Q3 2022 Revolution Medicines Inc Earnings Call

November 7, 2022

Operator 1: Good day, and thank you for standing by. Welcome to the Revolution Medicines Q3 2022 Earnings Webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Peg Horn, Revolution Medicines Chief Operating Officer, for opening remarks. Peg, you may begin.

Operator: Good day, and thank you for standing by. Welcome to the Revolution Medicines Q3 2022 Earnings Webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Peg Horn, Revolution Medicines Chief Operating Officer, for opening remarks. Peg, you may begin.

Good day and thank you for standing by welcome to the Revolution Medicine third quarter 2022 earnings webcast. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask a question during the session you will.

Need to press Star one one.

Telephone you will then hear an automated message advising your hands raised.

Be advised that today's conference is being recorded.

I would now like to hand, the conference over to pick one Revolution medicines, Chief operating officer for opening remarks, Doug you may begin.

Peg Horn: Thank you, and welcome everyone to our Q3 earnings call. Joining me on today's call are Doctor Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Doctor Steve Kelsey, the company's President, Research and Development, and Jack Anders, our Chief Financial Officer. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

Thank you and welcome everyone to our third quarter earnings call. Joining me on today's call are Dr. Dr. Mark Goldsmith Revolution medicines, Chairman and Chief Executive Officer, Dr. Steve Kelsey the company's president.

Research and development and Jack Anders our Chief Financial Officer, as we begin I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward looking statements within the meaning of the private Securities Litigation Reform Act.

These statements are subject to a number of assumptions risks and uncertainties.

Actual results may differ materially from these statements and except as required by law. The company undertakes no obligation to revise or update any forward looking statements I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release as well as all of the Companys filings with the SEC.

Peg Horn: 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.

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 Chief Financial Officer, Jack Anders, will provide highlights of our financial results. In Q3, Revolution Medicines continued advancing our pipeline of groundbreaking RAS-ON inhibitors on behalf of patients with a wide range of RAS-addicted cancers, which represent 30% of all human cancers. We are building momentum with our RAS-ON inhibitor pipeline, having now advanced 2 RAS-ON inhibitor development candidates into phase 1/1b dose escalation trials. With the transition of these RAS-ON inhibitors into early clinical development, we now have 4 compounds from our cohesive portfolio of RAS cancer-targeted therapeutics in human studies. This progress across our pipeline sets up an exciting and potentially data-rich 2023.

Good afternoon, and thank you for joining us today I'll provide an update on our corporate progress and our Chief Financial Officer, Jack Anders who will provide highlights of our financial results.

In the third quarter Revolution medicines continued advancing our pipeline of groundbreaking rason inhibitors on behalf of patients with a wide range of rasp addicted cancers, which represent 30% of all human cancers.

We are building momentum with our <unk> inhibitor pipeline heading now advanced to Rason inhibitor development candidates into phase <unk> dose escalation trials.

With the transition of these rason inhibitors into early clinical development.

We now have four compounds from our cohesive portfolio of Ras cancer targeted therapeutics in human studies.

This progress across our pipeline set up an exciting and potentially data rich 2023.

Mark Goldsmith: 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 entered the arena by advancing to clinical development the first two drug candidates from our highly innovative RAS-ON inhibitor portfolio. In a Phase 1/1b trial evaluating RMC-6236, our oral RAS multi-ON inhibitor, investigators are dosing patients who have tumors harboring various common KRAS G12 cancer mutations, which may include KRAS G12D, KRAS G12V, and KRAS G12R. We believe RMC-6236 is the first oral direct RAS inhibitor to be deployed against tumors harboring any of these prevalent RAS cancer drivers, and marks a significant step in our effort to serve the unmet needs of patients with RAS-addicted cancers.

I will now review a number of key achievements that reflect this recent progress regarding our pipeline of rason inhibitors in Ras companion inhibitors.

First we have entered the arena by advanced clinical development. The first two drug candidates from our highly innovative rason inhibitor portfolio.

In a phase <unk> trial evaluating RMC 63 six.

Oral RASK multi you're on inhibitor <unk>.

Investigators are dosing patients who have tumors harboring various common K Ras G 12 cancer mutations, which may include <unk> 12, D. K Ras <unk> NK Rasp 12 are.

We believe RMC 63, six is the first oral direct RAF inhibitor to be deployed against tumors harboring any of these prevalent Ras cancer drivers.

And marks a significant step in our effort to serve the unmet needs of patients with Ras evicted cancers.

Mark Goldsmith: In a Phase 1/1b trial of our oral KRAS G12C(ON) inhibitor, RMC-6291, investigators are dosing patients who have tumors harboring the KRAS G12C cancer variant. We have previously reported extensive preclinical data demonstrating the differentiated and promising antitumor profile of this highly selective covalent inhibitor of the activated or RAS(ON) state of the KRAS G12C variant found in lung and gastrointestinal cancers. RMC-6291 is the first of a series of mutant-selective RAS(ON) inhibitors that we intend to bring into the clinic. Next up is our oral covalent inhibitor of KRAS G12D, the most common RAS cancer variant causing human cancer, RMC-9805. IND-enabling work remains on track toward our goal of beginning clinical evaluation in mid-2023.

In a phase <unk> trial of our oral <unk> inhibitor <unk>.

RMC 69, one.

Investigators are dosing patients who have tumors harboring the <unk> cancer variant.

We have previously reported extensive preclinical data demonstrating the differentiated and promising anti tumor profile of this highly selective covalent inhibitor of the activated or Ras on state of the <unk> variant found in lung and gastrointestinal cancers.

RMC 69, one is the first of a series of mutant selective rason inhibitors that we intend to bring into the clinic.

Next up is our oral covalent inhibitor of <unk> D. The.

The most common Ras cancer, ovarian, causing human cancer RMC.

RMC $98 five.

IND, enabling work remains on track toward our goal of beginning clinical evaluation in mid 'twenty three.

Mark Goldsmith: 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, and our portfolio contains additional RAS(ON) inhibitors lining up behind this first wave. In parallel, we continue clinical evaluation of two class-leading RAS companion inhibitors, our SHP-2 inhibitor, RMC-4630, and our mTORC1 selective inhibitor, RMC-5552, both of which have shown clinical anti-tumor activity. These RAS companion inhibitors are designed to be deployed primarily as combination agents with direct RAS inhibitors.

This first wave of Rason inhibitor drug candidates RMC 63, 669, one and $90 five.

Has the potential to help serve the vast majority of patients with <unk> cancers.

And our portfolio contains additional inhibitors lining up behind this first wave.

In parallel we continue the clinical evaluation of two class clothing, Ras companion inhibitors.

But you would observe RMC for 63.

And our inventory one selective inhibitor, perhaps if I try to five years.

Both of which have shown clinical evidence.

Activity.

These Rad companion inhibitors, our designer who may deploy primarily as the combination agents with correct RAF inhibitors.

Mark Goldsmith: In Q3, our clinical collaborator, Amgen, reported encouraging preliminary evidence from its Phase 1/1b CodeBreaK 101 clinical study, suggesting promising and durable benefit from combining RMC-4630 with Amgen's KRAS G12C inhibitor, sotorasib, particularly in second-line treatment of patients with non-small cell lung cancer who were 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. Ultimately, we expect to evaluate our 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 priorities for the remainder of 2022 and 2023.

In the third quarter, our clinical collaborator Amgen reported encouraging preliminary evidence from its phase <unk> code break 101 clinical study.

Suggesting promising and durable benefit from combining RMC for six Rio with Amgen's <unk> inhibitor, so to rapid particularly in second line treatment of patients with non small cell lung cancer.

We're <unk> inhibitor nave.

We continue enrolling patients into our phase II study of this combination.

RMC for six Rio <unk> III.

In patients with <unk> non small cell lung cancer.

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

Now I'll shift to our corporate progress and comment on our priorities for the remainder of 'twenty three of 2022 and 'twenty three.

Mark Goldsmith: In the quarter, we completed a follow-on 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. With this strong financing behind us, we are focused on timely execution of the multiple development stage activities currently underway, and our highest priority is to deliver on important clinical milestones in the coming year. We continue deploying our development resources primarily in support of 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.

In the quarter, we completed a follow on 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.

With this strong financing behind US we are focused on timely execution of the multiple development stage activities currently underway at our highest priority is to deliver on important clinical milestones in the coming year.

We continue deploying our development resources, primarily in support of our three most advanced Ras on inhibitors RMC $63 six 6% to 91% 92, five and two clinical stage Ras companion inhibitors.

RMC for six <unk> and 555 two.

Mark Goldsmith: Despite this growing clinical pipeline, we continue our strong commitment to research activities that provide critical scientific insights to support ongoing development activities and that also leverage our proven RAS(ON) 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 by the end of the year, which will join a planned second wave of additional RAS(ON) inhibitor drug candidates, including our KRAS G13C inhibitor, RMC-8839. We anticipate advancing assets from this collection into development after 2023. With this R&D strategy, supported by current cash equivalents, and marketable securities extending operating runway through 2024, we are positioned to deliver on important milestones.

Despite this growing clinical pipeline, we continue our strong commitment to research activities that provide critical scientific insights to support ongoing development activities and that also leverage our proven RASK innovation engine to generate exciting new mutant selective <unk> inhibitors with <unk>.

Think profiles.

We expect to nominate our next rason inhibitor development candidate by the end of the year, which will join a planned second wave of additional rason inhibitor drug candidates, including our K Ras G. <unk> inhibitor RMC 83 nine <unk>.

Anticipate advancing assets from this collection into development after 2023.

With this R&D strategy supported by current cash cash equivalents in marketable securities extending operating runway through 2024, we are positioned to deliver on important milestones.

Mark Goldsmith: 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 provide preliminary evidence of superior activity for RMC-6291 in 2023, with this clinical profile potentially indicated by tolerability, safety, and/or antitumor effects, 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 top-line data from the RMC-4630-03 study of RMC-4630 plus sotorasib in H2 2023, and to disclose additional evidence of single agent activity for RMC-5552 in 2023.

And our rason inhibitor portfolio upcoming milestones are as follows.

To provide evidence of first in class single agent activity for RMC 63, 6% in 2023.

To provide preliminary evidence of superior activity for RMC $6 91 in 2023 with this clinical profile potentially indicated by tolerability safety and or anti tumor effects.

And to announce dosing of the first patient in a monotherapy dose escalation study of RMC 90, 805 in mid 'twenty three.

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

To provide top line data from the $4 six 303 study of RMC 463 hundred plus other asset in the second half of 'twenty three.

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

Mark Goldsmith: In summary, we remain deeply committed to our science-driven approach to treating patients with RAS-addicted cancers, and our development-stage pipeline and research efforts have entered an exciting and important phase. Our first wave of RAS(ON) inhibitors, which includes three distinct and highly differentiated drug candidates, has advanced significantly with patients now being dosed with RMC-6236 or RMC-6291 and RMC-9805 continuing its progress toward the clinic. Our differentiated RAS Companion inhibitors, RMC-4630 and RMC-5552, have each shown evidence of single agent clinical activity along the path towards strategic combinations with direct RAS inhibitors. Initial clinical evidence has now emerged in support of RMC-4630 as a RAS Companion inhibitor used in combination with a direct RAS inhibitor.

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

Our first wave of rasp inhibitors, which includes three distinct and highly differentiated drug candidates.

<unk> has advanced significantly with.

With patients now being dosed with RMC 63, 6% or 69 one.

RMC $9 five continuing its progress towards the clinic.

Our differentiated Ras companion inhibitors, RMC for six <unk> and $5 five two.

Each shown evidence of single agent clinical activity, along the path towards strategic combinations with direct rasp inhibitors.

And initial clinical evidence has now emerged in support of RMC for six Rio <unk> companion inhibitor use in combination with the direct Ras inhibitor.

Mark Goldsmith: As we intensify efforts to progress these assets to significant milestones in the coming period, we also continue to make a significant investment in pipeline expansion activities based on our productive RAS innovation engine. Building on this strong company momentum, I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack?

As we intensify efforts to.

Progress these assets two significant milestones in the coming period. We also continue to make a significant investment in pipeline expansion activities based on our productive Ras innovation engine.

Building on this strong company momentum I'll now turn to Jack Anders Our Chief Financial Officer to provide a financial update Jack.

Okay.

Jack Anders: Thank you, Mark. We strengthened our balance sheet in the quarter with the upsized public offering of common stock, raising gross proceeds of $265 million. Net proceeds were approximately $248 million, deducting accounts, commissions, and estimated offering expenses. Our ending cash and investment balance as of 30 September 2022 was $655 million, which is expected to fund planned operations through 2024. Revenue from our collaboration agreement with Sanofi was $3.4 million in Q3 2022, compared to $1.1 million in the prior year period. During Q3 2022, the company recorded a non-cash GAAP accounting adjustment that reduced collaboration revenue by $4.6 million.

Thank you Mark.

We strengthened our balance sheet in the quarter with the Upsized public offering of common stock raising gross proceeds of $265 million net.

Net proceeds were approximately $248 million deducting discounts.

Accounts commissions and estimated offering expenses.

Our ending cash and investment balance as of September 32022, with $655 million, which is expected to fund planned operations through 2024.

Revenue from our collaboration agreement with Sanofi was $3 4 million in the third quarter of 2022 compared to $1 1 million in the prior year period.

During the third quarter of 2022, the company recorded a noncash GAAP accounting adjustment that reduced the collaboration revenue by $4 6 million.

Jack Anders: This non-cash revenue adjustment was due to changes to the company's estimates of the accounting transaction price and estimated percentage of completion of work performed to date under the agreement, which resulted in a cumulative catch-up adjustment that reduced collaboration revenue. We also had a similar catch-up adjustment related to revised estimates during the prior year quarter, which reduced collaboration revenue by $8.5 million for that prior year period. Total operating expenses for Q3 2022 were $79.9 million, and increased by 47% over the prior year period. The increase in operating expenses was primarily driven by an increase in RMC-6236 and RMC-6291 costs as a result of commencing clinical trials during the year, as well as an increase in personnel related expenses related to additional headcount.

This noncash revenue adjustment was due to changes to the company's estimates of the accounting transaction price.

An estimated percentage of completion of work performed to date under the agreement.

Which resulted in a cumulative catch up adjustment that reduced collaboration revenue.

We also had a similar catch up adjustment related to revised estimates during the prior year quarter, which reduced collaboration revenue by $8 5 million for that prior year period.

Total operating expenses for the third quarter of 2022 were $79 9 million and increased by 47% over the prior year period.

The increase in operating expenses was primarily driven by an increase in RMC 63, six and RMC 691 costs.

As a result of commencing clinical trials during the year.

As well as an increase in personnel related expenses related to additional head count.

Jack Anders: Net loss for Q3 2022 was $73.3 million or $0.87 per share. We are reiterating our financial guidance and continue to expect full year 2022 GAAP net loss to be between $260 and $280 million, with non-cash stock-based compensation expense expected to be between $30 and $35 million. That concludes the financial update, and I'll now turn the call back over to Mark.

Net loss for the third quarter of 2022 was $73 3 million or <unk> 87 per share.

We are reiterating our financial guidance and continue to expect full year 2022, GAAP net loss to be between 260 and $280 million with.

With noncash stock based compensation expense expected to be between 30 and $35 million.

That concludes the financial update and I'll now turn the call back over to Mark.

Mark Goldsmith: Thanks, Jack. Our goal at Revolution Medicines is to outsmart RAS addicted cancers, and we continue to show our tireless commitment to patients in pursuit of this goal. 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.

Our goal at Revolution medicines is to outsmart Ras addicted cancers, and we continue to show our tireless commitment to patients in pursuit of this goal.

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 2: Thank you. At this time, to ask the question, you'll need to press star one one on your telephone. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from Alec Stranahan with Bank of America. Your line is now open.

Operator: Thank you. At this time, to ask the question, you'll need to press star one one on your telephone. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from Alec Stranahan with Bank of America. Your line is now open.

Thank you.

At this time to ask a question you will need to press star one on your telephone.

Please standby, while we compile the Q&A roster.

One moment for your first question.

And our first question comes from Alex Stranahan with Bank of America. Your line is now open.

Alec Stranahan: Hey, guys. Thanks for the questions. Just a couple from us. First on RMC-6236. Given there could be some overlap between the pan-RAS and the individual RAS inhibitors that you're developing in terms of patients who could benefit. I'm curious just how you're thinking about parallel development of these assets, and is the strategy just increasing second-line goal, or do you see discrete market opportunities either with mono or combo for each of these assets? Then secondly, when you look at RMC-5552, obviously some interesting early activity here as monotherapy.

Hey, guys.

Thanks for the question just a couple from us first.

First on <unk> six given there could be some overlap between the Pan RAF.

The individual rasp inhibitors that youre developing in terms of patients who could benefit I'm curious just how youre thinking about parallel development of these assets and as the strategies of increasing sales by goal or do you see.

Discrete market opportunities, either mono or combo for each of these asset.

And then secondly, when you look at 500 552.

Obviously, some interesting early activity here as monotherapy, but as you think about combination studies moving forward are there particular drug partners are tumor type.

Alec Stranahan: As you think about combination studies moving forward, are there particular drug partners or tumor types you think are more interesting to start with, or is this really gonna depend on the data update that we'll see next year? Thanks.

Do you think are more interesting to start whether is it feels like that depend on the data update that will be next year. Thanks.

Mark Goldsmith: Thanks, Alex. Appreciate your question. Maybe I'll comment on the first question, and then perhaps Steve can comment on the second. The first question is about RMC-6236 versus mutant selective inhibitors. You know, at this stage, I think we don't know enough to be able to say exactly which indications will best or most benefit from the multi-RAS inhibitor that hits multiple RAS variants, including wild type versus the mutant selective inhibitor. We have some ideas about that, but we're really gonna need to see what we learn in the clinic in order to guide that. Our guess is that it will depend on tissue type, other co-mutations, and perhaps even stage of disease. That's something we'll just have to learn. At this point, we're in dose escalation.

Thanks, Alex I. Appreciate your question, maybe I'll comment on the first question and then.

Perhaps you can comment on the second so the first question is about RMB 63, six versus mutant selective inhibitors.

At this stage.

I think we don't know what enough to be able to say exactly which indications will best for most of the benefit.

From the multi Ras inhibitor to that.

Multiple rastafarians, including wild type versus the mute selective inhibitor, we have some ideas about that.

Got it needs to see.

What we've learned in the clinic in order to guide that.

Our guess is that it will depend on tissue type.

Other co mutations.

And perhaps even even states youll see thats something we will just have to learn so at this point we are in dose escalation, we will figure out the optimal way to dose each of these compounds and then we will begin to see.

Mark Goldsmith: We'll figure out the optimal way to dose each of these compounds, and then we'll begin to see where the activity is and what the limitations are of each. Ultimately, we might see these put together in combinations anyway. It may be that RMC-6236 combined with RMC-6291 is the most effective way to preempt emergence of resistance mutations. The same could apply for RMC-9805 and other mutant selective inhibitors. It's just too early to tell at this point, and we'll play out all of these. As I said, our guess is that there will be certain circumstances in which one particular paradigm might apply more completely than another paradigm. We shall see. Second question is RMC-5552. Sure.

Where are the activities limitations are of each ultimately we might see these put together combinations anyway.

It may be that RMB 63, six combined with six to nine one is the most effective way to preempt emergence of resistance mutations.

The same could apply for 95 and other selective inhibitors.

Too early to tell at this point.

Play out all of these et.

Our guess is that there will be certain circumstances in which.

One particular paradigm.

More completely than another paradigm, we shall see.

Second question is <unk> 555.

Sure.

Steve Kelsey: The primary focus of the single agent dose escalation program that we've been running with RMC-5552 so far was really to assess whether or not we have a drug there that is worthy of further development in combination with our RAS(ON) inhibitors or companion inhibitor. I think we've so far demonstrated clearly that it is. We have shown on-target toxicity. We have PK exposures that are within the range that are consistent with activity in the preclinical models, and we have efficacy. We're fairly confident that this is worth taking forward to combine with RAS(ON) inhibitors. You know, there are really two classes of co-mutation that occur in combination with RAS mutations that are probably gonna be the initial focus of the development for RMC-5552.

The primary.

Okay.

The single agent dose escalation program.

Rami.

With Orange.

So far was really too.

But all in all we have a trough.

As would be all.

Further development in combination with <unk>.

So I think so.

Demonstrated clearly that it is.

We have shared on target toxicity, we have PK exposures that are within the range.

Consistent with our preclinical models and we have we have that.

So.

So any color on this as well.

Taking force combined perhaps all of it.

Yes.

Two classes.

Kurt.

Combination perhaps inflation.

Probably the kind of the initial focus.

Prior.

Steve Kelsey: They're in co-mutations where the mTOR signaling pathway is directly affected are the ones that are most common. They're obviously PTEN loss, PI3 kinase mutation, a couple of rarer mutations perhaps in mTOR itself. There are the other class mutations which are probably more familiar to you that tangentially seem to impact mTOR pathway signaling, and those are specifically STK11 and KEAP1. We have plenty of preclinical data now that RMC-5552 can act in, you know, very favorably in combination with our RAS(ON) inhibitors to really turn round, you know, tumor regressions in tumors that co-express KEAP1 mutations and STK11 mutations. As you know, the KEAP1 co-mutant tumors, at least for lung tumors, do not do so well with single agent RAS inhibition, at least the first generation RAS(OFF) inhibitors.

Yes.

Inflation is where the.

This whole signaling pathway directly affect the one color there also <unk> Ross.

China is mutation.

Rather the mutation.

And tore itself.

The other cloud mutations, which are probably more familiar to you.

Tangentially related.

So halfway safely.

SDK.

We have plenty of preclinical data.

Yes.

All right.

Two.

Vaccine.

Okay combination without rasp inhibitors too.

So very excited right.

Crashes and choose calix.

<unk> mutations.

So as you know Keith block.

Two most of these volume shifts do not do so well.

Relations.

It is the first generation Russell.

Steve Kelsey: It's a fairly linear development path for RMC-5552. Ultimately, down the road, there may be other things we could do with that compound, but the initial focus is the co-mutants. There are a lot of them. I mean, for instance, if you look at RAS mutant colon cancer, about a third of them co-express a mutation in mTOR signaling pathway.

So.

That's it.

Savi.

Development path for Oxy.

Ultimately down the road and maybe other things you could do that.

The initial focus.

There are lots of them.

For instance, if you look at perhaps the coal costs are about a third.

Co Express.

Absolutely.

Alec Stranahan: Got it. Thank you. Very helpful.

Got it thank you very helpful.

Operator 2: Thank you. One moment for our next question. Our next question comes from Jonathan Chang with SVB Securities. Your line is now open.

Operator: Thank you. One moment for our next question. Our next question comes from Jonathan Chang with SVB Securities. Your line is now open.

Thank you one moment for our next question.

Our next question comes from Jonathan Chang with SBB Securities. Your line is now open.

Francisco: Hi, guys. This is Francisco. Sorry for Jonathan. Wanted to ask if you could comment at all on pace of enrollment for the multi-RAS versus the mutant-specific programs like the G12C. Do you expect one to go faster than another? Do you also plan to provide any color as this study goes along on which dose levels have been cleared?

[Analyst] (SVB Securities): Hi, guys. This is Francisco. Sorry for Jonathan. Wanted to ask if you could comment at all on pace of enrollment for the multi-RAS versus the mutant-specific programs like the G12C. Do you expect one to go faster than another? Do you also plan to provide any color as this study goes along on which dose levels have been cleared?

Hi, guys. This is Pat on for Jonathan I wanted to ask if you could comment at all on pace of enrollment for the multi RASM first meeting specific programs like the <unk> 12 seat do you expect one to go faster than another and then you also plan to provide any color or is this study goes along honestly could go.

Those have been cleared.

Mark Goldsmith: Thanks for your question. You know, in terms of pace of enrollment, they're both doing fine. I think they're both on track with expectations. What were our expectations? Well, we expected that RMC-6236 would have an abundance of patients and investigators highly interested because of the absence of approved targeted therapies in most of those indications, and that's what we're seeing. We have very, very high demand for the, you know, the fixed number of spots that are available. Nonetheless, we are seeing enrollment in both of these studies. I'm sorry. Things are progressing per plan. Your second question was?

Thanks for your question.

In terms of the pace of enrollment, they're both doing fine.

Both are on track with expectations.

What we're our expectations, while we expected that pharmacy 63, six would have an abundance of.

Patients had investigators highly interested because of the absence of approved targeted therapies and most of those indications and thats what were seeing we have very very high demand for.

For the.

Fixed number of subs that are available.

Nonetheless, we are seeing.

Both of these studies I'm sorry.

Things are progressing per plan.

Your second question was.

Francisco: As the studies progress, do you plan to provide any color on which dose levels have been cleared?

[Analyst] (SVB Securities): As the studies progress, do you plan to provide any color on which dose levels have been cleared?

Thanks for asking you plan to provide any color on what your dose levels have been cleared.

Mark Goldsmith: Not as an isolated bit of information. It probably won't really mean much to anybody since these are entirely new compounds. You know, obviously, when we report some additional information about tolerability, safety, and/or activity, we'll provide dose information associated with that.

Not an isolated.

A bit of information that probably won't really be much to anybody is entirely new compounds.

Obviously, when we report some additional information.

About tolerability safety and to our activity will provide to us information associated with that.

Francisco: Got it. Okay. If I could ask one more, have you looked at how the chaperone protein levels change over time, as you dose? Is this a dynamic thing or are these kind of consistently expressed in the tumors?

[Analyst] (SVB Securities): Got it. Okay. If I could ask one more, have you looked at how the chaperone protein levels change over time, as you dose? Is this a dynamic thing or are these kind of consistently expressed in the tumors?

Got it okay, and if I could ask one more have you looked at how the <unk>.

Protein levels change over time.

As your dosing is this a dynamic thing or are these kind of consistently expressed in tumors.

Mark Goldsmith: Steve, do you wanna comment on that?

Steve you want to comment on that yes, the shop rent and credit Suisse are interesting slide you say today is hugely abundant.

Steve Kelsey: Yeah. The chaperone protein of interest is obviously cyclophilin A. It's hugely abundant in most mammalian tissues and certain human tissues and also in cancer. So far, we have struggled very hard to detect any meaningful change in the expression of cyclophilin A over time with really any given exposure to our RAS(ON) inhibitors. We don't expect that to be something that is gonna be possible to detect in the clinic, even if we had an assay that could deal with the massive overabundance of that protein.

If I may.

Tissues.

Human tissues and also in Canada.

And so far.

We have struggled with very hard to.

Two.

Any meaningful change in the expression.

Hey.

Over time.

But any given exposure.

So we don't expect patch.

We don't expect that to be subsequently.

It's going to be possible to detect.

Great.

Let's say.

Feel with the masses.

So that process.

Francisco: Got it. Thanks for taking our question.

[Analyst] (SVB Securities): Got it. Thanks for taking our question.

Got it thanks for taking my questions.

Operator 2: Thank you. One moment for our next question, please. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.

Operator: Thank you. One moment for our next question, please. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.

Thank you.

One moment for our next question please.

Yeah.

And our next question comes from Eric Joseph Joseph with Jpmorgan. Your line is now open.

Eric Joseph: Hi. Good evening. Thanks for taking the question. Actually a couple from us. Looking to initial data with RMC-6291 next year, Mark, what would qualify as superior activity in your view relative to the RAS(ON) inhibitors? Is that a statement in the PR sort of that's a function of PD or activity in RAS inhibitor, prior RAS inhibitor-treated patients, or perhaps better response rates in certain histologies? And to the extent it's the latter, are there certain tumor types that you're aiming to bias enrollment toward?

Hi, good evening, Thanks for taking my question actually.

A couple from us.

So looking to initial data with $62 91 next year, Mark what would what would qualify as superior activity in your view relative to the rosoff inhibitors is that it.

A statement in the PR sort of that's a function of the PD or activity in Ras inhibitor prior Ras inhibitor treated patients.

How is better response rates in certain <unk>.

Histology than to the extent its the ladder.

Are there certain tumor types that you are aiming to.

Bias enrollment toward.

Mark Goldsmith: Yeah. Thanks, Eric. Appreciate the question. You know, I think as we start to collect data, the things we're gonna see initially will be safety and tolerability. Then from there, we'll start to see. We expect anti-tumor activity. Obviously, objective responses are the things we'll see earliest, and durability is something we have to wait to collect that information. That's not something you see early. Any combination of those I think will be helpful to us. You know, keeping in mind that this is a new platform, and so we often hear from investors that they simply wanna see evidence that you can dose a patient, achieve exposure levels that should be active and then see activity from it. That's probably where things will start.

Yeah. Thanks, Eric I appreciate the question.

I think as we start to.

To collect data the things, we're going to see initially will be safety and tolerability.

And then from there we'll start to see we expect anti tumor activity and obviously.

Objective responses are the things we will see early yes, and durability is something we have to.

To collect that information that PVC early.

Any combination of those I think will be helpful to us.

Keeping in mind that this is a new platform and so we often hear from investors.

We want to see evidence that you can dose the patient achieved exposure levels.

Should be active and as the activity from it so that's probably where things will start and then from there over time.

Mark Goldsmith: Then from there, over time, we'll build the cumulative evidence about its superiority. I think to emphasize the big picture here, in the G12C space, it's very likely that combination therapy is really where the puck is going to be. We're already moving there, as you know. Focusing too much on trying to prove differentiation around monotherapy isn't probably the wisest thing for us to do, although we certainly believe mechanistically that's the case, and we think we will accumulate some data pointing in that direction. The real impact for patients is going to come from those combinations. Demonstrating that RMC-6291 can be combined effectively, tolerably, safely, with the other agents will be extremely important.

We'll build.

The cumulative evidence about.

Alrighty.

I think to emphasize the big picture here.

In the <unk> space, it's very likely that combination therapy is really where the puck is going to be we're already moving there as you know and so focusing too much on trying to prove differentiation around monotherapy isn't probably the wisest thing for us to do although we certainly believe that.

Domestically, that's the case and we think we will accumulate some data pointing in that direction, but the wheel.

The impact for patients is going to come from those combinations and so demonstrating that pharmacy 60, 91 can be combined effectively tolerably safely.

The operations will be extremely important in that that can only come after we get through.

Mark Goldsmith: That can only come after we get to reach a recommended Phase 2 dosing schedule, and then can move forward from there with those combinations.

<unk>, a recommended phase II dosing schedule and that can move forward from there with the with those combinations.

Eric Joseph: Okay. Got it. A follow-up, if I could, on the G12D, RMC-9805. I guess looking to starting patient dosing in mid next year, how should we be thinking about the therapeutic window for this compound? I guess relatedly, are you able to characterize the PK of the compound relative to the multi RAS and the G12C candidates? Thanks.

Okay got it and then a follow up if I could on the GE 12 D. RMC 90 805.

I guess looking to starting.

Patient dosing in mid next year, how should we be thinking about the therapeutic window for this compound and I guess relatedly are you able to characterize.

The PK of the compound relative to the.

The.

Thanks.

The multi ross in the GLC candidates.

Sure.

Okay.

Mark Goldsmith: I'm trying to process the second part of your question. For the first part of it, is it mutant selective? Well, it's highly mutant selective. You know, it is a covalent compound. It's the only known KRAS G12D covalent compound, and it carries all of the benefits of covalency, which is that even after you take away drug from the system, there's still covalently bound inhibitor that's blocking G12D in the on state. So it's highly mutant selective compared to, let's say, RMC-6236, which is sort of by definition equipotent against all variants of RAS, including wild type.

What kind of profit the second part of your question, but for the FERC the first part of it.

Is it is it viewed selective highly selective.

And it.

It is a covalent compounds the only known <unk> compound and that carries all of the benefits of covalent sandwiches that even after you takeaway drug from the.

From the system.

There is still covalently bound.

Inhibitor thats blocking.

In the off state so it's highly selective.

Compared to let's say RMC 63, six which is sort of by definition equally equal potent against all variance including wildfire.

Mark Goldsmith: There certainly is going to be a ceiling for dosing RMC-6236, at which point you would start to see on-pathway normal tissue RAS-mediated side effects. There shouldn't be the same sort of dose ceiling for RMC-9805. You know, those are just different, to some degree, technical characteristics. What really matters is can you dose either of them sufficiently to achieve the desired antitumor effect safely, tolerably? We project the answer to that is yes, based on pre-clinical results, but I have to demonstrate that in the clinic. The second part of your question, maybe you could unpack that a little bit for me, which is PK. I wasn't quite sure what you were trying to get at from the PK question.

There certainly is going to be a ceiling for.

Dosing pharmacy 63, six at which point you would start to see on pathway normal tissue Ras mediated side effects.

And there shouldnt be the same sort of ceiling for RMC high five.

But those are just different so some degree technical characteristics, what really matters is can you dose either of them sufficiently to achieve the desired.

In fact safely and tolerably.

We project the answer to that is yes based on preclinical results.

To demonstrate that in the clinic.

The second part of your question.

Maybe you could unpack that a little bit for me, which is PK.

TK I wasn't quite sure what you were trying to get out from the PK question I'd like to add.

Mark Goldsmith: I'd like to answer, I need to understand.

Eric Joseph: Yeah. No, yeah, absolutely. Some competitors in this space have noted challenges in coming up with an oral formulation similar to your approach with RMC-9805. I guess just looking for a little more color around the PK properties of your compound, how you feel about how investors should get comfortable with kind of a favorable oral bioavailability with that compound. I guess, is there a contrast with RMC-6291 that might be informative here?

Yes.

Yeah, absolutely. So some competitors in this space have noted challenges in coming up with an oral formulation.

Similar to your approach with 98, five so I guess I'm just looking for a little more.

Color around the PK properties of your compound how you feel about.

Hi.

How investors should get them comfortable with kind of a fair.

Favorable.

Bioavailability with that compound.

I guess are there.

Our contract is it a contrast with.

$62 91.

It might be.

Formative here.

Mark Goldsmith: Well, look, it's orally bioavailable across multiple species and, you know, at percents that are considered, you know, very much appropriate for oral drugs. You know, we have to demonstrate that in humans. Based on the preclinical species, it's an orally available drug. We'll have no difficulty getting above the IC50 or even IC90. It also has a relatively long half-life. It's also retained in tissues because of the covalencies. You put all of those pieces together, it behaves very much like RMC-6291 in terms of dose, PK/PD, efficacy, and selectivity relationships. Those are all fine. I don't think that the investigators are gonna have concerns about that.

Well look it's orally bio available across multiple species.

Thanks.

Sure.

Yes.

That are considered very much appropriate for oral drugs. So we have to.

To demonstrate that accumulates.

But based on the preclinical species is an orally available drug will have no difficulty getting about the IC 50 or even IC.

Sure.

And it also has a relatively long half life.

And then it's also retained and tissues because of the covalent <unk>. So you put all those pieces together.

Very much like RMB 69, one in terms of.

Dose PK PD.

Efficacy.

<unk> relationships those are all <unk>.

So I don't think.

Investigators are going to have concerns about their concerns about all the other drugs that are not orally bio available in October .

Mark Goldsmith: They should have concerns about all the other drugs that are not orally bioavailable and not covalent. I'm not sure there should be any particular issue about RMC-9805. Of course, we have to validate that in humans. You know what I've just described to you is the preclinical, but given how extensively they've been characterized, I guess we'd be surprised if those properties don't carry over into people.

But I'm not sure.

Any particular issue.

Pharmacy.

Of course, if at all.

What I've just described to you is the preclinical but.

Given how extensively characterized I guess would be surprised if those properties some carryover.

Eric Joseph: Great. Appreciate the color. Thanks for taking the questions.

Great I appreciate the color thanks for taking my questions.

Mark Goldsmith: Thank you.

Mark Goldsmith: Yeah. Sure.

Yes sure.

Operator 2: One moment for our next question. Our next question comes from Marc Frahm with Cowen. Your line is now open. Marc, your line is now open.

Operator: One moment for our next question. Our next question comes from Marc Frahm with Cowen. Your line is now open. Marc, your line is now open.

One moment for our next question.

And our next question comes from Marc Frahm with Cowen. Your line is now open.

Mark Your line is now open.

Marc Frahm: Thanks for taking my questions. Maybe just to start with RMC-6236, just, you know, that trial's been open for a few months now and actively enrolling for a few months. You know, and it has a pretty broad criteria in terms of mutations and tissue types that are eligible. Are you seeing any bias there of, you know, enthusiasm across different for specific mutations or specific tumor types that we, you know, that should be thinking about the population tending to be enriched in?

Hey, Thanks for taking my questions.

Maybe just to start with 63 six just do that trial has been open for a few months now and activating were only for a few months.

And it has a pretty broad criteria in terms of mutations in tissue types that are eligible or are you seeing kind of a bias there of.

Enthusiasm across different for specific mutations or specific tumor types that we.

Should we be thinking about the population tending to be enriched in.

Mark Goldsmith: Thanks, Mark. Nice to hear from you. There is a tremendous amount of interest in it, and there are far more patients who are interested in participating in this study than we've been able to release slots for. I don't think that there's any bias other than that epidemiologically, there are some mutations that are more common than others. G12D and G12V are significantly more common than other mutations, and they have no available targeted therapy. They are tending to show up. They're not the only ones showing up, they just are tending to show up. They're tending to show up in gastrointestinal tumors because that's where they're most prevalent, but they're not only showing up in gastrointestinal tumors either.

Thanks, Mark nice to hear from you.

There is a tremendous amount of interest in it and they are far more patients.

Who are interested in participating in the study that we've been able to release slots, Florida. So.

I don't think that theres any bias other than geologically.

There are some patients that are more common than others.

She told Peter are significantly more common to other mutations and they have no available targeted therapy.

And so they are tending to show up.

Only one showing up they just are tending to show up.

And.

They're showing tended to show up in gastrointestinal tumors, because thats, where they are most prevalent but theyre not only showing up in gastrointestinal tumors, either so I don't think theres anything from a from an investigator perspective.

Mark Goldsmith: I don't think there's anything from an investigator perspective that's biasing these. Now keep in mind, we've restricted enrollment based on genotype initially to the KRAS G12 mutations to a small number of those, essentially excluding G12C initially, because those patients have available to them a G12C inhibitor, including now RMC-6291 in the clinical trial. And eventually we'll come back to those G12C patients after we get to a dose that we think is gonna be most appropriate for those who have, for example, failed the G12C inhibitor. Other than that, I don't really think we've seen any particular finger on the scale.

Keep in mind, we've restricted enrollment based on genotype initially too.

Congrats to <unk> 12.

Mutations.

Small number of those essentially excluding <unk> 12 see initially because those patients have available that are associated with are including now RMB 69, one in the clinical trial.

And eventually it will come back to those two plus the patient after we get to.

Joseph we think is going to be most appropriate for those events.

Wholesale is <unk> inhibitor, but other than that I don't really think we've seen any particular figure on the scale.

Marc Frahm: Okay. Thanks. That's helpful. Can you kind of refer to these initial ones in the clinic as well as the G12D as kind of the first wave, and you have some of these other mutation-specific inhibitors that, you know, being kind of held back as wave two. Just what's your thoughts on kind of what do you need to see from the first wave of agents in order to kind of pull the trigger on wave two and start moving those into the clinic?

Okay. Thanks, that's helpful and then.

Can you kind of referred to these initial ones in the clinic as well as the detailed D. As can the first wave and you have some of these other mutation specific inhibitors.

I held back as we have to.

Just what's your thoughts on kind of what do you need to see from the first wave of agents in order to pull the trigger on wave to start moving those into the clinic.

Mark Goldsmith: Yeah, that's a very good question, Marc Frahm. I think our concept here is less about that they're being gated by a particular result in the first wave and more about our making sure we have the resources and focus to move those first three inhibitors forward as efficiently and effectively as possible. I think that's the main thing that's gating it. It's more about resources and less about, you know, getting to a particular result. With that said, obviously, among these first three inhibitors, we expect to see activity, tolerability, and safety that guide us to confidence that the platform itself delivers as expected and so on. And that will also likely increase the availability of resources as well. As you know, there's a relationship there.

Yes, that's a very good question Mark I think our concept here is less about that theyre being gated by particular results in the first wave and more about making sure we have the resources and focus to move those first three inhibitors forward as efficiently and effectively as possible.

So I think thats the main thing that scaling it as more of our resources and less about.

Getting to a particular result with that said obviously unless these first three inhibitors we expect.

To see activity Tolerability and safety that guide us to.

Confidence that the platform itself delivers as expected and so on.

And that will also likely increase the availability of resources as well as <unk>.

There is a relationship there so.

Mark Goldsmith: That, at least indirectly, would open up the availability of resources for the second wave. I mean, that's how we think about it. I don't think there's a particular result. There are a number of things we could see next year that would give us, and I think investors, confidence that the platform is valid and, that there should be things reading through to other inhibitors in the platform.

FTC directly with open up.

Availability of resources for the second wave.

So I mean, that's how we think about it I don't think there is a particular result.

There are number of things we could see next year that would give us that I think investors.

Confidence that the platform is valid.

<unk>.

There should be things reading through to other other inhibitors in the platform.

Peg Horn: Okay, thanks. Very helpful.

Marc Frahm: Okay, thanks. Very helpful.

Okay. Thanks very helpful.

Operator 2: Thank you. One moment for our next question. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is now open.

Operator: Thank you. One moment for our next question. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is now open.

Thank you one moment for our next question.

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

Michael Schmidt: Hey, guys. Thanks for taking my questions. I had two development strategy questions, perhaps first on 6291, the G12C inhibitor. So, you know, what are your thoughts on the, you know, possible registration pathway down the road in context of the sort of, you know, moving competitive environment in the KRAS G12C space where you probably have multiple, you know, RAS(ON) inhibitors fully approved in second line, perhaps registration studies ongoing in first line. How do you think that could affect, or what are your thoughts on the ultimate development strategy for 6291 in that context?

Hey, guys. Thanks for taking my questions.

How hard key development.

Two questions, perhaps first six to nine one.

The <unk> inhibitor or so.

Yeah.

What are your thoughts on the.

A lot of our registration pathway.

Down the road.

In context of diesel.

Moving competitive environment, and the Keiretsu 12 six space.

Yeah.

Multiple.

Yes.

<unk> inhibitors fully approved in second line, perhaps registration studies ongoing in first line, how do you think that could effect.

What are your thoughts on the ultimate development strategy for six to nine one in that context.

Sure.

Okay.

Mark Goldsmith: Yeah. Steve, do you wanna-

Yes.

Steve Kelsey: Sure. I can. Yeah. I think Mark has just laid out the first premise, which is that the most likely development path for RMC-6291 is gonna be in combination with something rather than as a single agent. I mean, we are not going to exclude development as a single agent if it's demonstrably superior to the approved KRAS OFF inhibitors. But the most likely thing is it'll be developed in combination. Then, you know, really in that context, it's gonna be a combination of efficacy and tolerability in combination with whatever the best companion is. We have the opportunity to combine with something, possibly even with RMC-6236, and go chasing after patients that have progressed or failed on a KRAS G12C OFF inhibitor.

Sure.

Yes.

Well I think Mark has just laid out the first premise which is that the.

Most likely development for <unk>, and I was going to be a culmination itself rather than as a single agent.

We have not.

<unk>, excluding developments in relation to its demonstrably superior to the <unk>.

Hey.

<unk> says.

But the mudslides and say is it will be developed in combination of that.

So really in that context it.

It is going to be a combination of.

C Tolerability in combination with whatever the best comparison.

As.

We have the opportunity to combine with something possibly even with RMC 63, six chasing off the patients.

Progressive available.

Hey, Ross T cell <unk>.

Steve Kelsey: We can go head to head with them in that second-line space, or we can go head to head with them in any of the first-line spaces that are currently all available to us. I think it really largely depends on what we see in the initial phases of the Phase 1 trial, which of course will include, you know, combination dose escalation components as we get further up the single agent dose escalation. I think, let's keep an open mind. We're very optimistic about the potential for RMC-6291. We're not shying away from pretty much all of the potential opportunities for developing it, Ryan.

We can go head to head with open that second line. So we can go head to head with them in any of the first slide spaces.

Currently all available.

To us and I think largely depends on what we see in the initial phases of the phase one trial, which of course will include combination.

Relation components as we as we get further up the situation dose escalation. So I think let's keep this in mind.

Are you optimistic.

<unk>.

Titanfall for Odyssey.

691.

We don't shied away from.

Pretty much all of the potential opportunities for us.

Mark Goldsmith: If I could add to Steve's comment there, I think he said a couple of important things I wanna tie back together. Preclinically, we of course showed a pretty extensive data set comparing it head to head with one of the leading KRAS G12C off inhibitors. That didn't necessarily foreshadow that that's going to be the primary path forward in the clinic. That was simply to demonstrate that the mechanism behind the inhibitor translates into the best possible RAS pathway expression and therefore, antitumor effects, regressions, and durability. We believe that. Steve is often fond of saying that in a combination treatment regimen for a RAS tumor, you wanna combine the very best RAS inhibitor you can with the very best companion or companions you can.

If I could add to Steve's comment there I think.

You said a couple of important things I want to tie back together.

Pre clinically we of course showed a pretty extensive datasets comparing it head to head with one of the leading <unk> inhibitors.

That didn't necessarily foreshadow that that's going to be the primary path forward.

That was simply to demonstrate.

The mechanism behind that the inhibitor translated into the <unk>.

Best possible Ras pathway expression and therefore.

<unk> tumor.

FX regressions and durability.

We believe that.

Steve It's awesome fond of saying that in a combination treatment regimens for a rash severity.

Find the very best RAF distributors, you can with the very best competing our companions you can kind of 69, one of the very best.

Mark Goldsmith: If RMC-6291 is the very best KRAS G12C inhibitor out there, then we will wanna combine it with RAS Companion Inhibitors. That, that's our default path. I think we assume that's sort of the main path. If it does stand out in monotherapy in ways that reflect what we've seen preclinically, significantly, that could open up a monotherapy path to approval. It's just not our primary assumption around this.

<unk> that are out there that we will want to combine it with with Ras companion inhibitor. So after default path.

We assume that sort of the main path, but if it does stand out in monotherapy in ways that reflect what we've seen pre clinically.

Significantly that could open up.

A monotherapy path to approval, but.

Not our primary.

Our primary assumption around this.

Michael Schmidt: Yeah. Okay, that makes sense. Then on RMC-6236, perhaps more near term, you know, once you have reached a recommended Phase 2 dose, in the Phase 1 portion of the study, you know, how do you think about pursuing specific tumor histologies or specific mutations, you know, in Phase 1b studies or in dose expansion cohorts down the road?

Yeah, Okay that makes sense and then on.

Three things.

More near term.

One leads to recommended phase two dose.

Phase one portion of the study.

How do you think about.

Pursuing specific tumor histology the specific mutations.

Phase one b study and dose expansion cohorts down the road.

Yeah.

Mark Goldsmith: Yes. Well, I'm gonna turn it over to Steve. He said we're open-minded, so maybe he can put some boundaries around how open-minded we are.

Yes.

Turn it over to Steve You said, we're open minded.

Put some.

Have your surround.

Steve Kelsey: I think it's pretty straightforward with RMC-6236. I mean, as you already said, the preclinical data shows that the activity definitely favors the G12 mutant tumors. We're planning to develop RMC-6236 really in three different ways. The first is as a single agent. We will test it as a single agent, and we will see whether the single agent activity in any of those histotypes is sufficient for a path to registration. The second thing we'll do is we'll do combinations, but only with things that don't have overlapping toxicity. The most obvious candidate there will be checkpoint inhibitors. The third plank of that is to use RMC-6236 as a companion inhibitor for our mutant selective RAS inhibitors.

I think I think it's pretty straightforward and RMC 63, 6%.

As we've already said.

The preclinical data shows.

<unk>.

That's what's exciting for us the <unk> shippers and so there are essentially three.

Got it.

So lung cancer pancreatic cancer and colorectal cancer.

And what are you planning to develop RMC 636 really in three different ways. The first is the single H, we will test and simulation, but we will see whether the single agent activity.

Can you give us just the types of sufficient for path to registration.

Second thing we will do is we'll we'll do a combination study with things that that have overlapping toxicity. So the most obvious candidates that will be checkpoint inhibitor Susan.

It does.

It's to use RMC 60 364.

<unk>.

Mutant selective <unk> inhibitors.

Steve Kelsey: The first up there will be RMC-6291. I think you can expect a fairly broad program for RMC-6236 once a recommended phase 2 dosing schedule has been established. The actual breadth and the focus will really depend on the degree to which it is active as a single agent.

The first one in the first half that will be RMB six nine.

I think you can expect steady growth program for RMB 636, once a recommended phase II dosing schedule.

As we establish.

The actual breadth from the focus for rig depending on the.

The degree to which does act as a simulation.

Mark Goldsmith: Michael, you were also asking, though, if we see a signal in both, let's say G12D and G12D, how would we prioritize one versus the other? Is that what you were asking about also?

Michael We will also asking though if we see a signal.

Firstly, <unk> B and <unk> C.

How would leave.

One versus the other.

That.

Is that what youre asking about also.

Michael Schmidt: Yeah, just generally. I mean, you know, there will be overlap,

Yes, just generally I mean.

There will be overlap.

Mark Goldsmith: Yes.

Michael Schmidt: With the selective inhibitors. There will be overlap in tumor histology as well. I'm just wondering how you know, put

Mark Goldsmith: Yes.

Michael Schmidt: With the selective inhibitors. There will be overlap in tumor histology as well. I'm just wondering how you know, put

You have selective inhibitors, there won't be overlapping tumor histology as well I'm just wondering how are you.

Mark Goldsmith: Yeah.

Michael Schmidt: you know

Mark Goldsmith: Yeah.

Michael Schmidt: you know

Yes right.

Mark Goldsmith: Right.

Michael Schmidt: prefer one with the other.

Yes.

Mark Goldsmith: Yeah, sure. Well, I mean, those are different axes, and we'll have to look at those, as Steve said. With regard to the mutations, I think one of the benefits of doing the backfill strategy that we have kind of loaded up for this is that we will collect additional information than just the information we need to dose escalate. We will also be able to enroll additional patients at the previous dose level and keep doing that as long as we wish to up the dose escalation scale. That allows us to sample more patients, which means more genotypes and more histotypes. It's not gonna give us a grid of 10 by 100. It's still gonna be relatively small numbers.

Yes, sure well I mean, those are different axes that we will have to look at those.

But with regard to the mutations I think one of the benefits of doing the back fill strategy.

That we have kind of loaded up for this is that we will collect additional information than just the information we need to dose escalate.

We'll also be able to enroll additional patients at the at the previous dose level.

And keep doing that as long as we wish you all.

The dose escalation scale and that allows us to sample more patients, which means more genotypes and more is to types.

But it's not going to give us a greater.

10 by 100.

That would be relatively small numbers.

Mark Goldsmith: We'll be very excited if we see signals across multiple histotypes and genotypes, you know. Maybe we'll have to decide what to prioritize or maybe not. We'll just have to see what information emerges there.

We'll be very excited if we see signals across multiple types of genotype.

Maybe we will have to decide what's prioritized or maybe not.

We'll have to see what information bridges there.

Michael Schmidt: Yeah. Okay, great. Thank you so much.

Yeah, Okay, great. Thank you so much.

Mark Goldsmith: Yeah.

Operator 2: Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. One moment for our next question. Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

Operator: Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. One moment for our next question. Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

Thank you.

As a reminder to ask a question you will need to press star one on your telephone one moment for your next question.

Our next question comes from Chris <unk> with Goldman Sachs. Your line is open.

Chris Shibutani: Thank you. Two questions. There was a recent RAS inhibitor. BridgeBio presented some initial preclinical data for their compound. They screened against a tool compound, RM-018. Can you provide us with any thoughts on whether you think this was an appropriate comparator for them to screen against? And potentially what differences this might have with respect to RMC-6291? Just to put some perspective on benchmarking.

Thank you.

Good question.

Okay.

There was recent.

Hum.

Great. Thank.

And then just some initial preclinical data with their compound.

They screened again.

Alright.

Can you provide us with any thoughts on whether you think this was an appropriate comparator for them screened again and potentially what differences that might have with respect to <unk> hundred 91, just.

With some perspective on benchmarking.

Mark Goldsmith: Yeah. You know, I guess, first in terms of the data that we've seen publicly, it seems as if their comparator was really KRAS G12C off inhibitors. We would expect to see a difference versus KRAS G12C off inhibitors. We've published, as you know, extensively on in vivo models, a large number of in vivo lung cancer models versus a G12C off inhibitor. I think they showed one or two models. So it's really hard to comment on how active that compound is. We're sort of comparing a very large data set with a very small data set. Don't know what to do with that. I think in terms of conceptually, it's not clear to us why having G12C off inhibitory activity is advantageous if you have a G12C on inhibitor.

Yeah.

Yes.

I guess first in terms of the data that we've seen publicly.

It seems as if theyre comparator was really.

Okay recipes youll see off inhibitors.

And we would expect to see a difference versus.

We still see opportunities.

We've published as you know extensively.

On the in vivo models, a large number of in vivo lung cancer models.

Versus a <unk> inhibitor I think they chose one or two one or two models.

So it's really hard to comment on.

Active that compound as we sort of comparing a very large data set with the very small data set on what to do with that.

I think in terms of conceptually.

Not clear to us why having <unk> inhibitory activity.

Is advantageous.

Chelsea on inhibitor.

Mark Goldsmith: In other words, the on form is the active pool. It's the oncogenic protein, and the off protein is not active. It's not clear to us then. Frankly, in experiments in which we've combined RMC-6291 with a KRAS G12C off inhibitor, we didn't see any advantage over RMC-6291 alone. Conceptually, we're not sure why there would be any advantage. From a data point of view, it's just comparing apples and oranges at this point. We just keep moving RMC-6291 forward.

In other words the on farm is the active pool as the oncogenic protein and the off protein is not active.

So it's not clear to us and frankly in experiments in which we can buy our C 69 to one with a <unk> inhibitor, we didn't see any advantage over our C 69, one alone.

So.

Conceptually, we're not sure why there would be any advantage from a data point of view.

Regarding apples and oranges at this point so we just keep moving 69 going forward.

Chris Shibutani: Using 018, which is quite a critical reference, anything to compare there with 6291?

And then using <unk>.

As a reference.

To compare there was 6% to 91.

Mark Goldsmith: Oh, RM-018. That was a tool compound that Ryan B. Corcoran reported. It's not an in vivo tool compound. I'm not really sure. I'm not sure why we would compare to a tool compound. I mean, RMC-6291 is the development candidate that's now being dosed in humans. I don't think that they've used. I think they used RM-018 because it was available.

Hello.

Oh that was a tool compound that Brian Portland.

<unk>.

And it is not an in vivo tool compounds.

So.

Im not really sure.

Not sure why we would compare to a tool compound RMC 69, what is the development candidate is now being dosed in humans.

I don't think that they use.

<unk> because it was available.

Speaker 15: Yeah.

[Analyst]: Yeah.

Mark Goldsmith: I don't think it's a relevant comparator.

Yes, I don't think its irrelevant comparator.

Speaker 15: Got it. Finally, you're going to be announcing a fifth RAS(ON) candidate. I think we'll get that disclosure before the end of the year. Any hints as to the potential venue for that?

[Analyst]: Got it. Finally, you're going to be announcing a fifth RAS(ON) candidate. I think we'll get that disclosure before the end of the year. Any hints as to the potential venue for that?

Got it and then finally, you are going to be announcing a pit rats on candidate I think we will get that disclosure before the end of the year.

First to the potential venue for that.

Okay.

Yeah.

Mark Goldsmith: Yeah, I don't know if it'll be disclosed just before the end of the year or just after the end of the year. We will select it by the end of the year. There may not really be much of a venue to do that. Once we get into the early part of 2023, there are some investor venues that might be available to us.

Yes, I don't know if it will be sourced just before the end of the year or just after the end of the year, but we will selected by the end of the year.

May not really be much of a venue to do that but once we get into.

The early part of 2023, there are some investor venues that might be available to us.

Speaker 15: Indeed. Okay, great. Thanks, Mark.

[Analyst]: Indeed. Okay, great. Thanks, Mark.

Indeed, okay, great. Thanks, Mark.

Operator 2: Thank you. One moment for our next question. Our next question comes from Jay Olson with Oppenheimer. Your line is now open.

Operator: Thank you. One moment for our next question. Our next question comes from Jay Olson with Oppenheimer. Your line is now open.

Thank you one moment for our next question.

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

Speaker 16: Oh, hey, thank you for taking the questions. We're curious to know your views on the collaboration that was announced today between Incyte and Mirati to combine Incyte's oral small molecule PD-L1 inhibitor with Mirati's adagrasib. Any comments you could share with us with regards to your thoughts about the deal and any plans you may have for partnering your RAS(ON) inhibitors with molecules in development at other companies in terms of types of combinations that would be synergistic, and whether or not you think it's important to have an all oral combination regimen versus combining your oral drugs with an antibody would be great. Thank you.

Jay Olson: Oh, hey, thank you for taking the questions. We're curious to know your views on the collaboration that was announced today between Incyte and Mirati to combine Incyte's oral small molecule PD-L1 inhibitor with Mirati's adagrasib. Any comments you could share with us with regards to your thoughts about the deal and any plans you may have for partnering your RAS(ON) inhibitors with molecules in development at other companies in terms of types of combinations that would be synergistic, and whether or not you think it's important to have an all oral combination regimen versus combining your oral drugs with an antibody would be great. Thank you.

Hey, Thank you for taking the question.

Curious to know your views on the collaboration that was announced today between inside and Marty to combine insights oral small molecule PD lone inhibitor with varieties added granted.

Any comments you could share with us.

With regards to your thoughts about the deal and any plans you may have or partnering your rason inhibitors with.

Molecules in development at other companies in terms of types of combinations that would be synergistic and whether or not you think it's important to have an all oral combination regimen versus combining your oral drugs with an antibody would be great. Thank you.

Mark Goldsmith: Yeah. Thanks, Jay. Maybe to take the last part of your question first. You know, KEYTRUDA is a, you know, big gorilla drug in the field today. It's used by everybody in first line therapy for lung cancer in particular. I don't think the fact that it's dosed parenterally, you know, really causes any challenge for anybody. I'm not sure that we're aware of the need for an oral agent. That's sort of my first comment. I don't know, Steve, if he's agreeing with that. With regard to Mirati's study, it's interesting. We always are interested to see what other people go do. It doesn't really change much. I don't think being successful with an oral agent will give them any particular advantage over being successful with KEYTRUDA.

Yes, Thanks, Jay maybe just to take the last part of your question first.

Sure.

Big Gorilla drug in the field today, it's used by everybody in first line therapy for lung cancer in particular.

I don't think the fact that its dose.

Press really really.

It really causes the challenge for anybody so.

Im not sure that we're aware of the need for an oral agents.

So that's sort of my first comment I don't know if you disagree with that.

And then with regard to <unk> study.

Interesting, we always are interested to see what other people go do it doesn't really change much.

<unk> been successful with an oral agent will give them any particular advantage over being successful with keytruda.

Okay.

Mark Goldsmith: Maybe your last question was a much, much bigger question, which is what are all the possible things we might combine with in the immunology field or elsewhere. Again, I think KEYTRUDA is the big gorilla, and doctors are used to using it. It's well-established. There's a lot of data to support it. I think it is important, particularly in immune responsive tumors like lung cancer, to find a way to combine with an anti-PD-1. The most well-validated anti-PD-1 antibody is KEYTRUDA, although there are others that are active as well. We're very interested in going sort of beyond that, but everything else beyond that is pretty exploratory at this point, and I think can't be considered a primary path.

Maybe last question was a much much bigger question, which is what are all the possible things we'd like to combine with.

In the immunology field or elsewhere.

Yes.

The big Gorilla.

Yes.

Doctors are used to using it.

Well established there is a lot of data to support it. So I think it is important particularly in immune response to tumors like lung cancer.

To find a way to combine with an anti PD one.

And the most well validated.

Is that true.

Although there are others that are active as well.

Yeah.

We're very interested in growing sort of beyond that but everything else beyond that is pretty exploratory at this point.

And I think can be considered a primary account I'd say stay tuned for that.

Mark Goldsmith: I say stay tuned, but for the moment, I think it's pretty well defined what one needs to do to get your drug in front of the right patients.

I think it's pretty well defined what one needs to do to get your drug to the right.

<unk>.

Speaker 16: Great. That's super helpful. Thank you for taking the question.

Jay Olson: Great. That's super helpful. Thank you for taking the question.

Great. That's super helpful. Thank you for taking the question.

Operator 2: Thank you. As there are no more questions in the queue, I would like to turn the call back to Dr. Goldsmith for closing remarks.

Operator: Thank you. As there are no more questions in the queue, I would like to turn the call back to Dr. Goldsmith for closing remarks.

Thank you.

There are no more questions in the queue I would like to turn the call back to Dr. Michael Smith for closing remarks.

Mark Goldsmith: Thank you, operator, and thank you to everyone for participating today. We appreciate support of Revolution Medicines.

Thank you operator, and thank you to everyone for participating today, we appreciate it.

Sort of Revolution medicines.

Operator 2: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.

Operator: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.

This.

Today's conference call. Thank you for your participation you may now disconnect everyone have a wonderful day.

The conference will begin shortly to raise your hand during Q&A you can dial one one.

[music].

Okay.

[music].

Yes.

Yeah.

[music].

Q3 2022 Revolution Medicines Inc Earnings Call

Request a DemoDemo

RVMD

Revolution Medicines

Earnings