Hi, everybody. My name is Alexa Deemer, and I am here with my colleague, Eric Schmidt, and we are a part of the Cantor Biotech Equity Research team. We are very honored this morning to be sharing the stage with Ameet Mallik, CEO of ADCT or ADC Therapeutics. Thank you so much for joining us this morning.
Yeah, thank you.
Unfortunately, we only have, I guess now, 27 minutes to get through a lot of topics, so why don't we get started? Ameet, maybe you can start by providing a brief overview of ADCT and ZYNLONTA and what you believe differentiates ZYNLONTA from other treatment options in DLBCL.
Sure. Well, thank you so much for the question. ADC Therapeutics is a commercial-stage antibody drug conjugate company, one of the pioneers, and we are really focused on our commercialized product, ZYNLONTA, which is an anti-CD19 ADC, using a novel payload of PBD. The way this product is differentiated is it works extremely quickly. When you get to a CR, those responses tend to be very durable, and it has a manageable side effect profile with a time-limited course of therapy. It is an outpatient therapy every three weeks, only 30-minute infusion, so it is very simple to administer as well, both in the academic and community settings. It is also a single-agent activity, which is quite unique within DLBCL. Outside of CAR- T and bispecifics, it is the only product that has ever been approved as a single agent and therefore also is combinable with other regimens.
We see the potential to not only expand into earlier lines of DLBCL, in particular with our bispecific study with glofitamab, our LOTIS-7 study, but also through our indolent lymphoma studies, which we're studying both in follicular lymphoma as well as marginal zone lymphoma.
Then I guess before we get into more of the expansion opportunities for ZYNLONTA, I guess what aspects of the story do you still think remain most misunderstood or underappreciated by investors?
Yeah, at the end of the day, we have an asset that's on the market that's approved that does about $75 million- $80 million a year. That's a starting point. We will be sharing data. The ASH abstracts will come out November 4th for both marginal zone lymphoma data and LOTIS-7 data, which is our combination between ZYNLONTA and the bispecific glofitamab. In prior data disclosures, we've shared best-in-class data in both of those settings, and we think that with the meaningful opportunity that we have there, with publications coming later and then getting into compendia in 2027, we do believe there'll be additional growth opportunity from our existing business, but also through some incidental use. We obviously, of course, will not promote off-label, but both of these markets have a lot of incidental use today. Finally, we think we have an opportunity even from a regulatory standpoint.
We're going to be filing for breakthrough designation for both the combination of ZYNLONTA plus glofitamab as well as in marginal zone lymphoma. We think we have a regulatory pathway to take this asset to over $600 million of peak sales. I think the value of what we have today and what we're going to have in the near term as well as in the long term for this asset is underappreciated.
Now you can elaborate a little bit more on where ZYNLONTA currently fits into the treatment paradigm in DLBCL and what the expansion opportunity into earlier lines of therapy looks like.
Sure. Today we are approved as a monotherapy in third-line plus DLBCL. We have about a 10% share despite having actually a lower CR rate than many of the combination regimens that are currently approved there. The reason we are used is you are typically getting into your best response at the first disease assessment, which is at six weeks. So after two cycles, you are typically getting into your best response. And those CRs tend to be very durable. So the median duration of CR was not reached even two years with two years of follow-up. So they tend to be very durable. And because it is a fixed course of therapy, most patients are getting three to four cycles of monotherapy. It is actually very easy for the physician to administer and easy to manage for the patient as well. So that is where we play today.
Where we are going is a real focus on the combination with glofitamab, which is one of the approved bispecific products from Genentech Roche. It has obviously excellent efficacy and a good profile on its own. So now you are combining two of the most potent single-agent drugs together, where in the data we have released up to this point on the first 49 patients showed additive or synergistic efficacy as well as actually a very manageable safety profile. Within that data, we demonstrated in the first 49 patients a 78% complete response rate and safety that was overall manageable with lower rates and grades of CRS and ICANS than we would otherwise see with glofitamab monotherapy.
All right. Oh, go ahead.
Can you talk about the size of that second-line opportunity as you see it for this combination, and then maybe also talk about how lymphoma is treated today in the second line?
Sure. When you move beyond frontline therapy, which is pretty standard, R-CHOP or pola-R-CHP-based therapy, when you get into the second line, it's actually quite fragmented. CAR- T has established itself as the most efficacious agents to date, not only because of the high rates of CR, but because of the durability of those CRs. But because of access, logistics, manufacturing requirements, the use of CAR- T has actually been limited to about 20% of the second-line plus market. In second line, you get about 20% CAR-T. In third line plus, you get about 20% CAR-T. But the market's sort of been capped at that despite having the most efficacy.
For off-the-shelf accessible therapies that are not only in academic centers but can be available in the community, you see a more fragmented approach. The only approved product outside of CAR-T that's a targeted product is MONJUVI lenalidomide. That's the only product that's approved. Of course, there's a lot of chemo use that's being used. There's off-label regimens. There's bispecific use. Already today, bispecific combination use in the second line where they're not approved, we estimate is already about 10%. Just because of the efficacy that's shown. So it's a pretty fragmented market. When you get to third line, it's also continued to be very fragmented. We believe there's an opportunity in that 80% of the market that's not CAR-T to clearly disrupt the market with a bispecific combination. We do believe that bispecific-based therapies will continue to grow in the second-line-plus setting.
Today, they're primarily given in the academic centers and the more sophisticated community centers. But if you look outside of lymphoma, there's now 14 different bispecific products that have been approved across oncology. As those products get increasingly adopted, we do think that the community, over time, will adopt these products as well. We think that over time, there's quite a big product, not only through compendia, but through the regulatory approval for us to grow ZYNLONTA in combination with glofitamab.
Earlier this summer, you presented results from the LOTIS-5 study. Maybe you can just remind us of the study design and what your main takeaways were from the data.
Sure. LOTIS-5 was our phase III confirmatory study. It was a 420-patient study, one-to-one randomization of ZYNLONTA plus rituximab versus R-GemOx. Within that study, the primary endpoint was PFS, key secondary endpoint of overall survival. While the study demonstrated, met the primary endpoint and demonstrated a positive PFS benefit, no detrimental effect on overall survival. We saw big differences in terms of the CR rate and duration of CR. There was an imbalance in the Grade 5 TEAEs, and that's led to some more uncertainty about the regulatory approvability of that combination.
That was going to be my next question. You recently had the pre-sBLA meeting with the FDA. What sort of feedback did you receive, and how are you thinking about this regulatory path forward?
Yeah. The FDA basically said that they have concerns about the benefit risk profile. Obviously, because they describe the benefit as smaller with an imbalance in TEAEs, Grade 5 TEAEs, and so that demonstrates the risk. We're evaluating different potential regulatory strategies, different risk mitigation subpopulations. But there's definitely higher risk now associated with any approvability in LOTIS-5. That's why in parallel, we're also preparing to have discussions on a new, let's call it a phase III with the glofitamab ZYNLONTA combination in second-line plus DLBCL.
Can we just step back for a minute, Ameet? You mentioned the imbalance in Grade 5 events. What makes you think that's not an issue for the product and is something potentially an issue with the design or conduct of the study?
Yeah. I think when you take a step back, we had about 13% Grade 5 TEAEs. The number one reason for that was infection risk. We know that there is infection risk associated with ZYNLONTA, with bispecifics, with rituximab, with a lot of different products. One of the things that was not in the protocol in LOTIS-5 was the telling physicians to prophylax. We know that the number one type of infection was bacterial. Just to contrast it with LOTIS-7, where we have prophylaxis in the guidelines, per actually the glofitamab label, there is prophylaxis not only for bacterial, but for viral, fungal infections in that protocol that was not in the LOTIS-5 protocol. We also saw some geographic differences. For example, in the U.S., there were no Grade 5 TEAEs. In other parts of the world, there were.
It is interesting when you speak to physicians in the U.S., they would say, "Well, we know how to manage infection risk because we are so used to giving products like CAR-T's and bispecifics where there can be infection risk." So they are measuring IVIG. They are prophylactically giving antibiotics. They are doing things proactively to manage the patient. That is not the case everywhere in the world, and because it was not specified in the protocol, it left for more chance. So we feel comfortable that this was a study issue, meaning not having it in the protocol as opposed to a molecule issue. In LOTIS-7, where in the first 50 patients, for example, we had very tough patients. We had the majority of the patients were primary refractory. Huge portion of patients that were post-CAR-T. We had very tough to treat population.
In those 49 patients, we only had a 4% Grade 5 TEAEs, which is in line with a lot of other therapies. So we do think it is manageable. With what we have done for LOTIS-7 and obviously what we put in a protocol for a new phase III design, we think it would be managed.
Had you had to update any other ongoing protocols for this prophylaxis and side effect management?
No, because it hasn't been an issue in the indolent lymphomas at all. We haven't seen it at all. Look, at the end of the day, if you look at the grade 3 or higher infection risk, actually LOTIS-7 looks similar to LOTIS-5. But what you don't see is the higher grade. I think that testing the immune system and giving the prophylaxis shows that even when you're getting infection risk, it's not as severe as what we saw in some of those patients in LOTIS-5. So we do believe we understand the issue. We do believe it can be managed through prophylaxis, and that is in the protocol both for LOTIS-7 and for any future trials.
You mentioned before that you're evaluating a path forward, potentially using the LOTIS-7 combo, so ZYNLONTA plus glofitamab. That could potentially be used to support full approval for ZYNLONTA. I guess in the meantime, how should we think about the existing accelerated approval status of ZYNLONTA?
Yeah, look, we're committed to working with the FDA to make sure that we have a satisfactory confirmatory study. If you just look, there's very few examples that I've ever been able to see a product being taken off the market. In this case, I can just tell you, when we had the discussion with the FDA, their concerns were about the combination, this trial. They didn't talk about the molecule. Again, we're going to work very proactively with the FDA. I think we're actually driving the timeline more than we're getting requests to talk about potentially another phase III design. So I feel confident that because of our commitment to work with the FDA to make sure that we have a satisfactory confirmatory trial that the product will stay on the market.
Do you anticipate any impact on your existing commercial business?
No.
In the third line?
No. I can't comment too much on beyond Q2 sales, but I would just say we do not believe there'll be any impact on our current sales.
All right. Let's get into LOTIS-7. Maybe you can just remind people in the audience and those listening in what the study design was and what the efficacy and safety that were reported to date.
Yeah, LOTIS-7 is a phase I-B study looking at the combination of ZYNLONTA plus glofitamab, very complementary mechanism of action. We enrolled 100 patients, which we completed in June of this year, and it's evaluating the safety and efficacy of that combination of those 100 patients. Last December, we disclosed data from the first 49 patients, and that's the data I referred to before, where we showed a 78% complete response rate, lower rates in grades of CRS and ICANS, and only a 4% Grade 5 TEAEs. So overall, the profile looked really good. Since then, what we've disclosed is we completed the enrollment of 100 patients. That's the full study. That study is over 50% primary refractory, between 50%-60%, in line with basically every other study that you see with bispecific combinations and in line with the population. We had a good number of post-CAR-T patients.
In August, we reiterated, we think that this combination could be best in class. That safety profile, knowing that that's a question on investors' minds, is consistent with the prior disclosure we had last year. We want to make sure that was clear. We obviously see all the data, so we want to make sure that the point is clear. Going forward, that study now is mature, and we've submitted an abstract to ASH, should be accepted. Abstracts for ASH are released on November 4, and then, of course, full data later in the year.
I guess. Oh, go ahead.
I was just saying, we also plan to publish that data as well, which we'll submit then to compendia.
I guess before we get into the ASH abstract, maybe you can just tell us how the data that you presented for LOTIS-7 compares to what other programs have shown in the second-line setting for DLBCL.
Yeah. If you look at CAR-Ts, obviously, which I think is the gold standard. If you look at the labels of the two leading, let's call it CAR-T products, they're about 65%-66% CR rates. Of course, the key with CAR-T is that the durability is really good. You get 30% of people that are essentially cured at five years. When you look at bispecific-based products, which are, I would say, the next in line in terms of efficacy, bispecific combinations, they range anywhere from 41%-61% CR rates. If you look at the competitive landscape across all the studies from phase I to phase III studies. Our data that we've shared up to date of a 78% complete response rate, we think is highly differentiating.
Not only will we be able to share later this year the data on those 100 patients, but data also with more durability. Things like DoCR at six months or 12 months and different time points, which allows for an understanding of how durable are those CRs over time. I think we're going to have more of an indication, of course, plus the full safety data on those patients.
Then maybe you can just elaborate a little bit more on the. You recently submitted an abstract to ASH. I guess, what should we be looking for in that data set with the additional patients and longer follow-up?
Yeah, I think, of course, the response rates are going to be good. I mean, as I said, the durability of those responses and all the key safety information. I think the abstract will contain even breakouts like primary refractory versus relapsed. I think a lot of the key data will be in the abstract. Of course, you're limited by words, so the full data, all the curves, everything, full safety tables will be at the presentation.
Will there be two different data cuts, or will this essentially be the same data set with an abstract-oriented, high-level view and then all the details at the conference?
Yeah. So because it depends on the publication strategy and what the publishers allow, we need to make sure that any publication is matching what's allowed. So TBD, but likely there will be an update.
What is your publication strategy? You alluded to it.
Yeah. So we're submitting for publication to also have a publication, ideally concomitantly by the end of the year.
You have submitted already?
Will be submitting shortly.
Then, I guess, what level of efficacy and durability would you need to see from this combination that would justify advancing it to phase III?
Look, what physicians have told us, and this has been pretty consistent, is that if you have a bispecific combination that has CRs in the mid-60%s, you already are above the pack. If you get to 70% or above, it is more transformative, and that really becomes a clear option, off-the-shelf option for patients. I think it is a combination. If we can get to 70% or higher CR rates with good durability and a manageable safety profile that can be given outpatient, ideally not only in academic centers, but increasingly in the community center by having a better CRS and ICANS profile. That is the sort of ideal profile that we would be shooting for.
I guess, what could a phase III study look like? So how are you thinking about the appropriate patient population, comparator arm, endpoints? Maybe you can elaborate a little bit more on what your ideal phase III study would look like.
Yeah, we cannot disclose all those details now, but you asked all the right questions which is exactly what we are going through. So we are in the process right now. We have a pretty advanced study design, but as you can imagine, we are also in discussions right now with a lot of KOLs that are involved in the study to get their feedback with some ex-FDA consultants who have worked in the division to make sure that we are thinking through the regulatory approaches as well as our partners who play a big role in the study design. So we are in the process of, I would say, refining all those, but it is exactly the points you hit, which is study population. There is a lot of nuances, especially as frontline therapies could evolve, too. You have to think about that.
With the comparator arm, we obviously do not want to go against something like R-GemOx, ox, and chemotherapy because I think there has been multiple studies now, which have had issues because of centering with R- GemOx. We want to make sure we are going against a really clearly and a more active control arm, whether it is one or investigator choice, and then again, the endpoint, likely PFS. So the different components, I would say we are still refining and we plan to discuss with the FDA and try to get alignment this year.
Okay. What is Roche's level of involvement in this phase of development?
Yeah. We're engaging with them on the design. Obviously, I can't say what the commitment will or will not be. I can't disclose anything, but I would just say that we obviously want to continue to work collaboratively with them. We've had a good partnership beyond study drug. We've learned a lot of insights. They know the molecule, their molecule inside and out. They know this DLBCL space inside and out. And they've had a lot of regulatory interactions as well good and bad that we can learn from. They've been great partners in terms of sharing insights, and their input into the phase III design is obviously very important to us.
Ameet, before we get to a phase III readout, you mentioned the publication strategy, and historically, of course, you've talked about a compendia listing. What can you do and what can't you do with a compendia listing?
You can't promote it. We will not promote off-label to be very clear. If it gets into compendia, it's just a way for physicians to have access to therapies. As I mentioned today, there's actually a lot of use of therapies that are not approved in the second-line plus setting, and it's a way for the medical community. First of all, NCCN and other compendia listings are made up of physicians and the experts in lymphoma that decide what's in the best interest of patients. That's an independent process. We can just submit the application. Should they decide to put this in preferred, it allows for reimbursement of the product, both from Medicare and from private insurers, and then will allow physicians to have that choice.
But we won't proactively promote it, but of course, our medical affairs folks can reactively answer questions if there's questions that come from the medical community about the regimen.
One question we get all the time is an example of a drug that has gone through a compendia process but doesn't yet have a label and how that commercial benefit might be evident.
Yeah. So there's a few examples within DLBCL. For example, when POLIVY was approved, when the study read out front line, which was a positive study where they showed a PFS benefit, the safety looked good overall versus our trial. You saw a pretty big uptake right away when that trial came out and it went into compendia. Of course, with approval, it was even much higher. Similarly, when you look at the bispecific combinations. So bispecific products today, like glofitamab and epcoritamab are approved in the third-line setting. But both of them with chemotherapy and with other regimens have shown very good data in second-line in combination. They're preferred in NCCN guidelines. Our estimation is in the first year post-compendia that the bispecific combinations gained about 10% share in the second-line setting.
I think at the end of the day, DLBCL is such an aggressive disease with such low cure rates beyond frontline treatment that physicians typically want to have the options to do what's best for their patients. That's the spirit at which these guidelines are usually written is just to make sure that physicians have the options to do what's best for their patients.
Maybe you can just quickly elaborate on some of the feedback that you've been hearing from KOLs about the combination of ZYNLONTA with glofitamab.
They're excited. They're really excited because I think they love bispecific products. That's clear. I think bispecifics are already the biggest part of the third-line plus market. I anticipate over time they may be the biggest part of the market overall. I think that they love bispecific products because of the efficacy, and increasingly, especially if academics know how to manage them. They love the fact that they really typically want to move away from chemo because some of the irreversible side effects, the lack of durability. Chemo works quickly. That's what they like about chemo, but it's got a lot of irreversible side effects and not durable. That's what they like about ZYNLONTA. The key thing they've said is, with ZYNLONTA around the side effects, it just makes you have a time-limited course of therapy.
That's one of the things we did with LOTIS-7 is we capped the number of cycles. That wasn't the case, for example, in our monotherapy approval. That's a key factor also as we think about a phase III, is capping the number of cycles to make sure that you get the benefit without the liability of side effects. That's an important piece of feedback they've given us as well. But there's a lot of excitement. I think we would have good enrollment and good participation in a phase III study.
Real quick, were there any other additional prophylactic measures that you incorporated into LOTIS-7?
It's really around infection, and it's not just bacterial, it's bacterial, fungal, and viral. What's in the protocol is basically identical to what's in the glofitamab label.
Okay.
There are specifics about the type of prophylaxis and how it's given.
Got it. Okay.
It's for all types of infections. Again, that's the leading issue with a lot of these more aggressive regimens. That's why it's in the labels of the bispecific products, and we put it proactively in the protocol.
Okay. Got it. Beyond DLBCL, you're also evaluating ZYNLONTA as a monotherapy in marginal zone lymphoma. Maybe you can quickly review the data that has been generated to date and outline the next steps for this program.
Yeah. Marginal zone lymphoma is an interesting market. It's about 3,000- 4,000 relapse refractory patients in the U.S. When you get to that relapse refractory setting, it's really dominated by BTK inhibitors, which have relatively low CR rates. They have higher. More of the patients are in a PR. Typically, patients are on those therapies until progression. They could be on. It's an indolent disease, so patients can be on for a year or two years, even longer at times. While it has the convenience of an oral therapy, it has the burden of having to take forever. We've even had physicians tell us beyond just the inconvenience of a patient have to take them forever, it's even just a financial burden because it's a Part D product where you're paying co-pays every single month.
What we've shown, the highest CR rate shown with a BTK inhibitor is around a 29% CR rate. In our data cut that we shared last year, it was the first 26 patients, we showed a 69% complete response rate.
Substantially higher than anything that's been seen, and that's with a time-limited course of therapy. On average, patients are only getting six cycles of ZYNLONTA monotherapy. It's actually very beneficial to have that, and the durability looks really, really strong. Now what you're going to see is mature data on a study that comes out in November. Today, if you look at the market, about 60% of the market is with approved regimens. It's basically one BTK inhibitor, R-squared, and there's a CAR-T product that's approved in the third-line plus setting. 40% of the market today, roughly, is incidentally used from other products, mainly BTK inhibitors, other BTK inhibitors.
Great. Then maybe quickly where you envision ZYNLONTA fitting in within this treatment paradigm in MZL?
Look, efficacy matters. Safety matters more than it does in tolerability, even more than DLBCL because it's an indolent disease. Some of the KOLs tell us it's one of the bad indolents. They really care about efficacy. You've already seen, for example, CAR-T because of that reason, which got approved in the third-line setting, gained some share because of how much more effective they are than BTK inhibitors. They do want an efficacious product, they want time-limited courses of therapy, and they want something that's manageable and tolerable for patients. That's what they want. I think we have a chance to really disrupt the marginal zone lymphoma market given the profile that we have, which is leading CR rates, strong durability, time-limited course of therapy, and a very manageable safety profile.
We do think we can have a meaningful impact for marginal zone lymphoma patients.
Okay, we only have two minutes left, but before we go, maybe you can quickly remind us what you plan to share at ASH.
Sure. The two biggest things, again, assuming acceptance, because we don't control that, but the two biggest are really the LOTIS-7 data with the combination with ZYNLONTA and glofitamab and the marginal zone lymphoma data. We do have a number of other abstracts which we think are meaningful as well, but those would be the two that I'd highlight as the most important ones that we submitted and hope to be accepted and be shared later this year.
Okay. All right. Last question from me. Maybe you can also remind us of your current cash position and runway.
Sure. Yeah, we ended Q2 with $219 million in cash, and we've reiterated the cash runway at least into 2028.
Okay. All right. Ameet, thank you so much for joining us today, and thank you for everybody in the audience and those listening in for also joining us. Have a great Friday. Thank you.
Thank you.
Thank you so much.