Good morning, everyone. My name is Gena Wang. I'm a SMID cap biotech analyst at the Barclays. Welcome to our annual Global Healthcare Conference. It is my great pleasure to introduce our next presenting company, Mirati. With us today we have Alan Sandler, Chief Medical Officer. We also have Ben Hickey, Chief Commercial Officer. With that, maybe, Alan, do you want to give a quick overview before we dive- Sure. -into- Yeah. -specific questions? Thanks, Gena, thanks for having us here today. I just wanna briefly mention a little background of Mirati. Mirati is a company that is dedicated to treating the difficult malignancies with a targeted therapy approach. Specifically, we've dedicated ourselves to KRAS biology and have a number of agents that we have in discovery and also in development targeting the KRAS G12C, G12D, next generation, as well as KRAS enabling agents as well. This has really established us, this experience has established us as a leader in KRAS discovery and development. As you know, not that long ago, a few months ago, we actually had our first approval and we're now a commercial-based company with approval in second-line non-small cell lung cancer for KRAS G12C mutations. We have our confirmatory phase III study, KRYSTAL-12, that's ongoing globally and is accruing very well, and I'd like to provide you with an update today on the design of the study. We've had discussions with the FDA, and the FDA has asked us to go back to the original design of the study, which is again maintained as a randomized phase III study, but with PFS as a primary endpoint, OS as a secondary endpoint, and we will be allowing crossover at time of patients' progression. This is, we believe is a very favorable outcome because it allows patients to receive regardless of the arm. They'll be able to receive the adagrasib, at some point in therapy. It also will allow us to reduce the size of the study to about 450 patients. Importantly, PFS remains an approvable endpoint, and we're anticipating that to occur in the first half of next year. We also still will have an opportunity to evaluate overall survival, which can serve as a differentiation factor for us with our competitors. We're very excited about that. It's a more efficient way to study this. We're looking forward to those results. The last part that I'd like to mention is we have some key outcomes coming out over the next year or so. With adagrasib, we're going to be updating you all on the first-line data with more patients, the combination of adagrasib and pembrolizumab, and also more mature data and another look at potential durability outcomes such as DOR and PFS. Sitravatinib is our agent in second line and combined with nivolumab, and that is a readout that's coming up in the second quarter of this year. We also have a catalyst with our PRMT5 inhibitor, and that has been doing very well in the clinic in our phase 1 study, and we're looking forward to having some early clinical outcomes for you later this year. Lastly, 1133, which is our KRAS G12D inhibitor. That is one that is going to be starting in the clinic this quarter. In fact, sites already are activated, and we're looking forward to our first patient on study to be dosed later this month. Look forward to further discussion, and thank you for letting me have the opportunity to give a little intro. Thank you. That's actually a lot of new information. Very important. Like, go back to KRAS G1 2D. Can you give a little bit more color? Like, you know, the, you went back to FDA, and they consider PFS as a primary endpoint. Like, maybe walk us through, like, you know, the, what does that mean in terms of the patient now, the study size now, and also the timing for the initial data report? Yeah. Great point. I think, key facts for this, again, PFS remains an approvable endpoint and the ability to still look at overall survival. Now, of course, it's, we have crossover, any potential aspect of a trend in favor of OS will be supportive for this. We do have an opportunity for OS to be an official endpoint as well. PFS is an approvable endpoint, which I think is a very key and important outcome. The size of the study has been reduced from the dual endpoint of around 600 patients to 450. This will provide us significant power for PFS and also for OS. As a result of this, we will maintain the ability to have a readout the first half of next year. All of that is maintained. I actually think that this is something that is very, you know, important for both patients and the investigators. I think everybody appreciates having a crossover because you have an opportunity to receive the experimental drug, in this case, not so experimental, the more efficacious drug, we believe, in both arms, whether or not you're getting it upfront or as subsequently after progression. I think it's a good outcome for patients and investigators as well. You do allow. Okay, two questions here. First is, regarding 450 patients, what's the status of enrollment? We're enrolling very well, at this point, we'd be over, you know, half. We're still looking forward toward an enrollment toward the end of the year and a readout next year, first half of next year. Okay. You expect complete enrollment end of this year, data H1 2024? Yes. Okay. Okay. Second question is, you allow patient whoever progress cross over, any concern on your OS impact the trend? Yes. you know, that's a fair question. When you do have crossover where all of the patients, that can obviously potentially mute the impact of overall survival. However, we do believe that there'll be a very good opportunity to be able to show minimally a trend moving forward. We're confident that overall survival will still be a supportive endpoint for our study. Okay. Can you remind us your assumption for PFS now as a, as a you know, single primary endpoint? What is the powering assumption here? We don't give the specific details for the stats, I think it's fair recall that docetaxel is the control arm, that's going to be the bar with which we must succeed. Okay. Should we use the standard or the other competitor data? Would that be a good benchmark? I think that's fair. I think that's fair. Yeah. Yeah. Do you have a reference point that can point it to us for docetaxel? It typically is around three, four months-ish. Mm-hmm. Of course, it varies minimally from study to study, it tends to. Okay. Okay, good. Okay, that's very helpful. Maybe from cost-saving perspective, by doing this, cutting down 150 patients and the timing-wise, how much, you know, the cost saving you can have by doing this? I don't think we would provide that specific a guidance. Okay. I think you can imagine that would not be an insignificant amount of money that's saved from this. Then the potential to be able to accrue even potentially a little bit faster, given the smaller numbers of patients and the fact that patients now are able to cross over, which I think enhances accrual as well. We're looking forward to a more efficient running of this particular trial. Okay, good. I recall, you know, I think, when the last time we discussed was that the purpose is OS can give you a better commercial opportunity. What made this change? That... Is that because the commercial uptake that you see, you know, the OS maybe like take one step back, you know? How do you see the commercial uptake now, and why the OS is not important now in terms of the commercial uptake? What I'll do is I'll answer. Mm-hmm. Of the study, and Ben will address the commercial aspect, right? Okay. The discussion was with the FDA, and the FDA was concerned about the heterogeneity of a study that did not require crossover. Again, you know, patients may have received, sotorasib, they may have received experimental KRAS inhibitors, they may have received, adagrasib. What they wanted was, a tighter control over that so that the crossover was defined in reducing the heterogeneity in the study. With respect to the ability to look, at overall survival, we'll still have that opportunity to look at that. Again, when you do have crossover like that, it may be muted, but we're confident again that we should be able to have the ability to at least see a trend which would be supportive of that study. I'll have, Ben... Yeah. To play as Alan said, it was a, you know, FDA request from the endpoint standpoint. From a commercial view, we believe that KRAS G12 gives us a great opportunity to differentiate on overall response rate, durability response rate, PFS, and then hopefully with the OS trend. We think if we put that package together, then that will still put us in a very strong position, both from a U.S. and from an ex-U.S. standpoint in regards to pricing and reimbursement. Okay, good. Maybe wanted to ask you now the real world experience since the drug is already launched. Any more color, I know it is still early phase of the launch stage. Several questions. You know, first is regarding the patient, can you give a little bit more characteristics? What are the patient are showing interest or like, you know, willing, initial scripts? You know, who are these patients? Are they naive patient, recent PD-1 progressor, or, you know, any additional color you can give? Yeah. Just as a reminder, we were approved in the middle of December last year. At our Q4 earnings call, we gave just some very early color on those first couple of weeks at launch. As we said at that time and even before, we expect the majority of the patients to be sourced from second line. That's the 7,000 patients which progress after IO and chemo. There. You know, we'll obviously give a more robust update at our Q1 earnings call, but there is, I think the work we've done prior to launch gives us comfort level that we'll be able to penetrate a large portion of that market and ultimately our goal is to become the number one KRAS inhibitor. I think there are several questions. One is, you know, what we saw is the capsule safety profile, and you do have better tablet safety profile. How do you communicate that with the patient and physicians, and when would you share that tablet data, safety data? As a reminder, our cohort A in KRYSTAL-1 was executed with a capsule formulation, and we filed with a tablet formulation. For a number of reasons, we thought that was easier from a manufacturing standpoint, as well as what we'd seen earlier on, and certainly we've heard anecdotally from physicians, which was a better GI tolerability. We're continuing to collect data. Now we're in the market, we're collecting real-world data around the tolerability of the tablet. Obviously, we're enrolling the KRYSTAL-12 study, which will be virtually 100% of patients will be on the tablet for that study, as they are across all of our studies now. We will either be putting... Most likely, we'll wait for the KRYSTAL-12 data because it is in the first half of next year to publish data. If we get to a big enough N size prior to that, we may consider some real-world data to help publish that. Most likely, it will be from the KRYSTAL-12 study, given that's the most robust registrational study ongoing at the moment. I remember, I think, the early days, you do have, like, a dozen patients or two dozen patients has, like, one or two cycle safety data. Will you be able to share that data with investors? Again, it's just about getting a big enough N size because most of the ongoing tablet studies are blinded or randomized studies, I should say. Mm-hmm. Disclosing that from an ongoing registrational study obviously is of concern to the FDA. I think it most likely will be from the KRAS G12 readout, will be the most robust read on the tablet. Okay, good. you know, Like, do you have a clear protocol stepping down if patient facing some safety or tolerability issue? Yeah. Yeah, you know, it's 600 milligrams twice daily to start. Mm-hmm. The first dose reduction would be 400 milligrams twice daily. Mm. If there's a need for an additional, it's 600 milligrams once a day. Once a day. Okay. Then that will be They're 200 milligram tablets. I see. That will be the last dose, right? The 600 mg QD. Yeah. Good. That's helpful. I know it's very early, like, Can you share the color, how many patients already being treated, and what is the real-world, you know, experience with PFS, DOR? Just to be clear, is this in relation to second line? Yes, second line. Is the question. Yes. Yeah. Yeah. We probably won't give a lot of guidance. We'll have to wait for the Q1 call to kind of represent this current quarter. I would say that the narrative around KRAZATI has been very well received by physicians. We've had, you know, a lot of demand coming in for medical information requests, which is a really good, you know, proxy for demand in the market. Our team is executing very well. Again, a lot more color to come on the Q1 call. I would say I'm very happy with how the team is executing. We have a very experienced lung cancer team in the market across medical access and sales. They have been executing at a very, very high level, so I couldn't be happier with how they're going about it. We're excited to share the update in Q1. Should we expect any meaningful revenue contribution in 1Q? It depends what you mean by meaningful, I think. Okay. I think we've seen the consensus estimates out there. We're relatively comfortable with the range that they're in through the course of the year. There is a lot of volatility in the early part of a launch, particularly when you know, whether it be demand, inventory, you know, patients who are coming onto insurance, changing insurance in January. A lot of volatility, but I would say that we believe that the overall market is going to grow at a relatively linear rate. We think that it is vastly underpenetrated currently. We think our source of business in the future will come from two places, and that is really the market growing over time, and we see that's got a long way to grow over the next one or two years. Additionally, from a market share standpoint, we really believe that we have a very competitive profile. Over 14 months of overall survival, our response rates of 44% and the CNS penetration, which has really been well received by physicians, will put us in a really strong position to ultimately become the number one prescribed KRAS G12C inhibitor. Okay. If I recall correctly, I think the first quarter revenue consensus only like $2 million-$3 million. That to me seems like insignificant. Maybe several layer questions. First, you know, should we expect inventory stocking? Like, what will be the norm? Usually, it's like 10-15 days. Would that be similar in your case? Do you think it will be initial, you know, huge inventory stocking and then over time will stabilize? Yeah. There are a couple of things to keep in mind. As a reminder, we are launching, about 18 months or so behind the competition. Mm. We will not see the initial bullish you get as a first class in the market with things like an EAP or with later lines of therapy. What we've guided to is our launch will be more of a linear adoption over time with the naive to second-line patients. There's only a certain amount of patients which are eligible at any one time. While we have heard anecdotal questions and feedback from physicians around, you know, can they switch when they have a CNS metastases or things like that, or when they're experiencing some hepatotoxicity. We believe the vast majority of our patients are likely to be those new to second-line patients. That's, that's point one. Point two, from an inventory standpoint, we do think it will stabilize over time. You know, in December, it would be, you know, proportionally it was a relatively large proportion because it was only a couple of weeks. We will be holding relatively a small amount of inventory. We have a direct ship model to the special distributors as well as specialty pharmacy. That is already, we expect that to stabilize and will not be a significant driver of the overarching picture for us. Okay. The scripts, if I recall correctly, you will block the scripts, right? We will not be able to. That's correct. We wanted to maintain blocking the data so you can't pick up the data from SHS or IQVIA or others and really get a read on the market. Mm-hmm. That's really because we believe that we can create competitive advantage at the local level. We really are focused in the community where we are, you know, we're hopeful to really see broad, very broad adoption. Okay. A consensus for 2023 is only $43 million, in my view, was very conservative. Do you think that you have very good chance to beat this consensus number? At what point you will feel comfortable to give a guidance? We're not planning to give guidance this year. Again, there's a fair bit of volatility in the early parts of launch. I would say we're generally comfortable with the range of where we see some of the analyst forecasts. That doesn't mean that we're, you know, we are, you know, we're a type A organization and are looking to exceed any target that we put out in front of us. I think it's too early to comment on that, in terms of the overall guidance, at this stage. Okay. That's fair. Also from the audience, if anyone have questions, feel free to raise your hands. Now switch gear to KRYSTAL-7, the Keytruda combo in the first line. I think, you know, last update, we saw that nearly one-third of patients actually showed a response after second scan. The last update, we only have two, three months median follow-up, right? A lot of patients haven't reached the second scan. With the later update this year, is it realistic to like, reasonable to say that we should see better response versus the last update that's 49% response rate, that we should be able to see better response? I think it's an important point. I think what we're going to see the second half of this year with the update will be, number one, there'll be more patients. We have over 100 patients on KRYSTAL-7 now. It was 53 at the time of ESMO IO. In addition, we'll have more patients that have that greater than six-month follow-up, which will allow us to see the so-called late responders, if you will. Those that respond beyond the first two cycles of therapy, as you pointed out. I'm confident that we will have a better evaluation of the data and the totality of the data. We'll have better opportunity to look at, DOR, maybe, landmark analysis, say a six-month landmark analysis for PFS to give us some idea as to the durability of these responses. We had hints before. We showed spider plots, and swim lanes before, but this will be larger numbers of patients with that, so. I think the short answer is yes. Okay. Okay, good. 100 patient, I assume you will also provide breakdown of TPS status- Yes. Right? With three categories. Yes, absolutely. Okay. We did earlier, and we'll- Yeah. continue to do that because it's. You know, that this front line is really three distinct groups of patients. The less than one, the one-49, and the greater than 50%. You know, the less than 50% are treated with chemo and pembrolizumab as a control, and greater than 50% monotherapy for pembro. They're treated a bit differently, and then their outcomes are different as well. We'll be looking at the results in that in that viewpoint. Okay. What will be I think last time you also have approved analysis as a benchmark, and I think some investor pushback is, you know, those seems too low, and everyone expectation a little bit higher. Now, you know, what would be your, you know, You said you have a six months landmark of PFS. You know, what would be the benchmark you will be looking for? Also the other data point will be the response. Like all the three category and the overall patient. Yeah. Breaking it down, like in the, in the less than one, response rates range from 25%-32%. 32% is where the all-comer. We believe, again, as we've talked about before, and I think others are evaluating. I know others are evaluating this as well, that do the KRAS G12C patients do less well than the all-comer or the wild type population. In that case, response rates would appear to be around 25%, with around a six-month PFS on the less than one. The PFSs have sort of maintained in that sort of six-eight month range throughout. Survival gets much better as you go into the up the scale of PD-L1 expression. The response rate also in the one-49 is about 35%-ish to 37%, and then about 40%-45% in the, in the greater than 50. Those are some of those initial benchmarks. Bear in mind that what, when we, when we look for decision-making on the phase 3 study, PFS, will be a primary endpoint along with OS as well. Response rates serve as a surrogate. Mm-hmm. When we're evaluating the phase II, but, PFS and OS are going to be those primary endpoints. With the phase III trial design for TPS less than 50% and versus equal higher 50%, are these still, you know, the initial trial design? Would that be evolving based on the update data later this year? What could change your thoughts on the trial design of these two phase III studies? Yeah. The way we'll look at this is, we're gonna be, you know, taking a look at the updated data for the doublet within KRYSTAL-7. Should that maintain or improve as we're looking for, we'll be looking at, you know, the doublet therapy versus pembro manu in the greater than 50. We'd be looking at to compare against the triplet combination in the less than 50, and breaking that down by less than one and one-49 so that it's officially powered for both groups as well. What we're also looking at is we actually have a KRYSTAL-17, which is another study where we're also looking to combine, add our doublet to chemotherapy as well as another potential opportunity depending upon the results we end up seeing in KRYSTAL-7 to give us another opportunity moving forward so that we can continue to lead in this particular frontline approach, being currently the only known KRAS G12C inhibitor that can combine with immunotherapy. Okay. I know we are running out of time, but quickly on G12D, and you already start dosing the first, the site activated. Yes. You haven't dosed the first patient. Have not done. Okay. No, we're looking toward that later this month. Okay. Later this month. Yeah. Maybe, you know, what, like the regarding the dose range, would that be QD, BID? How did you resolve the bioavailability issue and able to move the oral to clinic? Yeah. A couple of key points for G12D. Bioavailability has been an issue, but with the newer approaches that have been used, we're able to increase the bioavailability to about 15%. However, importantly enough, bioavailability, remember, is just one component on PK and PD. The other important aspect is this is a highly potent molecule measured in either picomoles or nanomoles. It is very sticky, we like to say that it binds very tightly to the receptor, both in the on and off phase. It has a greater than 50-hour half-life. All of this. The other aspect is it has a high percent of free fraction on non-protein bound. All of that put together allows for that 15% bioavailability in our opinion, to comfortably allow for doses where concentration's high enough for maximal inhibition throughout the 24-hour period. What will be the initial dose you will be testing? Um. Don't think we've disclosed. Don't think we've disclosed that just yet. Okay. Okay, good. Stay tuned then. We do believe it's going to be relatively close to therapeutic as we start. Okay. We won't be too far away. Will G12C a good benchmark at the dose range? Yes, it may be. We think that it might be around the 500 milligram plus range. We don't think it'll go beyond that. Okay. again. Um. As we move, that's why we do the studies in the phase I to see where we're at. Yeah, that makes sense. Well, thank you very much. Okay. Thank you very much. Thanks, Gena. Thank you. Okay. Yeah.