Okay. Looks like we're live, thanks so much. Good afternoon. Welcome to Barclays Global Healthcare Conference in Miami. You can just email me if you have any questions that need addressed. My name is Peter Lawson. I'm one of the mid-cap biotech analysts at Barclays. Really delighted to have on stage with us a management team from Exelixis. Peter Lamb, Chief Scientific Officer, and Andrew Peters, Chief of Strategy. Thank you so much today for your time. I guess maybe the first question just around the cabozantinib franchise. It's been fantastic growth engine and cash generator for the company. Just like, can kind of the puts and pulls, pushes and pulls we should think about for 2023 and the priorities around cabozantinib.
We kind of start asking the questions around deeper in the, in the franchise.
Yeah, happy to happy to get into it. Thank you for having us. I think this is the most number of Peters on a stage we'll ever have.
Never have too many.
Yeah. Before I begin, just as a reminder that to everyone we may be making some forward-looking statements today. Please see our relevant disclosure in our SEC filings. For 2023, as we talked about on our Q4 call when we gave guidance, you know, we do expect to see continued cabozantinib growth, primarily driven kind of by 2 functions and a continuation of both from the success that we've seen in the past. You know, first is really around continued market share gains and the strength of the CheckMate 9ER data, as well as kind of that longer duration, that stacking of patients as, you know, patients are living longer, staying on drug longer. You're seeing kind of that continued build and growth over time.
I'd point to, you know, the recent data, the 44-month update that we presented at the ASCO GU conference. Really a well-received update is a chance for our sales force, our commercial organization to continue to kind of reach out and touch base with, you know, physicians, patients alike and really kind of emphasize that balance of data that we really think has driven a lot of the adoption so far. It's a combination of the efficacy, the tolerability, and importantly, key things like, you know, secondary endpoints and quality of life that really have resonated with patients and physicians alike. It's a continuation of that. That, you know, market share gain, longer duration, continued traction in the community.
What's the triggers we kind of think out beyond 23 to continue to drive that growth around cabozantinib?
Yeah. you know-
Puts and takes.
Without kind of getting into kind of long-term guidance, you know, certainly we'd expect a continuation of, you know, the exact dynamics that I talked about. You know, beyond that, you know, we'll see how the Cabo franchise continues to develop from a clinical trial perspective. We've talked about our expectation for more mature survival data from the COSMIC-313 study. That's the Cabo ipi-nivo study expected later this year. You know, as a reminder, we did see positive top line data last year that was presented at a plenary presentation at the ESMO conference, which showed positive data on our primary endpoint of PFS. After discussing with regulators, we wanted to see a more mature cut of that data. That's expected later this year.
That's certainly a dynamic that we could look forward to. Similarly, CONTACT-02, that's the Cabo plus atezo versus a second NHT in NHT refractory castration-resistant prostate cancer. That's another one that we're expecting data later this year as well. That can certainly influence the opportunity. You know, we're planning to present data from CONTACT-03, which recently read out. You know, without kind of getting ahead of that data into the specifics, certainly, you know, we wanna look towards, you know, how Cabo performed, in particular Cabo monotherapy, to see if that has the potential to influence things like duration and market share in that second line setting going forward. Kind of a combination of all of those.
Just remind us where we stand for like IP and kind of how that then marries into how you think about investing in cabo versus the pipeline.
Yeah. Kind of to take that second part. The CONTACT studies, those are kind of the final Cabo studies, so to speak, that we're gonna be running with kind of a focus on the rest of our pipeline and portfolio going forward. From an intellectual property perspective, you know, we really see kind of two key buckets or two key updates with respect to kind of the ANDA challenge or MSN. MSN One was a trial last May that the decision from the judge came out earlier this year and upheld kind of the core composition of matter for Cabo to 2026.
At issue in MSN2 is a broader set of polymorph claims as well as some high purity Cabo claims around 2030 or so. As we think about Cabo and kind of the Exelixis story going forward, we model 2030 for all of our modeling, and that just really reflects kind of our continued belief in the strength of the Cabo franchise. Taking a step back, I think you may have framed it,
Well, in that we view Cabo as kind of the gas of the innovation, the Exelixis innovation engine going forward. That's kind of how we see the success of Cabo, the continued financial success of Cabo, is really as a way to invest in the future and, you know, really build towards being a multi-product oncology company. I'm sure we'll get to it later, as it relates to kind of a pipeline, but, you know, we're really excited about, you know, what we think are differentiated and, you know, relatively lower risk value propositions, whether it's ZANZA building upon all of the foundation from Cabo or XB002, building on, you know, Seagen's Tivdak. It's using that success of Cabo to kind of invest in the future.
Gotcha. Thank you. Just I guess on zanzalintinib kind of what now we should really be thinking about that filling in all the gaps that Cabo antineoplastic kind of left and newer gaps that are maybe emerging brain field opportunities.
Yeah. Maybe I'll take that one. Yeah, when we started the program that, you know, led to zanzalintinib, you know, obviously we were sitting on a very significant amount of cabozantinib clinical data. You know, we knew at that time, cabozantinib had been explored fairly broadly as a single agent. You know, we'd seen evidence of activity, and I think it was 20 different tumor types. You know, we also knew it was a very effective partner for immune checkpoint inhibitors, because of the spectrum of targets it inhibits. You know, cabozantinib on its own has some pretty interesting activity on, you know, both adaptive and innate immune cells in the tumor microenvironment, and obviously that then played out in the Cabo-nivo CheckMate-9ER study very nicely.
We really felt we had a kind of target profile in cabozantinib that was special. There's a core set of targets that we believe are very much involved in that activity. In developing zanzalintinib, we were looking to very much keep those targets in there in about the same ratios as they are with cabozantinib. It's to, you know, really enable us to exploit the clinical knowledge that we had from the years of developing cabozantinib. That's what zanzalintinib is, has the same target profile as Cabo. What we did do was to fine-tune the pharmacokinetics. Cabozantinib has about a 100-hour half-life in people, and you know, that has a couple of consequences. You know, when patients initially come on, we certainly spend some time educating physicians to stay on top of any emerging AEs.
That's because during the first three weeks of dosing, you know, cabozantinib accumulates. If you start having an AE during that period, you really wanna dose reduce or hold dosing, you know, pretty rapidly. Secondly, of course, if you have an AE during the course of treatment, you need to dose reduce or hold, there's a washout period of, you know, one week or so for cabozantinib. You know, that's some inertia there essentially in terms of getting the patient back onto cabozantinib or does it give them an opportunity to switch to a different TKI. We felt having a version which had a shorter half-life, would really enable physicians to enable adverse events much more crisply. That's what ZANZA is, again, about a 24-hour half-life.
In terms of the, you know, development path for ZANZA, it's very much along the lines of what you, what you're outlining. We're really looking to fill in the white space where we've not run registrational trials for cabozantinib. It's not a straight drop-in replacement. It's really looking at areas where we saw some evidence of activity with cabozantinib, but never put it into a registrational trial.
If you look at the first two phase IIIs that we initiated last year, with ZANZA or with STELLAR-303, which is in colorectal carcinoma combination with atezo, and the comparison there is regorafenib, that was really based on a CRC cohort from COSMIC-021, with Cabo/atezo, for example, and also some data from Cabo and Durva from the CAMILLA trial, in MSS stable CRC that looked quite promising. Likewise, STELLAR-304, which we got kicked off very end of last year. That's in non-clear cell renal cell carcinoma. Actually, there is no drug that's registered. There's no registered therapy for it. I mean, people certainly use cabozantinib. They use other TKIs as well in that setting. We know cabozantinib's active there.
obviously strongly believe that ZANZA is gonna be active as well. Yeah, we're looking at there doing a ZANZA- nivo versus sunitinib type of comparison. There's sort of a low-hanging fruit way of starting to fill in the filling those gaps. I would say finally, you know, the other big opportunity for ZANZA is to really go into, you know, novel or contemporary combinations that we haven't done historically with Cabo. Starting to elbow, and yes, we've got Cabo-nivo and, you know, we'll obviously get a little bit of experience with ZANZA and nivo, and that's actually ongoing. What novel MOA do you add onto that in RCC, for example?
You know, we certainly also have ongoing in collaboration with BMS, combinations with LAG-3 antibody relatlimab, just as an example. Looking to get into novel combinations that will really move kind of the needle clinically, when combined with ZANZA, and that, you know, would be novel rather than just trying to replicate the exact things that were done with Cabo.
Gotcha. Thank you. What would be the first pivotal data set we should expect?
It'll For ZANZA, yeah, that'll be the STELLAR-303 data set. That'll be the CRC data set. That primary endpoint there is overall survival.
The timing on that?
It's TBD. We haven't kind of guided on the exact timing yet.
Okay. where are you for like enrollment and-
Well, enrollment's ongoing. I mean, we don't. I can't really say much more than that. We generally don't give you know, precise updates on where we're standing with respect to enrollment. So.
I guess once it's complete, that's when we get an idea. You're Mention it's complete, and then from there, we can kind of work out when we could potentially see OS data.
Yeah. That's generally what we do. Yeah.
Yeah.
Yeah.
The contemporary combination. I mean, I've got to read into that. We're gonna see a lot more of these combination strategies develop pretty quickly for ZANZA.
I mean, if you look in some of the tumor types near and dear to our heart, RCC is obviously a great example of that. I mean, we're now in the era of looking at triple therapies, right? Again, you know, doing the Cabo-nivo-ipilimumab kind of combination is where it's at. A lot of the, you know, registered stuff is, has already double it. You know, looking ahead, we're gonna be looking at more, probably more triplets, in RCC and then even adding on from them.
It's a matter of, you know, what are the new or emerging mechanisms of action in RCC or any tumor type, where we have some belief that mechanistically it would be a good combination with ZANZA, and then we'll go and get some, you know, initial clinical experience and, hopefully advance it from there. Yeah, I think that's gonna be the future in these kinds of tumor types for sure.
Should we think of ZANZA just replacing Cabo eventually in RCC and the various combinations that Cabo has in RCC?
Well, I mean, ultimately, you know, what you're looking to do again is to, you know, provide a clinical advantage in whatever setting you're in, right? You know, provide additional clinical benefit over what's already there. In the Cabo sense, or the Cabo-nivo sense, it's with the ZANZA plus whatever the combination ends up being. You know, the test is, does it move the needle clinically, ultimately? If it does, then yes, it will take that. If it doesn't, then the Cabo will stay where it is. That's usually. You know, we're not gonna do, for example, we're gonna do ZANZA/nivo versus Cabo/nivo. That doesn't make any sense because we're not really expecting that to provide a substantial benefit in terms of, you know, PFS or OS.
I don't think that would be good for patients. You know, Zanza/nivo plus something else would be a very kind of rational way to approach it.
Gotcha. Okay. It's not, you know, IP replacement for where Cabo is now-
No.
You know, post 2030.
Call it clinical meaningful replacement.
It has to be.
Yeah. Clinically meaningful replacement.
You could potentially stack another drug in there, and then that could potentially replace that drop off...
Yeah . Exactly. If it's clinically meaningful, of course, along with that, you know, potentially comes longer durational therapy, and the like.
Gotcha. Thank you. Have you already kind of talked through this year for additional registrational studies for zanzalintinib?
I think what we've said publicly is it is our intention to start, you know, additional studies and hopefully multiple additional registrational studies for ZANZA. We haven't specifically laid out in what tumor types or patient populations that those are going to be in, but, you know, they will fall in under the general parameters that I just discussed in terms of how we're looking at at ZANZA development.
Gotcha. Okay. Thank you. I'd love to move on to your tissue factor ADC, I guess particularly in light of the Seagen acquisition. I guess, where you could differentiate versus Seagen's molecule?
You know, very excited about XB002. It's the first biologic in our pipeline, and obviously the first ADC. You know, what I took out of the acquisition is that ADCs is a good space to be in. But that's something that's, you know, it's an area we've been enthusiastic for a few years now and have obviously done a number of deals in to give ourselves access to a variety of, you know, antibodies, payloads, and conjugation technologies. So XB002 was a tissue factor targeting ADC that we in-licensed from a company called Iconic. And we thought that, you know, the rationale and the story there was really compelling. As commented, obviously Tivdak is out there. It's already been approved in cervical carcinoma.
There's a sense in which the target's been somewhat de-risked. Like, targeting tissue factor as for an ADC has been effective. I also knew a lot about the clinical profile of Tivdak and the spectrum of adverse events that it has. You know, as we were looking at the XB002 opportunity, we could see a number of areas of pretty crisp differentiation. The first really relates to the antibody. Just to go back to Tivdak, that antibody binds the tissue factor, and it does so in a way that blocks binding of factor VII. It's that binding that initiates a coagulation cascade. Tivdak interferes with coagulation, and you can see, you know, in their data and in their label, you know, fairly high rates of bleeding in patients because of that.
The 02 antibody binds to a different site on tissue factor. It does not interfere with factor VII binding, you know, certainly preclinically, you see no interference with coagulation whatsoever. You know, gratifyingly in the initial clinical data that we put out late last year in that, in those kind of phase I patients, we've not seen any bleeding at all to date. That seems to be transferring pretty well to the patient population. I think the second main point of differentiation is really around the linker payload. Again, in Tivdak, it's the classic, you know, pegylated val-cit auristatin MMAE-type payload, the microtubule disruptor. What we've used in 02 has been technology that came from Zymeworks called the ZymeLink linker payload.
It's still a microtubule disruptor, and it's still in the auristatin class, but it's fairly heavily modified. The net result of that, those modifications, I think has been an antibody with different properties, and in particular, it's a very stable antibody in terms of the payload staying on with the antibody and not falling off much in circulation. I think what got us really excited from the data set that came out last year was some of the PK data. Particularly, you know, we got patients with a 2 mg/kg dose cohort. 2 mg/kg is, you know, the dose that is approved for Tivdak.
If you look at the pharmacokinetics for XB002 at that dose, what you see is the exposure to the intact ADC is 2x that of Tivdak at the same dose. While at the same time, if you look at free circulating payload, the free circulating payload is 1/10 that you see with Tivdak. We think we've got a much more stable ADC. We think that's gonna be important for two reasons. First, just from a side effect point of view, you know, our view is that some of the AEs and side effects do come from free circulating payload, and some of them are like classic taxane side effects, like, you know, peripheral neuropathy, alopecia, for example. Which are certainly present with Tivdak.
We've seen no or very limited cases of those so far, so that could be one potential point of differentiation on the AE side as well. I think if you go to the efficacy side of the equation, the PK is giving us some confidence that we're gonna be able to see efficacy outside of cervical carcinoma. The original Tivdak phase I, they did look at cohorts of, you know, non-small cell lung cancer patients, urothelial carcinoma patients, and they did see some activity, but it wasn't really compelling, and they never really developed it as a single agent in those.
We think with the added exposure that we're getting at a tolerable dose gives us the opportunity to build on that initial efficacy signal and then, you know, potentially then to see efficacy in a wide variety of solid tumor types.
The plan this year with that, with XB002 is very much to push, you know, push it forward. We've got to get to a recommended phase II dose. We're then looking at opening up to 10 different expansion cohorts in a variety of solid tumors. We have started combination studies both with a checkpoint inhibitor, which is a very interesting, you know, area for combining with ADCs generally. We've also started a combination with bevacizumab. Actually that was really enabled by the fact that we don't have bleeding as a side effect. It would've been tricky to do if we'd had significant bleeding. We're excited about that. Yeah. Stay tuned.
How should we think about the, I guess, the initial pivotal studies, or where could it be approved first? Is it kind of think about it as Tivdak plus kind of thing, so it's cervical cancer, or is it elsewhere that we should be thinking sort of these other 10 different tumor types you were kind of talking through?
Yeah, I think it'll be data driven. It, you know, we're not gonna stage how we enroll in the various different expansion cohort tumor types. You know, we'll certainly enroll. One of them certainly will be cervical carcinoma, so we can sort of benchmark, if you like. Beyond that, it will. It'll be a on the basis of, you know, where do we see good efficacy and tolerability? You know, what are the competitive dynamics in that particular patient population? That's a decision we'll make at the time it and we'll be informed by the data that we have. We haven't pre-decided yet.
Gotcha.
Yeah.
What would the cervical cancer trial look like? Would that be kind of a head-to-head eventually?
You know, it's again, to be clear, again, we're not really seeing this as just a cervical cancer drug. That would be a relatively modest, you know, kind of opportunity. You know, I think we're more excited about the potential beyond cervical carcinoma. Again, you know, again, exactly how the trial will be designed really depends upon the data that we have at the time.
Gotcha.
Yep. I think Peter, kind of the key point again to what I was referencing earlier is, you know, we're building upon a foundation of kind of this validated target with this differentiated technology, differentiated antibody, differentiated linker warhead. We're kind of building upon and expanding the opportunity set as opposed to just trying to iterate on just the cervical opportunity, as an example.
Yeah.
That's why we're so excited and enthusiastic about the program is, you know, as Peter mentioned, you know, Pharmacology 101, twice the exposure of the one-tenth amount of free drug is a really good place to start, and that's why we're excited to, you know, move into expansion cohorts and kind of build from there.
Gotcha. It's that early data, the PK/PD, that kind of gives you that confidence that this is a potentially broader-
Yeah.
Yeah. Absolutely. Like I say, there were, there were hints of activity with Tivdak originally, and we think, "Well, if they could have dosed higher, the activity should get better." That, that's essentially what we're going to be able to do.
Okay.
We're gonna get patients more exposure to drug at a level that's still tolerated, and then, you know, there's more opportunity for clinical benefit.
Yeah.
Yeah, we think, if you think broadly, and if you think about what we're doing in ADCs broadly, we think there's a fair amount of opportunity there for coming in with next generation approaches to known ADC targets. The ones which historically, people have made ADCs, advanced them into the clinic, but they never got out of phase I because the therapeutic index just wasn't there. I mean, there may have been activity, but there was just too much toxicity. Another program we have in preclinical development right now is a next- gen 5T4 ADC, for example. It's built upon exactly that same premise. We're now making it using modern site-specific conjugation technology, using the kind of latest, you know, latest knowledge with respect to warheads and payloads and the like. That's one example.
I've no doubt we'll be doing more in the future as well.
Gotcha. The problem with that therapeutic window for many of these ADCs is just the toxin just ends up diffusing off.
Yeah. It's been twofold, this is something that's sort of bedeviled the field for a long time. I mean, you know, the idea of ADCs goes back, what? To 25- 30 years. There were a couple of initial, you know, ADCs that got registered, like Mylotarg, Kadcyla. After that, it was just a valley of death, basically, where nothing got registered. It was mainly the therapeutic index issue. It wasn't necessarily lack of efficacy, it was just too toxic. I know, you know, there are a number of things that play into ADC toxicity, but one is, you know, how much circulating free payload do you have? You know, others can be, you know, non-specific uptake of ADCs, which is much better understood now.
The third is, of course, if you have residual target expression on normal tissues, that can play in as well.
Yeah.
A lot's been learned in the last 20 years about what drives therapeutic index and what drives the kind of toxicities of ADCs. You know, you can see that in the renaissance in the field, right? We've got some dozen or so ADCs have been approved in the last three years, and it's really built on that and the improved manufacturing processes.
Gotcha. Is the industry getting better at kinda threading that needle between, you know, finding the right target that's not widely expressed and having a tighter bind with the toxin, et cetera?
Yeah. I would say absolutely, and I think it's, you know, evident in what I just said and this kind of burst of approval. Yeah, I think it's a great time to get in, to get into a space, right? Sometimes when it's first, you're faced with having to slog through a lot of the problems and kind of issues with a technology platform or a therapeutic modality. Yeah, we're building now on 20 years' worth of experience in ADCs and a lot of modern technology. You know, if you look at the deals we've done in the space, you know, with Catalent, with NBE, you know, with Ryvu, with Invenra.
I mean, our aim really is to assemble you know, panels of well-characterized antibodies, have access to kind of contemporary, you know, site-specific conjugation technology so that we can control the final product. We have access to a suite of different payloads and linkers, so we can really assemble the right ADC, you know, for the right tumor type and for the right patient population. We just think there's a lot of opportunity there.
Gotcha. You don't think there's one particular part of that equation that drives it, whether it's the site-specific conjugation?
No, I think it's the integration of everything. It's —t hat's why, you know, ADCs historically have been hard. You have to get, you have to get everything right to get it to be effective. You know, the upside is when an ADC is effective, you know pretty early on. I mean, you can know. You can see in phase I if you're getting activity, you've got a reasonable handle on what your tox is. So it's not normally a guessing game with ADCs, which is kind of attractive from a portfolio management point of view. You kind of get early data and make a go, no-go fairly crisply.
Perfect. Thank you so much. Thanks for allowing me to go into extra time, so.
Yeah. Thanks, Pete. Thank you.
Thank you.