Revolution Medicines Inc (RVMD) 2022 Q2 法說會逐字稿

Good day, my name is Christy, and I will be your conference facilitator today. Welcome to the Revolution Medicines' second-quarter 2022 earnings conference call. Today's call is being recorded. (Operator Instructions)

I would now like to hand the conference over to David Arrington, Revolution Medicines' SVP of Investor Relations & Corporate Affairs for opening remarks. David, you may begin.

Thank you, and welcome, everyone, to our second-quarter earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer; Dr. Steve Kelsey, the company's President, Research and Development; and Jack Anders, our SVP of Finance and Principal Accounting 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 press release as well as [follow] the company's filings with the SEC concerning these and other matters.

With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark?

Good afternoon and thank you for joining us. Today, I'll provide an update on our corporate progress. And our Senior Vice President of Finance, Jack Anders, will provide highlights of our financial results.

In the second quarter of 2022, Revolution Medicines, continued building strong momentum in the discovery and development of innovative medicines on behalf of patients with a wide range of RAS-addicted cancers, which represent 30% of all human cancers. We are advancing a deep and cohesive portfolio of RAS-targeted therapeutics led by our development-stage RAS(ON) inhibitors.

Recently, we reported significant progress across our pipeline, setting us up for an exciting period as our assets progress over the next 12 to 18 months. I'll now review a number of key achievements that reflect this recent progress regarding our pipeline of RAS(ON) inhibitors and RAS companion inhibitors.

First, we have advanced the first two drug candidates from our highly innovative RAS(ON) inhibitor portfolio into clinical development. In June, we began dosing patients in a Phase 1/1b trial, evaluating RMC-6236, our oral RASMULTI(ON) inhibitor in patients with tumors bearing various KRAS G12D mutations. The first patient treated with this drug candidate has advanced pancreatic cancer bearing the common KRAS G12D mutation.

RMC-6236, a bold compound that we have shown preclinically inhibits a wide range of RAS proteins that can drive cancer, is the first development candidate from our broad collection of RAS(ON) inhibitors to enter clinical development. And this step marks a significant milestone in our efforts to serve the unmet needs of patients with RAS-addicted cancers.

Additionally, I'm pleased to report that study site activation is underway for a Phase 1/1b trial of our second oral RAS(ON) inhibitor drug candidate, RMC-6291. And shortly, this study will begin dosing patients who have tumors harboring the KRAS G12C variant.

Unlike RMC-6236, RMC-6291 is designed as a highly selective covalent inhibitor of the activated or RAS(ON) state of the KRAS G12C variant that is common in lung and colorectal cancer. We have previously reported extensive preclinical data demonstrating its differentiated and promising anti-tumor profile. RMC-6291 is the first of a robust series of mutant-selective RAS(ON) inhibitors that we intend to bring into the clinic.

Our third RAS(ON) inhibitor drug candidate, RMC-9805, remains on track toward our goal of beginning clinical evaluation in mid-2023. We believe that RMC-9805 is the first oral covalent inhibitor of KRAS G12D, the most common RAS variant causing human cancer, particularly pancreatic, colorectal, and lung cancers.

Based on their preclinical profiles, we believe that, in aggregate, this first wave of RAS(ON) inhibitor drug candidates, RMC-6236, RMC-6291, and RMC-9805, has the potential to help serve the vast majority of patients with RAS-addicted cancers.

Second, in support of our goal to develop optimal treatment strategies directed to RAS-addicted cancers, we continued clinical evaluation of two class-leading RAS companion inhibitors -- our SHP2 inhibitor, RMC-4630; and our mTORC1 selective inhibitor, RMC-5552 -- both of which have shown clinical evidence of anti-tumor activity.

These RAS companion inhibitors are designed to be deployed primarily as combination agents with direct RAS inhibitors.

Our clinical collaborator, Amgen, recently reported encouraging preliminary evidence from its Phase 1b CodeBreaK 101 clinical study, suggesting promising and durable benefit from combining RMC-4630 with its KRAS G12C inhibitor, sotorasib, particularly in second-line treatment of patients with non-small-cell lung cancer who are KRAS G12C inhibitor naive.

We continue enrolling patients into our Phase 2 study of this combination, RMC-4630-03, in patients with KRAS G12C non-small-cell lung cancer. Additionally, Sanofi is now recruiting patients in its Phase 1/2 dose escalation and expansion study, evaluating RMC-4630 in combination with adagrasib in patients with previously treated lung cancer bearing a KRAS G12C mutation.

Further, we expect to evaluate RAS companion inhibitors in combination with our own RAS(ON) inhibitors in the future.

Now I'll shift to our corporate progress and comment on our focus for 2022 and 2023. In July, we successfully completed an equity financing, raising gross proceeds of $265 million to strengthen the company's balance sheet and overall financial position to support the continued development and expansion of our product pipeline.

Following this productive financing, in the remainder of 2022 and 2023, the company will take a disciplined approach to ensure a successful and timely execution of the multiple development-stage activities currently underway or planned. Our top priority is to deliver on important milestones during this time.

In this period, we intend to concentrate our development resources on our three most advanced RAS(ON) inhibitors, RMC-6236, RMC-6291, and RMC-9805; and two clinical-stage RAS companion inhibitors, RMC-4630 and RMC-5552.

Importantly, we maintain our strong commitment to research activities that provide critical scientific insights to support our ongoing development activities, and that also leverage our proven RAS Innovation Engine to generate exciting new mutant-selective RAS(ON) inhibitors with distinct profiles.

We expect to nominate our next RAS(ON) inhibitor development candidate in the second half of 2022, which will join a planned second wave of drug candidates, including RMC-8839, which we anticipate to begin clinical development after 2023.

With this R&D strategy and our current cash, cash equivalents, and marketable securities extending operating runway through 2024, we expect to deliver on important milestones. In our RAS(ON) inhibitor portfolio, upcoming milestones are as follows:

To provide evidence of first-in-class, single-agent activity for RMC-6236 in 2023, to announce dosing of the first patient in a monotherapy dose escalation study of RMC-6291 in the second half of 2022 and provide preliminary evidence of superior activity in 2023, and to announce dosing of the first patient in a monotherapy dose escalation study of RMC-9805 in mid-2023.

In our RAS companion inhibitor portfolio, upcoming milestones are as follows: to provide topline data from the RMC-4630-03 study of RMC-4630 plus sotorasib in 2023 and to disclose additional evidence of single-agent activity for RMC-5552 in 2023.

In summary, we remain deeply committed to our science-driven approach to treating patients with RAS-addicted cancers. And our pipeline and R&D efforts have entered an exciting and important phase.

The first wave of RAS(ON) inhibitors, which includes three differentiated drug candidates, has advanced significantly with RMC-6236 now dosing patients, RMC-6291 preparing to begin dosing patients shortly, and RMC-9805 continuing progress toward the clinic.

Our differentiated RAS companion inhibitors have shown evidence of single-agent clinical activity along the path towards strategic combinations with direct RAS inhibitors. And the first clinical evidence has now emerged in support of RMC-4630 as a RAS companion inhibitor combined with a RAS inhibitor.

As we intensify efforts to progress these assets to significant milestones in the coming period, we are also continuing to make significant investment pipeline expansion activities based on our productive RAS Innovation Engine.

Building on this exciting company momentum, I'll now turn to Jack Anders, our Senior Vice President of Finance, to provide a financial update. Jack?

Thank you, Mark. We are pleased to have strengthened our balance sheet in July with the upsized public offering of common stock, raising gross proceeds of $264.5 million. Net proceeds were approximately $248 million after deducting underwriting discounts, commissions, and estimated offering costs.

Our cash and investment balance as of June 30, 2022, was $461.4 million, which does not include proceeds from the financing. As a result of the financing and concentration of our development resources as described earlier by Mark, we are updating our cash runway guidance and now expect our current cash and investment balance to fund planned operations through 2024.

We have updated our 2022 financial guidance and lowered the top end of our 2022 GAAP net loss range by $10 million. We now expect full-year 2022 GAAP net loss to be between $260 million and $280 million. We are also lowering our estimated non-cash, stock-based compensation expense for the year and now expect full-year 2022 non-cash, stock-based compensation expense to be between $30 million and $35 million.

Turning to the quarter, revenue from our collaboration agreement with Sanofi was $9.1 million in the second quarter of 2022 compared to $8.7 million in the prior-year period.

Total operating expenses for the second quarter of 2022 were $71.2 million and increased by 34% over the prior-year period. The increase in operating expenses was largely due to expenses associated with our preclinical portfolio, increased headcount and related facilities and infrastructure costs, and stock-based compensation expense. Net loss for the second quarter of 2022 was $61.2 million or $0.82 per share.

And that concludes the financial update. I'll now turn the call back over to Mark.

Thanks, Jack. Revolution Medicines continues robust efforts to outsmart RAS-addicted cancers. And with recent scientific and business progress, we believe that the company is in an excellent position to fulfill our mission on behalf of cancer patients.

This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

(Operator Instructions) Marc Frahm, Cowen and Company.

Hey, thanks for taking my questions. (Technical difficulty) prioritization and making sure you prove out SHP2 and the companions on one side and the RAS(ON) makes a lot of sense.

But as you hopefully find some efficacy signals with the direct RAS inhibitors, Mark, how do you weigh the pros and cons of using your limited resources to rapidly expand out that positive signal with combinations versus using that as proof of concept for the platform and then rapidly falling behind with things like the G13C and more target-specific inhibitors?

(Technical difficulty) on inhibitor, which is our highest priority to move additional RAS(ON) inhibitors in the clinic, or to expand out the work around the inhibitor that's been shown to be active as monotherapy, is that your question?

Yes.

I'm not sure we're going to have to make a choice at that point. Clearly, once one has a clinical signal, the priority is going to be to move that asset forward and develop, as quickly as possible, a supporting package to move into a registration program, ending towards an approval. So we'll do whatever it takes to pull that off.

But I also think a fair point is that amongst the three initial routes on inhibitors that are going into the clinic, while they do cover the vast majority of our RAS-addicted cancers in aggregate, there is also real opportunity for specialized additional inhibitors that are targeting specific mutants beyond those.

And you mentioned KRAS G13C. We talked about and included in our pipeline a reference to other mutants that are of interest to us. So those are important, too. I don't think they'll really compete for resources at that stage. We'll continue company growth. I think this decision to be very focused, to be honest, is to be very focused on five assets in the clinic. It's not as if we pared back to a small program.

There's a lot going on, but we know that all eyes are on these first three progress RAS(ON) inhibitors and also to see the best companion inhibitors mature. And so, we just want to make sure that we are sufficiently focused. I think it's less about resources and more about concentrating our intellectual bandwidth and effort around those things at this stage.

Okay. That's helpful. And can you just remind us what you can view as [gating] from these initial trials with 6236 and 6291 before you might -- more so on 6291 -- before you might bring in the SHP2 inhibitor and start dosing the combination?

Okay, yeah. Maybe that's a question Steve Kelsey wants to comment on. I think the question is what would trigger expansion into combinations, which Marc had mentioned, but I think we'd have to include both RMC 4630 and RMC-5552 and also, of course, anti-PD-1 in the logic of checkpoint inhibitors?

Yes, it's a great question. I think the current strategy is to start the combination programs as soon as we can. And of course, then begs the question, what do we need to know before [we can]. And I think the very basics there are we really need to have just about enough information to believe we have a drug. There's not much point in combining with something that's inactive.

And then, on a tactical level, we really need to have a very good sense of what the schedule is because it's very difficult to do combination studies if you're trying to test more than one variable. And we really don't want to be testing the schedule -- different schedules in combination. So I think those are the two fundamental things that we really have to understand.

But the reality is, all along, even though we have expectations with RAS -- with mutant RAS, having been validated as a target for single-agent therapy, all along, I think we believe that combinations are going to ultimately have the biggest impact.

So starting those as soon as we can, hopefully, will give us a head start when we start looking at the optimal treatment regimens for getting into pivotal trials and particularly into the first-line space for any RAS mutant indications, of which there are really three major epithelial malignancies, all crying out for the treatments [that we have].

Okay. Thank you. Very helpful.

Thanks, Marc.

Alec Stranahan, Bank of America.

Hey, guys, thanks for taking the question. Just a couple from us. The combo data looked quite good from CodeBreaK 101 and tolerability through the dose escalation. No grade for adverse events. I guess, could you give us a sense of what dose of RMC-4630 is being taken forward in this context?

I imagine your own study could help further inform this, but it sounds like perhaps the highest 20-mg dose could be the one you ultimately go with. And as a follow-up to that, is your expectation that response rates could even improve, say, beyond 50% in the G12C-inhibitor-naive patients at the set dose and the expansion phase?

And then my second question, with your fifth RAS(ON) asset nominated later this year, how are you guys approaching which RAS(ON) to prioritize as to the size of the end markets, unmet need, drug ability of the target, potential for combos? I guess, what is leading your decision making here? Thanks.

Alec, thanks very much. I think maybe Steve can address the first two questions, the two-part question, and maybe then I'll comment on the RAS(ON)

Yeah, nothing has really changed from the last earnings call. The study design for the RMC-4630-03 study, which is the one that we are sponsoring, which is a global Phase 2 study, and it's completely restricted to patients who have not previously received the KRAS inhibitor.

The plan all along was to do a safety run-in at the 140-milligram dose level and then dose escalate to 200 milligrams and keep expanding at the 200-dose level until we either got a very clear efficacy signal or that we ran into issues with tolerability at that dose level.

And that's still the plan, and we're still enrolling that study. It's moving along. We haven't disclosed any data as to where we are, perhaps -- but it's rolling along very nicely right now.

Your question about whether or not the response rate is more than 50%, well, I think we would say -- there are two things I think that we would say. One is, of course, it's possible that the response rate for the combination will be 150%.

The initial signals that were presented at the World Lung Congress, even though the number of patients was very small, if you actually just look at the four patients who were treated as at the 140-milligram and 200 milligram dose level, which are the two doses being tested in the 03 study, there were only four patients who -- with lung cancer but were G12C naive and were treated with either of those two dose levels, and three of them responded.

So that gives you a 75% response rate, even though the denominator is only four. So the confidence [circles] around that 75%, extremely wide, of course.

The other thing to bear in mind is, of course, that just increasing the response rate is probably insufficient, partly because, really, what patients and investigators want is durability, and partly because any pivotal trial that we would do with that combination, response rate wouldn't be the primary endpoint. It would be progression-free survival.

So we have to keep a very close eye, not just on the percentage of patients with -- who have tumors that shrink, but also on the temporal endpoints as well. The number of patients with stable disease and the durability of that stable disease is just as important as the number of patients who have a [resist PR].

And this is Mark. I'll comment on your second question, which was how will we choose which additional inhibitors we would advance, or how will we prioritize them? It's a very complicated question versus a simple question with a complicated answer. There are a lot of different dimensions to consider.

The real strategy here, of which I hope we conveyed that it's worth reiterating, is that we're not taking the foot off the accelerator, creating these new assets. That work is still very vigorous. And essentially, what we're doing is creating a basket of additional development candidates.

The first one in the basket is, of course, RMC-8839 on G13C, but there are others that will come behind that as you pointed out our next one this year. And one would imagine there will be more to come after that. And so, with that basket, we'll get to choose, and we'll prioritize.

One of the important considerations here is we're going to learn a lot from RMC-6236, RMC-6291, and RMC-9805. And those are three very distinct molecules with very distinct features, and we will learn a great deal from the early clinical experience with those. And I think that may guide us. It may guide us as to genotypes where the unmet need remains the highest after we see something from these three.

It may guide us to which genotypes are most sensitive to RAS inhibitors. It may guide us to covalency versus non-covalency selectivity versus multiple targets, et cetera. So there are a lot of really important scientific and clinical questions varied into the signals that we'll get from this. And I'm sure that that will significantly impact us, probably more so than, let's say, market size or something like that.

But I wouldn't rule that out as some consideration. But I think the main thing we focus on tends to be probability. What's the likelihood that a given asset will actually provide clinical benefit in a given situation? And that's the kind of information we'll learn from these first three -- the first wave of RAS(ON) inhibitors.

Thank you.

Thank you.

Jonathan Chang, SVB Securities.

Hey, guys, thanks for taking my questions. First question, can you provide any color around the progress of the Phase 2 RMC-4630-03 study? Earlier in the year, the guidance was for topline data in the second half versus 2023 now. Also, can you help set expectations for how much and what kind of data could be available on the topline disclosure?

Yeah. Maybe I'll answer this. At least take first crack at it, which has to do with our notation that we will provide the next data readout will be the topline data set and that we won't provide an interim readout at the end of this year. That was really driven primarily by the fact that the CodeBreaK 101c data were going to be and now have been disclosed.

And so, in essence, one's already gotten a glimpse of what things could look like on an interim basis. And it didn't seem to us, and to a number of investors speaking to us, that anybody would really care about another interim update and that was really needed is a more definitive answer. Does RMC-4630 provide additive value to sotorasib in second-line, non-small-cell lung cancer?

And we think that the study will do that, but we just didn't see any value in giving another sort of drip-drip-drip of data on it. I think that's the main issue. A secondary factor or second factor is the enrollment pace wasn't quite on with what we expected initially. And so, we will continue enrolling some patients into the first part of 2023.

And so, again, not having every patient enrolled and having just a partial dataset to us didn't seem like it was meritorious. Your second question?

What readouts will we provide?

Perfect. Dr. Kelsey just provided the question, and he can provide the answer.

I mean, I think the answer I gave to the last question probably sums it up as best I can, really. The most obvious readout will be overall response rates because that is actually primary endpoint of this study. But as I said, it's becoming increasingly important to us not just to look at response rate, but to look at durability.

I think, given that the study started enrolling last September, by the time we get the response rate data on the last patient in of the progression-free survival duration -- progression-free survival data for the first [translation] is relatively mature. So I think you can expect to see both absolute response-rate data, durability of response, and progression-free survival from the cohort.

And hopefully, we will be able to make a meaningful comparison to the CodeBreaK 100 study, which was the pivotal trial of single-agent sotorasib. We tried to, wherever possible, match the CodeBreaK 100 study in the design of our study so that we -- specifically so that we can draw those comparisons. And I think that's hopefully what we'll be able to provide.

Obviously, the other thing you'll see is the tolerability profile as well because there's been a snapshot of that provide from CodeBreaK 101c, but the heterogeneity of the patient population that was presented [over the weekend] doesn't really give you a robust assessment of the tolerability in that exclusively defined G12C naive non-small-cell lung cancer population.

Got it. Thanks for taking my questions.

Thank you.

Benjamin Burnett, Stifel.

Hi, good afternoon. This is Neil Carnahan on for Ben. Thanks for taking our question. For the Phase-1 RMC-6291 study, can you characterize enrollment criteria a bit? More specifically, what patients had been previously treated with the KRAS inhibitor? Or will you be mainly pursuing patients that are KRAS inhibitor naive?

Yeah, there will be some component of both, I'm sure. But maybe Steve can lay that out for you.

Yeah, the answer is that the eligibility criteria for the study right now are very similar to the CodeBreaK 101 -- well, [CodeBreaK 100]. So in the initial phases of the study, pretty much anyone with any tumor harboring (inaudible) patients eligible, irrespective of whether they received the previous KRAS inhibitors or not.

As we get into the higher-level dose escalations, and certainly at the recommended Phase 2 dose and schedule, we will be deliberately enrolling defined cohorts with defined -- based on criteria defined by tumor histotype and whether or not they have or have not received the KRAS G12C inhibitor.

The primary population of interest for the study ultimately are, obviously, patients with lung cancer who have not received a G12C inhibitor because that way, you can make a comparison against the G12C(ON) inhibitor. There is some reason to believe that RMC-6291 might have activity in patients who have been in the G12C(ON) inhibitor.

That's not our primary focus as a single agent. It may become a very important focus when we start combining RMC-6291 with other drugs in our portfolio, particularly on RMC-6236.

Great. Thank you.

Thank you.

Noah Eisenberg, JPMorgan Chase.

Hi guys. This is Noah on for Eric. Thanks for taking our question. We're just wondering, given some of the data at World Lung this past weekend, do you think the observed tolerability profile of combining KRAS inhibitors and PD-1s could be a class effect or specific to individual molecules?

Yeah, hi Noah. Thanks for your question. Of course, it's a little bit hard to tell right now, but there have been a number of compounds, G12C inhibitors, that have shown a [liver signal], which one would not be surprised, and that that would be exacerbated when it's combined with a checkpoint inhibitor that has -- that can cause inflammation in the liver, at least elevated LFTs.

So that additivity, I think, isn't surprising if you have monotherapy LOCF analyses. Your question, though, is that due to a biological interaction between the G12C inhibitor and a PD-1 inhibitor is due to chemical features.

And we don't know but given that many of the first-generation G12C inhibitors share either an entire chemical scaffold or chemical moieties related to one another, it's not too surprising if those compounds all have a similar effect within the liver.

Now from our point of view, a big question is, does that read through to our compounds, which is, of course, what we're focused on developing. And there really isn't chemical similarity. We started from a completely different chemical starting point, binding to a completely different site on RAS, and binding to a really different state of RAS -- RAS(ON) versus RAS(OFF).

So there really isn't any obvious read through. And since we don't have a good hypothesis as to why a generic G12C inhibitor biologically should cause LFT abnormalities to full stop, we don't have any hypothesis around that. We don't see any reason why that ought to read through to the RVMD RAS(ON) inhibitor collection.

Great. Thank you, very helpful.

Thank you.

(Operator Instructions) Michael Schmidt, Guggenheim Securities.

Hi, this is Yige for Michael, thanks for taking our questions. And congrats on the progress with the first two KRAS inhibitors. Starting off a question on RMC-6236. You previously mentioned some preclinical rationale that RMC-6236 can be used as a targeted inhibitor for certain G12C mutants -- G12 mutants and also with a potential RAS companion inhibitor.

Now that the compound is in the clinic, how would you prioritize the two strategies, or are you going to evaluate them parallelly after RMC-6291 enters the clinic?

And then a second quick question on RMC-6291. It looks like you're evaluating both once and twice daily in the upcoming Phase 1. So just -- what are some of the considerations to test both schedules? And does the preclinical PK data provide any rationale that one could be better than the other? Thank you.

Okay. Thanks for your questions. The first question, which is, what's the priority with RMC-6236 to test it as monotherapy or to test it as a companion inhibitor? Well, as pretty straightforward for us, you have to evaluate it as monotherapy and demonstrate that it's tolerated and active before you really qualify it to be used as a companion inhibitor.

With that said, though, you don't necessarily require the complete data package to convince you that you have a path forward to registration as a monotherapy before you start the RAS companion combinations.

So in other words, I think we'd start that fairly soon after we have some confidence around its anti-tumor activity and how well tolerated and safe it is. I think we would look very much towards combinations with selected other RAS(ON) inhibitors but clearly phase in that way. The monotherapy is the thing to keep one's eyes on initially.

And the second question was -- ?

The scheduling of RMC-6291 --

Daily versus the IV dosing? I don't think we've ever talked much about the IV dosing. Is there something behind that question that you're that you're alluding to?

It's just based on information on [ct.gov]. It looks like both schedules are going to be evaluated, so I just wanted to get -- ?

Yeah. So I think the question there is really just about how much continuous exposure one gets from daily versus twice-daily dosing. There was a really great visibility around this topic with regard to the first-generation inhibitors RAS(OFF) inhibitors because if you're not covering them and keeping them trapped in the RAS(OFF) form, you have a really easy escape mechanism, which is [for the cell] to simply to shift the RAS(OFF) pool over to RAS(ON).

And so, as a result, the general feeling in the field is that you need to continuously cover the entire RAS(OFF) pool and try to keep it from converting to RAS(ON) at any point in time. And of course, Mirati made a point of that, both with regard to the long half-life of adagrasib and then subsequently to the IV dosing with a long half-life product.

It's not entirely clear that that concept applies equally well to RAS(ON) inhibitors. It's really a little bit of a different mechanism, and it's a dramatically different mechanism but different dynamic. And so, it's not really clear that that level of continuity is necessary.

And secondly, it's not clear that RMC-6291 given daily wouldn't provide that sort of continuous coverage. It may well -- in fact, in mouse studies, it covers it very, very well. So I think that's really in the protocol. You can comment on this, but I think it's in the protocol.

Simply acknowledging that continuous coverage is something we want to make sure we understand, whether that's needed, and make sure that we have a dose schedule -- a dosing schedule that could provide if daily dosing is not sufficient.

Yeah, we quite often write into our protocols the option to evaluate alternative schedules right upfront because it saves you having to write an amendment if you find that the PK is not tracking with your predictions, and you have to go back and test another schedule.

But I think, as Mark pointed out, our preclinical data suggests that we can cover the target in mice with once-daily dosing, and so, whether or not we'll ever have to test them at a different schedule in the clinic remains to be seen.

I think it needs some clinical PK data first before we can decide, but it's definitely not a done deal. We're not necessarily going to test another schedule. And even if we do, it's not necessarily going to be twice-a-day dosing.

That is very helpful. Thank you.

Thank you.

As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines. Have a good day.

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