Okay, we're going to kick things off. Good morning, everyone. Welcome again to the Cantor Conference. My name is Eric Schmidt. I'm one of the analysts here, and we're delighted to welcome as our next presenting company, ADC Therapeutics. We have the company's CEO, Ameet Mallik, with us. We have the company's Chief Medical Officer, Mohamed Zaki. We've got Pepe Carmona in the audience, Nicole in the audience. We've got the whole team, and we're going to give the A to Z rundown on what's going on at ADC Therapeutics. Let's first start with just a high-level overview. Ameet, maybe you can give us the two-minute update on what's important that we need to take part of or need to be knowledgeable about ADC Therapeutics.
Great. Thank you so much, Eric, for having us here. We appreciate it. ADC Therapeutics is a commercial-stage antibody-drug conjugate company. We're focused really on two main assets. Our lead asset, which is already an approved product, is ZYNLONTA. It's an anti-CD19 ADC where it's approved in a small indication right now, third line plus diffuse large B-cell lymphoma as a monotherapy. We have multiple trials to expand the use, both in diffuse large B-cell lymphoma as well as in indolent lymphomas. In addition to ZYNLONTA, we have a PSMA targeting ADC that's working towards getting IND ready by the end of this year.
Ameet, since you took over the reins a little over two years ago, the company's refocused itself and almost gone all in on ZYNLONTA in terms of the resources and attention that this molecule has received. Why is that the right strategy?
I think both the opportunity and the competitive landscape have changed quite a bit during this time. First, in terms of the opportunity, we see that the molecule itself has a very differentiated profile. It works from an efficacy standpoint, very fast-acting. When you get into responses, CRs tend to be very durable. The safety profile is very good, not only as monotherapy, but very combinable. In the data sets that we've generated, both with our LOTIS-5, LOTIS-7 trials, as well as in indolent lymphomas, have consistently shown best-in-class clinical profiles. We've seen great data. We've also seen, at the same time, setbacks from some of our competitors where the market opportunity we think has actually opened up more.
We're playing in a number of places that we think we can translate all this good clinical data into an opportunity for the product of $600 million - $1 billion of peak sales. We think it's a substantial opportunity in the product.
What are your top priorities for the next 6 - 12 months? What do you need to execute on in order to be a success in that period of time?
Yeah, we think we can really de-risk the company from a clinical standpoint over the next 6 - 12 months. Our LOTIS-5 study is our confirmatory phase 3 study that's looking at the combination of ZYNLONTA plus rituximab in the second-line DLBCL setting. Over the next 6 - 12 months, we will read out that study and prepare the submission to the FDA, the supplemental BLA for that study. For LOTIS-7, which is the combination that we're looking at right now with ZYNLONTA plus the bispecific glofitamab, Roche's approved product, we're currently enrolling 100 patients in that study. Over the next 6 - 12 months, we'll have that 100 patients completely enrolled and reading out that data as well. Finally, in the indolent lymphoma studies where we've already shown really significant data both in marginal zone lymphoma and follicular lymphoma, you can look forward to more updates there.
Last big picture question before we get into the LOTIS-5 and LOTIS-7 trials in more detail. What do you think investors are missing about the ADC Therapeutics story today?
You know, I think there's a common feeling that the space is very competitive. DLBCL is very competitive. What you see is in DLBCL, when standards of care start to develop, it actually doesn't get that competitive. In front line, where there's been a clear standard of care in R-CHOP or now polatuzumab-R-CHP, virtually every single patient gets it. In second line, I think there was always a feeling that CAR-T would emerge as the standard of care and kind of take over. Because of a lot of the accessibility issues and logistical requirements related to CAR-T, it's really been limited to only about 20% of the market, which means that 80% of that relapsed refractory market is pretty open for what could be a new standard of care.
I think given the data that we're generating, specifically with LOTIS-7, we think we have a chance to become that standard of care, which is a big market opportunity.
Why is it that only about 20% of patients in the second line are getting CAR-T? How do you think that might evolve over time?
Yeah, I think it's going to stay relatively stable. I mean, CAR-Ts were launched over seven years ago, and we've seen the market share over the last two to three years really stabilize at about 20%. I think it's a few different things. One is there's only about 150 centers in the U.S. that can actually administer a CAR-T. There are also a lot of logistical requirements for the patient. For example, the patient and a caregiver need to be at or near the center for about a month. We're talking about an elderly patient population. Two-thirds of these patients are over the age of 65. Many of them don't want to do it or don't have the means to do it. We've seen that play out now where the market share has been pretty stable over the last two, three years at 20%.
If you can't get CAR-T and you're one of the other 80% of patients, what are the options? Is there an emerging standard of care of any sort?
Not really, unfortunately. You know, right now, there's kind of two segments I think that have emerged in the relapsed refractory setting in DLBCL. One of the more complex therapies, which are like CAR-T transplant, and I think bispecifics fall into that category too, where you need specific capabilities within the facility, within the treating facility to be able to administer those sort of therapies. Then you have broadly accessible therapies. These are like chemotherapies, a lot of the more targeted therapies that any community physician can administer. We think that right now the standard of care, obviously, in the complex therapies has become CAR-T therapy, but that's a small segment. Only about 25% of patients are getting a CAR-T or transplant in the second-line setting. For the broadly accessible therapy, there really is no standard of care, and there's still a lot of chemotherapy use.
With our LOTIS-7 and LOTIS-5 trials, we think we're well positioned actually to win in both segments.
How do you size the dollar market for this 80% of the market that's not CAR-T? Where are you going to play?
Yeah, I mean, we think just even if we capture a chunk of that market, not the whole market, I mean, the whole market opportunity is obviously well over a $1 billion opportunity in that second line setting if you're saying 80%. We think just with LOTIS-5, when you double the number of patients from where we are today moving into second line, and we also extend the duration of therapy, we're seeing we're moving on average from three cycles to about five cycles. Of course, even if you were just to maintain the same 10% market share that we have in the third line setting, that's over a $200 million opportunity. We see overall a $200 million- $300 million peak opportunity just with LOTIS-5.
You add on LOTIS-7, and you can start not only competing, then you can start competing against the complex therapies and start expanding it, especially given the safety profile we're seeing. We think the total opportunity in DLBCL can be $500 million- $800 million for ZYNLONTA.
All right, let's start with LOTIS-5. This is your phase III study, ZYNLONTA plus rituximab. Data toward year end-ish, I think, is what we're saying. Maybe, Mohamed, you want to give us just a quick rundown overview of the study design itself?
Yeah, as we actually shared before, the study has completed enrollment a while back, and we're currently tracking the events. This is not really in our hands. Events come whenever they come. We kind of targeted the end of this year to see the events, plus or minus usually, I'm sorry, it could be plus or minus a month or two. It depends on really where the events are and, of course, the work that we do behind the scenes to make sure those events are accurate and reviewed and all of that. We are blinded, so really we don't know much about that.
To find good data, I think the primary endpoint is PFS?
That's correct. The primary endpoint is PFS. Is that the question, sorry?
Yeah, how would you define or give us a benchmark for what you'd hope to see in terms of a PFS benefit?
It's really, you know, we like to see somewhere around the range between, let's say, 8 - 12 months, like that's the typical. You know, of course, you go for something more than that, but that's the range that people like to see. Of course, in this disease setting, to be honest with you, PFS is much of less importance than the CR rate. That's really the driver of all the physicians saying, yeah, the tail could be long, all of this, but we want to see the CR rate. That's really quite important for second line plus setting, third line now, and everybody's looking for those complete responders. Yeah.
What would be a good, sorry, what was?
Just to say that the way the study is powered, though, in terms of the hazard ratio, what we need to show if our GemOx, we are assuming, shows about a four-month PFS, we'd have to show roughly a six-month PFS to have a positive study. That's really kind of the benchmark for a positive study.
In terms of the secondary endpoint CR, what would be a good CR benchmark that you would hope to show?
It could range. We have seen already in the safety run-in portion of LOTIS-5, which is rituximab plus ZYNLONTA or ZYNLONTA plus rituximab, 50% CR with a duration of response of about 8+ months and a PFS of 8.3 months. All that has been reported in the safety run-in in 20 patients. That's where we're hoping to get there. Anything actually in the range of about 40 %- 50% will be a very good solid CR rate that we expect to have a significant change in use, and people will respect that a lot.
Yeah, I mean, if you look at the broadly accessible therapies today, chemotherapy is typically around a 25% CR rate. If you look at some of the more targeted therapies, monoclonal antibodies and ADC-based therapies, they get up to about 40%. I think if you get to 40% or higher, we think it's a very significant result.
What are, in general, the reasons to be optimistic for success, the reasons to think that ZYNLONTA plus rituximab can beat out GemOx?
Many reasons, actually. As a single agent, ZYNLONTA in the third line plus, the median duration of complete response has not been reached after two years. That's a very important durability factor. The 50% CR rate observed in the safety run-in was actually a very important parameter for the agency, not even for us, to agree to a phase III. Everybody knows that rituximab by itself, post R-CHOP, is not going to work. If you see a 50%, where is that coming from? That's also a very good indicator that if you move early, you're almost doubling your 25%. That's the approval of ZYNLONTA in third line. You move to second line, it makes sense that you're moving around. Mostly, ZYNLONTA plus rituximab maybe will do some work there, but it's driven mainly by ZYNLONTA. Those are all good parameters.
Also, the durability that we've seen with this population, the rate of CR, it's really encouraging to us now. Of course, the size of the trial is very important. The power is 90%. The one-to-one rate. The agency at that time, and there'll be, you know, definitely something to be disclosed beyond just the PFS because the FDA will definitely look for it because other studies, their primary endpoint is OS. We have to do that. Typically, in second line plus, it's not very far. You'll see PFS close to OS. Many times, that's why the FDA will push and say, "Okay, give me more," rather than just take, because usually take PFS as a surrogate biomarker for OS, actually. If that's far from it, then they will take PFS.
If you're close to say, "Okay, I need to have some more events on OS to be able to more have confidence on your data," I hope that's what you're asking. Yeah.
How quickly can you recouple, assuming that LOTIS-5 is a success?
Typical timeframe, I think between three and four months max to be able to get everything ready because we're actually cleaning and working in terms of execution of this trial live. We don't have backlogs and everything is ready. The minute we get the top line data and get all the filing data, we're working on a plan for success. You plan everything, so you reduce the amount from readout to submission to the minimum, which is typically around three months - four months.
All right, let's transition to LOTIS-7, which is a phase II study. You've had some very, very encouraging data this year and last. This is a trial combining ZYNLONTA plus glofitamab, the Roche bispecific. Just briefly recap what we've already seen from this study.
Yeah, so there are two parts of the study. We had a dose escalation where we looked at different doses of ZYNLONTA plus glofitamab, no DLTs. We basically cleared all the doses, and then we did a dose expansion. We did the two higher levels of ZYNLONTA with a fully approved dose of glofitamab. Based on that, what we saw in the first 30 patients, this was presented at EHA and ICML, consistent results actually at both dose levels. In aggregate, we saw overall a 93% overall response rate and an 87% complete response rate in those first 30 patients. Also, a very favorable safety profile. We didn't see any new safety signals that are already known with either of the agents. The one major toxicity that was sort of overlapping in terms of the profiles was neutropenia.
Typically, you see about 30% grade 3 neutropenia or higher in either of those molecules, and we saw 24% grade 3 in the combination. We didn't really see additive neutropenia. When it came to CRS, particularly at the dose that we're moving forward with, we're moving forward with the 150 microgram per kilogram doses of ZYNLONTA with the fully approved doses of glofitamab, basically the fully approved doses of both products. The CRS levels that we saw were 24%, which is substantially lower than what you see with glofitamab on its own, and only grade 1. Overall, we see quite a favorable efficacy and safety profile.
Put that 87% CR rate into context for us, Ameet.
All right, so if you look at CAR-T , which is sort of the best efficacy that's been shown, typically CR rates are in the 65 %- 70% range. If you look at all bispecific combination studies in that second line plus setting, everything from phase one to phase three studies, those CR rates have been in the range of 47 %- 62%. You can see how 87% compares extremely favorably to any of those. Of course, beyond CR rate, durability matters as well. Typically, about 12 months out, although 47 %- 62% of the patients get into CR, about 63 %- 75% of those maintain a year later. What we've shown is a much higher depth of response at 87%. What we're going to be showing in future updates is also a lot more around the durability.
I think if we can also beat on that metric, I think that's going to be a favorable combination that we can have good depth and good durability. That's going to be the key, I think, for us with LOTIS-7.
What is the next update in terms of scope and in terms of additional information that we'd like to learn?
We have seen good pickup in the enrollment of the study. We're now enrolling 100 patients at the chosen dose levels. That study is moving well. We said that we're going to have it completed by the first half of next year. When we give an update later this year, we haven't announced when or in what forum, but when we do, it'll obviously be many more patients than we showed last time, also with longer durability.
Are you looking at MRD negativity in terms of depth of response?
We're collecting the samples. We haven't said when we're going to be able to update that data, but it's something we're collecting as well.
We had just under 30 patients, I think, at the last update. Sorry just over 30 patients.
We'll have close to 40 patients or 50 patientds by the year-end update or ballpark. Where are we going to be?
We haven't disclosed, but as you knew in May, we already said we had already enrolled 40 patients, more than 40 patients, and we're enrolling beyond that. You can imagine, and enrollment's accelerated, I would say, since we did the update in June. I think it'll be a pretty good size update.
Would that be at a medical meeting, or you've had a history of generally reporting data at medical meetings?
Yeah, I think we'll have to see. I mean, we haven't disclosed in what form we're going to do. Obviously, there's pros and cons. Obviously, having it presented at EHA and ICML just in June was very good. It really broadened the data out to the medical community. It created a lot of excitement for the combination. We've seen the enrollment, as I said, pick up. The downside, of course, in medical meetings is that you have to just put the data much sooner, and we can't disclose the latest data then to the market. I think we're debating that, and you'll see it in one of those forms this year.
Okay, the goal is to enroll that 100 + patients at the expanded dose cohort, higher dose of ZYNLONTA, and to do what with that data package once that's more mature?
We take 100 patients. If you look at all the precedents, there's been three different bispecific combinations that were added, preferred in NCCN guidelines earlier this year, all based on roughly 100 patient data. With that data, we plan to do two things. One is once the data is published, submit to NCCN guidelines, and we think 100 patients should be adequate. Secondarily, use that 100 patient data to also engage with the FDA because we think that's a robust data set to also drive engagement with the FDA on potential path forwards with phase III studies or other potential path forwards.
Roche is obviously the sponsor for glofitamab. They have interest, I assume, in the study. Can you talk about their participation? You alluded to setbacks in the second-line DLBCL field earlier. They've obviously had one. What's their involvement in the study?
Yeah, they've been a great partner. I mean, it started, I would say, initially with clinical drug supply, but they obviously know their molecule better than anyone. They've had, you know, they have really an excellent team there that's had a lot of regulatory engagement as well. I would say everything from the design of the study to how we think about our regulatory approach, how we think about our NCCN guideline approach, they've had a lot of experience. The partnership that we have and the insights they share with us throughout have been extremely helpful.
What about more financial support from Roche or more of a financial relationship?
Yeah, I can't comment further on any potential other things that could happen. I would just say that we're really pleased with the collaboration that we have with them, the partnership that we have, and the data that we're generating together with this combination.
Okay, should we go on to indolent lymphomas?
Sure.
Conclude there. We have about five minutes left in the session. Maybe just give us a quick update on kind of what you have been doing, both with regard to high-grade follicular and marginal zone lymphoma.
Yeah, so we have two different phase IIB IITs in relapsed refractory follicular lymphoma, as well as one in relapsed refractory marginal zone lymphoma. Both of them are being led by the University of Miami, but these are multi-trial sites. For follicular, right now the study is enrolling up to 100 patients. The latest data, which was just presented recently, showed a 97% overall response rate, 77% complete response rate. Really outstanding data when you think of this population. This is also in high-risk follicular lymphoma patients. Many of these patients were POD 24, about half the patients. It's really a pretty tough-to-treat patient population. We're seeing outstanding data. With marginal zone lymphoma, this data was just presented at ICML. Again, in the first patients cohort that was shared there, this is going to be a 50-patient study, of which it's well over half enrolled right now.
The data overall showed a 70% complete response rate. Just by way of context, in marginal zone lymphoma, the best data shown, if you look at agents that are approved or in guidelines, is about a 29% complete response rate. What we're seeing is substantially better results in this initial data.
With single agents.
Yeah, with single agent and marginal zone. That's a good point. Follicular lymphoma is the combination of ZYNLONTA plus rituximab. Marginal zone lymphoma is just ZYNLONTA monotherapy.
In the high-grade follicular data set that you mentioned, patients with progressive disease within 24 weeks, you mentioned a 97% ORR. Put that into some context for us.
Yeah, I mean, POD 24, so within 24 months.
Y eah, of progression. In terms of the overall response rate in that setting, you know, this is again substantially better. Now, durability matters a lot when you talk about indolent lymphomas because patients tend to live a lot longer. The overall response rate so far that we've seen and complete response rate is substantially better than anything else. Durability is going to keep mattering. As we get more patients and more durability, I think that data set is going to be really, we think, meaningful.
I mean, these are two pretty remarkable data sets. Are you seeing early uptake? Is there any avenue to reimbursement? What do you need to make happen here?
I think to get into guidelines, we need the 50 patients and 100 patients enrolled and published before I think we would be able to get into NCCN guidelines on the preferred regimen. Follicular already, with just a small data set, was actually added into NCCN non-preferred. I think to get real uptake, you need to be preferred in NCCN guidelines. I expect that to happen after the final results of these studies are published.
What kind of timeline are we on for either of the two indications?
For marginal zone, where we're more than half enrolled right now, we're saying that we could be at that point in the first half of 2027. Follicular, we haven't really guided exactly what the timing is going to be because it's a larger study with 100 patients.
Not 2027?
Could be by 2027. We could be getting specific guidance around marginal zone. I think the pathway also in marginal zone is much clearer. If you look at what's been added to NCCN guidelines, the most recent one was a BTK inhibitor with 36 patients. We think the sample size that we're talking about, and that was with, I think, a 3% overall CR rate. The highest CR rate ever in MZL that was submitted into guidelines was with a 29%. We think the pathway there is very clear. Follicular, because there's so many phase III studies that are out there, I think it's a little bit more uncertain than marginal zone lymphoma. That's why we haven't guided.
We've only got one last minute here. Maybe, Ameet, you can just sort of summarize what we've discussed in terms of the upcoming catalysts and also remind us of the cash position and cash runway of the company.
Yeah, we have multiple catalysts really within our cash runway. We ended Q2 with $265 million of cash. That gives us a cash runway into 2028. By the first half of 2027, we expect to have multiple different revenue catalysts. We expect to have full approval for LOTIS-5. We expect to be in the guidelines potentially for LOTIS-7, as well as potentially in the guidelines for marginal zone lymphoma. All those could be potential revenue opportunities starting in that first half of 2027 within our cash runway. Between now and then, of course, there's a lot of catalysts in terms of data readouts, filing LOTIS-5 with the FDA, hopefully getting approval. All these catalysts will happen basically between now and that first half of 2027.
Terrific. We're out of time. Thank you, Ameet, Mohamed, and the team at ADC Therapeutics, and thanks all of you for your attendance.
Thank you very much, Eric.