Q4 2022 Mirati Therapeutics Inc Earnings Call

Speaker 2: Please stand by.

Speaker 2: Good afternoon and welcome to the Maraudi Therapeutics 4th quarter 2022 earnings call. My name is Cynthia 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 the number one on your telephone keypad.

Speaker 2: If you would like to withdraw your question, press the star followed by the number two on your telephone keypad. It is my pleasure to introduce Ryan Acey, Vice President of Corporate Affairs at Meradi. Ryan, you may begin the call. Thank you Cynthia and welcome everyone to this afternoon's call. Joining me on the call today are David Meek, our Chief Executive Officer.

Speaker 3: 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. Laurie Stelzer, our Chief Financial Officer. Before we begin, I would 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 plug in to our YouTube channel. Thank you. Your Pathway to the reinforces Tube to find numbers easily

Speaker 3: Please review our annual report on Form 10K that's filed with US Securities and Exchange Commission. This afternoon, we released financial results for the fourth quarter and full a year ended December 31, 2022 and recent corporate updates. This press release is available on the Investor section of our website, netmaraddy.com. With that, they will turn the call over to you. Thank you, Ryan, and thank you for joining us on the call today. 2022 was a transformation year from Roddy, and I'm pleased to report we received our first approval and lost our first commercial product, Kuzati.

Speaker 3: And KRAS-G12C mutated locally advanced or metastatic non-small cell lung cancer.

Speaker 3: We deployed our highly experienced lung cancer commercial field force and made significant progress advancing our differentiated pipeline of targeted oncology products. Our team launched Cresati in mid-December, and while it is still in the early weeks, we are encouraged with Cresati's initial reception and its broader commercial potential. The initial launch feedback from clinicians, patients, and payers.

Speaker 3: reinforces our belief that Cresati is the best in class K-Res G12C inhibitor, addressing a multi-billion dollar market opportunity across multiple lines of therapy and tumor types, both as a monotherapy as well as in combinations. Additionally, our broad and differentiated clinical pipeline Good luck with encouraged outmoded PART Students fats that leading in the new era oflog hook

Speaker 3: has the potential to address unmet medical need for hundreds of thousands of people living with cancer as we endeavor to develop differentiated products that will play an important role in their care.

Speaker 3: As I step back and look at our products, capabilities, and people, it's clear we are well positioned to achieve near-term success and to drive long-term growth.

Speaker 3: Mor audience focus on creating best in class small molecules for the treatment of cancer. With a current focus on being a leader across K-RAS mutating cancers, our highly productive innovation engine has enabled us to develop K-RAS and K-RAS enabling therapies to treat a broad range of patients. We expect to dose our first patient with MRTX 1133.

Speaker 3: our KRAS G12D inhibitor in the first quarter. Moreover, our other earlier stage clinical programs, including our MCA cooperative PRMT5 inhibitor and our KRAS enabling SOSS1 inhibitor show tremendous progress. Furthermore, we have a potentially transformational opportunity on the horizon with citrobastidib and lung cancer in combination with PD-1.

Speaker 3: We believe this pipeline has vast potential to create significant value for our shareholders.

Speaker 3: Alongside the development of these programs, we have built a scalable and synergistic commercial organization, particularly in lung cancer. At present, our U.S. commercial team is exclusively focused on launching Crizati.

Speaker 3: Furthermore, Rani remains disciplined in how we deploy and invest our capital. We continue to focus on the combination of clinical data analysis and the corresponding commercial opportunity to drive our investment decisions.

Speaker 3: Looking back, 2022 was a year of remarkable execution and major treatments for Miroti. Key clinical highlights include accelerator approval for Crizade in the US, and second line and beyond, K-Rath G12c mutated non-small cell lung cancer.

Speaker 3: Best-in-class intracranial response rates with Adagrassin in patients with active and untreated CNS metastases. Differentiated clinical data demonstrating Adagrassin plus PD-1 combination is safe and tolerable with promising early signs of efficacy. Broader potential and third-line and beyond colorectal cancer indication.

Speaker 3: PRMT5 precision medicine for people with an MTAP-deleted tumor.

Speaker 3: And MRTX0902, our potential first-in-class SOSS-1 KRS signaling modifier program into clinical trials. Looking ahead, 2023 is a year with several important upcoming catalysts and ambitious goals, which we will detail on today's call. Thank you more now for

Speaker 3: We'll start with an overview of the Crozati launch, which is off to a strong start. I'll now turn the call over to Ben, who will provide you with an update on our early commercial experience. Ben?

Speaker 4: Thank you David and good afternoon everyone. I'm pleased to report that we're off to a strong start to the launch of Crizati. As a reminder, Crizati was approved in mid-December right before the holiday season, therefore I will limit my comments to that brief 4th quarter timeframe and look forward to giving a more detailed update on our first quarter earnings call.

Speaker 4: Our initial launch experience has been very positive and we're confident that we can successfully deliver on our commercial goals. As a reminder, our US commercialization team has specific and extensive experience in lung cancer supporting multiple launches.

Speaker 4: This includes a fully integrated team of market access, sales, digital marketing, and medical affairs. The team has already had extensive high quality interactions with key target accounts and are focused on ensuring an industry-leading experience for physicians and patients.

Speaker 4: For example, initial patients treated in December are receiving treatment within approximately 5 days of a prescription being written, versus industry analogs of closer to 10 days. And our unique patient and physician-centric approach to distribution and our patient access programs have been well received. We continue to leverage our experience in the community setting, where over 40% of our pivotal study was enrolled.

Speaker 4: with Medicare patients.

Speaker 4: Overall, we've made strong initial progress in establishing broad reimbursement coverage with no significant access restrictions to date.

Speaker 4: Our interactions with physicians have been highly positive and our key messages centered around a 44% response rate and 14.1 months of median overall survival as demonstrated in a pooled analysis of phase 1 and phase 2 non-small cell lung cancer patients and low treatment related discontinuation rates are resonating well. Additionally, data showing chrysanthesia activity in patients with central nervous system metastases will reduce the risk of serious skyrocketation cluster Small Progress Columb atop news earth and for consistencyHHISHicht chrysanthesia peak health addiction smooth stomach

Speaker 4: increasing both testing and identification of KRES-G12C eligible patients, particularly in the community setting. We estimate that the KRES-G12C testing rate at time of diagnosis is approximately 2-thirds, while testing rates for EGFR and ALT mutations are closer to 85%. So there is a significant opportunity to grow the market and meaningful opportunities to teach Zone 11 of those new sucked free

Speaker 4: to better identify patients with a K-RSG12 simulation at the local account level where we've established partnerships with community oncology providers. In summary, we believe that the important, different-changing clinical characteristics of Prasathe combined with an experienced and focused commercialization organization position Prasathe to ultimately become the market leading K-RSG12C inhibitor.

Speaker 4: Our commercialization team has a singular focus, delivering Cresati to the physicians and patients who could benefit from it. I look forward to providing additional information as our launch progresses. I'll now turn the call over to Alan for updates on clinical activities.

Speaker 4: team has a singular focus, delivering Cresati to the physicians and patients who could benefit from it. I look forward to providing additional information as our launch progresses. I'll now turn the call over to Alan for an update on our clinical activities. Alan.

Speaker 5: Thanks Ben and hello everyone. I'll begin by discussing Adagrassiv starting with non-small cell lung cancer. In first line non-small cell lung cancer we expect to share key updates across our multi-pronged development approach this year. As a reminder, our initial and most advanced Adagrassiv combination approach in first line non-small cell lung cancer is the concurrent dosing of Adagrassiv with pembrolizumab.

Speaker 5: Our experience with this combination provides us with confidence in the path forward based on three key points. First, there's a strong scientific rationale for improved durable outcomes with the combination relative to the existing first-line standard of care.

Speaker 5: Second, Atagrasib, in combination with Pembrolizumab, has demonstrated a safe and tolerable profile. And third, while the efficacy outcomes are still maturing, they are compelling, and we look forward to evaluating the clinical outcomes with additional follow-up and more patient data later this year. Overall, it looks like we have over 200,000 availableTER Psychedelic drainage systems that can meet the92 police

Speaker 5: the advancement of our first-line non-small cell lung cancer strategy will continue to be informed by data from ongoing clinical studies. We expect to provide an update in the second half of this year, which will include a first look at durability measures, such as duration of response and potential six-month landmark PFS analyses. Within the CRYSTAL-7 study, we're also evaluating etagrassives as a monotherapy in patients with TPS scores of less than one percent.

Speaker 5: by the tolerability profile we are seeing with adegrassib plus pembrolizumab.

Speaker 5: Phase 1b2 study evaluating this combination has been initiated as part of the CRSTL 17 study with an initial focus on the safety and tolerability of the combination. Finally, beyond the US, we are continuing to advance discussions with the European Medicines Agency.

Speaker 5: on their review of Adagrassives marketing authorization application.

Speaker 5: and then anticipate potential approval in the third quarter. I'll now move to Color Rectal Cancer, where we have several important upcoming milestones. At a graph that in combination with the Tux-a-map has shown a compelling and differentiated profile, and is our primary approach in Color Rectal Cancer moving forward.

Speaker 5: In the most recent results, which were represented at ESSMO in September of last year, the combination demonstrated a response rate of 46% and a median progression-free survival of 6.9 months. Notably, these results suggest the potential for a substantial improvement compared to the current standard of care of regaraffinib or chemotherapy.

Speaker 5: which has very poor outcomes with low single digit response rates and a progression free survival of only approximately two months. Based on recent input from the FDA, we will be moving forward with an accelerated approval pathway for the combination of Adagrassib plus the Tuximab in third line or later colorectal cancer. We expect to submit the supplemental NDA in the fourth quarter.

Speaker 5: A CRYSTAL-10 Phase 3 registrational study in second-line colorectal cancer patients evaluating the same combination of anagasib plus cetuximab versus chemotherapy continues to enroll well.

Speaker 5: We expect to achieve full enrollment of CRYSTAL-10 by year-end, and we anticipate reporting the final analysis of progression to pre-survival with interim overall survival in 2024 with plans for regulatory submission based on these results. In addition, other important development opportunities for etograssa include pancreatic adenocarcinoma,

Speaker 5: on citrovacinib, which is being studied in a registrational phase 3 study called SAPPHIRE. SAPPHIRE is on track for a top-line final analysis for overall survival in the second quarter of this year. While we remain blinded to the ongoing study, we believe it was sufficiently powered.

Speaker 5: to demonstrate both statistically significant and clinically meaningful outcomes.

Speaker 5: With that, I'll turn the call over to Jamie for an update on our earlier stage development pipeline. Thank you, Alan. Today, I will cover progress on our early clinical pipeline assets, MRTX1133, MRTX1719, and MRTX0902.

Speaker 5: I'll begin with 1133, a highly potent selective and potentially first in class oral KRAS-T12D inhibitor, which targets both the active and inactive states of the KRAS-T12D protein.

Speaker 5: The KRAS G12D mutation is predominantly associated with poor outcomes on standard therapy and several types of cancer. We estimate that just within pancreatic, colorectal, endometrial, and non-small cell lung cancers, there's a prevalence of approximately 180,000 patients with KRAS G12D mutations.

Speaker 5: in the U.S. and Europe . We believe that 1133 has the potential to be an impactful treatment option for these underserved patients. We filed an IND for 1133 and received clearance from the FDA in January . Activation of clinical trial sites is underway and enrollment of first patients in the Phase 1-2 study will begin this quarter.

Speaker 5: The study is designed to evaluate the safety, tolerability, BKPD, and anti-tumor activity of 1133 in patients with advanced cell tumors that harbor a KRAS-G12D mutation. The study will utilize a formulation designed to enhance oral absorption and increase systemic drug exposure. Positive attributes of 1133 include subdental or potency in tumor cells, high plasma-free fraction, and CheYolpamaz.

Speaker 5: long target residence time, and a long plasma half-life of greater than 50 hours. These attributes are all consistent with a low target plasma concentration threshold for maximal target coverage for the full duration of the dosing cycle. This has increased our confidence in a successful development path for 1133. 1133 has the potential to provide a transformative treatment option for the large and underserved ARAST-G12D patient populations. Now moving on to MRTX1719, our potentially best in class MTA cooperative pure MT5 inhibitor.

Speaker 5: 1719 is enrolling in a Phase 1-2 clinical study for patients harboring an M-TAP gene deletion. An M-TAP gene deletion occurs in approximately 10% of all human cancers.

Speaker 5: This translates to greater than 200,000 patients in the US and European Union annually.

Speaker 5: While 1719 has a potential to address a wide range of tumor types, initial priorities for our development program will include pancreatic cancer, lung cancer, mesothelioma, and malignant peripheral nursing tumors.

Speaker 5: 1719 has demonstrated promising preclinical data in these tumors and the potential to make a significant difference in treatment outcomes in these particularly difficult to treat tumor types. This may enable a rapid development path. Now as a reminder, 1719 selectively binds to the BRM-T5 MTA complex. This complex is uniquely present only in tumor cells, harboring and hemptaph gene delation.

Speaker 5: This results in extensive selectivity for eradication of 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 mentality compared with first-generation, non-selective PRMT5 inhibitors, which were limited by mechanism-based bone marrow and systemic toxicities. Finally, the greater than 70-fold selectivity of 1719

Speaker 5: is potentially the highest selectivity ratio for MTEP-deleted tumor cells relative to other reported PRMT5 MTA complex inhibitors. Our early clinical experience in the Phase 1 study has been encouraging.

Speaker 5: VK and systemic exposure are consistent with expectations to achieve therapeutically meaningful drug concentrations based on our preclinical projections, without the associated safety challenges that limited the utility of prior generation PRMT5 inhibitors.

Speaker 5: Also, as a reminder, we were granted fast track designation for 1719, which reflects the strength of our preclinical data and the potential for this agent to have a positive impact on these patients who have limited treatment options.

Speaker 5: We plan to share the initial clinical data in the second half of 2023. The focus of this update will be on safety and tolerability, with the potential to also report early signs of clinical activity. Finally, we've initiated a Phase I study for MRTX0902, our first-in-class SOSS I inhibitor. Preclinical data have demonstrated that 0902 has the potential to enhance the activity of ad-aggressive and is an example of our strategy to maximize the value of our KRAS by pursuing a broad range of KRAS targeting strategies and indications.

Speaker 5: We expect to initiate those escalation cohorts combining 09-02 and adagrasid in our presently ongoing Phase 1-2 clinical study in the second half of this year.

Speaker 5: In addition, compelling preclinical research support the utility of 0902.

Speaker 5: in augmentation of EGFR inhibitors and EGFR mutated lung cancers, other RAS pathway inhibitors and RAS mutated cancers, including the possibility of KRAS mutant allele specific inhibitors such as 1133.

Speaker 5: Overall, we're pleased with the significant progress we've made across our portfolio and look forward to providing additional updates in the near future. With that, I'll turn the call over to Lori. 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 fourth quarter and full year 2022 financial results.

Speaker 2: Revenue for the fourth quarter of 2022 was $0.9 million, which was driven by $0.7 million of Crazati sales and $0.2 million of license and collaboration revenues. This compares to revenue of $0.3 million for the fourth quarter of 2021, which consisted solely of license and collaboration revenues.

Speaker 2: As a reminder, Cresati was approved in mid-December, shortly before the holiday season. Of the $0.7 million of Cresati sales in the fourth quarter, a majority was associated with inventory in the channel. Research and development expenses for the fourth quarter of 2022 were $141.2 million compared to $153.8 million for the same period in 2021. The decrease is primarily driven by a reduction in manufacturing costs for the Adagrassa program following our 2021 NDA filing.

Speaker 2: partially offset by an increase in headcount-related costs, including share-based compensation and salaries associated with the growth of our headcount to support our growing portfolio. Selling, general, and administrative expenses for the fourth quarter of 2022 were $70.8 million, compared to $43.5 million for the same period in 2021. The increase is primarily due to an increase in headcount-related costs, including share-based costs

and diluted for the same period in 2021.

We ended the fourth quarter with approximately $1.1 billion in cash, cash equivalence, and short-term investments, which gives us a cash runway into 2025.

Cash burned from operations was $570.6 million for the full year of 2022. 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 return. We will continue to manage expenses closely and we expect our 2023 cash burn from operations to annualize within a similar range as 2022. Our 2023 cash burn expectations include the partial offset to

Before opening the call for questions, let me conclude by saying how pleased I am with the considerable progress our team has made in 2022 as we delivered our objectives across the key facets of the business. I'm proud of the work this team has accomplished thus far to execute our mission, but we know our work is far from complete.

We believe Marati is very well positioned for future success and value creation. Prasati combined with our clinical pipeline addresses patient populations amounting to multi-billion dollar potential market opportunities and our commercial organization is also a great start. We also have multiple near-term catalysts.

and we expect the case for Kuzaki to only strengthen over time as our adequate acid data matures.

We also have the citrobatin in phase 3 overall survival readout, initial clinical data for MRTX 1719 and MRTX 1133 entering the clinic with initial data expected in the first half of next year. In addition, we expect strong progress across the rest of our innovative pipeline of programs that could serve hundreds of thousands of patients with unmet needs.

At just one or two of our earlier stage programs demonstrate meaningful clinical activity, we expect it will have a substantial impact on the valuation of the company. As such, we are excited about our future and expect 2023 will be another standout year of execution and progress in our goals. On behalf of all of us at Roddy, thank you for joining us.

We thank you for your continued support and interest in the company. And with that, Cynthia, we are ready to open the call for questions. Thank you. I would like to remind everyone that if you would like to ask a question during this time, simply press the star followed by the number 1 on your telephone keypad. If you would like to withdraw your question, press the star followed by the number 2. In order to allow time for additional analysts to ask their questions, we ask that you please limit yourself to one question and one follow-up before re-entering the queue.

Please hold for a moment while we pull for questions. And your first question comes from Tyler Van Buren at Cowan & Company. Please go ahead. Hey, guys. Good afternoon. Thanks for taking the question. Glad to hear the positive early launch comments. Want to ask about testing since you mentioned it. How do you get the KRAS-GTC testing to ALK levels? Does that make sense?

G12C needs to be included on more tests or panels, or is your focus elsewhere to improve testing? Tyler, thanks. Ben will take that question. Sure. It's a couple of things, Tyler. One is to ensure that it is on all of the multiplex tests, and I think that's growing over the course of time, and we've seen that uptick quarter by quarter. And the second one is to create additional demand for a KRAS inhibitor, and with Cresati, we think with our promotional effort in the market, that will lead to just an increasing demand.

And we can see hopefully then the testing rate commensurate with the demand coming into the market. The next question comes from Salveen Richter at Goldman Sachs. Please go ahead. Hi, thanks. This is Matt on for solving.

Could you guys share any commentary on your expectations for Zadio sales ramp in 2023? And then at the end of the call, you mentioned you're exploring partnerships. Could you just discuss things you're thinking about and considering there? Thank you very much.

I can leave Ben. I can start. We're not providing guidance for sales this year in regards to partnerships. We'll defer to maybe Lori. Yeah, we think it's prudent to start that process and you know begin to have those conversations and explore the potential. So that's in the very early stages. That's what. I'm doing it now. Yeah, I'm doing it now. Yeah. Yeah. Yeah. That's what I'm doing now.

The next question comes from Gina Wang at Barclays. Please go ahead. Good afternoon. This is Hershida on for Gina. Thank you for taking our questions. First one on the Adagrassif launch. We understand it's early days, but are you able to comment on what percent of patients on Adagrassif thus far have been recent PD-1 progressives? And then second one quickly, can you provide some color on what you're hearing from physicians with regard to

their familiarity on the safety and tolerability of adegressive, you know, given that the label has the safety on capsule formulation and that you launch with the tablet. Thank you. Sure, I'll take the call first as David. I'll pass on to Penn. Regarding the metrics and so on, we'll save that for the next earnings conversation. We only have a couple of weeks on the market prior to the end of the year. So we look forward to sharing that in the May time frame. Is the launch of take second part of the question of the event and similar response really will be sharing more around that.

What's the balance of growth there being driven by market share versus the competitor versus market development from testing? Do you have goals on those fronts for 2023 and then maybe secondarily as we look forward to PD1 combo data update second half, what's the bar for duration and PFS there? Obviously there's been a lot of discussion about the rate Comstar and that's

in general is still very nascent and has a long way to grow. So we do think that will be a substantial part of the growth moving forward, but we also want to measure our competitiveness by our market share. We have a team that is out there super-energized and looking to take share as well. So more of that to come in the future, but just to, you know, to early this stage. Yeah, hi, I'll take the second question there with the update.

I think a way to look at it is as this evolves and shows and what we're gonna be seeing this information in peer-reviewed journals coming up, we would anticipate a significant improvement over what we've seen historically so that we have confidence moving forward in the first line studies in order to initiate phase III trials.

The next question comes from Michael Schmidt at Guggenheim. Please go ahead. Hey, guys. Thanks for taking my question. I had one on your strategy for atagrass-wing colorectal cancer. It sounds like you did have the FDA meeting recently.

Could you just fill us in a bit more on the feedback that you have received there and how we should think about the scope of the filing and also what needs to be accomplished before submission later this year as you mentioned?

feedback that you have received there and how you should think about the scope of the filing and also what needs to be accomplished before a submission laid this year as you mentioned. Thanks.

Michael, I'll start. As we said that we're going to go ahead and file for accelerated approval by the end of this year. We had a very good conversation with the agency based on the data that you've seen. It was presented as last year.

So understanding what the requirements are for the accelerated approval pathway, we've got all that laid out and now we just need X and Q on it throughout the year put together the Daucea and so on. You also saw that we received breakthrough therapy designation at the end of last year, which I think also speaks to the robustness of the data that we have in that third line plus setting in colorectal cancer, out of gas and combined with some plus med.

Alan, anything else you'd add? No, I think you summarized it quite well. We're gonna be working hard to get that done and we're enthusiastic about the opportunity. We would say that that's just the beginning with colorectal cancer. We also have our CRYSTAL-12 trial underway for second line colorectal cancer as well. And as Alan mentioned, that trial's enrolling well in CRYSTAL-10, so we'll have that data 2024. Thank you. The next question comes from Benjamin Burnett with Stifel. Please go ahead.

Yeah, good afternoon. This is Neil Carnahan on for Ben. When can we expect an update for more CNS data? And how important do you think that is to defining the drug profile?

in second line lung cancer patients? And then as a follow-up to that, are you evaluating the adegressive penbro combo in any frontline lung cancer patients with active brain mets? Thank you. Hi, Neil, I'll take the first part of that. So CNS, as you know, it continues to be important to differentiate the fours, but.

Part of the overall picture where, you know, the picture is really about overarching efficacy, including our overall survival response rates, as well as CNS penetration. We are expecting to have a publication in the not too distant future, which will be out and will be an update to the data that has initially been shown and continues to show promising results for Cresati.

And I'll pass maybe to Alan for the second part of the question. Yeah, I believe the second part of the question was looking at the combination in frontline and CNS metastases. I think the plan moving forward with K7 initially when you're looking at studies with these phase 2 studies you want to have the best group of patients possible so that includes stable.

well.

The next question comes from Eric Joseph at JP Morgan. Please go ahead.

Hi, this is Noah on for Eric. Thanks for taking our question regarding 1719. Is there a meaningful biomarkers for. I'm top deletions and top biology that can be used.

to further enrich for patients with sensitive tumors? And also, is there a distinction between targeting MTA 2A versus PRMT5 and MTAP deleted cancers? Sure, yeah, I think I would say, you know, we are looking at two types of biomarkers. You know, one would be to understand whether there are patients that could be further enriched over...

and otherwise we will continue to study those in patients. The second class of biomarkers we'll take a look at are those that give us insight towards the level of targeted inhibition that we can achieve in patient tumors. And here we believe we want to be at a 95% inhibition level for as much of the dose interval as possible.

They will be looking at symmetrical dimethyl-arginine as a target driven biomarker. We plan on doing that as the program advances. Then finally you touched on PRMD5 versus MAT2A. As you know, there has been some MAT2A data out there reported previously by AGOs, SNOS, must survey the results by using pairs of

is developing that molecule. IDEA has commented publicly on their program as well. I'd say, you know, really the key difference here is that, you know, we believe that in mTEP-deleted tumors where PRMT5 dependency is present, you really have to suppress the target biomarker. Again, this is known as SDMA to the full degree to drive anti-tumor activity.

And I believe that this is a more precise way in this tumor subpopulation to do this. Just note that for MAT2A, when you affect cellular levels of methylation, that you're probably affecting 20 plus methyltransferases. It's a less precise way with a different therapeutic index than PRMT5.

You know, we are looking at the possibility that you could combine PRMP5 inhibitors with MAT-2a inhibitors, but really no clear conclusion here. But, you know, again for M. teptalida tumors believe that the most precise way to target those tumors is through what we're doing with 1719.

The next question comes from Jason Gerberi, Add Bank of America. Please go ahead.

Hey, guys. Thanks for taking my questions. Just wanted to clarify. As you're thinking about a Phase 3 program for your KRAS overall in the frontline setting, it sounds like in the sub-50% PD-L1 expressing that that could move forward a little bit more quickly and that perhaps you're more wait and see.

on some of the other segments in monotherapy pending durability data in the second half. So, just maybe any decisions as it pertains to moving into pivotal phase 3 in the frontline outside of the sub-50% PD-L1 is a late 2023 decision on your end. And then just on PRMT5, Tango is going to have some data here, phase 1 data in the first half.

with their agent. And so just as you think about the molecules comparatively based on preclinical data that's out there, just your expectations, how you differentiate is the idea of your 70-fold collectivity. You're just sort of where the key differentiation resides in the approaches. Thanks.

Great, I'll start with the first line question and thanks for the question. I think a couple important points about the first line. You're right that there are in essence almost three different subsets, the less than one, one to 49, and the greater than 50%. Where and every line where the cell phone really meo You could have changed there way there or whatever Republicans would have changed or whatever other thing that is is being passed.

have K7, which is the doublet that is showing safety and also some preliminary efficacy in that particular setting. And we will be taking another look at the data in K7, the second half of this year. That will allow us to provide information regarding the durability and...

work on both areas, the less than 50%, we were able to go a bit faster from an administrative perspective because that we modified K7 via an amendment to be a phase three study and that less than 50%. For the greater than 50% it requires creating a protocol from scratch.

But we are moving forward with administratively on both areas and are looking forward to the updated data in K7, as I mentioned, the second half of the year. So we'll be able to have a data driven decision based on any and or all of those particular cohorts. Yeah, I think to touch on the PRMT5 question, you know, again, what we believe is operative here for the second generation molecules is the therapeutic index and in our hands pre-clinically.

We want to maximize the level of target inhibition into retissue. And really, again, with the biomarker here, we want to be almost that 98, 99 percent plus inhibition level for the full dose interval to maximize the inhibition of the target and maximize anti-tomer activity. This is one.

area where we believe the 70-fold selectivity for M-Tepti-Linotumous cells relative to other normal cells that don't harbor the M-Tepti-Linotumous cell is going to be very important to spare the mechanism-based bone marrow toxicity as well as some other you know, tolerability issues associated with the first generation inhibitors.

formulation, PK reproducibility, and generally we continue to escalate in the phase one study, inching up hopefully towards dose levels where we'll start expanding. But we are very pleased with what we see with respect to tolerability in our clinical studies so far.

The next question comes from Michael's at Morgan Stanley . Please go ahead.

Hey guys, good afternoon and thanks for taking the question. Maybe just a quick one on Crizati. You mentioned sales in December were driven by inventory stocking. Just curious as we think about one Q, should we anticipate additional inventory stocking? Thanks".

Yeah, you know, as always with the beginning of the launch, you see, you know, as you put the product out in the channel. And not all the sales in the fourth quarter and December were stocking, but a majority of them were. You know, we'll start to see demand really driving sales as we get into the first quarter. So more to come on that. So we'll get some insight into schooling, which helps you to back up get some time in the first quarter. So much to do.

Please go ahead. Hi, thank you for taking the questions. I just had a quick one on the phase 3 strategy on the first-line lung, specifically for the PD-L1 greater than 50. I was reading the recent February issue of Cancer Discovery, and specifically there's an editorial on the February 6.

entitled Frontline Promise for Adagrassib-Tembrilizumab Combination. And in that piece, it mentions that Marati's PD-L1 greater than 50 phase 3 trial design will be eta plus Tembro versus Tembro. I'm just wondering if you can confirm if that is correct, because I do not believe you've discussed the specific design as yet. Thank you. Sure. So, yeah, happy to comment on it.

So in the less than 50%, of course, the standard of care has been 189. And so that's why that study is designed with the doublet versus that triplet. In the greater than 50%, we've had preliminary discussions with the FDA that monotherapy for pembrolizumab is an appropriate control arm. And so therefore the doublet would go up against the pembrolizumab.

about the monotherapy, confirmatory phase three, the CRYSTAL-12. You've adjusted the study to allow crossover in patients once the PFS endpoint is achieved, which you expect in the first F24. Can you provide specifics on what patients are getting after they fail Dositaxel and the control arm and talk more about what ultimately gives you confidence you can succeed on overall survival? Yes, I think…

An important point for K-12 is the fact of having both PFS and OS as primary endpoints. And I think the most important aspect of that is that the PFS is a primary endpoint that has been accepted by the FDA as a means for approval. And I think that's important for a couple of ways because of the fact that PFS is not going to...

Thank you so much for taking the question. I want to touch a little bit on your commentary around potential collaborators or kind of some business development as you were highlighting. Are there any gating factors in your discussion or kind of that you need to achieve before a collaborator would come in or do you want a collaborator to come in and maybe provide us some colors to how you're thinking about potentially structuring these partnerships. You outline something. I guess.

I'm trying to get a sense as to how you're going to continue the business moving forward with the launch and with a lot of trials ongoing. Thank you so much. Sure Evan. What we would be looking for, we've started these early conversations, is an XUS partner for Addigrasson. So we have a US presence and we do not have an XUS presence at this point. So, we're going to continue the business moving forward with the launch and with a lot of trials ongoing.

conversations about who the right commercial and potentially development partner would be so we can maximize that and grasp sales globally.

So we're in those conversations now. The next question comes from Ami Fadia at Needham. Please go ahead. Hi, thanks for taking my question. I had a follow up question on the first line.

in the TPS greater than 50% of a stem versus temporal You've indicated that you've had a preliminary discussion with the FDA Is there anything additional that needs to be confirmed with the FDA or are you good to go with? You know going ahead with the trial and then at that, you know one

side of some additional inventory stock.

in the first quarter in terms of perhaps any kind of broader dynamics in terms of coverage and pricing. Thank you. I think I can take those. So regarding the TPS squared and 50% in the frontline setting, the comparator would be Pembro because, you know, monotherapy...

Conversations with the agency. So let's wait for the data mature and before we make the we pull the chargger on moving fourward to Phase three program greater than 50. but the meantime we're doing the ground work to development now to prepare for success. Regarding the launch of cazantti, we'll share this information in the very specics of how the launch is going in Q1, at the Q2 earnings calls, and we'll walk to those metrics of.

of sales and share and access and so on. We were just approved in mid-December, so it's very early weeks at this point, but we're excited to share the information in May.

The next question comes from CalPete Patel at BU Rylee Securities. Please go ahead. Good afternoon. This is Andy on for CalPete Patel. Thank you for taking questions. Regarding your exploratory combination of chemo plus edigrassab plus pumbro in front line, NSCO Steve MacSte Klein printing out your Cryo & Vimeo® EPZ Deep Three Jefferson Treble DO or

Can you give us some color on what doses of antigracid you are starting with to try and limit toxicity from this triplet and then when should we expect the initial data from this exploratory combination? You know thanks so this is going to be it's a study that's you know just getting started we're going to be looking at the adding as you mentioned they they have aggressive to 189

We'll do it in a sequential fashion adding to the maintenance portion first and then if it tolerated bringing it up forward to the concurrent. We anticipate being able to utilize the 400 milligrams dose starting. That's the combination with antigressivant and pembrolysmab. So we'll add that to the chemotherapy at that point and we'll be doing it, of course, next.

the usual phase 1 fashion. The next question comes from Jay S. Olson with Oppenheimer. Please go ahead. Oh, hey, thank you for the update and thanks for taking the questions. For 1133, can you talk about any lessons learned or read across from Revolution Medicine's preliminary data last night, which included some G12D patients?

And then for Sikra Vatnid, can you just talk about your expectations for the Sapphire readout in the second quarter? And since you're focused on a lot of criss-a-dee, are you doing any pretty large planning for Sikra Vatnid, given the similar indications for Sikra and criss-a-dee? Thank you.

Yeah, I think, you know, regarding RevMed, we are paying attention to what they're doing, but we'll probably not comment on RevMed at this point in time. Other than to say, you know, we continue to be excited about advancing 1133 into patients here imminently, and we also continue to explore in the preclinical setting different types of KRAS inhibitors, including those that inhibit different spectrums of mutations, including the G12V mutation, G13D, and Q61 mutations.

So we will be continuing to pursue this and when appropriate, can update on that fund. And on the sit-through question as a reminder, we'll see the final analysis for the SAPPY Study in Q2 of this year as events are tracking as expected. In regards to any of the pre-launch work, I think the learnings will take from launching at a grass-hip will be key here. We have a very experienced lung cancer team.

And we believe that we'll be able to leverage the existing team and the existing infrastructure to be able to launch Citrivax in a high degree of expertise as well as at a high rate. So no need for a lot of market building in that front. We think the mechanism is pretty well recognized and we have the team in place to, hopefully on the back of a positive study, move to file and then ultimately promote the product very quickly.

There are no further questions at this time. Mr. Meek, I will turn the conference back to you for any additional or closing remarks. Thank you, Cynthia. And thank you, everyone, for joining us this afternoon. We appreciate your interest in Maraudi, and we look forward to sharing additional updates

There are no further questions at this time. Mr. Mek, I will turn the conference back to you for any additional or closing remarks. Thank you, Cynthia. And thank you, everyone, for joining us this afternoon. We appreciate your interest in Maraudi, and we look forward to sharing additional updates