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

Good morning. My name is Peter Lawson. I'm one of the health care analysts, biotech analysts at Barclays. And welcome to Barclays Global Healthcare Conference in Miami. Really pleased to have up on stage with me, management from CytomX. And we have Sean McCarthy, CEO, Founder and Chairman.

And first question, really broad, we've seen various bits of M&A within the space and really interesting data. But just your approach with these kind of protected or prodrug versions of antibodies, cytokines, et cetera, really differentiated. Kind of as we think about your data and competitor assets, what's kind of helped validate the class for this kind of prodrug approach?

Yes. Thanks, Peter. Thanks for the invitation to be here today. Always a pleasure. So yes, we're developing, at CytomX, the Probody therapeutic platform. We've really been a leader in the space now for a number of years. And the core concept is to take potent biologic modalities like T cell engagers, antibody-drug conjugates and cytokines and to engineer them in a way that masks their binding to target in a protease-dependent fashion. So the masks are designed to be removed specifically and selectively in tumor tissue. And in doing that, the goal is to improve therapeutic window where there's room for improvement or to create therapeutic window where actually no -- none existed. And this, of course, at our company, at CytomX is all focused on developing the next generation of potent anticancer therapies. We've put -- we've generated a lot of data over the years at CytomX. We've really achieved many firsts for this idea of masking biologics. We're the first company to have shown that masking an antibody can be successful in the circulation of cancer patients that the masks stay on the majority of the -- Probody therapeutic stays masked in circulation for extended periods of time. We've shown I think across now multiple programs, both ourselves and our partners that masking -- unmasking happens in the tumor, resulting in antitumor activity, and the masking in the periphery results in decreased binding of target in peripheral tissues. We've done this across multiple modalities. We've been in the clinic with checkpoint inhibitors, with ADCs. We're now in the clinic with our first T cell engager CX-904, and will soon be in the clinic with our first masked cytokine, which is CX-801. So it's been a fun journey so far. And to your question, we are beginning to see others enter the field of biologic masking. Our leadership has been recognized, and we're seeing a number of other companies, organizations taking similar approaches to mask biologics to improve therapeutic window. And we're beginning to see clinical results, which are, I'd say, directionally -- are directionally encouraging and consistent with what we've shown over the years. This is a really exciting time for the field and happy to discuss our platform and our programs in more detail.

Perfect. I'd love to start on your EGFR T cell engager, kind of how is enrollment proceeding and where are you for in dose escalation?

Yes. So CX-904 is, as I mentioned, our first T cell engager in clinical trials. It targets CD3 on T cells and EGFR on solid tumors. And we have engineered CX-904 to be masked on both arms. So the CD3 binder is masked as is the EGFR binder. And so what we're looking for in the clinic, first and foremost, is to evaluate in cancer patients, the degree to which masking on CD3 can help manage, mitigate, decrease cytokine release syndrome and how by masking on EGFR can help to manage and mitigate what would be predicted to be EGFR-mediated toxicities of an unmasked molecule such as skin rash or gastrointestinal toxicities. So we're in a dose escalation with 904. We're making good progress. We are now above those levels that would be predicted for unmasked bispecifics to be not tolerated. So we're making good progress in our dose escalation. And the goal of our Phase Ia study is, first of all, to evaluate doses, schedules, safety assessment in order to select doses and schedules for Phase Ib and also, of course, to look for early evidence of antitumor activity with this EGFR-CD3 mechanism. The patient population that we're enrolling into this study is essentially -- we kind of see it as a basket Phase I study. We're enrolling tumor types that are generally known to express EGFR. We're not selecting patients for EGFR. So this will be a fairly mixed patient population early on because, of course, the primary objective is safety. But we do, of course, before moving into Phase Ib, want to observe at least some activity of the drug as a single agent to give us the package that we need to go to our partner, Amgen, in the second half of this year, and to develop our strategy for moving into Phase Ib in 2025.

Got you. Okay. And then as you're enrolling, escalating, is there a way of like backfilling with specific indications that bias the trial in any way to a particular indication?

Yes. So we've started to backfill certain cohorts. We began the dose escalation with an accelerated dose titration strategy, which enabled us to enroll a single patient cohorts for a period of time. That allowed us to move fairly quickly through the lowest doses in the dose escalation. And I should mention that as is typical for these really potent molecules, starting dose for T cell engagers in solid tumors is pretty low. And so it was good to be able to get through those early single-patient cohorts. We're now making progress having advanced to the backfill stage at certain dose levels. And that's really -- that really has 2 goals, the backfills. Principally, goal number 1, to gain additional experience at certain doses and schedules, again, to evaluate the safety and tolerability of this particular drug and to also begin to look for evidence of antitumor activity. But the backfills are not driven by selection of specific tumor types yet at this stage. They're driven more by evaluating safety and tolerability.

Got you. Will we see the recommended Phase II selection? Is it 1 dose? Is it multiple doses to move forward?

Well, we're learning a lot in this field about how to explore, optimize and select doses for mid-stage clinical development of T cell engagers. So I would I would point to really important data that was shared by Amgen, our partner, on 904, at ESMO last year for 2 programs. One was the tarlatamab DLL3 program in small cell lung cancer, the other being the [ Steep 1 ] T cell engager. And if you look at the path, the playbook, if you like, that they followed for those programs, they're similar but a little different in that. In both cases, they explored step dosing schedules that include early priming doses followed by a target dose, and in the case of tarlatamab, target doses of 10 and 100 milligrams. And they selected the 10-milligram dose to advance into their registrational study. And with the Steep 1 program, some fairly extensive fine-tuning of the dosing, the step dosing schedule as well. So really manage and in their case, with unmasked molecules, I should stress, to manage and mitigate in particular, cytokine release syndrome. So I think the field is still early in really understanding the -- how to best explore dosing of these really potent agents. And that also results in -- I would predict this would be the case for us as we transition from Phase IIa to Phase Ib, but you're still evaluating multiple doses, probably two doses in the Phase Ib setting. So that's not just a function of the fact we're still early in understanding this class of drugs, but also relates to the FDA and project Optimus, where I think there will be -- there is strong interest from the agency in really ensuring that sponsors are fully exploring the range of doses and schedules available for their candidates in this field.

Got you. And then your interactions with Amgen, do they kind of help you with that dosing schedule and the suggestions around step-up dosing, et cetera?

Well, we're absolutely thrilled to have Amgen as a partner. I think it's clear that they're really leading the space at the moment in the development of T cell engagers for solid tumors. And I think we all feel that we're on the verge of, as a field, breaking through with this important modality. And so yes, we have a very productive and constructive dialogue with our partner, and we'll be engaging in discussion with them during the second half as we develop and define the next steps for the program.

Got you. How should we think about the timing of data releases? Is there -- and then relative to like a potential -- further opt-ins from Amgen.

Well, our goal is for this -- for the second half of this year is to have generated sufficient data to have that conversation with Amgen in developing the Phase Ib strategy for the program. We are on track to have that conversation in second half and in conjunction with that to also present [ partially ] our initial findings in Phase Ia on this program. We haven't yet settled on exactly the venue or mechanism for that data disclosure. We're keeping our options open at this point in time. But we do -- our goal is by the end of this year to have reached a decision with Amgen on the Phase Ib strategy, which we would plan to kick off in 2025.

Is there a safety efficacy bar kind of essentially set in stone by Amgen of what they need to see to move forward?

I'd say we have some pretty good guide rails as to what we're looking for. But as with any drug development program, there's some level of latitude there, depending upon what we see. But clearly, we're looking with the masking strategy to, as I've already mentioned, really manage and mitigate CRS and typical EGFR toxicities to open a window wide enough to then really fully explore the activity profile of this drug in EGFR-positive tumors, where there's enormous potential because EGFR, of course, is expressed on many solid tumors and has been approved in several already. So the program over time, one would imagine, could explore multiple focused tumor types.

Got you. And then just your views upon the EGFR data from Janux and how it kind of helps essentially derisk the program.

Yes, I think it's encouraging to see from multiple companies who are now in the masking space, clinical progress being made. I think that there is evidence emerging from others, from Janux and others that masking as we've shown many times over the years is effective in decreasing systemic target binding. And I think the signs of clinical activity across these programs from various parties are also encouraging and again, consistent with activity that we've shown across multiple programs. And I really do think that this field of conditional activation, antibody masking is here to stay. And I think all of us in the field are committed to making the biggest difference we can for the benefit of patients.

Got you. What's the differentiation we should think about for your asset versus Janux's asset?

Well, I think it's still early days in interpreting data. I think if we take a step back, there is a dialogue around pharmacokinetics of different approaches, notably what's the optimal half-life in patients of a T cell engager or a masked T cell engager. I mean our view at CytomX is that there's no black-and-white answer to this question. There are certainly positions being taken and hypotheses being put forward. But drug development is complicated. PK is complicated. It can be particularly complicated for therapeutics for which there are large antigen syncs either in the periphery or peripheral circulation, for example, on immune cells or in peripheral tissues. And so I think we have to be careful in how we talk about this whole topic. And at CytomX, we are working with formats that are generally of antibody like half-life. And I would point out that the broadest data set that we've seen so far in the T cell engager field from any company is the tarlatamab data set from Amgen. And their format is a actually a half-life extended BiTE HLE format, which has been designed to have a longer half-life. So I think the question is an open one, and we all need to keep generating data. And at the end of the day, it's all about the therapeutic window we can develop for our patients and the clinical benefit that we can derive for them.

Got you. Where do you think 904 fits into the landscape of EGFR treatment?

Well, EGFR as a target with a lot of unrealized potential. We think about -- certainly from the biologic standpoint, the approvals of the antibodies, cetuximab, panitumumab and others are still limited across relatively few tumor types. And yet EGFR as a target is present on many, many solid tumors. And so we see a broad-based opportunity to find ways to leverage that EGFR address, if you like, to direct cell killing. And in our case, with 904 CD3-mediated, MHC-nonrestricted T cell killing. There are 3 programs specifically that we're aware of looking at EGFR-CD3, there's the Takeda program. I believe they're in Phase Ib expansion stage in several tumor types. We haven't seen any data yet from them. We look forward to seeing it. We have our program, and we have the Janux program. And I think that -- we all feel I'm sure that the space is large enough that there's room for more than one program. But we certainly are optimistic that we can demonstrate that ours is best-in-class.

Got you. I'd love to touch upon the Bristol collaboration, just with the -- I guess, firstly, with the discontinuation of the CTLA-4 program. And if we kind of talk about the scope of the project that's still there and the reason why they discontinued?

Yes, of course. So partnering has been a really central component of CytomX's strategy for many years. Really, since we got the company going, we always -- we're of the view that forming partnerships will be an important way to generate capital, broaden the pipeline and really explore a lot of science. And that's exactly the way it's played out. We currently have strong partnerships with Amgen, with Astellas, with Regeneron, with Moderna. And we continue to have a strong partnership with Bristol-Myers despite this recent setback on the CTLA-4 program. So specifically on CTLA-4, we're very disappointed that they have decided for portfolio reasons to deprioritize the program. What we understand is that they recently have conducted a broad-based portfolio review driven in no small part by a lot of recent M&A that they've done to really start to reshape their oncology pipeline. Our program doesn't seem to have quite made the cut in that analysis, and they informed us very recently of their decision to stop enrollment in the study and to bring the study to a close. We were very optimistic about the program. We think that the nonfucosylated CTLA-4 strategy, particularly in Probody form has a lot of potential. We still believe in CTLA-4 as a target. And we'll be having additional conversations with Bristol on the data, which we haven't seen yet and any potential next steps there. But the collaboration remains highly active. And importantly, just about all the work that we're doing with Bristol at the moment is focused in the field of T cell engagers, which is -- really appears to be coming into its own at the moment.

Got you. And it doesn't sound like it was a safety question. It was more of a...

No, we're actually very clear on that. So there was no safety signal, no new safety signal that led in any way to the termination of that program. That is very clear.

Okay. Perfect. And would we hear anything about the T cell engager program this year with Bristol or is that undetermined?

The Bristol programs are fairly early. I would say that we are making great progress across our collaborations. It's interesting actually that across Amgen, Regeneron, Astellas and BMS, the majority of our programs that we're currently working on with them are T cell engagers. And I think that's kind of an interesting data point. And we're making progress with multiple partners, particularly great progress with Astellas. And I do hope that we'll have some significant updates on that program and that collaboration to share over the course of this year.

So you're initiating the EpCAM ADC trial. What indications are you kind of targeting? And what the trial design look like?

Yes. So we're really excited about 2 new programs that we're putting into the clinic that we filed INDs for late last year. One of them is the EpCAM program. The other is our interferon alpha program. So EpCAM ADC is CX-2051, a wholly owned program. The target of EpCAM, a very broadly expressed tumor antigen with proven ability to show antitumor responses in patients. We're looking to open a therapeutic window by masking the antibody, we have a topo-1 inhibitor payload, which is indicated in particular, for the target indication where EpCAM is most highly expressed, which is colorectal cancer. So we'll be kicking off a Phase I study in the coming months. Again, enrolling an EpCAM expressing patient population with a bias towards CRC, not an entire bias towards CRC because EpCAM is on many different tumors. But yes, we're really excited to see what this drug candidate can do across multiple EpCAM positive tumor types.

Got you. Is there an EpCAM level you're looking for? Is that an exclusion...

Well, in CRC, it's interesting. I mean the CRC expresses EpCAM at more than IHC 3+ in more than 90% of patients. And so there's really no need to select. That's one of the beauties of the target.

Perfect. Okay. And then on the interferon alpha-2b, so the 801 program, kind of, again, is -- are there particular indications you're going after and kind of compare and contrast the competitive landscape there?

Yes. So interferon alpha, I mean, from a competitive landscape standpoint is relatively open compared to some other cytokines. We think that interferon has been a little bit overlooked. It's a very potent mechanism. It drives powerful antigen presentation in the tumor microenvironment. We've shown in our preclinical studies to, I think, very good effect that our mass interferon can turn cold tumors hot, activate an inflammatory cytokine program within tumor tissue, which synergizes them with PD-1 inhibition to cause tumor growth inhibition. So very exciting molecule. In terms of clinical execution, we are planning to focus our Phase I in tumor types where we already know that interferon has monotherapy activity. So that would be in melanoma, in renal and in head and neck cancer. And our goal in that study, we do, of course, want to see some level of single-agent activity for 801. But the real goal is to get into a combination with the checkpoint inhibitor, that's the whole strategy with this program in those tumor types and potentially others beyond. So we've got a very exciting 1 to 2 years ahead of us with 904 data coming second half of this year, data from the 2 new programs in 2025 and then broad-based progress across all of our collaborations.

Perfect. Perfect. Thank you, Sean. Always a pleasure speaking to you.

Thank you, Peter. Great being here.