Good morning, everyone. Thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here at the Jefferies. Please join me and welcome Mr. Ameet Mallik, CEO of ADC Therapeutics, for this fireside chat session. Welcome.
Thank you.
ADC space has been very active in making promising clinical progress and the BD transactions. How does this recent trends in the ADC space impact your long-term strategy with your technology platform?
Yeah, thank you, Kelly. So as you know, ADC Therapeutics is a commercial stage company, but also with a very rich platform as well. We already have a product on the approved in the market with Zynlonta, and we've been focusing up to this point, largely on PBD-based payloads. But if you look at the next generation of payloads, novel antibody constructs, and conjugation technologies that we're using, we have a whole slew of technologies with a proven research and CMC capability, as well as development capability to bring these new compounds to fruition. The space is certainly very exciting, as you mentioned, with a lot of deals going on in the space.
We're actively engaged in discussions as well around some of our platform, and we hope to share much more next year around the next set of compounds that are coming out with novel, constructs and novel payloads.
Terrific. On Zynlonta launch, based on what you have been, like, reported so far, what would be your strategy for the rest of the year and also into 2024, regarding your commercial strategy?
Yeah, the commercial strategy, you know, Zynlonta sales, and just like DLBCL, is focused on both academic and community settings. And we know that in the academic centers, particularly given the competitive dynamics in the U.S. with the introduction of bispecifics, CAR Ts moving earlier in lines, and even Polivy playing a bigger role, that space is getting much more competitive. But the community is still largely using a lot of older R-based chemos, and the penetration in the community of any new agent is still relatively low. We think the profile of our compound being a single agent, very fast-acting, typically the best response in six weeks, 30-minute infusion every three weeks, and really manageable safety profile fits very well within the community setting.
We recently launched a new commercial model in the third quarter to really target that community setting, and that's where we see the growth coming from in the coming quarters.
Terrific. Could you also elaborate on the penetration rate at community centers versus academic centers, and how does guide your effort moving forward?
Yeah, right now, the business is pretty split 50/50, but the potential is much greater in the community. We've had traditionally our business, like I said, 50/50, but if you look at the market, it's about 40% academic, 60% community. I would expect that over time, our business may skew closer to even 70% community, 30% academic. So we see there a lot of potential to grow in the community. The community in the U.S. is a pretty long tail. You have a pretty diffuse patient population. The average community doctor is seeing a patient every two to three months, a relapsed refractory DLBCL patient. So when you're launching a product in that setting, it takes a long time to penetrate the tail, but there are a lot of patients out there, and as patients progress, you see stickiness among accounts.
It's a slow penetration, but we do see a lot of growth potential still in the community.
Terrific. We also notice there are quite a few competitive agents in the DLBCL or like broadly NHL landscape. So how do you think this dynamic actually impact the long-term commercialization pathway?
Yeah, the competitive dynamics are... It's significant right now in DLBCL. Obviously, starting with the CAR T therapies, which started moving second line, and that's really shifted the dynamic quite a bit as CAR Ts are moving much more second line. Then the introduction of bispecifics, which happened around mid-year, the introduction of two different bispecifics. They're really playing a large role in the third line setting, post-CAR T in academic centers. We've seen almost no penetration in the community right now. So they're playing a big role there. And then we see Polivy, which posts the frontline approval, not only gain share in the frontline, is really moving actually pretty quickly into the frontline setting.
There's a bolus activity like you see with many other frontline approvals, where you start seeing some second-line and third-line share gains as well for the patients who didn't yet get it in frontline. We expect that to be a more temporary competitive dynamic. As it settles into the frontline setting, physicians have told us they're likely not to retreat Polivy across all lines of therapy. But certainly in this quarter, we saw share gains by Polivy across every line of therapy. So that certainly affected us. We think, though, as Polivy moves earlier in line, CAR T settle in the second-line setting, and bispecifics largely play a role mainly in the academic setting, it opens up a big role for us, not only for the CAR T and bispecific ineligible population in the academic setting, but the community setting more large.
Terrific. And also, do you have data, evidence to show in the post CAR T settings and also the post-bispecific, bispecific settings, how active Zynlonta is in those patient population?
Yes, we certainly have data post-CAR T in our pivotal study in LOTIS-2, which showed impressive data. Actually, our overall response rate was similar in the post-CAR T population versus the overall population. And that's why we were getting a lot of our use, actually, post-CAR T in the academic setting. That's one of the competitive effects that we felt once bispecifics got launched. So academics are quite comfortable giving Zynlonta post-CAR T or post-bispecifics. We're already hearing now, you know, bispecifics work for a subsegment of the population, but for those that don't, patients had to go through it pretty quickly. So we're already starting to see orders in the fourth quarter come back from institutions that didn't order in the third quarter from patients that were progressing through the bispecific. So I think there's a lot of comfort there.
There's obviously not data yet post-bispecific. There'll be real world data because it wasn't, they weren't available when we did our clinical studies. And then in the community, as I said, the penetration is very low, so this isn't really so much of an issue. Less than 25% of patients in the U.S., in the community, who are eligible for CAR T will ever get to a CAR T in any line of therapy.
Terrific. What about a bispecific's penetration rate at a community settings?
Very low. Because of the requirements or the strong recommendation around hospitalization with the first full dose, and because of the CRS and toxicity profile of the compounds, most community physicians don't feel comfortable giving a bispecific in that setting. So what you see is there's a few highly specialized community centers that are affiliated with hospitals and are more integrated centers of care, that are delivering bispecifics, but for the majority of community centers, they're not... There's not been any penetration at all.
Great. And, you also have a broad LOTIS clinical trial programs ongoing and trying to move Zynlonta into earlier line settings. I'm curious, ultimately, where do you think the sweet spot of Zynlonta across lines of therapy in DLBCL?
Yeah. So in DLBCL, we have two different studies. Right now, we're approved only in the third line, third line-plus setting, which is the smallest segment I think we're gonna play in with this compound. It's about 6,000 patients in the U.S. But as you move into earlier line to second-line therapy, it opens up a much broader population. There's 18,000 patients in the second-line setting. So we have two different studies. We have LOTIS-5, which is looking at the CAR T, the transplant-ineligible patients, in combination with rituximab. This is for second-line plus DLBCL patients. This will more than double the opportunity that we have today. We've already seen encouraging data from the safety run-in data.
This is the first 20 patients in the study where we saw an 80% overall response rate and a 50% CR rate with no new safety events. So it's a very good profile. I think that will be very competitive. When you look at even emerging other therapies in that second-line therapy, outside of CAR T, it really is competitive with anything. And then as we look to the bispecific combinations, this is where we think it could be, you know, even more transformative. We're working, in partnership with Roche for both looking at Zynlonta with glofitamab and mosunetuzumab in second line. We're doing right now, dose escalation in third-line DLBCL. The expansion, which has already been approved by the FDA, would move to second line.
We think this could be a really interesting combination because you're looking at bispecifics and Zynlonta, which are the two most active and potent single-agent therapies in DLBCL outside of CAR T. The goal is, if we're already getting 50% CR rates with Zynlonta plus rituximab, can we get north of that and get more similar to what CAR Ts are delivering? I think if you get that sort of CR rate, it's gonna be a very competitive profile, which could not only compete very well with any other emerging therapy being out there, but I think potentially even compete with CAR Ts, just given the inaccessibility that we see with those therapies across... for most patients.
Terrific. Can you also comment on the effort, like outside of U.S., what has been the regulatory path, and also what do we expect on the commercialization progress?
Sure. Yeah. So this is gonna be a global launch. We— our partner, Sobi, in Europe, has already launched in Germany, Austria, launching in now Northern Europe. Over the course of the next year, we'll launch in markets like the UK and across Europe, but also, launch in Brazil, launch in the Middle East. So we'll start to see this launch progressively grow across the board next year. In China, we have an accelerated approval. We expect approval next year, and then given the timeframe for China, expect a launch in 2025. And then most recently, our partner, Mitsubishi Tanabe, joined the LOTIS-5 study. So we completed the bridging study in Japan. We're now enrolling sites in Japan, and that LOTIS-5 study will be the basis for approval also for in Japan.
Terrific. You just mentioned the commercial model restructuring. Can you share details on that? And also, along with the Q3 sales, when do you expect this new model to actually have an impact on the launch curve?
Sure. Yeah, the new model, I mean, the traditional model that was used to launch Zynlonta was, say, a more typical sales model, where you divide up the country into certain territories, and it's more of a workflow-based model, where if a rep can cover 80 to 100 physicians, you just divide the country into 40 territories, and they can cover the country. But that's not the way healthcare is delivered in the U.S., and particularly on something like DLBCL, where you see a lot of referral patterns. You see real differences between academic and community care. One, because academics can give more complex therapies like CAR T and bispecifics, so there's a lot of referral going on.
But also, because relapsed refractory DLBCL is pretty rare in the community, oftentimes, a community doctor is gonna ask for a second opinion from an academic. So that interplay between the academic and community setting is very, very strong, and our foothold was more in the academic, actually. We had a higher market share in the academic than we did in the community. And so by reorienting to more of a key account model where we have teams, and I'll illustrate it through an example. In Florida, for example, where we had three different sales representatives covering the state, we still have three, a team of three, but now we have an account manager that's looking at large accounts like Moffitt, like Florida Cancer, these big either community or academic centers of care with two other sales representatives.
They work as a team so that you're not only working the formulary and the influence that's happening at the larger group setting, you're also pulling it through at the local community and satellite settings. That key account model is really key as opposed to just targeting individual physicians, because if you think of how decision making is done in DLBCL-... It's a more complex set of influences, and so we just reoriented the whole commercial model and launched it in the middle of Q3. We expect starting, you know, this quarter and as the quarters move forward, to steadily see growth occur as we see the fruits of the new model take hold.
Should we expect associated cost to increase on this new model implementation?
No, it was headcount neutral. It was really around getting the right skill sets. We did change quite a few people. About 50% of the people are either new to the company or new in role. So there's also a chance to make sure we had all the right skill sets to do these roles, and so we did make quite a significant change in the organization, but from a cost perspective, it's no more cost.
Do you plan to give sales guidance in 2024 for Zynlonta?
We'll see. I mean, right now, the market is, as you know, quite the competitive dynamics are very dynamic right now, with all the new launches that are happening right now, as well as some anticipated new launches and the new model settling in. So at this time, we're not providing any additional sales guidance.
Okay. Great. And, for the clinical program, for LOTIS-9, you recently actually discontinued. Could you actually share the thoughts behind?
Sure. Yeah, LOTIS-9 was a study looking at a very tough population. This is the frontline, frail, and unfit population that really didn't have any therapy. These are patients that were excluded not only from R-CHOP, but from mini-R-CHOP, really had no other treatments. We saw very high levels of efficacy, but as expected, you know, in this population, in a single agent trial, also higher death rates. This gets tough to show to compare in a single arm study, because even though the underlying death rate's high, when you're talking about patients, these patients were typically over the age of 80, with several comorbidities, so respiratory and cardiovascular comorbidities. In most of the cases where there were deaths, they were dying from those reasons. But we decided it was harder to move forward with a single arm study.
The only way to move forward in this population would be a comparative randomized study, which given the size of the population and the benefit, we just made the choice to focus more on other combination trials, like the bispecific combinations.
Terrific. And, you just shared a latest data from LOTIS-5 trial. I'm curious for the final readout, do you think the consistent result actually is competitive enough to get into the new competitive landscape of DLBCL? And also regarding the timeline, when should we expect a LOTIS-5 result, the impact commercialization?
Yeah, I think if we maintain 50% CR rate, that's competitive. Even if you look at the new agents coming on board, like some of the bispecific combinations that are coming right now, they are all around that 50% CR rate. So I think it's a very competitive profile with everything that's approved right now and things that are coming on the market. The trial's been enrolling very well. We expect to complete enrollment next year, and then with a readout likely in 2025. Obviously, it's an event-driven trial where PFS is the endpoint, so it depends, of course, on when the events happen, but that's our current expectation.
Terrific. And, anything to add for LOTIS-7 trials?
As I mentioned, I think LOTIS-7, there's a lot of new agents and combinations going after. DLBCL is a very crowded area. I think the way to break out is if the efficacy and safety profile clearly beats everything else, I think the market's actually gonna get simplified. Like you see with R-CHOP or now probably R-CHP, really is the standard of care in the frontline setting. Outside of CAR T, which is given to us, you know, only patients in the academic center, for the majority of patients, there is no clear standard of care still in the second-line therapy setting. I believe that Zynlonta with bispecifics has a chance to become that standard of care if the data emerges as we, as we think it may. So it-- we think it's-- this is a really big opportunity. As I said, we're in dose escalation.
The key is gonna be to make sure the agents combine safely. We're dose-escalating right now the Zynlonta portion, so we're working with the approved doses of both blinatumomab and mosunetuzumab and dose-escalating Zynlonta, starting with a 90-milligram dose, then we'll go to 120, and then 150. And we're not only studying it in DLBCL, but we're also studying it in follicular lymphoma and marginal zone, where we're also... You know, we've seen. We've already reported interesting data with Zynlonta and Rituximab in follicular lymphoma as well. So we think this has a chance to play not only in early lines of therapy in DLBCL, but in more indolent lymphomas as well.
What is your expectation on the added value of survival benefit to bispecifics?
Well, if you think right now, bispecifics in the third-line setting have CR rates of roughly 40%, and, that's where blinatumomab is, and Zynlonta is about 25%. As you move into earlier lines of therapy, you typically get higher CR rates. We've already seen 50% with Zynlonta plus rituximab, so I would, I would expect a number north of that, with a combination of bispecifics in Zynlonta. And if you get in that, closer to that 60% range of CR rate, that's now getting competitive with CAR T, if, the CRs are durable. So, you know, that's the sort of range that we would, we would hope to see with this sort of combination.
Both have been proved as very active agents, but curious on safety front, have you noticed any, like, overlapping toxicity signal, so that in the combination you actually should have some concern?
Yeah, so on the labels, there aren't any overlapping toxicities, and we're in dose escalation right now. As we speak, we're dosing patients. We haven't seen any toxicity concerns so far with the combination.
Terrific. You also have multiple programs progressing for tackling solid tumors, targeting AXL and also KAAG1. Could you actually share with us the progress and also when should we expect the first data update from each?
... Sure. So first is our program ADCT-601, which is targeting AXL. This is a very exciting program. We know AXL expression is high in a number of different tumors. We've been focusing right now, the dose escalation, largely in sarcoma patients, because even in an unselected population, you see high levels of AXL expression. That's been progressing well. We're finalizing the biomarker, which we expect to have ready in the early part of next year, and then we'll go to a more selected population in pancreatic cancer to a recent cohort that we added, as well as in lung cancer. We've already been testing lung cancer from a safety standpoint, and so far, as I said, the dose escalation is progressing well, and we plan to interrogate all three: sarcoma, pancreatic, and non-small cell lung cancer.
We expect to have some data in the first half of next year and even more data in the second half of next year across those different tumor types.
So first half, non-small cell lung cancer or, or all three?
We'll have more data certainly in sarcoma, obviously-
Okay.
because we're more progressed there, and that's a... You know, even in an unselected population. But we'll have data across the different tumor types throughout the year, all three, all three.
Okay. Based on what you have observed for the AXL agent, do you think this has the potential to be used as a single agent or in combination?
Yeah, clearly, we want to see single-agent activity. And I think that's critical for any agent, but it also has the potential to be used in combination. So we saw preclinically in sarcoma and in pancreatic models, the combination with gemcitabine had really additive efficacy. So, you know, we're gonna look at this both single agent and in combination.
Okay. What about the KAAG1? Do you need a biomarker for the patient selection?
For KAAG1?
Yeah.
Yeah, it's ADCT-901 targeting KAAG1. It's a very novel target. Also, going after a selected population, we're finalizing the biomarker, but that, that drug right now is going through, I'd say, one of the final stages right now of dose escalation, and then we plan to share that data in the first half of next year.
Okay. And also, any update from your CD22 program?
Yeah. So as you probably remember, last year at ASH, we presented some interesting data at the 50 microgram per kilogram dose, where we saw some deep responses in patients that were pretty refractory to other therapies, including some patients who had prior CD22 therapy, multiple CAR T or transplants. So we're continuing to dose expand at that level, and then in the progress right now of dose escalating, as well as adding more sites for the 602 program.
Terrific. And lastly, we do actually notice that the stock price under stress a bit recently. I'm curious what the investors actually are missing, and also, what will be the catalyst in the next 12 to 24 months that will help actually on the stock trend?
Yeah, I think the biosimilar combination will certainly be a key catalyst. I think we'll release a good amount of data next year, and I think if that emerges, well, I think that could be a big catalyst for the company, but also the three Phase 1 assets. And then finally, business development around any of those assets, plus our research platform. I think there's not a lot that's known yet, even about our research platform and what the next-generation technology looks like. We'll be releasing a lot more of that. So I think we plan to show progress on our sales trend, on the combination study, especially the biosimilar data that's gonna come out next year on all three, one of our Phase 1 programs, and on the research platform. So 2024, you know, 2024 is a big year of catalyst for us.
We have $310 million of cash. We have the cash runway through mid-2025, so we have the cash runway to read all this out next year.
Okay. Maybe one more. I caught you mentioned the next-generation technology. Could you actually share some more, like, color on that? Or are you talking about the new toxin linker or actually the combination, like, what's behind this next-gen?
Yeah. So I think, well, first of all, there's a lot of new emerging targets that are coming out right now that I think are gonna be amenable to ADCs. And, you know, as I mentioned, historically, the company worked more just with PBD-based payloads, which are highly potent and, and can really work well with a specific set of tumors. But the key to interrogate a broader set of biological targets is having a bigger toolkit. And so over the last year and a half, we've really expanded the toolkit, not only in terms of payloads, linker, and conjugation technology, but also in terms of novel antibody constructs. This is all formed into the next set of development candidates that we'll be sharing next year, going after what I think are very important molecular targets for ADCs.
That next generation of compounds, we'll start sharing more information next year.
Okay, terrific. Thanks for a very insightful discussion, and thanks to everyone for attending this session.
Thank you, Kelly. Appreciate it.
Thank you.