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

So we're going to get going with our next session. It's my pleasure on behalf of Barclays to introduce our next presenting company, CytomX. For those of you that don't know the company, it's a really leading company in the area of protein engineering and in the area, specifically masked conditionally active biologics. The company has an ability to deliver various payloads to tumors in a very precise way and a broad pipeline. So we're very fortunate to have their CEO and Chairman, Sean McCarthy; and their CFO, Chris Ogden, here to catch us up on the story. Thanks so much.

Thank you, Jim, and thanks very much to the Barclays team for the invitation to the conference. Always great to be here. I will, of course, be making certain forward-looking statements over the next 25 minutes, and I refer you to our SEC filings. So, CytomX is a South San Francisco-based company in the oncology space, addressing major unmet medical needs. We are focused on a innovative platform technology we call the Probody platform. This is a novel antibody masking strategy for tumor localization and enhancement of therapeutic index. We currently have 2 clinical programs we're highly focused on: CX-2051, which is an EpCAM-targeted Probody antibody drug conjugate with a topoisomerase-1 inhibitor payload; and CX-801, which is a Probody interferon alpha-2b. We're fortunate to have many excellent partners. Business development has been an integral component of our business plan over the years. We're currently partnered with Bristol Myers Squibb, Amgen, Astellas, Regeneron, and Moderna. And the majority of this partnered work is in the field of T-cell engagers. We're in a strong financial position. We just announced last week on our earnings call, $101 million of cash at the end of 2024, which provides runway into Q2 of 2026. And that excludes any potential milestones or new business development under our business development strategy. We have 70 terrific employees and integrated R&D capabilities. So we're very focused on this clinical pipeline, CX-2051 and CX-801. And both of these programs are on track for initial Phase I readouts in 2025. CX-2051 we're conducting a highly focused Phase Ia dose escalation in the advanced colorectal cancer setting, and we are on track for an initial look at that Phase I program in the first half of this year. CX-801, we're also in Phase I. We initiated towards the end of last year a Phase I dose escalation, also a very focused study, this time in advanced melanoma, and we're on track to have initial translational biomarker data for that program in the second half of this year. One of our key goals for that program is to initiate the combination with KEYTRUDA also in second half. Both of these programs are wholly owned by CytomX at this point in time, and we really are entering a data-rich period in focused indications with very high unmet need. Our platform technology, the Probody platform, has really brought multiple firsts to the field of conditional activation. I refer to CytomX as the original masking company. We were indeed the first company in this space to show clinical responses with masked biologic therapeutics. We were the first to show molecular activation of masked biologics in patient biopsies and the first to achieve clinical responses with T-cell engager with minimal cytokine release syndrome. The concept that underlies the Probody platform is that protease biology is fundamentally dysregulated in tumor tissue relative to normal tissues. We've known about this for a long time. There are many, many publications in the scientific literature speaking to the role that activated proteases play in the process of tumor cell transformation, migration, invasion and metastasis. That tumorgenic process requires protease activation. And unlike in normal tissues where proteases are highly regulated, in tumor tissue, they are dysregulated. And we leverage this protease activity to cleave off peptide masks from these masked antibody therapeutics. That's what gives a differential in terms of binding of these therapeutics to tumor tissue relative to normal tissue and is designed to improve or create therapeutic window for novel drug candidates. So let me move to our ADC program, CX-2051. This is an EpCAM-targeting Probody topoisomerase-1 antibody drug conjugate. Now, those of us in the oncology field have been familiar with EpCAM for actually quite some time. EpCAM was, in fact, one of the first tumor antigens to ever be described. And that's because it's very highly expressed on many different solid tumors, including colorectal cancer where it was first characterized. EpCAM is expressed on multiple tumors, including ovarian, triple-negative breast cancer, lung cancer and many others besides. And it's always been thought of as a great target for targeting tumor cells. The problem has been that EpCAM, Epithelial Cell Adhesion Molecule, is also present on many normal tissues, as the name would imply. So efforts to drug this target over the years have been challenging. It has been particularly difficult to drug EpCAM despite its high potential with systemic therapeutics. Interestingly, though, locally administered anti-EpCAM strategies have been quite effective, offering a level of validation to this target. And there are 2 therapeutics in particular that I'd like to point out. One, Vicineum, which is a fusion protein, previously characterized by others that was shown to induce potent antitumor activity in bladder cancer. This is a fusion protein of an anti-EpCAM antibody, a single chain FV fused to a bacterial toxin Pseudomonas Exotoxin A. So this, if you like, early generation antibody drug conjugate is known to have clinical activity, but can only be administered locally because it's too toxic to be given systemically because of EpCAM presence in normal tissues. A second program, an EpCAM CD3 bispecific formerly commercialized in Europe as Removab, was also shown to be quite clinically active in the area of treating malignant ascites in patients with various GI and gynecologic malignancies. This drug actually is being reapproved and relaunched in Europe in real time. It just had a positive opinion from the European regulators in February this year and is coming back to the market under a new brand name KORJUNY, and it really is quite effective in clearing and treating malignant ascites in these patients. So these 2 -- but it has to be given locally into the peritoneal cavity. And these 2 therapeutic strategies really underpin the validation of EpCAM, but how can we target EpCAM systemically because that's been very difficult to do, as shown on the right-hand side of this slide. There are various approaches that have been taken over the years by others that have run into toxicity roadblocks early in dose escalation, including antibodies that induce pancreatitis, or the EpCAM CD3 BiTE, that was initially developed by Micromet, that ran into significant tox problems in the GI tract and also showed significant liver toxicity before approaching or reaching therapeutically active levels of the drug. So what we're looking to do with CX-2051 is to build on this body of evidence from the past and open a therapeutic window for EpCAM with a therapeutic -- a systemic therapeutic strategy. And that's what CX-2051 is. So a first-in-class EpCAM-targeting antibody drug conjugate, it is a DAR-8 ADC, a masked high-affinity anti-EpCAM antibody and the mask is linked to the antibody via a protease cleavable linker, that we've shown in previous clinical work is efficiently cleaved in tumor biopsies. The payload is we call CAMP59. This is a novel Topo-1 inhibitor that we licensed from ImmunoGen, and we entered this program into the clinic about 1 year ago in Q2 of 2024. Preclinically, CX-2051 delivers a broad therapeutic window for EpCAM. On the left-hand side of this slide, you can see that the unmasked ADC here, referred to as CX-2052 shows, equivalent potency to the masked ADC at the dose of 6 milligrams per kilogram administered Q2 week for 3 doses. So this is strong evidence that the masked therapeutic is as active as the unmasked. In contrast, in Cynomolgus monkey models of toxicity, we can dose substantially higher with the masked ADC. You can see that 10 milligrams per kilogram of the unmasked ADC is not tolerated by cynos, and this is principally due to gastrointestinal toxicities, whereas the masked ADC 2051, we can dose as high as 60 milligrams per kilogram, potentially even higher. It's not until we get to 90 mg per kg that we see the same toxicities that we see at 10 mg per kg of the unmasked. So taken together, these efficacy and safety results from preclinical studies suggest that we have opened a broad therapeutic window with a wide predicted active range to be explored in the clinic. We've also shown in our preclinical studies that CX-2051 has equivalent activity, in this case, in models of colorectal cancer to a deruxtecan conjugated version of this same anti-EpCAM Probody. So we think of this molecule, 2051, think of it as functionally and broadly equivalent to nHER2, except that instead of HER2 being the target, the target here is EpCAM. And EpCAM is, in fact, expressed at HER2-like levels on colorectal cancer in more than 90% of patients. On the right-hand side of this slide, we show another important experiment, which is that we have validated and confirmed that 2051 has activity in the post-irinotecan setting. We, of course, expect that in CRC, most, if not all, patients that we bring on to our study will have experienced irinotecan therapy at some point in their journey. This evidence shows strongly that in irinotecan-resistant models, CX-2051 can potently [indiscernible] tumor regressions. This will be important not just for CRC, but also for other tumor types that we may expand into in the future in patients that have already seen -- may have already seen irinotecan at some point in their treatment journey. So as I mentioned, we are highly focused today in developing CX-2051 initially in metastatic colorectal cancer. This is where EpCAM is most highly expressed. It's most broadly and most consistently expressed. More than 90% of CRC patients express EpCAM at high levels. Of course, the CRC market is very large on a global basis. In the U.S. alone, there are more than 100,000 patients treatable annually here in the United States. Most of these patients express EpCAM at high levels. And the incidence of CRC actually is one of the few cancers where incidence is growing, and it's also growing rather alarmingly in younger patients. So there is a very large unmet need. And current standard of care is hugely inadequate, particularly in the third and fourth-line setting. Treatment of metastatic CRC today is still largely dominated by chemotherapy in the first and second-line settings. By the time we get to third line and beyond, options for patients are severely limited. And in fact, we hear from our KOLs that many patients in the third line setting are actually being queued for clinical trials because current options are so inadequate. And the next slide shows exactly how inadequate they are. You can see, for example, Lonsurf, which is trifluridine/tipiracil here on the top of this table, either as a -- either alone or in combination with bevacizumab or the TKIs, regorafenib or fruquintinib, they have dismal outcomes for patients. Response rates are in the single-digits. The median PFS, particularly in the fourth line is just a couple of months with very, very poor overall survival. So there is an enormous unmet need here. And quite frankly, this is an area of oncology where there's been very little, if any, innovation over the last 2 decades. So we think this is a very important place to be, and we believe we have a very important contribution to make with 2051 in this cancer type. So we commenced our Phase I dose escalation study for 2051 in Q2 last year, and we've made excellent progress in the clinic to date. We began with single patient cohorts and quickly cleared the first 2 dose levels, allowing us to escalate, and we're currently enrolling at dose level 7. This is -- this study is enrolling patients generally fourth line or later. So I want to emphasize this first analysis of 2051 is being conducted in a very late-line setting, as you would expect for a Phase I study. We are currently at levels, we believe, that are predicted to be clinically active based on that data I showed you earlier of the calculation of the preclinical therapeutic window analyzing our antitumor activity and our safety in Cynomolgus monkeys, but also by reference to what we know about other Topo-1 ADCs, either that have been approved or that are in late-stage development. So in these current dose levels, we believe we're in the predicted therapeutically active range. And for that reason, we have begun to backfill certain cohorts to really explore and begin to probe for clinical activity of this drug in this late-line CRC setting. The significance of having succeeded thus far in dose escalation with this target is also that we have achieved something that others have not achieved before, which is to reach predicted therapeutically active levels in the context of the overall safety profile. So we're encouraged by the safety profile to date, particularly as it relates to the typical EpCAM toxicities that others have seen in the past, that we believe so far to be manageable. Now we do expect, as we continue escalation and we push to MTD, of course, that we will see ultimately payload toxicities for this class. Topo-1 inhibitors are known. The tox profiles are well understood for irinotecan in both the chemotherapeutic setting and also in the ADC setting. And we do expect to see as we hit those higher doses, the typical cytopenias, upper GI tox, potentially lower GI tox in the form of diarrhea. That's what's likely to determine our MTD. Once we have MTD determined, we will select our doses for expansion and further evaluation of this drug in CRC. So really great progress to date, very encouraged and escalation continues. Beyond CRC, I want to really emphasize that the breadth of EpCAM really offers a pipeline in a product opportunity. If we see a therapeutic window in late-line metastatic colorectal cancer, that will ungate many other opportunities across multiple solid tumor types where EpCAM is highly expressed. So we really do see this as a huge value builder for our company in the medium to long-term. So next steps with CX-2051 in Phase Ia, continuing complete dose escalation and backfills to further evaluate and fully characterize safety and efficacy, determine Phase Ib doses for potential expansions. And as I mentioned, additional -- evaluate additional opportunities in CRC, particularly in combination and opportunities in additional EpCAM expressing indications in the future. Moving to our second clinical program, CX-801. This is our Probody interferon alpha-2b. Why interferon alpha? Well, interferon alpha was the first immunotherapy to ever be approved in the treatment of melanoma. It's been known to be a powerful anticancer agent for decades. It's been severely limited by systemic toxicities. But interferon alpha is a highly potent regulator of the immune system. And it's also a multifactorial immune system regulator having in addition to direct tumor cell killing activity, the ability to modulate multiple immune cell populations, including dendritic cells and antigen presentation, NK cell biology, and it's a potent activator of T cells as well. The challenge with interferon is that it's fallen into disuse because of its systemic toxicities. It's very poorly tolerated by patients, and its single-agent activity is in the single-digits. And so, the overall risk benefit for patients has not justified its use. But if we can harness the powerful immunobiology of interferon alpha, we think this could be an ideal combination partner for checkpoint inhibition with providing a novel opportunity to turn cold tumors hot and actually treat patients who are refractory or have become resistant to conventional immunotherapy. So CX-801 is a double masked version of interferon alpha-2b. We have a mask on the cytokine and then a mask -- an Fc steric mask, both of which are protease-cleavable. Our preclinical data, which we presented previously at SITC, really underscores the power of this agent in mouse models. We have potent synergistic activity with PD-1 inhibition. We have dramatically increased tolerability in animal models of the masked interferon relative to unmasked interferon. And we've also shown the ability to activate or inflame the tumor microenvironment in animal models whilst maintaining a quiescent immune phenotype in the periphery. This is exactly what we wanted to see with masking, and we're now translating this powerful preclinical profile into the clinic. And we're focused in a similar way to how we're highly focused in CRC with 2051. We're focused with 801 in melanoma in our Phase I dose escalation in third line or later, where, again, there's significant unmet medical need. Once melanoma patients have progressed through immunotherapy in the case of BRAF mutant patients, BRAF inhibition and then rechallenge with various immunotherapies in the second line setting, patients have very, very few options. So we see a terrific opportunity in this patient population to leverage the powerful immune biology of interferon in combination with KEYTRUDA, which we have access to under a collaboration supply agreement with Merck. So we began dose escalation late last year. We've also made terrific progress here. We're currently enrolling dose level 4. We've already exceeded dose levels of conventional unmasked interferon in this study with a great tolerability profile. So we feel that masking again is delivering in allowing us to reach potentially therapeutically active levels of this drug in these late-stage patients. And our goal for the second half of the year, now that we've cleared those first few dose levels, is to initiate the combination with KEYTRUDA and really see what this drug can do in combination with PD-1 inhibition. We're on track for initial data in the second half, and that data is likely to be translational biomarker data for monotherapy in the melanoma setting, where we've got such a broad understanding of interferon biology that we are able to measure -- make very direct measurements of interferon stimulation of the immune microenvironment in the form of activation of interferon responsive genes, for example, which will give us a really good handle on how this drug is performing in the tumor and in the periphery in the context of initiating that checkpoint inhibitor combination in the second half. So for 801, our goals and next steps, so continuing escalation, initiating the KEYTRUDA combination and presenting translational data before the end of the year. In terms of future opportunities for 801, we see, of course, the opportunity to bring this combination earlier in the treatment paradigm for melanoma and also to move into additional immune responsive indications where interferon has also been validated, including renal and head and neck and in the longer run broadening out to patients who are responsive or refractory to current immunotherapeutic strategies. So to wrap up, looking ahead to the year -- to 2025. CX-2051, our EpCAM Probody Topo-1 ADC on track for an initial data disclosure in the coming months in the first half of this year. Very excited about the prospects for this molecule. This will allow us to determine our Phase Ib doses for expansion cohorts as we also evaluate combination strategies and moving 2051 into the many other potential tumor types we could study this innovative ADC in. And just to underscore, we are the first and to our knowledge, only company currently studying an EpCAM-targeted ADC in the clinic. So we're a long way out in front with this program. 801, our goal is to initiate the KEYTRUDA combination in the second half of the year in advanced melanoma to present initial translational data by the end of this year and to drive towards potential combination data with KEYTRUDA as we move into 2026. So, thank you very much for your time today. It's always a pleasure to be here and happy to take any questions.