Good morning, everyone, and welcome to the Jefferies 2024 London Healthcare Conference. My name is Kelly Shi, one of the senior biotech analysts here. And in this fireside chat session, we are very pleased to have Mr. Ameet Mallik, Chief Executive Officer of ADC Therapeutics. Welcome, Ameet.
Thank you, Kelly.
Maybe we can start on, like, at a high level for the company, what has been the achievement for the last 12 months?
Yeah, we've done a lot. I mean, as you know, we're a specialized ADC company with end-to-end capabilities. We've made a lot of progress in terms of our pipeline. Our pipeline is focused both in hematology and in solid tumor. So on the hematology side, our commercial product continues to do well in the face of a lot of competition. We're on track to complete our phase three study to move the product into the second line plus DLBCL setting, our LOTIS-5 study. We're expanded also to combine with bispecifics, and that trial will have initial data later this year as well. And then we've continued to progress on very novel solid tumor pipeline forward as well.
Fantastic. And maybe start with the commercial for Zynlonta. Where are you right now in terms of, like, third line market penetration? And what do you think about the expansion opportunities through the ongoing trials you just mentioned?
Sure, yeah. So we're right now approved. Zynlonta's approved. It's an anti-CD19 ADC, approved in the third line plus DLBCL setting as a single-agent drug, and a couple of things that make it very interesting is, one, very rapid, deep, durable responses with a manageable side effect profile that can be given very conveniently in an outpatient setting with a 30-minute infusion, so that profile in the single agent already does quite well in the third line plus setting. It's already a commercially profitable product, and despite all the competition, still has gained quite a bit of share in the third line plus setting, but the bigger opportunity, of course, comes as we move to expand into earlier lines of therapy. We have a couple of different opportunities.
We have our phase 3 LOTIS-5 study, which is looking at the combination of Zynlonta plus rituximab in the second line plus DLBCL setting. We expect this to triple the revenue opportunity by doubling the patient population and increasing the duration of therapy. That study is set to complete enrollment this year with a suspected readout by the end of next year. We also have our combination LOTIS-7, which is looking at the combination of Zynlonta plus glofitamab, the bispecific product which is approved in DLBCL by Roche. We have a clinical collaboration looking at this combination. We expect to share some initial data, both safety and efficacy, on this combination by the end of this year and additional data in the first half of next year, and then beyond DLBCL, we're looking at Zynlonta in follicular lymphoma and marginal zone lymphoma.
We have two different presentations that will be at ASH this year highlighting the data in these indolent lymphomas.
Fantastic. Maybe also on the commercial or launch metrics, what has been your learnings? and, for example, in terms of the use at academic centers versus community centers, and also next to CAR-T bispecifics, what physicians actually prefer for Zynlonta in terms of both efficacy and the safety features? and how do those actually guide your future commercial strategy?
Yeah, so I think when physicians are making a choice, they're looking at three different parameters for an individual patient. They're looking at the efficacy, they're looking at the safety of the product, but also the accessibility. So CAR-Ts obviously have the highest efficacy, but they come with, you know, fairly high levels of CRS and ICANS. And because of the specialized capabilities needed to deliver a CAR-T, only about 150 centers in the U.S. can actually administer a CAR-T. So it's not really accessible for most patients. The penetration is roughly 20% of patients will get a CAR-T at some point, but that means 80% will never get it because of some of those factors, despite having the highest efficacy.
Bispecifics are playing a big role, and they clearly have, you know, very strong efficacy right now, but also come with CRS and ICANS, which can be tougher for all physicians to manage. So what we've seen is very high penetration in the academic centers and some of the more sophisticated community centers. But the majority of community centers can't yet administer a CAR-T or a bispecific and are oftentimes referring those patients increasingly to the academic centers to do some of the step-up dosing. So you see what physicians really want in this kind of environment is a really highly efficacious treatment that has a manageable side effect profile that can be given by all physicians, whether it be in an academic or community setting. And that's why I think the field is moving more and more towards novel combinations.
That's where we're excited, not only about the profile of our current compound, but about the combinations that we're doing. The bispecific products and Zynlonta are the only single-agent drugs approved outside of CAR-T. And so we think the single-agent activity of these powerful drugs, when put in combination, has a chance to really transform the care for patients with relapse refractory DLBCL.
Okay, fantastic. Maybe let's focus on LOTIS-7 you just mentioned as the data actually imminent. Maybe from the biology perspective, why do you see synergy between CD19 ADC and CD20 bispecifics? And also, how should we expect a safety profile given, like, two different modalities combined?
Yeah, so if you look at the DLBCL landscape, once patients move beyond the front line, very few patients get cured. CAR-T can be curative for a subset of patients, but unfortunately, most patients never get access to it, and so that's where these novel combinations play a big role. We're so excited about Zynlonta plus Glofitamab because of the complementary mechanism of action. You have a CD19 ADC with a CD20, CD3 bispecific agent. So these are complementary mechanisms of action with the two most important mechanisms in DLBCL and the two most powerful agents approved as single agents combining together. The hypothesis we have is that this can not only have additive or synergistic efficacy versus either agent alone, but also, because of the non-overlapping, non-hematologic toxicities, have a very manageable side effect profile.
In addition, the way we're dosing the products, we dose the Zynlonta a week before the first dose of Glofitamab. The reason is to debulk the tumor, to reduce the peripheral B cells, and ideally to reduce the bulkiness of the tumor, which we hope will lead to lower grades and rates of CRS and ICANS. And what we've seen so far in the escalation, the dose escalation, is we didn't see any high-grade CRS, no grade three or grade four CRS, no ICANS, and we didn't have any DLTs in the study. We're currently now in the dose expansion where we're looking at two different dose levels of Zynlonta plus the full dose of Glofitamab. Again, with this dosing sequence where we dose a week before to debulk and then give the two together for a fixed duration of time, both are Q3 week dosing.
So the dosing lines up really well together. We give the Zynlonta for up to eight cycles, and then beyond that, just continue the Glofitamab on its own. What we hope to see, you know, when we give an update later this year is additive or synergistic efficacy, a manageable side effect profile, and a profile that ideally can be given in the outpatient setting for all physicians, whether it be in the academic or community setting.
Okay, fantastic. And can we say ideally you'd eye on the ultimate, I mean, the ultimate safety you'd eye on is actually should be better than either CD20 engager or CAR-T? And for efficacy, what would be your reference point for this novel combo?
If you look right now, you know, most if you look at the data with bispecific combinations that are emerging now in the second line plus setting, they typically have CR rates in the 50%-60% range. That's typically what you're seeing the data kind of emerge right now, but with side effect profile that still has some high-grade CRS and ICANS, so from an efficacy standpoint, we'd want to be on the upper end of that 50%-60% range. We want to be able to deliver in that range, but with a more manageable side effect profile, and I do believe if we can deliver best-in-class efficacy with a more manageable side effect profile than the bispecific on its own, it's a really winning combination for patients.
Great. And for also the year and the data, could you give more specifics in terms of patient number, follow-up time, and what kind of, like, efficacy safety data point we should focus on? And also for the 2025, how much more we should expect?
Sure. So we're going to be sharing data on 15-20 patients looking at the combination of Zynlonta plus Glofitamab. We're going to be sharing both efficacy and safety data. And this is every patient that's been dosed with the combination from part one dose escalation as well as part two dose expansion to date, where we have scans available. So we're going to be sharing all the data completely. We plan to share that data sometime in December through a company-sponsored event. And then in the first half of the year, we'll also be sharing additional patients with longer follow-up.
And also you have another combo trial ongoing, LOTIS-7. Can you give us more specifics on that? And how is it positioned next to LOTIS-7?
Sure. So LOTIS-5 is our combination. This is our phase 3 study because Zynlonta was approved via the accelerated approval pathway. And so LOTIS-5 is our confirmatory phase 3 study. It's looking at Zynlonta plus Rituximab versus R-GemOx. This study, we expect to complete enrollment this year, and we expect a readout by the end of next year. When you look at the safety run-in data of this study, the first 20 patients before we went into the randomized portion, the data look very compelling. An 80% overall response rate with a 50% CR rate, which in this data, especially when you look at the combination, it's very compelling with a very manageable safety profile. We're now completing the randomized portion and then expect a readout later this year.
In terms of where it's positioned, I think, you know, when you take a step back, the front-line treatment, which can be curative for 60% plus of patients, is really R-CHOP or Pola-R-CHP. There's more innovations being studied in the front-line therapy to keep improving that. But once you move to the second-line and beyond setting, unfortunately, most patients aren't cured. And they really have four classes of therapies that they can get access to: cellular therapy, bispecific-based combinations, ADC or antibody-based combinations, and chemotherapy. We really believe that the bispecific and ADC combinations are the ones that are likely to win in the end. CAR-T, despite the strong efficacy because of some of the hurdles in terms of administration and safety, have basically plateaued at about 20%.
We think if the bispecific combinations continue to improve in terms of efficacy, that may also erode, especially with less referrals that go to academic centers. On the other hand, chemotherapy, which we know has really a strong rapid response, the efficacy doesn't tend to be very durable, and there's a lot of irreversible toxicities where physicians are trying to really move away from systemic chemotherapy-based regimens beyond the front line setting in DLBCL. The two remaining classes are bispecific-based combinations and ADC-based combinations, both of which we expect to have better efficacy and safety profile versus other novel combinations that exist today. Our LOTIS-7 is playing with the bispecific combinations, and our LOTIS-5 is an ADC combination that we think can deliver very compelling efficacy. We saw 50% CR rates already in our safety run-in with a side effect profile that's very manageable.
In the end, the reason you need these choices for patients is that you're talking about a patient population where two-thirds of the patients are over the age of 65, oftentimes have comorbidities, and you need different profiles of efficacy and safety. And what we've heard from physicians through extensive market research is if you get to the 50% plus range of CR rates, 50%-60% is pretty similar in terms of efficacy. They're going to decide a lot on safety and the accessibility of the product. And that's why we think having both LOTIS-7 and LOTIS-5 as options will help us to provide combination therapy that can be good for really virtually any patient.
How should we anticipate the regulatory path forward for LOTIS-7?
Yeah, so for Lotus-7 , right now, because of Project Optimus, we're basically looking at the dose expansion. We're looking at 20 patients in each of the two dosing cohorts. So we have our approved dose of 150 micrograms per kilogram with Zynlonta with the full dose of Glofitamab. We also have one dose lower just to test two different dose combinations. We're going to have 20 patients in each dose combination. We'll have that completed next year, and based on that data, we plan to talk to the FDA and discuss the path forward for a phase three confirmatory study.
Great. And besides the DLBCL, what are other indications in non-Hodgkin lymphoma that Zynlonta actually could pursue and well-position the next two CAR-T and bispecifics?
Yeah, so the other two indications we're studying right now are relapse refractory follicular lymphoma and relapse refractory marginal zone lymphoma, both of which have still quite a bit of high unmet need, and both of which we're going to have data presented at ASH this coming December. So when you look at marginal zone, just to start off with, marginal zone lymphoma is about 3,000-4,000 patients in the U.S. Typically, if you look at what's approved, there's very few agents actually approved. Most things are in the NCCN guidelines, and that's where the majority of products are used. You typically see CR rates that are below 30%. And so although it's a very indolent lymphoma where patients progress slower, the response rates are not very high right now. And so there's still a need for higher response rates.
You can't compromise safety because, again, it's a more indolent lymphoma. You need to balance getting higher efficacy without compromising safety. So right now, there's a phase two IIT out of the University of Miami that's studying Zynlonta as a single agent in this patient population. The first 20 patients, which were evaluable, which will be presented at a poster presentation at this year's ASH, showed that the CR rate in the first 20 patients was 75%. So when you look at the reference point that nothing has been above 29% so far, we're already at 75%. Just to give you a sense, the data that's been in NCCN guidelines approved is all based on patient sample sizes of 36-68 patients. This is a study that we're enrolling 50 patients right now, 20 of which will be presented at ASH.
We think there's a compelling opportunity here, both in terms of pursuing a regulatory pathway as well as NCCN guidelines. The market opportunity is pretty meaningful for Zynlonta in this tumor type. Now, if you turn to relapse refractory follicular lymphoma, there's a lot of phase 3s and confirmatory studies that have happened in follicular lymphoma and a lot of advances that have been made. Where the unmet need really still exists right now is really in the high-risk population. When you look at the POD24 patient population, which is about 20% of all relapse refractory FL patients, and then you add on also the high-risk patients, those are patients that typically progress much quicker, that have poorer outcomes than the broader population. We're exclusively studying in that high-risk population. There's a study ongoing in another phase 2 IIT looking at 100 patients.
This will be an oral presentation at this year's ASH. The best CR rate in this study amongst the first just over about 35 patients is 80%. So it's very, very compelling when you look at most things in this population have a CR rate of only roughly 40%. So in both of these indolent lymphomas, we're seeing extremely compelling data right now with Zynlonta in MZL, with Zynlonta as a single agent, and in follicular lymphoma with Zynlonta in combination with rituximab, the same combination that we're looking at for LOTIS-7. So we think both of these could be interesting opportunities as these studies mature and read out because obviously we need to not only enroll, but you need to have sufficient follow-up given the indolent nature of this disease, of these diseases.
We plan to talk to both the regulatory authorities and NCCN guidelines to pursue a path forward for both of these indolent lymphomas.
A lot of data events for Zynlonta by the end of the year. Looking forward to it, and maybe now moving to earlier line and solid tumors. Could you walk us through your decision to deprioritize AXL, ASCT2 programming in solid tumors, especially in the context that you pursue the next generation exatecan-based ADC platform? Thanks.
Yeah, this is a pivot in strategy also where we're pursuing. We decided that now, with the termination of our AXL program, really deprioritize the focus of PBDs and solid tumors. And we're really shifted our focus to our novel exatecan platform. We have four different targets there that we're pursuing: claudin-6, PSMA, NaPi2b, and ASCT2, all of which we think we have a pretty differentiated position. We know that with our novel ADC platform focusing on exatecan, because of the novel linker that we have, we've been able to really offset the hydrophobicity that you typically see with pure exatecan with a highly hydrophilic linker. And we've seen a lot of differentiation versus other topoisomerase I inhibitor platforms. For example, we have lower risk of multidrug resistance. We have greater bystander effect, greater potency. We haven't seen any ILD.
A lot of the things that you see with other platforms, we haven't seen so far. In addition, we know that for a number of these, like for example, for PSMA and claudin-6, these are clinically validated ADC targets. And we believe we're the first in class with an exatecan-based platform against these targets. We think we have a lot of compelling areas within our platform. We plan to pursue at least one on our own that we've funded with our last financing through IND. And then we're also in different discussions right now around research collaboration so that we can pursue a broader portfolio of these solid tumor assets.
Okay. And on this next gen platform, you have noted NaPi2b, Claudin-6, PSMA, were advanced in IND enabling studies, and also you selected ASCT2 targets. Just curious, what are the general principles for the target selection? Is it particularly compatible to this next gen platform, or it's more from a market perspective?
It's both. I think we really look at the competitive landscape. And when we're looking at the ADC landscape, we're not only thinking of target competition, we're thinking of payload competition because oftentimes you may have multiple targets expressed on the same solid tumor or solid tumors. And so we're looking at, you know, one is the target really amenable to an ADC approach. Is it differentially expressed on the cancer cell versus a healthy cell? Can you internalize an ADC and really deliver the drug in a targeted way? What other targets that could be amenable to ADCs are expressed on that cancer cell? And when you look at the pipeline, are there others that have the same platform?
So for example, we wouldn't want to compete with the same targets with the exact same payload because that would be, in a way, payload competition, even though you may have a different target. So we do look at the competitive landscape. We look at what the market opportunity is. We look at where we think there's a differential opportunity both with the target and the combination of the payload that we can deliver, you know, a strong efficacy safety profile and one in which is going to have significant commercial upside.
What would be the milestones in 2025 for the solid tumor pipeline?
So we'll disclose more. We haven't disclosed what all the milestones are. We'll disclose that as we go into next year. But we certainly will disclose one of the programs that we're moving forward on our own, as well as the stages of advancement for the rest of the portfolio.
Okay, fantastic. We will wrap up here. And thanks for a very insightful discussion. And thanks for everyone for attending this session.
Thank you, Kelly. Appreciate it.
Thank you.