All right. Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Goldman, the Biotech Analyst here, and it's my pleasure to introduce the team from Mirati Therapeutics, including James Christensen, CSO, on the far left, Ben Hickey, Chief Commercial Officer in the middle here. And just as a quick reminder, format for today is a fireside chat. We'll keep it informal, so if anyone in the audience has a question, please feel free to raise your hand, and we will get that addressed. Before we get started, I just need to read a quick disclosure. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Ben and Christensen, thanks for sharing your time with us today. And maybe, Ben, I'll hand it over to you to make some introductory comments, and then we can hop into the Q&A. Sure. Thanks, Mike, and great to be here in New York. Mirati is a commercial-stage targeted oncology company. We are currently on the market in second-line non-small cell lung cancer with KRAZATI, and have a very robust pipeline, through the KRAS with a G12C, G12D. We also have a PanRAS program, as well as our PRMT5 MTAP deleted program. So we have a lot going on and a lot of catalysts in the not-too-distant future, which I'm sure we'll talk about today. Yep. So great. Why don't we start with KRAZATI, the launch in second-line lung, and maybe just talk about trends there, how it's going, maybe future drivers. Sure. We launched back in December of last year. We've had a very successful launch. The team's executing very well. We closed Q2 with $11.7 million in sales, which represented about just over 40% of new patients, so taking on share at a rapid rate. The experience with physicians has been very positive. They've confirmed that they, you know, they like our CNS penetration. We're the only ones that now have a NCCN listing around our CNS ets in on untreated and active brain mets, as well as having overall survival of over 14 months and a response rate in the mid-40s. So the message has been received very well. Our team has been able to penetrate both academic as well as community clinics. So far, so good. We are seeing the market grow at over 20% on an annual basis. So, good, good performance to date, but a long way to go. Can you maybe talk about the dynamic in the academic versus the community setting and maybe where you're at today and where you expect to be in the future? Sure. We have had very quick adoption in the academic setting, which is what you might expect from some of the opinion leaders, and that's where to date, the majority of our growth has come from. We're now beginning to see the community really pick up the drug, and that's where we see longer term is the largest opportunity with, you know, north of 70% of lung cancer being treated in the community. We were very clear in our strategy when we actually studied the drug, because we studied the drug not just in the academic sense, but also the community setting. And a lot of our promotional efforts are based upon particularly the community networks. So we, we've seen strong adoption there. It takes a little while to educate folks and make sure they're comfortable with both the efficacy and the safety profile, but we're growing rapidly there and I expect that to continue. You mentioned, physicians sort of appreciate the CNS penetration of the molecule. I'm just curious if you're seeing... So that's obviously one area of differentiation, but are you seeing any potential switching from Lumakras at this point, or do you expect that to, you know, evolve over time? Yeah. As we reported in Q1 or Q2, we do see a relatively small subset of patients, which have been previously treated with a G12C inhibitor. The two reasons that we see that they come on to KRAZATI, one reason is if they've experienced hepatotoxicity, and the other one is if they have experienced a CNS met, where physicians view our data as being pretty stand out in that setting. And keep in mind that about approximately 40% of patients will unfortunately develop a CNS met through their journey with non-small cell lung cancer. So it's an important differentiator for us. But I would say the majority of our business is coming from that de novo, new to second-line patient population. Gotcha. Maybe if you can comment, over the weekend at the World Lung Conference, you gave some sort of follow-up there and from your second-line, KRYSTAL-1 study. Maybe you can just highlight the, the key takeaways there. Sure. We presented our two-year pooled data set, where the continuation of the efficacy story was very clear, with over 14 months of overall survival, similar median PFS in the mid-6s, and importantly, a very tolerable profile. We haven't seen any cases of Grade three hepatotoxicity for patients who have had IO therapy in the last 30 days. So I think strong confirmation of the long-term survival, with over 30% of patients alive at two years, and clearly, a tolerable profile, which we hope to then see confirmed in the KRYSTAL-12 study, which we'll read out next year. Yeah, maybe you can talk a little bit about that confirmatory study in terms of design, and maybe any changes there. No changes. It's a PFS primary endpoint with a secondary overall survival, which is what the FDA had requested, that designed us to be that way. Enrollment has been very strong. We expect to have the data read out in the first half of next year, and we are hopeful not to see only, you know, strong response rate and PFS data, but also a positive trend, at least a positive trend, with overall survival, which again, will be a wonderful opportunity to differentiate versus the rest of the class, which we're looking forward to. I guess, maybe just to follow up there, you know, your competitor recently had an adcom. Maybe you can share your thoughts on any read-through to KRAZATI there? Yeah, we don't really see a read-through. We have a very distinct molecule. Our pharmacokinetic profile is very distinct and unique, so we don't think that there is gonna be much read-through there. And I think having the data read out in the first half of 2024 is very timely for us to again to establish that it is a better therapy than docetaxel. And again, hopefully, we'll have a trend on overall survival, as well as some patient-reported outcomes. Keep in mind that the K12 study was enrolled with the tablet formulation versus our initial indication, accelerated approval, which was enrolled within the capsule formulation. We do believe that the tablet is better tolerated, particularly around the GI toxicities, so we're hopeful to see an improvement in the side effect profile, and that would ultimately be reflected in our label with a confirmatory study. How long do you think it would take to maybe, assuming that's the case, how long would it take to update the label, you think? So we will present the data at a medical conference as soon as we possibly can, once we see the data, you know, next year. Then we would very quickly submit the data to the FDA and seek the confirmatory approval. We would expect within the normal, you know, eight to 10-month window. Gotcha. Maybe last question on KRAZATI, just your ex-U.S. strategy, and how things are going there? Yeah, we were disappointed to have a negative CHMP opinion. We examined the dataset and we came to the conclusion that we actually thought that the CHMP actually missed a couple of things, and so we have actually resubmitted or are in the process of resubmitting a package and seeking them to reevaluate that decision. We will have that decision in Q4 of this year. So we are hopeful there. There has been precedent previously, with decisions being overturned, and the CHMP did describe our data as having a positive efficacy or benefit risk profile. So we're hopeful there. If not, we'll rely on the K-12 data, and the K-12 was always going to be our entry way into the European market, particularly given the pricing and reimbursement dynamics and having a comparative study versus PFS with a trend in OS, was always what we planned on from a pricing, reimbursement, and launch standpoint. So, hopeful to get those CHMP reversed. If not, we'll be delayed just a little bit, but not too far to our K-12 pivotal readout. Got it. Maybe we can shift to the frontline lung strategy and, and maybe to start there, if you can, maybe talk about the different approaches in the different buckets. In other words, you know, greater than 50, less than 50, et cetera. Sure. So, you know, at our Q2 earnings call, you know, we elaborated on some of our data in the TPS greater than 50 population. As a reminder to the audience, you know, de facto standard of care for TPS greater than 50 is pembrolizumab monotherapy, which is utilized in about two-thirds of patients. So, it is a control. You know, it's a reasonable comparator for a controlled study. You know, our data continues to indicate that the profile for the combination is well tolerated. We have good dose intensity, and the adverse event profile is manageable. You know, I think there's been quite a bit of interest in whether the hepatotoxicity that's been reported is indeed a class effect. You know, I think our data with pembrolizumab indicates a fairly low rate of grade three adverse events that are associated with hepatotoxicity. That is in a, you know, kind of low double-digit%. The vast majority of those events are lab function or lab test abnormalities, an ALT or an AST increase, but with no underlying sequelae associated with hepatotoxicity. We have not seen Hy's Law cases, bilirubin increases, or any other indicators of hepatotoxicity in the vast majority of patients, and the discontinuation rates has been quite low in general. With regard to the activity for the combination, this is, of course, a single-arm study, but we're very pleased to see that the PFS remains immature, but it's trending out to a meaningful point. So, you know, modeling this PFS tells us that it's likely that our PFS, median PFS, is gonna land at least 13 months, but most likely, you know, would go out further, perhaps even beyond 16 months. As a reminder to the audience, you know, what we're basing essentially our measuring stick is for this is the outcomes for the KEYNOTE-024 and KEYNOTE-042 studies for pembrolizumab monotherapy, where PFS essentially was a little bit more than seven months and a little bit more than 10 months in those two studies, respectively. So we do believe we are seeing a meaningful differentiation for what we would expect for pembrolizumab by itself. You know, as a result, we have started activities related to a pivotal trial. The good news for us here is that we are able to use our phase II, you know, essentially study, but to redesign it and utilize the sites that are already contracted and available to enroll patients. So we will be starting to enroll that study, late this year. And then just in terms of what we will be looking at is a study of, you know, greater than 500 patients, but likely below 600. And then we will be looking at PFS as a primary endpoint. We have talked to the agency about this, and we're confident in our approach moving forward with that. And then finally, the control arm in this study would be pembrolizumab. So that basically covers the TPS greater than 50. Can I have a couple follow-ups before we go there? Yeah. I guess since the path forward would eventually be a sort of head-to-head superiority study, what do you think the minimum delta would be on a PFS that would be sort of considered meaningful? Yeah, I think the agency, you know, generally points us to at least three months, and the more that we go beyond three months, you know, I think the greater confidence we have in an approvable study. You know, just a reminder again, as you know, the amalgam of seven and 10 months, you know, we are tracking, you know, a PFS, you know, performance of the control arm, you know, at something around eight to nine months. And again, if we're trending out, you know, at least 13, but perhaps as much as 16 months, you know, it bodes well, for the study as well. You know, we'll just say that, you know, the FDA continues to reinforce the importance of overall survival. They recognize that in a long study, like frontline non-small cell lung cancer, that overall survival can be something that's confounded by subsequent therapies. And I think really what they would be looking for is a very, you know, it's a positive PFS with a good magnitude of effect in delta, you know, that they're consistent with what their definition of clinical benefit is, and then a positive trend on the, on the overall survival side. You've mentioned just, feedback from the FDA in terms of the trial design. Is that sort of firmed up at this point, or, or is there still more discussion in particular areas? Yeah, we finalized our discussion with them and have finalized our protocol and are moving forward based on that discussion. Yeah, sure. And then remind me, just timelines, when you can start the study, when? Right. First patients will begin starting late this year. I think we do expect the conduct of the study to be ongoing for approximately three years. Okay. And then the readout would be after that. I, Ben, do you have further comments on? No, I, we're ready to go. We have a lot of sites ready to go, so we think that we'll start enrolling this year, and we think it will enroll rapidly. There's a lot of interest in the design, and our physicians have patients ready to go. Yep. And when will we get the next update on that data set from the things? Yeah, we'll be talking about that this fall. Okay. Gotcha. And, and maybe now we can just shift to TPS less than 50. What's the current strategy and, and when we might sort of get more data? Sure. Yeah, we've talked about the less than 50 a bit at our earnings call as well. And I think, you know, really the take-home message in terms of where we are now is that we have seen positive trends in the less than 50 population as well. However, to be confident in the magnitude of benefit in those patients, we do believe that chemo and immunotherapy combination is likely to have a higher probability of success. And so we've designed a study called KRYSTAL-17 to look at the combination of adagrasib plus pembrolizumab plus platinum-based chemotherapy. We will be looking at two regimens in this study. One is in the maintenance setting, treatment with post-platinum, and we will be also looking at the combination up front. You know, essentially, we'll be looking at safety and tolerability to determine that we have a path forward there. We have seen some interesting trends in our ongoing KRYSTAL-7 study in the less than 50 population that would point us towards an interesting pattern, you know, of activity in patients with selected co-mutations. And, you know, one reason that we have not talked about this at our earnings call is we do believe that we can leverage this information and that it, you know, essentially acts as a proprietary advantage for us in the development of the drug in this setting. So we will be integrating the evaluation of mutations that co-occur with KRAS, and we will, if we get to a pivotal study design, be integrating some considerations in the statistical analysis plan to evaluate the impact of those. Suffice to say that, you know, we're very excited about, you know, seeing the outcomes emerging from the KRYSTAL-17 study, landing on a go-forward regimen and proceeding positively. I will also say that, you know, although the chemo immunotherapy is our primary approach, we do have additional activities ongoing with adagrasib that may eventually have, you know, read through and, you know, provide additional options in the frontline or even the second-line setting, post chemo immunotherapy. And that is, you know, we've identified some mechanisms of pathway feedback that may limit the effect of the KRAS inhibitor. So we have looked at SOS1 combination with epidermal growth factor inhibitors, as well as nab-sirolimus as targeted options. Those are ongoing in exploratory clinical trials. If they should declare themselves as interesting, we would, you know, proceed accordingly with, you know, determining if we can get those onto a pivotal path as well. So we have a primary option, but we will continue looking at every meaningful option that we can. Makes sense. Maybe we can shift to the KRAS G12D, MRTX1133, I think. Maybe just give us a brief history there, what you've seen pre-clinically also that kind of gives you some, I guess, confidence or- Sure. Yeah, MRTX1133, for the audience, is a selective KRAS G12D inhibitor that binds in the Switch II pocket. It has about 700-fold selectivity for KRAS G12D versus wild-type KRAS. It can bind to KRAS in both on and off states, which may have an advantage with regard to limiting feedback reactivation of KRAS, or in terms of resistance, so it's a positive property moving forward. 1133 has a number of positive attributes. First of all, it's a very metabolically stable molecule. It's highly potent, with picomolar potency in cells. It has a long predicted human half-life, perhaps exceeding as much as 60 hours. And it has very high intrinsic solubility. So a lot of factors that are very supportive. You know, the physicochemical properties of the MRTX1133 molecule are interesting. So there are features of the molecule, such as polarity, you know, kind of polar surface area, lipophilicity, that are necessary to gain the type of binding affinity for KRAS G12D, necessary to have drug-like potency. And the end result of that is low intrinsic oral viability. So what we've done is spent some extra time preclinically devising ways to enhance the oral uptake of 1133. And, you know, really where we stand with that is we've started the clinical trial. The clinical trial has started with a very straightforward formulation of drug and capsule. That allows us to get into patients earlier, get an experience with dose escalation, understanding tolerability, and understanding, you know, kind of unassisted PK properties of 1133. We have in parallel, been developing an oral formulation with factors or excipients that are designed to increase the oral absorption in the upper and lower GI. And preclinically, that's resulted in a tenfold greater oral absorption than what we have seen with just 1133 administered in solution. So we do believe that this formulation has a chance of augmenting the oral viability and increasing our probability of success in the clinic. We're just right on the cusp of escalating that formulation, and we will be talking more about the 1133 clinical data coming up here in 2024. That's essentially where the program sits at this point. When we get data early next year, maybe give us a sense, to the extent you can, maybe patients, what endpoints will we see, what endpoints should we be focused on? Sure. Yeah, I think, you know, there are a lot of read-throughs to the collective experience with G12C inhibitors that read through to G12D. So you know, and just a reminder here, I think, you know, the G12D mutations are present in nearly 40% of pancreatic ductal adenocarcinoma, about 12% of colon cancer, about 6% of non-small cell lung cancer, mostly with an adenocarcinoma focus. All three of those populations are around the same size, and they're quite sizable opportunities, so they will make up the majority of patients enrolled, although we will allow any solid tumor onto the clinical trial. You know, I think in terms of the read-through for G12C, we do believe that if this drug does what we think it can, that we would be seeing, you know, a response rate potentially in the 40% range in the non-small cell lung cancer setting as a monotherapy. In pancreatic ductal adenocarcinoma, our experience with adagrasib tells us that a response rate of around 40% with good durability is achievable. And then in colon cancer, we do see responses as a monotherapy. However, it's very clear that epidermal growth factor can limit the activity of KRAS inhibitors, so the combination with EGFR inhibitors, like cetuximab, would be key for C inhibitors, certainly, and then also G12D. We do believe that any of these three could represent an accelerated development opportunity for the program and get us onto an accelerated approval path for the drug. But we do recognize that the patient population here is over three times greater than it is for G12C. This would give us the opportunity to take on multiple activities in parallel, including the combination with frontline standard of care in lung cancer, to move up to frontline in pancreatic cancer, and then to move up lines of therapy in colon. In terms of the dataset that we would see, you know, really, we would have a standard phase 1 dose escalation experience with two different formulations. We would be looking at safety, tolerability, and early signs of clinical activity. In that setting, we would be looking at that, you know, those information by dose. So I think that that's roughly where we would stand. You know, I think it would be reasonable to expect, you know, more than 20 patients' worth of experience by the time that we were to present. Yep. Perfect. Maybe in the last 6 minutes here, we switch to your PRMT5. That's 1719. You shared some recent data with us that was very exciting, so maybe you can just sort of walk us through that program and the recent data. Sure. Yeah, I think, you know, we have had MRTX1719 ongoing in clinical trials now for over a year. You know, just a note for those in the audience, you know, the MRTX1719 has a unique way of inhibiting PRMT5 that differentiates it from the first generation PRMT5 inhibitors that essentially were limited by mechanism-based toxicities, mostly pancytopenias, but a high level of Grade three events and dose modifications. The way MRTX1719 works is it binds to and stabilizes methylthioadenosine in the active site, or the methyl donor site, of PRMT5. Why this is important is we can specifically leverage the biology of MTAP-deleted tumors, which result in a 10- to 20-fold increase in methylthioadenosine or MTA. This is a specific Achilles heel for those particular tumors and gives us a 70+ fold selectivity index for killing MTAP-deleted cells while sparing cells that are normal. I would say our clinical trial experience so far mirrors this. You know, we have been able to start at a 50 milligram dose, work our way up to 800 milligrams once a day. We have defined this as the top dose of the study. We have now cleared a 600 milligram once a day dose, and this represents, along with the 400 milligram dose, a potential go-forward dose for the program. Overall, collectively, for our overall experience, including the high dose levels, the agent has been well tolerated. We've seen a very low level of dose-limiting toxicities in the study so far. The frequency of these are between 10% and 15%, so very manageable. We've seen a very low level of any sort of dose interruption or dose reduction, so we've been able to maintain good dose intensity overall, and we haven't seen some of the pancytopenias or target-related adverse events that were seen for the first generation. In terms of early signs of antitumor activity, we had 18 evaluable patients on the study at dose levels that were greater than 100 mg QD, which is actually a dose level that's consistent with achieving clinical exposures that inhibit PRMT5. And in those 18 patients, we observed six responses to date. All six have confirmed. They include tumor types such as mesothelioma in a couple patients, non-small cell lung cancer, cholangiocarcinoma, melanoma, and peripheral nerve sheath tumors. We do believe the activity is going to be broad and go beyond those tumor types, but that's really what we have to date. So moving forward, we will continue to expand the dose levels, especially with focus on the 400 and 600 dose level. Those dose levels, respectively, are five or eightfold above our predetermined, preclinically defined efficacious plasma exposures. So we are confident that we are covering the target. We've demonstrated clinically at doses as low as 200, that we see complete target inhibition of symmetric dimethylarginine, so we're confident in the doses moving forward. We would be declaring a recommended phase II dose, most likely by the end of the year, and then starting enrollment in key phase II cohorts, which would include a mixed histology cohort and non-small cell lung cancer, both adeno and squamous. It would include pancreatic ductal adenocarcinoma, and it would include mesothelioma. We also have a basket cohort where we can continue to explore the activity of MRTX1719 across a variety of solid tumors. This will give us two, two things. You know, one is, do we see signals in other solid tumor types that would merit further exploration in that given tumor type? Or if we see a reasonable response rate, let's just say, for the purpose of this, this discussion, 40% or higher with reasonable durability, it's not out of the realm of possibility that this could be a tumor-agnostic approval opportunity, similar to NTRK inhibitors or checkpoint inhibitors in MSI high tumors or otherwise. So that's really where we are and where we're going with the program. You mentioned selecting a recommended phase II dose, probably around year-end. Should we also anticipate another sort of data update at that point, or? I think it's most likely that we present at a major medical conference next year at AACR or ASCO. However, we continue to keep our eye on the data. It's an open label study. We'll continue to monitor the field as well, and if it merits an earlier update, we can always consider that at that time. Okay. I guess... anything we didn't cover that we should in the last minute here? Maybe just, how about maybe just back to PRMT5 and maybe a last question for you in a minute, just competitive landscape there and, and any other assets we should be paying attention to. Sure. I, you know, I think... You know, kind of the next generation of PRMT5 inhibitors has emerged that are, you know, comparable in mechanism to 1719, so that includes AMG 193 from Amgen. It's likely that they are leaning towards an update this fall as well. And then Tango has two inhibitors, a first-gen and a second-gen. So I believe they're starting their second-generation trials now. We're very confident in the properties of 1719 with regard to potency, selectivity index, and pharmacokinetic properties, and do believe that there's a reason to believe that, based on all the information out there, that this could be a best-in-class molecule. Okay, great. I guess the last thing to mention about PRMT5 is we do think there are monotherapy accelerated opportunities, but there's also some exciting combination opportunities, including immunotherapy, selected targeted therapies, and even chemo, chemotherapy. Good. All right, great. Two seconds left. We'll end it there. Thanks so much, Ben and James. Appreciate it. Thanks, Mike.