CytomX Therapeutics, Inc. (CTMX) Earnings Call Transcript & Summary

Great. So good afternoon, and my name is Peter Lawson. I'm one of the biotech analysts at Barclays. Welcome to Barclays Global Healthcare Conference. I just want to thank everybody for taking the time out of their day. And if institutional investors have questions, do ping me, [email protected] or you can ping on Bloomberg. It gives me great pleasure today to introduce the CEO from CytomX, so Sean McCarthy. And just with that, Sean, just your kind of view on the differentiation of CytomX in this kind of broad landscape of oncology companies and various assets being developed.

Yes. Great. Thanks, Peter. Thanks for having us on today as part of the conference. Pleasure to be here. So I think one of the things that CytomX -- we've always had going for us is our intrinsic differentiation. So we began life as a company that set out to reinvent therapeutic antibodies about a decade ago, actually. And the basic concept of the prodrug antibody, the conditional antibody, if you like, that we've invented is an entire new class of therapeutic. For the time being focused on oncology, we do see applications potentially outside of oncology in the future. But right now, very focused on oncology. And I think over the last few years, we have continued to differentiate ourselves by building and maintaining a leadership position in a lot of different ways. So we are the company with the broadest exploration in the clinic so far of conditional antibodies. We've got 5 assets in the clinic. Four them are in Phase II across 9 different cancer types. And we've learned a lot about how to do this, and we'll continue to learn a lot. And we aim to continue to lead the field. And it's been quite exciting actually to see others entering the field over the last few years because I do think the idea of conditional biologics is here to stay, and it's going to be an important addition to the oncology world for some time to come. In addition to the broadest clinical exploration, we've also formed the strongest partnerships. We have formed multiple partnerships with oncology leaders over the year, and those deals have continued to be very successful. We put programs in the clinic. We've owned significant milestones and pretty substantial amounts of non-dilutive capital as well has been an important part of our business plan. We've raised the most money of any company in this field by quite a long way as well. And we aim to continue to aggressively finance the company because this is a long-term game. We're building a broad pipeline, a long-term company, and it takes significant capital to do that. Hence, the combination of nondilutive capital from partners and equity-based capital, including our most recent raise that we did in January, which was heavily oversubscribed and very successful. We also believe we have the [ deepest in central ] properties. We think that differentiates us from the field as well. So all part and parcel of leading and continuing to lead in an area of real differentiation of therapeutic antibodies for cancer.

Thank you. I guess one [indiscernible] you talked to me, just like the conditional biologics, who else should we be thinking about entering that field? Because you have kind of defined these beside your prodrugs for antibodies.

Yes. Well, rather than maybe call out individual companies, I might talk about a couple of different approaches. I do think, I mean, obviously, our approach that we find out has been to leverage one of the hallmarks of the cancerous state of the transformed state, which is the disregulated protease activity in tumors, which has been published on that for decades. There are thousands of papers that have been written on this. We have a very good idea of what drives proteases and differential proteases. That's one approach. I think a pH-dependent approach is interesting. I think modulating antibody binding affinities through modifications of CDRs, I think, has some merit. I think we'll see that become probably more important over time. I see one company I won't mention, which is, I think, particularly pertinent this week that was just acquired yesterday, Maverick, a company doing something in the bispecific space, fairly unique and somewhat complex but rather creative approach to the formation of a bispecific T-cell engagers on the cell surface, also involving a proteolytic step. That company was acquired by Takeda yesterday. I think, beginning to show, the broad-based interest in this type of conditionality, and I think we're going to continue to see. I mean we already know that pharma has been interested because of the deals we've done with BMS, with Amgen, AbbVie, Astellas. But it was interesting to see that acquisition yesterday of Maverick. So those are just a few thoughts.

Yes. Kind of led on to my next question just around, do you think kind of, I guess, the rise of bispecifics in a sense kind of help reduce toxicities? So that's kind of another validation point for your approach.

Yes, that's right. I think the goal overall -- one of the things that we've worked hard on over the years and demonstrated now with the clinical and preclinical we've published is that our platform has an intrinsic versatility to it in that we've been able to apply our masking technology, our protease dependent masking, to multiple antibody formats. So antibody checkpoint inhibitors, drug conjugates, so ADCs that we call Probody drug conjugates, conditional ADCs, to bispecifics, particularly CD3 T-cell engagers. And we think we can apply masking to additional biological formats as well. In fact, we'll be presenting some data in a couple of weeks on some work we've been doing in the cytokine space, which we're particularly excited about. So in each of those different areas, whether you're masking a checkpoint inhibitor or a drug conjugate or bispecific or a cytokine, the ultimate goal, of course, is to improve therapeutic window. And we're either trying to improve where there's room for improvement -- for example, I work with CTLA-4 with Bristol or to create a therapeutic window where there wasn't one previously for first-in-class targets, like the work we're doing in drug conjugates with targets like CD166 and CD71. The T-cell engaging world is kind of somewhere in between in that we're looking to, in some ways, both open and create therapeutic window for CD3 T-cell recruitment on targets that have previously been validated in other modalities, but not yet in such potent modalities as bispecifics. And that will be, for example, EGFR, where we continue to work with Amgen on EGFR-CD3 bispecific.

Okay. Maybe the -- your ADC, sort of anti-CD166, maybe we could walk through kind of what we should be expecting. I guess, in Q4. We get an additional readout, I guess, the initial data readout from your Phase II expansion. So just what we should expect to see there tumor types. I know there's kind of 2 clusters of gene that you're working through. So maybe we could start off with HER2, HER2-negative, HR-positive tumors initially?

Yes. So just a recap on that program. So CX-2009, this is a conditional ADC to CD166. It's an interesting protein. It's very highly expressed on most solid tumors. Its biology is not super well understood. But that isn't really of high importance to us. We tend to think of this protein as an abundant tumor antigen that serves to deliver payload into cancer cells. But it's not been explored by anybody previously in the clinic because it's present on all normal cells at pretty high levels. So it basically breaks the rules of the typical approach to selecting ADC targets. But we've flagged it for a long time because it's so highly expressed on different solid tumors. So we took this construct into the clinic. We ran Phase I dose escalation. And the key successes from that Phase I were, first of all, seeing safety in that we didn't see any obvious on-target toxicity. We saw clinical activity, as we said, in the hormone receptor-positive, HER2 non-amplified setting and also in triple negative. And we also were able to pretty straightforward to get to a Phase II dose of 7 mg per kg given every 3 weeks, which is the dose that we've taken into Phase II. So the Phase II that we're running, it's a 3-arm study. The first arm is looking at monotherapy, 7 mg per kg given every 3 weeks in hormone receptor positive, HER2-negative. And I'll come to TNBC in a moment. We did see -- again, we saw [indiscernible] in Phase I in that fairly difficult-to-treat disease because almost inevitably in Phase I you get pretty late-stage patients who've gone through many different cycles of therapy previously, including hormonal therapy, then chemos, CDK4/6 inhibitors at such length. And so the clinic activity was encouraging. Also the clinical benefit rate, CBR 16 and CBR 24 was encouraging as well because these patients can be difficult to measure objective responses because often the disease is prevalent in bone, not -- a lot of non-measurable disease. So you're looking really as one key measure of success, it's the clinical benefit rate over that 16 to 24-week period. So we're encouraged by the signing. So now in Phase II, we aim to enroll 40 patients in this monotherapy arm. And we're not guiding on specifically what we're looking for. We know what other ADCs have begun to do in this setting, and we'll be looking for something that can work in a similar kind of way. It's a large market, the hormone receptor-positive, as you know, it's one of the biggest market in breast cancer, biggest opportunity, biggest unmet medical need. And there's a lot of room to maneuver, we think, with a novel mechanism and a novel target, such as we have. So maybe I'll continue on to triple negative and what we're doing there now as well. So with triple negative, again, so evidence in clinical activity in Phase I. Interestingly, including in the sacituzumab refractory setting, which is exciting, we're enrolling patients in 2 arms in triple negative, first of all, monotherapy, definitely in combination with our proprietary Probody checkpoint inhibitor, the PD-L1 Probody CX-072, which we also now refer to as pacmilimab. Now the -- again, the goal there is we're not requiring -- we're not selecting patients that have -- we're not acquiring patients that have had sacituzumab in this arm, but of course, a significant number of them likely will have, particularly, here in the U.S. But we do know from Phase I that our drug can show activity in that setting. And again, there's a lot of room to maneuver in the late-line setting because none of these therapies cures it for this very aggressive disease. We also know for the combination that both 2009 and the PD-L1 Probody have single-agent activity in this setting. So we're really excited about that combination to see what it can do. And we're combining with the Probody rather than with an antibody, PD-1 or PD-L1, because our clinical data that we'd most recently updated at ASCO last year shows that the PD-L1 Probody, in addition to having potent anticancer activity, appears to have, when you look at immune-related adverse events and advantaged safety profile. So we see it as an attractive and potentially differentiated combination partner for a drug conjugate like 2009.

And the reason why you're not selecting for patients that already had sacituzumab, is that because you kind of want to have both data sets in hand and potentially [indiscernible]...

I think we just want to get a sense of -- I mean it's not required at the moment that we do that. And so we think it will give us a broader view of what the asset can do both in the monotherapy and, of course, ultimately in the combination setting as well.

Got you. How -- and then, I guess, how that kind of frontline and maybe second-line setting has kind of changed over the past year or so. Has that changed the way you have to think about that trial? Is it -- is that kind of integrated?

No, not really. I mean we did have an opportunity to rewrite the study last year because we halt enrollment about a year ago actually when COVID began to rear its ugly head. And we rewrote the study. It was originally designed as the extension of the Phase I. That is not unusual. We rewrote it as a formal Phase II study. That allowed us to tweak the inclusion, exclusion criteria a little bit, but we still decided to maintain the -- an open approach with sacituzumab. And remember, it's been approved as an accelerated approval. Doesn't have full approval yet. And there's still -- even with that drug, there's still a lot of unmet need because patients -- again, it's not curative.

Got you. Okay. Just keeping an eye on time. So maybe we could pivot over to your CD71 ADC, so which is this transferrin receptor. I guess how much data could we see in 4Q for CX-2029?

Yes. So let me just, again, recap what we're doing here, so CX-2029, a Probody drug conjugate against CD71, a transferrin receptor. The clinical signals that we saw in Phase I, the clinical efficacy that just popped out from the study, as sometimes you get lucky, was in squamous, non-small cell lung and head and neck squamous tumors. So those are the first -- those are 2 of the 4 expansions that we're running at the moment. So in collaboration with AbbVie. The other 2 are esophageal -- gastroesophageal junction tumors, where we saw robust preclinical activity. And the fourth indication is DLBCL, where, again, we saw preclinical activity in many, many tumor types with this agent. And DLBCL is another one. It's the first move into hematologic cancer that we've made as a company. And that obviously is in very close collaboration with our partner, AbbVie. We're guiding that we're working towards presentation of data for the first 2 cohorts by the end of this year, so for the lung and the head and neck. The esophageal and, particularly, the DLBCL are going to take a bit longer to enroll because we carry the momentum from the first 2 indications from Phase I into Phase II, which obviously is exciting for the investigators. So I think the first 2 cohorts or what we're expecting to read out this year, the other story in the early part of first half of this year.

Just as we -- as a broad question just around ADCs. Have you seen side effects that potentially preclude you? I know there's some kind of pre dosing, but are there -- are you seeing that with one target or one toxin versus another?

Yes. It's an important question because the very deliberate approach that we took to selecting precedented payloads early in the design of these molecules, these programs, has really paid off for us in the clinic so far. Let me explain what I mean by that. So the first payload DM4 for the CX-2009 program, a well-understood payload, a lot of clinical experience with it, particularly with ImmunoGen, and we know what to look for in the clinic in terms of its toxicities. That was important because going into the clinic with such novel targets like CD166, with CD71, we wanted to be able to tease apart any on-target tox that we might see from payload toxicity. And we reason that if we had taken a new payload into the clinic for these first assets, it could have been a lot more complicated to really explain the data. And that's actually how it's played out. So with the CX-2009 program, we can say with some degree of confidence that we're not seeing any obvious on-target toxicity. We don't see GI tox or liver tox or skin tox, where the target is abundant. We do see payload toxicity, which we expect in principally ocular toxicity, which is really the dose-limiting toxicity of the [ main enhancing payload ]. That's something that we know we can manage. ImmunoGen has managed it effectively. We actually saw 0 Grade III and above ocular events at the Phase II dose, the 7 mg per kg dose in our Phase I study. And we're implementing prophylactic measures in Phase II. For the CD71 program, the payload is MMAE, so again, well understood payload, the payload on ADCETRIS, and there are several other approved drug conjugates. With MMAE, we know that one of its principal side effects is anemia. And so that's something we were looking for in the clinic. We have seen that at the upper dose levels, and we are gathering more data on that as we execute the Phase II studies, but we're not particularly concerned about it. It's something that oncologists are used to seeing. They know how to manage. We've got multiple ways that we can manage it, including transfusions, growth factors, dose reductions, dose delays. And the clinical activity that we saw in Phase I was not impeded by the anemia. And in fact, no patient in our Phase I study came off drug for anemia. So it is a validation, if you like, of that early strategy. As we move into the next drug conjugates, and specifically, an EpCAM targeting drug conjugate that we're preparing to file an IND for, there, we are now beginning to take a bit more risk on the payload front. DM-21 from ImmunoGen, a next-generation payload, is more potent than DM4. We don't have any clinical experience yet, but we now feel confident enough in our understanding of the clinical performance and the clinical behavior of the platform to be able to take on a bit more payload risk with the goal of getting to increased levels of potency with that new payload.

Great. Okay. Now that -- when would we see kind of data around that new payload for the EpCAM?

Well, it's got a first things first, I guess, which is to get the IND filed and get into Phase I. So we're not guiding to when that data will be available. I think it's -- the team's really highly focused right now on getting into the clinic, and we'll provide more of an update once we get there.

Okay. The -- maybe just pivoting back to 2029. Just that mix of patients that we can see year-end, is there any subset that's enrolling faster? Or you're kind of -- any sense if we'd get more head, neck versus lung versus esophageal?

Well, like I said, I think in a situation like this where this study is being run, the 2029 expansions are being run as expansions of the Phase I study, so there's an intrinsic momentum to that study. And as is always the case, areas that you see signals in Phase I tend to carry into Phase II, and that's what we're expecting to happen here. And that's why we're guiding that the data from the lung and the head and neck cohorts is what can most reasonably be expected by the end of the year. If we're fortunate and we get there with esophageal as well, that will be super exciting as well. DLBCL is kind of -- that's definitely going to take some more time. But I would focus mostly on those first 2 cohorts of the lung and the head and neck. And again, the clinical activity that we saw in Phase I was really encouraging in those 2 indications. So we're, obviously, optimistic about what we might see there.

And the patients you're getting for lung, head, neck, that's kind of, I guess, on lung post PD-1, do you know what kind of lines of therapy -- number of lines of therapy [ are only fine ] enrolling?

So all I'd say is that the Phase II -- our objective in the Phase II expansion is to enroll patients that were somewhat less pretreated than in Phase I, more like 1 to 2 versus 2 to 3 or more. It's a little different in the breast cancer setting where the median number of prior treatments there for 2009 was between 8 and 9, and that's one of the critical success factors for the breast cancer Phase II study, is there we're clearly going to be able to enroll patients who are significantly less heavily pretreated.

Great. If we could pivot briefly, at least to the kind of the BMS collaboration, I guess, some kind of nice kind of reading between the lines expansion into different tumor types. Kind of what do you think that means and the rationale as well for BMS having 2 different CTLA Probodies?

Yes. So we're really pleased with the progress there with BMS. So the 2 different assets, the Probody version of ipi, which we call 249 and the Probody version of a nonfucosylated ipi that we call 288. Both are in the clinic. With 249, the expansion of the clinical work that BMS has now embarked upon is, we think, quite significant. So they, about a year ago, initiated the randomized Phase II expansion in frontline melanoma. And that's a really important experiment because there they're comparing ipi/nivo to Probody ipi/nivo in, obviously, a very relevant tumor type. So enrollment continues there. The 3 additional indications are HCC, prostate and triple negative. In HCC, of course, there's an accelerated approval in the second-line setting for ipi/nivo. So we know that there's a baseline on which we assume they'll be looking for improvement in some shape or form with the Probody, with -- that was CheckMate 040 that supported that accelerated approval. CheckMate 650 in prostate has demonstrated activity -- evidence of activity of ipi/nivo in prostate as well. So we know that these indications can respond to the doublet. The goal here is to see what the Probody can do in terms of its advantages, in terms of being safer and potentially more effective. And then in triple negative, of course, we know the immunogenic tumor response to checkpoint inhibition, that kind of speaks for itself. So really exciting that they're doing that work. Also, the nonfucosylated Probody, which, if you look back at the AACR data that BMS presented last year, the rationale here for the nonfucosylated is that it's -- the nonfucosylation of the Fc of the nonfucosylated ipi and enhances this binding affinity for CD16. And what that does is it increases its ability to deplete intratumoral T-REx, which, as you know, is sort of underlying the potency of anti-CTLA-4 therapy. Now the challenge with doing that, you make a more potent version of ipi, perhaps not surprising, it becomes more toxic. If you look closely at the data that BMS presented at AACR last year, they showed that the -- that ipi Probody, the highest non-severely toxic dose, the HNSTD for the ipi Probody was 5x higher than ipi. So we have a fivefold improvement in safety, but the efficacy was the same. So essentially a fivefold increase in therapeutic window in the preclinical studies. And so that's what they're now in the clinic with. With the nonfucosylated 288, they saw a threefold improvement in HNSTD for a much more potent version of ipi, and that's what they now have in Phase I dose escalation, plus/minus nivo. So we're excited about the work with Bristol, it's going great. And not sure when they're going to have data, when they'll be able to read those studies out. But the platform really is -- again, if you look at that preclinical data, the platform really has performed very, very nicely.

That's fantastic. Maybe last 30 seconds, anything you can say about the Analyst Day in April?

Yes, I'm sorry, you said the Analyst Day?

Yes.

Yes, yes. So the goal of the day really is to talk about our drug conjugate programs, really, with a focus on 2009 and 2029; to talk about the concept of the Probody drug conjugates or the conditional ADCs; talk about the design of our Phase II studies, the execution of those studies and where we're headed with these programs, the overall concept behind the conditional ADC. So we've had a lot of conversations with investors over the last 6 months, including in our financing. And we just feel like it will be helpful as we come up to this data towards the back end of this year to just sort of level set the science and the approach, and that's ready to go.

Perfect. Thank you so much. Absolute pleasure chatting to you, Sean, and thanks for joining us at Barclays Global Healthcare Conference. We could definitely speak for longer because there's so much going on under the hood, it seems, so I'll hand the line back to the operator.

Great. It's always a pleasure, Peter. Thanks very much. Take care.