All right, welcome to this Fireside Chat with ADC Therapeutics. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim. And with me today, I have Ameet Mallik, CEO of ADC. Welcome, Ameet. Thanks for joining us.
Yeah, thank you so much, Michael. I appreciate it.
Jumping right to Q&A. ZYNLONTA is obviously your franchise product, which is approved actually in 3rd-line DLBCL. Sales have been relatively stable there, but we all know you're working on key label extension opportunities. Maybe on the commercial side, as we're sort of nearing some of the important data readouts next year, what are the key learnings from the commercial experience today that perhaps can be applied to future label expansion opportunities?
Yeah, so I mean, overall, we're pleased that ZYNLONTA is one of the only drugs that's been approved as a single agent. In any line of therapy, that's very rare within DLBCL. Outside of CAR-T, it's only been the bispecifics and ZYNLONTA. We know that ZYNLONTA, the attributes of the product, physicians really appreciate. And we're getting used right now 50/50 between Academic and Community. I think some of the key lessons we learned is, one, in the Academic Setting where they're seeing a lot of patients, we're getting used in the majority of Academic Centers right now. In the community, you see a little bit of a bifurcation. Some of the larger centers have more awareness, continue to see the patients, can treat them in the later lines. Some of the other centers tend to refer out much more. It becomes less relevant.
I think as we think about the future indications of which we have two different combinations to move into the 2nd line+ setting, it'll be making sure we can capitalize on the strong support we have in the Academic Center. We kind of relaunch in the broader community, especially as we move into an earlier line of therapy where they see many more patients.
Right, that makes sense. Then, yeah, just thinking ahead, LOTIS-5 , which is your second line DLBCL phase three study, I think you guided to data in the 1st half of next year. Yeah, maybe stepping back, what is your confidence level in the success probability in the 1st place?
It's good. I mean, so it's a phase three study. Obviously, we have it's well powered with 420 patients randomized one-to-one, 90% power. We think it's a very and we believe the execution of the study has been really good. That's one thing that gives us confidence is a large, well-run study. Second of all, when you look at the safety running portion of the data with this combination of ZYNLONTA plus Rituximab, in those 1st 20 patients, we saw an 80% overall response rate, a 50% complete response rate, and a median PFS of 8.3 months with no new safety signals. That was a good indicator before we went into the randomized portion of the study.
OK. Did this, I mean, I think the study overenrolled almost 100 patients, is that right, based on some of the CT that got findings that we saw? Can you confirm that? If so, how should we interpret that?
Yeah, no, I wouldn't say over-enrolled. From the original assumption when we started the study was that we'd do 330 randomized patients. One thing we announced about two years ago was that because of some of the earlier censoring that happened in the study, we wanted to make sure that we could hit the same prespecified number of PFS events, which was 262. That's not untypical, to be honest, in a DLBCL study that you see some level of censoring early on, especially when you have a control arm like R-GemOx, which is not as favorable sometimes as a treatment arm. It was something that we wanted to make sure that we had a very well-powered study that we could hit the 262 events in a timely manner.
We decided, together with approval from the FDA, that we add another 90 randomized patients to the study.
Right, understood. There is obviously a lot going on in 2nd line DLBCL right now. There are CAR-T Cell Therapies, there are bispecific antibodies that are approved targeting CD20. There is Polatuzumab, another ADC in the market. As we think about the LOTIS-5 opportunity, how would you characterize that?
OK, maybe I'll frame it in the context of the overall market dynamics to understand what the opportunity looks like. When you look at the front line setting, about a third of patients are treated in academic, 2/3 in the community. There's a pretty clear standard of care. Almost all patients are either going to get R-CHOP or Polatuzumab vedotin with R-CHOP, irrespective of which treatment setting they're going. As you go through subsequent lines of therapy, 2nd line and beyond, basically, the therapies kind of go into two major categories. One is complex therapies. These are things like CAR-T, Transplant, Bispecific-based therapies. These are therapies that require some sort of Unique Infrastructure and Patient Management Skills. Not all patients have access to those therapies. Then you have more broadly accessible therapies. That's the 2nd segment of which all patients can get access to it.
As you move up in line, more and more referrals happen, so more and more patients get access to these complex therapies. We know that CAR-T, for example, is restricted to about 150 sites. Bispecifics, while they're more accessible, still are limited mainly to Academic Centers and the more sophisticated Community Centers. They're not available across the whole community. These two segments, we believe, will continue to exist. When you look at the 3rd line setting, for example, where we play, about 60% of patients get a complex therapy, 40% get a broadly accessible therapy. In the 2nd line, it's only about 35% of patients that get a complex therapy. 65% get a broadly accessible therapy. The benefit of our strategy is that we want to have leading efficacy in both of these segments. Why are there two segments?
Because not every patient has access to complex therapies, but not every patient is suitable either. You have to think of the comorbidities, the age, and other patient characteristics. That helps to determine what type of therapy is best for the patient. Our LOTIS-5 fits in the broadly accessible therapy. One of the reasons we're so optimistic about the positioning of the product is, if you look at one of the most widely used regimens, it's chemotherapy. It's Rituximab-based chemotherapy. They have about a 25% CR. That's similar to what our monotherapy is. When you look at the other targeted agents, either antibody or ADC-based therapies, they're around 40%. What we saw in our safety run-in portion of the study was 50%. We believe we have a chance to have leading efficacy amongst those broadly accessible therapies.
When you look at the complex therapies, bispecifics on their own have about a 40% CR rate. Combos have 50%-60%. CAR-Ts are around 65%. What we showed in our initial data, the 1st 30 patients, so that data was 87%. We really believe both of these segments are going to exist. They're going to exist in differing degrees, whether you talk about the Community or Academic. Having regimens that can be leading in both segments is really important.
Right. You just mentioned the LOTIS-7 study, which is a phase II study, is obviously super interesting where you're combining ZYNLONTA or ADC with CD20 bispecific. I think the data we saw earlier this summer was really exciting. Yeah, just help us understand maybe at this point where you are with your LOTIS-7 study. I know there's an update pending later this year of what expectations should be for that.
Yeah, so we shared data. As you mentioned, this is a combination of glofitamab and ZYNLONTA, both of which are approved single agent drugs. We know that they have complementary mechanisms. The great thing is very little overlapping toxicities. We knew these things hopefully could combine well. We're in the dose expansion where we enrolled 20 patients in each of two doses of ZYNLONTA plus the full dose of glofitamab. The data look good. We'll share data on all of those 40 patients plus some additional ones. As we continue to expand our approved 150 dose with the full dose of glofitamab, we're currently enrolling up to 100 patients.
When you get the next data disclosure, which will happen this year, it'll be on those 40 patients in terms of the initial dose expansion, as well as a small additional set of patients that have at least a minimum of six months of follow-up. We're going to show an excess of those 40 patients with a minimum of six months of follow-up so that we can address not only the depth of response, which looked really good in the earlier updates, but also the durability of those responses and continue to provide safety update as well.
Gotcha. I know you just mentioned you evaluated two doses, right, 120 and 150 micrograms per kg ZYNLONTA with the approved dose of glofitamab. Is that correct?
Correct.
You selected the higher dose, I think, for expansion. There was not a clear dose response in terms of ORR. Maybe talk a bit about the thought process behind selecting the higher dose.
Yeah, so maybe taking a step back, the dose escalation, we tested actually three doses. All three had no DLTs. We expanded at two doses, the 120 micrograms and 150 micrograms, which that's the approved dose of ZYNLONTA with glofitamab. The reason we decided to expand at our approved dose of 150 with glofitamab, although the Overall Response Rates and CR rates were identical between the two arms, we saw three distinct benefits to the 150 dose. One is a faster time to CR. Time is also important when you get to this relapsed refractory setting. It is not just can you get to a complete response, how quickly does it take to get there? The second thing we saw is better PK data. A lot of the PK Modeling suggests that 150 is the optimal dose. It is our approved dose as well.
Finally, we saw lower rates and grades of CRS. One of the things that we do uniquely with how we're dosing ZYNLONTA is Obinutuzumab is already typically given a week in advance of the step-up dosing of glofitamab, really to debulk the tumor. It was not sufficient because you still see glofitamab on its own as a single agent has about 70% CRS, mostly grade one and two, but there is some grade three and four, which is what leads to the hospitalization during that step-up dosing. What we saw when we did the 120 dose, that CRS dropped to 55%, still mostly grade one and two, but there was one incidence of grade three. When we went to the 150 dose, which is the dose we're expanding on, it dropped all the way to 24% and only grade one.
We see a better profile of CRS as well with that combo.
Gotcha. And then, yeah, I mean, you mentioned earlier, but how do you think the LOTIS-5 regimens, the Rituximab combination, and ultimately the LOTIS-7 regimen may be positioned in the 2nd line space in terms of use patterns, perhaps?
Yeah, I think, again, usually a physician's going to ask two questions. What do I have access to to give this patient? Am I in a CAR-T center? Can I administer it? Do I have access to a bispecific, either by administering it myself or being able to refer out to a center that can administer it? What therapies do I have access to? Are there unique patient characteristics that I need to consider in the treatment decision? For example, if a patient has a risk of infection, has autoimmune disease, you may not want to give a bispecific. Maybe someone who's really refractory after CAR-T and really going down quickly where you need a fast response, you may want something that's going to work very, very quickly.
It depends a lot on those two attributes to say, what's the set of therapies in which I'm going to consider? Once you determine am I in the complex therapy bucket or the broadly accessible therapy, you want to optimize efficacy. What we like is, irregardless of how the world's going to turn out, will bispecifics get adopted in the front line? Will they get adopted more in the community? There are a lot of open questions that we can all speculate about how the future of this market develops. What we feel really good about is that we have the LOTIS-5 combination, which we think can have leading efficacy amongst broadly accessible therapies, and LOTIS-7, which we believe can have leading efficacy among the complex therapies.
Right, makes sense. Maybe just going back to the is it too early to get visibility on PFS at this point?
Yeah, I would say the, I think the indicators of durability we're going to have is percentage of CRs that are maintained over time. Typically, when you look at other bispecific combinations, as I mentioned, they're anywhere from 47%-62% if you look at all the bispecific combo data outside of ZYNLONTA and glofitamab. When you look at the durability, about 83%-85% of those CRs are maintained at six months. About 63%-75% of those are maintained at 12 months. We have data from other trials which give an indication of what percent of those CRs are maintained over time. We want to have comparable measures to be able to show not only the depth of response, what percentage of patients achieve a CR, but what percentage of those are maintained over time at 6 months or 12 months.
Maybe just so will you have 12 months data or is it going to be 6 months?
Mostly 6 months. There's a limited set of patients that will get to over 12 months.
Gotcha. You said the bar is 80%-83% for approved?
If you look at the EPCO and glofit GemOx combinations, which are the two that are currently in guidelines, the glofit combination is 85% of the CRs are maintained at 6 months. EPCO, 83% are maintained at six months.
The goal is to match that or?
Yeah, ultimately what you want is you want the greatest number of patients that are at CR at a given point in time. It's almost multiplying the two numbers. What percent of my patients achieves a CR? What percent is maintained? Overall, that gives you what percent of patients are at a CR at six months. If we can maintain that level, we're going to be higher in terms of the percent of patients that have a CR because we're starting with a higher CR rate, right? If you can do even better, you may be able to differentiate on both dimensions and get an even higher percent of patients that can be at a CR at different points in time.
Gotcha. That makes sense. I know you've talked about sort of an NCCN Listing Strategy with the LOTIS-7 data once it's complete the next year. I guess how impactful would you think listing alone will be on the commercial opportunity as opposed to perhaps considering a formal company-sponsored registration study with a combination?
Yeah, so obviously with Compendium, we can't promote, right? So that does limit some of the opportunity because you can't promote the drug. The one thing I'd say is if you look at all the bispecific combinations, none as of today have been approved. So they're all in Compendium only. If you look at the mosun, glofit, and EPCO combinations, so far they're only in Compendium. Yeah, we believe, especially with the EPCO and glofit ones, we'll be at parity, meaning that they're all going to be there. While we will promote, it's up to physicians to decide what's in the best interest. That's typically why NCCN gives the freedom when there's good clinical evidence to be able to give the freedom for physicians to choose and for payers to reimburse. We think we'll be at a level playing field.
We think with the data that we're going to generate, we could be having final results as well as into compendia sometime between the end of 2026 and the 1st half of 2027.
Gotcha. OK. And then I know you're running this combination with glofitamab, but there are obviously other bispecific antibodies available in lymphoma. And yeah, are you considering doing additional combinations beyond that one?
Yes, we have a couple of IITs right now, one in Europe, one in the U.S. with EPCO. Those are really the two main bispecifics. Those are the two most potent bispecifics that are approved. That is what we are focused on.
Right. OK, great. I know that there is data from investigator-sponsored studies also emerging on ZYNLONTA in indolent lymphomas. I do think maybe you can confirm, but I did think there were some additional updates coming at ASH as well from some of those studies. Perhaps just remind us of some of the key studies that you see perhaps supporting the commercial opportunity for ZYNLONTA longer term in indolent lymphomas and then what additional updates we will sort of learn at the ASH conference.
Yeah, so we're really focused, I would say, in terms of indolent lymphomas mainly on Relapsed Refractory Follicular lymphoma and Relapsed Refractory Marginal Zone lymphoma. The Marginal Zone lymphoma, the last data update was at ICML in June showing approximately a 70% CR rate. When you compare that to really what's best in class, mainly Marginal Zone lymphoma was about 29%. So we showed really outstanding data in about 2/3 of the population of the study that's enrolled, which is about a 50-patient study. When you look at Follicular lymphoma, actually data was recently presented in September at a medical meeting showing over an 80% complete response rate. Again, that compares very favorably when you look at other regimens within that relapsed refractory setting. Those have been the main focus areas. There won't be any new updates on those two at ASH.
We do have an oral presentation in Waldenstrom's. This is something out of Dana-Farber looking at ZYNLONTA in Waldenstrom's. We also have a number of posters. One I'd highlight is from MD Anderson looking at consolidation therapy of ZYNLONTA post CAR-T. For patients that have a PR post CAR-T to consolidate with ZYNLONTA, that's one of the key posters that'll be presented at ASH this year.
OK, helpful. Yeah, remind us of, in terms of the incremental commercial opportunity that the follicular and MCL listing, once it gets into NCCN guidelines, could support perhaps on the back of the, at that point, presumably second line DLBCL opportunity.
Yeah, so if you look at the DLBCL opportunity with approval and with compendia, that could be anywhere from $500-$800 million of peak revenue potential. The indolent lymphoma, similarly with compendia and regulatory approval, could be in the neighborhood of $100-$200 million additional.
OK, super helpful. OK. And then assuming success with LOTIS-5, LOTIS-7 in the future, how much expansion of your commercial footprint do you need to support in terms of your sales infrastructure?
Yeah, not much because we already have about coverage of about 90% of the total opportunity. As we kind of get into the launch of the next set of indications, we would have to do small expansions, but I would say marginal compared to the footprint that we have today.
OK, super helpful. I know in terms of your ADC pipeline, you have been focusing on PSMA, which is obviously a well-known target addressing a very large market. Maybe just remind us of the status of your PSMA program and what some of the initiatives are that you're undertaking.
Yeah, so we're on track. This is an exotegen-based PSMA ADC, so topar summary payload. Right now, it's on track to be IND, all the IND enabling work to be completed by the end of this year. The strategy is not to continue to invest beyond that, but to partner the asset. We're in different discussions to look to try to partner the asset for phase one development and beyond, more of a strict sort of outlicensing agreement. We think it's a differentiated asset.
Great. All right, awesome. I think that's all I had. Really looking forward to the upcoming LOTIS-7 update and then presumably the LOTIS-5 data in the 1st half of next year. That should really drive increased potential of ZYNLONTA in the future. Thank you. I really appreciate the time.
Yeah, thank you. Really appreciate it.
OK.
All right.
Bye.