The biotechnology equity research analyst here at RBC, and we're pleased to have ADC Therapeutics with us today. Joining us from the company is the Chief Executive Officer, Ameet Mallik. Ameet, it's good to see you.
Good to see you as well. Thanks for having me.
Great! Well, let's get right into it. It's been a busy time for ADC Therapeutics, and maybe for those less acquainted with the ADCT story, just give us a brief overview of the company, the ADC platform, and how it fits into the broader landscape even.
Okay. Well, thanks, Ray. Yeah, so ADC Therapeutics is a commercial stage, integrated company with end-to-end capabilities. As you know, we have a commercial product, ZYNLONTA, for DLBCL, where there's multiple expansion opportunities for that product. We also have a robust clinical stage pipeline, both in hematology and in solid tumors. We have a platform that goes beyond what our current payload has been, which traditionally has been PBDs, into several other different payloads and linkers and conjugation technologies. Most advanced is an exatecan-based platform with a novel hydrophilic linker that we're using, and we have a robust preclinical pipeline as well.
Great, great. You've had some interesting updates even just over the last week, just starting with ZYNLONTA. Of course, we're gonna—we're gonna talk about the market dynamics and the current commercial positioning of ZYNLONTA. Maybe just talk a little bit about the recent data update on marginal zone lymphoma. Just explain the significance of that, the efficacy signals that were observed, and just help us put that into context.
Well, maybe just taking a step back and thinking of the landscape of marginal zone lymphoma. You know, for patients who get marginal zone lymphoma, first of all, some aren't even treated. About 70% are treated, and then those that are treated typically are treated with an anti-CD20-based regimen. And once you fail systemic therapy, then, of course, the unmet need goes much higher. There's only a couple of treatment options. Largely, you're gonna either recycle and get another anti-CD20-based regimen or a BTK inhibitor. When you look at the competitive landscape, the best CR rates are less than 30%, and oftentimes these therapies require systemic therapy until progression. And so there's a lot of room for unmet need. You know, there's a lot of unmet need and a room for improvement.
When you look at the data we just presented, we're running a multicenter 50-patient IIT right now, focused on those 3,000-4,000 marginal zone lymphoma patients that are treated in the U.S. Of the first 15 patients treated in this study, 13 achieved a CR, one achieved a PR, and one had stable disease and later progressed. Of those 14 patients who responded, all of them are still in response as of the data cutoff, and the tolerability profile was consistent with the known profile of ZYNLONTA. So we see this as a big opportunity for us. As the study progresses and we get to the full 50 patients, assuming the data looks good, we plan to go to regulators to talk about this, as well as to NCCN guidelines.
When you look at what's been approved by the FDA or what's in guidelines, typically, it's been sample sizes of roughly 36-68 patients, either in single-arm studies or subsets of larger studies. So we think the study we're running of 50 patients is robust.
Excellent. And just outline maybe some of the efficacy and durability thresholds, maybe that could be met for registration or for the compendial list in marginal zone.
Yeah. So if you look at current therapies, as I mentioned, CR rates are typically below 30%.
Yeah.
Actually, there was a new agent just recently added to guidelines two weeks ago with a CR rate of about 3%. Durability in the space ranges anywhere from 12-24 months, but oftentimes requires systemic therapy and, and treating to progression like BTK inhibitors. So when we talk to doctors and say, "Well, what's the ideal profile? What would really change the game for that second-line plus MZL patient population?" What we hear is a few things. One is that you can get to 40% CR rates if the durability can approach 18 months, if you get a tolerability profile that's manageable and it's fixed duration. Those are the parameters in which, you know, doctors would love to see MZL therapy going. So far on the profile we see, we're seeing that.
We're seeing CR rate, obviously, when you do 13 out of 15 patients, that would translate to 87%, right? Then you look at the safety profile, in line with the safety profile of ZYNLONTA. So far, all patients progress... who are, who are responding, which is 14 of the 15 patients who have had a response, are still in progression, the longest of which is 20 months, and it's a fixed duration of only six cycles. So we think that we have a profile that can really, you know, meet a meaningful unmet need for patients.
Yeah, and translating that unmet need to the commercial opportunity, which you cited as attractive, just provide a little more color about the MZL commercial opportunity.
Yeah. So if you take, you know, the 3,000-4,000 patients that are second-line plus that are treated in the U.S., multiply it by-- We assume that patients are gonna get... Not every patient will get the full six cycles, so discount that a little bit, so 5-6 cycles of ZYNLONTA, multiply it by the net price of ZYNLONTA. When you do that, you get roughly a $500 million total addressable market opportunity for our product, meaning for every 10% share we can capture, that's an incremental $50 million in peak sales opportunity. So that's meaningful, especially when you look at our current cost basis. Roughly $200 million-$250 million revenue opportunity for ZYNLONTA in total, would help get this company towards profitability.
Great. Great. And then another IST ongoing, just shed some light for us on the efficacy profile in follicular lymphoma. You know, what thresholds might we be thinking about to prompt a transition to a company-sponsored development there?
... Yeah, so follicular is also an indolent lymphoma, and so like MZL, you're balancing the efficacy with a really manageable safety profile. So unlike DLBCL, which is such an aggressive lymphoma, it's all about efficacy. Here, you want to balance the two again. Patients oftentimes with follicular may take up to five years before you progress onto the next therapy. Many patients don't even die of the disease, so you want to balance efficacy and safety. The study we're running right now, which is a 100-patient, multicenter, phase II IIT right now out of the University of Miami, is looking at the high-risk patient population. Most of these patients are POD24, meaning they're progressing within 24 months. So these are the highest-risk patients with the worst prognosis.
In the first 27 patients that were evaluable, this is data that was presented at an oral presentation at the most recent ASH, the investigator showed that there was a 96% overall response rate, 85% CR rate. This is unprecedented. When you look at second-line plus therapies that are either approved or included in NCCN guidelines, typically CR rates are less than 40%. Once you get to later lines of therapy, you see some CAR T use, which is a bit higher. But CAR T, like in marginal zone and in follicular, are rarely used. It's only about 10% or less of cases in the third-line plus setting, just given the safety burden of CAR T. So they're rarely used in those very late-line settings. For all other therapies, you typically see less than 40% CR rates.
So we clearly think we have a profile that's really interesting, especially in the high-risk population that we're studying right now.
Great. Great, and then let's turn to just the marketing position of ZYNLONTA, just to turn to DLBCL. How are you seeing this play out in the third-line setting? I think that the go-to-market strategy was very important. We sort of call it a reset. I think we're kind of beyond that now, but it's really key to kind of getting to that commercial model that you envision. What's the latest on the commercial dynamics there in DLBCL?
Yeah, you know, it's interesting. When you look at DLBCL, in the frontline setting, there's a true standard of care, either R-CHOP or Pola-R-CHOP. Whether you're treated in an academic or a community setting, you're essentially going to get the same therapy. Then once you move to the second-line setting, again, there's a standard of care, which is CAR T-
Mm-hmm
... in the academic centers. The community doesn't really have a clear standard of care. Then when you move to the third-line setting, there's again, not really a clear standard of care. Bispecifics, again, are emerging now as a really important therapy, but again, limited primarily to the academic setting. I think for us, as we relaunched the commercial model last year, it was really about how do we, in the face of more competition coming from bispecifics in the academic center, make sure that we can grow our base there and continue to grow in the academic center, but more importantly, in the community where there's really not a clear standard of care, establish ourselves in a longer tail of community accounts?
So I think what's good is if you look at the last couple of quarters, we've been growing both in the academic and the community. We grew strong double-digit, you know, Q4 versus Q3. In Q1, we grew 7% to get to $17.8 million in sales in Q1. And importantly, we're growing in both segments. So despite bispecifics gaining more and more share in that third line plus academic setting, we're still growing, and in the community setting, we're growing as we expand the number of sites that are using ZYNLONTA. So that was the core of the model, was to make sure that we tailor the model more to the local healthcare ecosystems, and we can leverage a lot of the advocacy that we've developed in academic institutions-
Mm-hmm
... towards the community. The local teams that we have now working in these areas is working quite well.
Great. And then just as you mentioned, with considering the launch of CD20 bispecifics, have those effects been fully observed? Where are we there as far as its influence on the market?
Yeah, they're still growing quite a bit. I mean, if you look at their sales, even in Q1, both the bispecifics from, you know, from AbbVie and Roche are growing still quite a bit. So I think there's still more room to grow, but primarily they're being used in the academic centers. You see some limited use in some of the larger, more sophisticated community centers, but primarily in the academic centers where there's... where we've seen them being used. The opportunity, of course, is, I think, bispecific combinations. If, if the profile can be such that they can be given outpatient, obviously, that's the basis for our LOTIS-7 study-
Mm-hmm
... that combines ZYNLONTA with glofitamab.
Mm-hmm.
If the combination is able to deliver more efficacy and with a safety profile that's amenable to the community, I think that's the much bigger opportunity.
Let's just drill down on that. What is that market potential with ZYNLONTA and CD20 with... Maybe just touch on LOTIS-7 a bit.
Yeah, so LOTIS-7, in LOTIS-7, we just completed a dose escalation, where we looked at the combination of ZYNLONTA plus both of the Roche bispecifics, glofitamab and mosunetuzumab. We did the dose escalation in the third-line plus population. Importantly, we cleared with no DLTs, there were no ICANS, and there was no high-grade CRS. So that's a really important profile. When you look at our dose escalation, just in the glofitamab arm, as an example, we had 33% CRS levels. Of the nine patients, two had grade 1 CRS, one had grade 2. Just when you compare it to the glofitamab label on its own, which is a third-line plus setting, there's about 70% CRS levels, and there is some small levels of grade 3 and grade 4, which is one of the reasons that there's a hospitalization-
Mm-hmm
... with the drug. So we believe if this profile continues, because we're giving the ZYNLONTA a week before the glofitamab to debulk the tumor, we think that's what's contributing to the lower levels of CRS, not only lower rates, but lower grades of CRS. If that continues, as we've now entered the dose expansion, we think that's going to be a very important profile. And then in addition, if we can have additive efficacy, efficacy that's clearly better than the bispecific on its own, that's going to be a really meaningful profile. So as I mentioned, we completed the dose escalation. We're now in dose expansion. We're studying two different doses in LOTIS-7 with a full dose of glofitamab in second-line plus DLBCL patients. We plan to enroll 40 patients by the end of the year, so 20 patients in each dose cohort.
And, we expect to have not only safety data, but at least efficacy data on a portion of those patients that have at least completed the 12-week scan by the end of this year, and then the full 40-patient data set in the first half of next year. Again, if we can deliver a profile where the bispecific ZYNLONTA combination can be given in an outpatient setting without hospitalization, with efficacy that's in the 50%-60% levels from a CR rate standpoint, and with good durability, we think it can become the new standard of care outside of the CAR T setting. And just as a reminder, if you look at CAR Ts in second line, they're about 20% share. Eighty percent of patients in second line, CAR T.
Yes.
When you look at the sales of the CAR T products and add them all up over the last six quarters, it's basically been flat, and we estimate, again, it's about 20%. So for that 80% of the second-line market, where there's not a true standard of care, we believe this ZYNLONTA/glofitamab combination has an opportunity to become that standard of care.
Right. That's great.
It's a big opportunity for us.
That's fantastic. And then just the current progress on LOTIS-5 and the potential for a 2026 approval, what that will mean for even the revenue potential. And I think it's helpful to just think about the LOTIS-7 and LOTIS-5 and the layers of the commercial opportunity to get from where you are now to the next horizon.
Yeah. So we're approved right now as a single agent, third line plus setting. We had sales of $69 million last year.
Mm-hmm.
We think the peak opportunity in third line with a single agent drug is roughly in the $80-$100 million range. As you move into second line, especially in combination, not only do we have triple the patient population, better efficacy, more competitive efficacy profile, but also longer duration of therapy. So all those things we think contribute to the LOTIS-5 population, which is the combination of ZYNLONTA plus rituximab in that second line plus DLBCL setting, to a peak total opportunity for ZYNLONTA of roughly $250-$300 million. That would already take the company, if you look at our current expenses, towards profitability. So it's meaningful for us. Why do we think it's so interesting?
One is, if you look beyond the patients that progress off of R-CHOP or Pola-R-CHP, one of the most common treatments is R-based regimens, again.
Mm-hmm
... in a second-line setting. So for those patients who are not getting a CAR T, one of the most commonly used drugs is to use R-based chemo. So using an R-based ADC is a very common would make a lot of sense. And when you look at the CR rates right now, again, outside of CAR T, typically CR rates are in that 40% range. What we saw in our safety run-in, the first 20 patients before we went to the randomized portion of the study, was an 80% overall response rate, 50% CR rate, and very durable. The safety profile showed no new safety signals versus the single agent drug. So we can maintain that profile. We think it'll be really competitive and play in where the 70% of patients that are treated in the community-
Mm-hmm
... where doctors like to treat, which is R-based regimens. And if we can have an R-based ADC, we think it's gonna fit in really well. In terms of the timing, we'll complete the enrollment of study this year. We expect that it's an event-driven trial. So, you know, PFS is the primary endpoint, so that'll determine the timing. But we currently estimate that we expect to read out later in 2025, which could lead to an approval as early as the late 2026.
All right, great. Well, there's more to ADC Therapeutics than just ZYNLONTA, so do you want to spend maybe the rest of the time talking a bit about the pipeline evolution, solid tumors, and next gen ADCs? Certainly, on the AACR presentation and your updates there, maybe just starting with AXL, what's the development plan for 601? How is this a priority relative to other ZYNLONTA combos and the exatecan-based ADCs?
Yeah. So, well, the nice thing is ZYNLONTA is the core priority of the company because that alone, that's where a lot of our capital allocation is going, and that alone, we believe, will take the company towards profitability.
Mm-hmm.
So then solid tumors is one in which we're, we're gonna be very data-driven. And I anticipate, just given the size of our portfolio, we'll pursue a combination of pursuing some compounds on our own and others through partnership. But specifically around AXL, we successfully completed the dose escalation in soft tissue sarcoma. We started there because we know that the expression levels of AXL are extremely high, 90%-95% expression levels, we look at soft tissue sarcoma patients. So it was a good way before we had a validated biomarker to test and make sure we got to the right dose. These are patients, you know, although it was to get to the right dosing level, we did get to the right recommended dose of 13 mg. From an efficacy standpoint, we also, in patients that typically have 3-4-month overall survivals-
Mm-hmm
... and stable disease is considered good when you get to that third, fourth, fifth line of sarcoma, we saw a couple of partial responses, which are durable, in monotherapy and in combination with gemcitabine. So the efficacy signal is also encouraging as an early signal. We're now optimizing the dose and expanding in sarcoma. We also now have validated our biomarker, which is approved by the FDA, and we're expanding right now as we speak in pancreatic cancer, so we're enrolling patients right now. This will be an enriched population, so we're looking at different levels of AXL expression to determine, you know, what the correlation between response and expression level is. And then we'll move to non-small cell lung cancer in a selected population in the second half of this year.
We expect to have a robust amount of data available by the end of this year, and even more in the first half of next year.
Great. Just on the broader pipeline, just recapping, please, Ameet, just the rationale behind the target selection for the next gen ADCs. What's the current trajectory of development there?
...Yes, we start with just tumors, right? Tumors that have high unmet need, that are large in size, that we think an ADC approach can be amenable, where chemotherapy oftentimes is used when ADC approach maybe could offer advantages. So tumors like non-small cell lung cancer, colorectal cancer, prostate, and others, ovarian. There's several tumors like that, that are large tumors with high unmet need, where we believe an ADC approach can be amenable. Then we looked at targets on those where there's less ADC competition, but we think an ADC approach can be interesting, where there's higher levels of expression of the target on cancer cells versus healthy tissue, where internalization capabilities look good, and where we think we can develop a really good binding antibody towards that target.
And then we went after targets also where and tumor types, where we knew that topoisomerase inhibitors were likely to work, where there was some clinical validation for the payload. And we've shifted now towards an exatecan-based payload. We know how well DXd has done, you know, Daiichi Sankyo's platform. It's obviously has very strong efficacy data, really strong bystander effect. What we see now with the novel hydrophilic linker that we've developed is the ability to bind and conjugate directly to exatecan, which has a lot of advantages over DXd. It has more potency, better bystander effect, and importantly, from a safety standpoint, no interstitial lung disease. We now have four different compounds, so NaPi2b, Claudin-6, PSMA, and ASCT2, which are the four targets that we're going after.
All four are at or near the ADC stage, and from that point, it's about 18 months to get to IND. With the recent fundraise that we just did, where we just raised $105 million last week, one of the sources of funds, of course, is to extend the cash runway to mid-2026. Another source is that we will progress on our own into the clinic, but we're also actively in partnering discussions to make sure that we can advance a broader set of the portfolio forward because we know that we can't do everything on our own.
Yeah. And what are you looking for with some of those partnership discussions? How are you assessing the value add and potentially the selection of moving forward with the partner?
Yeah, I mean, you know, since we're in a number of discussions, and there's interest across all the different targets, I really want to make sure that we have a partnership where we think it's, you know, clearly the party that has the capabilities that can clearly add value, where we think there's a synergy between the two parties. And we want to advance as many of these compounds as we can. And again, I think if we can find the right partner with the right capabilities, that can complement what we have, not only from a financial standpoint, but from a capability standpoint in these tumor types, that's the ideal partner for us to move, you know, again, a broader portfolio forward.
Great. Great. Just want to pitch it to the audience. Any questions for Ameet? Okay. Well, I have to ask again, if we're standing here next year, where, where will ADC Therapeutics be? We've got several, several catalysts coming up over the next year and, and, and beyond. Maybe just highlight some of those, and we'll go from there.
Yeah. So I mean, if I just say by the end of this year, we'll be a company that the sales will already be, from a commercial P&L standpoint, profitable, meaning our sales will more than offset the total commercialization, medical affairs cost of the whole organization, both in terms of people and spend. So that means it starts becoming a source of funds. LOTIS-5, our pivotal phase III study, will have completed enrollment by the end of this year, and by later in 2025, we expect it to read out. LOTIS-7 will have enrolled by the end of this year, 40 patients, and already have an efficacy readout from a good subset of those.
By the first half of next year, if we're sitting here, we'll have the full efficacy and safety readout from all 40 of those patients, and at that point, making a decision to go into pivotal studies, pivotal phase III, if the data looks good. We'll have additional data, I expect, from marginal zone and follicular lymphoma over the course of the next 12 months, which could be encouraging with a larger patient set and with longer duration of follow-up. We'll be well on our way towards actually having not only data in sarcoma-
Mm-hmm.
and pancreatic by the end of this year, but certainly by the first half of next year, we'll have lung cancer as well. So over the next 12 months, we'll have generated data across all those tumors, and then we'll be well on our way to progressing at least one of those compounds towards IND, and hopefully have a partner, at least one partnership, for some of the other assets. So I think overall, it's an exciting time frame, and now that we've extended the cash runway into mid-2020, it allows us to do all those things over the next 6-12 months.
That's great. That's a great place to leave it. Ameet, thank you very much.
Yeah, thank you.