Mirati Therapeutics, Inc.

Good afternoon and welcome to the Merati Therapeutic first quarter 2022 earnings call. My name is Kevin 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. If you would like to withdraw your question, press star followed by the number two. It is my pleasure to introduce Ryan AC, Vice President of Corporate Affairs at Merati. Ryan, you may begin the call.

Thank you, Kevin. Welcome everyone to this afternoon's call. Joining me on the call today from a couple of different locations are David Meek, Merati's Chief Executive Officer, Dr. Chuck Baum, Merati's President, Founder, and Head of Research and Development, Dr. Jamie Christensen, Merati's Chief Scientific Officer, and Vicki Reed, Merati's Chief Accounting Officer. Ben Hickey, Merati's Chief Commercial Officer, is also with us and will be available for the Q&A portion of the call. Please note that this conference call will include forward-looking statements. 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 31, 2022, and recent corporate updates. This press release is available on the investor section of our website at Mirati.com. With that, David, I'll turn the call over to you. Thank you, Ryan.

Good afternoon, and thank you for joining us today. On this afternoon's call, I will provide initial remarks before turning to Chuck to share an update on our clinical development programs, to Jamie to comment on our preclinical portfolio, and Vicki to summarize our first quarter financial results. I will then provide a few concluding remarks before taking your questions. 2022 is a critical and transformational year for Mirati, and in the first quarter, we made significant progress on the ambitious goals we established for ourselves. We continue to execute well across our portfolio, and there continues to be significant enthusiasm across all areas of the company for the work we are doing. The progress we are making and the life-changing impact we are having on patients living with cancer. We are pleased that our first new drug application is under review with the FDA. The FDA is reviewing our NDA for Adagracib as a treatment for patients with previously treated non-small cell lung cancer who harbor a KRAS G12C mutation for accelerated approval under the FDA's real-time oncology review pilot program. We remain confident in the approvability of the NDA and will be fully launch ready in the third quarter. Securing a U.S. approval and executing a commercial launch of Adagracid in the second line non-small cell lung cancer setting is a key priority for the company. But it is also just the beginning of the full potential of where we believe this investigational product can help patients. With Adagracid, we're advancing a broad development plan beyond previously treated non-small cell lung cancer is both a single agent and in combination with other therapies including in earlier lines of therapy and across a number of solid tumors. This includes the work we are doing in first-line non-small cell lung cancer in combination with pembrolizumab and in a broad range of other tumors, such as colorectal and pancreatic cancers, where we have previously presented compelling early results. In addition to adagracin, we continue to advance and expand our broad target oncology pipeline. For citravacinib, We recently completed enrollment in the phase three SAFIRE registration trial and expect to reach the number of events needed to trigger an interim analysis for overall survival in the fourth quarter of 2022. If positive, citrinacin would be a highly synergistic commercial opportunity without aggressive. As a reminder, in the US and Europe, there are over 100,000 patients with second or third line non-small cell lung cancer who derived prior clinical benefit following treatment with a checkpoint inhibitor and approximately 70,000 of these patients are of the non-squamous histology. MRTX1719, our MTA cooperative PRMT5 program is enrolling patients in an ongoing phase one, two clinical trial with proof of concept clinical data expected next year. Our earlier stage target oncology pipeline, including MRTX1133, our KRESG12 inhibitor, and MRTX0902, our SOS1 inhibitor, continue to advance toward investigational new drug applications in the second half of 2022. We have a tremendously productive in-house discovery capability that continues to discover and advance novel mechanisms and put us in a position to have as many as five unique yet synergistic programs in terms of the clinical execution and future commercial call points in clinical development in the next 12 months. We continue to be in a strong financial position to execute on our strategy, which provides us with the flexibility to invest for success across our target oncology pipeline and in preparation for a successful and aggressive launch pending potential FDA approval later this year. As we grow and advance our pipeline, We are continuing to strengthen our capabilities to better enable us to achieve our objectives. With that, I'll turn the call over to Chuck.

Thank you, David. I'll begin with an aggressive update. We continue to work with the FDA as they review our new drug application based on our real-time oncology review and breakthrough therapy designation. We continue to work closely with the FDA to complete the review as quickly as possible. We are pleased with how the review is progressing and remain confident in an accelerated approval in the United States this year. Outside the United States, we are making progress and expect to complete the submission and validation of our marketing authorization application to the European Medicines Agency in the second quarter of 2022. In 2022, we will report a number of significant clinical updates for the Adagrassib program, beginning with ASCO. We are pleased to have two abstracts accepted by ASCO for oral presentation. The first presentation is for the results of the Registration Enabling Phase 2 cohort of the CRYSTAL-1 study evaluating adagracib in patients with previously treated non-small cell lung cancer whose tumors harbor the KRAS G12Z mutation. In addition, the presentation will include data across several important patient subgroups based on PD-L1 status, genomically defined patient populations, including co-occurring mutations like STK11, as well as patients with previously treated stable central nervous system or CNS metastases. The second presentation will highlight the activity of adagracib in patients with G12C mutated non-small cell lung cancer tumors with untreated CNS metastases. This presentation will be the first clinical data with a KRAS inhibitor showing activity in patients with active and untreated CNS metastases. CNS activity is an important attribute because up to approximately 40% of KRAS G12C patients with non-small cell lung cancer present with CNS metastases, and the frequency of these mutations increases over time with the current standard of care. Together, These presentations reinforce Adagrasib's unique molecular profile and underscore our commitment to advancing Adagrasib's full development program as a single agent and in combination, where we are pursuing a broad development approach, including combinations with Pembrolizumab, Cetuximab, SHP2, SOS1, TDK4-6, and a MECHGRAPH dual pathway inhibitor. We are actively enrolling patients worldwide in aggressive clinical studies that are generating additional data in patients with a wide range of cancers. Our phase three confirmatory study in previously treated non-small cell lung cancer patients with a KRAS G12C mutation, known as CRYSTAL-12, in which patients are randomized to adagracib or docetaxel, continues to enroll well worldwide. In first-line non-small-cell lung cancer, we continue to explore adagracib monotherapy in certain underserved subpopulations, including patients harboring KRAS-G12C and STK11 commutations, as well as KRAS G12C mutated patients with TPS scores of less than 1%. We expect to provide additional clarity on a potential regulatory pathway for accelerated approval in these subpopulations this year, as well as sharing initial data from these cohorts in 2023. Also in first line non-small cell lung cancer patients, We are aggressively exploring adagracib in combination trials with a focus on the combination with pembrolizumab. This adagracib plus pembrolizumab combination, which is using 400 milligram BID dose of adagracib with full-dose pembrolizumab in the Phase 2 CRYSTAL-7 study is enrolling well with strong interest from both patients and physicians. We plan to share an update from this combination study this year, which will include an analysis of patients stratified by TPS score. Based on the results from CRYSTAL-7, we plan to initiate a Phase III trial evaluating the combination of Atagrasib and Pembrolizumab in first-line non-small-cell lung cancer patients later this year. Beyond lung cancer, we are advancing enrollment in in patients with colorectal cancer both in late line and in the second line settings. The ongoing phase three registration enabling study in combination with cetuximab in second line colorectal cancer continues to enroll well and potentially provides us with an opportunity to be the first to market in this patient population. We continue to enroll patients with G12C mutations in other solid tumors including pancreatic, biliary cancer, gastrointestinal, and others, and we'll continue to explore potential accelerated regulatory approval pathways in these patient subpopulations. We expect to provide additional clarity on a potential pathway for accelerated approval of Atagracib and late-line CRC, as well as sharing next steps in other solid tumors later this year. Now to move on to citravatinib. As David mentioned, we recently completed enrollment in the Phase III SAFIRE trial, which is being conducted in patients with second- or third-line non-small-cell lung cancer who have derived prior clinical benefit following treatment with a checkpoint inhibitor. We are on track to reach the number of events needed to trigger an interim analysis for overall survival in the fourth quarter of 2022. If positive, the interim analysis could be the basis for full approval in the U.S. and Europe, with regulatory filings in both markets being submitted by the middle of next year. For MRTX 1719, our MTA Cooperative PRMT-5 program, We are enrolling a phase one dose escalation and dose expansion study in patients whose tumors harbor MTAP deletion, which make up to 10% of solid tumor patients. We will explore MRTX1719 as a single agent and through rational combination strategies identified in non-clinical translational studies across several tumor types, including mesothelioma, pancreatic, lung, malignant peripheral nerve sheath tumor, and a basket cohort of other MTAP-deleted tumor types. We expect to share the initial clinical data for this program in 2023 after we have selected a dose and generated sufficient data to demonstrate clinical proof of concept. With that, let me hand it off to Jamie to discuss our preclinical programs.

Thanks, Chuck. I'll briefly touch on our pipeline of preclinical programs, including our SOS1 inhibitor, MRTX0902, our selective KRAS C12D inhibitor, MRTX1133, and our next-generation spectrum selective platform to target additional KRAS mutations. We recently presented preclinical data for 0902 and 1133 at the American Association for Cancer Research Annual Meeting, also known as AACR. O902 is a selective SOS1 inhibitor which shifts KRAS into its inactivated state and enhances inactivation of KRAS by adagracin. This combination is anticipated to address feedback reactivation of KRAS and to address intrinsic and acquired resistance to KRAS inhibitors. At AACR, we disclosed the chemical structure and profile of O902 along with its broad antitumor activity in KRAS G12C preclinical models in combination with adegrazib. O902 is also anticipated to complement additional agents in the variety pipeline and exert an impact on KRAS mutated cancers irrespective of the KRAS mutation type. O902 also has the potential to target additional mutations within the MAP kinase pathway. These include the opportunity to combine with other MAP kinase pathway inhibitors. This agent is currently in IND-enabling studies, and we are on track to complete the IND filing in 2022. 1133 is a potent and selective non-covalent KRAS-G12D inhibitor that binds the switch-to pocket with high affinity in either the active or inactive state of KRAS-G12D. At AACR, we shared additional preclinical data reinforcing the broad antitumor activity of 1133 including marked regression in the majority of pancreatic cancer models. This presentation also provided insight towards combinatorial strategies to augment the activity of 1133. We continue to pursue IND tract development of 1133 with focus on long-acting injectable formulation strategies, including stealth liposomal strategies, and continue to focus on filing the IND in 2022. Additionally, we continue to pursue targeting of additional mutant variants of KRAS through our spectrum-selective KRAS inhibitor program. This is a potential platform approach which could yield multiple development candidates targeting various KRAS mutations with differing mutation selectivity profiles and ratios of potency for targeting KRAS wild type versus these selected mutations. We have a goal of identifying potential development candidates for this program in 2022. With that, I will turn it over to Vicki.

Thank you, Jamie. We ended the first quarter with approximately $1.3 billion in cash, cash equivalents, and short-term investments. Research and development expenses for the first quarter of 2022 were $131 million compared to $104.1 million for the same period in 2021. The increase in research and development expenses is primarily due to costs associated with the ongoing advancement of our adagrassive and citrobatinib clinical programs, preclinical and early discovery activities, employee-related expenses, including an increase in salaries and share-based compensation, as well as professional services, facilities, and IT expense. General and administrative expenses for the first quarter of 2022 were $54 million compared to $28.4 million for the same period in 21. The increases due to growth in employee-related expenses, including salaries and share-based compensation, and costs related to the growth of our business as we continue to prepare for commercialization. Net loss for the first quarter of 2022 was $188.4 million or $3.40 per share, basic and diluted, compared to a net loss of 135.7 million, or $2.67 per share, basic and diluted, for the same period in 2021. Please see our press release from earlier this afternoon for additional details about our first quarter 22 financial results. David, I'll hand it back over to you.

Thank you, Vicki. As you can hear from the team, there is a lot happening at Verani. We're excited about the progress we've made and about both the short and long-term potential of the opportunity that lies before us. We have the products, capabilities, people, and capital we need to not only execute the short-term, but also to drive long-term sustainable growth. Our targeted oncology pipeline is broad, spanning multiple targets and tumors, and gives us a strong platform to support tremendous value creation and significant operational and commercial synergies across the portfolio. As Vicki indicated, we have the financial resources to enable us to continue to appropriately and prudently invest in the advancement and expansion of our clinical and preclinical portfolio, and also in preparing to become a commercial stage company. We have continued to advance our commercial preparations and execute on our commercial strategy as we prepare for a successful adagressive launch. subject to FDA approval. Our objective to launch and further develop a market-leading KRAS G12C inhibitor, optimizing the full and tremendous potential of this important product remains the critical priority while we also invest to drive sustainable growth with the other exciting and innovative target oncology assets in our portfolio. I continue to be grateful and impressed By the talented, committed, and passionate team we have at Mirati, we're asking a lot of every member of our team. They continue to not only meet but exceed expectations as we strive to improve the lives of patients. With that, we're ready to take questions.

I would like to remind everyone that if you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star followed by the number two. To ensure all participants have the opportunity to ask a question, we ask you please limit yourself to one question and one follow-up. Please hold for a moment while we poll for questions. And the first question comes from Salveen Richter of Goldman Sachs.

Hi, thanks for taking our question. This is Tommy on for Salveen. And our question is about how Amgen has talked about how many KRAS patients are being diagnosed, but that the KRAS status isn't necessarily showing up in the patient files as they progress to later in line. So what steps or actions can you take to facilitate patient identification and ensure that patients are being treated with a KRAS inhibitor? Thanks so much.

Great question, Tony. Thanks, Bob. We've got Ben here, our Chief Commercial Officer, so he's been looking at this closely with his team, so I'll turn it over to Ben. Yeah, thanks for the question.

I would say, first of all, that it is a real issue in regards to the patient identification, and a number of these lung cancer patients are being treated in the community. So we've spent a lot of time, first of all, ensuring that our study actually included lung cancer patients from the community is one. And then secondarily ensuring that as we get commercially ready, we're spending a lot of time, particularly with community networks, and understand their patient flow, how they're recording patients within the EMR, how they're flagging that patient as a G12C patient. And we really believe that the market will mature over time. And over time, as they become tested in front line, more of those patients will become available in second line. But I would say the market is still immature. and he's taking some time to fully present himself.

Our next question comes from Tyler Van Buren of Cohen.

Hey, guys. Good afternoon. Congrats on the progress, and thanks for taking the questions. I wanted to ask about the Phase II presentation on Friday at ASCO. Should the bar for median duration of response be the prior sartorius world lung data set or the more recent AACR data set? And do you think Adagrassive could improve upon it? Or how should we think about the potential to treat CNS mets and its ability to impact DOR and PFS when comparing to Sutorcin?

Yeah, Tyler, hi. First of all, regarding the data that's going to be released at ASCO, I think it's best that we reserve that conversation until we see the data. We're certainly excited to share all the data that's going to be presented at ASCO. So I think we can have that conversation at ASCO.

Okay, understood.

The next question comes from Ben Burnett of Stifel.

Good afternoon. This is Neil Carnahan on for Ben. On the pembrolizumab combo, are you now able to characterize the safety profile for the 600 milligram VIB dose? And then could you also say if you evaluated any doses Any add aggressive doses below the 400 milligram BID that you're pulling forward? Thank you.

Sure. Yeah, we'll have Chuck answer that question for the team.

Okay. So, yeah, we're going to have, in the second half of the year, we were planning to present the data fully for those patients with an emphasis on the 400 milligrams because that's our, as we've indicated, that's our go-forward dose. But the doses that we've looked at were, the study started with 600 milligrams BID in full dose pembrolizumab. And then we, as we had talked about previously, that the tolerability there was not as good. So we switched to the 400 milligram BID. And that's the patient population we're enrolling now. So we'll have a substantial number of patients treated at 400 milligram BID in full dose Pembroke. in the second half of this year, and that'll put us in a position to make the go-no-go decision on the phase three, which we intend to make by the end of the year. So, so far, things are looking good at the 400 milligrams. So, we talked about seven of those patients last year, and we continue to follow those as well as all the new patients. And we're pleased with the results thus far. But as I said, in the second half, we'll present the data in a more fulsome way.

Our next question comes from Gina Wang from Barclays.

Thank you. I just follow up regarding also the PEMBRO combo first-line data, safety data. So, Chuck, you know, based on the data you've seen so far, Do you think that, you know, 400 milligram BID plus PEMBRO dosing is the path forward? Or do you think, you know, the liver tox, do you agree that liver tox is a drug class effect? Or you think it's a specific, unique to specific compound? And then another question is regarding the ASCO update.

for crystal one full data do you expect to show definitive differentiation versus the luma crust i.e you know one to two months better pfs or dor so for the first question uh we are going forward with the 400 milligram bid dose we're happy with that dose at this time we're accruing a lot of patients and we'll have patients at all the entire TPS range, which will give us a good sense of what the next step should be and what the design of the phase three trial should be. So all of that continues as planned and is growing quite well. So we're encouraged by that. In terms of liver toxicity, you know, I think that that can be sort of compound specific, not necessarily class specific. But part of the challenge is that we really haven't seen the full data from competitors. So we've heard about it, but we haven't really seen it. So I'm hoping that as we present more data and they present more data this year, that we'll have more clarity around what the nature of those results is. But I would say at this point, we're not, for our programs, that is not a high level of concern in terms of liver tox.

Yeah, I might just add a few comments to Chuck's here. I think, first of all, from the new chemical entity perspective that adagracive and psoriasis are distinct small molecules with different physiochemical properties, different tissue penetration, different peak to trough ratios at steady state with regard to the PK properties. So, Although they share the mechanism of being able to irreversibly modify KRAS-G12C, they are distinct small molecules. I think it's also fair to note that in the field today, you know, looking at TKIs, for example, the split kinase or VEGFR TKIs, when you kind of look at their ability to combine with immune checkpoint inhibitors, for whatever reason, you know, these molecules have the same set of shared targets. But pembrolizumab and sinitinib, for example, were deemed to be non-combinable, as was crizotinib with immune checkpoint inhibitors. And in contrast, our own citrovatinib, other drugs like cabizatinib, were quite combinable and effective in combination. So there's, I think, a couple examples historically of different drugs within a target class that differentiate with regard to their tolerability. I think the last point to make is just what we've seen so far with regard to liver function and anything that might be deemed as hepatotoxicity. So as a monotherapy, we have seen, you know, grade one and grade two liver function test elevations. We've seen a small fraction of those being grade three. We have not seen patients discontinue due to liver function tests, abnormalities, or hepatotoxicity. We've seen no high-law cases with respect to hepatotoxicity to monotherapy. In combination, as Chuck mentioned, we're fairly happy with what we've seen so far at the 400 mg BID dose level. But I think one thing to add to that is that we do not see a signal with respect to one underlying toxicity, including hepatotoxicity, to be dose-limiting with respect to dose intensity or patient discontinuation. So I think all of our signals to date look fairly positive with respect to the pembrolizumab combination. Okay. And I think there was another question.

Jonathan Miller from Evercore.

Hey, guys. Thanks so much for taking the question. I guess following up on that PD-1 combo question, obviously everybody's looking forward to data later this year, but I also want to ask how rapidly you could move to larger Phase 3s. It does seem like you're getting a little bit more comfortable with the strategy here and the safety profile and combination here. So what are the gating factors at this point on pivotal trial starts, and when should we expect that to happen?

I'll jump on that. Yeah, Chuck, I was going to say, maybe start and jump over to you. Yeah, folks, we're at a couple different locations as a team. You know, I think we're getting, we're advancing the program. We haven't discussed what those gating points are. I think as the year evolves, as we share the data, we'll certainly discuss what some of those gating options are. But as we did say, we're preparing for a phase three start later this year.

And we can go to Evan Segerman of BMO Capital Markets.

Hi, guys. Thank you so much for taking the question. Looking ahead to the ASCA data, can you just talk about, I know you discussed the brain penetrability of the drug, but what are your thoughts on whether or not the drug actually can stick around in the brain? I've heard some reports where we're seeing or I've heard theoretically that the drug may be expelled and not actually kind of getting the target engagement you want. Any thoughts on that would be super helpful. And any color on the enrollment of the phase three confirmatory?

Sure. Yeah, I would say with regard to the CNS penetrance of adagracib, we've looked at this both preclinically and clinically. And I would say that adagracib actually has a unique mechanism to enter the CNS relative to other drugs. Point number one is it has favorable physicochemical properties with regard to tissue distribution. you know, appropriate log D lipophilicity and polar surface area to get into tissue. And that is, I think, the first principle of any drug that would have brain penetrance. The second is, and you brought it up, related to efflux. So it's true that adagrassive is a PGP, peak glycoprotein, or efflux substrate. But what's unique is that at concentrations that we achieve clinically, We also are a PGP inhibitor, and thus the drug actually inhibits its own efflux out of the CNS. And when we've looked preclinically at dose levels that are associated with achieving the clinical dose levels, you know, let's say translation of mouse to human, we see a KPU or a partition coefficient in CNS tissue relative to the free fraction plasma that is between 0.4 and 1.0. meaning we get in extensively into the CNS at the dose levels we achieve clinically. When we've measured that in patients at the 600 BID dose level, we see a KPU of 0.47, again, meaning we're getting extensive tissue distribution. Smirknib is an example of a drug that has CNS activity. Its measured KPU is generally lower than antagrassib, around 0.3 to 0.4, depending on which study is cited. electinib and lorlatinib are additional examples of ELK inhibitors with CNS penetrants. And we'll just say that their systemic response rates and their intracranial response rates are comparable. Our evidence of seeing uptake into the CSF are consistent with what we've seen there. So I think that's point one. Point two, you mentioned the ebb and flow and efflux out of the CNS. Just to remind you here that our drug has about a 24-hour half-life. We're administering BID. The effective half-life at steady state is around 60 hours, and the peak to trough variation of adagrassive at steady state is only around 10% to 20%. And we never drop below concentrations that are associated with being able to inhibit the target. We believe that that's relevant both for peripheral disease as well as... as well as the metastases. So, so far, so good there. And, of course, we'll be talking about the actual intracranial response here upcoming at ASCO. The second question, I believe, was the pivotal study, and I think David is going to take.

I'll answer that quickly. Regarding our phase three confirmatory, this is the CRYSTAL-12 study. We're pleased with the enrollment. As you know, we're enrolling in the U.S. and Europe. Also, Zai, our partner in China, will also help drive enrollment. So we're pleased with the rate of enrollment we're seeing. at this time, and this study should be fully enrolled in the first half of 2023.

The next question comes from Michael Schmidt of Guggenheim.

Hey, good afternoon. This is Paul for Michael. Thanks for taking our questions. Just another quick one on the upcoming data at ASCO and patients with brain mets. Sort of based on your conversations with physicians, is there a CNS response rate that you expect physicians to find clinically meaningful? And then secondly, just any color on how many patients we could see in the adagraphs plus PEMBRO combo data this year. Thank you.

So let's talk first about CNS, what the physicians expect. You know, we think it's in that 20% to 25% range to see activity would be well accepted. That's the research and the conversations we've had with physicians in the community as well as academic centers.

Yeah, I would say, you know, we'll continue to build on the program. You know, I think that that is what we anticipate with respect to monotherapy. We know, you know, a lot of our combination strategy evolves around combining antagrassive with additional targeted or immunotherapies. You know, the ability to enhance response rate and combination should apply to our drug being able to get into the CNS as well. So, we'd expect our ability to augment the intracranial response rate as we advance in the program.

The next question comes from Mike Oates of Morgan Stanley.

Hey, guys. Thanks for taking the question. Maybe just another one on some of the ASCO updates we'll get in a month or so here. You mentioned some subgroup analysis from the K1 study, and in particular, based on PD1 status. Can you maybe clarify that? And is it specifically in TPS less than 1 patients?

Sure. We will be presenting data at ASCO on cohort A that goes into molecular subtypes. So that includes both PD-L1 status and would say that, you know, this data set that we will present will have a significant number of patients to be able to draw conclusions about whether different TPS strata categorically or continuously are related to the response to adagracib. Secondly, we'll be looking by mutation subtype. That includes things we've talked about before, like STK11, but also common mutations like TP53 and CDKN2A. So we will be able to provide perspective on all those. I think as you also know, we are pursuing strategies in the first line, non-small cell lung cancer related to molecular subtype. TPS less than one, for example, and STK11, for example. Just to remind you all that You know, those are two particular subtypes. When they're seen with KRAS mutation, they're particularly non-responsive to chemoimmunotherapy, thus creating an opportunity for potential accelerated path development in that setting. And would just say in general that we continue to be pleased by what we see in those particular subpopulations and are continuing the enrollment of those first-line studies. But bottom line is, you know, we will be presenting that data as part of the ASCO presentation.

Gotcha. That's helpful. Maybe just a follow-up there. What's the bar for adagressive monotherapy based on TPS stratification, less than one and greater than one?

I would just say, knowing what's out there, we do not anticipate that a TPS score would have a major impact on the response to KRAS inhibitors. But we do know, based on subset analysis of Keynote 189, work out of major medical institutions or otherwise, that those same patients have a poor response to chemoimmunotherapy. Notable here with PD-L1 Lesson 1, if you look at the Keynote 189 subset analysis, the response rate was around 30% for that particular subset. If you look at the STK11, you know, again, either in Keynote 189 or at major medical institutions, the response rate is 25%. Note here that these are treatment-naive patients, so they have never seen chemoimmunotherapy, and this is their response to chemoimmunotherapy. So in a way, that creates a bar for us to shoot for, and if our data continues to hold up for KRAS inhibitor or Adagras, even as a monotherapy, reason to believe that we should be able to exceed the response rates seen in those unmet medical need populations.

And we can go to Yigal Nakanamitz of Citi.

Hi, this is Carly on Free-A-Gall. Thank you for taking our questions. Just to follow up on some of the prior questions on the combo with Hembro, can you share any preliminary thoughts on how you're thinking of designing a potential phase three I know it'll depend on the data from Crystal 7 later this year, but any early thoughts on the different options on the table would be helpful. And then we did notice on clinicaltrials.gov that the adagrassive combo study with Boehringer-Ingelheim's SOS1 inhibitor stopped recruiting. So if you could give any more color on the reason for that, that would be helpful as well.

Thank you. Yeah, sure. I'll start. I'll turn it over to Chuck regarding the combination study, CRYSTAL-7, and then what could evolve into a, will evolve into a Phase III trial. Just a reminder, we'll share more data the second half of this year, but we'll give you maybe some really high level at this point, you know, where we're thinking of for a registration trial, but it's preliminary. Chuck?

Yeah. Yeah, it's still early, obviously, but I think we might have had a conversation previously where we're thinking that the optimal opportunity for us initially would be in those patients with a TPS score of less than 50% versus the 189 regimen. So that's the thoughts right now. It's not solidified yet, but we're working on that We're not ignoring the greater than 50% population. We continue to study that, and we'll have more data there. But that would be a larger and longer trial. So in terms of sort of first priority, doing the trial that's more doable and could get us to a first-line approval faster, we think would be in the less than 50% PPS score. And then you mentioned the BI study. Yeah, we did discontinue. As you probably also noted, we have a SOS1 of our own that's going to enter the clinic in the second half of this year. And we think that it has potentially favorable properties. And so that's where we're going to focus our efforts going forward.

I think just one thing to add to Chuck's comment as well is, you know, the basis for stopping that study was not related to any antagrass-related toxicities or adverse events. And as Chuck mentioned, we remain quite enthusiastic about our own program, which we hope to start enrolling patients by the end of this year after we file the ID.

The next question comes from Andrew Behrens of SVD Securities.

Thanks for taking my question. I assume you had some additional dialogue with the FDA And since there's still some concern about the reason you didn't get a priority review despite having breakthrough designation, I was wondering if you could give us some more color on what you think happened. I know you may be reluctant, but I do think it would help investors feel more comfortable with the outcome of the review process since it does seem to be a lingering concern that I continue to get questions about.

So, you know, as Chuck and I both mentioned in our opening comments, we remained very confident in the approvability. of the new drug application for Atagrassive. You know, we're working with the FDA, leveraging our breakthrough therapy designation in the real-time oncology review pilot program we have. There's good, active dialogue, productive, and we think it's progressing well. And while we do have a standard review, there's many examples where drugs have been approved before the PDUPA date, and we're going to be fully launch-ready in Q3. So that's where we are with the MDA review. It's progressing and we remain optimistic.

The next question comes from Jay Olson of Oppenheimer.

Hey, thanks for taking the question. I appreciate it. Can you talk about what is required for tumor agnostic path forward for adagracib and non-long and non-colorectal tumor types? And then maybe just a big picture question. What are some of the lessons learned from adagracib you can apply to the development of 1133. And do you plan to have the first FDA-approved KRAS G12D inhibitor? Thank you.

Sure.

We'll start with Jamie on that. Sure.

Yeah. Regarding the agnostic path, you know, I think you are familiar with what we've shown in pancreatic cancers and then also other GI cell tumors. And we've seen, you know, what I would call as response rates that look compelling with early signs of the type of durability that would be associated with a tumor agnostic approval. We know the regulatory precedent here with immune checkpoint inhibitors looking at patients with MSI high. We also know of this with respect to NTRK inhibitors as well as BRAP inhibitors. So do believe that there's a path there, both based on the activity that we've seen with the drug so far, as well as having a regulatory precedent due to the infrequency of the KRAS T12C mutation in tumors other than lung and colon, we wouldn't anticipate that it would take a large number of patients to get a tumor agnostic approval. But we do anticipate that it would be valuable for us to have as many different tumor types enrolled on the trial so that we can show the diversity of tumors that would respond to the drug. So I think we remain optimistic that that's going to be a path for us. Regarding the G12D read-through from G12C. So, you know, we have been evaluating our G12D inhibitor and models of colon and pancreatic cancer. And the read-through from antagrassive is, you know, that we have been able to see activity, particularly in combination with cetuximab, in patients with third-line plus, you know, heavily pretreated colon cancer. And the response rates and durability hold up with response rates over 40%. And then, you know, we will be talking about the duration of response and activity in the colon cancer setting later this year. But just suffice to say that we are, you know, encouraged by what we see there so far. On the pancreatic side, you know, the response rate of around 50% with the durability that we've seen so far, you know, seems supportive of monotherapy and KRAS being a driver in the pancreatic cancer setting. What we've seen preclinically with the 1133 compound is very consistent with that. With a monotherapy, 1, 1, 3, 3, we see about a 20% response rate in the colon cancer models. When we combine with cetuximab, that response rate starts to go up in the models to around 40% to 50%, just like what we're seeing clinically with G12C. And then regarding pancreatic cancer models, we've seen 8 out of 11 responses. So, you know, response rates over 50%, probably consistent with what we've seen with adagrassive monotherapy. We also know that combining with EGFR inhibitors or monoclonal antibodies in the pancreatic setting seems to be a promising approach based on our preclinical data. So we do believe that if we are able to advance 1133 into the clinic at a dose level that really covers the target, that we would be confident that KRAS is a driver and that we can come up with therapeutic strategies to advance the molecule forward. I am blanking on your last question. I think you pretty much hit it.

I would add, just to elaborate a little bit more, the lessons learned from Adagrassif into 1133, what's very comforting for us is the team that transitioned the program from discovery through development. That team is here in Maradi, and certainly there's lessons learned from the Adagrassif program that we can apply. to the G12D program, so we think that will help. Some of the synergies we talked about earlier, there are significant synergies we have in the development organization as well as the portfolio expands with the tumor types and academic centers, study sites, and so on. So we're excited about that.

Yeah, I guess just to hit on your last question, competitive state. So, you know, probably can't answer that question directly, whether we would be the first G12D inhibitor approved, we would certainly hope and aspire to that. But just to say, you know, we've been following the patent literature and publications, and, you know, we haven't really seen much out there that would indicate that the entry of another G12D inhibitor into the clinic is imminent. And, of course, we'll continue to keep a pulse on that as we advance our program.

The next question comes from Sylvain Torkin of JMP Securities.

Thank you very much for taking my question, and congrats on the progress in the quarter. In my opinion, the theme at AUCR were obviously much earlier stage KRAS-on inhibitors and also the potential emergence of pan-KRAS inhibitors. Could you just tell us about how they would compare or contrast to direct KRAS inhibitors such as yours that are already in the clinic?

Thank you. Sure. I think first to note that we remain interested in that space as well. We have our own spectrum-selective KRAS inhibitor program. We've learned in that program, as well as our G12D program, that there are legitimate ways to target the active state. We continue to look at that with respect to our programs. With regard to the read-through for G12C. You know, G12C is among the most rapidly cycling mutations for KRAS, meaning that it shifts significantly between its GTP and GDP bound state. And as you know, adagracib does bind in the inactive conformation of KRAS G12C. One advantage we think adagracib has with that respect is that although it binds irreversibly in the inactive state, we remain above target plasma concentrations for the full dose interval. So even though active state inhibitors may be able to bind effectively to the active state, due to the kinetics by which that G12C cycles, we still believe that we are, at least with G12C, able to achieve the level of inhibition regardless of whether the active state or inactive state is present. Also to note that with regard to inhibitors, you know, the, you know, targeting the active state. There are other mutations, you know, like G12R or, you know, some of the Q61 mutations that actually predominate then in the active state. And to go after those mutations, it's, you know, probably is desirable to target the active state. And, you know, we do believe that that is something we're able to accomplish with our pipeline. And finally, you know, I think you kind of asked about competition there. So for the pan-KRAS setting, Really, all we're aware of right now is kind of the Boehringer-Ingelheim and Revolution Medicines Program. And we know that Boehringer-Ingelheim has talked a lot about ProTac-based strategies and that RevMed has talked a lot about strategies to kind of engage the cyclophilin machinery We know what we're looking at is distinct from that. So bottom line is, you know, we think we can target the active state with a differentiated mechanism of action.

The next question is from Marie Raycroft of Jefferies.

Hi, thanks for taking my question. I was wondering for the dose attacks alarm in your at aggressive phase three, What kind of PFS are you expecting in these patients? And is there anything to suggest that KRAS G12C patients could do better or worse than the general patient population on docetaxel? And then lastly, can you remind what proportion of patients in the confirmatory are coming from China?

Sure, I could take that. So we've done a meta-analysis or a meta-like analysis of all the published data for docetaxel-controlled studies where KRAS was looked at as a subset. And generally, you know, our conclusions from those studies is that the PFS falls around 2.8 months if you look at the conglomerate. So, you know, a little bit worse than what you would expect from the overall population. When we look at overall survival, you know, generally the numbers are landing at around 8% based, again, on historical data. So, again, you know, the data suggests a little bit less than the overall population, you know, I think one caveat to note is that immunotherapy and chemoimmunotherapy are present, and those studies are older, but the preponderance of the evidence suggests that KRAS is a poor player in that KRAS mutated subpopulation. Regarding the China question, I think David is going to take that.

Sure. Regarding the CRISPR-12 trial, the confirmatory trial, the trial is currently enrolling in the U.S. and Europe. China has not yet come online. It will come online later this year. So by the study finishing in the first half of next year, China will be a relatively small amount of patients that are contributed to the total enrollment, primarily Europe and U.S.

And our next question comes from Jason Terbury of Bank of America.

Oh, hey, this is Chiang for Jason. Thanks for taking our questions. Two from me, one on monotherapy and one on SHIP2 combination. So, on monotherapy, I'm curious, have you explored the 400 mg BID dose with monotherapy in second line lung patients, specifically looking at sort of how the response rate and safety profile compare to the 600 mg BID? It looks like from the combination with PEMBRO, you're getting better therapeutics window with the PD, with the 400 milligram combined with PD-1. So, and then secondarily, you know, on the same amount of question, based on your understanding of Project Optimist, do you think the body of work of an aggressive motor therapy is going to satisfy that requirement? And then on shift two combination, you know, I think there was initially quite a bit of excitement because of the mechanistic rationale and also preliminary clinical data by a limited number of patients. But we haven't quite seen a lot of data since then, and there was some timeline push from players across the industry. So, but lately, Novartis indicated They are starting at phase three with a SHIP-2 combination. Obviously, you cannot speak to what other companies' rationale, but from a variety perspective, where are you at right now regarding the opportunity with the SHIP-2 combination?

Thank you.

So, yeah, I would say a few things. You know, number one is we're highly confident in the approvability of the 600 milligram BID dose as part of our submission package. And you had mentioned Project Optimist. So, you know, the agency, you know, does continue to, you know, really enforce the importance of Project Optimist. And as part of the collaboration with the agency, we're looking at the 400 milligram BID doses of monotherapy. We do anticipate that this is, you know, kind of a post-approval commitment, and we're going to continue to work with the agency on that front. And then noting your question about 400 megs BID. So several things to note. One is that it covers our target plasma concentration of 1.5 micrograms per mil, and that is a concentration derived both from preclinical models suggesting if we remain above that target for the full dose interval that we are near completely inhibiting KRAS, and the 400 dose appears to accomplish that. That data is also derived from our ability to look at PKPD and repeat biopsies in the clinic, Again, at the 600 milligram dose, I think we have data suggesting that we are near completely inhibiting KRAS and modifying KRAS as a target. We, of course, continue to look at our own data clinically, and we're confident that the 400 meg dose level is covering the target based on exposure response analysis. In short, that is looking at the concentrations that would be anticipated at the 400 meg dose level and looking at the response rates and noting that those response rates are fairly consistent across the various, you know, kind of quartiles of exposure observed. So, we're confident in the 400 dose in general, especially, you know, in combination as we see increased dose intensity in combination with hembrolizumab. And then, I think your last question was related to SHP2. You know, we do have plans to continue in our exploration of Adagrasib in combination with SHP2 inhibitors as part of our overall development program.

Ladies and gentlemen, that concludes the question and answer session for today's conference. I'd now like to hand over to David Meek for any additional or closing remarks.

Well, thanks for joining us this afternoon. In closing, I'll reinforce the relentless focus We have Emirati on translating novel science into innovative therapies to bring hope to patients. We're excited about the path we're blazing, and we're confident in our ability to successfully execute. And we look forward to speaking with many of you, sharing additional updates in the coming weeks and months, and see you at ASCO. Take care, everybody.

That concludes today's call.

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