Mirati Therapeutics, Inc.

Good afternoon, and welcome to the Mirati Therapeutics first quarter 2023 earnings call. My name is Justin, and I will be the operator for today's call. All lines have been placed on mute to prevent any background noise. After the conclusion of the speaker's prepared remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by number one on your telephone keypad. If you would like to withdraw your question, press star 2. It is my pleasure to introduce Ryan Acy, Vice President of Corporate Affairs at Mirati. Ryan, you may begin the call.

Thank you, Justin, and welcome everyone to this afternoon's call. Joining me on the call today are David Meek, our Chief Executive Officer, Dr. Chuck Baum, our President, Founder, and Head of Research and Development, Dr. Alan Sandler, our Chief Medical Officer, Dr. Jamie Christensen, our Chief Scientific Officer, Ben Hickey, our Chief Commercial Officer, and Laurie Stelzer, our Chief Financial Officer. Before we begin, I'd like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31st, 2023, and recent corporate updates. This press release is available on the investor section of our website at merati.com. With that, David, I'll turn the call over to you.

Thank you, Ryan, and thank you all for joining us on the call today. On this afternoon's call, I will provide initial remarks before turning the call over to Ben, Alan, Jamie, and Lori to provide updates. I'll then provide some closing remarks before we open the line for questions. I'm pleased to report that 2023 is off to a great start. I'll touch on the key highlights from the first quarter, starting with the Corsati launch performance. We are delighted to see the rapid acceptance of Corsati, which was driven by Corsati's differentiated profile and our highly experienced lung cancer commercial team. We also began enrolling patients in a clinical study for MRTX1133, our highly selective and potent oral KRAS G12D inhibitor, Our MTA-cooperative PRMT5 inhibitor and our KRAS-enabling SOS1 inhibitor continue to move in a positive direction. In addition, we expect to communicate the top-line outcome of the Phase III SAFIRE study this quarter. A positive result would be a transformational milestone for Merati. Furthermore, in this quarter, we continue to employ a data-driven approach to capital deployment and remain fiscally vigilant and continue to explore XUS partnerships as a source of capital and risk sharing, and as a means of further strengthening our balance sheet. We continue to be optimistic and very excited about the future of Merati. The full potential of Krizati, combined with our innovative pipeline, represents an opportunity to help hundreds of thousands of people in need and create substantial value in the process. I'll now turn the call over to Ben, who will provide an update on our Krizati launch. Ben?

Thank you, David, and good afternoon, everyone. We're very pleased with the strong launch performance of Cresati in the first quarter, following FDA approval in mid-December. Our pre-launch preparations are clearly paying off. In our first quarter, full quarter of launch, Cresati generated $6.3 million of net revenue. Our experienced, long-focused field force achieved strong access to prescribers in both the academic and community settings. We estimate that Cresati achieved approximately one-third share of new KRAS G12C patients, highlighting the rapid and broad adoption across both the academic and community settings. As of the end of the first quarter, we had reached over 90% of all target accounts, which constitute approximately 95% of the market potential. In addition, Cresati is already being prescribed in 80% of the top 50 accounts. The first quarter sales included a modest bolus of patients early in the quarter, some of whom had transitioned from treatment on another KRES G12C inhibitor and some more heavily pretreated late-line patients. The majority of our patients were second-line patients who were naive to treatment in the KRES G12C class. From a reimbursement, access, and coverage perspective, we are pleased with our rapid progress as our access team has achieved broad, unrestricted coverage with minimal access barriers for patients. Similar to physician feedback, payer feedback has been positive based on the clinical value of CRISATI. Additionally, our patient services have been well received with patients able to obtain drug in less than one week of an oncologist's prescription, which is significantly ahead of analogs closer to two weeks. CRISATI was also included in the National Comprehensive Center Network, or NCCN guidelines, within one week of approval, aiding coverage and reimbursement decisions particularly with Medicare patients. Feedback from oncologists, office staff, and, importantly, patients has been extremely positive. Importantly, for those oncologists who are familiar with Crisati, intent to prescribe is approximately 90%. Looking ahead, we believe that significant opportunity remains to grow our market share in a second-line setting by increasing the breadth of our prescribing base, increasing depth of use, and expanding the addressable market. We will accomplish this by focusing on attributes that differentiate Cresati and by accelerating market development. Our key messages centered around a 44% response rate, 14.1 months of median overall survival, and low treatment-related discontinuation rates are resonating well. Additionally, data showing Cresati's activity in patients with central nervous system metastases has been favorably received by physicians. who recognized the importance of the approximately 40% of patients known to have CNS metastases. Cresati was recently added to the NCCN guidelines for patients with CNS mets, the only KRAS G12C inhibitor which received this designation, further highlighting the differentiated profile of Cresati. From a market development perspective, we believe there are significant opportunities to expand the second line KRAS G12C non-small cell lung cancer market. Our team continues to focus on increasing both testing and identification of KRAS G12C eligible patients, particularly in the community setting. We now estimate that the KRAS G12C testing rate at time of lung cancer diagnosis is approximately 70%. Testing rates for other targeted therapies, such as EGFR and ALK mutations, are closer to 85%. So there is a significant opportunity to grow the market and meaningful opportunities to better identify patients with a KRES G12C mutation at the local account level, where we've established partnerships with community oncology providers. We expect the G12C market to grow at a robust rate in 2023. In summary, we believe that the important differentiating clinical characteristics of Crisati combined with an experienced and focused commercialization organization positioned Crisati to ultimately become the market-leading KRAS G12C inhibitor. I'll now turn the call over to Alan for an update on our clinical activities. Alan.

Thank you, Ben. Hello, everyone. I'll begin by discussing Adagracib, starting with first-line non-small-cell lung cancer, where we expect to share key updates across our multi-pronged development approach in the second half of this year. Our most advanced antagrassive combination approach in first-line non-small cell lung cancer is the concurrent dosing of antagrassive with pembrolizumab in our Phase II CRYSTAL-7 study. Our update in the second half of 2023 will include a first look at durability measures such as duration of response and landmark PFS analyses stratified by TPS score. In the meantime, we are preparing for Phase III studies by laying the administrative groundwork and this will enable us to quickly begin enrollment of patients this year if the data are supportive. Given the tolerability profile of the double combination of adagracin plus pembrolizumab, we initiated a Phase II study called CRYSTAL-17, evaluating adagracin in combination with the keynote 189 regimen of carboplatin, pemetrexid, and pembrolizumab. The initial focus of this study is on the safety and tolerability of this combination. We'll now touch on antagrassive and second-line non-small-cell lung cancer. Discussions with the European Medicines Agency are advancing well on their review of antagrassive's marketing authorization application. We anticipate potential approval in the third quarter. Episode 12, our confirmatory phase 3 study, is enrolling well. to share progression-free survival data in 2024, which will be the basis of our regulatory filing for full approval. In colorectal cancer, we have several important upcoming milestones. Metagracib in combination with cetuximab has shown a compelling and differentiated profile, and our registrational strategy represents a fast-market opportunity. Based on dialogue with the FDA, We are pursuing an accelerated approval pathway for this combination in third-line or later colorectal cancer. We are on track to submit the supplemental new drug application in the fourth quarter of this year. Our CRYSTAL-10 Phase III Registrational Study in second-line colorectal cancer patients evaluating the same combination of antagracid plus cetuximab versus chemotherapy continues to enroll well. especially following the recent New England Journal of Medicine publication and breakthrough therapy designation granted in December of last year. We expect to achieve full enrollment of CRYSTAL 10 by year-end 2023, and we anticipate reporting the final analysis of progression-free survival and interim overall survival in 2024, with plans for regulatory submission based on these results. We believe that anagracia plus bupuximab combination can potentially offer substantial improvement compared to the current standard of care in the second-line setting. Based on real-world and retrospective data in patients with KRAS G12C-mutated colorectal cancer in the second line, we estimate that the median progression-free survival is less than five months, and median overall survival is less than 10 months on the current standard of care in the setting. In addition, we presented compelling updated data in the largest phase two data set evaluating KRAS G12C tumors beyond non-small cell lung cancer and colorectal cancer at the ASCO virtual plenary series in April of this year. In the study, pedagraphs have demonstrated clinically meaningful activity in a variety of KRAS G12C mutated solid tumors, including pancreatic cancer, for which no standard of care treatment options currently exist. Based on these compelling results, Adagracid was added to NCCN guidelines last week for KRAS G12C mutation positive pancreatic cancer patients. This is in addition to the inclusion that was previously granted for patients with second line non-small cell lung cancer with CNS metastases. We'll continue to explore potential accelerated regulatory approval pathways in these patients' subpopulations, and we expect to gain clarity on our approach later this year. Finally, I'll briefly touch on citrobathinib, which is being studied in a registrational Phase III study called SAFIRE. SAFIRE is on track for a top-line final analysis for overall survival this quarter. While we remain blinded to the ongoing study, We believe it was sufficiently powered to demonstrate both statistically significant and clinically meaningful outcomes. With that, I'll turn the call over to Jamie for an update on our earlier stage development pipeline.

Thank you, Alan. Today, I'll cover progress in our early clinical development pipeline, including MRTX1133, 1719, and 0902. I'll begin with MRTX1133. are potent, selective, and potentially first-in-class oral G12D inhibitor, which targets both the active and inactive states of the G12D mutant protein. The KRAS G12D mutation is predominantly associated with poor outcomes on standard of care therapy in several types of cancer. We estimate that there is an annual incidence of approximately 125,000 patients across lines of therapy with KRAS G12D mutations in the U.S. and Europe. Positive attributes of 1133 include sub-nanomolar potency in tumor cells, high plasma-free fraction, long target residence time, and a long plasma half-life. These attributes are consistent with a low target plasma threshold for maximal target inhibition for the full duration of the dose interval and have increased our confidence in a successful development path for 1133. As David mentioned, we initiated the Phase I-II study which is designed to evaluate the safety, PK, PD, and antitumor activity of 1133 in patients with advanced solid tumors that harbor a KRAS G12D mutation. The study began enrolling patients in March. Overall, 1133 has the potential to provide a transformative treatment option for the large and underserved KRAS G12D patient population. Now, moving on to MRTX1719, our potentially best-in-class MTA-cooperative PRMT5 inhibitor. 1719 is enrolling in a Phase I-II clinical study for patients with tumors harboring an MTAP gene deletion. MTAP gene deletions occur in approximately 10% of all human cancers. We estimate that there's an annual incidence of greater than 200,000 patients across lines of therapy in the U.S. and Europe. The potential to make a significant difference in treatment outcomes for these patients with high unmet medical needs may enable a rapid development path. 1719 selectively binds to the PRMT5 MTA complex, which is uniquely present only in tumors harboring MTAP gene deletions. This results in extensive selectivity for MTAP-deleted tumor cells compared with normal cells. The wide therapeutic index and ability to safely achieve near-complete target inhibition with 1719 provides a clearly differentiated therapeutic modality compared with non-selective PRMT5 inhibitors. which were limited by mechanism-based bone marrow and systemic toxicities. Finally, the greater than 70-fold selectivity of 1719 is potentially the highest selectivity ratio for MTAB-deleted cells relative to other reported PRMP5 MTA complex inhibitors. Our early clinical experience in the Phase I study has been encouraging. 1719 continues in dose escalation, and current dose levels are achieving consistent PK properties and plasma exposures which now well exceed levels predicted to demonstrate durable and near-complete inhibition of PMT5 in MTAP-deleted tumors, all based on our preclinical modeling. At the present dose levels and predicted therapeutic plasma exposures, we are now observing any dose-limiting toxicities, including mechanism-based dose-limiting toxicities consistently reported from non-selective pure MT5 inhibitors. We look forward to sharing initial clinical data in the second half of this year, including safety and potential early signals of clinical activity. Finally, our phase one study for MRTX0902, our potential first-in-class SOS1 inhibitor, continues to enroll well. This agent has the potential to be synergistic with KRSG12C, D12D, and EGFR inhibitors. This is an excellent example of our strategy to maximize the value of our KRAS portfolio by pursuing a broad range of KRAS targeting strategies and indications. We're on track to initiate dose escalation cohorts combining 0902 and Adagrassive in our ongoing Phase 1-2 clinical study in the second half of this year. Overall, we're pleased with the significant progress we've made across our portfolio this quarter and look forward to providing additional updates in the near future. With that, I'll turn the call over to Lori for our financial update.

Thank you, Jamie. I will begin by walking through our income statement and touching on a few other key financial metrics. Please see our press release from earlier this afternoon for additional details about our first quarter 2023 financial results. Revenue for the first quarter of 2023 was $7.2 million, which was driven by $6.3 million of Cresati sales and $0.9 million of license and collaboration revenues. This compares to revenue of $0.7 million for the first quarter of 2022, which consisted solely of license and collaboration revenues. The gross to net discount in the first quarter was in line with other similar small molecule oncology therapies and our expected steady state rate moving forward in the range of 20% to 25%. However, this may fluctuate from quarter to quarter. Cost of product revenue for the first quarter of 2023 was $0.6 million. A substantial portion of the inventories sold during the first quarter were manufactured prior to the FDA approval and therefore were expensed to research and development prior to 2023. Research and development expenses for the first quarter of 2023 were $126.7 million. compared to $131 million for the same period in 2022. The decrease was primarily driven by a reduction in clinical development costs for citravatinib as we completed enrollment in the SAFIRE Phase III clinical trial in the second quarter of 2022 and lower clinical manufacturing costs to support ongoing clinical trials for adagracin. These decreases were partially offset by increases in our earlier stage clinical development programs such as MRTX 1133 and an increase in salaries and other employee related expenses to support the advancement of our portfolio. Selling general and administrative expenses for the first quarter of 2023 were $73.5 million compared to $54 million for the same period in 2022. The increase was primarily due to an increase in headcount related costs, including share-based compensation and salaries and commercial related costs to support the marketing and sales of Cresati. Net loss for the first quarter of 2023 was $184.6 million, or $3.18 per share, basic and diluted, compared to a net loss of $188.4 million, or $3.40 per share basic and diluted for the same period in 2022. We ended the first quarter with approximately $900 million in cash, cash equivalents, and short-term investments. Net cash burn was $181.5 million in the first quarter, and the first quarter will be our highest cash burn quarter of the year. Drivers of the higher net cash burn in the first quarter include the 2022 bonus payments, a milestone payment to Pfizer, and timing of vendor payments associated with accrued expenses. We recognize that a disciplined, data-driven approach to capital deployment is critical as we advance our pipeline, invest in innovation, and effectively launch products to drive sustainable long-term growth. We have focused our investments on our highest priority opportunities, those that have the greatest potential to benefit patients, create value, and drive shareholder returns. We expect our 2023 net cash burn to annualize within a range of $525 to $580 million. Our current cash runway is into 2025. And with that, I'll turn the call back to David for closing remarks.

Thank you, Lori. As you've heard, there is an abundance of positive activity and opportunity for Merati in the near term and beyond. Much of our confidence centers around our belief potential to address a billion-dollar-plus market opportunity across multiple lines of therapy and tumor types, both as a monotherapy and in combinations. We are also proud of the quality of the commercial organization we have assembled. It gives us confidence that Krizati and any future products will be well-represented in the marketplace. We also continue to make meaningful progress advancing our broad and differentiated pipeline of targeted oncology programs. In closing, I will reiterate an important point I made earlier. Our clinical pipeline is deep and has the potential to address unmet medical need for hundreds of thousands of people living with cancer, and that motivates us to succeed each and every day. On behalf of all of us at Mirati, we thank you for your continued support and interest in the company. And with that, Justin, we are ready to open the call for questions. Please proceed.

Thank you. If you would like to signal with questions, please press star 1 on your touchtone telephone. If you're joining us today using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Please limit yourself to one question and one related follow-up question. Again, that is star 1. If you would like to signal with questions, star 1. And the first will come from Michael Smith with Guggenheim.

Hey guys, thanks for taking my questions. I had one perhaps for Jamie on the updated CRYSTAL 7 data that we'll get in the second half of this year on the first line lung cancer combination study and just help us understand how potential outcomes here will influence your phase three plans. Is it simply a powering question or are there any other considerations as to how the data might inform next steps? The other question was really on where you are with any potential pursuits of monotherapy in first-line non-small cell lung cancer. Is that still on the table at this point? Thanks so much.

Sure. Thanks, Michael. I know you directed that question to me, but Alan's going to be handling the aggressive-related questions today.

Great. Thank you for the question. The data, again, we'll be looking at the data and having that data available the second half of this year. The data will be able to help guide us toward a data-driven approach in frontline, which, as you know, encompasses different types of patients, the greater than 50%, the less than 50%, which is also divided into the less than one and one to 49%. So evaluating all that data in K7, which is predominantly the doublet combination of antagrassive and pembrolizumab, will provide us with information to guide that. And also, there is a monotherapy group for that monotherapy antagrassive that we're looking at in the less than 1%. And we'll have updates on that as well the second half of the year. So all of this will help guide us toward an informed decision-making process. at that time.

And our next question will come from Salvine Richter with Goldman Sachs.

Hey, thanks. This is Matt at Home for Salvine. Just a few on the Corsati launch. First, what kind of share do you think is likely by the end of the year? And do you know what was driving the switches from LumaCross? And then finally, just given the stronger than expected quarter, are you still expecting a linear trajectory for sales? Thank you.

Sure. We'll have Ben address those questions.

Sure. So as we said in my prepared remarks, we saw about a third of new patients starting on Crisati. And keep in mind that that's new patients, which only constitutes about 10% of patients at any one time, but is really the mark for what you could expect to see in the future. So we're very excited about the growth to date there. In regards to some of the switches, which came from LumaCraft, the two Most common reasons around that were where physicians had seen some hepatotoxicity and were looking to switch, as well as we had some reports of physicians moving patients, again, from the other G12C inhibitor where there was a CNS met present. Again, we estimate that at around 20% of our Q1 volume, but we're still, you know, getting a better hold on that as we move forward. And then in regards to growth moving forward, yes, we have kind of guided to that linear type adoption. We think that because the testing rate is still beginning to increase or still increasing as well as this patient identification is increasing too, that we do think more of a linear adoption for the patients in play will occur. And ultimately, we believe we will be the market-leading KRAS. We're not directing at which particular time, but we're confident that we'll get there.

And our next question will come from Tyler Van Buren with TD Cowen.

Hey, guys. Thanks for taking the question, and congratulations on all the progress, encouraging comments on the Cresati launch. I wanted to ask on KRAS G12D or MRTX 1133, can you tell us if the early bioavailability and pharmacokinetic data in the early patients being treated is looking as expected based upon what was anticipated from the preclinical data?

And Tyler, Jamie will take that, obviously. Sure, Tyler.

Yeah, I think, you know, so far, you know, there's been a lot of enthusiasm among investigators to open the trial, so the patients have been readily available and quite interested in the studies enrolling well. You know, so far, our experience has been good, but it is our plan to really provide a fulsome update at a later time, likely in 2024. to cover all of the PK tolerability and early sense of clinical activity in context. So that's our plan currently.

Okay. And just for a follow-up for that update in the first half of 24, is the plan to hopefully reach a recommended phase two dose by then?

Yeah, it would be our goal to have a recommended phase two dose, you know, at some point this year and then be able to present data related to the recommended phase two dose in the 2024 timeframe.

And our next question will come from Jenna Wing with Barclays.

I have two questions. The first one, just want to confirm, when you said 20%, I wanted to make sure that's the brain mass patient out of all the patients you treated, including both the new patient, the naive patient, and also experienced patient with G12C. And my second question is also regarding the G12D patient. Just wondering how many dose levels have you already explored? If 500 milligrams do a good assay for optimal therapeutic window, and also what kind of cancer type enrolled the quickest?

Gina, we'll have Ben first, and then Jamie will take the G12T questions. So, thanks for the question, Gina.

Yeah, the characterization of approximately the 20% was inclusive of both late-line patients as well as those with CNS met. So, it's a kind of a composite across those. Again, we'll get better color in the next couple of months for maybe an update towards the middle of the year. But 20% is kind of more of an all-encompassing of those different sources.

Sure. And then, yeah, on the T12D question, you know, it's early days in the trial. We are in dose escalation. We haven't guided to what escalation cohort we're currently in, but again, the study is making good progress. PK predictions we've done for 1133 and do believe a modest dose level at or below 500 milligrams on a daily basis could be approaching the level of therapeutic exposure. So we continue to monitor the study. It's an open-label study. And again, as soon as the data looks like we have a reasonably sized data package, we would be updating likely in the 2024 timeframe.

And our next question will come from Jonathan Miller with Evercore ISI.

Hi, guys. Thanks so much for taking my question. I'd also like to follow up on G12D. That first half next year update, I just want to get a sense that we'll have a meaningful amount of data at that RP2D, you know, would you expect to be able to give reasonable estimates of ORR at that point, for instance? And secondly, on formulation, I know originally this was expected to be IV. Could you give a little bit of color on how this has evolved and what's giving you confidence that you're going to get the PD you need from an oral formulation?

Yeah, Jonathan, it's David and I'll pass on to Jamie a 2nd and appreciate all the questions coming in around the enthusiasm is there and we're, we're very enthusiastic about the program as well. But just just want to let everybody know, we're not going to do piecemeal data with, you know, we're going to come out with the awesome data package. you know, as we go through the phase one program, and we think that's the most appropriate way to release data. So, as things play out, you know, and certainly we'll go as fast as we can, and we are doing that, but we'll give the full some data package when it's ready. I'll pass it on to Jamie now.

Yeah, I think just to build on David's comment, you know, of course it is our goal to reach a recommended phase two dose, but we want to make sure we get it right. So, we will be exploring dose schedule and formulation in our clinical trial. So that is, I think, the first part of the question. The second part is related to formulation. So we have been developing multiple formulations in the preclinical setting. We have identified a formulation that we believe will achieve the therapeutic exposure and has given us a lot of confidence in the ability to reach those therapeutic exposures via oral administration. In the preclinical setting, we have identified formulations that, you know, have increased the AUC or oral exposure by up to tenfold or greater. We have seen evidence of bioavailability in preclinical studies at or exceeding 10%. And when you couple that with the low threshold to hit the target with regard to systemic exposure and concentrations has really given us the confidence that we can reach the goal with this particular oral formulation. Of course, we'll be continuing to manage this program throughout its lifecycle, and we'll be exploring a number of ways to administer the drug, including continued work with the IV. But here we would like to, you know, assure the oral has, you know, full opportunity and may be important with regard to maximizing target coverage for the full dose interval, which we believe is important for KRAS inhibitors.

And moving on to Mike Oles with Morgan Stanley.

Hey, guys. Thanks for taking the question. Maybe just another one on Cresati. Just curious, since the launch back in December, if you've noticed an inflection in testing for KRAS G12C, or is the sort of rate of increase been steady since the launch? Thanks. That'll take that.

Sure, Ben. I'll take that. The testing right now, is in the low 70s, and keep in mind that that's in frontline or a diagnosis. And we continue to see, you know, some improvement in regards to patient identification. That's where we're really spending a lot of time and effort because, again, even if you've got those 70% of patients in frontline being tested, unfortunately, still a number of those records are not immediately available to the physician. So we've developed a number of local community oncology working plans as well as have some partnerships in place to make sure that we're helping physicians identify those patients. Again, we think the market is really a nascent market and has a great deal of room to grow, both on a testing front as well as from a patient identification standpoint.

And with that... in this marketplace.

Got it. Thanks.

And our next question will come from Ben Burnett with Stiefel.

I agree. Thank you. I actually had a question about the basket study of adagrassib that you spoke about earlier. It looks like you're seeing results across a variety of tumor types. Is there a tumor-agnostic regulatory path for adagrassib? with the FDA, or do you see a path for the various treatment guidelines to recognize out of grasp, in addition to the pancreatic cancer update that you mentioned?

Sure, Ben. Alan's going to take that.

Thanks for the question. So, it's an important one, and one that we are in communication with the FDA, and we'll be discussing that with this year. As you've mentioned, there are actually, you know, two different approaches that can be taken. We're looking toward a tumor agnostic approach, and we'll have discussions with that. There also is that backup plan, as you mentioned, of having individual, potential individual indications with, say, pancreatic cancer and potentially, you know, cholangiocarcinoma, two of the diseases that had sort of a higher response rate.

So we should be able to give you an update on that later this year on the regulatory path forward there. Okay.

Okay, that's great. And if I could also ask just a follow-up question on the PRMT5 program, MRTX1719. I believe you mentioned that you're not seeing DLTs at this point. I was just wondering if you just maybe give us a sense of where you are in that dose escalation schema relative to where you'd expect to see activity based on preclinical work.

You know, I'll put that over to Jamie in a 2nd, you know, caveat that with what we said about our program as well. You know, we're, we're excited about 1719. we're not going to release piecemeal data. We will have a full sum of data update. The plan is for later this year to have this update on 1719. and with that, I'll pass it over to Jamie. Sure.

Yeah, I think we've been able to make very nice progress in the program. Again, the investigators, I think, are increasingly enthusiastic and are looking for these patients, and we've been able to enroll rapidly through the dose escalation cohorts, and now we're several dose escalation cohorts in. As mentioned, dose-limiting toxicities have not limited our ability to continue to escalate at this time, so now there are key questions about looking at early signs of clinical activity and tumor pharmacodynamics as a way to guide our selection of dose. And having said that, you know, we are at a point when we have taken our preclinical data, looked at what the target therapeutic exposures would be, and do believe that we are now at dose levels that well cover those targets. So, you know, I'd say good progress to date, and we'll look forward to being able to talk about that later this year.

And we have a question from Jason Geberry with Bank of America.

Oh, hey, guys. This is Chiang for Jason. Thanks for taking our questions. I'm wondering if you can quantify the number of patients that were treated in Corsati. And I think you said one-third. I think Corsati had one-third of the new shares, of the new patient share. Your competitor used to, like, you know, provide some level of numbers instead of new patient numbers. I'm hoping if you can quantify that part as well. That would be helpful. Thank you.

I'll pass it on to Ben. Yeah, we've tended to go right to this stage around the accounts because we think that's the more robust data set. We see that within some of the patient physician numbers, a little bit volatile, particularly in the launch window. So could consider that in the future. What we have been really happy about has been the field team's execution. And again, being able to actually access and promote to 90% of key accounts and then actually be adopted and written in 80% of the top 50. So, again, very happy with where we are today. Great execution, not only from a field sales standpoint, but very strong access as well. And we can consider kind of opening up and talking about additional data measures in the future.

Yeah, we're really pleased with the momentum and the one-third, you know, new patient starts of the KRES-T12C inhibitor class already.

And moving on to Maury Raycroft with Jefferies.

Hi. Congrats on the update, and thanks for taking my question. I was just wondering if you can share additional perspective on how Cursati is being prescribed in relation to prior anti-PD-1 use, including timing between the prior Pembro treatment. And for those patients that switched from Lumicrast with hepatotox or the patients with the CNS meds, how are they doing on Cursati? Any perspective from real-world observations there?

Absolutely, Ben. Yeah, so thanks for the question. We have seen and heard anecdotally that one of the benefits of CRISATI is the ability to write it in close sequence to the prior IO therapy because we have not seen, as we've displayed with some of our first-line combination data, we've seen a very tolerable profile from a hepatotoxicity standpoint. So that is something that's come up multiple times, particularly in the academic setting. And as a reminder, actually, with our O12 study, We're not requiring actually a washout period there because we think we have advantages from a profile standpoint. In relation to the patients which have been switched due to either hepatotoxy or CNS mets, it's just a little bit too early to get a strong sense of that. We will be following up with physicians who have these anecdotal case studies and be considering that for publication purposes in the future. but very early from this standpoint to really have a clear sense on how they're doing.

And we have a question from Sylvain Turcan with JMP Securities.

Yeah, thank you. Congrats on the update and thank you for taking my question. Just regarding the update in frontline non-small cell lung cancer that we are anticipating for the second half of the year, Could you tell us a little bit about, I understand how we have the doublet in the three TPS score patient populations here, but without having data with the chemo PEMBO, so the triplet, how can we make a decision in the front line? If you could just talk a little bit about the options that you're seeing here. Thank you very much. Sure, Alan.

Yeah, thanks for the question. So, yes, with K7, of course, we'll have the update moving forward, which is predominantly with the doublet, which is in patients across all of the cohorts, the greater than 50 and less than 50 as well. And we'll be awaiting for the data update on that, although you will recall we did have some encouraging data in the greater than 50% at SMOIO. In addition, what we're doing is we have a study that has started that has activated and is ongoing now, K17, which essentially looks to add Adagrasib to the Keynote 189 regimen. So that's the four-drug regimen. We're looking at that as well as an opportunity in the less than 50%. Upon review of the data for K7 in the second half of this year, and then also some of the data that emerges with K17 the latter part of this year, which is predominantly in a safety evaluation, we'll be able to look at the totality of the data and be able to make an informed decision as to what direction to move forward and into which cohort utilizing the best approach.

And we have a question from Eric Joseph with JP Morgan.

Hi, good evening. Thanks for taking the question. And thanks for the caller on the launch so far. I'm wondering if there's any inventory bill that's contributing to the first quarter print. And you also laid out gross net expectations in the range of 20 to 25%. I guess, how should we be thinking about the fluctuation sequentially here in second quarter? And then on 1719, if I could, I guess, just given the breadth of addressable tumor types with this mechanism, any particular bias or concentration of tumor histology so far in the dose escalation phase of the Facebook trial?

Thanks. Lori will take the first part, then Jamie will take the second.

Yeah, so for inventory, you know, we have seen out of the 6.3 million in sales just a modest amount of inventory. Based on our model, our specialty distributor and pharmacy model, we don't see, you know, we don't expect large inventory build. On the discount rate, 20% to 25%, you know, that's in line with our expectations as we kind of move through the year. We will see fluctuations quarter to quarter, especially given, you know, kind of the early days of launch. But that range is kind of where we expect it to be. It's in line with other oral oncology products, and, you know, we expect that to hold for the year.

Yeah, and I think on the 17-19 front, you know, first, your question about the, you know, different types of tumors, we've seen a broad spectrum of different tumors enroll on our Phase I escalation. So, I think, you know, we have a lot of different representative tumor types with MTAP gene deletions. I will say that, you know, a number of our sites, we have thoracic oncologists, for example, as the PI, and in other cases, we have good involvement for GI units or otherwise. So, You know, we do believe, based on both our preclinical data in terms of seeing responses in the preclinical models, as well as the frequency of MTAP gene deletion in different tumor types, there may be certain settings, like non-small cell lung cancer, both adenocarcinoma and squamous cell, pancreatic ductal adenocarcinoma, smaller indications like mesothelioma, where we would expect both strong monotherapy activity, as well as a reasonable frequency of these mutations that If we see the requisite response rate, it's possible we could develop this drug as a monotherapy in somewhat of an accelerated setting using response as a primary endpoint. And that's driven the design of our clinical trial as well as the selection of our investigators.

And we'll take a question from Yagel Nokomovitz with CITI.

Hi, thanks for taking the question. Ben, just a few more for you on the launch. Could you comment on the split between the academic and community uptake of Cresati? And then I think you made a comment regarding the intent to prescribe being 90%. Could you comment on the conversion rate for the intent to prescribe there? And then third, with respect to the discontinuation rate, how is that comparing in the commercial setting versus what you've seen in the clinical experience? Thank you.

Sure. I'll start with the academic to community split. It's actually been a bit more weighted to the academic. It's about 60-40 in the first quarter, which is encouraging because obviously you have your thought leaders in the academic setting. So it's great that we've seen such strong adoption across the academia. We do expect the community to follow, and that's been a big focus of our Salesforce efforts. So over time, expect that to constitute closer to 70% to 80% of the mix longer term. In relation to intent to prescribe, yeah, that's part of a survey that we conducted in the first quarter. And it's in relation to those physicians who are familiar with the profile and may or may not have written Crisati. And for those that stated that their intent to write the product in the future is around 90%. So that's just a very positive indicator of intent. I don't have the exact conversion rate of what that looks like, but again, from a survey standpoint, a very strong indicator of intent there. The third part of the question was, just remind me, oh, yes, on the discontinuation rate. We're not seeing anything unusual here. It's very early to, you know, to really comment more broadly than that. But no surprises here as we're beginning to see refill rates come through. Again, obviously the first quarter, of our performance is very early. We only launched the product in late December, mid to late December, so very early to comment on that. But we're not seeing anything out of the usual from that standpoint.

And we'll take a question from Evan Singerman with BMO Capital Markets.

Hi, guys. This is Malcolm Hoffman on for Evan. We wanted to ask, how do you think about the second line and third line colorectal markets for antagrassib in relative size to the non-small cell lung? And are there any synergies you would be able to leverage with the non-small cell cell teams when entering those markets? Thanks.

Yeah, well, then I'll take that. Sure. Colorectal, in addition to pancreas cancer, are really important indications for us because it really shows the breadth of the efficacy that's possible with CRISATI. And that's particularly important in the community where the vast majority of prescribers are actually writing across therapeutic areas and across tumor types, which is very important. In regards to the numbers, there's about 3,000 patients with the CRC from second line and beyond, and we think we have an opportunity there. And then in addition is a couple of thousand in relation to pancreas and other indications as well. So not only are the numbers and our ability to help these patients who really have a diet unmet need, but we think it's really supportive of the overall profile of Quisati. And from a synergy standpoint, we've built the infrastructure we need. We don't need to add to that. We've got a super experienced, energized field force, and they would be able to cover off those colorectal targets as well. So, yeah, excited about the opportunity there and, you know, more to come on that.

And we have a question from Kalpit Patel with B. Reilly Securities.

Hey, good afternoon. This is Andy Fleischer on for Kalpit. Thank you for taking the question. A couple from us regarding the potential timelines for publication. First, you presented some unpublished clinical outcomes in frontline non-small cell lung cancer. from the Dana-Farber Cancer Institute in December. When should we expect these data to be published, and how many centers and patients' worth of data are we expecting? And then second, are there any timelines surrounding when we could see a preclinical publication showing data with the oral formulation of the GCLD inhibitor that you discussed a bit earlier?

Okay, sure. Yeah, I think regarding the clinical outcomes on frontline, Some of that data, you know, has been published. The manuscript from Dana-Farber is out there. There's another manuscript that is going to follow from Memorial Sloan Kettering, and MD Anderson is working on this as well. So, you know, we do, you know, anticipate additional color being out there in the public domain. In addition to the academic center institutional experience, which often is covers both clinical trials and patients that enroll on a given regimen within the institution. We've been working with large providers like Tempus, where additional data has been put together, and we do plan on disclosing that in collaboration with that organization at some point. And just as a reminder, I think overall, when you look at the outcomes in the less than 50% population in the KRAS G12C subset, there is likely a strong unmet medical need there. Regarding the G12D, I think our forward-looking publication strategy will likely be linked to tying any preclinical data in with clinical data. So I think, again, we'll be looking at the updates for 1133 likely being in the 2024 timeframe.

And our next question will come from Jay Olson with Oppenheimer.

Oh, hey, guys. Congrats on all the progress, and thank you for taking our questions. There have been a few recent data presentations on emerging KRAS G12C inhibitors at AACR and other conferences. Can you talk about the key points of differentiation across the G12C landscape And how do you expect your field to evolve? And then I had a follow-up on PRM T5, if I could. Thank you.

Sure. Yeah, I think on the G12C front, of course, we monitor that space closely and are looking at, you know, the competitors. I think there are a number of points for Edagrassive where we do believe that there are some positive attributes that we can leverage. You know, one of those is, you know, kind of the long half-life in the BID schedule where we have very little peak to drop. variation, and I think that comes in in two places. One is the ability to really hit the target hard for the vast majority, if not the full dose interval, and then to avoid high peak concentrations. The second place where that particular aspect comes in is if we can avoid peak concentrations, you know, I do believe that the hepatotoxicity observed has been associated with facilitating an immune response due to off-target immunogenic captains. And the ability to have a fairly flat profile may help us have a cleaner profile when it comes to this hepatotoxicity or immune-related toxicity issue. Another attribute of Adagracib that also helps, you know, for the therapeutic index, especially when it relates to immune-related AEs, is the fact that this drug has a favorable K and K-I ratio. It has good non-covalent binding affinity, and we've been able to dial the reactivity down to the point where I don't think we're going to run into off-target immunogenic haptens as a driver of therapeutic index. We do believe that we maybe have a best-in-class profile with regard to brain penetrance, and Ben had covered that in his presentation. We do believe that this is another area we can leverage for antagrassinib. You know, we continue to monitor the space, but we do think we have a number of advantages here. And one of those advantages, I think, is emerging, and that is the ability to combine with immunotherapy and leverage that to gain a presence in the frontline setting.

Yeah, Jamie, thank you very much. I'd just add on to that, you know, what we've been able to, you know, present at various conferences, our approval of CRISATI, our response rates, our overall survival data, and CNS activity, the combined bill with other agents such as immuno-oncology, EGFR inhibitors is also a nice advantage we have in the marketplace. And then across multiple tumor types, we've shown that too. And I'd say finally is we're years ahead of folks too. So we feel that as a KRAS G12C inhibitor market leader, we're well on our way.

Great. Thank you so much. That's super helpful. And then for your MTA cooperative PRMT5 inhibitor, can you just talk about what we should expect from the initial data later this year? And is there any read across from the Tango Therapeutics Program?

Yeah, I think I'll mention a few things there. So our data, you know, this year, you know, we are on a dose escalating phase one study. We hope shortly to be in the phase one B expansion where we can enroll additional patients. perhaps at two different dose levels, and that would expand our patient pool. But I think to set expectations, we are in dose escalation, and we're escalating with cohorts of three to four patients apiece. So that should provide color towards the number of patients that we would have. I think the second point here is that our goal would be to present PK, PD, tolerability, and any early signs of clinical activity One advantage we think our program does have is this 70 to 80-fold ratio of being able to target MTAP-deleted tumor cells relative to cells that don't harbor this deletion. And I think the important take-home here is that we believe we need to be at a pharmacodynamic inhibition level for PMT5 and PMT5-dependent STMA that achieves about an IC99. And if we're able to achieve an IC99 in an MTAP-deleted tumor cell, That will allow us to avoid the levels that have historically been associated with off-target myelosuppression, neutropenia, thrombocytopenia, and other issues. And I think that that's what, you know, is needed preclinically to see tumor responses. And we do believe that this is a potential feature of differentiation for 17-19 relative to some of the other programs out there.

And we'll be able to give that fulsome update the second half of this year.

And we'll take a question from Amin Fadia with Needham.

Hi, good afternoon. Thanks for taking my questions. First on MR-TX1133, could you give us some color on the size of the dataset you will be presenting? Sounds like you want to wait to achieve the recommended phase two dose and then present a more wholesome dataset. So if you can give us some color on the size as well as the histologies that you expect to be able to cover by that time? And what would be a benchmark that we should keep in mind as we get some of that data? Thank you.

MRTX 1133, just a reminder, we just started the phase in march of this year so it's early days with the program as mentioned by jamie you know we will present that you know fulsome update in the first half of 2024. um so it's what is early days might be a little bit premature to talk about how many numbers we'll have at that point in time um yeah i think david i agree i i you know it's hard to provide a lot of color other than to say this is a dose escalating phase one with the opportunity to have phase 1b dose expansions

And really the size of the data set depends on how many dose levels it takes to get up to a reasonable and a recommended phase two dose. And, you know, how much additional optimization is ongoing in that study. I think you alluded to a second question is what to expect. So, you know, I think our learning opportunity is really with adagracid and a G12C space where we do know that there are single agent development opportunities based on response rate. Clearly in the long setting, you know, we had mentioned earlier in the pancreatic ductal adenocarcinoma and biliary tract setting where we're seeing monotherapy response rates and durability associated with being able to develop the drug as a monotherapy, potentially in a single arm accelerated path there. And then finally to note that, you know, 12% of colon cancer also has a KRAS D12D mutation. You know, we do think the cetuximab combination strategy there looks very good preclinically and will likely apply clinically. So, you know, really, I think that provides a clear development path should the drug do what it's supposed to do in those particular settings.

So we're moving as fast as we can. This is a significant opportunity. The patient population is, as Jamie mentioned, there's over 120,000 patients a year in the U.S. and Europe. We've got an opportunity for first-in-class, so it's all hands-on deck here at Mirati for MRTX 1133.

Investigators are very enthusiastic about this, so we're moving as fast as we can.

And that does conclude the question and answer session. I'll now turn the conference back over to you for any additional or closing remarks.

Well, thank you, everyone, for joining us this afternoon. We certainly appreciate your interest in Mirati, and we look forward to sharing additional updates with you throughout the year.

Thank you. That does conclude today's conference. We do thank you for your participation. Have an excellent day.