Revolution Medicines, Inc.

Good day and thank you for standing by. Welcome to the Revolution Medicine Q4 and year-end 2022 earnings conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Peg Horn, Chief Operating Officer. Please go ahead.

Thank you and welcome everyone to the fourth quarter and full year 2022 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President of Research and Development, and Jack Anders, our Chief Financial Officer. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings release, press release, as well as all of the company's filings with the SEC concerning these and other matters. During this presentation, we will be referring to a number of slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Good afternoon, and thank you for joining us. Today, I'll provide an update on our company progress. Steve Kelsey will provide additional information about our RMC6236 clinical program, and Jack Anders will provide highlights of our financial results. Revolution Medicines is advancing our pipeline of groundbreaking RAS-on inhibitors and RAS-companion inhibitors on behalf of patients with a wide range of RAS-addicted cancers, setting up an exciting and data-rich year. We have advanced into clinical development the first two drug candidates from this highly innovative RAS-on inhibitor portfolio. RMC6236 is a groundbreaking RAS inhibitor with the potential to treat all or nearly all RAS cancer patients due to its highly differentiated mechanism of action, facilitating broad activity across major RAS variants. RMC6291 is the vanguard of our mutant selective RAS-on inhibitor portfolio, which also includes our oral and covalent KRAS G12D inhibitor, expected to enter the clinic mid-year, and a second wave of inhibitors designed to treat a range of RAS mutant cancers. Together, the two Phase I programs will provide key insights into the potential of each exciting drug candidate and initial information to validate our tri-complex RAS-on inhibitor platform as a whole. RMC-6236 and 6291 have been well behaved so far in the dose escalation portions of the RMC-6236-001 and RMC-6291-001 clinical studies, respectively. Both compounds have exhibited oral bioavailability, leading to increasing exposure levels with increasing dose, consistent with our preclinical projections. They've both been generally well tolerated, We've cleared several dose levels for each compound with a once daily dosing schedule, and we have not yet reached a maximal tolerated dose or defined a recommended phase two dose for either compound. Today, we'll expand further on the findings related to RMC-6236 in particularly. Momentarily, Steve Kelsey will share with you additional information coming from the RMC-6236-001 trial. You'll hear about initial pharmacokinetics, molecular and radiographic findings from the early stages of this study supporting our belief that we are dosing this compound in a pharmacologically active range and observing anti-tumor activity consistent with clinical benefit with acceptable safety and tolerability. Although the data Steve will describe today are early, we believe these findings are quite encouraging for RMC6236 itself as a drug candidate. They are insufficient to define the full profile and potential of 6236, including response rates or long-term durability in any tumor type, which will require more data and time. Nevertheless, we feel these data are important as they significantly de-risk key aspects of our broad portfolio of multiple clinical and preclinical Rason inhibitors that all share a number of fundamental properties. Let me offer additional context by reminding you of some key elements regarding the compound RMC-6236. Our description of 6236 as a RAS multi-on inhibitor has three components. It is designed to bind selectively to RAS proteins. It binds to and inhibits all or nearly all forms of RAS, including every known oncogenic mutant and wild type form we've tested. and it binds RAS exclusively in the on or activated state in contrast to first-generation KRAS G12C inhibitors that bind RAS in the off state. 6236 shows high potency in cellular assays, inhibiting RAS signaling typically at low nanomolar to sub-nanomolar concentrations, and frequently driving deep and sustained RAS pathway suppression in RAS-dependent tumor cells. And we've shown extensive preclinical evidence that 6236 induces deep and sustained regressions in diverse in vivo cancer models representing multiple tumor types and multiple RAS mutant genotypes, especially KRAS G12X mutants, a RAS inhibitor profile that is, to our knowledge, unprecedented. Overall, the design of RMC6236 as a RAS multi-on inhibitor not only chemically and pharmacologically breaks new ground in the field, but also serves the bold, biological goal of leveraging its ability to inhibit all or nearly all forms of RAS including both the primary mutant RAS driver and normal or wild type RAS forms to maximally suppress RAS signaling overall in cancer cells that are addicted to RAS. A fundamental question being evaluated in the RMC 6236-001 clinical trial is whether 6236 with this biological profile can be dosed in patients at levels that deliver clinical anti-tumor impact without also causing unacceptable effects on normal tissues due to the compound's intentional activity against wild-type forms of RAS that would also be anticipated in normal cells. The extensive preclinical evidence of dramatic anti-tumor activity in multiple animal models came from studies at dose levels that did not induce concomitant intolerability. and the RMC6236-001 clinical study is a first test of these aspirations for this drug candidate in patients. Steve Kelsey, our president of R&D, will present our first report of clinical experience with a Rasa on inhibitor, RMC6236. Steve?

Thank you, Mark. As we've stated previously, based on extensive preclinical studies of RMC6236, Our working assumption is that the on-target effects of inhibiting wild-type RAS in normal tissues will ultimately determine the maximum tolerated dose in people. We have consistently represented that we believe RAS-mediated toxicities will be predictable, manageable, monitorable, and reversible. We have also presented preclinical data suggesting that the slower clearance of RMC6236 from tumors compared with normal tissues may enhance the therapeutic index for RMC6236 and contribute to achieving meaningful anti-tumor activity for tolerated exposures. Meaningful clinical activity includes both reduction in tumor size and durable inhibition of tumor growth, represented most frequently as progression-free survival in clinical trials. In the clinical program to date, patients have been treated in five dose cohorts, ranging from 10 milligrams daily to 120 milligrams daily. To calibrate you, based on measured drug exposures in these patients, the 10 and 20 milligram doses fall at the lowest end of exposures we evaluated preclinically and were associated with some degree of tumor growth inhibition in xenograft models. Drug exposures seen in patients treated at 40, 80, and 120 milligrams daily are similar to those associated with more significant anti-tumor effects in preclinical studies. These included dose-dependent tumor regressions and delay in time to tumor growth in in vivo studies of several RAS mutant cancer models. But with these doses in patients, we haven't yet reached exposure levels achieved at the dose we studied the most preclinically, that is 25 milligrams per kilogram daily. Thirty-six patients have been evaluated for initial safety and tolerability in the clinical trial so far. As shown in the table of drug-related adverse events on slide 11, treatment across all dose cohorts has been generally well tolerated. Some patients have exhibited predicted on-target normal tissue effects, presumably due to inhibition of wild-type RAS. These are primarily grade 1 or 2 skin rashes, similar to those observed with EGFR inhibitors, and a range of mild to moderate severity gastrointestinal toxicities, usually nausea or diarrhea. The frequency and severity seem to be dose-dependent and thus far have been manageable with standard supported care. One patient required a brief dose hold for skin rash and resumed dosing at a reduced dose. Skin RAS and gastrointestinal toxicity are recognized consequences of suppressing RAS signaling in normal tissues based on a wide experience in the field with other drugs and drug candidates, including EGFR, MEK, ERK, and SHIP2 inhibitors. Skin rash has been historically viewed as a biomarker of pharmacologic activity by some of these drugs. Therefore, the clinical findings further support our belief based on PK data that we are achieving exposures of RMC63-6 in patients that are in an active range without inducing unacceptable toxicity. Among all 36 patients evaluated so far, one related serious adverse event has been observed. This patient with metastatic pancreatic cancer and a KRAS G12B mutation entered the study with extensive abdominal disease, including a large and deeply invasive tumor implant in the serosal wall of the large intestine. About one week into treatment at 80 milligrams daily, the patient experienced an unfortunate bowel perforation that occurred at the invasive tumor site, accompanied by radiographic evidence of tumor reduction at that location and other metastatic sites. No evidence. or clinical symptoms of colitis or colomic ulceration were seen preceding the event or observed on subsequent imaging. Based on abdominal CT scans and the opinions of the clinical investigators, we believe that this event is likely attributable to shrinkage of the tumor by RNC6236 in the heavily infiltrated bowel wall, even within this short treatment period. rather than to a direct toxic effect of RMC-6236 on the normal bowel wall. Similar events attributed to tumor shrinkage in the bowel wall have been occasionally described on treatment with BRAF inhibitors and with chemotherapy. We have treated patients with RMC-6236 in a higher dose cohort, 120 milligrams, without observing additional serious adverse events so far. and expect to continue dose escalating even further towards a recommended phase two dose. Let me provide some information on the anti-tumor activity we have seen in the study. Consistent with study eligibility criteria, patients with a range of tumor types in which KRAS G12X mutations are common have been enrolled, including major epithelial cancers such as non-small cell lung cancer, pancreatic, colorectal, and other tumors, including ovarian cancer, appendiceal, and bile duct cancers. The KRAS mutations in those tumors cover the range of KRAS G12 mutations, G12D, D, A, S, R, with D being the most heavily represented so far. This is consistent with the epidemiology of RAS mutations in human cancers. Patients enrolled in this study have been previously treated with a standard of care and or other regimens, with an overall median of three prior therapies, as is typical for an oncology dose escalation phase one study. At the 10 milligram and 20 milligram dose levels, radiographic imaging showed either stable disease with some tumor reduction or disease progression as the best responses. Interestingly, in several patients at these lower dose levels, we have measured significant reductions in tumor variant alleles in ctDNA, For instance, in one patient with a KRAS G12V non-sorcer lung cancer, treatment at 20 milligrams daily was associated with initial stable disease and 100% clearance of all RAS mutant alleles and all other concurrent tumor variant alleles. These earliest signs were consistent with our expectations at these low dose levels and were encouraging. We'd like to show you more detail regarding early and preliminary treatment-related activity at the 40, 80, and 120 milligram dose levels. We're focusing on non-small cell lung cancer and pancreatic cancer, since those are the two histologies most likely to be sensitive to ERAS inhibitor monotherapy based on the G12C experience. We will report on other tumor types, including colorectal cancer, in future updates. The waterfall plot of tumor volumes on slide 12 shows our experience so far with the nine pancreatic cancer patients and three non-small cell lung cancer patients that have been treated at 40 milligrams daily or higher and are efficacy-evaluable. All 12 of these patients have exhibited stable disease or better as their best response and remain on study from approximately one and a half to four and a half months as of the data cutoff date. 10 of 12 patients have shown some degree of tumor volume reduction by races. One patient with KRAS G12D non-small cell lung cancer achieved a partial response on first restaging scan and was subsequently confirmed with a follow-up scan. One pancreatic cancer patient with a KRAS G12D mutation also achieved a thus far unconfirmed partial response a case study I will describe more fully in a moment. Even at this early stage with short follow-up, small patient numbers and doses below the anticipated recommended phase 2 dose, we believe that these data compare favorably with chemotherapy regimens for advanced pancreatic cancer, where disease control rates rarely exceed 60% and the response rates are low. The durability of disease control is of high importance for conferring clinical benefits and ultimately regulatory approval, particularly in advanced pancreatic cancer. Follow-up continues on all of these patients, as we've noted. In some cases, tumors continue to reduce in size beyond the first response evaluation. Let me now describe for you a particular case that is still ongoing and requires further data collection while the patient's treatment continues. but even at this stage provides a view into the therapeutic potential of RMC6236. As described on slide 13, this patient is a 76-year-old male with metastatic pancreatic cancer harboring the KRAS G12D allele and associated gene copy number loss in tumor suppressor genes to CDKN2A and N2B, as well as the associated putative tumor suppressor, NTAP. After both neoadjuvant and post-surgical adjuvant chemotherapy, he developed metastatic disease in the lungs and progressed following the third course of chemotherapy. He received RNC 6236 at 80 milligrams daily, which, as noted earlier, we project to be in the mid-range for anti-tumor activity and is below the anticipated recommended phase two dose. The patient is tolerating the drug well. At baseline, the patient had three distinct lesions, one in the right lung and two in the left lung, that are being followed radiographically. These lesions are identified on the upper row of the three CT images on slide 14. All three lesions underwent significant reduction over 12 weeks of therapy. At six weeks, all three tumor lesions were reduced in size, with an overall 17% reduction in tumor size by resits. On the 12-week scans, shown in the second row of CT scans, target lesion 1 has disappeared, and target lesion 2 is considerably reduced. The single non-target lesion is barely detectable. In addition, the density of the residual tumor has changed. Resyst quantifies response by measuring only the unidimensional longest axis for each target lesion and does not consider density or three-dimensional volume. As the first target lesion has been assigned a minimum measurement of five millimeters, this patient has formally achieved a 70% tumor reduction and a clear partial response by Resyst, even though volumetrically, the reduction in tumor burden appears greater. He continues on study. and the partial response needs to be confirmed with a follow-up scan. We must emphasize that it is too early to project the frequency or durability of responses or comparative results across tumor types and genotypes. The numbers are small. The dose levels are likely to be below the recommended phase two dose, and follow-up is short. Nevertheless, the totality of data across these 12 patients reinforces our growing conviction about the potential for RMC6236 to exhibit promising clinical anti-tumor activity in patients with advanced RAS mutant tumors at doses that are well tolerated. And now I will turn the call back to Mark.

Thank you, Steve. The collection of data just presented is, to our knowledge, the first ever clinical data to be presented on any inhibitor designed to target the on-state of RAS. any RAS-targeted therapy used to treat a patient with a tumor bearing the KRAS G12D mutation, or any oral RAS-on inhibitor used to treat a patient with lung or pancreatic cancer bearing KRAS G12D or various other non-G12C mutations. While initial data from the patients described today are quite encouraging overall in terms of tolerability and antitumor activity in multiple tumor types with multiple RAS genotypes, And the case report shows a dramatic effect in KRAS G12D pancreatic cancer at a tolerated dose. We will need additional data to project response rates or durability in pancreatic lung or other cancers and across different RAS mutations at the recommended phase two dose and schedule. We show these early data today to illustrate what may be possible with a RAS on inhibitor. As represented by the boldest compound in our collection, with arguably the greatest a priori therapeutic index risk profile, and we will continue to develop more clinical information. These findings are quite encouraging about the ability of a rationally designed tricomplex Rasson inhibitor to be taken orally, for it to exhibit drug-like pharmacokinetics, and for the tricomplex mechanism of action to drive inhibition of Rasson proteins and confer promising antitumor benefit in patients without being accompanied by extraordinary toxicities. We confirm our intention to provide a more detailed public update on 6236 mid-year, including further follow-up from patients described today and information we expect to collect from additional patients in the dose escalation phase of the study. Let's briefly touch on RMC6291, our mutant-selective KRAS G12C-on inhibitor, for which we also have some early experience that allows us to build on the earlier comments about general drug-like behavior and tolerability. Based on initial PK, molecular data, that is CT DNA, and radiographic imaging data, that is serial CT scans, we believe that we are also dosing this compound in a pharmacologically active range and so far with acceptable safety tolerability. We plan to provide a more substantive update in the second half of this year. Based on the aggregate early evidence from the 6236 program, as updated here, and initial experience with 6291 I summarized briefly, we believe these findings serve as growing validation of the distinctive chemistry, pharmacology and biology, and therapeutic vision for our Rason inhibitors more broadly. Of course, much more information is needed for more definitive conclusions to be drawn about each individual drug candidate, which we expect will be forthcoming over time but we believe the information we've shared intended to represent our experience with two RAS-on inhibitors so far increases the probability of success for these two assets and may well read through to other assets we are developing. Next up in our RAS-on inhibitor collection is our mutant selective inhibitor of KRAS-G12D, the most common RAS variant causing human cancer, RMC9805. This compound that we introduced last year is administered orally engages the on form of KRAS Q12D, and executes a covalent attachment selectively to the oncogenic aspartic acid. IND enabling work remains on track toward our goal of beginning clinical evaluation of this exciting compound in mid-2023. Last month, we also introduced a new Rason inhibitor drug candidate. RMC 0708 is an oral, mutant-selective, non-covalent inhibitor of KRAS Q61H. It has now entered development to prepare it for clinical evaluation after the first wave of RAS-on inhibitor drug candidates, that is, 6236, 6291, and 9805. It represents the fifth drug candidate we've disclosed in our portfolio of RAS-on inhibitors. We have now described both RAS multi- and mutant-selective drug candidates directed to each of the three common mutation hotspots in RAS proteins. Finally, let me provide brief updates on two clinical stage RAS companion inhibitors in our portfolio. RMC4630, our SHIP2 inhibitor, continues under study in patients with KRAS G12C non-small cell lung cancer in combination with Sotiracib in our global phase two trial, RMC4630-03. The study is fully enrolled now, and we continue to expect to read out top line results in the second half of 23. And RMC5552, our mTORC1 selective inhibitor, continues under study as monotherapy in patients with tumors carrying mutations associated with hyperactivation of mTORC1 signaling. We expect to provide a more detailed update from this study later this year, and our aim is to bring it together with one or more Ras-on inhibitors to test as combination treatment in patients with tumors harboring both Ras mutations and mTORC1 pathway activation. Now I'll shift to our corporate progress and comment on our priorities for 2023. With a strong balance sheet, we entered this year with an explicit focus on the timely execution of the multiple development stage activities currently underway, with our highest priority being to deliver on important clinical milestones in the year. We continue deploying our development resources primarily to ensure we meet the goals of our first three most advanced RAS-on inhibitors, RMC-6236, 6291, and 9805, and two clinical stage RAS companion inhibitors, RMC-4630 and 5552. While interim in nature, we at ResMed view the information shared today as quite important and impactful on our own assessments of technical probabilities of success. With greater confidence that our innovation engine is delivering assets that deserve to be progressed, and can earn the right to be deployed on behalf of patients, part of management's bandwidth is now directed toward defining the paths and steps we need to take now and over the next several years to ensure that we can maximize the value of these exciting product candidates and others in our growing portfolio. Building on this momentum, I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack?

Thank you, Mark. As shown on slide 34, we ended the year with $645 million in cash and investments, which is expected to fund planned operations through 2024 based on our current operating plan. Revenue from our collaboration agreement on SHIP-2 inhibitors with Sanofi was $15.3 million in the fourth quarter of 2022 compared to $9.5 million in the fourth quarter of 2021. The increase in revenue was due to a $7.6 million non-cash adjustment related to the acceleration of revenue resulting from the termination of the Sanofi agreement, which has an effective date in June 2023. As a result of the termination of the agreement, we adjusted our estimates of the accounting transaction price and estimated percentage of completion of work performed to date, which resulted in a cumulative catch-up adjustment that increased collaboration revenue in the quarter. Collaboration revenue for full year 2022 was 35.4 million. Total operating expenses for the fourth quarter of 2022 increased to 77 million, largely driven by R&D expenses, which totaled 66.1 million. Total operating expenses for full year 2022 increased to 293.7 million, with R&D expenses increasing to 253.1 million. The increase in total operating expenses in 2022 was primarily due to the advancement of RMC-6236 and RMC-6291 into clinical trials. as well as an increase in personnel-related expenses related to additional headcount, an increase in research expenses associated with the company's preclinical research portfolio, and an increase in stock-based compensation. Net loss for the fourth quarter of 2022 was $56.5 million, or 63 cents per share. For full year 2022, net loss was $248.7 million, or $3.08 per share. Turning to financial guidance for 2023, we expect full-year GAAP net loss to be between $335 and $365 million, which includes estimated non-cash stock-based compensation expense of $40 to $50 million, The increase in expected gap net loss for 2023 is a result of increased expenses associated with the advancement of our RAS-on portfolio and a decrease in expected collaboration revenue. And with that, I'll now turn the call back over to Mark.

Thank you, Jack. We are highly encouraged with the progress of our rich development pipeline, particularly by the body of clinical evidence developed so far that provides initial validation of our RAS on inhibitor platform and is described here, promising early evidence that RMC-6236 can be dosed in patients to induce significant anti-tumor activity without unacceptable side effects. We look forward to sharing further information on our collection of exciting clinical and preclinical assets throughout the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors and shareholders, and, of course, the tireless efforts of ResMed employees in pursuit of our mission to outsmart RAS-addicted cancer. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the question and answer session.

As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from Jonathan Chang with SVB Securities. Your line is now open.

Hi, guys. This is Hassel Koshyid on for Jonathan. I wanted to ask, so you reported on those 12 patients who were treated at 40 mgs and above with lung cancer and pancreatic cancer. What's the denominator on that number, like how many patients were treated there, as in like how many were excluded for being non-invaluable or how many were excluded for having another tumor type?

Steve, do you want to comment on that?

Sure.

We didn't report on the patients treated at 10 and 20 basically because there really was no evidence from the preclinical models that we were going to be anywhere near the exposures required to see anything worth reporting, to be honest with you. The actual data is restricted largely to reductions in ctDNA. And we haven't reported on the colorectal cancer patients at all because it's a completely different disease. And there is no precedent right now for a RAS inhibitor being effective as a single agent in breastfeeding colorectal cancer. So it is quite likely that we will compile information on the colorectal cancer patients as it reaches a critical mass with a view to putting together a more comprehensive strategy for the treatment of patients with Rasputin, Colorectal, Paxil, and RMC-1636. So, essentially, the data that we're showing you right now is the data that we're showing you, and all of the rest of the data will be in the more formal update in the middle of the year.

Please stand by for our next question.

Our next question comes from Michael Schmidt with Guggenheim Partners. Your line is now open.

Hey, guys. Thanks for taking my questions. So it sounds like the preclinical data has been pretty predictive as it relates to dosing ranges and, you know, some of the dose response, et cetera. Based on that, I guess, Mark, what is your prediction what the MTD might be in this study and how much more room to increase those do you think you'll have on the phase one study here?

Yeah, hi, Michael. Thanks for your question. You know, I think we just don't know how steep the curve will be in humans. I think that's the point of the experiment right now. So, you know, we're clearly from all the sessions we've had internally that it's the sort of thing that you'll know when you see it. I don't know if Steve wants to add any more color to it, but I would just want to confirm. I think that the preclinical data have been very predictive of what we've seen in humans, and we tried to convey that sort of in a soft way, you know, back in January, but now we're providing concrete data to support that statement. Steve, do you want to?

No, I mean, other than that, as you can see from the adverse event table that we've included, the tolerability profile right now, even at 170 milligrams, say, is pretty benign. I think Mark is correct in that at some point, we are going to be hitting wild-type rats in normal tissues at a point which will make the compound or the dose but it's really hard to predict how high we can go there. Just to be clear, I mean, we dose mice at 25 milligrams per kilogram daily, routinely, and that's because if we increase to 40 milligrams per kilogram daily, we saw some intolerability. Right now, you know, we're dosing way below the equivalent, the varying equivalent of 25 mg a kilogram daily. So, we think that's a reasonable amount of headroom left to go, but it's very difficult to say exactly how much.

Yeah. So, it sounds like you have some additional upside on the dosing. And then, I guess, When we think about, you know, read through of this data to your mutant selective KRS inhibitors, where I guess one would expect less on target toxicities, you know, how should we think about that, you know, in terms of the dosing ranges? And I guess, you know, how much wider would one expect the therapeutic index to be as it relates to that?

Yeah, well, we fully expect the therapeutic index to be wider with the mute-selective inhibitors by definition. If it's not wider, if they're having wild-type RAS effects, then they're not mute-selective. So, you know, there will be a wider therapeutic index. I think as we talked about before, I mean, ultimately the issue isn't therapeutic index, it's how high can you dose and what's the absolute impact at that dose level but it will all converge around 1.0 as you have talked about before because that's the point of mpd you know dosing but i think just to go back to the big picture we're obviously quite encouraged by a significant level of anti-tumor activity that we've seen at 236 is sort of the highest risk molecule from that perspective. And today's information, you know, in our view, substantially lowers our calculation around that risk profile.

Yeah, great. And then could you, looking at the waterfall chart on slide 12, could you just comment on the response kinetics? You know, did they all Did you see these, you know, responses early at the first scan? You know, did they happen later? Did they deepen over time? How should we think about that?

Yeah, well, there is a row across the bottom that says most recent scan, and that was designed to give you the information of what the bar represents. And you'll see that, you know, it varies. Some of them are in cycle three, day one, which would be the first post-treatment scan. and others are at cycle five, day one. I think the case that Steve described is pretty informative there, where on the first scan, which would have been cycle three, day one, it was an aggregate 17% tumor volume reduction by resist criteria. Although the scan was a little more impressive than that, that's what it was, but by cycle five, day one, you know, it's pretty clear that the tumor's nearly obliterated across all three of those lesions. And so that score exists, you know, in the 70% range, and probably in terms of tumor content, it's far more than a 70% reduction. You know, that's what we have. That's what we're seeing so far. As we get to higher doses, possibly it will take fewer cycles to see that. Who knows? But it might also just be the kinetics of the tumors. That's the sort of thing we need more information on to be able to get a more precise answer.

All right. And just in terms of the study conduct going forward, do you plan to enrich for certain tumor types, perhaps lung cancer and PDAC, or are you still continuing with the all-comers approach at this point?

Well, I think as we've described it publicly, and I think we'll say with this, is that the backfill patients really give us the greatest opportunity to put a finger on the scale, if you will, And clearly we're showing some information that we think is exciting and the investigators think is exciting. So I would imagine you'll see more of some of these patients, you know, in the back fills. There's always this tension, and I know you and I have also talked about this before. There's a tension between wanting to sample across tumor types and genotypes, because that's important information too, versus wanting to get a deeper data set. So, we end up with a larger data set with G12D and pancreatic cancer, not surprisingly. But we'll continue involving patients across these eventually with some enrichment by the investigators.

Yeah. All right. That makes sense. All right. Well, thank you for taking my questions, and congrats on the data update today.

Thank you. Thank you.

Please stand by for our next question.

Our next question comes from Mark Fram with Cohen. Your line is now open.

Thanks for taking that question and congrats on the data and, you know, seeing that 6036 is active in the clinic. Maybe just to follow up on one of the earlier questions to start, Steve, I think there's 20 patients dosed at 40 milligrams and above in the AE table, and then there's 12 in the waterfall plot. Can you just explain those incremental eight patients? It sounds like maybe a few of them are colorectal cancer patients that you just don't have enough to talk about monotherapy with. And then are there more patients who are just on study but haven't been scanned yet versus people who may have dropped out before the first scan?

Yeah, there's far more patients on study that have not yet been evaluated for epilepsy than there are patients with colorectal cancer in the study. I was deliberately vague about the other histotypes. But that's because we will provide an update later in the year which addresses that. But the reality is that the discrepancy is due to the speed at which this study is enrolling and the fact that patients have to be on study for six weeks before they get their first scan. So if you enroll a whole bunch of patients within the last six weeks, they are available for

Full safety, but no privacy. Yeah, and that's the key point there, Mark, is that they're on the table for adverse events or they're considered as part of that calculation once they start dosing. But they need to be on study for six weeks before you get a scan.

Okay, thanks. That's helpful. And then maybe just to the point of the preclinical modeling being pretty predictive, I guess one – Given the exposures you're seeing so far, I guess, what dose level do you think might be equivalent to that 25 milligrams you tested mostly? And then also kind of related to that, is there any sign preclinically that G12D alterations might be, you know, maybe modestly more sensitive than the other alterations and make sense that they would start responding first? Or do you think this is just kind of the noise in the system of seeing a lot of different tumor types and a lot of different mutations?

Yeah, on the second question, not so much. I mean, when we, I think we shared data on the G12X versus non-G12X in various presentations, not necessarily corporate, but at some of the scientific meetings to give it a further breakdown. And without any doubt, the G12X, as a group, showed enrichment for higher sensitivity on average. But then you start to get into fairly small numbers. trying to compare D to B to A to S. In some cases, we only have a couple models of one particular gene type or another. So I don't think we can say that today. And I don't think we would conclude that D is more sensitive in the waterfall. It's just not enough. Nine out of, sorry, eight out of 12 are D in the waterfall plot. and three are B and one is A. So it's just really no way to determine sensitivity from that yet. We need to collect more information. Your first question was, what dose will we get to? What dose will we get to, yeah, or how does it match up?

What dose, you know, given the exposures, you've got a fair amount of clinical exposure data now to start building the human model, not just the extrapolation from animals. But based on that, where does that 25 milligram animal dose fall on? Is that 240? Is it 400 milligrams?

Higher than 120, I think, is what we can share today. We'll give you that information. It's not 10 miles away, but I think we'd rather give that to you in the context of showing PK curves, and by then we'll have more information. It just seems... you know, potentially misleading to sort of give you a projection that's not showing you the data to go with it. So I think we'll stay where we are.

Okay. That's very helpful. And then completely understand your points in your prepared remarks about, you know, it's pretty early to – it's too early to be talking about, you know, specific response rates and efficacy and, you know, individual tumor types or genotypes. Do you think you'll be in a position to start saying that for some tumor types and genotypes in the middle of the year at that update?

We hope so. You know, I mean, that's an ambition. That's a hope.

Okay. You know, of course, it's a matter of opinion, but adjusting, you know, 10 out of 12 patients at 40 milligrams above showing some degree of tumor volume reduction with some clear evidence that more time on drugs gives you a greater chance at actually hitting a PR threshold is quite encouraging. But I just, it's hard to say, and I feel like anything we say here probably will not be rewarded with anything positive. So in the spirit of not to break into jail, I think we'll just stay with where we are.

Okay, fair enough. Thank you, and congrats again.

Please stand by for our next question. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.

Hi, good evening. Thanks for taking the questions. On the 20 milligram cohort, with it being larger than the others, I just want to confirm that that's a result of backfilling. and that there wasn't necessarily some kind of safety event that triggered further expansion of that cohort. And then maybe just secondly, can you just sort of state where you are right now in terms of further enrollment of the 120 milligram cohort? And if you do in fact proceed through further dose escalation, would you kind of move through 40 milligram increments as well?

Eric, it's a combination of two things. One is there were a few patients that were backfilled after the escalation to 40 milligrams, but we also built in a food effect study at that dose level. And so six of the patients were in a food effect study. We don't have the results yet from the food effect study, but dose level and have been evaluated for safety, which is why the denominator for that dose level is somewhat larger. The 120 milligram dose level is fully enrolled, and it'll read out. We'll know shortly whether or not we can dose escalate to the next dose level. And that dose level, by the way, is determined by a conversation between us as the sponsor and the investigators. So I'm not really in a position at the moment to tell you what that dose level will be. But it will be some sort of similar increment, 160 or 180, something in that range.

Okay, got it. And I guess if we're just trying to prepare ourselves for the scope of the readout that you're planning for mid-year, I guess any sort of rough guidance in terms of additional patients you would expect to have accrued to the trial and I guess additional follow-up that you'd want to have for the valuable patients that you're describing here today?

Well, there's clearly going to be additional follow-up on all these patients. I mean, you'll get more information on whether or not, well, firstly, there's a bunch of patients that have been There will be more durability data, hopefully, for the patients that are currently on study. You know, as Mark said, the investigators are beginning to lean into the selection of patients for this study, and it's heavily biased towards multiple cell lung cancer and pancreatic cancer. And the epidemiology of that means that around half of them are going to have a K12B mutation. and probably a third of them are going to have a G12B mutation, and the rest will be a scattering of other things. So I would expect there to be a substantially larger database predominantly focused on pancreatic cancer and lung cancer, with G12D and G12B being the major mutational forms that we report on.

Yeah, I would just say, Eric, we have discretion about when we do this mid-year update. You know, mid-year isn't a date or a time. It's just kind of a time of year. It's a season. And so, you know, obviously we're giving you some information now, which wasn't necessarily contemplated previously. So we're going to collect some more information. We're going to try to make the next update, you know, a meaningful update incremental to this. But there's no sort of prescribed formula, which is why asking is more about what we'll have. We'll have more patients and we'll have more follow-up, that's for sure.

So, Mark, with that comment, I take it that you're not necessarily targeting presentation at a major scientific meeting. Perhaps there's some expectation that you guys would look to present at ASCO.

Well, I said the point. unspoken. If we do do a scientific meeting, we may still have a corporate session. And if we don't do it at a scientific meeting, we'll probably still have a corporate session and then do a scientific meeting after that. So it's sort of all of the above are in play here.

Okay, great. Understood. Thanks for taking the question, guys. Congrats here.

Please stand by for our next question. Our next question comes from Chris Chubutani with Goldman Sachs. Your line is now open.

Hi, everyone. This is Charlie on for Chris. Thank you so much for taking our questions and congratulations on the data thus far. Just real quick from us, regarding the 120-meg dose cohort, just wondering if you can give us a sense of how long these patients have been at this dose level and being dosed at this level. I understand that it's probably on the lower end of the range of duration of therapy that you guys gave us some color on there. But just trying to get a sense of how long they've been on drug. And also, if you can give us a sense of the kinetics with the appearance of adverse events such as rash, like how long does it typically take for the rash to show up? And is there the potential for the severity of rash to increase dramatically? over time in subsequent cycles.

Thank you very much.

Let me address the second question first, because it's a more concrete question for which we actually have data. The duration, the time to onset of rash is between one week and two weeks into dosing, depending on the dose being used. So the higher doses, it tends to start but not usually before one week of dosing has been completed. The severity does not increase over time. In fact, if anything, it either stays the same or improves. We have had reports of patients whose rash has got better And we have reports of patients whose rash remains unchanged and is easily manageable with cream and just like putting up with it. These rashes are very much like EGFR associated rashes in that they occur in different parts of the body. in different people. Sometimes it's just the face, sometimes it's just the arms or the trunk. But nobody seems to think that it's terribly debilitating. We've actually only had one patient who had to stop for a couple of days and then restart. And that wasn't actually because of rash, it turns out. It was because of an associated vertical itch that was associated with, that seemed to accompany the rash. So I think, you know, that's pretty much all I can tell you at the moment.

And then in terms of the duration on 120 milligrams, I think the only thing we can fully tell you is that the three patients who are on that waterfall plot, you can see that the bar that's shown there is associated with the first scan.

Got it. Thank you so much. Yeah, understood. That makes sense. Thank you. And if I could just sneak in one more, just based on the safety profile that you're seeing thus far, are you still considering the potential for intermittent dosing in the future, or has this given you more confidence for the potential for just the once daily? Thank you so much for taking our questions.

Yeah, thank you, Charlie. Appreciate it. I think we're very much where we were, you know, in January when we commented on this, that quite encouraged by the once daily dosing. All of the data we're showing you here is based on once daily dosing. We've gotten away with it quite well with very good tolerability and safety profile and clear evidence of anti-tumor activity. So it's not looking to us as if intermittent dosing is on a critical path to defining our first recommended phase two dose to schedule for monotherapy. With that said, We also indicated in January, and I think we'll stand by this, we're likely to test an intermittent dosing schedule. It's not our highest priority at the moment, and to the extent that we can move forward with monotherapy on a daily basis, we want to do that, but we would want to determine at some point whether we're leaving anything on the table in terms of potential clinical benefit, but so far it doesn't appear to be so.

Please stand by for our next question. Our next question comes from Ben Burnett with Stiefel.

Your line is now open.

Hey, thank you very much. I wanted to ask about the patient you just mentioned. So the one patient that stopped treatment due to an itch, but then was restarted. Can you comment, were they restarted at the original dose? And also, how long did they pause dosing?

I think, I'm just going from memory, so forgive me if what I say subsequently turns out to be slightly inaccurate. But my recollection is it was only for a couple of days that they actually stopped dosing. And then when they restarted, they started at a dose level below the one that they had originally been on. And that patient remains on.

Okay. Okay. That's helpful. Thank you. And then just going back to, so can you comment on what the median follow-up time is in the adverse event table overall?

The median duration of, it's really short. I mean, the median is really short. I would have thought, right, again, it's, we haven't actually formally calculated it, but I would be surprised if it was in excess of a couple of months.

Okay, okay.

Let's try to follow through with the records. No, we haven't calculated it, but it's really short, and I think the, you know, the data that we're showing you is, deliberately a very preliminary snapshot of what we're seeing and not something that we can necessarily claim will persist over time.

That's helpful. Okay.

Also, in the 40 to 120 milligram group with pancreatic or lung cancer, they're all still on. Oh, yeah. No, they're all still on.

Yeah, patients who have been evaluated for efficacy are all on study. The lung and pancreatic cancer patients that we evaluated are still all on study.

Okay, that's great. And then I also wanted to ask, going back to that intermittent dosing conversation, you know, is there, can you frame the level of toxicity that's tolerable, and is it likely to be different in different indications? Like, could there be a scenario wherein you may have intermittent dosing for CRC or for, you know, certain tumor types but not others?

Not so much because of differences in tolerability, but there could be differences in sensitivity across tumor types. And so if it somehow, I think that was really the point about not wanting to leave activity on the table. I just realized the metaphor is you want to leave it all out on the field, but you don't want to leave anything on the table. So it makes those two metaphors. You know, so one can imagine that there may be some benefits in some settings if you can achieve a higher dose intensity for particular tumor types or if there's a particular combination in which that's particularly logical to do. But, I mean, we're out really overseas, for my third metaphor, to say anything like that at the moment because it's just not what we're experiencing. And, by the way, preclinically, as you know, The vast majority of what we showed was daily dosing. Admittedly, it amounts to different pharmacokinetics, but nonetheless, we had target coverage for 24 hours a day, and we were able to do it. So what's happening in humans seems to reflect that, at least within the limits of what we can detect so far.

Interesting. Okay. Okay. Thank you.

I think this does contrast with, you know, and I think it does contrast. Maybe I have one other bit of color here. where in humans, really, to get the kinds of overall dose intensity that we felt would be needed, it was mandatory, in our view, to go to intermittent dosing. And preclinically, the anti-tumor activity, even at the best optimized shift to inhibitor

I see. Okay, so it's like the guiding light here. Is it really like the PK, and are you achieving the concentration thresholds that are needed, or is it really about efficacy?

I think the guiding light here is how much efficacy can we get at a tolerated dose.

So far, we're encouraged by the efficacy signal we're seeing so far at tolerated doses. The PK is not going to make a decision for us. It's going to be the clinical outcomes.

Yep. Okay. Okay. Thanks so much. I appreciate it.

Please stand by for our next question.

Our next question comes from Alex Stranahan with Bank of America. Your line is now open.

Hey, guys. Thanks for taking our questions. Congrats to you as well on your initial responses. Interesting that the two PRs are G12D. Could you give us a sense of the G12X makeup for the other 10 patients in the FTC group? Was it entirely G12D and G12C or something else?

Well, there's no G12C patients in this study. Right now, those patients are all being channeled into our KRAS-G12C in the study RS-69-1. The patients in the group overall really cover the full range of KRAS-G12 mutations. And the ones on the waterfall are indicated. So you can see that there are really only three types here, G12V, G12D, and G12A. And if I'm counting correctly here, there are one, two, three, four, five, six, eight of the 12 have G12D mutations. So that just, I think, is completely consistent with the epidemiology of the ARAS mutations in these particular histotypes.

Got it. Got it. That's helpful. And just to follow up, thinking through the balance of safety, efficacy, you know, you said your goal is to maximize responses. But would this be through the lens of taking this forward as a monotherapy, or would you take a hit on efficacy at a lower dose if safety is good with an eye towards combinations, since I know you've shown in the past some preclinical data combining 6636 with the MPPD ones?

Yeah, that's a great question, but I don't think we're there yet. I just don't think that we know enough about the tolerability profile or what's going to be dose limiting to know whether either, you know, to know at what level of toxicity we would be prepared to tolerate as a single agent or indeed in combination with anything. So it's really too early. It's a very reasonable question, but it's just one which each we don't have an answer to right now. Because as you know, toxicity is not all created equal. I mean, some toxicities are very well managed and easily tolerated, and some are absolutely horrible and unpleasant and are going to be clearly decimating. We're just going to have to keep those escalating and following these patients and see what happens. With a view to maximizing the dose for response, that's not actually the primary not the primary driver here. The main driver is durability. We're looking for durability because there are only two approvable endpoints that are going to make people prescribe this drug. One of them is progression-free survival and the other is overall survival. A response rate, per se, without either of those two things is not particularly helpful for patients. And so we're really looking for We're really looking not just for tumor shrinkage, but for durability of that. Yeah, and I'd like to add just one small point.

Yeah, one small point. You know, on the combinations, we've shown data that 6236 can combine with, for example, 6291 effectively at a dose lower than the dose that we typically use for monotherapy studies in the mouse. So we have a lot of flexibility in the combination realm. And so, determining the recommended phase two dose for monotherapy doesn't necessarily dictate the limits of what we're going to do in combinations where we may lower the dose. In fact, I'm sure the combination study will start with a lower dose.

Okay. Okay. That makes sense. And just on the duration. versus ORR point, it sounds like the mid-year update, you know, the median follow-up is just not going to be long enough to get to that duration question. And it's going to be more about just the gross responses, correct?

I can't answer that because we don't really know. But, you know, again, note, all 12 of these patients are still on study. You know, in pancreatic second-line cancer, one doesn't have to wait 18 months to find out whether or not you've got a drug that's active compared to standard care. So, I think one has to really talk about individual indications in order to know what the reference, you know, the benchmark is for that particular indication.

Okay. Okay, one last quick one, if I may. Just on the differences between 6236 and 9805 as it relates to the binding to G12D, you know, whether it's covalent inhibition or another aspect that you think could result in different clinical profiles beyond just the therapeutic window that was mentioned before.

Right. Well, you know, it has the

differentiating feature that it is selective for G12D. It forms a covalent, but selective bond with the G12D RAS, and hence is basically irreversible. RMC6236 is non-covalent, and it's reversible. So its binding will go up and down with whatever the plasma levels are. RAS proteins that might be part of the overall gene addiction for a RAS tumor cell. So there are trade-offs between those, and I think it's just really yet to be determined which of those is more favorable. Obviously, what we're late on top of that is tolerability, how much dose can you give, etc. But I just think it's too early to be making projections about which is better. I tend to think that if portfolio the way we did.

Okay. Thanks and congrats again on the progress. Thank you.

Please stand by for our next question. Our next question comes from Amy Faria with Needham. Your line is now open.

Thank you for taking the question and the data. My first question is just around how to interpret the evolution of response with duration of treatment. If I'm reading the chart on slide 12 correctly, some of the patients who were in the chart are cycle 7, day 1, on stable disease. But then there are the last two patients in that chart, which are cycle 5, And they seem to have shown a response rate. I'm just trying to understand. So those patients clearly were on treatment longer. Is that a fair way to look at it? And, you know, overall, is this just too short of a duration for us to really interpret, you know, responses over time?

Well, we definitely need more data, and we need more time on study to collect those data, but you're right. So that lung cancer patient who shows cycle seven day one, that means that patient has been on long enough to have likely a third scan. That's what cycle seven would be. Cycle seven day one would be a third scan. So that patient at 40 milligrams, if I'm interpreting this correctly, if we're talking about the same patient, has stable disease with some tumor volume reduction, but not a PR. We don't know if they'll go on to achieve a PR. We're not trying to imply that they will or won't. We don't know. We'll have to follow them. So I don't know how else to comment on this.

Yeah, I don't know. No, I mean, I think that you, you know, directionally, you are correct in inferring that whether a patient has a response virus is is a function of both dose and time on treatment. And clearly, what this chart is beginning to perhaps indicate is that responses at 40 milligrams might be uncommon, which is why we dose escalated to three times that dose level, where we are beginning to see responses if we wait long enough. And as Mark said earlier, we don't know whether there is a dose at which the majority of responses will be seen as a first response evaluation or not. It's just not clear to us whether increasing the dose changes the kinetics of response. Again, I want to really, I want to reemphasize here that these two diseases are diseases where chemotherapy induces responses, but it doesn't last forever. And that's what we're trying to solve for. We're trying to solve for the very short duration of response or benefit that patients get with cytotoxic chemotherapy. The median time to progression for patients with pancreatic cancer that have received prior therapy is three and a half months. And we're trying to solve for that. So it's really about how long it takes the tumor to get to 30% or 31%. reduction isn't really the point. The point is how long do they stay on study before they progress again? And we would like to push that beyond three and a half months.

Yep. Okay. That's helpful. And just clarify for me, after how many cycles did a patient receive a scan? Is it every two cycles?

Every two cycles.

Yeah. Okay. Got it.

Every two cycles for the first

means they've completed two cycles. It's the day after they've completed two cycles.

Got it. Got it. Okay. Just with regards to safety, you know, you mentioned that you dosed up to 40 milligrams per kg in sort of the preclinical models before you started to see some safety. What type of safety emerged at that point? And you know, what was that? And then maybe, you know, what duration of treatment?

Okay. So this is very species specific. So mice, we just see weight loss. The tox species were mice and cinnamolgus monkeys. And obviously the monkey is a little bit more representative of what happens in humans. And there we saw very clearly wild-type grass-mediated toxicity, predominantly gastrointestinal toxicity, and some suppression of myelohemopoiesis. Now, interestingly, in the human studies so far, we have seen some GI toxicity. It's a little bit diverse in terms of the exactly which part of the GI tract is affected and how that manifests itself. So sometimes we've seen nausea, sometimes we've seen diarrhea, sometimes we've seen loss of appetite, for instance. It's a constellation of gastrointestinal effects that almost all of them have either been grade one or grade two and very easily manageable. But the predominant toxicity, the one that's coming through with increased frequency is skin rash, which we were not able to detect in the preclinical tox species, largely because we're limited by what we can detect in those species. But it is interesting, the one organ in which we showed In our J.T. Morgan presentation, we showed that it is the one organ where the clearance of the drug is slightly delayed compared with the other organs. Nowhere near as much as tumor, by the way, but it is that the clearance of the drug from skin is slower than from, for instance, colonic epithelium or other organs in the body. So it may be that the tissue kinetics of 63-6 contributes into the skin rash. And that makes the pattern of toxicity a little different in humans compared to the preclinical species.

Understood. Okay. Please remind me, I don't know if you mentioned exactly what dose the patient was on, the patient that had to pause the dose and then restart at a lower dose.

I don't remember. I'll have to take that.

I'll have to tighten up lines. I'm sorry, I don't remember. Okay. I think we have time for one more question. Is that right? I think there's one other person in the queue.

Please stand by. Please stand by for our next question.

Our last question comes from Jay Olson with Oppenheimer. Your line is now open.

Oh, hey. Thank you for the update and for taking the questions. We had a couple on 6236. What are you expecting to be the minimally effective dose? Is there any saturation of target occupancy that could lead to a plateau of efficacy? And what dose would you see that plateau? Since the AE table excluded events that occurred in fewer than four patients, can you just comment on what those AEs were and if any of them were grade three or four? Thank you.

Well, it's easy to answer the second question. We haven't seen no grade three or grade four events other than that one bowel perforation that we described, which was a grade four and also a serious adverse event. But as you said, the bowel perforation was most likely due to the efficacy of the drug, not due to the toxicity of the drug on the gastrointestinal epithelium. So the question about MAD... There is no plateau in our dose response. We continue to see increases in efficacy up to the point where the drug becomes intolerable due to inhibition of wild-type rats. So there is no expectation of a plateau as we continue to de-escalate. And this is really important because this compound, so far, everything we know about RMC6236 does not follow the paradigm for Project Optimus. We continue. to see increase in efficacy as we see increase in toxicity. They are absolutely related to each other, but we are seeing efficacy at doses that are tolerable, and that is incredibly important both for the platform and for the further development of the compact.

Okay, great. Thanks for taking the question.

Thank you. I would now like to turn the conference back to Mark Goldsmith, Chief Executive Officer, for closing remarks.

Thank you, operator. Thank you to everyone for participating today and for your continued support of Revolution Medicine.

This concludes today's conference call. Thank you for participating. You may now disconnect.