Thank you for joining our next fireside chat. Again, I'm Robert Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined by the CEO of ADC Therapeutics, Ameet Mallik. Ameet, thank you for joining us today. Well, thank you. Thank you for the opportunity. Awesome. So why don't we start off just from a high-level overview of the company, you know, for those who may be unfamiliar with ADC Therapeutics? Sure. So ADC Therapeutics is a commercial-stage antibody-drug conjugate company. Obviously, with the approval and with a rich clinical pipeline, we also have end-to-end capabilities. We have a focus both on the hematology side and on the solid tumor side. We have an approved product on the heme side called Zynlonta, which is approved in third-line plus DLBCL. Multiple opportunities to expand into the second-line setting, as well as into indolent lymphomas. That product alone can help the company achieve profitability. Beyond our heme side, we also have a solid tumor pipeline. One is a clinical asset targeting AXL, which we'll talk about, I'm sure, later, which has shown interesting signs in our dose escalation. We're now in dose expansion. Then an earlier stage pipeline, where we've now expanded the platform. We have an exatecan-based platform with a novel linker, and four different preclinical targets that are progressing towards the clinic, and all of which, we're progressing with a cash runway, given our recent financing, to mid-2026. Okay. You know, one of the things I'm sort of curious about, if we look at the revenue for Zynlonta over the past four quarters, obviously, we've seen a bit of choppiness. So I want to get a sense as to, you know, what occurred to actually have that result, and how do you view the potential future sales of Zynlonta moving forward, not just in the third-line setting, but as we begin to think about and discuss the second-line opportunities and beyond? Yeah. So I think that's an important pre-comment, because where we're playing right now is in the third-line plus DLBCL setting. Last year, our sales were about $69 million. We think the peak opportunity in third line plus, which is a pretty late stage, there's only about 6,000 patients in the U.S.- Mm. Pretty fragmented. Our cycles are about three to four cycles if you look at the duration of therapy. Mm-hmm. So when you look at that opportunity, we think the peak opportunity in third line only with a single agent, Zynlonta, is in the $80 million to $100 million range. Mm-hmm. We'll progressively grow to get there. As we've seen the last couple of quarters, we've had progressive growth. The bigger opportunities as we move into earlier lines of therapy and into indolent lymphoma. We have our LOTIS-5 study, which is combining Zynlonta plus rituximab in the second-line plus setting. We think that alone could take the opportunity to $250 million to $300 million. We have a combination with bispecifics. Mm-hmm. We're progressing now the combination with glofitamab- Mm-hmm. in the second-line plus setting. That works. We think the drug could be over $500 million drugs. Yeah. We also have two different indolent lymphoma plays, both in follicular lymphoma and in marginal zone. Yeah. So, you know, let's focus on the LOTIS-5 trial. Obviously, that trial is Zynlonta plus Rituxan versus Rituxan plus gemcitabine and oxaliplatin. You know, you had some safety run-in results last year that were presented at SOHO. So I wanted to see if you could provide a broad, just a brief overview on that. And then, how do you view the competition for those, those monotherapy CD19 cell therapies and CD20? And then we'll talk about as they move into the earlier line setting. Yeah, so what's interesting is, you know, the only true standard- Mm-hmm of care in DLBCL is frontline. Okay. - which is basically R-CHOP or Pola-R-CHOP- Yeah Now that Pola-R-CHOP has been approved. Roughly, over 80% of patients, basically anyone who's fit enough, gets those therapies, and there's about a 60% cure rate. So they work. Actually, frontline treatments work pretty well in DLBCL. The issue is when you progress, and then when you progress, the standard of care really varies, depending on if you're one of the one-third of patients that are treated in an academic center versus the two-thirds of patients that are treated in the community. So for the academic treated patients, CAR T is the, is the go-to therapy in the academic setting. CAR Ts have, I think, roughly peaked right now. Yeah. If you look at the sales of all three CAR T products that are approved in DLBCL, over the last six quarters, they've basically been flat. They've reached about a penetration of 20%. So of that, 35% of patients treated in an academic center, 20 of that 35 are with CAR Ts, 15 are other things, whether it's clinical trials or transplant or other targeted therapies. But 65% of the patients are treated in the community. What's one of the biggest things that they use is R-based chemo, and there's a big move towards moving away from systemic chemo, given the toxicity, the lower therapeutic index. So an R-based ADC approach fits right along with how community doctors like to treat. CAR Ts tend to have CR rates in the range of 70%, so they really are effective. But again, only 20% of patients get them. For the rest of the patients which are getting other therapies, CR rates are typically around 40%. What we saw in the safety run-in data in the first 20 patients of the LOTIS-5 study, combining Zynlonta plus rituximab, we saw an 80% overall response rate and a 50% CR rate. I think it's very competitive with anything that's been approved or that's being studied right now. Mm-hmm in combination, and it fits along with how community doctors like to do, which is recycle CD20-based therapy Mm-hmm with Rituximab, along with a different toxic agent. And so ADCs, I think, will fit really well there. If you think of competition, as I said, CAR Ts are, have been sort of, I would say, fixed at about 20% share. Even if they move frontline, I think, again, it's going to be largely an academic center. Okay. I think the referrals will be pretty low, because given that you have a high cure rate already- Yeah ... with R-based chemo, I think the desire for people from the community to get a frontline treatment of CAR T, I think, is going to be minimal. So there may be some cannibalization within that academic share of the 20%. Mm-hmm. I don't think it'll affect the broader market. Bispecifics are the other big, you know, modality, obviously, that are playing a role. They're very efficacious drugs, but they come with a toxicity profile that includes some high-grade CRS and ICANS. They're currently approved in the third-line plus setting... and again, largely being used in the academic center. There's a number of bispecific combination trials that could move bispecifics into earlier lines, including potentially frontline. Yeah. I think, again, this paradigm of recycling CD20-based therapies as a backbone therapy, I think will continue. So I think there's a role, even if you see a bispecific move into frontline, I think rituximab and Zynlonta could play a big role, second line. But we also have a combination study with bispecifics, which we think can actually change the game completely. Yeah. It's interesting that you said that it's viewed as a backbone. That's sort of analogous to what we saw with the CD38-targeted Darzalex- Yeah in the multiple myeloma treatment paradigm, right? It's, it's being used across that treatment perspective, regardless if you received it in a prior line. So that, that's an interesting analogy that you brought up there. Shifting to the LOTIS-7 trial, obviously, it's in combination with glofitamab or mosunetuzumab in the relapsed refractory setting. Could you discuss that trial design, and as well as the initial findings that you've released previously? Yeah, so there's two parts to the phase 1 study. There's the dose escalation and then dose expansion. So part one, with the dose escalation, we escalated Zynlonta at three different doses and combined with the full dose of glofitamab in one arm and mosunetuzumab in the other arm. Mm-hmm. What we wanted to test is the safety, right? And make sure that these drugs were combinable. Across all the doses in both arms, there were no DLTs, there was no ICANS, and no high-grade CRS that we saw at all. If you look at the glofitamab arm, which is the focus for where we're gonna do the expansion, we saw a 33% CR level. There were, of the 9 patients, 2 grade 1 CRS, which were largely able to be managed with Tylenol only, and 1 grade 2, which was able to be managed with toci and steroids without hospitalization or ICU stay. So we think that's a really good profile to have a lower CRS rate, but also no grade 3 and grade 4. Mm-hmm. We think that's the key for for potentially eliminating hospitalization in the, in the future. And we think, given how strong and how potent bispecifics are, if you can get additive efficacy with Zynlonta and by dosing earlier, we dosed the drug a week before to debulk the tumor. If it can reduce the grades of CRS, not just the rate, but the grade of CRS- Yeah ... and eliminate the small percentage that are grade three and grade four and eliminate hospitalization, this has the chance to bring bispecific combinations more broadly into the community. Yeah. You know, one of the things I'm sort of curious about, as we think about that CD20 landscape, obviously, first one that comes to mind for me is epcoritamab and subcutaneous delivery. I don't believe glofitamab is currently subcutaneous, so, you know, how do you see that evolving? I know it's being studied as subcutaneous, and there probably will be a switchover at some point. You know, do you think that that subcu administration route confers a significant advantage currently to epcoritamab versus glofitamab? I don't think so. And you look at the sales, they're both growing actually pretty well. Yeah. Glofitamab also has a simpler dosing regimen- Mm-hmm ... I would say, and it's every three weeks. So patients are used, and with a fixed duration, too. Mm-hmm. That's an important distinction between glofitamab and epcoritamab. It's a fixed duration of 12 months. And so I think getting a three-week, you know, every three-week infusion, which lines up exactly with Zynlonta's- Yeah, it's perfect. -dosing, I think will fit well. I don't think it's a big advantage to going subcu, personally. Okay. I don't think that's affecting the share. Both products are growing, actually- Yeah ... quite well right now. Yeah. You know, obviously, we've seen the data generated by the CD20 bispecifics in, in relapsed refractory NHL. So, you know, given that historical objective response rate that we've seen there, you know, what sort of OR delta do you want to see in your combination trial to really get excited and say, "Okay, we really should be moving this, this forward? Yeah, I mean, we've already seen with Zynlonta where we're talking about a 50% CR rate, right? If you look at, let's say, mosunetuzumab and polatuzumab, the data from their safety run was also around that 50% range. So clearly, you want to be north of that. Yeah. I think if you get in the 50% to 60% as close to the 60% as possible, now you've really closed the gap with CAR-Ts. Mm-hmm ... which are around 70%. You know, you've really made a strong, viable option for patients who can't get to a CAR-T. The 80% of patients who are not- Yeah ... getting a CAR-T therapy, and nothing is approaching that 60% level right now. Mm. If we could do that in a way that also you can improve upon the toxicity profile to allow the bispecific combinations to be given outpatient in a community setting without a hospitalization requirement, I think that it has the chance to become the new standard of care in that second line setting for non-CAR-T patients. Yeah. You know, one of the things I'm sort of curious about too, obviously, we're expecting a LOTIS-7 update later this year. Can you help frame the expectations around that data release? Yeah, I mean, we have a lot of interest in this trial. We're gonna dose 40 patients, so we're expanding at two different dose levels. Mm-hmm. The approved dose of Zynlonta, which is 150 micrograms per kilogram, plus the full dose of Glofitimab, and also the 120 microgram per kilogram dose level of Zynlonta, plus the full dose. Because we cleared every dose, we're picking the two highest doses. We're expanding 20 patients each. Mm-hmm. We expect to have all 40 of those patients dosed by the end of this year, and we will share the data from all patients which have at least a 12-week scan. Because obviously, any responses we would want to make sure are confirmed. So we'll share the safety and efficacy data from all those patients, and then in the first half of next year, from all 40 patients. That, depending on, of course, how the data looks, that would form the basis then for regulatory discussions on- Yeah ... you know, ideally moving to a pivotal phase 3 at that point. Okay. You know, one of the things that investors should be aware of is obviously the recently released data for Zynlonta in relapsed refractory MZL. While that was from an investigative-sponsored trial, I'm curious to get a sense as to how you're thinking about the opportunity in MZL, marginal zone lymphoma, relative to follicular lymphoma. ... Yeah, we're excited about the data that we've been able to generate in both marginal zone and in follicular. So, you know, in marginal zone, there's just recently at the Lymphoma Research Foundation, Dr. Lossos presented data from the first 15 evaluable patients. So this is part of a 50-patient multicenter study. If you look right now at the landscape of marginal zone, it's largely anti-CD20-based regimens, or like there's only really two different classes of drugs. When you look at the CR rates, the best CR rates are 29%. Mm-hmm. With a relatively, you know, reasonable duration of therapy, anywhere from, you know, one to two years, but there's room for better efficacy. The thing is, with an indolent lymphoma, you can't, the doctors aren't willing to give up on the tolerability profile- Mm-hmm. because patients tend to progress more slowly. What was shown in the first 15 patients is 13 of the patients had a complete response rate, and one had a partial response rate. So that's really good efficacy for the first 15 patients. Again, this study has only been enrolling at two sites. It's going to be expanded to five sites with 50 patients. If you look at the two drugs that have been approved, acalabrutinib and zanubrutinib, as well as the multiple others that have been added to NCCN preferred guidelines, they've all been based on patient numbers of 36 to 68 patients. So we think the 50-patient trial we're running right now will be sufficient to- For compendia listing. Either for compendia and or potentially approval, too. Okay. So we will talk to the FDA at the same time as we submit to NCCN guidelines. If you think what could this opportunity be? There's about 3,000-4,000 treated patients right now, drug-treated patients in the second-line plus setting in marginal zone. If you were to take those 3,000-4,000 patients, multiply by, we think we'll get five to six cycles. On average, we had about 5.5 cycles so far treated, and the Zynlonta price, that translates to a total addressable market opportunity of $500 million. Mm-hmm. Meaning for every 10% share, if we're successful, it would be a roughly $50 million incremental annual peak sales opportunity. So that's meaningful. Yeah. Given... You know, when you look at our expenses right now, roughly $200 million, you get to about $250 million or so of sales at our current expense level, and the company becomes break even. Yeah. So we think it's a meaningful additional potential opportunity. In follicular, we're also excited about the data. There was an oral presentation at ASH in December, which showed that Zynlonta plus rituximab demonstrated in the first 27 evaluable patients an overall response rate of 96% and a CR rate of 85%. Again, that's- It's phenomenal. This is phenomenal data, I think. This is in high-risk patients. Most of these patients were POD24. So these are the patients that typically have the worst responses. That study has now been expanded to a 100-patient study, multicenter study also. So more data to come on that. I think in both cases, we will talk to the regulators and talk to compendia in parallel. Mm-hmm. Okay. You know, why don't we shift a little bit away from, you know, the hematological malignant space and more towards the solid tumors. And in particular, I want to focus for the time being on your AXL-targeted ADC, ADCT-601. Obviously, you know, we've seen a ton of other approaches going after AXL. The majority of them have yielded disappointing results. You know, with that said, I wanted to get your thoughts as to, you know, what do you think differentiates 601 to have a greater probability of success relative to those the prior approaches? I think there's a few differences. One is just the targeting binding affinity of the actual our antibody. Mm-hmm. I think there's a lot of differentiations in there. The payload, obviously- Yeah ... is quite differentiated, and we know that with AXL, and some of the tumors that we work with are very tough-to-treat tumors, so having a more potent payload, we think, can play a role. But patient stratification plays a big role, too. Mm-hmm. We just recently had the biomarker approved by the FDA for clinical use or for patient selection. We think all three of those parameters can help to differentiate. We've gone through the dose escalation in sarcoma. These are heavily pretreated sarcoma patients where typically, you know, the overall survival in these patients can be three to four months. Mm-hmm. In the dose escalation, we saw a couple of partial responses. In monotherapy, we saw a couple also in combination with Gemcitabine. I think it's an initial, you know, encouraging early sign, at least of anti-tumor activity. Now, we're into the dose optimization and expansion. In sarcoma, we've also started dosing patients in pancreatic cancer, and then we'll move to a patient selection approach. Mm-hmm. in non-small cell lung cancer in the second half of this year. Okay. You know, obviously, as we think about the back half of this year, we're expecting to see an update from 601. You know, what can investors be expecting around that data release? I would say more robust data around sarcoma, I think a meaningful number in pancreatic cancer- Mm-hmm. You know, in that 10 to 5 patient range. And then I think as we move into the first half of the year, there'll be even more data on both those tumors, plus lung cancer as well. Okay. Why don't we shift to your earlier stage pipeline? Because I, I'm really intrigued with what you got going on under the hood there. Obviously, you've got a slew of targets you can go after. You've presented some preclinical data at AACR for two of them. So can you talk about the targets you're pursuing and discuss the advantages that those agents harbor over all of the other similarly targeted ADCs, for example, the exatecan payload? Yeah, I mean, Exatecan, I think, and there's a few other companies going after Exatecan. I think, you know, topoisomerase inhibitors have been validated with DXD, and DXD, obviously, is, you know, had phenomenal results in terms of the profile and the impact that it's had. So I think it was a big step forward from a payload standpoint for the ADC space. Now, one of the issues with DXD, it's a modified, it's a modified version of Exatecan, because Exatecan is highly hydrophobic.... So you can have aggregation and other issues which make it very tough to work with. So we developed a novel hydrophilic linker, which allows the traceless release of Exatecan- Mm-hmm. Once it's internalized. And so the linker for us is the key differentiator. I would say in the whole thing, because obviously, Exatecan, other companies can play with it. We believe the linker is the, the key differentiator. What we've seen so far preclinically, we're going after four different targets, NaPi2b, Claudin-6, PSMA, and ASCT2. What we've seen preclinically is a very high therapeutic index, higher than you could see with DXD. Mm-hmm. We've seen higher potency, more bystander effect when you look directly, and we haven't seen any. We've done now in non-human primate studies, we've studied three of these compounds. We haven't seen any ILD- Okay. - which you saw with DXD already preclinically. Yeah. So if we can again have better potency, better bystander effect without the ILD, is a real advantage. And so we're now moving forward with these four. We announced with the recent fundraising that we did, we'll move at least one of these forward on our own, but also in partner discussions to potentially move a broader portfolio forward. Okay. You know, at AACR, you presented preclinical data for the Claudin-6-targeted ADC, and then NaPi2b ADC. Now, I note that other agents have been developed against those two targets. One would be, you know, the Roche, Genentech, NaPi2b-targeted ADC, back in the day, and currently BioNTech and TekSeva and BNT211, the Claudin-6-targeted cell therapy. You know, given the data we've seen with those two agents, how are you thinking about patient selection as well as market opportunity here for those two targets? Yeah, I think you hit it. I think there's a lot of differences in terms of the platform, the payload, and the patient selection approach. So I think having the right biomarker and really looking at, you know, a very validated biomarker to do the patient selection, as you've seen with other approaches, for example, in NaPi2b, a lot of changes in the patient selection approach. Yeah. So I think that is the key, is getting the right patient selection and having the right platform to do it. What we're seeing right now preclinically, and, you know, we had a research day, which showed a lot of comparison. Mm-hmm. We think we have pretty differentiated data. I think when you look at the data we presented at AACR, we presented even more at our research event, just right following AACR. I think shows that we believe we have higher potency and a better tolerability profile and overall higher therapeutic index. So we feel really comfortable with those targets as well as with the others, PSMA and ASCT2. Mm-hmm. I guess last question for me, you know, given that early stage, the breadth of that early-stage pipeline, how are you thinking about BD opportunities? Because you did just mention that, you know, you want to take one forward by yourself, but do you have, you know, enough dry powder to pursue all four of those targets simultaneously, you know, in the future? You know, give me some thoughts around that. Yeah, no, I think given where our market cap is and given the cost of capital and the environment, we're focusing most of our capital allocation towards Zynlonta- Mm-hmm ... where we think there's a de-risked pathway to get the company towards profitability. So that's where the majority of our capital is going. As you mentioned, given the breadth of our solid tumor portfolio and also the early stage of it- Mm-hmm ... by definition, higher risk, higher return. We want to move at least one forward on our own, but we are looking to partner as a way to bring in non-dilutive capital and to move a broader set of the portfolio forward in parallel. Okay. That's really all the questions for me. If anyone has questions for beyond, so we'll, we'll get a mic to you. Yep. Yep, we'll get you. Thank you. Hey, Ameet, very nice chat. So, my name is Leon Tang. I run a cross-border BD consulting firm and also advise a few VC fund. And one trend right now, I remember there was a debate, probably one week ago on a Biotech Hangout, the debate between ADC and T-cell engager. And I, I believe, like, Josh Schimmer was on the camp of TCE, like, Eric Schmidt was on the camp of ADC. So it looks like you are combined both, right, in your trial. But one thing is, like, you know, what do you see this combination, maybe ADC and T-cell engager, the other indication, because, you know, both of them have their own baggage, right? They have their unique adverse events. How would you see that, especially when you combine them in, like a front, like a front line, early line of the treatments? That's a first question. Second one is, obviously, you know, the elephant in the room, if you're talking about ADC, there's a lot of, BD transaction with the China-derived innovation, including the recent one, right, ProfoundBio and Genmab. You can argue whether that's a China biotech company or not, but, they have 100 people in China, and there's a lot of, you know, GSK, you know, Merck, AstraZeneca, you know, listen, a lot of us, including some of them, actually, the target overlap with you. How do you view the either, you know, collaboration or competition from those China-derived, ADC biotech company? Two question. Thank you. Yeah, two great questions. First, in terms of the combination with ADC and bispecific, I think what we see in most oncology areas, as long as you can solve ways to develop modalities that have non-overlapping toxicities, I think non-systemic chemo-based combinations is the future of oncology, and the key is how do you combine them? So for example, for us, with Zynlonta and Glofitimab, we're trying to resolve the toxicity of both. We're looking at different doses of Zynlonta. We're also dosing Zynlonta before we give the Glofitimab to debulk the tumor. So if you can limit the CRS, which is the baggage, let's call it, with a bispecific, but still have the strong efficacy, which is persistent, you know, with durability, with a longer... We also have a fixed duration to make sure that you can limit the toxicity from the ADC. So I think a lot is playing around with the dosing schedule and how you dose these things to combine together. But ultimately. I think the combination of these different modalities, like ADC and bispecific, can lead to better efficacy with a better tolerability profile than what you're seeing right now, which is systemic-based chemo. So I do believe there's a these modalities aren't always competitive, but they actually can be complementary. Bispecifics and ADCs, especially Zynlonta and the bispecifics and DLBCL, are the only approved single-agent drugs in any line of therapy, too. So they're very potent. So that's why we played around a lot with the dose schedule and dose levels to combine these drugs. But we're encouraged by the safety, by the dose escalation, that what we saw was very combinable, and the safety profile was actually better than the bispecific alone, by the way we're dosing these products. So that gives us encouragement in terms of where the space is moving. In terms of China, I think there's a lot of great innovation going on when it comes to the ADC space in China, in particular. There's a lot of high-quality science going on. There's a lot of high-quality technology being developed. We look at the technology spaces, no one company can own it all. The space is moving too quickly when you look at linker, conjugation technology, even antibody moieties. The space is gonna move towards bispecific ADCs, dual conjugate ADCs, a lot of payload, innovation, even beyond toxin payloads. So we look at Chinese companies as a source of innovation for sure, just like other companies. There's a good source of innovation, but I think it takes more than that to develop an ADC and get it to market. You know, if you look now, there's only been about 6 companies. If you look at the origin company that have actually gotten an ADC over the finish line, we're one of them. And it requires a lot of capabilities in CMC, that's that I would say I wouldn't underestimate how hard the CMC part of this is. And, you know, all the capabilities you need in terms of preclinical development, translational development, clinical development. So I think we, we've had multiple products that we've brought through the IND stage into the clinic and had a product approved. So we think that's also a differentiator, too. But there's certainly a lot of, you know, interesting technologies out there and that we access too. I'd say, when I look at our technology, we've developed some things in-house, like our novel linker. Many of our payloads, we've bought from in-house, from other companies. All right, well, I think that's all the questions. Ameet, thank you for joining us today.