Hey, everyone. I'm Alex Kelly. I'm one of the research associates on Marc Frahm, and Phil Nadeau's team here to introduce CytomX. So as I'm sure many of you know, CytomX is a pioneer in the field of tumor-activated therapeutics, which is an area that's really gotten a lot of investor attention, especially in recent weeks. So CytomX has four clinical-stage Probody therapeutics, all of which demonstrate tumor-specific activation. And you know, we just view this as a really high-potential space, with potential to kind of widen the therapeutic window. We look forward to Sean here, the CEO, kind of giving us a little bit more information on the current programs and any kind of updates we can look forward to in 2024 and beyond. So kind of without further ado, I'll just hand it over to Sean, and you can take it away, Sean.
Thanks very much. Pleasure to be here. Appreciate the invitation to the conference. I will, over the course of the next 30 minutes or so, be making certain forward-looking statements, and I refer you to our SEC filings. So in my presentation today, I will review our multimodality pipeline of Probody therapeutics, which are designed to address major unmet needs in oncology through tumor-specific activation. Let me start with a brief company snapshot. We are a South San Francisco-based clinical-stage oncology company, developing a pipeline centered on our unique and differentiated Probody therapeutic platform. Our platform is designed to localize the activity of potent anticancer biologics, including T-cell engagers, antibody-drug conjugates, and cytokines, into the tumor microenvironment, increasing therapeutic index. We've spent more than a decade pioneering, researching, and developing this approach.
Given the high level of strategic interest in ADCs and T-cell engagers currently, we see the company as very well positioned right now. Our lead programs are CX-904, a Probody T-cell engager targeting EGFR and CD3; CX-2051, a Probody ADC targeting epithelial cell adhesion molecule; CX-801, a Probody version of interferon alpha-2b, the potent cytokine; and BMS-986288, which is an anti-CTLA-4 Probody being developed by BMS. We have a very broad integrated R&D capability at the company, and our leadership over the years has attracted major partners, including most recently Regeneron and Moderna. CytomX is financially strong, with cash runway well into the second half of 2025. Our vision is transforming lives with safer, more effective therapies. We aim to build a long-term multi-product, ultimately commercial-stage company. At CytomX, we have developed a sophisticated product design strategy that leverages our unique technology platform.
The Probody platform is designed to localize the activity of potent biologic modalities into the tumor microenvironment, increasing therapeutic index. Now, we achieve this localization by adding a protease-activatable masking domain that we call the pro-domain to the underlying antibody. We are the first to have conceived of this idea. We're the first to have moved this strategy into the clinic. Our prior foundational clinical work with this strategy has achieved many firsts. We've opened a broad field into which we have seen, multiple new entrants, in recent years. We're currently focused on a generation of product candidates that integrate key learnings in how to optimally utilize our Probody technology, progressively enhancing the probability of technical success. Our current lead programs focus on validated targets, for each of which substantial potential remains to be realized by increasing therapeutic index across multiple tumor types.
By employing our masking strategies and fine-tuning the Probody domain, which is the mask and the protease cleavable substrate that confers tumor conditional activation, we tailor our product candidates in preclinical studies to optimize therapeutic window. Since our Probody approach is so versatile, we can apply it to a multitude of biologic formats. This allows us to select the optimal effector modality, for example, a T-cell engager or an ADC, in order to maximize anti-tumor activity. The demonstrated versatility of our platform really distinguishes us from other companies in this field, together with the depth and breadth of our R&D capabilities. Across our lead programs, and our collaborations, we're highly active in T-cell engagers, ADCs, and cytokines. Using the product design strategy that I reviewed on the previous slide, we have built a multimodality clinical pipeline designed to address large areas of a medical need.
We see three of our newest programs as major value drivers for the company, starting with CX-904. This is our Probody T-cell engager targeting EGFR and CD3. With this product candidate, we're seeking to utilize EGFR as an address to redirect T-cell-mediated tumor killing, and achieve anti-tumor activity. The opportunity here is broad applicability in EGFR-positive tumors and, in fact, regardless of their mutational status. Moving to CX-2051, this is our EpCAM targeting Probody ADC. The goal here is to increase therapeutic window for EpCAM through tumor localization and also utilizing a tailored topoisomerase I inhibitor payload, which is a camptothecin derivative licensed from ImmunoGen. The opportunity here is very broad across EpCAM-positive tumors, of which there are several hundred thousand, in the U.S. alone, several hundred thousand patients in the U.S. alone. Thirdly, CX-801 represents our entrance into the cytokine field.
CX-801 is a masked Probody version of interferon alpha-2b, which we see as having broad impact to harness the potent immunobiology of interferon alpha and potentially become a cornerstone of combination cancer therapy moving forward. As we continue through 2024, our multimodality clinical-stage pipeline is at a really exciting stage, and we anticipate several key milestones this year. CX-904 is in an ongoing phase IA study. The program is partnered in a global co-development relationship with, with Amgen, with whom we share in U.S. commercial rights. Dose ranging is ongoing in unselected patients with EGFR-expressing solid tumors. We anticipate initial phase IA data in the second half of 2024. These data will be reviewed with our partner Amgen and, if positive, will lay the foundation for advancement of this program into phase IB in 2025. Our newest clinical programs, CX-2051 and CX-801, are entering the clinic in real time.
The INDs recently cleared, and we're very excited to get these moving. The fourth clinical-stage program is the anti-CTLA-4 Probody BMS-986288, for which our partner BMS is running studies in non-small cell lung cancer and CRC. We have a very busy and important year ahead of CytomX. Let me now review our three lead programs in some more detail. Beginning with CX-904, our conditionally activated Probody T-cell engager targeting EGFR and CD3. Now, we're all well aware that initial breakthroughs in the T-cell engager modality really came in the hematology field, beginning with Blincyto, the CD19/CD3 program now commercialized by Amgen. You know, much progress continues to be made in the hematology field. In solid tumors, it's taken longer to really see meaningful advances. But we are starting to see success as this field is now at a really important inflection point.
As an example, tebentafusp, the Immunocore asset, has seen approval in uveal melanoma. This is a bispecific GP100-directed CD3 T-cell engager. And more recently, the really impressive data from Amgen, highlighted at ESMO 2023, for DLL3 targeting the DLL3 targeting T-cell engager tarlatamab, in small cell lung cancer. Really important proof of concept showing that the field is beginning to break through in bringing T-cell engagers to solid tumors. Now, for this modality to truly enter the mainstream, there are still, we believe, at CytomX, there are still significant challenges to overcome. And we see this area as an excellent application of the Probody therapeutic technology. Moreover, global pharma leaders are highly active in this field. And in fact, some of them are listed here. And we can actually add Merck to this slide, given their recent acquisition of Harpoon. So how do we see this field at CytomX?
Well, our Probody T-cell engagers are designed to really directly address the key limitations of conventional T-cell engagers in solid tumors. What are these limitations? Well, we all know what they are. They're on-target toxicities resulting from CD3 engagement, which typically manifest as CRS, cytokine release syndrome, and ICANS, neurotoxicity. In addition, in the solid tumor context, because solid tumor targets are almost always expressed to some degree on normal tissues, and these agents are so potent, they are unforgiving in terms of binding to normal tissues and causing immune-mediated, T-cell-mediated damage. So with conditionally activated Probody T-cell engagers, we're designing these programs to retain potent anti-tumor activity while having less systemic toxicities by masking on both the CD3 binding domain and the tumor antigen binding domain. And in the case of CX-904, that's CD3 and EGFR. We have a broad pipeline of T-cell engagers.
We're doing a lot of work in this space, not just 904, but also two major collaborations, one with Astellas and one with Regeneron. We really are well positioned as a key leader and expert in this field. Let me tell you a little bit more about 904. So the molecular design of CX-904 is shown here. This is the optimized design. We have an EGFR binding domain that is based on cetuximab that we've masked with a protease cleavable peptide, peptide linker. We have a CD3 T-cell engager, which is also masked with a peptide, and adjacent to which is a protease cleavable linker. And this construct is designed to minimize binding to EGFR and CD3 in normal tissues throughout the body, but for the mask to be removed specifically and selectively in tumor tissue by tumor-associated proteases, achieving tumor localization, and increasing therapeutic window.
We've shown in our preclinical studies a more than 60-fold increase in MTD for the Probody masked T-cell engager when compared to the unmasked CD3, EGFR. This program represents a substantial commercial opportunity. We're targeting EGFR-positive tumors, for which in the United States, there are more than 400,000 addressable patients across a multitude of indications. Even though we've seen previous approvals of certain EGFR-targeting biologics, this is a very underserved field in terms of how biologics are currently utilized in the treatment of EGFR-positive tumors. I should also say, and I already mentioned, earlier on, because we're using EGFR as an address to redirect T-cell killing, this should be independent of EGFR mutational status. So this is a very broadly applicable opportunity across EGFR-positive tumors. We're in phase 1a. Phase 1a is ongoing in patients with advanced solid tumors with known EGFR expression. This is in unselected patients.
The backfilling of certain dose cohorts was initiated in Q4 of 2023. We anticipate initial phase IA data in the second half of this year. This will lead to a discussion with Amgen to talk about the progression from phase IA to phase IB in 2025, to be initiated in 2025. We would anticipate, again, assuming positive data from phase IA, that we would be initiating tumor-specific EGFR-positive cohorts at specific doses and schedules, and most likely more than one dose and schedule to fulfill Project Optimus criteria in 2025. So we're excited about this program. I think this and the other work we're doing in this field really positions us as a leader in tumor-activated T-cell engagers at this very exciting time in the field.
Let me switch now to our work on CX-2051, excuse me, which is our conditionally activated Probody ADC targeting epithelial cell adhesion molecule. Now, we're all well aware of the absolutely remarkable advances in ADCs over the last decade, some of which has come quite recently. And we're seeing terrific progress in solid tumors, including ADCs coming earlier and earlier in lines of therapy across multiple tumor types, in fact, with the promise in certain solid tumors of ultimately replacing frontline chemotherapy. We're also seeing powerful combination activity of ADCs with immunotherapy. And despite, you know, all of this activity, in many ways, I think we can all conclude that the best is still yet to come.
The progress over the past years has prompted very, very active dealmaking in this space, almost unprecedented dealmaking, including, of course, CGEN's acquisition by Pfizer, ImmunoGen's acquisition by AbbVie, and very recently, the acquisition of Ambrx by J&J and many very large licensing deals. This is a very highly active area for pharma, understandably so, given the multitude of products that have made it to commercialization and the many, many products coming through company pipelines. So let's talk about EpCAM for a couple of minutes. Epithelial cell adhesion molecule, what is it about this target that we like at CytomX so much? Well, there are several things. First of all, EpCAM has been clinically validated as a target, although not with a systemic therapy. So what, what do I mean by that?
Well, we know that certain strategies targeting EpCAM, for example, the Removab bispecific, which is an EpCAM CD3, and also the fusion protein, formerly developed by Sesen Bio, which is a single-chain Fv FV targeting EpCAM conjugated or fused to the Pseudomonas exotoxin A toxin, that these drugs have demonstrated significant clinical activity in various tumor types, most notably the almost 40% three-month complete response rate seen with the single-chain Fv Pseudomonas exotoxin construct in non-muscle invasive bladder cancer. The challenge with this product is it has to be administered locally, intravesicularly into the bladder because systemic administration is too toxic. Why is that? That's because EpCAM, as the name suggests, epithelial cell adhesion molecule, is broadly expressed on all epithelial structures. So with a conventional antibody or a conventional bispecific or even a conventional ADC, it would be predicted that EpCAM would not have a therapeutic window.
But it is a very high potential target because its expression is really high on colorectal cancer and many other tumors besides. Moreover, the biology of EpCAM is particularly interesting. It is involved in epithelial mesenchymal transition. It contributes to stemness. It's actually used as a marker of circulating tumor cells. It's involved in adhesion and migration. So we believe that targeting EpCAM has broad potential as a potential systemic anti-cancer therapy. So what is our approach to the optimized design of our molecule here? Well, it's shown here on this slide. So CX-2051 is an antibody to EpCAM that we have masked again with our Probody technology. The mask is engineered to have a protease cleavable substrate adjacent to the mask to be activated specifically in tumor tissue. The masking will block binding in normal tissues. And we have a payload, which is a topoisomerase I inhibitor.
It's a camptothecin derivative, which is optimized particularly for where EpCAM is expressed the most highly, which is in colorectal cancer. We aim to move this program into the clinic in the coming months. The one of the really exciting things about this asset is that we've done head-to-head comparisons with a DXd conjugate, DXd, of course, being the very effective payload that's on Enhertu , the Daiichi drug. We've shown that CX-2051, with our topo I payload, that we license from ImmunoGen is equipotent with DXd, which is great to see. And we've also shown in terms of tolerability in cynomolgus monkeys that we can dose monkeys to significantly higher levels with the masked ADC compared to the unmasked. So masking works. Masking improves tolerability and opens therapeutic window for us now to move into the clinic with this really exciting asset.
There's a huge commercial opportunity with EpCAM, more than almost 300,000 EpCAM-positive addressable patients, we believe, in the U.S. alone across many solid tumors where there is substantial unmet medical need, not only colorectal, but also lung cancer, gastric, ovarian, and endometrial. So we're very, very enthusiastic to begin our clinical journey with this program. And phase I is being started in real time. We plan to use an adaptive strategy to evaluate a variety of doses in phase I and quickly move into expansions, including colorectal and other tumor types, depending, of course, upon what we observe in our phase I dose escalation. And we expect first phase I data for CX-2051 in 2025. This is a wholly owned program. Moving now to our first entry into the clinic with a Probody cytokine and specifically our Probody version of interferon alpha-2b.
Now, I think we would all agree that, despite very substantial progress in the field of immuno-oncology over the last decade or more, that significant unmet need remains. And this creates a major opportunity for CX-801. In IO-sensitive tumors, we typically see responses of 10%-50% in terms of overall response rates with single agent. In IO-resistant tumors, we see response rates of less than 10%. So even in the IO-responsive setting, most, most patients still don't respond. And in the IO-sensitive, IO-resistant or refractory setting, very few patients respond. So there are major opportunities to find ways to improve immunotherapy, particularly in the combination setting. And this is exactly where we see the potential for CX-801. So 801 is based on interferon alpha-2b.
This is a very powerful cancer immunotherapy with a dual mechanism of action, which we believe has ideal properties to combine with checkpoint inhibition such as a PD-1 inhibitor. But why interferon alpha-2b? Well, it's, we think it's been a little overlooked as a cytokine. There's a lot of work from a lot of companies ongoing with IL-2, IL-12, IL-15 in the cancer immunity cycle. Interferon alpha-2b can both kill tumor cells directly and also plays a powerful role in driving antigen presentation in the tumor microenvironment. In fact, the interferons were first described as driving antigen presentation in the context of viral infection. Interferon alpha-2b was actually the first immunotherapy to ever be approved way back in 1986. And of course, it fell out of favor because it has a very narrow therapeutic window. Interferon does have single agent anti-tumor activity.
It's been approved in melanoma, in bladder cancer, in renal cancer. But it fell out of favour because of broad-based systemic side effects that make it a very difficult drug to use. It has come back to relevance, though, in particular with the recent approval of a drug commercialised by Ferring, called Adstiladrin. And this is a drug which is a gene therapy, adenoviral gene therapy that encodes interferon alpha-2b. So the same cytokine that we're using in our construct. This gene therapy is administered locally, again, intravesically into the bladder to treat non-muscle invasive bladder cancer. And it's very effective. The drug's been approved. And recently, Royalty Pharma purchased a royalty in this drug from Ferring for up to $500 million. And the predictions are that this gene therapy could become a $1 billion drug or $1 billion plus drug.
So interferon, if you can harness its potent immunobiology by decreasing systemic side effects, it has incredible potential for cancer patients across a range of tumor types. It's also been shown by the Merck team that interferon alpha can synergize very effectively with PD-1 inhibition. The challenge being here, despite this 60% overall response rate seen in melanoma, a 49% incidence of grade 3/4 adverse events. So our goal with CX-801 is to have less systemic toxicity, better exposure, improved systemic delivery, an increased therapeutic window, and of course, all leading to improved combination therapies. So CX-801, the optimized design is shown here. We've pursued a dual masking strategy for CX-801. We have a peptide mask that binds to the cytokine. And we have an Fc domain, which also improves overall PK, upon systemic administration.
Both masks are designed to be cleaved in vivo in the tumor, leaving the cytokine alone in the tumor to affect the appropriate impact on the tumor microenvironment. Our preclinical profile suggests potent synergy of CX-801 with PD-1 inhibition, as shown here on the top left-hand panel, in a 25-model experiment in 15 different tumor types. You can see the addition of our Probody interferon alpha to PD-1 therapy, in the blue shows a substantial change of reduction in tumor burden in most models treated. On the top right-hand panel, you can see that we are inflaming the tumor microenvironment with this agent by locally activating interferon in the tumor. In mouse models, in the bottom left-hand panel, we can achieve substantially higher dose levels in mice compared to the unmasked interferon. Again, it's a consistent theme with our platform. Masking improves tolerability consistently across multiple modalities.
We also see much less activity of this interferon in the periphery, as shown in the bottom right-hand panel, where you can see that the unmasked is active even in lymph node and spleen, whereas the masked interferon is not. So, we're well positioned to translate this data and this program into the clinic. And we are in real time opening clinical sites to initiate, again, an adaptive phase 1 study to dose escalate and achieve dose levels with which we can rapidly initiate combination studies with checkpoint inhibition. And our goal here is to enroll patients in phase 1 in melanoma, renal and head and neck cancer, which are three tumor types where we know interferon has already demonstrated single agent activity. In closing, I'd like to just spend a couple of moments on our strategic partnerships.
Business development has been a very important strategic engine for CytomX over many years now. It has resulted in alliances with BMS, Amgen, Astellas, Regeneron, and Moderna. We've raised more than $500 million of funds from these collaborations. We have more than 10 active preclinical programs in these alliances. And in many cases, we retain commercial rights. And we have significant near- and long-term milestones. And we're particularly excited to have entered a collaboration with Moderna about a year ago, which not only takes us into the very exciting area of RNA-based, mRNA-based biologics, but also for the first time outside of the oncology therapeutic area where we see potential, broad potential for protease-activated biologics. The most advanced program in our partnerships is the BMS CTLA-4 program, which, as I've already mentioned, is advancing in lung cancer and in CRC.
BMS's most recent public guidance, issued in September of last year at their R&D day, was potential for data availability in 2024. So wrapping up on outlook and milestones in my last couple of minutes here. So CX-904, our tumor-localized EGFR CD3 in phase I dose escalation, phase IA data anticipated second half of this year with potential initiation of phase IB in 2025. CX-2051, our EpCAM ADC, IND has been cleared. Clinical site activation is in process, initiating phase I in the first half in EpCAM-positive tumors, including colorectal cancer with initial phase I data in 2025. CX-801, similarly, the team has been very busy. IND also recently cleared. And phase I initiation ongoing in melanoma, renal, head and neck with initial phase I data expected in 2025. And then BMS, we would expect to see continued updates from our partner.
Research collaborations will be ongoing over this period of time. We have built a very broad and deep company at CytomX. We're excited to have a very differentiated multimodality platform, a multimodality pipeline, large market opportunities, very high-quality partners. We're in a strong financial position, having most recently reported $194 million on the balance sheet at the end of Q3 2023. I'm very proud to work with an immensely talented organization. Thank you very much for your time today.