CytomX Therapeutics, Inc. ($CTMX)

[Audio Gap] in addition to not seeing any of the classic abcam toxicities like pancreatitis because I'm asking is delivering.a We see low rates of hematologic toxicity, actually really unusually low rates of heme tox for an ADC and particularly for a topo1 ADC. And I want to underscore that this is a novel linker and payload that we're using. This is the first time this triallinine CAP-59 construct has been explored in the clinic. And so far so good in terms of the tox profile, low rates of neutropenia, anemia and thrombocytopenia. For some reason, the AbbVie and Merck drugs do show significantly higher rates of hematologic toxicity in the form of all 3 of those hemetox profiles. And that's clearly something to watch as those drugs develop. So we think -- on top of that, it looks to us, I mean, a bit more work to do here, but we believe we may have the most active drug as well. So we do see [ Force ] as being intrinsically differentiated from the other ADCs. There are, of course, other innovations coming in colorectal across immunotherapies. We're obviously watching closely the Exelixis TKI in combination with atezolizumab, which may come to the market before too long. But again, we just feel like the intrinsic activity, quite honestly, the remarkable activity of in late-line colorectal is highly differentiated, and we're just really excited to get the drug into its first pivotal study beginning of next year.

In that March update, you mentioned earlier, showed activity across the prioritized doses, the 8.6 mgs per kg and the 10 mg per kg. You've completed enrollment in your dose optimization cohort. How should investors think about the overall clinical profile?

Yes. So we're progressively and systematically developing Viasat initially for late-line CRC. And that systematic development plan has involved, of course, initially dose escalation, dose expansion where we reported the results recently from the expansion of 3 doses, 7.6 -- [ 7.2 8.6 ] and 10 mg per kg given every 3 weeks. And those expansions led to the efficacy data that we just reported. -- again, remarkable antitumor activity in late-line colorectal and also talk to us a lot about the integrated safety profile of the drug and how to further optimize those as we move towards that first pivotal study. So what we elected to do and what we're in the middle of right now is we further narrowed the dose range to the top 2 doses from expansion, so 8.6 and 10 mg per kg, and we are now enrolling about 20 patients at each of those dose levels in the dose optimization phase, where we've also implemented a couple of additional measures to further refine and help us select the optimal dose, where we've employed upfront prophylaxis with these 2 dose levels, treating patients with the anti-motility agents, [ pyramid ] and the nonabsorbable corticosteroid budesonide. And we're also evaluating the role of adjusted Idea-body-weight dosing to reduce the number of patients who when they come into clinic, are -- have high body weights, particularly patients who may be obese, where under conventional actual body weight dosing, they probably get a little too much drug such that they can -- as a risk of overexposure and that can lead to increased toxicity. So we're using, I say, exploring AIW dosing to decrease the number of patients who get this outlier exposure. And we believe all of these measures will go to further improving the safety profile of the drug and specifically the incidence of high-grade GI toxicity. And that will allow us in the context of the activity that we're looking at for these 2 dose levels to then zeroing on which of these 2 really great choices we've got actually for the pivotal study, which of these 2 doses we move forward. into the first registrational design.

You've articulated publicly vision of expanding NCRC through combos and early line [indiscernible] Can you talk a little bit about that strategy, the combinations that you're starting to explore in [indiscernible]?

Yes. So there's -- I'd say there's a healthy debate out there right now in the investment community regarding , which we think is great regarding [indiscernible]. There's a lot of interest in this drug. A lot of interest in what we're doing and a lot of questions being asked and one of them is the our ability to bring Arcata earlier in the treatment paradigm. And let me tell you how we're going to progressively do that. So obviously, we're beginning in the late line. That's where the unmet need is the highest, that's where we've conducted our clinical work to date, and that's where we have unquestionable activity, and we believe a clear path to registering the drug in late-line colorectal. That doesn't seem to be much of a debate at the moment. I think everyone is onboard with that, yes, this is an execution story now about getting the drug approved in late-line colorectal and we're confident in our ability to do that. In terms of bringing the drug into the earlier lines, we're also confident there. We need to do the work. And so what are we doing? Well, first of all, as I said, we're working very hard to further characterize the safety profile and very specifically, reduce the rate of grade 3 diarrhea that we see in patients treated with [ VARACETAM ]. We showed a very strong start in our March 16 update with the first 20 patients treated in dose optimization where we had reduced the incidence of grade 3 diarrhea to 10%. And our goal over time is to keep that rate in the 10% to 20% range. That is going to be an exceptional range of grade 3 that everyone we talk to in the clinical community says that's going to -- that will be manageable, particularly in the context of the incredible benefit that the drug is bringing to the CRC patients. So in the context of that dose optimization work, we're beginning combination work, and we've started to combine [indiscernible] with bevacizumab. That's an obvious choice, of course, because BEV is so frequently used in -- really across the treatment paradigm in colorectal from early lines into the late line. And so we want to get that experience because we absolutely anticipate the combination of [indiscernible] will be ability in earlier lines of therapy. We're also in the second half of the year, beginning combination work with chemotherapy. And the reason to do that is to -- it's a big step towards realizing our ultimate vision for [ VarceTAM ], which is to replace rinotecan in the treatment paradigm. So [ irinotecan ], TEP1 inhibitor has been well established in the treatment of CRC for many years now, and it's used often in the front line, more typically in the second line in the context of [ FOLFIRI ] plus bevacizumab. And it's pretty effective in second-line setting. Our goal is to combine with the [ non-erinitecane ] components of the [ FOLFIRI ] regimen, and of course, to evaluate it with bevacizumab as we gain experience with that combination as well. So we're laying the foundation. We're bringing the drug earlier to the treatment paradigm by #1, improving how to predict and manage the safety profile and optimize the sage profile; number two, pick the optimal dose for late-stage development; number three, gaining experience with bevacizumab for gaining experience with other -- with chemotherapy. So you can see in my comments how this program is broadening in real-time. We are significantly broadening the scope of the [indiscernible] program and really excited to see what we can deliver across the treatment paradigm for [indiscernible].

You talked about broadening and CRC. Let's talk about broadening outside of CRC. EpCAM, as you mentioned, expressed in many other tumor [indiscernible] as you think about the potential to move into other tumor types, how would you prioritize where to go first?

Well, with colorectal, we certainly feel like we've done the hardest experiment first. We really intentionally designed for us to be active in colorectal. And it is. It's highly active in colorectal. That was a big decision that we took as a company to focus our Phase I study entirely in metastatic late-line CRC. And that decision, we believe, has really paid off. Because we've done the hardest experiment first, we are now very excited to move [indiscernible] into other tumor types. And there's a long list of cancers that we can potentially address. [ Abcam ] is expressed in many, many other solid tumors, and we do plan to start that work in the coming months. We do like some of the other GI tumors. If you think if you like, franchise adjacent to colorectal as being areas of significant unmet medical need, tumors that are, in many cases, responsive to [ Top 1 ] inhibition. -- and where Abcam is expressed at high levels. In some of those patients that may require a patient selection strategy. We have a fully validated [ Abcam ] selection, [ IAC ] assay ready to go. So that's something that we're looking at right now. We're working our way through a list of priorities, and we'll be sharing later in the year. specifically what our non-CRC- or what the first steps in our known CRC strategy are going to be. Of course, our ultimate goal is to secure a pan-tumor label for [ Abcam ] given its broad expression. That will take a while to get to, but these will be the first few steps along the way.

Shifting gears a little bit. There's a lot of, I think, very understandable investor focus on [ Verceta-M ]. But your second program, 801 is also in the clinic. You're advancing in dose escalation with [indiscernible]. Can you give a little bit of an overview of the program and what makes you excited about it?

Absolutely. We've already touched on some of the immunotherapy applications of the [ Probody ] platform in the context of our ongoing and now expanded work with Regeneron in bispecific immunotherapies. And as I said, we absolutely see those types of strategies as being very natural places to go to leverage the power of masking to improve therapeutic window. But the cytokine field is another whole universe of application of the Probody strategy. And we're working on a number of cytokines in the company, and the [ interferon ] program is the most advanced. So CX801 is a duly masked version of interferon alpha to be Interferon alpha she was the first immunotherapy to ever be approved. It's a very powerful cytokine. There's multiple things in the tumor microenvironment to drive [ Agogen ] presentation, T-cell activation. It actually has direct antitumor activity as well through interferences expressed on the cell surface of tumor cells. And for that reason, it's been utilized extensively in the clinic over many years and has been shown to have single-agent activity in a number of cancers, including in melanoma. But interferon fell out of use because it's very poorly tolerated when given systemically. It causes a range of significant debilitating side effects. Patients have a very poor experience on systemic interferon alpha, including fever, including chills, including neuropsychiatric challenges. And so the risk benefit for unmaasked interferon alpha has resulted in falling out of use over the years. But when we come back to its fundamental immunobiology and the way that interferon alpha modulates the tumor microenvironment in the inflammatory microenvironment, it does have all the hallmarks of a cytokine that can drive or, if you like, restore sensitivity in the post checkpoint inhibitor setting to a wide range of cancer types. And in fact, it's been shown, it was shown by Merck some years ago that the combination of interferon alpha-2b with PD-1 inhibition is highly active in melanoma. In fact, in frontline melanoma has a 60-plus percent overall response rate, but the challenge is that combination is poorly tolerated with, again, conventional systemic interferon. So the experiment that we're doing in the clinic in real-time is focused on melanoma with our July [ mast Itron ] 2B, we call it 8[indiscernible]. It has a peptide mask on the cytokine. It has an [ Fc ] mask, both of which are protease-cleavable., The combined effect of those 2 masks shuts down the peripheral activity of the cytokine by about 5,000 fold. So it's very, very quiet in the periphery. But the goal is when it gets to the tumor that those marks would be removed and that should allow us to activate interferon biology in the tumor and then restore checkpoint sensitivity. And as you know, this is one of the biggest questions in immunotherapy today, how do we restore activity in patients who have been on checkpoint inhibition? Or how do we create activity in patients who are resistant or recalcitrant nonresponsive in the first place? So we've been in the clinic now for about a year, and we have already reported some clinical data. Last year at [ SITC ], we showed results in the first 5 patients treated with monotherapy CX-801. The data we shared was pharmacodynamic analysis of on-treatment tumor biopsies in the first 5 patients treated with CX-801. And it looks really exciting. -- where clearly, the drug is activating multiple layers of interferon alpha-2b biology in the tumor. We're activating interferon responsive genes, we're inducing checkpoint proteins, including PD-1 and PD-L1. And really dramatically, we see profound infiltration of cytotoxic T cells into the tumor bed in conjunction with the activation of local chemokines. So mechanistically, the first few patients we've treated, the drug is working exactly as we've designed, has also been very well tolerated. We haven't seen what we've already achieved those levels in the clinic that have exceeded the clinically approved dose of [ intefrinalpha ]. And at those doses, we're seeing this powerful intratumoral modulation of the immune system, which really sets up the perfect foundation [Audio Gap]. On the real experiment that we're doing here in melanoma, which is to combine [Audio Gap] well into the combination escalation of 801 with KEYTRUDA, we're enrolling at our third dose level and we're on track to have initial clinical data for 801 in a handful of melanoma patients by the end of this year to look at what kind of activity and tolerability we're seeing with the combination in this late line post checkpoint inhibitor, metastatic melanoma patient population.

Great. In our closing time, maybe taking a step back, looking the next several years for CytomX, how do you see the company evolving as [indiscernible] sort of M&A 801 evolves or continues in the clinic [indiscernible] as well as continue to evolve the broader body platform?

Well, we're absolutely setting our sights on bringing [ Viracta ] to the market, building CytomX to commercial stage. Time will fly over the next few years, and we'll be there before we know it. We are well funded at the moment. We raised, as you know, in mid-March on the heels of our March 16 update. We also, of course, had the cash infusion from the Regeneron expansion, which further strengthens the balance sheet and puts us in a robust position to continue to execute. So for [indiscernible] monotherapy driving that to its first approval based on the first pivotal study that we'll initiate first half of next year. Looking further down the road, bringing the drug into earlier-line settings. And by the way, not just second line, we're also setting our sights on the potential of in the front line in colorectal. And this market is absolutely enormous, and the unmet need is huge. So a lot of work ahead of us there. And then continuing to broaden the pipeline both ourselves and with our collaborators, bringing 801 forward to clinical proof of concept potentially bringing other ADCs into the clinic and just continuing to build the company around this very unique technology that we've been working on for a number of years, which is now absolutely delivering for us in this most remarkable way.

Fantastic. Well, thank you, Sean, for joining us today.

Thanks for having us.