Revolution Medicines, Inc.

selective inhibitors behind these and we look forward to sharing more as these assets progress. Regarding our SHP2 inhibitor RMC4630, decisions about future development will be made after analysis of a complete data set from the RMC4630-03 study and other considerations including the potential of RMC6236 as a RAS companion inhibitor. Likewise, The future development of RMC5845, our SOS1 inhibitor, which is not expected to offer an advantage over RMC4630, will be evaluated following analysis of the complete RMC4630-03 dataset and other factors. Additionally, we are continuing to evaluate RMC5552 mTORC1-4-EBP1 as a single agent in a Phase 1-1B clinical study with the aim of studying it in the future as a RAS companion inhibitor for use in combination with RAS-on inhibitors, particularly in patients with RAS-addicted tumors exhibiting hyperactivation of the mTOR signaling pathway. We expect to provide additional characterization of the single agent profile for this compound at the upcoming triple meeting in October. Turning to important business news reported last Tuesday, We announced that Revolution Medicine signed an agreement to gain more than $1 billion in additional capital through the acquisition of EQRX, a deal that is focused entirely on strengthening our cash position. We summarized the terms and timing of this transaction last week and provided further details in our 8-K filing, which I encourage investors to review. With significant additional capital that is supportive of the enormous opportunity created by the scientific advances and clinical momentum we have established to date, this deal will reinforce and help us sustain our parallel development approach for our extensive Rasson inhibitor pipeline in multiple RAS-driven cancers by enhancing our balance sheet, thereby increasing our company's financial certainty in a challenging macro environment. We're pleased that initial feedback we've received from investors on the transaction has been very positive, And with important clinical updates in October and the anticipated close of the acquisition in November, the second half of this year promises to be action-packed. I'll now turn to Jack Anders, our CFO, to provide a financial update. Jack?

Thank you, Mark. Turning to our second quarter financials, we ended the quarter with $909.5 million in cash, cash equivalents, and investments. Total revenue for the second quarter of 2023 was $3.8 million, consisting of revenue from the company's now-terminated collaboration agreement with Sanofi. Total operating expenses for the second quarter of 2023 were $112.6 million. The increase in operating expenses over the prior year was largely due to clinical trial and manufacturing expenses for RMC-6236 and RMC 6291, research expenses associated with our preclinical portfolio, and an increase in personnel related expenses resulting from additional headcount. Net loss for the second quarter of 2023 was 98.3 million or 92 cents per share. We are reiterating our financial guidance and continue to expect full year 2023 gap net loss to be between 360 and 400 million which includes estimated non-cash stock-based compensation expense of 40 to 50 million note that we are pleased to strengthen our balance sheet further through the acquisition of eqrx a transaction we expect will close in november of this year but that our current financial guidance excludes the impact of this proposed transaction. And with that, I'll now turn the call back over to Mark.

Thank you, Jack. Reflecting on the quarter and looking ahead to the second half of the year, it is an exciting time for Revolution Medicines. With important clinical updates for both RMC 6236 and RMC 6291 in the fall, planning underway for late-stage development of RMC 6236, and a new clinical study of our first intra-pipeline combination featuring RMC-6236 and RMC-6291, RMC-9805 entering the clinic, and the anticipated close of the EQRx acquisition to help supercharge our work, we have a very full plate. Our first-grade team is passionate and highly energized about fulfilling our mission of discovering, developing, and delivering pioneering RAS on inhibitor drugs on behalf of patients with RAS-addicted cancers, and we are working hard to provide hope to these patients. Importantly, our work wouldn't be possible without the support of our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.

Thank you. We'll now conduct a question and answer session, as mentioned, 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 1-1 again. Please limit yourself to one question and one follow-up and rejoin the queue if you have additional questions. Please stand by while we compile our Q&A roster. Our first question comes in the line of Mark Fram with TD Cohen. Please proceed.

Thanks for taking my questions. Maybe to start on the finances, there's obviously a fair amount of step-up in R&D expenses on a quarter-over-quarter basis, and the guidance kind of implies relatively flat the rest of the year. But then you're also talking about kind of quote-unquote supercharging costs. you know, the R&D work. How should we think about the trajectory of R&D spend as we get late into the year and into next year? You'll close the deal. You know, hopefully the data looks pretty good and, you know, it's justifying a lot more trials for 6036. Hey, Mark.

Thanks for the question. This is Jack Anders here.

that was as well. And then carrying that forward into next year, should we think of step changes as you expand out the program, or is it more incremental?

So we haven't provided any guidance relative to for spent at a future date.

Thank you. One moment for our next question. This is from the line of Jonathan Chang with Larrink Partners. Please proceed.

Hey, guys. Thank you for taking the question. This is Faisal Khashid on for Jonathan. I wanted to ask if you could provide a little bit more color on what the single agent path forward could look like for 6236. how you're thinking this could be positioned relative to standard of care, and also where you are on regulatory interactions for those studies and what steps need to occur before initiating those.

Hi, this is Mark Goldsmith. a little more visibility into what we're thinking, but we'd like to base that forward-looking set of comments on the actual data. So I think at this point, stay tuned, and we'll share more when we're able to do so.

Appreciate it. Thank you.

Thank you. One moment, please. Our next question comes from the line of Chris Shubitani with Goldman Sachs. Please proceed.

Hi, everyone. This is Charlie on for Chris. Thank you so much for taking our questions. Maybe real quick on 6236. Just wondering, as the dose escalation study continues to push higher, how should we be thinking about the selection of a go-forward dose, particularly with respect to combination settings? Just wondering, Is there the potential for different doses to be selected for different combos as you look for these combination studies to start next year? And just wondering with respect to a further widening therapeutic window. Thank you.

The selection of the optimal single-agent dose for pivotal studies is currently ongoing and we, like many other people, are feeling our way around that in the context of Project Optimus. But obviously we have a big vested interest in ensuring that we get the dose right or as close to right as we could possibly get in the context of Phase 1 dose escalation and expansion. I think you just have to trust that we'll do as good a job as we need to do and that we will choose a dose that is efficacious and tolerable over the long term. With regards to the potential for different doses in combination, I think we will always reserve the right to alter the dose of RMC6236 in combination if it is necessary to do so. As of today, the safety and tolerability profile that we're seeing does not automatically suggest that we will need to do that, but obviously as we start those I don't think we're expecting that we will have to modify the dose for combinations, but if we need to, then we reserve the right to do so.

Okay, that's helpful. Thank you so much. And maybe just a quick follow-up just on the data coming up for 6236. I know that this is going to be for the lung and pancreatic patients in the study. Just wondering if there's an update on the CRC cohort in the study. Thank you. We, as we

Phase 1 study, and there are a number of reasons for that. The intention is to get as close to a recommended Phase 2 dose as we can and then look at the activity and safety profile of RMC6236 in colorectal cancer without dose being a variable. So that's something that will happen in due course. Having said that, the update on safety and tolerability that we will provide will include a few patients with colorectal cancer, but I don't anticipate that being terribly informative for anybody from the perspective of efficacy. to evolve.

Okay, thank you. One moment, please. Our next question comes from the line of Jay Olson with Oppenheimer. Please proceed.

Oh, hey, thanks for taking the questions. Can you walk us through the rationale behind the doses that you've chosen for dose escalation of 6236 and the timing for when you expect to have a recommended phase 2 dose?

I think the question is, how are doses chosen in the dose escalation of 6236? I guess he's asking a question. What's the timing for getting to a recommended phase two?

Yeah.

Well, the dose escalation schema that we used was, we drew from a reasonably conservative assessment of what we saw in the GLP toxicity studies. And that led us to start at a relatively low dose of 10 milligrams daily. The percentage increase in dose from then on followed what has been somewhat perversely described Right now, we're investigating 400 milligrams daily. 300 milligrams daily was considered reasonably well tolerated. There were some toxicities observed, but not anywhere near enough for it to be called a maximum tolerated dose. And really, the timing for declaration of a recommended phase two dose really depends on what we see at the 400 milligram dose level. The cadence for Each dose level right now is somewhere between six weeks to two months per dose level. That's to get all the patients screened, enrolled, and treated, and then evaluated. So we'll see. I really don't know how close we are to the maximum tolerated dose or a recommended phase two dose and schedule at the moment. We just know that we're We're dosing and we will continue to dose escalate until we hit the top dose.

Okay. Thank you. Understood. And maybe just as a follow-up, can you elaborate on the timing of the initiation of pivotal studies for 6236 next year? And what factors will impact your decision on the number of pivotal studies you'll be initiating next year? Does it depend on closing the EQRX deal?

No, it's really not about the EQRx deal. It's much more technically driven. You and Steve just had a conversation about selection of the recommended phase two dose, which absolutely would be required. It would require FDA evaluation, consideration, and then their input into what that dose is. So that process in and of itself just takes a while. And that's after we have the data. And as you and Steve just discussed, we don't yet dictate a timing next year and you know that's pretty straightforward of an answer to it and then your second half of that sentence was you were asking a second part to that question how many face how many critical trials yeah one we're planning for one or more and You know, the details of that, again, would be best discussed in the context of data that will be disclosed at the ESMO meeting.

Thank you.

One moment, please.

Our next question comes from the line of Ami Fadia. With Needham, please proceed.

Hi, good evening. Thanks for taking my question. With regards to RNC 6236, can you talk about the current standard of care for patients in lung cancer and pancreatic and what is kind of the competitor there in terms of either response rates or duration of effect? And, you know, we've seen some preclinical data from 6236, which gave responses somewhere in the vicinity of 60% overall response rate. Where do you think data in the clinic could fall relative to that? Thank you.

Well, we certainly can't answer the last question, but we can try to answer the first question, and Dr. Kelsey is in the best position to do that.

It's easier just to focus on what happens to patients with non-small cell lung cancer and pancreatic cancer once they've failed their first line of chemotherapy for advanced disease, I think. Otherwise, I'll probably be here for about an hour. Most of the patients, all of the patients Right now, if you don't have a G12C mutation, then the standard of care is docetaxel. You know, there's an option to give a VEGF inhibitor such as raviserumab with the docetaxel, which has some impact on, a favorable impact on ANCA, but that's essentially the, that's the regulatory standard to which any way would be held. in that particular scenario of sort of, you know, grassroots all sorts of lung cancers failed platelet-double chemotherapy as a checkpoint inhibitor. And I think the, you know, the conventional outcomes are readily accessible from looking at the comparator arm from the angioscopic in the docetaxel on that study is a reasonable representation of what would happen in the real world with docetaxel. Patients with pancreatic cancer, it's very, it's much more complicated because there's not really a single established standard of care. Patients who are really thick can probably tolerate something like folferinoxal. And if they fail that, which they all do, there's not an awful lot left in the therapy to go on and enter it. So a lot of patients go on to clinical trials. Most of the clinical trials that have been published have been experimental versions of cytotoxic drugs. And frankly, the outcomes have been pretty poor. I mean, the response rates... are around 10% to 14%. And progression-free survival is anywhere between three to three and a half months. So those are the sort of standards that we're looking to be with RMC6236. But as Mark said, the data that we have, which won't be final data by a long shot because we're still dose escalating, the data that we will get at the data cuts immediately before the presentations will be what they are at the time. And neither Mark or I or you, unfortunately, can predict what we're going to see at this stage. All we know is that, you know, we presented some preliminary data back in February, and the data that we have coming in in real time has been directionally favorable.

Great. Thanks.

And maybe just a quick follow-up on 6291. Can you sort of talk to how you're thinking about what is sort of the bar in terms of safety that you'd like to see to be able to sort of explore combination therapy in first line?

Yeah, I think that's

I mean, firstly, the tolerability of any drug has got to be better than single-agent docetaxel. But when specifically with regards to RAS inhibitors, particularly RAS-G12C inhibitors, you know, the real test, I think, of whether any KRAS inhibitor is going to beneficial to patients in lung cancer is whether or not it can be combined with a checkpoint inhibitor. Checkpoint inhibitors are well established now in standard of care in non-small cell lung cancer. And it's very hard to find a niche where they're not recommended. I mean, even the meta-analysis of the food and that combining chemotherapy with an anti-PD-1 or anti-PD-L1 inhibitor is beneficial across the entire representation of patients with non-small cell lung cancer. So I think that's the real barometer of the safety tolerability profile for a RAS inhibitor. for stopping Pepronizumab. But of course, there's still a lot of Pepronizumab floating around in the blood, even a month after the last dose. So that's really the key, I think.

Thank you. One moment, please. Our next question comes from the line of Alex Stranahan with Bank of America. Please proceed.

uh hey guys thanks for taking our questions um two from us first um just to put a finer point on six two three six pivotal studies um obviously appreciating that the majority of this will will happen after the data at esmo but assuming that you see activity in say two or three tumor types or two or three different k-ras mutations Would the plan be then to pursue all of those in parallel for the broadest label possible, or would you prioritize certain tumors or certain mutations first and then seek for label expansions down the road? Then I've got to follow up.

Yeah, I think there are two parts to the answer. The first part, Alex, is very much we're committed to as much of a parallel approach to late stage development as is practical and as makes sense. And in fact, that's part of the motivation for the, you know, the EQRx acquisition is to make sure that we have the financial depth to be able to do so. So we are committed to pursuing things in parallel when there's a compelling, you know, path to do so. Obviously, that's are also now other external factors like the IRA that makes it much harder to pursue a serial program where you just continuously add on indications at the back end. That just becomes pretty meaningless from a commercial point of view. So I think both for good reasons and for extraneous With regard to your second question, or the second part of this, exactly which things will be included in that parallelized approach will depend on exactly what the data show. options around that. And it's just too early, though, to convey any of that until we can link it to data that you are able to see.

Okay, great. Thanks. And then just quickly on 5552, any framing you can provide around the update, we should expect at the triple meeting, given there was some single agent activity and the prior update, you know, number of patients, duration of follow-up, just broad strokes if you can. Thank you.

Yeah, well, I think it's important to keep in mind that the goal that we have for RMC5552 is to qualify it as a potential RAS companion inhibitor to be used in combination with RAS inhibitors, and particularly in combination with our RAS-on inhibitors. So that's really what we've been doing, and we've We felt that we had the time to do this carefully and to do dose optimization, which is really what we've been doing, dose optimization, and primarily to develop a dose going forward that we can work with in combination with Ransom inhibitors. So that's what you'll see is sort of more of that dose optimization. We don't the future, and we don't have yet today a plan to lay out for you about that.

Thank you. One moment, please. Our last question comes from Ben Burnett of Staple. Please proceed.

Hey, thank you. I want to just also ask about RMC 6236, the RAS multi-program. As you dose higher, are there plans to assess different dose schedules, or will the focus really be on a single schedule like a different dose is?

Yeah, I think we've made that pretty clear for the last number of maybe six months that we're using a daily dosing schedule that seems to be behaving well. We get good coverage over many hours after dosing. clear to us. It certainly isn't clear why one might increase the frequency of dosing. And the only advantage of decreasing the frequency would be if we could somehow drive to higher exposure levels at peak and then balance that with some sort of tolerability benefit by allowing exposures to fall over the interval. At the moment, we don't have explicit plans to evaluate those alternate kinds of schedules. We retain the flexibility to do so. We, of course, have a lot of experience with that from our RMC-4630 shift to inhibitor program, but we don't have any immediate plans or concrete plans to do so because the daily dosing is working out very well for us.

Okay. Okay, that's great. Now, if I could just add one more follow-up on RMC-6236. recognizing that you recently provided a bit of an update last week, but do you have any more clarity as to whether or not we might get to see some patient data at that 400-meg dose level in either of the October updates?

Don't know.

No, as in no patient data at 400-megs or no more clarity? Oh, yeah.

That was it. But I don't know the answer to the question of whether or not there will be any 400-milligram patients. If we have evaluation data at the time that we do a data cut, then we'll include those data. I mean, we're not handpicking which patients to include, but that's...

The answer is hopefully we'll have some early data, but I don't think we can guarantee that. Okay.

I appreciate it. Thank you all.

Thank you. I'm showing no further questions at this time. I would now like to turn the conference back to Dr. Mark Goldsmith for closing remarks.

Thank you, Operator. for your continued support of Revolution Medicine.

This concludes today's conference call. You may now disconnect.