Q2 2022 Revolution Medicines Inc Earnings Call

August 9, 2022

Operator: Good day. My name is Christy, and I will be your conference facilitator today. Welcome to the Revolution Medicines Q2 2022 Earnings Conference Call. Today's call is being recorded. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a question-and-answer session. To ask a question at that time, please press star, then the number 1 on your telephone keypad. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to David Arrington, Revolution Medicines SVP of Investor Relations and Corporate Affairs, for opening remarks. David, you may begin.

Operator: Good day. My name is Christy, and I will be your conference facilitator today. Welcome to the Revolution Medicines Q2 2022 Earnings Conference Call. Today's call is being recorded. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a question-and-answer session. To ask a question at that time, please press star, then the number one on your telephone keypad. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to David Arrington, Revolution Medicine's SVP of Investor Relations and Corporate Affairs, for opening remarks. David, you may begin.

Good day My name is Christie and I'll be your conference facilitator today welcome to the resolution Medicine second quarter 2022 earnings conference call today's call is being recorded.

At this time all participants are in a listen only mode. Following management's prepared remarks, we will hold a question and answer session to ask a question at that time. Please press Star then the number one on your telephone keypad. If anyone has difficulty hearing the conference. Please press star zero for operator assistance I would now like to.

I hand, the conference over to David Errington resolution medicines.

P of Investor Relations and corporate affairs for opening remarks, David you may begin.

David Arrington: Thank you, and welcome everyone to our Q2 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.

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 Companys, President research and development and.

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. The 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 except as required by law. The company undertakes no obligation to revise or update any forward looking statements.

David Arrington: I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release, as well as all of 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.

I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release as well as <unk>.

All with the Companys filings.

With the SEC concerning these and other matters with that I will turn the call over to Dr. Mark Goldsmith.

Evolution medicines, Chairman and Chief Executive Officer Mark.

Mark Goldsmith: 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 Q2 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.

Good afternoon, and thank you for joining us today I'll provide an update on our corporate progress.

Our senior Vice President of Finance, Jack Anders, who 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 will now review a number of key achievements that reflect this recent progress regarding our pipeline of Ras on inhibitors and Ras companion inhibitors.

Mark Goldsmith: 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 RAS multi(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. This step marks a significant milestone in our efforts to serve the unmet needs of patients with RAS-addicted cancers.

First we have advanced the first two drug candidates from our highly innovative rason inhibitor portfolio into clinical development.

In June we began dosing patients in a phase <unk> trial evaluating RMC 6236.

Oral Ras multi <unk> inhibitor and.

Patients with tumors bearing various <unk> mutations.

The first patient treated with this drug candidate has advanced pancreatic cancer bearing the common <unk> mutation RMC.

RMC 63, 6% a bold compounds that we have shown pre clinically 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.

Mark Goldsmith: 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. 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 antitumor 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.

Additionally, I am pleased to report that study site activation is underway for a phase <unk> trial of our second oral <unk> inhibitor drug candidate RMC six to 91 and.

And shortly this study will begin dosing patients who have tumors harboring the K Ras <unk> Steve area.

Unlike RMC 63, six RMC 60, 91 is designed as a highly selective covalent inhibitor of the activated or Ras on state of the K Ras <unk> variant that is common in lung and colorectal cancer.

We have previously reported extensive preclinical data demonstrating its differentiated and promising antitumor profile.

RMC 69, one is the first of a robust theories of mutant selective <unk> inhibitors that we intend to bring into the clinic.

Our third Rason inhibitor drug candidate RMC 98 O five remains on track toward our goal will be getting clinical evaluation in mid 2023.

Mark Goldsmith: 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 continue 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 antitumor activity. These RAS companion inhibitors are designed to be deployed primarily as combination agents with direct RAS inhibitors.

We believe that RMC 95 is the first oral covalent inhibitor of <unk>, the most common rasp areas, 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 60, 366 to nine one and $90 five <unk>.

<unk> 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 continue clinical evaluation of two class leading Ras companion inhibitors are shipped two inhibitor RMC for six <unk> and our <unk> selective inhibitor RMC $5 55 to both of them.

Which have shown clinical evidence of antitumor activity.

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

Mark Goldsmith: 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 II 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 I/II 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 our RAS Companion Inhibitors in combination with our own RAS(ON) inhibitors in the future.

Our clinical collaborator collaborator Amgen recently reported encouraging preliminary evidence from its phase <unk> code break 101 clinical study.

Suggesting promising and durable benefit from combining RMC for <unk> with its <unk> inhibitor soda rasset, particularly in second line treatment of patients with non small cell lung cancer <unk> inhibitor naive.

We continue enrolling patients into our phase III study of this combination RMC for <unk> three in patients with <unk> non small cell lung cancer.

Additionally, <unk> is now recruiting patients in its phase <unk> dose escalation and expansion study evaluating RMC for six Rio in combination with <unk> in patients with previously treated lung cancer bearing a <unk> mutation.

Further we expect to evaluate our Ras companion inhibitors in combination with our own rason inhibitors in the future.

Mark Goldsmith: 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 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.

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 companys 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 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.

Mark Goldsmith: 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 H2 2022, which will join a planned second wave of drug candidates, including RMC-8839, which we anticipate to begin clinical development after 2023.

In this period, we intend to concentrate our development resources on our three most advanced grass on inhibitors pharmacy, 63, 669, 1% and $90 five and two clinical stage Ras companion inhibitors RMC for six REO and 555 two.

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 raskin of Gen engine to generate exciting new mutant selective rason inhibitors with distinct profiles.

We expect to nominate our next Ras on inhibitor development candidate in the second half of 2022, which.

Which will join a planned second wave of drug candidates, including RMC $83, nine, which we anticipate to begin clinical development after 2023.

Mark Goldsmith: With this R&D strategy and our current 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 H2 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.

With this R&D strategy and our current cash cash equivalents in marketable securities extending operating runway through 2024.

We expect to deliver on important milestones.

Rason inhibitor portfolio upcoming milestones are as follows to provide.

Evidence of first in first in class single agent activity for RMC 63, six in 2023.

To announce dosing of the first patient in a monotherapy dose escalation study of RMC 60, 91 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 nine 805 in mid 2023.

Mark Goldsmith: In our RAS companion inhibitor portfolio, upcoming milestones are as follows, to provide top-line 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.

In our Ras companion inhibitor portfolio upcoming milestones are as follows.

To provide topline data from the 460 <unk>, both three study of <unk> plus <unk> in 2023.

And to disclose additional evidence of single agent activity for RMC $555 two in 2023.

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

The first wave of Rason inhibitors, which includes three differentiated drug candidates has advanced significantly with RMC six to $3 six now dosing patients.

690, <unk> preparing to begin dosing patients shortly and RMC 98, five 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 rasp inhibitors.

Mark Goldsmith: 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 a significant investment in 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?

And the first clinical evidence has now emerged in support of RMC for six Rio as a Ras companion inhibitor combined with the Ras inhibitor.

As we intensify efforts to progress these assets two significant milestones in the coming period. We are also continuing to make a 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.

Jack Anders: 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 30 June 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.

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 32022, with $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.

Jack Anders: We now expect full year 2022 GAAP net loss to be between $260 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 and $35 million.

We now expect full year 2022, GAAP net loss to be between 260 and $280 million.

We are also lowering our estimated noncash stock based compensation expense for the year and now expect full year 2022, noncash stock based compensation expense to be between 30 and $35 million.

Jack Anders: Turning to the quarter. Revenue from our collaboration agreement with Sanofi was $9.1 million in Q2 2022 compared to $8.7 million in the prior year period. Total operating expenses for Q2 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 pre-clinical portfolio, increased headcount and related facilities and infrastructure costs, and stock-based compensation expense. Net loss for Q2 2022 was $61.2 million or $0.82 per share. That concludes the financial update. I'll now turn the call back over to Mark.

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, or <unk>, $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 head count and related facilities and infrastructure costs and.

And stock based compensation expense.

Net loss for the second quarter of 2022 was $61 2 million or <unk> 82 per share.

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

Mark Goldsmith: Thanks, Jack. Revolution Medicines continues robust efforts to outsmart RAS-addicted cancers. 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?

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 will now turn the call over to the operator for the Q&A session.

Later.

Operator: As a reminder, if you would like to ask a question during this time, simply press star, then the number one on your telephone keypad. Again, that's star one. Your first question comes from the line of Marc Frahm with Cowen and Company. Your line is open.

As a reminder, if you'd like to ask a question. During this time simply press Star then the number one on your telephone keypad again Thats Star one.

Your first question comes from the line of Marc Frahm with Cowen <unk> Company. Your line is open.

Marc Frahm: Yes, thanks for taking my questions. The prioritization and kind of making sure you prove out SHP2 and the companions on one side and the RASons makes a lot of sense. As you hopefully find some efficacy signals with the direct RAS inhibitors, Mark, how do you weigh the kind of pros and cons of, you know, using your limited resources to rapidly expand out that, you know, positive signal with combinations versus, you know, using that as proof of concept for the platform and then kind of rapidly following behind with things like the G13C and more, you know, target specific inhibitors?

Hey, Thanks for taking my questions.

Prioritization.

Sir you prove out ship too.

Canyons on one side and the rats on it makes a lot sense, but you guys you hopefully.

Efficacy signals with the direct the direct Ras inhibitors.

How do you weigh the pros and cons of using near limited.

Limited resources to <unk>.

Happily expand out that.

Positive.

Signal with combinations versus.

You think thats proof of concept for the platform and then rapidly following behind with things like the <unk> and more.

Target specific inhibitors.

Okay.

Mark Goldsmith: inhibitor, which is our highest priority to move additional RAS(ON) inhibitors into the clinic or to expand out the work around the inhibitor that's been shown to be active as monotherapy. Is that your question?

So an inhibitor.

Which is our highest priority to move additional lessor inhibitors in the clinic.

Or to expand out the workarounds.

<unk> inhibitor has been shown to be active as monotherapy.

This does answer your question.

Marc Frahm: Yep.

Yes.

Mark Goldsmith: Yeah. You know, I'm not sure we're gonna have to make a choice at that point. You know, clearly once one has a clinical signal, the priority is gonna be to move that asset forward and develop as quickly as possible supporting package to move into, you know, a registration program in towards an approval. So we'll do whatever it takes to you know pull that off. But I also think a fair point is that amongst these three initial RAS(ON) inhibitors that are going into the clinic, while they do cover the vast majority of RAS-addicted cancers in aggregate, there is also real opportunity for specialized additional, you know, inhibitors that are targeting specific mutants beyond those.

Yes.

Hi.

I'm not sure we're going to have to make a choice.

At that point.

Clearly.

<unk> has a clinical signal the priority is going to be the move.

And move that asset forward and develop.

It's possible supporting package to move into.

Registration program.

And towards an approval.

So we will do whatever it takes.

You can pull that off but I also think a fair point is that amongst the three initial rasp inhibitors that are going into the clinic, while they do cover <unk>.

Vast majority of addicted cancers in aggregate.

There is also real opportunity for specialized additional.

<unk> inhibitors that are targeting specific.

And those.

Mark Goldsmith: You mentioned, you know, KRAS G13C, we talked about and included in our pipeline 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. You know, we'll continue company growth. I think this decision to be very focused, you know, to be honest, is to be very focused on five assets in the clinic. It's not as if we paired back to a small program. You know, there's a lot going on, but we know that all eyes are on, you know, these first three RAS(ON) inhibitors and also to see the RAS Companion Inhibitors mature. We just wanna make sure that we are sufficiently focused.

And you mentioned.

<unk>, we've talked about.

Included in our pipeline Rep.

Reference to other et cetera are of interest to us.

Those are important too I don't think they'll really compete for resources at that stage.

Well continued company growth.

I think this decision to be very focus.

To be honest is to be very focused on five assets in the clinic, it's not as if we pair.

<unk> back to a small program, there's a lot going on but we know that.

<unk> are on these first three Ras inhibitors and also to see the Ras companion inhibitors mature.

And so we just want to make sure that we are sufficiently focus I think less about resources and more about concentrating our intellectual bandwidth.

Mark Goldsmith: I think it's less about resources and more about concentrating our intellectual bandwidth and effort around those things at this stage.

Around those things SSD.

Marc Frahm: Okay. That's helpful. Can you just remind us what you view as gating from these initial trials with RMC-6236 and RMC-6291, more so on RMC-6291, before you might bring in the SHP2 inhibitor and start dosing the combination?

Okay.

It's helpful. And then can you just remind us what you.

You can view is gaining from these initial trials with 63 6691 before you might have.

<unk> hundred 60, 91 before you might bring in the ship two inhibitor.

Start dosing the combination.

Mark Goldsmith: Okay. Yeah, maybe that's a question that Steve Kelsey wants to comment on. I think the question is what would trigger expansion into combinations which, you know, Mark didn't mention it, but I think we'd have to include both the RMC-4630 and RMC-5552, and also of course, anti-PD-1 immunological checkpoint inhibitors.

Oh, Okay, yes.

Maybe that's a question Steve Kelsey wants to comment on I think the question is what would trigger.

It's a combination switch.

Mark had mentioned it but I think we'd have to include both RMC.

505, two and also of course anti PD one.

The logic checkpoint inhibitors.

Stephen Kelsey: Yeah. It's a great question. I think the current strategy is to start the combination programs as soon as we can. That of course then begs the question, what do we need to know before we can? 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. Then at a sort of 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. We really don't want to be testing the schedule, different schedules in combination. I think those are the two fundamental things that we really have to understand.

Steve Kelsey: Yeah. It's a great question. I think the current strategy is to start the combination programs as soon as we can. That of course then begs the question, what do we need to know before we can? 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. Then at a sort of 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. We really don't want to be testing the schedule, different schedules in combination. I think those are the two fundamental things that we really have to understand.

Yes.

Great question.

The.

I think the.

Colorado.

Jean.

Is <unk>.

Combination programs.

As we.

And then thanks for the question.

Needs, what do we need to know before.

And I think the.

Thanks.

We really need to.

Just not enough information.

Thanks, Rob.

Another point and combine it with something that synapses.

And this works.

The skill level, we really need to have a very good sense.

Because it's very difficult to do.

Combination studies that you're trying to assess the one variable.

Really don't want to see.

Testing the schedules.

And competition. So I think those are the two.

Fundamental.

Things that we really have to.

Stephen Kelsey: The reality is that I, you know, 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 the combinations are going to ultimately have the biggest impact. 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 indication, of which, as you know, there are really three major epithelial malignancies all crying out for the better treatments like that.

Loans.

Yes.

Steve Kelsey: The reality is that I, you know, 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 the combinations are going to ultimately have the biggest impact. 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 indication, of which, as you know, there are really three major epithelial malignancies all crying out for the better treatments like that.

But the reality is right.

Even though.

Issues.

Congrats.

<unk> as a target.

Simulation World.

Thank you for the call.

The result ultimately.

So.

<unk> seen those as soon as we can.

Hopefully it will give us.

When you start looking at me.

Optimal treatment regimen of soul.

Getting into pivotal trials, particularly into the slot of.

Or any.

Any rough.

Visitation, which as you know.

Really three major off the table.

Got it.

Treatments.

Marc Frahm: Okay. Thank you. Very helpful.

Okay. Thank you very helpful.

Stephen Kelsey: Thanks, Mark.

Steve Kelsey: Thanks, Mark.

Thanks, Bob.

Operator: Your next question comes from the line of Alex Stranahan with Bank of America. Your line is open.

Your next question comes from the line of Alec Stranahan with Bank of America. Your line is now.

Yeah.

Alex Stranahan: Hi. Hey, guys. Thanks for taking the questions. Just a couple from us. The combo data looked quite good from some CodeBreaK 101, tolerability through the dose escalation, no grade four or adverse events. I guess, could you give us a sense of what dose of RMC-4630 is being taken forward in this context? Like, I imagine your own study could help further inform this, but it sounds like perhaps the highest 200 mg dose could be the one you ultimately go with. 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 sort of the set dose in the expansion phase?

Alec Stranahan: Hi. Hey, guys. Thanks for taking the questions. Just a couple from us. The combo data looked quite good from some CodeBreaK 101, tolerability through the dose escalation, no grade four or adverse events. I guess, could you give us a sense of what dose of RMC-4630 is being taken forward in this context? Like, I imagine your own study could help further inform this, but it sounds like perhaps the highest 200 mg dose could be the one you ultimately go with. 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 sort of the set dose in the expansion phase?

Hey, guys. Thanks for taking the question just a couple from us.

Combo data looked quite good from some code break 101, tolerability with the dose escalation and no grade four.

Adverse events.

Can you give us a sense of what dose of RMC 46, 30 is being taken forward in this context, but I imagine your own study could help further inform that it sounds like perhaps the highest 200 Meg dose could be the one that ultimately go with and as a follow up to that is your expectation that response rates could even improve.

Beyond 50%.

And the <unk> inhibitor naive patients.

At sort of the set dose in the expansion phase and then.

Alex Stranahan: My second question, you know, with your fifth RAS asset nominated later this year, you know, how are you guys approaching which RAS variants to prioritize? Is it the size of the end markets, unmet needs, druggability of the target, potential for combos? I guess, what's sort of leading your decision-making here? Thanks.

Alec Stranahan: My second question, you know, with your fifth RAS asset nominated later this year, you know, how are you guys approaching which RAS variants to prioritize? Is it the size of the end markets, unmet needs, druggability of the target, potential for combos? I guess, what's sort of leading your decision-making here? Thanks.

My second question with your fifth rats on at that number.

M&A is later this year, how are you guys approaching which raspberry prioritize with the size of the end markets unmet need drug ability of the target potential for combos, I guess, what sort of leading <unk>.

Isn't making sure thanks.

Mark Goldsmith: Alex, 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 one.

Alex 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 on the Russell.

Stephen Kelsey: Yeah. 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 140mg dose level and then dose escalate to 200 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. That's still the plan, and we're still enrolling that study. It's moving along.

Steve Kelsey: Yeah. 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 140mg dose level and then dose escalate to 200 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. That's still the plan, and we're still enrolling that study. It's moving along.

Yes, no nothing nothing has really changed from the last earnings call.

The study design for the <unk>.

Three seven which is the one that we are sponsoring which is global.

Phase III study.

And it's completely restricted to patients who have not previously received a <unk> inhibitor.

The plan all along was to do.

Do a safety run in as the 140 milligram dose level and then.

Thanks, then dose escalate to 200, and keep expanding 200 dose level until we either got a very clear signal that we run into issues with tolerability at that dose level and that's still the plan I was still enrolling.

That study is.

Stephen Kelsey: We haven't disclosed any data as to where we are, but it's rolling along very nicely right now. Your question about whether or not the response rate is likely to be 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 higher than 50%.

Moving along we haven't disclosed the study.

Steve Kelsey: We haven't disclosed any data as to where we are, but it's rolling along very nicely right now. Your question about whether or not the response rate is likely to be 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 higher than 50%.

As to where we are.

But it is rolling along very nicely right now.

Your question.

<unk>.

The question about.

Whether or not their risk.

That's right.

50%.

Okay.

I think we would say.

Two things I think no.

One is of course as possible response rate for the combination will be.

Stephen Kelsey: You know, the initial signals that were presented at the World Conference on Lung Cancer, even though the number of patients was very small, if you actually just look at the 4 patients who were treated at the 140- and 200-mg dose level, which are the two doses being tested in the 03 study, there were only 4 patients who, with lung cancer that were G12C-naive and were treated at either of those two dose levels, and 3 of them responded. That gives you a 75% response rate, even though the denominator is only 4. The confidence interval is around that 75% extremely wide, of course.

Steve Kelsey: You know, the initial signals that were presented at the World Conference on Lung Cancer, even though the number of patients was very small, if you actually just look at the 4 patients who were treated at the 140- and 200-mg dose level, which are the two doses being tested in the 03 study, there were only 4 patients who, with lung cancer that were G12C-naive and were treated at either of those two dose levels, and 3 of them responded. That gives you a 75% response rate, even though the denominator is only 4. The confidence interval is around that 75% extremely wide, of course.

The initial signals that were presented.

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 at 140, and the 200 milligram dose level, which of the two doses being tested in the <unk> III study there were only four patients with.

With lung cancer, <unk> naive and were treated with either of those two dose levels and three of them responded. So that gives you a 75% response.

You will note that the novel nature is only four so the confidence is around that 75% of extremely wide of course.

Stephen Kelsey: 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. We have to keep a very close eye, not just on the percentage of patients 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 registered PR.

Steve Kelsey: 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. We have to keep a very close eye, not just on the percentage of patients 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 registered PR.

The other thing to bear in mind is of course, just the increasing the response rate is probably sufficient.

Partly because.

Winning what patients and investigators want is geo redundancy and partly because any pivotal trial that we would do with that combination response rate wouldn't be the primary endpoint would be progression free survival. So we have to keep a very close not just on the.

The percentage of patients.

We will have achieved shrink, but also on the technical 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.

Hey al.

Yes.

Mark Goldsmith: This is Mark. I'll comment on your second question, which was how will we choose which additional heme inhibitors we would advance, or how will we prioritize them? It's a very complicated question, or it's a simple question with a complicated answer. There are a lot of different dimensions to consider. The real strategy here, which I hope we conveyed, but it's worth reiterating, is that we're not taking the foot off the accelerator creating these new assets. That work is still, you know, very vigorous. Essentially what we're doing is creating a basket

Yeah.

And this is mark I'll comment on your second question, which was how would we choose which additional inhibitors would advance or how we prioritize them.

Very complicated.

Question for a simple question with a complicated answer there are a lot of different dimensions to consider.

The real strategy here.

I hope we conveyed that it's worth reiterating is that we're not taking the foot off the accelerator, creating the new assets that work is still very vigorous and essentially what we're doing is creating a basket.

Mark Goldsmith: Of additional development candidates. The first one in the basket is, of course, RMC-8839 on G13C. There are others that will come behind that, as you pointed out, our next one this year, and, you know, one would imagine there will be more to come after that. 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. Those are three very distinct molecules with very distinct features. We will learn a great deal from the early clinical experience with those. 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.

Additional development candidates. The first one in the basket is of course <unk> hundred nine.

On June 13 fee, but there are others that will come behind that as you pointed out are excellent this year.

Yes.

We would imagine there'll be more to come after that and so with that basket will get to choose.

And.

We will prioritize.

One of the important.

Incineration theories, we're going to learn a lot from 63, 669, one and $90 five 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 May guide as to as to genotype, where the unmet need.

<unk> remains the highest after we see something from these three it may guide as to which Jim types are most sensitive to <unk>.

Mark Goldsmith: 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. There are a lot of really important scientific and clinical questions buried into the signals that we'll get from these. I'm sure that will significantly impact us probably more so than, let's say, market size or something like that. I wouldn't rule that out as some consideration. 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? That's the kind of information we'll learn from these first three, the first wave of RAS inhibitors.

It May guide us to covalent versus non covalently selectivity versus.

Multiple targets et cetera. So there are a lot of.

It really important scientific and clinical questions buried into the signals that we will get from me.

And I'm sure that that will significantly impact us probably more so than let's say market size or something like that but.

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 thats. It.

Information will learn from from these first three.

The first wave and platform.

Alex Stranahan: Thank you.

Alec Stranahan: Thank you.

Thank you.

Mark Goldsmith: Thank you.

Thank you.

Operator: Your next question comes from the line of Jonathan Chang with SVB Securities. Your line is open.

Your next question comes from the line of Jonathan Chang with SBB Security. Your line is open.

Jonathan Chang: Hey, guys. Thanks for taking my questions. First question, can you provide any color around the progress of the Phase 2 arm C RMC-4630-03 study? Earlier in the year, the guidance was for topline data in H2 versus 2023 now. Also, can you help set expectations for how much and what kind of data could be available in the topline disclosure?

Hey, guys. Thanks for taking my questions.

First question can you provide any color around the progress of the phase two arm C 46300, <unk> III study.

Earlier in the year the guidance was for top line data in the second half versus 2023 now.

So can you help set expectations for how much and what kind of data could be available in the topline disclosure.

Mark Goldsmith: Maybe I'll answer this, at least take the first crack at it, which has to do with our notation that we will provide the next data readout will be the top line 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. In essence, one's already gotten a glimpse of what things could look like on an interim basis. It didn't seem to us and to a number of investors speaking to us that anybody would really care about another interim update. That what was really needed is a more definitive answer.

Yes.

Maybe I'll.

And through this let's take the 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.

What's really driven primarily by the fact that the Colgate <unk> <unk> data.

We're going to be and now have been.

Those and so in essence, one has 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.

The body would really care about another interim.

Date.

And what was really needed is a more definitive answer does <unk> hundred 60, <unk> I'll provide additive values et cetera.

Mark Goldsmith: Does RMC-4630 provide additive value to sotorasib in second-line non-small cell lung cancer? We think that this study will do that, but we just didn't see any value in giving another sort of 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 par with what we expected initially, and we will continue enrolling some patients into the first part of 2023. Again, not having every patient enrolled and having just a partial data set to us didn't seem like it was meritorious. Your second question?

And second line non small cell lung cancer.

<unk>.

We think that this study will do that but we just didn't see any value in giving another sort of.

Jeff.

Data on it I think thats the main issue.

Secondary factor the second factor is the enrollment pace.

Right 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 data set to us didn't seem like it was.

Floris.

Your second question.

Stephen Kelsey: What readouts will we provide?

Jonathan Chang: What readouts will we provide?

What we have so.

Mark Goldsmith: Perfect. Stephen Kelsey just provided the question, and he can provide the answer.

Perfect. That's it healthy just provided the question if you can provide.

Stephen Kelsey: Yeah, I think, 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 rate, because that is actually the primary endpoint of this study. 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 sort of last patient in, the progression-free survival, the duration of progression-free survival data for the, you know, the first treated patients are relatively mature. I think, you know, you can expect to see both, absolute response rate data, durability of response and progression-free survival from the cohort.

Steve Kelsey: Yeah, I think, 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 rate, because that is actually the primary endpoint of this study. 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 sort of last patient in, the progression-free survival, the duration of progression-free survival data for the, you know, the first treated patients are relatively mature. I think, you know, you can expect to see both, absolute response rate data, durability of response and progression-free survival from the cohort.

I mean.

The answer I gave to Ross' question Potently.

As best I can.

Most all of the.

Right It will be overall response rates.

But as I've seen.

Primary endpoint of the study, but as I say is becoming increasingly important for us not just to look at response sorry.

Let's see.

Thank you.

Given the study started enrolling last September .

By the time, we get the response rate data on the the sort.

Last name the progression free survival duration of progression free survival data for <unk>.

The first translations in relatively mature so I think.

New panics.

Both.

Absolutely.

Thanks.

Durability of response and progression free survival from the <unk>.

Stephen Kelsey: Hopefully, we will be able to make a meaningful comparison to the CodeBreaK 100 study, which was the pivotal trial of first single agent sotorasib. We tried to, wherever possible, match the CodeBreaK 100 study in the design of our study so that we can draw those comparisons. I think that's, hopefully what we'll be able to provide. Obviously, the other thing you'll see is, you know, the tolerability profile as well, because, you know, there's been a snapshot of that provided from CodeBreaK 101C. The heterogeneity of the patient population that was presented at the weekend, doesn't really give you a robust assessment of the tolerability in that exquisitely defined G12C-naïve non-small cell lung cancer population.

Steve Kelsey: Hopefully, we will be able to make a meaningful comparison to the CodeBreaK 100 study, which was the pivotal trial of first single agent sotorasib. We tried to, wherever possible, match the CodeBreaK 100 study in the design of our study so that we can draw those comparisons. I think that's, hopefully what we'll be able to provide. Obviously, the other thing you'll see is, you know, the tolerability profile as well, because, you know, there's been a snapshot of that provided from CodeBreaK 101C. The heterogeneity of the patient population that was presented at the weekend, doesn't really give you a robust assessment of the tolerability in that exquisitely defined G12C-naïve non-small cell lung cancer population.

Cohort and hopefully we will be able to make meaningful comparison.

100 study.

Which was the pivotal trial of single agent <unk>, we try to wherever possible.

Last October at 178, Mrs that have offset it so specifically so that we can drill those comparisons and I think that hopefully we'll be able to provide obviously the other thing youll see is.

Is that the tolerability profile as well.

Because.

Theres been a snapshot of that provides 100 wanted to see but the heterogeneity of the patient population.

We can.

Doesn't really give you a robust assessment of the polo, but let's see.

Exclusively.

<unk> non small cell lung house population.

Jonathan Chang: Got it. Thanks for taking my questions.

Got it thanks for taking my questions.

Stephen Kelsey: Thank you.

Steve Kelsey: Thank you.

Thank you.

Operator: Your next question comes from the line of Benjamin Burnett with Stifel. Your line is open.

Your next question comes from the line of Benjamin Burnett with Stifel. Your line is open.

Yeah.

Neil Carnahan: 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, will patients have been previously treated with a KRAS inhibitor, or will you be mainly pursuing patients that are KRAS inhibitor naive?

Hi, good afternoon.

This is Neil Carnahan on for Ben Thanks.

Thanks for taking my question for the Phase one RMC six to nine one study can you characterize enrollment criteria a bit.

More specifically, we will patients have been previously treated with a <unk> inhibitor or will you be mainly pursuing patients that are K Ras inhibitor naive.

Mark Goldsmith: Yeah, it'll be some component of both, I'm sure, but maybe Steve can lay that out for him.

Yes, it will be some component of both I'm sure, but maybe Steve can.

Lay that out for us.

Stephen Kelsey: The answer is that the eligibility criteria for the study right now are very similar to the CodeBreaK 101 or CodeBreaK 100 study. In the initial phases of the study, pretty much anyone with any tumor harboring a G12C mutation is eligible, irrespective of whether they've received the previous KRAS inhibitor 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 based on criteria defined by tumor histotype and whether or not they have received a KRAS G12C inhibitor.

Steve Kelsey: The answer is that the eligibility criteria for the study right now are very similar to the CodeBreaK 101 or CodeBreaK 100 study. In the initial phases of the study, pretty much anyone with any tumor harboring a G12C mutation is eligible, irrespective of whether they've received the previous KRAS inhibitor 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 based on criteria defined by tumor histotype and whether or not they have received a KRAS G12C inhibitor.

Yes, the answer is yes.

The eligibility criteria for the study right now very similar right.

101, more quick 100.

In the.

<unk> phase of the study pretty much anyone with any tumor harboring with equal seeing patients eligible irrespective of whether they received the previous tariffs and what not.

As we get into the.

Late at a higher level of dose Escalations, certainly a recommended phase two dose and schedule.

We will see.

Deliberately enrolling in defined cohorts.

Find crestwood.

Some criteria defined by Ciena is decide whether or not they have will have not received the <unk> C inhibitor.

Stephen Kelsey: The primary population of interest for the study, ultimately, are obviously patients with lung cancer who have not received the G12C inhibitor, because that way you can make a comparison against the G12C(OFF) inhibitors. But there is some reason to believe that RMC-6291 might have activity in patients who are failing the G12C(OFF) 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 RMC-6236.

Steve Kelsey: The primary population of interest for the study, ultimately, are obviously patients with lung cancer who have not received the G12C inhibitor, because that way you can make a comparison against the G12C(OFF) inhibitors. But there is some reason to believe that RMC-6291 might have activity in patients who are failing the G12C(OFF) 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 RMC-6236.

The primary population of any threat for the study ultimately obviously patients with lung cancer, who have not received the <unk> proceeds.

That way you can make a comparison against <unk>.

So ultimately there is some reason to believe.

69, one by half.

It's in patients so a thing in the <unk> inhibitor.

That's not our primary focus as a single agent.

They become a very important focus when we start combining <unk> with other drugs in our portfolio, particularly on such institutions.

Neil Carnahan: Great. Thank you.

Great. Thank you.

Stephen Kelsey: Thank you.

Steve Kelsey: Thank you.

Thank you.

Operator: Your next question comes from the line of Noah Isenberg with J.P. Morgan. Your line is open.

Your next question comes from the line of Noah Eisenberg with Jpmorgan Chase Your line is open.

Noah Isenberg: Hi. 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 molecule?

Noah Eisenberg: Hi. 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 molecule?

Hi, guys. This is Noah on for Eric Thanks for taking our question.

Yes.

We're just wondering given some of the data at World lung. This past weekend do you think.

<unk> tolerability profile of combining <unk> inhibitors and PD ones.

It could be a class effect or specific to individual molecules.

Okay.

Mark Goldsmith: Yeah. Hi, Noah. Thanks for your question.

Yeah, Hi, Thanks for your question.

Yeah.

Noah Isenberg: Sure.

Noah Eisenberg: Sure.

Mark Goldsmith: You know, 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 would be exacerbated when it's combined with a checkpoint inhibitor, it can cause inflammation in liver, at least elevated LFT. So that additivity, I think, isn't surprising if you have monotherapy LFT abnormalities. Your question, though, is that due to a biological interaction between the G12C inhibitor and a PD1 inhibitor, is it due to chemical features? We don't know.

Thanks.

Of course, it's a little bit hard to tell right now, but there have been a number of compounds <unk> inhibitors that have shown.

The liver signal.

Which one would not be surprised in that that would be exacerbated when it's combined with them with the checkpoint inhibitor that has that can cause.

Inflammation and liver resulted in <unk>, so that activity I think isn't surprising if you have monotherapy.

LST abnormalities.

Your question, though is is that due to a biological interaction between an <unk> inhibitor.

And a PD one inhibitor is due to chemical features and we don't know.

Mark Goldsmith: 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, you know, from our point of view, a big question is, well, 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've started from a completely different chemical starting point, binding to a completely different site on RAS and binding to a completely different state of RAS on versus RAS off. So there really isn't any obvious read-through. Since we don't have a good hypothesis as to why a generic G12C inhibitor biologically should cause LFT abnormalities, just full stop. We don't have any hypothesis around that.

But given that.

Many of the first generation <unk> 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 where does that read through to our compounds, which is of course.

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 RASK and binding to a completely different state of Ras RAF on versus last off so there really isn't any obvious read through and since we don't have.

Have a good hypothesis as to why.

Generic <unk> inhibitor biologically it should.

Cause LLC abnormalities as a whole.

Soft we don't have any hypothesis around that.

Mark Goldsmith: We don't see any reason why that ought to read through to the RevMed RAS(ON) inhibitor collection.

We don't see any reason why that ought to read through to the Revlimid Rasp inhibitor collection.

Noah Isenberg: Great. Thank you. Very helpful.

Noah Eisenberg: Great. Thank you. Very helpful.

Great. Thank you very helpful.

Stephen Kelsey: Thank you.

Steve Kelsey: Thank you.

Okay.

Operator: Again, if you would like to ask a question, please press star one on your telephone keypad. Again, star one. Your next question comes from the line of Michael Schmidt with Guggenheim Securities.

Again, if you would like to ask a question. Please press star one.

On your telephone keypad again Star one your next question comes from the line of Michael Schmidt with Guggenheim Securities.

Yeah.

Yige Guo: 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 as 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, you know, 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 upcoming phase 1. So just curious, what are some of the considerations to test both schedules?

Hi, This is E mail for Michael Thanks for taking our questions and congrats on the progress with the first two kiosks inhibitors.

Starting off a question on 62 36, you previously mentioned some preclinical rationale that $60 36 can be used as a targeted inhibitor for certain <unk> mutant <unk> mutants and also with the 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 personally.

After $6 91 entered the clinic.

And then a second quick question on $62 91, it looks like you are evaluating.

Those once and twice daily in upcoming Phase one so just what are some of the considerations to test both schedules in.

Yige Guo: Does the preclinical PK data provides any rationale that one could be better than the other? Thank you.

The preclinical PK data provides any rationale that one could be better than the other thank you.

Mark Goldsmith: 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, that's 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 a complete data package to convince you that you have a path forward to registration as a monotherapy before you start the RAS companion combinations. In other words, I think we'd start that fairly soon after we have some confidence around its antitumor activity and how well tolerated and safe it is. I think we would look very much towards combinations with selected other RAS(ON) inhibitors.

Okay. Thanks for your questions.

The first question, which is west of priority with currency 63, six to tested as monotherapy or tested as a companion inhibitor.

That's pretty straightforward for US you have to evaluate it as monotherapy and demonstrate that.

Tolerated and active before you really qualify it to be used as a companion inhibitor.

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

The Ras companion combinations. So another words I think we'd start that fairly soon after we have some confidence around the anti tumor activity and how well tolerated and safe it is.

I think we would look very much towards combinations with selected other.

Other rasp inhibitors, but clearly phase and that way. The monotherapy is the thing that coupon size on initially.

Mark Goldsmith: Clearly phase in that way, the monotherapy is the thing to keep one's eyes on initially. The second question was-

And the second question was.

Stephen Kelsey: The scheduling of RMC-6291.

Steve Kelsey: The scheduling of RMC-6291.

Naturally in the system on one system.

Mark Goldsmith: 62 daily versus BID dosing?

Daily versus the IV dosing.

Stephen Kelsey: Mm-hmm.

Steve Kelsey: Mm-hmm.

Mark Goldsmith: I don't think we've ever talked much about BID dosing. Is there something behind that question that you're alluding to?

I don't think we've ever talked much about CIB dosing is there something.

Is there something behind that question sure that Youre alluding to.

Yige Guo: Yeah, it's just based on you know, information on ClinicalTrials.gov. It looks like you know, both schedules are gonna be evaluated. Sort of just want to you know, get-

Yes, it should be.

Based on information on <unk> Dot Gov. It looks like both schedule, Sir can it be evaluated sort of just wanted to get.

Mark Goldsmith: Yeah.

Yeah.

Yige Guo: Um.

Mark Goldsmith: I think the question there is really just about how much continuous exposure one gets from daily versus twice daily dosing. You know, there was really great visibility around this topic with regard to the first-generation hit 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 simply to shift the RAS-off pool over to RAS-on. 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.

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 <unk> inhibitors wraps off inhibitors, because if youre not covering them and keeping them trapped in the grass off form you have a really easy escape mechanism, which is sort of sales simply to shift the Ras al pool.

Over to Ras on and so as a result, the general feeling in the field is that you need to continuously.

The entire rosoff pool and try to keep it from converting the rest of it any point in time and of course variety made a point of that both with regards to the long half life of <unk> and <unk>.

Mark Goldsmith: Of course, Mirati made a point of that both with regard to the long half-life of adagrasib and then subsequently to BID dosing with the long half-life of product. You know, 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. It's not really clear that that level of continuity is necessary. 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 well. I think that's really in the protocol.

And then subsequently to be IV dosing with a long half life.

Product.

It's not entirely.

Harley clear that that cause.

Concept applies equally well to rats on inhibitors, it's really a little bit of a different mechanism and its a dramatically different mechanism, but different dynamic.

And so it's not really clear if that level of continuity as necessary.

Secondly, it's not clear that honestly 60, 91 get them daily wouldn't be it wouldn't provide that sort of continuous coverage. It may well in fact in both settings. It covers a very very well. So I think thats really in the protocol Keith 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 understood.

Mark Goldsmith: Steve can comment on this, but I think it's in the protocol simply acknowledging that continuous coverage is something we wanna make sure we understand whether that's needed and make sure that we have a dosing schedule that could provide it if daily dosing is not sufficient.

And whether that's needed and make sure that we have a dose schedule and.

A dosing schedule that could provide if daily dosing is not sufficient.

Stephen Kelsey: Yeah. We quite often write into our protocols the option to evaluate alternative schedules right up front because it saves you having to write an amendment if you find out the PK is not tracking with your predictions, and you have to go back and test another schedule. I think, you know, to Mark's point, our preclinical data suggests that we can cover the target in mice with once daily dosing. Whether or not we'll ever have to test a different schedule in the clinic remains to be seen. I think we need some clinical PK data first before we can decide. It's definitely not a done deal. We're not necessarily going to test another schedule. Even if we do, it's not necessarily going to be twice a day dosing. Yeah.

Steve Kelsey: Yeah. We quite often write into our protocols the option to evaluate alternative schedules right up front because it saves you having to write an amendment if you find out the PK is not tracking with your predictions, and you have to go back and test another schedule. I think, you know, to Mark's point, our preclinical data suggests that we can cover the target in mice with once daily dosing. Whether or not we'll ever have to test a different schedule in the clinic remains to be seen. I think we need some clinical PK data first before we can decide. It's definitely not a done deal. We're not necessarily going to test another schedule. Even if we do, it's not necessarily going to be twice a day dosing. Yeah.

We quite often.

Right and so our protocols the option to evaluate alternative schedule slide upfront because it saves you having to write an amendment.

And find out the PK is not tracking with your predictions.

To go back and test another schedule.

I think it's a lot.

Point <unk>.

Preclinical data.

Suggests that we can recover the call that a modest with once daily dosing and so whether or not we'll add lots of Tesla a distant schedule in the clinic remains we see are that need some clinical PK data first before we can decide but it's definitely not a done deal we're not we're not.

We're not necessarily going to test another schedule and even if we do not necessarily down to be twice a day dosing.

Yige Guo: Got it. That's very helpful. Thank you.

Yeah got it that's very helpful. Thank you.

Stephen Kelsey: Thank you.

Steve Kelsey: Thank you.

Okay.

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

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

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

Well. Thank you operator, and thank you to everyone for participating today and for your continued support of Revolution medicines every day.

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

This.

Today's conference call you may now disconnect.

Okay.

Yeah.

Okay.

[music].

Okay.

[music].

Yes.

Okay.

Yeah.

[music].

Yes.

[music].

Okay.

Yes.

Okay.

Yes.

Okay.

Sure.

[music].

Okay.

[music].

Okay.

Sure.

[music].

Okay.

Yes.

[music].

Yes.

Okay.

Yes.

Thank you.

Yes.

Okay.

Yes.

Okay.

[music].

Yes.

Okay.

[music].

Okay.

[music].

Sure.

[music].

Okay.

Yes.

Okay.

Yes.

Okay.

[music].

Yes.

[music].

Sure.

[music].

Yes.

Okay.

Sure.

Yes.

[music].

Okay.

[music].

Yes.

Okay.

Yes.

Okay.

[music].

Okay.

Sure.

Okay.

Sure.

Yes.

[music].

Okay.

Yes.

[music].

Okay.

Yes.

[music].

Yes.

[music].

Okay.

[music].

Okay.

Yes.

[music].

Yes.

Okay.

Yes.

Okay.

Sure.

[music].

Okay.

Yes.

Okay.

Yes.

Okay.

[music].

Okay.

Yes.

[music].

Okay.

Sure.

Okay.

Yes.

[music].

Thank you.

Sure.

Yes.

Okay.

Yes.

Thanks.

Okay.

Yes.

Okay.

<unk>.

Yes.

Okay.

Yes.

Okay.

Yes.

Sure.

[music].

Thanks.

Yes.

Okay.

Thank you.

Yes.

Okay.

Yes.

[music].

Yes.

Okay.

Yes.

[music].

Yes.

[music].

Yes.

Sure.

Okay.

Yes.

Okay.

Yes.

Okay.

Thank you.

Okay.

[music].

Okay.

Yes.

Okay.

Right.

Okay.

Thanks.

Yes.

Okay.

Yes.

Thanks.

Okay.

Yes.

Okay.

Sure.

Yes.

Sure.

Okay.

Yes.

Okay.

Yes.

Okay.

[music].

Okay.

Yes.

Okay.

Sure.

Yes.

Sure.

Thanks.

<unk>.

Sure.

Okay.

Yes.

Okay.

Sure.

Yeah.

Yes.

Okay.

Yes.

Okay.

Thanks.

Yes.

Okay.

Yes.

Okay.

Yes.

Okay.

Yes.

Okay.

Sure.

Okay.

Thanks.

Yes.

Sure.

[music].

Yes.

Thanks.

Yes.

Sure.

Yes.

Okay.

Yes.

Okay.

Sure.

Okay.

Yes.

[music].

Yes.

Okay.

Yes.

Yeah.

Yes.

Okay.

[music].

Sure.

Okay.

Yes.

Okay.

Yes.

[music].

Okay.

Yeah.

Okay.

[music].

Okay.

Yes.

Q2 2022 Revolution Medicines Inc Earnings Call

Request a DemoDemo

RVMD

Revolution Medicines

Earnings