there's an opportunity to improve the profile.
Right. And so this is coming around ASCO, is that right?
Well, we expect to share the dose escalation data sometime in Q2. We haven't disclosed where. And then, the efficacy data from a dose expansion, because we're, per the protocol, we're gonna move from... Right now, we're testing the dose escalation in heavily pretreated patients. These are not only third line, typically fourth, fifth, sixth, seventh-line patients. But as we move into dose expansion, it's gonna be focused on glofitamab and ZYNLONTA in DLBCL and moving into the second line, and second-line plus setting. So it's gonna be earlier line, more representative of the population we want to go after. We expect to share efficacy data that's clinically meaningful by the end of this year.
Okay. Then you mentioned the marginal zone lymphoma data in the second quarter as well. Just remind us, what's coming here and what, what should investors be looking for?
Yeah, so marginal zone, you know, it's a smaller lymphoma, but it's one that's really high unmet need. If you look at the best response rates of any therapy that's approved in marginal zone lymphoma, it's about 29% CR rates, but there's really high unmet need. Most things that have gotten used in marginal zone lymphoma have typically been about 50-patient studies that have been, when you show an improvement, incorporated into NCCN guidelines. So we do have a 50-patient study that's ongoing right now. The futility analysis was set at 19 patients. We expect that to be hit and the data to be shared in the second quarter. This is a monotherapy ZYNLONTA study, so that'll give, I think, an indication of where that study is, and then the total of 50 patients is currently enrolling right now.
Okay. Then real quick, you have another ADC in the clinic, your AXL ADC. Just remind us, again, where you are in the phase I study and if we see any data this year?
Yeah, so AXL is a target that's overexpressed, you know, in tumors like sarcoma, pancreatic cancer, non-small cell lung cancer. We started doing the dose escalation in sarcoma, just given the high levels of AXL expression. While we were validating and finalizing our biomarker assay, it was a good way to work in an unselected patient population. What we've seen as we've gone through the dose escalation is in, again, heavily relapsed refractory sarcoma patients, where typical overall survival may be three-four months in these patients, we've seen tumor shrinkage in a number of patients, and at the dose level that we selected, we saw two PRs as well. So that was a clear sign of clinical activity. We're expanding in sarcoma. We also recently announced that we're starting to screen in pancreatic patients.
This will be an enriched population using our biomarker, where we're looking at high and low expressers of AXL. Then finally, we're gonna move into non-small cell lung cancer. This will be a very selected population of high expressers in AXL. We'll be looking at these agents as monotherapy, but also in combination, and we expect to generate substantial clinical data this year.
Okay, so looking forward to that. And lastly, I know you have, so this is your basically legacy ADC platform, right? Which is DNA-acting payloads. I know you've recently started working on new, a new platform technology in the ADC space. Just talk about that real quick. What are you trying to do there?
Yeah, sure. I mean, we have, I would say, multiple ways in which we've been able to manipulate the antibody, multiple linker technologies, conjugation technologies, and of course, payloads. One of the more advanced ones is a exatecan-based payload. We know DXd, how potent it works, but there's clear advantages that we've seen preclinically, where we're generating a therapeutic index of 12-15. We're seeing clinical activity right now with our exatecan-based payload, which uses a very novel hydrophilic linker, so that combination is patented as well as, you know, patents on all the different molecules we're going after. We're seeing clinical activity at the low single-digit mg per kg level, and we're seeing safety that goes up to 40 mg+ per kg.
We've also tested three of our compounds in monkeys, and we haven't seen any signs of ILD, which is one of the, you know, downsides right now of the DXd platform. We're seeing higher potency, higher bystander effect. So this is playing out now in four different targets right now that are at or near the DC stage, and, you know, once you get to that stage, it's about 18 months to get to IND.
All right. Super, super exciting. So thank you so much, and I'll... I think the next company is Mineralys.
All right. Thank you.