All right, it looks like we're started. Thanks everyone for joining. I'm Stephen Sloan, an analyst on the biopharma research team here at Goldman, and I'm happy to present or do a fireside chat with Exelixis. We have Andrew Peters here, Senior Vice President and Head of Strategy. I know on the schedule, it said Michael Morrissey, but we have Andrew Peters, which we're very happy to host. To kick this off, for those of you who might not be as familiar with Andrew, do you want to give a bit of background on yourself? This is very much in line with what Salveen Richter would be doing, so let's kick it off here.
Yeah, no, happy to be here. Thanks for the invite. Before I begin, likely to be making some forward-looking statements today, please see our relevant SEC filings for appropriate disclosures about the risks to our business, et cetera. Yeah, so I've been at Exelixis since about 2018 or so. I actually came from your side of the fence, you know, covering sell-side analyst, and had known the Exelixis story for quite some time, and really kind of what intrigued me about it was this idea of cabo is great, but what's next? You know, my role in strategy is, you know, quite interesting in that I get to see across, you know, the whole company basically, to understand, you know, what do we look like in 5 years? How do we get there? What are the sorts of areas that we should be investing in and really drive long-term value? You know, really has been quite an opportunity, and it's an exciting time to be at Exelixis. I'm sure we'll get into it, but lots going on right now.
Yeah, no, exactly. I think to frame it, this year will be poised to be the biggest year for cabozantinib sales, as well as multiple pipeline assets to continue to advance. Yeah, just to start off broad, can you frame the company's key strategic priorities for the year, and then maybe we can dig into more strategy?
You know, I think when I think about, you know, Exelixis' big picture, there's really kind of three key pillars that drive the company and kind of drive our vision of long-term value. The first is to expand and defend cabo. You mentioned, you know, our guidance for this year is gonna be continuing to grow, and as a global franchise, did about $1.9 billion in revenue last year. We'll continue to expand the franchise through continued growth, both in our kind of core existing businesses, and we do have a couple of additional clinical readouts later this year.
That kind of success, that, you know, gas, is gonna then fuel the Exelixis engine, which is the second part of that, is to invest in both zanzalintinib, which is kind of the next generation VEGF-R targeting TKI, as well as XB002, that's our Tissue Factor targeting ADC. Those, you know, two kind of both share the same vision of taking established products and, you know, de-risking them to some extent with a differentiated profile and really kind of investing smartly. The third pillar is also investing, you know, strategically in both internal and external innovation to kind of build out that earlier stage pipeline. It's that cabo gas that's driving the engine, both on the zanzalintinib side as well as, you know, the earlier portfolio. And I mentioned before, kind of lot's going on, so, you know, it's exciting time.
Yeah, definitely. In terms of the pipeline, something that has been extremely topical over the past year, Inflation Reduction Act, IRA, and the potential drug pricing negotiation implications. Can you just comment on how this is affecting the way Exelixis looks at some of its capital allocation priorities, which pipeline assets to advance? Obviously, the later stage pipeline is kind of set on a path, but maybe earlier stage, how that's influencing some of your decisions, given the favorability towards biologics versus small molecules.
I think the best way to answer that is to take a little bit of a step back and, you know, go back to 2018 or so, and the restart in earnest of the Exelixis discovery effort. You know, prior to that, we had essentially shut down all early stage discovery at the company, really to focus on cabo development. At the time when we restarted discovery at the end of 2018, we really had the chance to kind of step back and understand where is biology going, where is the industry going, and importantly, where is the treatment of cancer patients ultimately going? At the time, you know, we obviously had a background and expertise in small molecule chemistry, and we're gonna continue to that.
We also realized that biologics, you know, and largely combinations of both small molecules and biologics, would play a real role in the treatment of cancer going forward. We were then able to kind of invest in earnest in a biologics capability as well. You know, really a blending of those two is really the antibody-drug conjugate space, where we think we've, you know, really developed and built out, what we think is, you know, an industry-leading capability. You know, as we look at something like the IRA, it really is reasonably aligned with our kind of existing portfolio of programs right now, both on the biologic side and then, you know, strategic investment and small molecules.
Okay. Maybe one last strategic question, we can move into the pipeline, asset-specific questions. Exelixis recently announced a transition of a few board members, including three new board members that will join. Just curious, I think this has been a hot topic for investors recently. Will this lead to any significant change in the way that the company thinks about R&D strategy broadly?
You know, I think it's been about a week and a half since the new board members joined. Still a little bit early in terms of seeing how that dynamic is ultimately going to play out. You know, a couple of things on that. I think historically, our board has had very constructive and vigorous debate on how we should run the business overall. You know, I'd expect with the new board members, that sort of dynamic to continue. You know, secondly, you know, as I laid out originally, kind of, we think that we have a really kind of smart strategic plan for value creation. You know, ultimately, it may sound simple, but our job is to drive benefit for patients. The better patients do, the better our business does, the better our business does, the more value we can drive for shareholders. Ultimately, as we do things like expand and defend CABO and invest in ZANZA and XB002, that's ultimately to drive kind of longer lives for patients, longer lives for cancer patients, and that's what we think drives value. In terms of that debate, you know, we're going to continue to defend what we think is a smart strategy, and historically, we've been, you know, pretty successful at that, I'd say.
Okay, great. Obviously, Exelixis is very focused on oncology. We just came out of ASCO, one of the premier conferences, where Exelixis did have a number of presentations as well as some investigator-sponsored trials and other studies looking at cabozantinib. Could you maybe highlight the key takeaways as it relates to Exelixis? Is there anything that you want to highlight? I know I do want to touch on CONTACT-03 and some of the investigator-sponsored trials, but just at a broad level first.
You know, conferences like ASCO are, you know, incredibly busy from our perspective, from my perspective, in particular, in that we kind of have multiple stakeholders that we're all meeting with in a meeting like that. Obviously, our commercial team is very active and engaged, meeting with, you know, the clinician community to continue to drive those discussions about, you know, why cabo is and will, we think, will remain the number one TKI and number one TKI combination in RCC. It's kind of driving those conversations. Secondly, it gives us a chance to talk about kind of what's next.
ZANZA, I'm sure we'll get to later, you know, ASCO provided a venue to have a lot of conversations with prospective collaborators, you know, KOLs, companies with IOs, because we really think that the emerging profile for ZANZA looks, you know, truly differentiated. You know, some of the dynamics that we'll get into later, you know, would certainly be suggestive of a, you know, good partner to combine with, both in novel doublets and triplets. Really, you know, I think you alluded to kind of the CONTACT-03 study. You know, while that study was unsuccessful, I think it really, you know, further cemented cabo as kind of the preferred and well-established TKI in RCC.
For the audience and those who are unfamiliar, Contact-03 was a phase 3 study looking at the combination of cabo plus atezolizumab versus cabo in a checkpoint experience population in RCC. What it really showed and answered the clinical question that I think the entire community had been asking is: Can you rechallenge a patient who had previous exposure to a checkpoint inhibitor and still see activity? You know, I guess in hindsight, unsurprisingly, the answer is no, but in part, that's really driven by kind of the robust activity that cabo as a monotherapy saw. You know, again, in hindsight, unsurprisingly, those CD8-positive T-cells that were really activated on kind of that initial treatment with the checkpoint inhibitors aren't going away. They're still in circulation.
When you're adding cabo on top of that existing activated, immune system, you know, patients are still seeing that benefit. What that does is kind of further establishes cabo as, you know, the evolution of the monotherapy activity from METEOR now to CONTACT-03. You're seeing this evolution of that second-line patient population, but also really just shows that Exelixis truly is at the forefront of clinical innovation. You know, coming out of the discussion of that data and a lot of the conversations afterwards, it was really, you know, made me proud, as an employee of Exelixis, that we're really kind of at that cutting edge. You know, we run the real right experiments to ask those questions, and it really engenders this goodwill and awareness in the KOL and the clinical community that we think is just so crucially important as we think about development broadly, you know, for something like ZANZA. ASCO was a great conference and, you know, yeah.
Okay. There are a few more in-depth points I'd like to cover here. I think for CONTACT-03, just post-IO study that you were just referring to, there was some debate about the choice of the checkpoint inhibitor. I believe also there's this thought that, even though patients had been refractor to the checkpoint inhibitor, their disease progressed, there may have been still some biological activity of those drugs as they entered this trial, and so that maybe all patients were exposed in some sense to a checkpoint inhibitor still. Will you take any of those learnings, or I guess, what's your thought there, and would you take that into, say, a zanza study? I know you're not really continuing development of cabo here, does that have implications for zanza?
You know, as I mentioned before, you know, with those patients having previous exposure, those CD8-positive T-cells certainly aren't going away. You know, what it really shows is that going forward with these kind of novel combinations that we're planning for Xanza, likely kind of the best use of that IO plus TKI combination really is in earlier lines of therapy. When we think about Xanza development, you know, our focus is really about breadth of studies that we're planning to run and looking at indications and lines of therapy where, you know, there are certainly sensitive tumor types or signs of activity from earlier studies, whether it's, you know, ISTs like CAMILLA, which drove our interest in CRC, or, you know, the large 1,000+ patient COSMIC-021 study looking at combinations of atezolizumab. We're really identifying those kind of signals, for Xanza to help inform going forward. As it specifically relates to O-three, you know, I think one of the learnings there is certainly a focus on earlier with IOs is better.
Okay, got it. Something that caught my eye, I think there were a couple ISTs focused on various sarcomas, where cabo had some interesting activity. Is that a potential area that you're considering with Xanza?
Yeah, you know, what we've said for Xanza is again, as I mentioned, you know, the way we think about it is really about the breadth of development. The profile of Xanza, and again, for those in the audience who are less familiar, what we did with that program is phenocopy the kinase inhibition profile of cabo, a profile we know drives, you know, pretty compelling activity, and then really engineered out what we think is the biggest, you know, Achilles heel for that, which is its four-day half-life. What that means practically for cabo patients is, once you do see these tolerability issues that inevitably pop up for all VEGF-R targeting TKIs, that dose reduction and washout period can be on the order of a week to 10 days or even longer.
Purely from a patient management perspective, that presents a challenge. Similarly, from a combination potential, as a combination partner, it's also a challenge. What our team did was engineer a metabolic liability into that kind of core cabo scaffold to reduce the half-life from 4 days to a little under 24 hours. What that allows us to do is really have a more user-friendly cabo-type molecule that in early data has really shown to be potentially differentiated on the tolerability side, and looks very compelling on the efficacy side, you know, coming back to that data that we mentioned, you know, on the, on the earnings call. Y ou know, your question on sarcoma and, you know, some of those early signals that we're seeing with cabo, certainly, we use the cabo experience to guide where we're going in with Xanza, and don't want to, you know, get ahead of, you know, the studies that we're planning on running, but we certainly use that to inform where we're likely to go next.
Okay. No, we definitely look out or look forward to learning more about that development program. Let's dig in more to zanzalintinib. I'll probably say Xanza, this is a little easier to say. Like you mentioned, you recently disclosed some Phase 1b data and later line clear cell RCC. At ASCO, we saw, I think, the trial in progress poster for STELLAR-303, the colorectal study. Just curious, can you give us a cadence of how we should be thinking about the cadence of data releases? I think a key question that investors ask us is, okay, how can I build confidence around this development program? Yes, there are learnings from cabo, this is a different molecule. Like you highlighted, there's different PK/PD properties. Yeah, just talk about when we'll learn more about data and some of the indications that you're targeting in the phase threes?
Yeah. I guess, again, taking a little bit of a step back. We first reported data from that program at ESMO of last year, and, you know, from our perspective, it was exactly what we had hoped for. If you compare kind of that early phase 1, all comers, late-line population versus the similar CABO experience, they were virtually superimposable. Importantly, kind of the PK certainly checked the box on that we were able to achieve that shorter half-life. On the tolerability side, you know, there are really kind of four key adverse events that are often seen with VEGF targeting TKIs. It's, you know, fatigue, nausea, diarrhea, and PPE.
What we saw in that kind of early data was both a reduction in the frequency and severity of those kind of four horsemen of the VEGF TKI space. Unsurprisingly, kind of, you know, once we moved into more homogenous patient populations, these expansion cohorts, that's when we're really starting to understand more of the clinical profile a bit more. As I mentioned before, we teased that top line data in the clear cell RCC grouping. You know, we saw, I think it was around a 34% response rate in that third line plus population, but importantly, a 50% response rate in a cabo-naive setting. Kind of two key takeaways there. You know, one, the drug is clearly active.
You know, as I mentioned before, I spent a lot of my time looking externally at smaller companies and opportunities from a business development perspective, and frankly, there aren't many drugs with a 5 in front of the response rate. To me, that's what, you know, drives a lot of our confidence and conviction. But secondly, you know, the activity that we're seeing in the cabo experience population is certainly compelling and also kind of validates this approach of, you know, keep patients on drug longer. You know, once patients who were on cabo ultimately have to discontinue or dose reduce that window of time that they're washing out, you know, provides, unfortunately, the cancer an opportunity to come back. If you're shortening that window, can that drive some of that activity?
Both of those signals, both in the cabo-naïve and cabo-experienced patients, certainly, drove our enthusiasm. As I mentioned before, ASCO was an incredibly busy conference for us because, while it may have gone largely unnoticed, in kind of the sell-side Wall Street community, it certainly didn't go unnoticed, from folks who do this kind of every day and think about those sorts of combinations. The fact that that drug in particular is being signaled out as, you know, a real compelling opportunity wasn't lost on us, so.
Great. Now we look forward to seeing more of that data. you know, like you mentioned, one of the key aspects with Xanza is tolerability for combination work. I think so far you've announced combinations with nivolumab and ipilimumab, as well as nivolumab and relatlimab, the LAG-3 antibody. Can you comment on the progress of this combo work, and is Exelixis considering additional combinations? I'm curious if you see one of these avenues of the combinations as being kind of the right way to go mechanistically.
Yeah, I mean, I think, again, big picture, the way that we view zanzalintinib development going forward as, is as part of novel doublets and triplets. We think that, you know, there's very compelling mechanistic rationale for having a kind of zanzalintinib as a backbone therapy. As we look to, you know, sensitive tumor types for various IO combinations, that's likely where we'll go. You know, the STELLAR-002 study, you know, the nivolumab relatlimab combinations, you know, certainly are ongoing, and we're really gonna let kind of data drive that, so kinda stay tuned there. Again, from our perspective, really, the key here is, novel doublets and triplets with this user-friendly, differentiated profile, zanzalintinib, as a, as a backbone.
Got it. Okay. I think something that's attracted interest is STELLAR-304 zanzalintinib in combination with nivo in frontline non-clear cell RCC. This is an indication that cabo is approved for, but doesn't necessarily have a recommendation or clear kind of leading data. This study could position zanzalintinib as having best-in-class data. Can you just high-level talk about this indication, what it means commercially? I think we did see some data ASCO, KEYNOTE-B61 of one of the Merck's TKI. Can you talk about the read-through to your study and how you think about this?
Non-clear cell RCC, that and colorectal were kind of the first two pivotal studies that we're running with Xanza. The way we've really kind of framed and viewed those as kind of the low-hanging fruit, so to speak, of this waves of development. For non-clear cell, as you mentioned, while cabo's label does cover non-clear cell, there really hasn't been any data set to truly establish a standard of care in that setting. This is an opportunity to really identify Xanza as that kind of label-defined, standard. There's been a lot of previous data looking at cabo in this non-clear cell population. Again, coming back to the conversation earlier, it's certainly a sensitive tumor type to a cabo or Xanza-like study or molecule. This is a study that, you know, we think has a particularly high, you know, degree of interest and just from the community to understand, you know, can this combination be effective in this population? That's, you know, about 10%-15% of all RCC. It's, you know, definitely kind of a good first part of this first wave of Xanza studies.
Okay. Maybe can you speak to what you view as the current standard of care in the non-clear-cell patients frontline, and then the comparator arm for STELLAR-304? Like, if patients would be willing to go on that, if you think that could be an impediment to a speedy enrollment.
I mean, I think the standard of care or what patients ultimately receive in non-clear cell is a little bit of a mixed bag. I think it's entirely driven by the reasons that we said, is that there's no real defined standard. All of the VEGF-targeting TKIs kind of have a label that, you know, covers non-clear cell. It's a little bit of physician choice, physician preference, you know, using some phase 2 data to certainly inform that. You know, the PAPMET study, for example, for cabo, but there's no kind of defining, driving data set that's suggesting this is the clear, comprehensive standard in one setting. You know, it's a trial design that, you know, we were particularly thoughtful about and, you know, we think gives us a good shot at being successful there.
Okay. Let's spend a minute on the CRC trial, STELLAR-303. We did see a poster at ASCO on the overall design, where there is a focus on RAS wild-type versus the RAS mutant population, where I think part of cabo data suggested greater anti-tumor activity in that wild-type population. Can you just dive in there? Is there a biologic rationale why this population would be more prone to seeing responses here? You know, how are you thinking about efficacy in that mutant population as well? I know they are being recruited, but they're not in the primary endpoint.
Again, as a reminder for the audience, that's the first pivotal study that we're running with zansa, and that's looking at a combination of atezol and zansa versus regorafenib in that kind of third-line MSI-H colorectal cancer population. You know, as I mentioned before, really view it as kind of that initial first wave of relatively low-hanging fruit for zansa, and that's in part driven by, you know, what's relatively ineffective, unfortunately, for patients, standard of care and regorafenib. You know, the early data that t he cabo data that we, you know, use to help kind of drive our interest in that setting, both from COSMIC-021 as well as the IST CAMILLA, both saw some pretty compelling data for cabo plus a checkpoint inhibitor in that population. As it relates specifically to kind of the KRAS versus wild-type, you know, the data certainly show a difference. You know, I can't say that there's any one thing that we can point to as to what's driving that, but certainly there's really clear, consistent, and compelling differences. You know, as you mentioned, we're kind of looking at that overall population, but also the differences between the two.
Got it. Okay. Let's move on to XB002, what I would say is the leading ADC from Exelixis's pipeline, Tissue Factor targeting. And I believe you can obviously give your view on this as well, but positioning to date has been that it's non-competitive with Factor VII, thus bleeding rates would be expected to be much lower than TIVDAK, relevant competitor. And early data has shown greater drug exposure at similar doses with, I think you call it a tenth of the free drug exposure. Can you frame how meaningful these will be in terms of clinical efficacy, clinical safety?
Again, kind of taking a step back here. XB002, as you mentioned, is our first foray into the biologics. We really view it kind of along the same lines as ZANSA or even CABO. This idea that learning from previous generations, previous iterations of validated and well understood biology. In the instance of ZANSA, obviously building on kind of the backbone of CABO, and for XB002, it's building on TIVDAK, you know, the approved Tissue Factor targeting ADC from Seagen and Genmab. One of the reasons that kind of first got us interested in this target is, if you look at Tissue Factor expression, it's actually relatively broadly expressed across a pretty wide range of tumor types.
You know, what's interesting to me is if you look at a lot of coagulopathies that cancer patients see, it's actually in part related to kind of that aberrant Tissue Factor expression. It establishes kind of proof of biology, that this is a strong mechanism. Where the first generation of Tissue Factor targeting ADCs really run into trouble, is around this idea of an antibody that's competitive with Factor VII, so it impacts the coagulation cascade and ultimately drives some of the increased bleeds that you see, and is reflected in the label. XB002 is differentiated, we think, on all the aspects of an ADC. On the antibody side, the antibody is non-competitive with Factor VII, so we wouldn't expect and haven't seen the same bleeding risk in our early studies.
On the link of warhead side, you know, the stability relative to kind of that 1st-gen valine-citrulline MMAE is much higher. I think you mentioned it, the data that we showed at the Triple Meeting last year really establish again, that kind of the molecule is behaving exactly what we hoped for. At equivalent doses, we're seeing, you know, at least 2x the exposure and one-tenth the amount of free drug. If you think about pharmacology 101, exposure is driving the efficacy, and with ADCs, that free drug is really driving a lot of the toxicities, whether it's the neuropathy, the neutropenia, the cytopenias. Using that kind of profile as a starting point, as we continue to dose escalate, go into combination studies and then expansion cohorts, you know, that's a really good starting point.
We think it's a differentiated molecule, but built on a validated target, that, you know, we can further improve upon from there. Second to that, you know, what we're calling our Tissue Factor franchise, is we have XB371, that molecule takes the same antibody that we use in XB002 and add the topo warhead to that. Again, the reason that we're excited about that, as I mentioned before, Tissue Factor is broadly expressed across a wide range of tumor types. Some are particularly chemosensitive to auristatin-based cytotoxics, some are more sensitive to topo-based cytotoxics. Using this differentiated antibody, we're able to kind of cover the landscape, so to speak, in areas where we think Tissue Factor is a particularly relevant target.
Got it. Between those two molecules, would you anticipate any differential safety or tolerability profile?
Yeah, I mean, obviously there are differences between auristatins or modified auristatins and topos. It's really gonna be kind of a, you know, an understanding of, you know, the relative differences between those two. Really kind of the idea behind having this multi-molecule franchise around Tissue Factor is that we do think it's a very compelling target, and we've been particularly rational about how we think about, you know, antibody drug warhead across all of these different tumor types.
Okay, great. Data to date on XB002 has included dosing up to 2 mgs per kg. Could you just remind us of the initial study design, what doses you will be escalating to, and if we should expect kind of meaningfully higher doses to be the go forward?
Yeah, we haven't broken out specifically kind of where we are in that dose escalation process. But, you know, it's not only just about kind of the absolute dose of XB002, but also kind of the exposures that we're seeing as well. As I mentioned before, kind of stay tuned as we go from finding the MTD to starting to look at these expansion cohorts, to really get an understanding of how that molecule is behaving. Kind of stay tuned there in terms of the next updates.
Got it. Okay. In the last few minutes we have here, I wanted to talk about a few of the collaborative agreements that Exelixis has made recently, including Cybrexa and Sairopa. With Cybrexa CBX-12, this is a peptide-drug conjugate, and it doesn't have necessarily a cellular target, but rather it's activated by kind of the low pH environment. Curious what got Exelixis interested in this technology and kind of what areas of oncology do you see this to be most useful for?
The Cybrexa molecule that's, you know, biologically quite interesting in terms of its mechanism, and it's a pretty good example of how we think about external innovation. As we go kind of across the risk spectrum, so to speak, of assets, we're able to structure deals in a way that allow us to gain access to these technologies through option type structures, where we're able to low upfront capital efficient, essentially get to a proof of concept before we can formally opt in to the program. We're running that study with our partners, or they're running the study with our help, to really get to that true POC. The molecule itself is quite interesting.
It's kind of an unformed peptide in normal tissue, but it takes advantage of some pretty interesting biology and a pH differential in the tumor, specifically, where that unstructured peptide becomes specifically helical, which then allows it to insert into the cell membrane and then be taken into the cancer cell. It's a way to kind of, similar to the antibody-drug conjugate, where approach, where you're using the antigen as kind of a signaling mechanism or a targeting mechanism. This uses the kind of interesting biology around pH differential to kind of accomplish a similar goal. With the Cybrexa compound, uses a exatecan warhead, which, you know, has been well established to be quite effective as a cytotoxic agent, but poorly tolerated when given systemically. The approach here is, you know, is this a better way to deliver, you know, a highly potent cytotoxic in a way to kind of spare some of those AEs? Stay tuned there, but it's a way for us to, you know, really look into some of this cutting-edge biology in a capital efficient way.
Got it. That was very helpful. Maybe in the last minute we have here, let's touch on business development. Like I just mentioned, there are a couple of deals they've done recently. There doesn't seem to be necessarily a need, but can you talk about Exelixis's appetite for external business development, whether that's partnerships, acquisitions, and what the focus would be there in terms of modalities, targets, indications?
Yeah. I mean, just in the last couple of seconds here, I think there's a strong appetite for really quality assets. I emphasize that last aspect, because we're not in that position, we're not thinking about it, you know, let's do a deal for the sake of doing a deal. If you look at the company over the last several years, we've been fairly disciplined in terms of how we think about external innovation and in capital use. We're gonna continue to do that. It's really gonna be, you know, a mix of these capital efficient option type deals. If we do identify something later stage or higher conviction that we do like, we view our balance sheet as a strategic asset that allows us to be opportunistic. You know, going to a conference like ASCO and seeing compelling, interesting data that lets us continue to, you know, do real deep diligence on this stuff, that's the, that's how we move forward. It's really about the quality of the asset as opposed to anything else.
Perfect. Well, Andrew, thank you very much. You're a great representative for Exelixis today. We thank everyone for coming along and listening.
Yep. Thanks again.