Okay, thank you so much. Good afternoon and welcome to Barclays Global Healthcare Conference. Do reach out to myself or my associates if you have any questions by email on Bloomberg as well. I guess, yeah. My name is Peter Lawson. I'm one of the biotech analysts with Barclays. I cover mid-cap biotech, absolutely delighted to have management from CytomX with us today. Sean McCarthy. The first question is Perfect. That's better. Thank you. Good afternoon, everybody, and welcome to Barclays Healthcare Conference in Miami. Do, you know, raise a hand or ping myself or one of my associates if you have questions that need to be addressed. My name is Peter Lawson. I'm one of the biotech analysts at Barclays, cover mid-cap oncology, biotech companies.
Really delighted to have up on stage with me, Sean McCarthy from CytomX. First question really is kind of the differentiating factor that we have around your approach, kind of how is that resonating in the sense of partnerships and, you know, how partners are perceiving that activation of a kind of a prodrug antibody?
Yeah. Thanks, Peter, pleasure to be here. Thanks for the invitation. Just to briefly recap the core technology that we've been developing at CytomX for now more than a decade. Our belief is that biologic therapies, as they continue to become increasingly potent, whether it's antibody drug conjugates or bispecifics or cytokines, they will benefit from increased localization into tumor tissue and indeed potentially in other disease areas as well. You know, we firmly believe that localization will be the future of biologics, actually. We've been pioneering our Probody platform for the last 10 plus years.
In short, our approach is to take an antibody or a biologic drug and to mask the drug, typically with a peptide, and mask it in a protease-dependent manner so that the mask is removed specifically and selectively within disease tissue. The overwhelming amount of work that we've done over the last few years has been in the oncology space. We've known for a very long time there are thousands of publications in the literature showing that protease biology is dysregulated, turned on in tumor tissue. In fact, protease biology plays a fundamental role in tumor cell invasion, migration, and metastasis. We realized some years ago that we could leverage this protease activity to activate these localized biologics in tumor tissue by removing the mask.
The technology really has an intrinsic differentiation to it. We're the first company to do this. We have seen, given the progress that we've made in the field, including bringing the company to the public markets in 2015, we have seen a number of new entrants into the field, some somewhat related in terms of masking strategies, other companies taking other approaches to localization of biologics. In our case, you know, the leadership that we've shown has attracted partners. We've been very proud to form six major partnerships over the years with Bristol Myers, Amgen, AbbVie, Astellas, and most recently with Regeneron and Moderna.
I think these two recent deals in particular, continue to underscore the leadership and the differentiation in our technology in that both of these partners, our newest partners, are coming on board to access the latest generation of technology of our platform, of our platform technology, and also to take advantage of the more than 500 patients of clinical results that we've generated over the last few years as well. We're very thrilled to have these new partners and continue to be making significant progress across all of our alliances.
Gotcha. Thank you. That's always impressive, like 500 patients, essentially a safety database and understanding on how the molecules work. The Moderna collaboration, I find that pretty fascinating. Kind of how does that integrate with their kind of mRNA approach, and how did they come to pick you versus others?
It's a very interesting convergence. As we've said in our discussions of the deal since we announced in January, you know, the two companies do, you know, share a lot in common in terms of investing at the interface of biology and technology. The basic concept of the foundation of the alliance is to use Moderna's mRNA platform to encode and express Probody therapeutics or conditionally activated therapeutics. The foundational work that Moderna has published that led to this discussion was first published a couple of years ago. Actually, during the pandemic, they were working on things in addition to the vaccine of course.
This work demonstrated that the intravenous administration of mRNAs encoding a therapeutic antibody could actually elicit, in a dose-dependent manner, therapeutically active levels of the antibody in healthy human volunteers. It's a remarkable study and a foundational study, as I've already said, in showing that mRNA delivery can achieve therapeutic levels of a biologic, opening the door to using the mRNA platform to encode a wide range of different biologic drugs. In a way, Moderna is taking two big steps forward with this collaboration. Firstly, they're utilizing their platform to use mRNA as opposed to the more conventional manufacturing strategies that one would go through to make a biologic and put it into a vial and administer that to the patient. They're able to basically bypass that entire manufacturing step for a typical biologic drug.
Also coming to us and leveraging our conditional activation, take yet another step in localizing the biologic once produced by the mRNA into disease tissue. Now, one other very interesting feature of this deal is that it's our first alliance that actually takes us outside of oncology. As I said, the vast majority of the work that we've done over the years has been in oncology. We are a very oncology-focused company, but we will be working with Moderna in some non-oncology therapeutic areas for application of mRNA-encoded biologics. We haven't said very much at all yet about exactly what that will look like, but we're thrilled to be taking that step, and it potentially opens the door to additional work that we could do potentially with new partners in the future in non-oncology areas as well.
Good. Thank you. Just thinking about the pipeline, CD71 ADC, kind of when should we get updates around kind of go forwards around that partnership with AbbVie?
Yeah. The CD71 program is our CX-2029 asset. This is an ADC, a masked ADC targeting CD71. CD71 is very interesting cell surface protein. Its biological role is as the transferrin receptor. It's a protein that in the course of its ordinary biological role, cycles off the cell surface very, very quickly, actually within seconds, actually, to deliver the transferrin complex into dividing cells. No one has succeeded thus far until CytomX in actually opening a therapeutic window for targeting CD71 with a therapeutic, and in our case, with an ADC, even more impressive, we believe.
We have shown in our clinical work to date clinical activity in several tumor types, including head and neck cancer, squamous non-small cell lung, and most recently, reported in January in squamous esophageal cancer. The drug clearly has single agent activity in several tumor types. The drug has an overall well-tolerated profile. Anemia is the principal dose-limiting side effect we can perhaps discuss in a moment. As I said, the drug candidate is partnered with AbbVie. CytomX has been responsible for running all of the clinical studies so far, so our responsibilities are now beginning to wind down. We've run phase one dose escalation. We actually published that work. We completed the phase I- B, or if you like, phase II expansions.
We've passed that data now on to AbbVie. The next step will be to determine the next clinical pathway for the drug. AbbVie is reviewing that data. We expect to hear from them this year on their potential next steps. As I said, we have seen activity in several tumor types. We look forward to hearing the direction for the future development of two oh two nine.
Gotcha. If they handed it back to you, would you partner that again or would you move forwards with it? What's your kind of approach to-
Yeah, I think like with any of these decision points that one comes up to with a major partner. There's always a scenario where the asset comes back. We haven't fully thought through what we would do exactly. We've got some ideas, but we'll cross that bridge when we come to it.
Gotcha. Okay. You mentioned the anemia, kind of the strategies there to kind of control it.
Yeah. The principal side effect of CX-2029 has been anemia, and it in part likely relates to the biology of the target itself. The reason that no one's been successful developing an unmasked ADC to CD71 in the past is because of the central role that CD71 plays in iron metabolism. Because of the central importance of iron metabolism to erythroid development, to red blood cell development, preclinical results would predict that there is a zero therapeutic window for a non-masked ADC because of this impact on hematologic processes. What we've been able to do by masking the ADC is open the window wide enough to achieve therapeutic exposures in cancer patients that have resulted in clinical activity, as I've already mentioned, in several tumor types.
Clear single agent activity at the recommended phase II dose of 3 mg per kg dosed every three weeks. At these doses, and indeed, we push the dose to 4 and 5 mgs per kg in dose escalation, we do see hematologic impact, particularly anemia, but we have shifted the dose response curve such that the anemia is predictable, reversible, and we believe manageable with a combination of interventions. Those interventions include red blood cell transfusions, dose reductions, and dose delays. As we've gained more experience with the drug candidate over the last couple of years, and particularly last year, as we were working with the esophageal cohort, I would characterize the anemia management as follows.
That the paradigm that's beginning to emerge as we gain more experience has been that because this is an ADC, if patients are going to respond, they will likely respond fairly quickly, so over the first few cycles of the drug. When a patient comes in for their first scan, certainly by their second scan, you know, an investigator will have a pretty good sense as to whether the patient is responding to the therapy. Most patients will get anemia. We have 70%+ of patients that get grade three. It is very predictable. Most patients will get it. If the patients are in response, what we've been seeing is the investigators are working with the patients to leverage these mitigation strategies, transfusions, dose reductions, dose delays, to try to maintain the patient in response.
For patients who have shown activity, whether it's been stable disease or actual confirmed PRs, they've typically been able to stay on drug for, you know, significant periods of time, for three or four to six months or longer. You know, we'll continue to learn about the drug. We have explored erythropoiesis-stimulating agents like darbepoetin. You know, we haven't seen a lot of impact on the anemia to this point. There may be more we can do there in the future. It is, yeah, I think it's important to say that, you know, we have been gaining more experience as time has gone on, and this does remain, I think it's important to note, still an experimental drug candidate that we'll learn more as we move forward.
Gotcha. I mean, the base technology here, the pro-drug approach is exceptionally powerful. Just your ideas about exploring, like, I guess, different toxins, different linkers, or different ways of linking. Is that another approach that at some point you wanna explore?
Absolutely. Just to take a step back in terms of the company's evolution over the years. I mean, we have been successful in raising substantial sums of capital for the company, both through our equity raises over the years, and importantly, through the multiple partnerships. We've actually been able to generate more than $500 million of non-dilutive capital from partners. What that's enabled us to do is to go really deep on the science and continue to innovate over the years and make sure that we maintain our leadership position in biologics localization and conditional activation.
One of the ways that we're doing that and continuing to capitalize on learnings is evidenced in two new INDs that we'll file this year that incorporate learnings from those many hundreds of patients that we've now got clinical experience with to go back to the lab and optimize the platform. I'll start with a drug candidate called CX-2051, which is our next-generation masked ADC targeting a very interesting protein called EpCAM. EpCAM is epithelial cell adhesion molecule. It's one of the first tumor antigens to ever have been described, actually. It's broadly expressed on most solid tumors at high levels. It's also, as the name of the target might suggest, epithelial cell adhesion molecule. It's present on most epithelial normal tissues. People have tried to drug EpCAM over the years and failed because of its normal tissue expression.
Antibodies to EpCAM have failed in the clinic due to toxicity. However, we do know that local administration of anti-EpCAM therapeutics can be very effective in shrinking tumors. That's been shown with a bispecific and also with a toxin fusion protein developed by others. It's a validated target with the potential for significant activity in a range of tumors if we can find a way to dose it systemically. Our masked ADC-2051 is that's our strategy to achieve the drugging of EpCAM. The payload that we've selected for 2051 also reflects our learnings over the years.
The first two ADCs that we put into the clinic, 2009, which we deprioritized last year, and 2029, which we've just discussed, the CD71 program, they respectively have leveraged payloads called DM4 and MMAE. The 2051 program has a camptothecin payload, which is a topoisomerase I inhibitor, which we anticipate will have a broader therapeutic window, but is very similar to the payloads on Daiichi's Enhertu and on Gilead's Trodelvy. We believe that we've got a great target in EpCAM. We've got a great payload in camptothecin. We have a, we think, a very optimized masking strategy, and we think that the probability of technical success for this asset is correspondingly higher as we now move it towards the clinic by filing the IND this year.
Gotcha. Thank you. I'd love to pick your brains on the Bristol collaboration. They've moved one of the molecules forwards, the non-fucosylated version. What's your TL reading around that?
It takes a little bit of time to work through the multiple programs. We're doing so much with BMS, just bear with me for a moment. We are working with BMS on two particular Probody approaches. One is a Probody version of ipilimumab itself, so Yervoy. That's called BMS-986249. We're also working with them on a Probody version of what's called BMS-986218. BMS-986218 is Bristol's non-fucosylated anti-CTLA-4 antibody. It's a non-fucosylated version of ipilimumab. The design of that program, the goal of BMS-986218 of their antibody, is to be a more potent version of ipilimumab.
The Probody version of 218, we call 288, is designed to be a masked version of 218, so it's meant to be a safer, more effective version of the non-fucosylated ipilimumab. At their earnings call a few weeks ago, BMS announced their prioritization of that non-fucosylated Probody, which now is the leading edge of their next-generation CTLA-4 program. We're really excited about this. It means that CytomX technology is on the leading edge of BMS' next gen CTLA-4. If you look at the data that BMS presented at SITC last year on 218, the non-fucosylated antibody, you can see that they made a lot of progress in phase I. They showed that the drug has clear activity. It showed intriguing activity in MSS-CRC, so microsatellite stable colorectal cancer.
They were able to escalate to doses of about 70 milligrams. You could infer from that poster that there may be some value in dosing higher. That will be one of the things that I would anticipate they'll be looking at with the Probody. The reason I say that is that the 249 ipilimumab Probody that they presented phase one data on at ESMO last year, updated phase one, they were able to take to very high doses in phase one because of the masking. We know masking works. We know masking can achieve higher doses, and it's gonna be very exciting to see where BMS takes the 288 program now as they progress into phase two. They also announced the advancement from phase one to phase two at earnings.
We're thrilled with the progress with our partner BMS on next gen CTLA-4.
Commence. Yep, that's great, great data. Great, great collaboration there. Kind of where do you think they'll end up prioritizing the molecule, moving forward?
Yeah. We really don't know at this point. Their strategy, their phase II strategy is under development. I mean, obviously they have a long-standing interest in big franchise in melanoma. I think the activity that they've shown in CRC in these two recent posters for 249 and 218, is noteworthy. That's a major unmet area of medical need where ipilimumab is not currently indicated itself. I wouldn't be surprised to see them move into other tumor types as well. We're excited to see where they take it.
Gotcha. Then guess in the last minute or so, just on your T-cell engager, EGFR T-cell engager, again, another interesting construct. When can we see initial data, and when do you think we get a recommended phase II dose?
Very excited about CX-904. This is our first masked bispecific entered into the clinic. This program is partnered with Amgen in a global co-development relationship. We retain significant U.S. commercial rights. The vision of the program is to target EGFR-positive tumors with this bispecific immunotherapy to essentially increase the immune cell activity in EGFR-positive solid tumors. We are in dose escalation. We're making progress. We have announced that we have cleared initial single-patient cohorts in early phase I, so moving along nicely, and we're now in the 3+3 phase. We're not quite ready to guide on timing of data, but we are thrilled with the progress and looking forward to seeing what this program will do for patients.
I would emphasize, also that, of course, phase I is principally about safety and attaining a recommended phase II dose to move into subsequent expansions, and that's the main goal of the work that we're doing right now.
Gotcha. Where do you think it would fit into current treatment regimens?
Well, I think there's a lot of places it can fit in. If we just think about EGFR therapy itself, you know, we have the EGFR antibodies, of course, cetuximab, panitumumab, that have their place. We have the TKI inhibitors, which have their place. You know, a different strategy, of course, inhibiting, mutated kinases in various tumor types. This is a very different mechanism and a very different way to leverage EGFR, from an immunobiology standpoint. I think there's a wide range of potential applications. We'll have to see, as always, where the early clinical data guides us.
Perfect. Gone into extra time, so thank you so much. With pleasure.
Thanks very much, Peter. It's been a pleasure.