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

All right. Let's go ahead and get started. Welcome, everyone, to the JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Malcolm Kuno, Priyanka Grover. Our next presenting company is CytomX. And presenting on behalf of the company, we have CEO, Sean McCarthy. Sean?

Thank you, Anupam, and good afternoon, everybody. Real pleasure to be here. So let's dive right in. I will be making certain forward-looking statements over the course of the next 30 or 40 minutes, and so I refer you to our regulatory filings. So CytomX Therapeutics is addressing major unmet needs in oncology, and we're doing that with our Probody therapeutic platform. This is a unique antibody masking strategy for localizing potent biologics into the tumor microenvironment underway from normal tissues, thereby enhancing therapeutic index. And this is a field that we've pioneered over many years at CytomX. We now have seen a number of new entrants into the space over the last several years, a lot of progress being made. And I really do believe that antibody masking is increasingly being established as a fundamental new approach or addition to the field of therapeutic antibodies and biologics broadly. And I think it's also fair to say that CytomX occupies a position as the original masking company. We currently have 3 clinical programs, 2 of which are wholly owned. The first is CX-2051. This is our anti-EpCAM antibody drug conjugate in Phase I dose escalation in colorectal cancer. And our second wholly owned program is CX-801. This is a masked version of interferon alpha, which we are also in Phase I dose escalation focused in melanoma. We have a partnered program in clinical trials. This is CX-904, this is the first T-cell engager, the first masked T-cell engager that we moved into the clinic. It targets EGFR and CD3. This program is partnered in a global co-development alliance with Amgen. And we presented initial Phase Ia data for this asset in the first half of last year. On the topic of partnering, it's been a very central component of our strategy really from the beginning. We're thrilled to be continuing to work with a number of major partners: Bristol-Myers, Amgen, of course, as I already mentioned, Astellas, Regeneron and Moderna. And actually, a good deal of the work we're doing in those partnerships is focused on the T-cell engager space, which we are very excited about in the long run. In terms of financials, we last reported $180 million on the balance sheet at the end of Q3. That is cash runway into Q2 2026. And that excludes any additional milestones that we might earn under these partnerships and, of course, any new business development that we might consummate over that period of time. And the organization currently has 70 employees. We're located in Oyster Point, South San Francisco and have integrated R&D capabilities. So this slide shows our current pipeline, just a little more detail. We believe it's important to continue to explore and apply masking technology in a multi-modality fashion. So the 3 programs we're currently exploring and developing in the clinic are all asking different questions and leveraging masking strategies in slightly different ways. So as I mentioned, CX-2051 is a masked antibody drug conjugate targeting epithelial cell adhesion molecule, EpCAM. We are on track to have initial Phase Ia dose-escalation data in the first half of this year. And our goal is to quickly advance to selecting doses for Phase Ib expansions, we hope, by the end of this year. That is a wholly owned program. CX-801, our masked version of interferon-alpha 2B, being developed, again, another focused development program focused in late-stage melanoma is in dose escalation. Our goals for this year are to present initial data by the end of the year for this program and to initiate a combination study with KEYTRUDA that we have access to through a collaboration and supply agreement with Merck. And the third program, CX-904, our EGFR-CD3, we are continuing dose escalation with that program. Our plans are to continue Phase Ia dose escalation this year. And next steps with that program are currently pending ongoing dialogue with our partner, Amgen, concerning resource allocation and next steps in Phase Ia as we move further forward towards potential Phase Ib. Just to recap the strategy that underlies our pipeline and our entire company. The Probody platform, this technology enhances therapeutic index for potent biologics by reducing on-target toxicity. And the way it works is we mask antibodies with peptide masks. The peptide mask is selected specifically for each antibody or each biologic that we advance into the clinic. And the masks are connected to the antibody by protease cleavable linker or substrate. And this really is some of the core technology that CytomX has innovated over the years. These multi-selective protease-cleavable substrates allow for removal of the mask in tumor tissue and thereby enable the antibody to now bind to its target and elicit its biological effect. We are the first company to have developed this technology. We are the first company to have demonstrated clinical responses with masked antibodies, the first company to show molecular activation and unmasking of masked biologics in patient biopsies, and the first company to achieve T-cell engager clinical responses with minimal cytokine release syndrome. So a lot of progress. We really do believe our platform is industry-leading deep expertise across the pipeline and our partnerships. So I'd like to now speak in some detail about our currently -- our top priority program as we move into 2025, which is CX-2051, our masked Probody ADC targeting EpCAM. EpCAM, for those of you who have been in the oncology field for a while, will be a familiar target. It was first identified many decades ago as a colorectal cancer antigen, and it is widely expressed on many solid tumors, including CRC. In fact, it's so widely expressed that it has pan-tumor potential. So if we could develop a successful therapeutic against EpCAM, it has enormous potential across many tumor types and has the potential to make a really big difference for many, many patients. It has moderate expression on normal tissues. It has particularly high expression, though, in the gastrointestinal tract. And that's been one of the barriers to the development of EpCAM therapeutics to this point. Some progress has been made in the past towards targeting EpCAM, but not as a systemic therapy. Any approach that has to date been able to show antitumor activity against EpCAM has needed to be given locally. But there are a couple of very interesting molecules that have validated this target through local administration. One of them is a protein called the Vicineum. This is an anti-EpCAM single-chain Fv that was linked to a biological toxin, a component of Pseudomonas exotoxin A. And when delivered by intravesicular administration into the bladder, it's actually very effective at treating or shrinking non-muscle invasive bladder cancer. In fact, a 40% CR rate was seen with that drug showing that if you can target EpCAM safely, you can shrink tumors. In addition, a trispecific antibody was approved some time ago in Europe. It's called Removab, an EpCAM-CD3 Fc receptor, trifunctional antibody, again delivered by intraperitoneal infusion, was approved in Europe actually for the treatment of malignant ascites, but it had to be given intraperitoneally. That drug was removed from the market after initial launch by Fresenius, but it's actually coming back to the market. There's a European company called Pharmanovia that recently announced that they will be relaunching Removab in Europe. And they actually reran the clinical trial in malignant ascites to get a positive opinion from the European regulatory authorities just in the last couple of months. So that's actually quite significant because this would be a commercially launched product targeting EpCAM. But again, the key point here is that these have to be given locally. Because the target is present on normal tissues, they're just too toxic if you give them systemically. A number of approaches have been taken to try to drug EpCAM systemically over the years, but they've all run into significant tox roadblocks in the GI tract: pancreatitis, upper GI inflammatory conditions and liver enzyme elevation. So what we're doing at CytomX is we're building on this body of work that has been done over the last many years to develop CX-2051, which we think uniquely addresses EpCAM as -- with a potential systemically administered antibody drug conjugate. So CX-2051 is a first-in-class EpCAM targeting ADC. It has a topoisomerase-1 inhibitor payload. And we selected that payload specifically to be able to treat topo-1 sensitive tumors and, in particular, colorectal cancer, which, as you know, is treated in the first and second line. First and/or second line today is the current standard of care with irinotecan-containing regimens. So CX-2051 is a DAR8 ADC, it's a masked antibody. So this antibody should be much reduced in its binding of target in the periphery. It should be able to bind target in the tumor, where the mask is removed by tumor-associated proteases. And as you can see, the payload here is what we call TAL-CAMP59. We licensed this from ImmunoGen. It's a camptothecin derivative. This actually is the first in man for this particular payload, but it -- you can think of it as functionally equivalent to other topo-1 inhibitors, like, for example, DXd. The linker is a trialanine cleavable linker that has been optimized for bystander effect. In preclinical models, the masked ADC, CX-2051, has equivalent potency to the unmasked ADC, and this is important, right? Because we need to be able to show -- we want to be sure that when the mask is removed in the tumor, that this drug will have the equivalent activity to the ADC. That's shown on the left-hand panel. However, when we move into animal models of toxicity, and shown here in the middle panel, specifically in cynomolgus monkeys, when we treat a cynomolgus monkey with an unmasked ADC, even 10 milligrams per kilogram of that drug candidate of that molecule is not tolerated because of expression of EpCAM in normal tissues. It's severely toxic. And this is why no one has been successful yet in developing an anti-EpCAM ADC, a conventional ADC. However, when we put the mask on the ADC that makes CX-2051, you can see that we can achieve substantially higher doses in cynomolgus monkeys. Substantially higher doses. And this is consistent with work we've done in the clinic over many years across many targets. Masking consistently reduces binding to targets in normal tissues. So taken together, the efficacy data on the left, where we maintain potency, and the safety data in the middle, give us a model of therapeutic window on the right-hand side, where we would predict that an unmasked ADC, we would not be able to get to therapeutically active levels in patients because it's just too toxic. However, based on our modeling from these preclinical results and also taking into consideration work from other topo-1 inhibitor ADCs, we believe there's a wide predicted therapeutically active range to be explored with this drug candidate in patients, and that's exactly what we're doing. So we're focused in early clinical development in late-stage colorectal cancer. Every patient that we're enrolling into this Phase Ia study is currently a patient with CRC. The patient population is fourth line or later. So it's a heavily pretreated Phase Ia CRC patient population. Just to give you a sense of the target expression in colorectal cancer, more than 90% of CRC expresses EpCAM at high levels when assessed by immunohistochemistry. And so one of the great advantages here in CRC is that there's no need to select patients in this Phase I study. And I don't anticipate there would be a need to select patients even further down the road as we hopefully move this drug into later-stage development and ultimately to commercialization. The market also is very large. The unmet need in CRC is huge. The patient population is very large on a global basis. And obviously, this is a drug that could make an enormous difference for patients if it shows us what we hope it will. And obviously, we believe build tremendous value for our shareholders. The current standard of care for colorectal cancer, as you well know, in the first and second line involves chemotherapeutic regimens, which involve, at some point, the topo-1 inhibitor, irinotecan. By the time patients get into the third and fourth line, options are very limited, very low response rates for these agents in the third and fourth line. And because we have a topo-1 inhibitor payload on this ADC, we see a terrific opportunity, not just to impact late-line disease, but also to potentially bring this drug forward fairly rapidly into the treatment paradigm of colorectal cancer. So this has the potential to be a multifaceted, multilayered, multiyear clinical development program to really progressively build value and move into earlier lines of treatment of this devastating disease. We've shown -- I don't have this data in this presentation, but one question would be how active we would expect a topo-1 inhibitor payload to be after patients have already experienced irinotecan? And there are a couple of data points I'd like to cite here that support our clinical experiment. The first is we have shown in irinotecan-resistant primary human tumor models that 2051 is very effective at regressing tumors in animal models. And then more recently, evidence from the AbbVie program, ABBV-400, which is the c-Met-targeting topo-1 inhibitor, has shown interesting clinical activity, again, in late-line CRC in the post-irinotecan setting. So we're pretty confident that this drug has the potential to show clinical activity in late-line CRC, laying the foundation to bring the drug earlier in the treatment paradigm over time. This next slide just highlights the severity of the unmet need in late-line colorectal cancer, options in the third and fourth line result in single-digit response rates, relatively low PFS in the form of 2, 3, 4 months. And so this really underscores that late-line CRC. And I would say CRC in general is really primed for the kind of innovation that CytomX is bringing to the table with this drug candidate. So we're in the clinic. We began this study in Q2 of 2024. So we've been in the clinic for about 9 months, and we've made really good progress so far. So this shows the dose-escalation scheme. We began dose levels 1 and 2 with single-patient cohorts. That allowed us to fairly quickly progress through those first couple of cohorts. We're now enrolling dose level 6. This is essentially a 3+3 escalation that does, per protocol, have an adaptive element, if we need it, called the BOIN, which some of you, I'm sure, are familiar with. We're enrolling unselected advanced colorectal cancer patients, generally fourth line or later, in this initial first-in-man study, enrolling the 6-dose level. We have initiated limited backfilling at the upper dose levels. And we are at those levels that are predicted based on our modeling to be now in the predicted therapeutically active range. So the program has made very quick progress. And we're also encouraged by the safety profile so far. We know what the typical EpCAM toxicities are, just to recap. They are pancreatitis, they are upper GI inflammation, and they are liver enzyme elevation. And so far, as we've escalated, we feel we're encouraged by the management of those EpCAM adverse events. And I would predict that the MTD of this drug, as we continue to escalate, will be defined by the payload toxicities, not by the EpCAM toxicities, which will be a successful masking. The payload toxicities that we're looking for, as we continue escalation, are well characterized for topo-1 inhibitors: they're nausea, vomiting, some lower GI diarrhea and, of course, typical cytopenias like neutropenia and anemia. So encouraging progress to date, escalation continues, and we are on track for an initial data disclosure during the first half of this year. Now beyond CRC, where we are focused at the moment, there's a very broad opportunity for EpCAM given how widely it's expressed in solid tumors. So you can see here: in lung, gastric, triple-negative ovarian, endometrial, and this is just a few of the tumors in which EpCAM is highly expressed that we will be interested in further exploring once we show a signal in colorectal cancer. So a very broad program. Our 2025 goals are to obviously continue dose escalation and backfills to assess safety, assess efficacy, look for initial signs of tumor stabilization, tumor reduction, again, in this very late-stage CRC patient population, quite frankly, any evidence of clinical benefit and tumor reduction will be exciting to us. If we start to see resist responses in this late-stage patient population, we'll be even more excited. And that would be a finding that would ungate not just additional significant investment in CRC but would also ungate studies in other tumor types. So you can see that this drug really does have a pipeline and a product potential. And we see it as a major value driver, which is why, given the progress that we've made over the last few months, we've now brought it to the forefront of our capital allocation strategy at the company. So now moving to our second wholly owned program, this is CX-801. This is a masked version -- so switching gears into cancer immunotherapy, a masked version of interferon alpha-2b. Now this was -- those of you, again, who have been in the field a long time, you may recall or know that interferon alpha was actually the first immunotherapy to be approved in way back in 1986, and it's fallen out of use. It's fallen out of favor with clinicians. It's a very difficult drug to use. It has a relatively low single-agent activity, and it has very widespread and sometimes unpredictable systemic toxicities. Meaning that patients just can't tolerate the drug very well at all. But it's a very powerful modulator of the immune system, and it has 2 mechanisms of action that we see as attractive as an anticancer therapy. First of all, interferon alpha can use direct tumor cell killing by binding to interferon receptors on the cell surface of cancer cells. But I think even more significantly, interferon biology is central to antigen presentation. And so this biology, if we can harness it within the tumor microenvironment and dampen down those systemic side effects, we believe there's an opportunity here to leverage the power of interferon biology to synergize with other immune immunotherapies, particularly checkpoint inhibitors. So this molecule 801 is a duly masked interferon alpha. We have a peptide mask on the cytokine itself, and then we have a protease-cleavable Fc domain. And these 2 masks serve to really clamp down the biologic activity of interferon so that when we -- we predict that when we administer this to patients, it should remain very quiet systemically. And as a result, lower side effects, and enable patients to tolerate the drug and stay on drug much longer than they can conventional interferons. The protease cleavable linkers are designed to be removed in the tumor by protease-cleavable, but by tumor-associated proteases. And it's that unmasking in the tumor that is designed to give us an improved therapeutic window. So this is a validated target. There's a very well-understood biology behind interferon. And we've really brought the full force of our technology to bear in making this program. Just a little bit of the preclinical data that underscores the program. On the left-hand panel here we have shown in mouse models that 801 synergizes effectively with PD-1 inhibition. This is exactly what we want to explore in the clinic. And we've also shown similar to that EpCAM experiment that I showed you a little earlier, that the masked version of interferon is substantially more tolerable in animal models than the unmasked. So again, preclinical data is supporting a wide therapeutic window. And that translates into other measures of the immunobiology of interferon in animal models, where we've shown that we can blunt the systemic immune cell activation by masking, but we maintain the ability of the interferon to modulate interferon-regulated genes within the tumor microenvironment because we're removing the mask in the tumor through the protease biology of the tumor microenvironment. So this study, in particular, which we presented at SITC 2023, shows that 801 preferentially inflames the tumor microenvironment, and this is exactly what we want to see. So we have the potential, of course, to turn cold tumors hot with this very powerful immunobiology. So this is another very focused clinical development program that we're running. We are developing 801 in melanoma. We're working with a world-class clinical site, University of Pittsburgh Medical Center. And we see a significant opportunity in late-line melanoma for this drug, particularly in combination with KEYTRUDA. And the clinical strategy that we're pursuing is, of course, initially single-agent dose escalation in advanced melanoma. We've started this study in the second half of last year. We've made really good progress already. We're at dose level 3. Dose level 3 already exceeds the approved dose, the approved clinical dose of interferon alpha-2b. So the dose escalation has already made good progress. We plan to continue monotherapy dose escalation this year with the goal of advancing into the combination by the end of the year. And we do plan to release initial data later in 2025, which will be quite translationally focused. One of the great things about working on interferon is there's so much known about the biology. We've got great tools to track how the masking is working in the periphery, how the unmasking is happening in the tumor by tracking the cell biology and also the interferon-regulated genes being activated, we hope, in the tumor, and that will give us encouragement then to move into the combination setting. So goals for this program over the course of this year, continued Phase I dose escalation, start the combination study, evaluate safety and preliminary efficacy of this exciting drug candidate. And in the long run, beyond melanoma, interferon is also a utility in a number of other tumor types, as you probably know, renal cancer, head and neck cancers. And moving it even further forward, we believe there's an opportunity for this novel wholly owned program in indications that are not responsive or have been refractory to conventional immunotherapies. Let me wrap up with 904. This is our masked Probody T-cell engager targeting EGFR and CD3. We have made really good progress with 904 over the last several years. We've been in the clinic for now about 3 years. These programs, I think all of us in the field are learning. They do take time to develop. One needs to conduct very thoughtful dose-escalation studies. But this is, as I said, a masked T-cell engager, the first one that we advanced into the clinic. And the data that we presented last year was up to the target dose level of 10 milligrams. We showed evidence of single-agent activity with confirmed objective RECIST responses in pancreatic cancer and also tumor stabilization and reductions across a number of other tumor types. And we continue dose escalating with 904. We have not yet hit MTD. We do plan to continue to increase the dose over time. And because this is a partner program and also partly because it's taken, quite honestly, a little longer to develop than we had originally anticipated because we are still escalating, we have entered conversations with our partner, Amgen, regarding a potential additional resource allocation to this program. In the capital-constrained environment that we currently find ourselves, we're prioritizing our capital mostly to 2051 and 801, the wholly owned programs. But 904 is an ongoing program. We have enrolled now 70 patients in this study. And our goal this year is to continue dialogue with Amgen towards developing plans for Phase Ia completion as we continue dose escalation with this very interesting molecule. So just to wrap up with our key 2025 milestones. I've already reviewed them more, but just to recap. With 2051, the EpCAM targeting ADC in colorectal cancer. We're on track to have an initial Phase Ia data set in the first half of this year and move towards potential Phase Ib dose selection by the end of the year. That program has advanced very well. CX-801, our goal is to continue monotherapy dose escalation in melanoma and work towards initiating the KEYTRUDA combination by the end of the year with initial data, with a particular focus on translational data in second half of this year. And then our EGFR-CD3 program, continue to work with our partner Amgen regarding Phase Ia strategy as we evaluate resources available to continue to explore that very interesting mechanism. So thank you for your time today. It's been a pleasure, and I think now we'll take some questions.

Thanks, Sean. So I just want to remind folks, there's 3 ways to ask a question. You can raise your hand, and I'll call on you. You can submit a question through the portal and/or you can just e-mail me, and I'll ask the question. So, oh, we have a question.

[indiscernible] So how does it work with tumor-specific extracellular proteases?

The question is about tumor-specific extracellular proteases?

Yes. Is that the mechanism of action?

Yes. Yes. So there's actually a very, very broad literature on the role that protease biology disregulation plays in tumor biology. Tumor cell -- really, from the very early stages of tumor cell transformation, proteases are disregulated, they play a role in tumor cell migration, invasion metastasis. And there are multiple secreted proteases and cell surface proteases that we've characterized that we use as the basis to cleave the mask off of the masked antibody. And we've shown now across multiple programs in the clinic in on-treatment patient biopsies that mask removal is an efficient process that is independent of dose and also independent of tumor type.

And highly specific?

And highly specific. That's right. Yes, because we've also shown that in the periphery, you see very low levels of activation, typically, of these drugs in the periphery of patients. The masks are quite stable. And if you actually go even further back in the protease literature, it's actually quite hard to find protease activity in normal tissues because it's very tightly regulated, as it needs to be in the context of normal physiology.

Very interesting. Thank you.

Thank you.

I just wanted to quickly ask a strategic question on -- I realize that you've made 2051 your lead, right? But it seems like you did outline why you need more resources than 904. But it still seems like you're full steam ahead on 801, right? So it felt like you have co-leads, right, in terms of resource allocation, right?

Yes, it's a great question. The 2051 and 801 programs, of course, are both wholly owned, which is an important consideration in our prioritization. And the 801 program is at a stage in its development where it's a relatively small number of patients that we plan to actually enroll this year because we think that can give us some powerful initial translational data. So it's still the majority of our resources are going to 2051.