ADC Therapeutics SA (ADCT) Earnings Call Transcript & Summary

Welcome, everybody, to our next fireside chat. It's my pleasure to host Chris Martin from ADC Therapeutics.

So Chris, let's just dive right in. You guys are -- by the name of your company, are focused on the antibody drug conjugates. Can you just discuss the PBD-based antibody drug conjugates? What makes them different from some of the other approaches out there?

Certainly, Boris. The PBDs were developed specifically to be active in tumor cells, which were either primary refractory or had acquired resistance. They're very potent. They're at least 100x more potent than drugs like the auristatins, mytomycins, [indiscernible], which themselves, of course, are much more potent than systemic chemotherapeutics. But the really important thing about the PBDs is that they cross-link into the DNA, binding 2 strands together. And they do this in a way which doesn't -- isn't seen by the DNA repair machinery. And this -- which means that they can kill both rapidly and slowly dividing cells. But most importantly, that they have this activity in otherwise very hard-to-treat tumors. So I think you can see with our long-path lead program, Lonca, that it's really achieving this, that we have this breadth of activity across patients, even patients that never respond to any prior line of therapy, we have over 30% response rate. So that's really what makes PBD special. We're using a later generation of PBDs. The early PBDs were quite oily, not very water-soluble. Once we use are much more water-soluble. They have at least tenfold superior therapeutic index-based on preclinical models.

And can you comment in terms of manufacturing? Is there anything unique in terms of making these PBD, ADCs versus some of the other approaches? And who does it for you guys?

Yes. Like all toxins these days, the process is polysynthetic, and it's -- synthetic chemistry process, obviously, very high potency at the end. And the drug -- and the one thing that is different about PBDs is that the linker and the toxin are built together. Quite often, the toxin is built separately and the linker is added on to it. But with the PBDs, they are one unit. And they're manufactured for us by Lonza.

Great. So let's dive into your leading asset, Lonca, antibody drug conjugate against CD19. Can you bring us up-to-date where you are in terms of the regulatory process? And then let's engage in a discussion in terms of how you see it fitting in competitively into the CD19-targeted DLBCL market.

Yes. We have a PDUFA date of May 21 for accelerated approval in the third line plus DLBCL. So obviously, we're some way through the BLA review process now and very much looking forward to the PDUFA date.

Great. Is there any site inspections or major things that are still required to do? Have those things been done? We're just trying to also assess that in the context of COVID-19 and any travel limitations that people may have.

Yes. So clearly, we're a fair way through the process now, and the interactions with the FDA have been as expected. The people that manufacture the antibody -- the drug link, which is Lonza and also the drug product, which is BSP, they all manufacture antibody-drug conjugates or components of those 4 commercial products. And they've all been inspected by the FDA previously. So we're not anticipating any delays on that front.

Great. So let's switch our discussion to the commercial side of things. If approved, can you tell us how you see this fitting into the treatment paradigm for DLBCL, particularly in the context of some other antibody drug conjugates as well as CD19-targeted therapies?

Yes. As I say, our launch will be in the third-line-plus setting. And the way we developed Lonca, in line with the activity of the PBDs, is right across the population in the third-line-plus setting. So that included, as I mentioned, patients who were primary refractory -- truly primary refractory, never responded to R-CHOP, which is standard of care upfront; patients with adverse prognostic factors like double hit, triple hit genetics, transformed disease. And we treated both patients who were eligible for stem cell transplant and patients who were ineligible. So we were quite unusual. If you look at other drugs approved recently in DLBCL, for example, Monjuvi, lenalidomide or pola with bendamustine and rituximab, they were tested in the transplant-ineligible patient population, hence, didn't treat the primary refractory patients with adverse genetics in terms of Monjuvi. So we see ourselves fitting in, really, in the third-line setting, broadly both transplant eligible and ineligible. It's a single agent. It's very convenient. It's a 30-minute infusion in an outpatient setting on a 3-weekly schedule. And you see responses from Lonca quite quickly with a median of 41 days. So this resonates very well with physicians treating patients. If you think about it, they've come down through -- to prior lines of combination therapy. They've either not responded or relapsed on those. Some of them would have had transplant. So the physicians sponsored drug which has activity, particularly in those hard-to-treat patients, where that activity can be seen quite quickly, which has a manageable tolerability profile. So we think Lonca has the potential to be standard of care in the third-line-plus setting. But we're also doing other studies to move into earlier lines of therapy.

So we'll get to that in a second. But let's just -- you mentioned the advantages in adverse genetics and transform disease. Is this something you anticipate in some way, shape or form being mentioned in the label? Just trying to understand how you could market that message out there.

Yes. So the labels both for PBR, pola, bendamustine, rituximab and the Monjuvi, lenalidomide are for DLBCL NOS, where NOS stands for "not otherwise specified." So this excludes the harder-to-treat aggressive versions of DLBCL. Usually, the FDA will give a label, which reflects the patient population that you treated. So if they follow that guidance really, in our case, then we would expect to have just DLBCL without the NOS restriction on it. So that would be something that we would be able to use commercially.

Got you. So let's talk about then maybe your strategy for earlier lines of therapy and combination strategies for Lonca.

So our confirmatory study is in transplant-ineligible patients in combination with rituximab in the second-line setting. So we're currently running that study. We also reported data at ASH last year on the Phase I part of the combination with ibrutinib in DLBCL patients with a non-GCB characterization. And based on those data, we initiated a pivotal Phase II study in combination with ibrutinib, both in non-GCB and GCB patients, and we're including the mantle cell patients there as well on an experimental basis. So that potentially provides us a route into the transplant-eligible second-line setting. Later this year, we'll be initiating an umbrella combination study as well. We've seen a number of compelling synergistic combinations in preclinical setting, with strong rationale for those combinations. And we'll be testing those out in the clinic, as I say, later this year. And we'll also be initiating a dose-ranging study in the frontline setting alongside R-CHOP. And if you think about it, it's those frontline patients, and R-CHOP cures are around 60% of patients. So those 40% of the patients have a poor prognosis. And with the breadth of activity that we're seeing in the third-line setting, we think Lonca is very well positioned, particularly with its manageable toxicity profile to sit alongside R-CHOP in that frontline setting.

So let's maybe talk a little bit about the frontline R-CHOP that you just mentioned. There's been a number of drugs that have been added on to R-CHOP unsuccessfully. Can you comment on what gives you confidence in terms of Lonca? Is there any kind of patient selection that you think could enhance the outcome of this study? What are your thoughts on that?

Yes. We haven't -- sorry, we haven't discussed in detail the patient population we would be looking for. But I think what you're saying makes sense because, as I mentioned, 60% of patients are cured upfront with R-CHOP, and it's the patients that have the poor prognostic factors who tend to be the ones that don't respond or relapse quite early and then have a very poor prognosis. But I think also the people who've tried to either add to R-CHOP or replace one of the components of R-CHOP really have been limited by 2 things: one is the breadth of single-agent activity that they go into that combination with; and the second one is the overlapping toxicities with R-CHOP. So we think Lonca's particularly well suited for that combination because we have few overlapping toxicities. The ones that there are, are hematological and manageable in the hematological settings generally. And also, we have this breadth of activity in those harder-to-treat patients. So that's why we're confident that this will be an interesting conversation -- confirmation in that frontline setting.

Do you have a time line of when you're planning to at least start a frontline study?

We'll be starting later this year with the dose-ranging study. And then clearly, on the back of that, it will determine where we go after that.

Can you talk about your second-line strategies?

Yes. So in second line, as I mentioned, we have the combination with rituximab in the transplant-ineligible patients. And we're testing out the ibrutinib combination currently in the third line. That looks good. We will move that into the second line. But we also have the umbrella study, as I say, with these combinations. These are very good preclinically. It also provides the potential for combinations in the second-line setting.

So in the ibrutinib combo, can you comment what would we like to see in terms of the efficacy in that combination to justify further development?

So I think if you think about the transplant-eligible part of that second-line setting -- and that combination could be used right across the second line. Current induction really has a complete response rate of around 40%. So you'd want to see a complete response rate in a similar size to that. Lonca -- sorry, the Lonca plus ibrutinib combinations to date has been really well tolerated. And the transplant induction regimes are quite aggressive. So Lonca would be quite favorable if it was able to match that kind of CR rate. On the transplant-ineligible side, it's slightly different because you're looking there at duration of response and also the quality of patient life.

Got you. Okay. So that makes sense. Before we move on to Cami, do you want to summarize the key data updates we anticipate for Lonca over maybe the next year?

Yes. So clearly, the kind of key event for us is the PDUFA date. Then beyond that, we will have some data on the combination with ibrutinib at a hematological conference late this year and an update on the duration data generally from the pivotal study again at a conference late this year.

Great. So let's continue on with Cami. Can you briefly comment on CD25 as a target, particularly in oncology? What makes it an attractive target? And what can we learn for some of the history of naked antibodies used against CD25 in the past?

Yes, it's a very interesting topic. As you suggested, it's been used for many, many years in transplant patients to manage rejection or -- host-versus-graft disease. It's expressed on T-cells, particularly on regulatory T-cells. So the naked antibodies really have been used to suppress T-cell immunity. But you can't have an oncology impact with the naked antibodies. There's not a sufficient impact on the T-cells, and in particular on the regulatory T-cells. And if you use it in Hodgkin lymphoma, it's not capable of having a significant impact on the Sternberg cells, which also express CD25. So we were attracted to this because when we -- in the early days of ADC Therapeutics, we were collaborating with University College London. They had a radioimmunoconjugate, which they were testing in Hodgkin lymphoma patients, looked very, very active. And we thought that a PBD ADC would be the ideal way, much more convenient use, more potent. So we took that into initially the HL setting. We saw this really very good efficacy. I mean if you think in the late stage, we've got over 80% overall response rate in median seventh line patients who had failed frontline plus rituximab and the checkpoint inhibitor. And even in those patients, we have over 80% complete -- sorry, 80% overall response rate. So really looking at that level of activity, we decided to look at the immune effect and ran early preclinical models and established even in solid tumors that had high levels of infiltrating T-cells, which you could target the regulatory T-cells with Cami. In the absence of the regulatory T-cells, the T-effector cells expand and have a potent antitumor immuno-oncology effect. So based on this preclinical data, we took that into the clinic. And last year, I presented data showing that in patients during the dose escalation study, with paired biopsies on their solid tumors, you see the same thing. You see that regulatory T-cells being knocked out and an expansion of the T-effector cells. So we're now taking that forward in the combination study with pembro in a basket of solid tumors, and very much looking forward to seeing the data from that, which will probably be early next year.

So you've had a clinical hold, actually 2 clinical holds in Hodgkin's lymphoma for this drug. Can you just tell us a little more about that, what you've learned from that? And how we should be thinking about this drug in solid tumors versus liquid tumors?

Yes. So they are partial clinical holds, and they were due to Guillain-Barre or GBS syndrome. And what we found -- this is a demyelinating autoimmune disease. It starts in the periphery and descends. If the patients are treated rapidly with standard of care for GBS, which is plasmapheresis or IgG, they've recovered to baseline usually within weeks or couple of months. But the reason that we had the partial clinical hold is that we weren't expecting this toxicity, and we hadn't seen it preclinically. So with the FDA, we put the study on hold, while we did a safety review and added some screening of the patients for prior infections. We've only seen this in Hodgkin lymphoma. We've treated over 140 patients with non-Hodgkin lymphoma, leukemia and solid tumors, and we haven't seen GBS in those patients. And there is an association in the literature between Hodgkin lymphoma and GBS. It's a risk factor. So in the HL setting, we think that the benefits that the patients receive outweighs the potential for the GBS side effect, which has proven to be treatable in the majority of cases. And in the solid tumor setting, as I say, we haven't seen it outside the HL and solid tumors or in leukemia or non-Hodgkin lymphoma. I think all immuno-oncology agents have some degree of autoimmune toxicity. And you probably remember the days of the PD-1 checkpoint inhibitors. But people learn to manage those, clearly, the mainstream of therapy in a number of disease areas now. So I'd not say we'll never see any autoimmune -- if you're knocking down regulatory T-cells, the whole idea is that you're activating the immune system in the microenvironment. But we think that is an exciting new modality in immuno-oncology.

Great. And we have just a minute left. You have a pipeline of 601 602, 901, 701. Obviously, we can't get into the details of that, but maybe you could -- do you want to highlight something out of your pipeline or your kind of catalyst out of the earlier pipeline for the rest of the year?

Yes. We're very excited to be filing the IND on the KAAG1 targeting program in the first half of this year. It's a very novel ADC target expressed on multiple solid tumors, including triple-negative breast and ovarian. So I think that's interesting. And we'll also be initiating a Phase Ib combination study with our AXL program again later in the second half of this year after a successful Phase Ia dose escalation study. So I think with those 2 solid tumor programs kicking off during this year, one with a very novel targeting, the other one with AXL, which is becoming an interesting target across multiple solid tumors, those are interesting programs that we look forward to.

Great. And with that, we are out of time. I'd like to thank Chris for participating and our audience for listening. Thanks, everybody.