Good morning. My name's Peter Lawson. I'm one of the healthcare 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. It's the first question, really, a broad one. 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, etc., really differentiated. Kind of as we think about your data, competitor assets, what's kind of helped validate the class for this kind of prodrug approach?
Yeah, thanks, Peter. Thanks for the invitation to be here today. Always a pleasure. So yeah, we're developing at CytomX the Probody Therapeutic platform. We've really been a leader in this 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, whether there's room for improvement, or to create therapeutic window where actually none existed. And this, of course, at our company at CytomX is all focused on developing the next generation of important anticancer therapies.
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 anti-tumor activity, and that 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 we'll soon be in the clinic with our first masked cytokine, which is CX-801.
So, it's been a fun journey so far. 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. We're beginning to see clinical results, which are, I'd say, you know, directionally are directionally encouraging and, you know, consistent with what we've shown over the years. So 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's enrollment proceeding, and where are you in dose escalation?
Yeah, 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 binder 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 dose levels that would be predicted, but unmasked bispecifics, to be not tolerated.
So we're making good progress in our dose escalation. The goal of our phase I-A study is, first of all, to evaluate doses, schedules, safety assessment, in order to select doses and schedules for phase I-B, and also, of course, to look for early evidence of anti-tumor activity, with this EGFR CD3 mechanism. The patient population that we're enrolling into this study is essentially 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, you know, this will be a fairly mixed patient population early on because, of course, the primary objective is safety.
We do, of course, before moving into phase I-B, 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 I-B in 2025.
Gotcha. Okay. Thank you. 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?
Yeah, so we have started to backfill certain cohorts. You know, we began the dose escalation with an accelerated dose titration strategy, which enabled us to enroll 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 two goals, the backfills.
Principally, you know, going above one 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 anti-tumor 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.
Gotcha. Thank you. Will we see the recommended phase II selection? Is it one 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, our partner on 904, at ESMO last year for two programs. One was the tarlatamab DLL3 program in small cell lung cancer, the other being the STEAP1 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 STEP1 program, some fairly extensive, you know, fine-tuning of the dosing, the step dosing schedule, as well to really manage and in their case with unmasked molecules, I should stress, you know, to manage and mitigate, in particular cytokine release syndrome. So I think, you know, the field is still early in really understanding the, you know, how to best explore dosing of these really potent agents. And that also results in and I would predict this would be the case for us as we transition from phase I-A to phase I-B, that you're still evaluating multiple doses, probably two doses, in the phase I-B 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 FDA and Project Optimus, where I think there is, you know, 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.
Gotcha. Thank you so much. And then your interactions with Amgen, do they kind of help you with that dosing schedule and, you know, the suggestions around step-up dosing, etc.?
Well, we're absolutely thrilled to have Amgen as a partner. I, you know, 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. I think we all feel that we're, you know, we're on the verge of, you know, as a field, we're breaking through with this important modality. So yeah, 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.
Gotcha. How should we think about the timing of data releases? Is there, and then relative to, like, a potential or further opt-ins from Amgen?
Well, our goal for the second half of this year is to have generated sufficient data to have that conversation with Amgen in developing the phase I-B strategy for the program. We are on track to have that conversation in the second half and, in conjunction with that, to also present publicly our initial findings in phase I-A 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 our goal is by the end of this year to have reached a decision with Amgen on the phase I-B strategy, which we would plan to kick off in 2025.
Thank you. Is there a safety efficacy bar kind of essentially set in stone by Amgen of what they need to see to move forwards?
As I'd say we have some pretty good guardrails 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.
Gotcha. Thank you. Then just your views upon the EGFR data from Janux and how it kind of helps essentially de-risk the program?
Yeah, 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 JANEX 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.
Gotcha. What's the differentiation we should think about for your asset versus JANEX asset?
Well, I think, you know, 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, you know, there's no black-and-white answer to this question. There are certainly positions being taken and hypotheses being put forward. But, you know, drug development is complicated. PK is complicated. It can be particularly complicated for therapeutics for which there are large antigen sinks either in the periphery or in 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 dataset that we've seen so far in the T-cell engager field from any company is the tarlatamab dataset from Amgen. And their format is 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.
Gotcha. Where do you think 904 fits into the landscape of EGFR treatments or?
Well, EGFR is a target with a lot of unrealized potential. We think about certainly from the biologic standpoint, you know, 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 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-independent T-cell killing. There are three programs, specifically, that we're aware of looking at EGFR CD3. There's the Takeda program. I believe they're in phase I-B 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.
Gotcha. I'd love to touch upon the Bristol collaboration just with, I guess, firstly, with the discontinuation of the CTLA-4 program. If you could kind of talk about the scope of the project that's still there and the reason why they discontinued.
Yeah, of course. So, you know, partnering has been a really central component of CytomX strategy for, for many years, really, since we got the company going. We always were of the view that forming partnerships would 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, you know, 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 didn'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. You know, we were very optimistic about the program. We think that the non-fucosylated 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, you know, the data, which we haven't seen yet, and any potential next steps there. But the collaboration remains highly active.
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, you know, really appears to be coming into its own at the moment.
Gotcha. 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. 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, you know, 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. I think that's kind of give it's an interesting data point. We're making progress with multiple partners, particularly great progress with Astellas. I do hope that we'll have some significant updates on that program and that collaboration to share over the course of this year.
Okay. And so you're, you're initiating the EpCAM ADC trial. What indications are you kind of targeting, and what would the trial design look like?
Yeah, so we're really excited about two 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 EpCAM of very broadly expressed tumor antigen, with proven ability to show anti-tumor responses in patients. We're looking to open a therapeutic window by masking the antibody. We have a topoisomerase I 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's on many different tumors.
But yeah, we're really excited to see what this drug candidate can do, across multiple EpCAM-positive tumor types.
Gotcha. Is there an EpCAM level you're looking for, or 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, are there particular indications you're going after and kind of compare and contrast the competitive landscape there?
Yeah, so interferon alpha, I mean, from a competitive landscape standpoint, is relatively open, compared to some other cytokines. We think that interferons have been a little bit overlooked. It's a very potent mechanism. It drives powerful adjuvant presentation in the tumor microenvironment. We've shown in our preclinical studies to you know to I think very good effects that our masked interferon can turn cold tumors hot, activate an inflammatory cytokine program within tumor tissue, which synergizes them with PD1 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 will be in melanoma, in renal, and in head and neck cancer.
Our goal in that study, we do, of course, want to see some level of single-agent activity for CX-801. But the real goal is to get into combination with a 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 one-two years ahead of us with CX-904 data coming second half of this year, data from the two new programs in 2025, and then broad-based progress across all of our collaborations.
Perfect. Perfect, Time. Thank you, Sean. Always a pleasure speaking to you.
Thank you, Peter. Great being here.