All right, welcome to this fireside chat with ADC Therapeutics. My name is Michael Schmidt, biotech analyst with Guggenheim. And with us today, we have Ameet Mallik, CEO of ADC. Ameet, welcome. Thanks for joining us.
Yeah, thank you.
So just to set level set expectations here, could you just help us with a quick background on ADC Therapeutics, and then we'll go into Q&A?
Sure, yeah. So ADC Therapeutics is a specialized end-to-end capability company focused, of course, on antibody-drug conjugates. We're a commercial-stage company with one product on the market, Zynlonta, which is approved in the third-line plus DLBCL setting, a number of different opportunities to move that in combination in earlier lines of DLBCL as well as into lymphomas, and then beyond our focus there in hematology, we also have a very novel solid tumor portfolio focused on our exatecan payload.
Great. So maybe just starting out about Zynlonta and its sort of existing market, which, as you mentioned, is approved for third-line DLBCL for some time now. Sort of what are the key differentiating attributes of Zynlonta relative to other approved therapies in lymphoma, for example, bispecific antibodies, Pola out there, or perhaps even CAR-T?
Sure. Yeah, so I mean, Zynlonta, I would say, is one. It's a single-agent drug that's approved in the third-line plus setting. The reason I say single-agent is almost every therapy in DLBCL is combination therapy. And so what's already remarkable is, as a single agent, it has very strong efficacy, strong safety, and a strong accessible profile. So if you look at efficacy, 48% overall response rate, 25% CR rate, which is very durable, too, because those CRs tend to get there very quickly, mostly within two cycles, and then they tend to last very long. So the median duration of response for the CRs hasn't even been reached after two years. The safety profile, you don't have any of the irreversible toxicities that you get with chemo. You also don't have any of the ICANS or CRS that you get with bispecifics or CAR-T.
So the safety profile is very manageable, and it's a very easy outpatient infusion of just 30 minutes. So it's very accessible across all care settings.
Great. And yeah, so I think you've talked about sort of having sort of commercial break-even, basically, with the product right now. But how should investors think about the near-term growth opportunity in its approved indication?
Yeah, in the approved indication, I mean, last year, our sales were $69 million. So we think that the peak opportunity within this current indication is $80 million plus. Despite a lot of increased competition, especially from the bispecific class, which have taken over probably about a third of the market in the third-line plus setting, we've been able to maintain our volume during that whole competitive race, I think, really because Zynlonta has a clear place for physicians, both in the academic and the community setting. So I believe we'll continue to have slow and steady growth and to get to that $80 million plus peak potential in this indication. As you mentioned, already, we're commercially profitable, meaning the sales already is generating more than the total commercial and medical affairs spend of the organization.
Right, great. And so you have, obviously, some additional opportunities for Zynlonta. And there's some very interesting phase 2 data out there on its potential in indolent lymphomas, including relapse refractory follicular and marginal zone lymphoma. I think you presented some data before. There's two ASH abstracts out and presentations coming up on updates on that. So yeah, just remind us of the data and how it perhaps validates the profile of Zynlonta and the opportunity. And more importantly, is there perhaps a near-term commercial play as that could potentially be included in NCCN guidelines?
Sure, yeah. No, we're really excited about the two phase 2 IITs that we have in indolent lymphomas. They're both out of the University of Miami. The first is relapsed refractory follicular lymphoma. These are only high-risk follicular lymphoma patients. It's part of a 100-patient multicenter study that's ongoing. As you mentioned, the first 35 patients will be presented in an oral presentation this year, following an oral presentation last year in this study, and showed a best complete molecular response of 80%, which is really outstanding anywhere in follicular lymphoma, let alone in the patients that are high risk. All these patients have either a high tumor burden or a POD24. So it's really a high-risk patient population. That data will mature.
We plan to enroll 100 patients in that study and then, based on that, go to either the regulatoPry authorities and/or NCCN guidelines to pursue a pathway there. With marginal zone, I think the unmet need is maybe even higher because you typically have, if you look at all the approved drugs right now, either in terms of approvals or in guidelines, the highest CR rate achieved has been about 29%. In this 50-patient multicenter study, in the first 28 evaluable patients, what you see is a CR rate of 75%. So it's really outstanding early data. The furthest duration of response so far has been 23 months because, of course, the patients are still maturing. So as that data matures with more and more patients and longer follow-up, we also plan to, again, go to the FDA to talk about a regulatory pathway as well as towards NCCN guidelines.
Great. And yeah, any learnings from those two studies about the clinical profile of Zynlonta and perhaps translation into other opportunities that you're actively pursuing?
Yeah, so I think, well, in follicular lymphoma, we're talking about the same combination, so it's Zynlonta plus rituximab. This is the same combination regimen that's going to be used in our LOTIS-5 Phase 3 confirmatory study in second-line plus DLBCL, so seeing that strong efficacy in indolent lymphoma, I think, is very encouraging with that combination. Also, the safety profile was very manageable. In both of these IITs, the safety profile was very consistent with the known profile of Zynlonta, and then also, as monotherapy in the MZL study, again, to see that degree of efficacy and durability with a very safe profile was encouraging, so it's just further data supporting the profile of Zynlonta.
Great. And then, yeah, good segue to talk about your company-sponsored activities. And you mentioned LOTIS-5. So remind us of your overall strategy to advance Zynlonta into perhaps earlier treatment settings in DLBCL?
Yeah, maybe just taking a step back. If you look at the space, in front line, 60% plus of patients are cured with either R-CHOP or Pola-R-CHP, but when you move beyond that front line setting, most patients are not cured. And physicians will be faced with a choice of four different classes of therapies: cell therapy, largely driven by CAR-T, which has basically plateaued at about 20% share. If you look at the sales across the last two years, it's basically been pretty much flat across manufacturers. Then on the other extreme, you have chemotherapy, which is the oldest treatment, which is still used quite a bit in the community, but although you get some level of activity, the durability of that activity and efficacy is not very good, and you have a lot of irreversible toxicities.
I believe both of these classes will likely decline at the expense of the other two classes, which are likely to grow. Those classes are bispecific-based combinations. You already see a number of bispecific-based combinations that are in the 50%-60% CR range. So they're starting to close the gap from existing therapies towards CAR-Ts. And with a profile, though, that has still some CRS and ICANS, which makes it a little bit less manageable. So although the efficacy is really improving, the safety profile still makes it not fully accessible in all treatment settings. And then you have ADC and antibody-based therapies, which today are more in the 40% range of CR rate, but we think they can be improved and offer a very strong efficacy and strong safety profile. So we're basically making two different clinical bets. One is in the bispecific space.
We have our LOTIS-7 study. This is a phase one study right now where we're combining with the approved CD20, CD3 product by Roche, their bispecific, Glofitamab. We believe these are the two most powerful single-agent classes of drugs combining now. And so we're excited about that combination. And then LOTIS-5, which is our phase three confirmatory study, combining rituximab with Zynlonta. And again, what we saw on the safety run-in data from that trial was about a 50% CR rate with a very manageable safety profile. So we believe with both of those combinations, we have a chance to essentially replace chemo as a backbone with an ADC combined with both bispecifics and rituximab and deliver a better efficacy profile along with a better and more manageable safety profile.
Great. Maybe then a question on LOTIS-5. I think on the earnings call last week, you said you hope to disclose top-line data by the end of next year, 2025, and just remind us sort of what are our expectations for control arm and how is the study powered?
Sure. As you mentioned, we plan to complete the enrollment of the study this year, and we expect it's a PFS-driven trial, so we can't predict timing exactly, but we expect that the trial will likely read out by the end of next year. The way the study was powered is to show a PFS difference of two months between Zynlonta plus rituximab versus the control arm, which is Rituxan Gemox. If you look at the most recent data on R-Gemox, which is in the STARGLOW data, the control arm had about a 3.6-month PFS, and typically, if you look at other R-Gemox data, it's always in about the four-month range, so we're going to have to show a two-month difference to have a positive study. That's how the study is powered.
Great. And I know you had a futility analysis done earlier on LOTIS-5. So any learnings from that, or what were the takeaways from that futility analysis?
Yeah, we were really encouraged. So the IDMC can look at the data, of course, unblinded. We only see the data blinded right now until the study reads out. And the IDMC periodically looks at the data, especially early in the study, and does safety reviews. But recently, in July, there was a pre-specified futility analysis with pre-specified boundaries for PFS, looking at the efficacy as well. And this is after there were about a third of the total events that will be needed for the PFS. So it was pretty far along that passed the futility with no issues. And again, there were no safety issues. They weren't consistent with the known profile of these drugs. So that was very encouraging to have that efficacy and safety look by the IDMC.
Right. No, it sounds definitely very promising. And yeah, again, I think you mentioned already the profile of Zynlonta. But again, DLBCL, a lot of moving parts in terms of competition. And how should investors think about the commercial potential based on LOTIS-5 in a second-line setting?
Yeah, I think LOTIS-5 can triple the potential from where we are today because, essentially, you go from an addressable patient population, which in the third-line plus setting is roughly 6,000 patients, to 12,000. So you'd basically double the patient population. We're also doubling the CR rate because you're going from what we've seen in our single agent, 25%, and what we've seen in the first 20 patients is a 50% CR rate. And we also are seeing a longer duration of therapy. So where we typically get three to four cycles right now in monotherapy in the third-line plus setting, we expect to see five to six cycles. So when you just double the patient population, increase duration of therapy by 50%, even assuming the same share, you triple the opportunity.
So that takes the opportunity from $80 million to a $250 million plus opportunity we expect with LOTIS-5.
That any share gains would be upside to that, obviously.
Exactly.
And then, yeah, so you did mention LOTIS-7, which is, again, combining Zynlonta with glofitamab. And you did have some early phase one data disclosed early this year. Can you just talk about the takeaways from that and speak about your plans and dose expansion cohorts?
Sure. So we looked at the combination of Zynlonta plus glofitamab in a dose escalation study. We also looked at mosintuzumab, but more as a backup strategy. The focus was really to see if we could combine well with glofitamab. Because we didn't know how these drugs combined, we looked at the full dose of glofitamab, and we studied Zynlonta at three different dose levels, the approved dose of 150, but we also looked at two lower doses, 90 and 120. I think the good thing is across all of those three dose cohorts, there were no DLTs. There was no CRS, no high-grade CRS, and there was no ICANS. So we only saw CRS rates at roughly 33%, which compares to glofitamab on its own, if you look at the label, about 70%. And importantly, no grade three or four events. Efficacy, we saw strong anti-tumor activity as well.
And so that allowed us to now move into the dose expansion phase. So we're dosing currently right now. The plan is to dose 20 patients in each of two dose cohorts, the 120 microgram per kilogram Zynlonta plus glofitamab dose, and then the 150 microgram per kilogram dose. We plan to share data on the first 15-20 patients. And we're going to share data from both the part one dose escalation as well as part two, the dose expansion for all patients that are getting Zynlonta plus glofitamab at those two doses in second-line plus DLBCL. And that data, we plan to share later this year.
Great. And so you have basically LOTIS-5, LOTIS-7, and then Glofitamab now soon to be approved in second line. So what should investors expect in terms of the data in terms of CR rates, perhaps relative to what we know about Zynlonta and Glofitamab, and also in terms of safety, anything we should be looking out for?
Yeah, so I would say if you look at bispecific combinations on the whole, because beyond the STARGLOW data, there have been a number of earlier stage data. And then typically, bispecific combinations, CR rates are typically in the 50%-60% range. So that's typically the range that you see for most of these data. We'd like to see something similar to that, I think, to be competitive, but also with a safety profile that we hope to be better, meaning without the irreversible toxicity of chemotherapy, which is used in some of these regimens, and without the high-grade CRS. So those would be the goals of the therapy. One thing to note also is oftentimes when these CR rates are reported in bigger studies, these are the best CR rates. These are the best overall response rates.
We're going to be sharing data wherein oftentimes there may only be two scans. Some cases, there may be three or four scans for a patient. It's still relatively early data. Best CR rates typically improve over time because PRs and SDs can convert, as we've seen with glofitamab monotherapy. We've seen it with Zynlonta monotherapy as well. I think that's the benchmark for us is to have a competitive efficacy profile and a competitive safety profile versus anything that's out there, ideally improve on both dimensions.
Right, and then I know you talked about presenting sort of mature phase 1b data next year, 2025, on the entire study population, and yeah, can you just talk about how you think about then assuming that's supportive next development steps and perhaps positioning relative to the LOTIS-5 indication?
Sure. Yeah. So as you mentioned, once we get through the 40 patients and have more mature follow-up in terms of durability, we do plan to talk to the FDA to talk about what the regulatory pathway forward is, really, ideally to move right to a phase three study because, again, these are both approved drugs. We'll have done the dosing work required at two different dose levels required with Project Optimus with these 20 patients to move forward with a recommended phase three dose and ideally move right into a registration study, so that'll, of course, depend on the regulatory discussion with the FDA, but that's our plan forward, and in terms of how these two things fit together, I would say that two-thirds of the patients, when you look at relapsed refractory DLBCL, are over the age of 65.
One-third of these patients are over the age of 75. So when a physician's making the choice, again, in front line, it's very easy. You're going to give R-CHOP, Pola-R-CHP, the R-CHOP. You're going to cure about 60% of the patients. But when you move to that mostly non-curative setting and that relapse refractory setting, physicians are looking at efficacy, but they're also looking at the safety profile and what's tolerable for the patient, what's the duration of the therapy, fixed cycle versus not, and how accessible is it. Not all patients can get access today to a CAR-T or a bispecific therapy. That's why you still see drugs and regimens that have lesser efficacy but have better safety and accessibility profiles. We believe that having both approaches, LOTIS-5 and LOTIS-7, kind of allows us to play across the spectrum for all patients.
So on the one hand, we have LOTIS-5, which is going to be very effective if it gets to the 50% range. It's really kind of in the ballpark of any other treatment, but with a very strong safety profile. And it can be accessible in any treatment setting. With LOTIS-7, we hope to improve upon what bispecific combinations can do by being at the upper end of efficacy and with a better safety profile. And I think this allows a physician to have two very competitive regimens that could be great for their patients.
Right. And how do you think sort of as we think about potential phase three in combination with glofitamab? I know you already have a trial collaboration with Roche, right? How do you think about strategically conducting additional registration studies on your own in-house or perhaps partnering the asset with Roche or someone else longer term?
Yeah, I think right now we're focused on generating the right data. So we're going to have, of course, LOTIS-5 complete enrollment this year and then read out next year. So the bulk of the cost of LOTIS-5, which is our biggest single development expense, is going to go away by the end of next year, right? So that's one thing. That's right around the time that we would, if we're going to ramp up a LOTIS-7 study, would kind of be in that same timing, right? So from a cost standpoint, the timing works out well. Whether we move alone or we do it in partnership, I think, is to be seen. Right now, what we're focused on is testing the data, making sure that this combination really makes good sense and that there's a good path forward.
But we do believe we have the potential to have the best-in-class profile, given that these are the two most powerful single agent drugs approved in this class.
Right. Makes sense. Okay. Then maybe shifting gears to some of your earlier stage pipeline candidates. And I know there's obviously growing interest in the ADC space. And I know you've been working on sort of platform capabilities beyond Zynlonta using Exatecan-based payloads. So can you just talk about what you've been doing in terms of platform development and some of your pre-clinical product candidates?
Sure. Yeah. No, I mean, we really pivoted our strategy towards the exatecan payload in terms of our most advanced pre-clinical candidates. We believe topoisomerase inhibitors have really high potential from an efficacy standpoint. Also, we've been able to one of the difficulties typically, traditionally, of working with exatecan is the high hydrophobicity of the payload. So that's where you see a lot of derivatives with other platforms like DXd and others because of the high hydrophobicity of working with exatecan. So that required us to have a very novel hydrophilic linker to be able to conjugate to the payload. And we think we really have a very differentiated platform between our linker and the exatecan. Now, we've applied this platform, which has a very wide therapeutic index. So the therapeutic index is greater than 10, which is a very wide therapeutic index.
We don't see some of the downsides like ILD that you see with some of the other derivatives of topoisomerase inhibitors, nor do we, but we also see greater bystander effect. So we're seeing a very high TI, very high bystander effect without some of the downsides like ILD. We've applied that, so we think it's very validated, topoisomerase inhibitors. We think we have a differentiation approach. We're applying it largely to pretty validated targets where we have a chance to be first in class with an exatecan-based payload in many cases. So Claudin-6 is an example, which has obviously become clinically validated as an ADC target. We believe we have the chance to potentially be the first in class with an exatecan payload. PSMA, which again is a clinically validated ADC target, we have the chance to be first in class there.
We have a novel target, ASCT2, where we're not aware of other compounds going there, and then we, of course, have NaPi2b, where there are some other exatecan approaches, but all very early, like where we are in the pre-clinical phase one stage, so we think we have a competitive set of targets that are really interesting, that have a large degree of clinical validation in the topoisomerase space and a differentiation in terms of how we're approaching exatecan.
Right. And I'm curious. There is a lot of industry focus right now on Exatecan-based payloads and topoisomerase inhibitors in general, perhaps partially driven by the success of Enhertu, but it's been, I think, a payload that the industry has been trying to address over many years. And is there differentiation among the different techniques that are being used, and how have you solved this sort of chemistry problem, I suppose?
Yeah. I think the key is the linker because, to your point, Exatecan, if you can have a very stable linker and really release the Exatecan into the cell, the drug Exatecan is the same. So one is there's differentiation between Exatecan and other topoisomerase inhibitors in terms of derivatives because you see a very strong efficacy profile. The key for us to solve in terms of the chemistry problem was the linker. And to make sure that the linker and conjugation technology could stably deliver Exatecan in the cancer cell. And we think that's why we're seeing such high TI and such differentiation in our pre-clinical models.
Okay. Exciting and you mentioned the different targets you're pursuing actively in-house right now. How do you think about prioritizing or allocating resources to those different programs? Are some of those perhaps assets that you plan to pursue in-house versus partnering? How do you think about that basket of targets strategically?
Yeah. So when we think of it, we, of course, think of the scientific evidence, but we're also looking at the competitive and therapeutic landscape, right? And there's not only we have to think of target competition. We have to think of payload competition because sometimes multiple ADC targets can be on the same tumor type, right? So we have to think about where do we think we can differentiate and fit in the most and have the highest chance of making an impact for patients. And so we do that analysis. We've definitely prioritized our portfolio. I won't disclose yet what the priority is. We will disclose that next year because we've already picked one that we're going to move forward on our own while we are in partnering discussions.
The reason we haven't disclosed it yet is because we are in a number of partnering discussions because we know with our current focus on Zynlonta, which can help take the company towards profitability, we can make selective bets in our solid tumor portfolio, but we can't do all, we can't pursue the whole thing on our own. We're going to do some on our own, some in partnering, but we really think our portfolio is very attractive.
Very good, and maybe just one more then. Which of the four disclosed assets is closest to an IND filing, or are they all even in terms of development?
Yeah. So if you look at CLDN6, PSMA, NaPi2b, they were already all achieved development candidate stage, meaning they're all in the IND-enabling stage right now. Typically, from DC to IND is roughly 18 months. It varies by program, but that's kind of a rough benchmark. And ASCT2 is moving towards the development candidate stage, and that will be completed by the end of this year.
Great. All right. With that, I think it's time to wrap up. Ameet, really appreciate the time. Yeah, looking forward to the next step, the LOTIS-7 data later this year.
Yeah. Thank you so much. Appreciate it.
Thank you. Appreciate it.
Bye.