Okay, great. Maybe we'll go ahead and get started here. Thanks, everybody, for joining us or tuning in here at Piper Sandler's Annual Healthcare Conference. I'm Joe Catanzaro, one of the Piper's biotech analysts. It's my pleasure to kick off this section with Exelixis. Joining us is their SVP of Strategy, Andrew Peters. Andrew, thanks so much for joining us. Maybe we could just sort of jump right into questions here and start off with a high-level one. I know there's been a lot of recent effort at Exelixis around sort of building up the pipeline and diversifying away from Cabo.
Maybe you could speak to the overall strategy for the pipeline, what you see as the most capital-efficient way to bring those assets into the clinic and establish proof of concept, and then maybe we could sort of tick through some assets along the way.
Yeah, happy to get into that, and thanks for the invite to speak with everyone today. So before I get into that, just as a reminder, I'm going to be making forward-looking statements today, so please see relevant disclosures in our SEC filings. So, at Exelixis, you know, we've talked about this a lot, but really, our top priority as a company is to develop what we think are clinically and commercially differentiated oncology assets in large market tumor types, where we can really be a part of shifting the standard of care and driving kind of differentiated data to really help patients live longer, better lives. That's kind of our core mission and really is kind of our overarching strategy here at Exelixis.
You know, so as part of that, we like to say, you know, we view everything through the Cabo lens in terms of understanding kind of how we're gonna generate that data. In the case of Cabo, it's, you know, learning from prior generations of VEGF targeting TKIs, bringing in and, and highlighting the importance of some of the other kinases like MET, AXL, MER, kind of the TAM kinases. And then with Zanza, which we'll-- I'm sure we'll talk about later, kind of further iterating on that. So it's, it's that strategy to bring to market commercially and clinically differentiated, assets, kind of, in using that, that lens and that insight into how exactly we're gonna drive the standard of care, whether that's in combination, whether that's in novel mechanisms, novel modalities, to really kind of shift that standard.
In terms of kind of the capital efficiency, what I can highlight is, you know, historically, Exelixis has been very, you know, focused and thoughtful about that dynamic. If you look at the development history of Cabo with, you know, 14-plus pivotal studies that we've run, we've been very efficient there in terms of how we've partnered, collaborated, with folks like Ipsen and Bristol and Roche, to help offset some of those costs and ultimately ask the right clinical questions to drive data, which ultimately is what has made Cabozantinib so successful commercially. It's, you know... That's kind of the core focus and the core strategy.
You know, I'm sure I'll mention this a lot today, but certainly want to highlight that we're gonna be having an R&D day December twelfth, where we're gonna talk at you know, pretty extensive detail about a lot of this. But again, kind of that core strategy is really to develop molecules that are gonna you know, drive differentiated data, and ultimately, that's what makes things successful commercially.
Yeah. Maybe since you mentioned it, the upcoming R&D day in a couple weeks, I guess, you know, what do you hope the take-home message there to be? Is it more high level around sort of the pipeline strategy, or are there asset-specific messages that could be important there?
Yeah, I think kind of any and everything about both of those dynamics. What we talked about to kind of level set expectations on the last earnings call is really the R&D day, which is gonna be the first that we've done in quite some time, is really to talk about the science and strategy behind Exelixis now. Earlier this year, we've talked about Cabo being kind of the gas that fuels the Exelixis engine going forward. So the R&D day is gonna be a chance to really talk about what those assets in particular are. You know, we've talked at length about ZANZA, just presented some compelling data at the IKCS conference, talked about XB002, our tissue factor ADC.
But beyond that, it's gonna be an opportunity to really, you know, again, talk about some of these earlier stage programs that we do think have the potential to drive that differentiating efficacy data in, tumor types that are commercially important and commercially relevant. Because I think that's something that's, that's often overlooked, and, you know, we've talked about quite extensively, actually, is, you know, me-too programs with kind of undifferentiated data have not been successful commercially. And then, you know, the flip side of that is, you know, compelling data and unfortunately, you know, smaller populations have also struggled commercially as well. So that's kind of a, something that, that we keep in mind from a portfolio perspective, that we wanna make sure we're really have the ability to drive that differentiating data in commercially relevant populations.
So maybe one last question on sort of strategy and the portfolio before we dive into some specific programs. Obviously, you guys have done a lot of work in filling in the pipeline. Do you think you're now at a point where the pipeline has been right-sized for the Cabo revenue base, or is there still some more work to do?
... Yeah, again, and not to kind of be a broken record about this, but it really kind of underscores the philosophy we have at Exelixis, is it's really about not the number of assets in a portfolio, but really the quality of those assets and the ability for those assets to drive differentiating data that are ultimately going to change the standard of care for patients. And so we don't necessarily think about it quantitatively in terms of the number of assets. It's about qualitatively, are these the right assets? Are we going to be able to generate data to make that go, no-go decision?
Because if the data are good, we're going to continue to develop it, and I think our history has shown that if the data, you know, don't meet expectations, we're certainly willing and have a history of kind of killing things quickly as well. So it's about that idea of constantly refreshing the portfolio with assets that we think can generate differentiating data.
Great. So maybe with that, we can move to specific programs and actually just start with a few on CABO. I guess maybe first one, as we look into 2024, what do you guys see as some key potential levers that you could continue to pull to drive growth within specifically the first-line RCC market?
Yeah, kind of without getting into kind of 2024 guidance, you know, stay tuned there. You know, what I'd certainly say is a lot of the things that, that P.J., you know, our Head of Commercial, talked about on the last earnings call are certainly all relevant. You know, since we launched the 9ER regimen, the combination of CABOMETYX and frontline RCC, we've seen more, you know, about a doubling of revenue from the CABO monotherapy. And that's really been driven by kind of two main things: market share increases and duration of therapy. And so, you know, we're still seeing, again, as P.J. mentioned, you know, underlying demand remains strong for CABOMETYX.
It's the number one IO TKI in frontline RCC, certainly driven by what we think were very strong data from the 44-month update at the ASCO GU conference earlier this year, which just continued to underscore that totality of data, that balance of data, that's been so successful with both physicians and patients, not only on the efficacy side, but the tolerability side, and importantly, things like quality of life, which really matter to patients. And so those are the dynamics that are going to continue to change. You know, long term, obviously, with CABO, you know, the opportunities from CONTACT-02 and prostate cancer, as well as CABINET and pNET and EP-NET, are certainly, you know, important dynamics to consider. But, you know, those are kind of, broadly speaking, some of the main drivers that we'll see.
Yeah. So that's perfect, 'cause I had a couple of questions on CABINET and CONTACT-02, and maybe first with CABINET, that's sort of a two-parter. You know, how do we think about the potential leg up that opportunity could potentially provide for CABO? And I think you guys have spoken about, you know, there's a discussion that needs to be had between yourselves and the FDA once you get this data set in-house. What are some of those questions that need to be answered before you could decide whether CABINET could actually support a regulatory filing?
Yeah. So, you know, P.J. and Amy will get into a lot of this in much more detail at the R&D Day, but you know, a bunch of different factors kind of to keep in mind here. So, you know, as we talked about on the earnings call, you know, one of the important next steps is really to get that data in-house at Exelixis. Obviously, CABINET was a cooperative group-run study, and certainly we have an experience translating those cooperative group studies into you know, commercial opportunities. Mainly the CABOSUN study in frontline RCC as CABO monotherapy was a cooperative group study.
So we have that history, that experience to understand what needs to be done, how to do it, how to kind of translate that data into a package, to then have discussions with regulators. What's clear in the NET opportunity, pNET and EP-NET, is really kind of the patient population truly has an unmet need in this area. The data that were presented at ASCO, ESMO, sorry, certainly, you know, are compelling in our perspective and were certainly very well-received and just showed that, you know, this is an opportunity for a well-known, well-established drug like CABO to further, you know, drive standard of care and help patients.
Maybe one quick follow-up on that. I've always heard that getting data from cooperative group studies in-house can sometimes be a very burdensome and timely process. Any sense of expectations of when you could have that in-house and have that discussion with FDA?
Yeah. So a little bit too early to kind of give specifics on, on timelines there, but again, I'd highlight, we have a history and experience doing exactly that. You know, so certainly when we designed, CABINET, a lot of the learnings from the CABOSUN experience kind of played into that. And so, it's something that, that we think we have a pretty good handle on, and, you know, we want to make sure that we're moving as fast as possible to help bring this, therapy to patients.
So, maybe last one on CABO. You mentioned CONTACT-02. We've obviously seen some top-line data there, but await mature OS data. Any expectations for timing around that? And then similarly, I think you guys have said, like, once OS matures, there's maybe a conversation that needs to be had with the FDA to discuss a couple of key topics. What would some of those key topics be if there is, in fact, an OS benefit that's demonstrated?
Yeah. I mean, you know, as we talked about on the last call, following discussion with regulators, we're going to wait to see a little bit more mature data on overall survival before we make the decision whether or not to submit. You know, certainly overall survival is important, but PFS benefit in this patient population with high unmet need is certainly highly important as well. You know, as again, as we've talked about before, you know, waiting for that more mature data, I think Amy had said sometime next year, in terms of that survival readout. And then, you know, just other things to keep in mind about the study. You know, this is a slightly different and an important patient population, the high unmet need.
So CONTACT-02 enrolled specifically patients with prostate baseline visceral mets, as well as external adenopathies, which is really a high unmet need group that tend to have kind of worse performance, and importantly, allowed us as a company to really ask a pretty you know thoughtful experiment, clear experiment. You know, does the combination of a TKI and a checkpoint inhibitor have real clinical responses as opposed to kind of some complicating factors around what is PSA doing and, you know, bone scan? All of those complications were kind of you know mitigated by the design of CONTACT-02. So certainly important to keep that in mind.
All right, maybe last one on Cabo around the sort of ongoing patent litigation. Anything you could say or provide there? I guess mainly in terms of next expected disclosure from the second MSN trial that just sort of wrapped up.
Yeah. So, you know, as a reminder for the audience, just had at the end of October, you know, MSN 2, it's our second patent case, in the case with a generics company called MSN. You know, trial concluded and really can't give specifics on timelines as it really is ultimately up to the judge. So don't want to to get ahead of that there. But certainly, you know, confident and pleased with how kind of the events and all of the topics at issue came out at trial. So, kind of stay tuned there.
Great. Maybe with that in the next 10 minutes, we could sort of tick through the pipeline to some degree and start with Zanza. You mentioned you guys recently just presented some data from the ccRCC cohort at the kidney meeting. Maybe just sort of speak to what you now know about Zanza and ultimately how it's comparing to the early days of Cabo.
Yeah. So, you know, as a reminder and kind of tie back into something I mentioned earlier, so really kind of the goal of Zanza was to further iterate and create a next gen version of a VEGF targeting TKIs. In the way that Cabo iterated and improved upon earlier generation VEGF TKIs, Zanza does the same thing. So you know, it's well known that one of the biggest liabilities, so to speak, for Cabo is its long half-life, you know, about four-day half-life. And the clinical and practical challenges of that, you know, in terms of accumulation, where, you know, that washout period once adverse events ultimately do pop up, can be ten days to two weeks.
That's a, you know, a challenge both for patients, as well as clinicians when they're kind of managing through that. So what Zanza does is phenocopy the kinase inhibition profile of Cabozantinib, but engineered in a metabolic liability that takes that four-day half-life and down to a little under 24 hours. And so there are numerous, we think, potential advantages there. You know, one, just in the user-friendliness of potential combinations. So going forward, we're certainly going to be interested in novel doublets, novel triplets with Zanza. But there are also some potential implications around things like tissue distribution and, you know, things like that, which could ultimately, you know, play a role in tolerability and efficacy as well.
So, the data we presented recently at the IKCS conference was really that first data set from a kind of mature, homogenous cohort of clear cell RCC patients, kind of in that second-line plus. And certainly the data that we saw there were especially encouraged by and really kind of underscore our enthusiasm for, you know, our aspirations for Zanza, the breadth of development and what it can be. Most notably, you know, we saw around a near 40% response rate. But if you break that down into Cabo-naive and Cabo-experienced patients, and we saw about a 60% response rate in Cabo-naive patients, and we actually still saw some pretty good responses in Cabo-experienced patients. And so both of those dynamics are certainly important.
On the tolerability side, certainly encouraged by both the frequency and severity of adverse events, and certainly play into our excitement and enthusiasm for developing it broadly. As I said, you know, our aspirations for Zanza are about, you know, what are the Cabo-sensitive or Cabo-like TKI-sensitive tumor types, where novel combinations can be effective, different lines of therapy, as well. So those are the sorts of dynamics that we think about about Zanza going forward.
So you mentioned the data specifically within the subset of the post-Cabo RCC patients. You know, when I looked at that and then looked at some recent data from the HIF inhibitor from, from Merck in a later line, RCC population versus everolimus, I started wondering whether there's actually an opportunity here for Zanza within a post-Cabo later line RCC as a, as a monotherapy, given that 30+% response rate that, that you're seeing.
... Yeah. So again, kind of, you know, we've already announced now three pivotal studies with Zanza, first in late-line colorectal, non-clear cell RCC, and then head and neck cancer. And we've talked about our goal and our desire to initiate additional pivotal studies. So don't want to get ahead of kind of where and when those are gonna be, but certainly we know RCC is a sensitive tumor type for Cabo and Zanza. And so the question really is kind of that balance of how and where can we generate that differentiating data? What are those commercially relevant indications, and what are those sorts of novel combinations that we can use to generate differentiating standard of care?
Again, you know, with the goal of, you know, right-shifting that curve, both from a progression perspective, from a survival perspective, and importantly, kind of keeping in mind that tolerability is important as well.
So, maybe last question on Zanza. You've mentioned sort of the later stage development programs that have been initiated. When you look at sort of the development strategy and you look out into the future, what do you see as sort of the key potential inflection point for Zanza?
Yeah, I mean, ultimately, this business is about data, so it's gonna be about generating data, both for kind of our late-stage pivotal studies and then, emerging data coming out of the STELLAR program. So STELLAR-001, so STELLAR-002 are looking at, you know, novel monotherapy, you know, indications as well as, combinations, doublets and triplets. And so the STELLAR data is certainly gonna be informative, to help us think about where we're gonna develop, Zanza going forward.
So maybe now we could shift gears to some of the sort of earlier stage pipeline and start with XB002, which I think you mentioned at the top, the tissue factor ADC and Tivdak, the sort of first gen tissue factor ADC, just established survival benefit in cervical cancer. When you look at that program relative to XB002, where do you see its shortcomings? Where do you see the opportunity for XB002?
Yeah. So XB002, again, for the audience, it's a tissue factor targeting ADC. You know, I'd probably again point to that's an asset that we view through the Cabo lens of, you know, an established therapy that we think we can generate differentiating data. So if you think about the ADCs, are really three components. There's the antibody, the linker, and the warhead, and we think XB002 is differentiated versus kind of the predicate molecule, Tivdak, across all components. So first, on the antibody side, one of the things that we think is important and differentiated about XB002 is the antibody itself is not competitive with factor VII.
So if you think about the role of, you know, how the antibody binds to tissue factor and the role of factor VII and tissue factor in the coagulation cascade, you know, unsurprisingly, Tivdak does see increased bleeds. Bleeding risk is in the label, and to date, we haven't seen that, you know, in the data that we've presented for XB002. So certainly, that's a point of differentiation. Secondly, on the linker warhead side, you know, some of the earlier generations of ADCs, you know, tend to be relatively unstable. And so free drug can be associated, free warhead can be associated with some adverse events, in particular with MMAEs, neuropathy, neutropenia.
And so the data that we presented at the Triple Meeting, you know, show that at equivalent doses, we see about twice the exposure and one-tenth the amount of free drug for Tivdak. And so to me, kind of again, through that Cabo lens, we're looking at a validated target that's known to have a broad expression profile across a wide range of tumor types, with an antibody that's differentiated in a linker warhead that's much more stable. And so we actually, you know, think about tissue factor as a tissue factor franchise, because behind XB002, we have XB371, which again takes that same antibody but conjugates it to a different warhead. That's a topoisomerase-based warhead. So what that does is it allows us to look at all of the different tumor types that express tissue factor.
Some are more sensitive to an auristatin-based warhead like XB002, some are more sensitive to a topo-based warhead like XB371. So it gives us a way to really interrogate and develop kind of a, you know, what we think is a really strong target across a much wider range of tumors. And so again, that's kind of the lens that we tend to view it as: Is this an asset that we think can generate differentiating data?
When is the next potential disclosure from the JEWEL study? I think you guys have said you've sort of established some move forward doses. So when can we see, you know, next clinical data readout, what would it include? Do we start to see initial combination data from that trial?
Yeah. So I'd point to kind of the Zanza experience as a, as pretty, you know, as a pretty good example of how we tend to think about development and disclosure. So, you know, Zanza, we presented data at ESMO last year, kind of showing the phase I experience, kind of standard phase I, all-comers population that asked the question, does this molecule do what we set out to have it do? And, you know, Cabo with a shorter half-life, so to speak, and all sorts of caveats about that. And then once we had that all-comers population, we went into tumor types, expansion cohorts that we knew were more sensitive and more homogenous to get a better sense of what is this profile actually look like? And so that's what the IKCS data were in clear cell RCC.
So similarly, at the triple meeting when we presented the PK data for XB002, that was kind of that phase one all-comers experience. And then we've begun enrolling expansion cohorts in tumor types that are known to express tissue factor, and that's really gonna give us a much better answer on what does this drug actually look like? And so our focus historically, from a disclosure perspective, has been when data are mature, stable. You know, we haven't practiced this kind of biotech-y phenomenon of, "Here are seven patients' data and, you know, do with it what you will. We're gonna try and raise money," all this stuff. You know, we're not in that phase as a company. We're profitable, we don't need to raise money, we have a strong balance sheet, and so our focus isn't about kind of trying to hype data sets.
It's really talking about, "Here's the data when it's mature, here's what it looks like." And so those next disclosures are gonna be from those homogeneous expansion cohort populations in, you know, to really give a good view on what the molecule looks like.
So we're just about out of time, but I, I wanna ask one more question. A lot of things we didn't discuss in the earlier stage pipeline. If you had to pick one sort of asset that maybe doesn't get in a lot of attention, but you think should, what are you sort of most excited about?
Yeah. So good thing we have an R&D day coming up, so we can, we can get into, all of that fun stuff. I mean, it's really gonna be a great event to talk about exactly that. You know, this is the first one we've had in a long time, and obviously, Cabo focus and IP questions and Zanza and 002 have certainly been kind of the primary topics that we've discussed with investors. But just beyond that is this whole portfolio of assets that we really do, think have that potential, again, to drive differentiating data. And so that's what we're excited to talk about, in a couple weeks, and it's really gonna be a chance to really frame at a high level, kind of that science and strategy that's driving the Exelixis engine.
Perfect. Well, with that, we're out of time. I wanna thank you, Andrew, for your time.
Thank you.
Thanks, everybody, for joining. Take care, and enjoy the rest of your day.