Good morning, almost afternoon. Thanks very much for sticking around for the last session. It’s my pleasure to introduce Exelisis. We have Mike Morrissey, CEO, to give a presentation.
I’ll just quickly read our forward-looking statement. During the course of this presentation, we will be making forward-looking statements regarding future events or the future performance of the company. Actual events or results, of course, could differ materially. We refer you to the risk factors section of our most recent form 10-Q filed with the Securities and Exchange Commission on May 3rd, 2012, for a description of factors that could cause actual events to differ materially from those contained in any forward-looking statements including risks related to potential failure of cabo to demonstrate safety and efficacy in clinical testing, Exelixis’ ability to conduct clinical trials of cabozantinib sufficient to achieve a positive completion, the sufficiency of Exelixis’ capital and other resources and the uncertainty of the FDA review and approval process.
Okay, good morning, thank you Charles, thank you Rachel. Thanks for joining us today. I’ll give a brief update on Exelixis and on our lead compound cabozantinib. Again, we’re heading into ASCO. Abstracts were published yesterday, we will have a pretty good presence at the meeting with nine presentations. I’ll talk more about that later. I will have four oral presentations, four post-group discussions as well, so I think a very good opportunity to review the broad clinical activity of cabo in prostate cancer, we’ll have the ability to talk about the MTC pivotal trial data as well, as well as a variety of other tumor types. So, important meeting for us as always, and looking forward to getting to Chicago.
So, cabo, let’s talk about cabo. Again, this is a unique compound that we’ve been focused on for the last several years now. It’s certainly a compound that has a differentiated clinical profile, and its unique activity profile can be looked at in several different ways. I think this is a good slide, certainly a very colorful slide, and describes I think the broad activity we see with cabo in terms of different compartments in the human body, where primary tumors form or where metastases from those tumors travel to. And cabo is probably one of the only compounds that we’re aware of that actually is active against either primary tumors or metastases in nodal regions, nodal disease, visceral disease in the lung and the liver, CNS disease, as well as bone disease. So, very broad activity across the various compartments that again can harbor either primary or secondary tumor metastases.
In terms of other differentiation, again we’ve seen broad activity to-date with cabo. Again, to-date we’ve studied 13 different tumor types across Phase 1, Phase 2 and now Phase 3. We’ve seen objective responses in 12 of those 13 tumor types. So, again, very broad activity across multiple different kinds of tumors, tumor indications, cystologies, again that’s relatively rare for a compound that targets a (inaudible). We’ve seen, again, in terms of the resolution of these metastatic bone lesions, we’ve seen that broadly across multiple different tumor types, most predominately in prostate cancer, since that’s where tumors metastasize to at the main location, but across other tumor types as well, including thyroid cancer, renal cancer and other tumor types as well, melanoma, so very broad activity that again is somewhat provocative in terms of being able to go after a tumor that has metastasized to bone.
That’s more than just an imaging artifact, it’s more than just an imaging finding. We’ve been able to show, and this is a big highlight from last year’s ASCO meeting with Maha Hussain that we’ll get a follow-up this year from Dr. Matthew Smith that these bone scan responses or resolution actually associates with a variety of correlates with clinical benefit. We see pain decrease, we see narcotics decrease, we see an increase in PFS, et cetera. So the activity in the bone in prostate cancer appears to associate very well with clinical benefit.
I think one of the challenges of cabo, as with many TKIs, is around tolerability. We’ve used prostate cancer as an example to very exhaustively study lower doses, where we have a large population of patients who have bone disease as a main component of their disease. Using that situation and looking very exhaustively with the bone scan response and CTC responses, we’ve been able to show that we can actually achieve very good activity at lower, well-tolerated doses. That was the big update we had at the EORTC meeting back in the fall. We’ll have more information about that again at ASCO, but it’s a very important finding to have very good tolerability, in fact maybe even leading levels of tolerability, in this molecule class, in terms of lower doses, using the biomarker of a bone scan response and CTC response to be able to show that we can maintain and induce good activity. So that’s very important from the standpoint of either earlier lines of therapy, combination therapies, in prostate cancer, other tumor types, and I think that will again come out more at ASCO in a couple weeks.
So we clearly have a clinically differentiated profile. Our goal, through what’s going on right now at Exelixis with investigators across a variety of different clinical trials in our development plan, is to really build in commercial differentiation with cabo as we go forward. I’ll tell you more about that in a few minutes.
Here’s the range of activity. First, talking about what’s happening beyond MTC, beyond prostate cancer. Again, we’ve seen a variety of tumors be sensitive to the actions of cabo. You can bin this, if you will, into three different categories. Certainly prostate cancer is a very prominent one for us, in terms of its broad, unique activity which we, again, believe differentiates cabo clinically and potentially commercially in this space. Again, many tumor types go to bone. If you think about, say lung cancer, how prostate cancer, thyroid cancer, renal cancer, all involve, to a certain degree, bone metastases. Again, we can focus on that as another component. And then finally, other tumor types that can again metastasize to soft tissues, visceral or CNS tumors. So these three different bins are all very important to pursue as part of our overall strategy for developing the broadest potential of cabo as we go forward.
A list of sensitive tumor types is shown here on the right. I won’t belabor the point now, but go into this in more detail in a few minutes. Again, many of these we’ll talk about in individual presentations at ASCO coming up in a few weeks. And again, we’re very excited to be able to share that data with both investigators and the investment community.
So our development plan is shown on this slide, and again it has three different components to it, to again maximize the value for both patients and shareholders as we pursue this broad development plan and really try to maximize the impact that cabo can have across different tumor types. Internally, again we’re focused on MTC, medullary thyroid cancer, and prostate cancer. Again, we had top-line data readouts for our exam trial, I’ll talk about that in a few minutes, last fall. The filing is ongoing. Our goal is to have that completed and submitted in the second quarter of this year. And then of course we have a broad, pivotal trial program in prostate cancer that we’ll also talk about. So, internally we’re focused on MTC and CRPC. We have other components, one being focused on investigator-sponsored trials, or ISTs, that we’re using to really explore potential new indications for cabo to expand the list of different sensitive tumor types that cabo can go after, number one. And then recently, a signed agreement with NCI and CTEP to then look more, I would say broadly, at active tumor types as well as new tumor types, to be able to really help us then prioritize what would then move forward next as part of our pivotal trial program.
The CTEP CRADA involves up to 20 trials per year for five years. We recently announced the initial program of 13 planned clinical trials, including four randomized Phase 2 trials to really underscore what we’re doing here, from the standpoint of taking initial single arm Phase 2 data, doing randomized studies to be able to help prioritize what would then move forward then into potential pivotal trials as we move out in time.
So here’s maybe a higher-resolution snapshot of the development plan. Again, Phase 3, the EXAM trial read out in the fall of last year, we’ll have an update on that at ASCO coming up in a few weeks. We have two distinct pivotal trials, randomized pivotal trials, in metastatic CRPC, one for overall survival, COMET-1, and we plan to start that this quarter, and a second one, COMET-2, that’s focused on pain palliation and the reduction of narcotics. That trial was initiated at the end of last year, we have sites up and running, we’re screening and enrolling patients, and that’s moving forward. So, those are the main label-enabling pivotal trials. I’ll talk about that in more detail in a few minutes, why we’re doing two for survival and pain. We think that’s important from the standpoint of, again, building a differentiated commercial profile, a label that will allow us to market effectively in what’s certainly a very competitive and dynamic marketplace.
Phase 2 efforts, again we’ve been very focused here with our initial RDT looking at nine different tumor types, going back a few years now, looking at glioma, breast cancer, lung cancer, et cetera, as well as other indications that are planned as part of CTEP in liver cancer and renal cancer, non-small cell lung cancer and ovarian cancer. So, again, a broad, emerging Phase 2 effort in terms of randomized trials, which are very important to help us prioritize how we can move forward with new indications in the pivotal trials. And then obviously, a wide range of either single agent or combination trials looking at different tumor types in terms of how cabo can then be effective, looking at other important tumor types that are either, again, bone-focused like multiple myeloma or other tumor types that are focused more on soft tissue and visceral disease. So again, very important developments here that we hope to be able to build upon as we move forward.
So, for MTC, again the oral presentation of the exam data will take place on Monday, June 4th at ASCO, at 11:30 central time, and I’m looking forward to having Patrick Schoffski from Belgium share that data with you. Again, we’re on track to complete the NDA by the end of the second quarter. We plan to request for priority review and if that’s the case we would expect to have a (inaudible) date sometime near the end of this year.
We have a publication that’s been drafted that should be submitted shortly to a high-profile journal. Again, it’s a very important part of our plan for thyroid cancer, for prostate cancer, other tumor types, is to get publications out as soon as possible to really, again, further reinforce the activity and the really notable nature of the cabo story in peer review journals. So you’ll see more of that hopefully throughout the year.
In terms of prostate cancer, again this is our main focus internally, now that the EXAM trial has been done, the submission is almost completed. Again, we have two pivotal trials here that really, as I’ll show you on the next slide or two, focus on the unique attributes of cabozantinib in this very important disease setting. Again, COMET-1 is focused on overall survival. We have sites that are ready to start shortly, and we again plan to formally initiate this in the second quarter, so that’s on-track with the overall goal that we had articulated at the end of last year. COMET-2, again, is the trial with pain palliation and narcotic reduction, which is enrolling currently. So again, our goal here, because of the activity we’ve seen with cabo in Phase 2, is to be able to use the clinical differentiation around increasing PFS, these bone scan responses, pain reduction, direct any tumor activity with measurable disease hemoglobin increase, to really address the key features of this disease as it progresses locally to the bone and then drives the morbidity and the mortality in these patients. Our view is that with two distinct trials, we can capture the survival data and the pain reduction data in a very accurate regulatory-friendly fashion, that would allow us, if successful, to seek approval and a label which contains both components, and that’s the goal, and we’ve made great progress over the last six or so months to move both trials forward.
So, in terms of the actual data, and we talked about this a lot, and certainly the presentations by Matthew Smith on Tuesday at ASCO as well as a poster from his group on Saturday looking at the low-dose IST work, really underscores the data that we have and the experience that we have to-date with approximately 350+ patients to-date in this tumor type with cabo. Again, this is, prostate cancer has been an area that’s seen a lot of success in the last several years, compounds moving forward in terms of post-chemo and now pre-chemo. There’s lots of movement in terms of that landscape and we think it’s an opportune time for cabo to come in with a different focus mechanistically, a different profile clinically, that could aid in, if successful, in the pivotal trials that we’ve got planned with a very strong commercial opportunity relative to being able to be a player, both as a single agent but also in combination. So, part of the overall strategy to really build maximum value with cabo.
So, what have we seen to-date? What was the data that we had as ASCO at a high level, certainly very strong sign of any tumor activity, we’ve seen nodal disease shrink, we’ve seen visceral disease shrink, certainly as we talked about at ASCO last year and our R&D day in the winter in December, dramatic reduction in circulating tumor cells, or CTC cells. It’s a very clear sign of direct anti-tumor activity, which obviously, based upon the hazard ratio from the MTC trials, further underscores that cabo is primarily an anti-tumor compound. We talk about it being a bone drug, we talk about it being a prostate cancer drug, but the reality is this is a very potent anti-tumor compound. We’ve seen, again, very consistent, rapid and dramatic bone scan responses, like no other has been shown to-date, so very interesting data there. That combination of the anti-tumor activity and the bone activity I think is what’s driving the very rapid and durable pain improvement that we’ve seen and documented prospectively in the non-randomized extension cohorts that we talked about at EORTC last fall and will further update at ASCO on the Monday session that Matthew Smith’s providing.
That’s also led to, I think, some very interesting observations that we’ve seen both in the randomized discontinuation trial as well as in the non-randomized extension cohort of actually patients reducing or to a pretty good extent actually eliminating their narcotics. So it’s a very, I think, a very important impact of clinical benefit on these patients to be able to have their pain reduced to the point where they can go off narcotics and avoid the serious side effects that come with that medication.
So, and then of course as we talked about at both ASCO-GU last year, as well at ASCO with Dr. Hussain, in the randomized portion of the RDT trial in the prostate cancer cohort then showing that we have an increase in the median PFS comparing the cabo arm to the placebo arm. So, a very different, unique clinical profile. Our goal is with COMET-1 and COMET-2 is to build in commercial differentiation with those trials, to be able to then allow us to effectively commercialize these compounds in an area that is certainly very competitive and very dynamic as we go forward with new compounds that have either been approved or will be approved probably in the near term.
In terms of the other components for our development plan, we’ve got a variety of different activities going on here. Our ISP program was initially focused, again, in prostate cancer, looking at the lower dose work that’s going on at Mass General, looking at different combination strategies, a very important component of our effort here is to move cabo up in line of therapy by combining it with either a taxotere pre-chemo, which is ongoing, which will be ongoing shortly, with part of the CTEP program. We have a Phase 1B trial at Dana-Farber combining cabo with abiraterone, looking, again, doing a dose-finding study which would then be expanded at the appropriate time into Phase 2. Also very interested in combining cabo with MDV3100, again as part of the overall plan to go early with all the major players and to be able to really build up the biology that we’ve seen to-date, where as tumors, as prostate cancerous tumors become resistant or refractory to hormonal therapies, they often do so by upregulating MET, and when you look at early metastases in the bone, after the patients have progressed on hormonal therapy, they often have very high levels of MET-signaling. So it’s a very important, I think, biological rational to go after, and we’re going to hit this really hard across all the various components.
Other ISTs, very exciting IST going on at Mass General right now, looking at hormone-positive breast cancer with Dr. Jose Baselga, focusing on women with hormone-positive breast cancer with predominate bone metastases, again playing off the data that we saw as far as the initial RDT and the prostate cancer, as well as others. So, this will evolve, again, lots of interest in cabo, I think the oncology community has really embraced this compound as a very novel agent and one that we hope to be able to continue to work with them to expand and evolve its activity profile.
CTEP, again, was an early addition recently around a program that would allow us to work with the NCI to profile other indications, I think from my point-of-view, the randomized Phase 2s that are on-track, including the first line renal cell carcinoma trial comparing to cabo to sunitinib is a very important one. Again, we had I think very interesting, compelling early data at ASCO-GU this year looking at a very late line of therapy in RCC showing a good response rate, a reasonably high median PFS, with all the caveats. It’s a small trial, single arm study, all those things, but certainly I think caught the attention of a lot of KOLs in this space with the data. Again, HCC looking second line as well, very interesting update there in that setting at ASCO on Saturday, and then lung data as well as ovarian data, or trials, in the randomized space. All these should start end of this year, early next year. Again, important next step in terms of having the initial wave of pivotal trials going in MTC and prostate cancer, but then these randomized Phase 2 trials setting the stage in terms of the activity, to help us prioritize what would then go next as these trials read out.
Other Phase 2 and Phase 1 trials are shown on this slide, I won’t belabor the point here, a variety of other, either single-searching or signal-validating trials, both single agents and combination in melanoma and non-small cell lung cancer, bladder cancer, sarcoma, very interesting biology there as well in regard to MET and (inaudible). So, lots to do here but we’re very excited to be working with CTEP to be moving this first wave of trials forward and we’re constantly hearing from investigators about new ideas, new plans they’d like to see us pursue relative to the activity, so very excited about this whole initiative in terms of a very economical way to move the program forward and broaden the program while we’re focused on thyroid cancer and prostate cancer in-house.
So just to move on, kind of wrap up real fast, we have from our previous business model eight different compounds that are being pursued by partners that are, again, have the responsibility, both financially and developmentally, to move compounds forward. This slide has five of those compounds in the oncology space. Our MET inhibitor with Genentech/Roche, our two PI3Ks with Sanofi, cabo’s cousin if you will, XL880, a second dual MET/VEGF inhibitor with GSK, and then our hedgehog antagonist, XL139 with BMS. These five compounds are all in mid-Phase 2. The different trial totals are shown in the fourth column. I won’t belabor the point here. I think what’s important to note is that we’ll have five different abstracts presented on these compounds at the ASCO annual meeting, one for our MET inhibitor 518 in combination with Genentech’s PI3K inhibitor 973, XL765 will be presented I think in combination with a different MET inhibitor as part of the strategy to really target both the MET kinase pathway and the PI3K pathway simultaneously.
For (inaudible), we’ll have two posters, one on breast cancer, one on HTC, and then XL139 will have a poster as well. So, additional information about our broader pipeline, one that we’re not investing in ourselves right now, but certainly one that we hope to build value with, both for patients and shareholders, as we go forward.
In terms of ASCO, I’ve been through this several times. I won’t go through the different presentations. Again, we’ll have a very busy day on Saturday at the meeting. We’ll have seven different presentations, two orals and the rest are posters and poster discussions. Those are shown here. And then we’ll have five different presentations throughout the day on Saturday, and then we’ll have a presentation on Monday with the EXAM data as well as the presentation on Tuesday with the NRE data from Dr. Smith.
Finally, I’ll close with just a reminder that we’ll have an investor briefing like we normally do at ASCO on Monday evening at 6:30 at the Hilton. That will be webcast. We have a very distinguished panel of guests and KOLs, including Dr.s Baselga and Smith from Mass General, Dr. Kareem Fizazi from Paris, a major European KOL and prostate cancer, Patrick Schoffski, one of our PIs and our presenter of the EXAM data, Steve Sherman, who has been one of our key advisors in the MTC space, and then Dr. Dan George from Duke, a very well-known and articulate and very prominent GU oncologist focusing on both prostate cancer and renal cancer. So, that’s a big opportunity for us to again reinforce some key messages, have a different format this year, have more of a Q&A format, and I think issues being discussed as opposed to presenting a lot of slides, so I’m looking forward to having people either join us at the meeting or certainly listen to us on the webcast.
So, last slide then, just to kind of reiterate, I think we’re moving very aggressively in 2012. Cabozantinib has a unique clinical profile, which we believes provides us with an opportunity to strongly differentiate cabo in the commercial setting based upon our existing development plan around prostate cancer, MTC, and others as time goes on. I think the EXAM data for MTC certainly has provided very compelling data that cabo is a potent anti-tumor compound. The hazard ratio was .28 in terms of the PFS, so it’s a very prominent signal and I’m excited about that. Certainly we’ve got two pivotal trials planned, one ongoing, one should start shortly, in prostate cancer, that we expect to, again, move forward and that were strengthened over the last six months or so. And with that, I will again stop here. Thank you for your time, and we’ll go from there. Thank you.
So I’ll just ask a couple of questions. It’s pretty late in the day. I guess for cabo, how do we think about the Phase 3 survival benefit? Maybe – can you just review the data that you have in Phase 2 and how we should think about the power in Phase 3?
Yes. So we’ve powered the COMET-1 trial with the following assumptions; that the control arm, which is prednisone, is modeled off the COGO301 studies of Abi, where Abi is the – using the Abi arm. If you look at the mean OS, or around 15 months, and the median time on drug, it was about eight months. And again, of course, we just repeated the progression by pure resist or PSA progression. So they got drug longer, as long as they were driving clinical benefits.
So that delta of seven months, is the same delta that we would see with patients who, again, were in the case of say post-abi, they saw Taxotere and progressed, they got abi and progressed. So starting the clock when they got abi then is the event going forward and looking at that seven-month delta.
And cabo is in part a 10-month PFS, or 10-month OS benefit median LS based upon the variety of data we’ve got from the RDT.
So I’m sorry, so ten months versus what?
Versus seven for the control arm.
Okay. Great. And then you mentioned in the Phase 2 data, you saw 10 months?
We haven’t published that data yet, so we have – we have estimated that 10 months based upon data that is unpublished and right now is not public.
Okay, and then you mentioned both Medivation and abiraterone. With those studies, how is that being done? Is Medivation actually agreed to do a combination? I guess they would because it’s not publically available yet and are you funding that or is that cooperation with J&J?
So the IV combination is – that’s ongoing right now, so that’s an IST that we’re doing with Dana Farber using commercial abi. So that’s relatively straightforward. It’s a simple dose range, a study to find the optimal dose range of cabo with a dose of abi. That’s ongoing right now. The combination with MDV3100 is not ongoing. We’ve had discussions with Medivation; they have a partner, obviously, which complicates that. So to a certain degree, we’ve got to put a call – draft – so whether we do it before this approves or we do it after it gets approved, we’ll come out with the details on how we are going to move forward. But we’re prepared to move forward by ourselves with the, you know, with the KOL doing the trial and using commercial MDV150.
And just from a [inaudible] perspective with abirarterone, is there – are you doing a dose ranging study to establish the base first and then expanding the cohort?
You’ve got – so it’s a classic 3.3 dose range finding study using full dose abi and then a dose range finding the dose range of cabo. Now, the low-dose work that we’ve done at [inaudible], certainly forms that, so we have a very relatively narrow dose that we’re looking at in that combination.
And it’s kind of an unusual time in prostate cancer because all these new therapies are coming to market and just given where you are with Phase 3, is your expectation that cabo will ultimately be used in combination with these drugs, or is there a segment of the market – and/or, is there a segment of the market where just cabo would be used?
Well, I think our initial approach is to go after fetal agent cabo. It’s the, simply designed the [inaudible] in terms of the criteria to consider the possibility then, which is looking more likely now based upon some of the movement with abi in the pre-chemo setting. That the new prehormonal therapies would move up in line of therapeutic pre-chemo. That would create an opportunity post-chemo in the second-line setting for a compound like cabo, again, post-abi, either hormonal therapy and Taxotere to be able to stay in a relatively good sized marketplace. Estimates there range between 15 to 20,000 patients, without, arguable, a lot of competition there.
So that’s our first focus in terms of our kind of commercial population, we’ve focused on that. But clearly, we want to move cabo up. Whether we do that as a single agent or in combination, we’ll consider both options, but certainly the dose range finder, we’ll get going on with Taxotere, with abiraterone and then potentially with MDV3100 would reinforce the idea of combining cabo with both of those agents. And I think in the – and the biology there is very compelling in terms of the role that plays in driving resistance. So it makes sense biologically as well.
And then the last question, just a timeline for [inaudible], how long would it take to enroll and approximately how long would it take to collect data from that?
So we’re guiding that, but we think both trials, COMET-1 and COMET-2 read out in the first half of 2014. Our view is based upon prior experience with COURGAR301 with the Affirm study. We can probably enroll COMET-1 in approximately a year. We’re going to have 250 or so sites globally and it will be a very simple trial. And there seems to be a lack of competition for patients right now, certainly in that population but in general based upon the number of large pivotal trials that are running.
So we’ve got a variety of global KOLs on board who are helping us plan the trial, run the trial.
Okay, thank you.
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