Good morning, everyone, and thanks for coming out today. My name is Eric Schmidt, and I'm one of the biotechnology analysts at Cantor Fitzgerald. My pleasure to welcome you all back to the Cantor Global Healthcare Conference, and also, I think, welcome for the very first time our next presenting company, ADC Therapeutics. Delighted to have with us today the company's CEO, Ameet Mallik. We also have the company's CFO sitting in the front row, Pepe Carmona, as well as, from the IR team, Marcy Graham. So, team, thanks for coming out. Maybe, Ameet, just for those a little less familiar with ADC, start off with a high-level overview of the story.
Sure, yeah. So we're ADC Therapeutics, as you can tell from the name, is an end-to-end company that's focused on antibody-drug conjugates. We have a commercialized product in Zynlonta, as well as a rich pipeline. Overall, we focus our technology, which is pretty broadly based across different types of antibody constructs, linkers, conjugation technology, and payloads, really focusing in two different areas: hematology and solid tumor. Within hematology, we have an approved product, Zynlonta, where we're currently approved in the third-line plus DLBCL setting, but we're also doing a number of studies to move into earlier lines of DLBCL, as well as into indolent lymphomas, and then we have a rich solid tumor pipeline that we're developing as well.
You've been on the job now approximately two years. Tell me how the company has evolved, and what's your strategy going forward in terms of prioritization?
The ADC space is obviously very promising, but it's evolving very quickly. There's a few things that we wanted to make sure that we did. One is streamline the portfolio and focus where we think we could really win and differentiate, not only within the ADC space but across all the different modalities. That was one big thing we did, was not only around the Zynlonta lifecycle management plan but also in terms of our solid tumor strategy. The second big thing is on the research platform side. Traditionally, the company was focused almost exclusively on the PBD payload. We've really broadened that out now to expand to multiple different payloads, linker, conjugation technologies, but also even antibody constructs. And then the final thing we did is really take the cost base down.
As we focused the portfolio strategy and revamped the research strategy, we also really took down the cost base by about 25%-30% during this two-year period.
Okay, so some pretty substantial changes. Let's dive deeper into Zynlonta and the currently approved indication. That's third-line DLBCL. As you mentioned, this is a CD19-directed ADC. Why is this an important drug for patients? Let's start there.
Yeah, I mean, Zynlonta is one of the only drugs that's approved actually as monotherapy in DLBCL. DLBCL, across all lines of therapy, are largely around combinations, and when you move beyond the front line, the cure rates are extremely low. So R-CHOP and Polivy R-CHOP, which are given in the front line, have 60-plus% cure rates. But when you move beyond that, the cure rates are actually very, very low. Very few patients get cured, and so you really want to make sure that you can have a product that delivers strong efficacy, safety, and accessibility. And I think Zynlonta hits on all three of those, which is why it suits not only well in our current indication but will be very combinable as we move into other indications. You know, specifically, if you look at efficacy, what do physicians want?
They want a rapid, deep, and durable response from a drug. We typically get to our best response within six weeks after the second cycle. We have a CR rate that, as a single agent, late lines is 25%, and those CRs are very durable. So even after two years of follow-up, we haven't even hit the median duration of response. In terms of safety, very manageable side effects, and we don't have some of the other issues that come with other classes, so we don't have CRS and ICANS that are typically associated with classes like CAR-Ts or bispecifics. We also don't have the irreversible toxicities that are common with chemotherapy. So we play in a very good role from a toxicity standpoint, and we're accessible. Very simple Q3 dosing.
We don't have any REMS or inpatient hospital stay requirements like you see with other classes as well. So it fits a good place as a single agent, but I think it's gonna have even more potential as we move into earlier lines and combine.
So in that third-line setting, the total addressable market opportunity, in your estimation, is roughly where, and where are you in penetrating that?
Yeah, so we're about $70 million or so, in the $70 million-ish range of sales. We think the total peak opportunity in this third-line setting is about $80 million-$100 million.
And when we talk about going earlier lines of therapy, just remind us of the lymphoma treatment paradigm. We're starting with R-CHOP, as you mentioned, in the front line. That can be curative. In cases where it's not, we go toward what?
So there's really four classes of drugs that are emerging. You have cellular therapy, right, which is either CAR-T or, or a transplant. About 20% of patients get a CAR-T, and that number has pretty much flattened out for various reasons around safety and accessibility. Although CAR-Ts offer very strong efficacy, they've sort of plateaued. There's only about 150 specialized centers in the country that can give a CAR-T. So for the other 80% of patients, they're typically going to get other therapies. What's emerging, what will start emerging is bispecific-based therapies starting next year. They're currently approved in the third line, but they're gonna start emerging in the second line, and I expect them to grow in the second line.
ADC and antibody-based therapies, of which Zynlonta will be one, is a class that exists today, and I expect as the efficacy improves in that class, that class is gonna grow. And then finally, there's chemotherapy, which still play a big role, but I expect them to decline going forward.
Okay, so what is your strategy for penetrating that earlier line, that second-line opportunity?
So we're really playing in the two segments, the bispecific-based therapy as well as the ADC antibody-based combination therapy, the two segments that we project are gonna grow at the expense of cellular therapy and chemotherapy. Specifically with the bispecific therapy, we have a combination trial right now ongoing with Glofitamab, the approved Roche bispecific. I expect that bispecific combination therapies will play a big role and can even potentially eat into some of the share of cellular therapy, just given the strong efficacy but better tolerability and accessibility. We have a phase I study that's ongoing, where we successfully completed the dose escalation, with Zynlonta plus Glofitamab. Importantly, we didn't see any high-grade CRS. We didn't see any ICANS. We didn't have any DLTs. We went right away from that into dose expansion, where we're combining Zynlonta plus Glofitamab in second-line plus DLBCL.
We're enrolling 40 patients, which we expect to have enrolled by the end of this year. We expect to read that fully out by the first half of next year. Then we also are playing in that other segment, which is the antibody ADC space, with Rituximab plus Zynlonta. We have a phase 3 study called LOTIS-5, where we're comparing Zynlonta plus Rituximab versus R-GEMOX, which is still R-based. Chemotherapies are still used quite frequently, especially in the community setting. We're going head-to-head versus that, and we expect to complete enrollment this year and to have a readout likely by the end of next year.
Okay, let's maybe start with LOTIS-7, or do you want to start with LOTIS-5?
Either one.
Let's go back to the bispecific combination, which is the LOTIS-7 study.
Mm-hmm.
You mentioned that there's a forty-patient expansion cohort that's being enrolled. We'll have full data from that cohort first half of next year. Are we also going to see some earlier data later this year?
Yeah, we expect to share earlier data later this year. What we'll show is a subset of the data that we have. Again, we expect to enroll all 40 patients this year. We'll share a subset of the data where we have 12-week scans.
Okay, and what type of forum might that be?
We expect to do some sort of a company event near the end of the year. As you can imagine, we have multiple different potential data readouts that can happen, but LOTIS-7 will be one of the key data readouts.
And I help set the benchmark for success in that study. What would we expect from bispecifics alone or other competitive regimens?
Obviously, there was the STARGLO data that came out, which showed CR rates in the 58%-59% with about a 13% PFS. I think that sets a bar for efficacy, but that came also with toxicity, both still high levels of CRS and ICANS, but also some of the irreversible toxicities from the GEMOX. We hope to be able to have competitive efficacy. I think the bar has been set now in terms of what competitive efficacy looks like, but hopefully with also a more manageable safety and tolerability profile by... You know, but the way we're dosing Zynlonta versus the Glofitamab is we're dosing it a week before. The reason we're doing that is to debulk the tumor and reduce some of the peripheral B cells that are oftentimes associated with the CRS and ICANS.
What we saw, like I mentioned before, is in, at least in the dose escalation, was about half the rates of CRS and no high-grade CRS compared to glofitamab alone. We hope to see that again in the dose expansion. And then we also want to make sure that we can eliminate the irreversible toxicities with GEMOX by replacing the chemo component with an ADC. So we believe this combination has a lot of promise.
Okay, so the benchmark around a high 50%, 60% or so of response rate with better, hopefully even better tox, if possible. We'll see.
Yeah, and I think-
CR rate
At least in terms of initial scans, we'd clearly want to see over fifty because we know that a lot of our PRs convert to CRs, right?
Sure. Fair enough.
So when you look at Zynlonta single agent, about 30% of patients who start with a PR actually convert to a CR. So ultimately, we want to get to a best response that's in that upper 50s or 60% range. But I'd say if at the initial scans we were even already showing over 50, that would give good promise that the efficacy is going to be very encouraging.
Remind us what role Genentech/Roche is playing in this study.
Yes, we have a clinical collaboration. They provide study drug, but they were also instrumental in the design of the drug. For example, the idea around debulking the tumor, that was a key insight from them. And we meet with them regularly, typically every month, in terms of the conduct of the trial and how the results are playing out.
What would be the next steps, either clinically or for a potential collaboration here?
Yeah. So I think, you know, first is to read out this data. I think at that point, we'd want to make sure that we can then meet with the FDA to talk about what the next steps would be from a regulatory standpoint. Ideally, it would be a phase III confirmatory study, because what we're talking about is two approved drugs that are approved as single agents in this exact disease. And so I think if we clear the safety hurdle, which we've seen so far in the dose escalation, confirm that in the dose expansion with promising efficacy, the idea is that ideally, we move right to a phase III study. What the collaboration looks like, I think, is still to be determined. You know, the discussions have to continue, obviously, around that front.
What would a phase III be of similar design as STARGLO?
Yeah, I think the question. I think typically when you see phase III studies in DLBCL in the second-line plus setting, they're in that 350-400 patient range. Up to this point, all of the second-line studies have had R-GEMOX as a control arm. I think that'll be the question is: What does the FDA want to do around the control arm? But I think we feel comfortable that if we see good data in phase I, we'd want to move forward irregardless of what the control arm would be.
Okay, great. So maybe shifting to the LOTIS-5 opportunity, which, as you laid out earlier, is combination with Rituximab in a phase III study that's ongoing, with data readout next year. I believe we know this study passed a futility analysis. Can you shine some light on, what what hurdle that might have represented?
Yeah. So obviously, we look at the data. When we see data, we're only seeing aggregate data because it's blinded, right? We don't see data that's unblinded by arm, but the IDMC, the Independent Data Monitoring Committee, does. And so before July, typically when they were doing reviews, periodic reviews, they were looking at it from a safety standpoint. Does the safety and the combination of Zynlonta plus rituximab, is it suitable and safe? And so far, everything has passed, and there's been no amendments and no changes to the trial. So the last one was in January. Then in July, it was actually a futility analysis looking at efficacy. So there were pre-specified PFS endpoints for the arms that needed to show some separation in order to pass, and they were looking at over a third of the total aggregate events of the final analysis.
So we need to get to two hundred and sixty-two events. That's when the study is going to read out. This is more than a third of those events that the IDMC looked at. And, happily, you know, there's no changes again. They said to continue to proceed as we expect. So the next readout on will be now the final analysis. There's no more interim checks of the data. This was the one efficacy look that they were able to see with unblinded data.
Was there an early potential stoppage for efficacy?
No, it wasn't designed. It would've... but it's more the opposite. If there wasn't-
Sure.
Separation, then it could be stopped for that reason, but it wasn't designed or powered to have an early stop for efficacy.
What can we say about the statistical parameters around futility, if anything?
We haven't given any details, but obviously it had to be better than one, so it had to show some improvement, right?
Trend.
It had to show a trend, and again, I think, you know, when I just take a step back and say, when we powered this study versus R-GEMOX, we were thinking the control arm could do as well as five months. We have to show about a two-month difference. If you look at the STARGLO data, which had the same exact control arm in the real world, in that clinical trial, actually, R-GEMOX was about 3.6 months, so it actually is performing worse than our assumption. We were pretty conservative in terms of our assumption.
I see. Okay.
We need to show about a two-month difference. That gives us some confidence. The IDMC review, where they're looking at the data unblind and saying, "Continue as is," you know, gives us confidence as well. Obviously, the safety run-in data, because before we went into the randomized portion of the study, we did 20 patients of safety run-in. What that data showed was an 80% overall response rate and a 50% CR rate. If that data holds, it's a very competitive profile, because outside of CAR-T and bispecifics, which not everyone's going to get access to, that would be the best efficacy of any class of drugs. We think it, if the data holds with what we've seen in the early data, it's going to be a very competitive profile.
Okay. We have been kind of hopping back and forth across different metrics of efficacy here with regard to OR and PFS and maybe even a little bit of OS, which I know was shown in STARGLO. So maybe just again, delineate very specifically for us what a relevant CR or OR rate is in terms of second-line disease for LOTIS-5, and then also a PFS endpoint.
Sure.
That's the primary endpoint of the study, PFS.
Yeah. Yeah. For overall response rate and for CR, I would say if you look at outside of bispecifics and CAR-Ts, which is I think where LOTIS-5 is going to compete with is other antibody-based-
Mm.
Other ADC-based therapies and chemotherapy, the best CR rates are around 40%. So north of that level, I think you get very competitive efficacy. That's why I say the 50% to me would be very, very competitive. I think if you look at our PFS, which we saw on the safety run-in data, with even immature data, was just over eight months, I think that would be a competitive PFS because chemotherapy tends to have very short PFS. And if you look at some of the other drugs that have been studied in that class, they excluded a number of different groups, like high-risk groups. So I think if we get to that eight months or so, it would be a competitive PFS for the setting we're competing with. I think for bispecifics, obviously, for the LOTIS-7 trial, STARGLO kind of set the-
Yeah
Parameters, right?
Okay.
Which is about thirteen-month PFS with about a, you know, upper fifties, right, in terms of CR.
But in LOTIS-5, the control arm PFS is expected to be somewhere four or five months-ish.
Right.
LOTIS-5.
Yeah, yeah, that's what we planned it for, and what we saw in STARGLO is actually-
Seemed short.
It was even less, right? It was three point six months.
Okay. Terrific. So we'll look forward to the readout, the full readout from LOTIS-5 next year. Should either of these opportunities be successful, you know, you mentioned what the layout is of the landscape in terms of second-line DLBCL. Why aren't more centers adopting CAR-T, which still does have premium efficacy? And is that going to change, in your opinion? Are we going to see a wave towards cell therapy ever?
Yeah, I mean, they are very efficacious, and-
I know they're very dear to your heart as well.
Yeah, I was part of the first launch about seven, eight years ago, the first CAR-T, so in this space. So I know the space pretty well. You know, there's a lot of barriers, and I think initially, I think people almost thought it was more because there's manufacturing issues, but I think it goes beyond that. I think, one, is you do have manufacturing turnaround time. Remember, when you relapse or are refractory post-frontline therapy, it's a very aggressive disease, so not every patient can wait the time to even get the material back, right? Some people need faster response. Sometimes that can be done with bridging, but that's a consideration. You then think about the patient characteristics. Not every patient is suitable and fit for a CAR-T. The other thing is there's a constraint in the infrastructure.
So there's only about 150 CAR-T centers in the U.S., so most patients don't have access to a CAR-T center, even including referrals. And finally, there's a lot of logistical barriers. Typically, you need to be away for weeks. Beyond the inpatient stay, you need to be in the area, and you need someone with you. So many people can't afford to, don't have the ability to do it... and frankly, some patients don't want to leave their local community doctor. So there's a lot of reasons why all these barriers play a role in limiting the uptake, and when you, when you look at the sales overall and you add up all the sales of every CAR-T product-
Mm-hmm.
They're basically flat.
Yep.
They're not. It's not a growing segment at all, and I do believe as bispecific and other therapies start to close the gap on efficacy, but with a much more-
Yeah.
accessible, safe option, it has an opportunity to actually eat share into some of the CAR-Ts.
So you frame the size of the current Zynlonta market in third-line DLBCL. What do you think the opportunity-
Mm
Should either LOTIS-5 or LOTIS-7 be successful in second-line, either combination with like antibodies or with bispecifics or both together?
Yeah. So right now, we play in third line. We're about $70 million in sales. We said it's about $80 million-$100 million peak opportunity within this setting. LOTIS-5, which allows us to double the number of patients with double the efficacy. If we look at the CR rate, right, it's about double so far what we've seen in the patient run-in that we've seen, with 50% more duration of therapy. So we typically see three to four cycles right now. In LOTIS-5, we're seeing about five. So if you just double the number of patients and increase the duration of therapy by 50%, that would triple the opportunity, not even taking into account the big efficacy advantage.
We estimate that it's somewhere between $250 million-$300 million peak sales opportunity in total with LOTIS-5 and our current indication. LOTIS-7 would be on top of that. LOTIS-7 in total could bring the opportunity of ZYNLONTA to over $500 million, right? Obviously, it'll cannibalize some LOTIS-5, it'll cannibalize some of the current indication. That could be over $500 million opportunity, and then we have additional opportunities with some of the work we're doing in lymphomas.
Let's talk about that. What's going on in indolent lymphomas?
We have two different studies going on, two different phase II IITs, one in follicular and one in marginal zone. In follicular lymphoma, this is a multi-center, 100-patient study looking at Zynlonta plus rituximab, in high-risk, patients with follicular. Most of these patients, more than half of them, were POD24, meaning they progressed within 24 months, unlike a typical follicular patient, which they progress after five years or more. These are the highest-risk patients. There was data presented in an oral presentation at ASH, last December, which showed a 96% overall response rate and an 85% CR rate. When you look typically in follicular lymphoma, most therapies don't have more than a 40% CR rate. But obviously, durability matters a lot, especially in indolent lymphoma.
We're gonna have to have more patients with longer follow-up to see what the true benefit can be, and we plan to share... The investigator plans to share more data at upcoming medical congresses with more patients and longer follow-up, and I think that's gonna be the key for us to show. Typically, in follicular lymphoma, you know, there's a lot of large phase III studies required to get approvals. We're going after a more niche strategy, looking at the high-risk POD24 patients. POD24 is about 20% of the population, but these are the ones at highest risk and what we're showing is the highest benefit. We're hoping to find a path with both the regulatory authorities at and/or NCCN guidelines within that population.
Will that update be this year at a medical conference?
I can't comment. I would just say that we plan to share it at an upcoming meeting, either this year or sometime next year.
Just remind us of the size of the data set you had previously and what size data set we might expect at the next update.
Yeah. So we had 27 evaluable patients. So clearly, you know, more patients. I can't go to the exact number 'cause depending on when the update will be, but also with longer follow-up. 'Cause at that point, we had a very small number of patients that had... Typically, what you need is two years or more follow-up, and we'll have more of those patients, too. So it'll be both number of patients and longer duration.
And the opportunity for an NCCN guideline or compendia listing, how does that shape out?
I think when there are more patients with longer follow-up, what you require is a publication in order to do that in a peer-review journal, and at that point, we would approach NCCN guidelines.
After the next update, or would the next update be sufficient for a publication?
I think it's unlikely for this one. I think it would be the soonest we'd probably be ready with an update for both follicular and MCL to go to NCCN guidelines, I think, is end of 2025 or early 2026, where there would be sufficient number of patients. So I can't tell you if there'd be an update before then, but I think that's the timeframe. That would be the soonest timeframe where I think there'd be enough patients and with enough follow-up with the publication that you give to NCCN-
You'd want to go together? We haven't talked about follicular so much yet, but would you like to take both of the-
No, they could go separately.
Okay.
I just think that's around the timeframe where you'd have enough patients, enough follow-up-
Okay
In terms of how they're accruing.
So where are we in the follicular development? What are you doing there?
Marginal?
Uh, yes.
Yeah. So with marginal zone lymphoma, we have a 50-patient multi-center study that's ongoing. Again, in marginal zone, there's about three to four thousand patients in the U.S. We're typically pretty high in unmet need. You know, if you look at the CR rates, they're typically 30% or less. They're based on very small patient sizes. And one of the most common treatments given are BTK inhibitors, which it's not a fixed-duration therapy. You have to actually treat to progression. So some of these patients are on for years, which is a big burden for the patient in multiple different dimensions. So what we have the chance to offer is a fixed-duration therapy of Zynlonta monotherapy in marginal zone lymphoma patients. What we've seen so far in the first 15 evaluable patients, 13 had a CR, one had a PR, and one progressed.
None of those responses, all of them were completely durable at the time of the data cutoff. So again, the key now for future updates is gonna be more patients with longer follow-up, but the data right now is extremely good, and we think there's a pathway both to talk to the FDA, just given. If you look at, you know, what's been included in terms of patient sample size, either in NCCN guidelines and preferred or in approvals, it's all based on sample sizes of 36- 68 patients. So we're doing a 50-patient trial. We think it's of the right size to have that conversation.
Okay, great. So we've only got four or five minutes left. Maybe we should turn our attention to your solid tumor portfolio.
Sure.
Everything so far we've talked about is Zynlonta-based, but you do have another candidate in the clinic, 601. Tell us about that and why it's interesting.
Yeah, so 601 is targeting AXL. This is, there's been other work that's validated AXL as a potential target, not all with the right, potency, and so we're using a pretty potent payload. This is our only solid tumor asset using a PBD payload, which is a highly potent payload. We know that AXL is overexpressed in sarcoma and pancreatic cancer and in non-small cell lung cancer, and we're currently. We completed the dose escalation. We're doing a dose optimization and expansion in those tumor types. We expect, you know, if we see a strong signal in those areas, the idea then at that point would be to try to do some sort of a BD deal. I mean, I think given the capital allocation strategy of the company, we're focusing most of our efforts in Zynlonta.
But we expect to share some update, particularly in sarcoma and pancreatic cancer, by the end of this year, as we've been able to roll the study pretty well.
That would also be in the company-sponsored forum, at year-end?
It may-
Yeah.
It may not be at the same one, but we plan to disclose the data through a company-sponsored forum somehow. Yeah.
Okay, thank you. And then the rest of the pipeline, you mentioned earlier that you're working with different toxins these days. What do you have ongoing there?
The most advanced, we have a number of different payloads that we're working on. The most advanced is Exatecan. I think you're certainly aware, but probably many others know how much topoisomerase inhibitors have taken off as offering really a great payload for ADCs. This was validated obviously by in HER2 with the DXd platform, which showed you know really strong data. But one of the tough things about working with Exatecan is it's highly hydrophobic, and it's actually a tough molecule to work with. And that's why oftentimes like DXd or other platforms are modifications of Exatecan. We're able to with a very novel linker design which manages some of the hydrophobicity of the Exatecan bind it stably to an ADC.
We have four different compounds that we're going after different targets, so Claudin-6, PSMA, NaPi2b, and ASCT2. With these targets, they're all progressing forward. We have very encouraging preclinical data. We're planning to progress at least one of these on our own, but also we're in a number of discussions, confidential discussions around a potential research collaboration for the others.
When will you tell us which of your four candidates is being nominated?
We'll tell you. Given that we're in a number of different potential partnership discussions, that's the reason we have disclosed, 'cause we're in discussions around a number of these different compounds, and so I think as we get more clarity on that, we would disclose which one we plan to move forward.
Okay. So maybe just touch on your cash, your cash runway, and maybe remind us of then the next milestone, say, for the next six or so months.
Okay, sure. So as of June thirtieth, so at the end of the second quarter, we ended with about $300 million of cash. That gives us a cash runway into the middle of 2026, and it really allows us to fund and read out all the major data catalysts within our cash window. So if you think about what's gonna go forward between now and the end of this year, we will have complete LOTIS-5 enrollment. We'll have initial data on LOTIS-7. We'll have initial data on AXL. And then as we look forward to the first half of next year, we'll have a complete readout for both AXL and LOTIS-7, potentially some more indolent lymphoma data coming in this timeframe. And then, as we get into the second half of 2025, we'll have the full readout of LOTIS-5.
So really, all of our data catalysts are well within our cash runway.
A lot going on for a smaller-sized company. So thanks, Ameet, for being here. Appreciate the time.
Yeah, thank you. I appreciate it.