Q4 2021 Revolution Medicines Inc Earnings Call

February 28, 2022

Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q4 and Full Year 2021 Financial Results Conference Call and Webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star key followed by 1 on your touchtone telephone. Please be advised that today's conference is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q4 and Full Year 2021 Financial Results Conference Call and Webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the * key followed by 1 on your touchtone telephone. Please be advised that today's conference is being recorded. If anyone has difficulty hearing the conference, please press *0 for operator assistance. I would like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good day, ladies and gentlemen, and welcome to the Revolution medicines fourth quarter and full year 2021 financial results conference call and webcast. At this time all participants are in listen only mode.

Operator: Good morning, ladies and gentlemen, and welcome to Revolution Medicine's fourth quarter and full year 2021 financial results conference call and webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star key followed by 1 on your touchtone telephone.

Management's prepared remarks, we will hold a Q&A session.

To ask a question at that time. Please press the star key followed by one and your Touchtone telephone.

Please be advised that today's conference is being recorded if anyone has difficulty hearing the conference. Please press star zero for operator assistance.

Operator: Please be advised that today's conference is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would like to hand the conference over to Peg Horn, Revolution's chief operating officer, for opening remarks. Peg, you may begin.

I'd like to hand, the conference over to Tag Horn Revolutions, Chief operating officer for opening remarks Peg you may begin.

Peg Horn: Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer; Dr. Steve Kelsey, the company's President of R&D; and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meanings of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. 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.

Good afternoon, everyone and thank you all for joining US today joining me on today's call are Dr. Mark Goldsmith revolutions chairman.

And Chief Executive Officer, Dr. Steve Kelsey, the company's president of R&D, and Jack Anders Our senior Vice President of Finance and principal accounting officer.

Peg Horn: 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.

As we begin I'd like to caution you that our presentation today will contain forward looking statements within the meaning of the private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business he stay.

Statements are subject to a number of assumptions risks and uncertainties.

<unk> 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.

Peg Horn: I encourage you to review the legal disclaimer slide we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?

Courage you to review the legal disclaimer slide we are presenting today as well as all of the Companys filings with the SEC concerning these and other matters.

This presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call with that I will turn the call over to Dr. Mark Goldsmith Revolutions, Chairman and Chief Executive Officer.

Peg Horn: With that, I will turn the call over to Dr. Marc Goldsmith, Revolutions Chairman and Chief Executive Officer. Good afternoon, and thank you for joining us. We're very pleased to report that during the fourth quarter of 2021, Revolution Medicines continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatment on behalf of patients with a wide range of RAS-addicted cancers, representing some 30 percent of all cancer patients. As depicted on slide 5, RAS-addicted cancers are induced primarily by mutations that cause RAS-on proteins to behave as cancer

Arc.

Mark Goldsmith: Good afternoon, and thank you for joining us. We're very pleased to report that during Q4 2021, Revolution Medicines continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatment on behalf of patients with a wide range of RAS-addicted cancers, representing some 30% of all cancer patients. As depicted on slide 5, RAS-addicted cancers are induced primarily by mutations that cause RAS-on proteins to behave as cancer drivers. Often, these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways. We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS-on inhibitors to suppress the primary RAS drivers, as well as RAS companion inhibitors to suppress the cooperating proteins. In many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit.

Good afternoon, and thank you for joining us.

I'm pleased to report that during the fourth quarter of 2021.

Alicia medicines continue building momentum with our targeted therapeutics pipeline advancing our mission to improve treatment on behalf of patients with a wide range of Ras mutant cancers, representing some 30% of all cancer patients.

As depicted on slide five <unk> cancers are induced primarily by mutations that cause Ras on proteins can behave as cancer drivers.

Peg Horn: But often these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways. We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS-on inhibitors to suppress the primary RAS drivers, as well as RAS-companding inhibitors to suppress the cooperating proteins. We expect drugs of these two types may be combined to deliver the greatest clinical benefit.

But also in these countries also supported and maintained by other soluble proteins, we call RASK cooperating targets and pathways.

This is important particularly can match our treatment strategies to this biological cooperativity.

Developing rash long exhibitors to suppress the primary last Rogers as well as Ras companion inhibitors to suppress the cooperating proteins.

In many instances.

We expect drugs that these two types, maybe combined to deliver the greatest clinical benefit.

Mark Goldsmith: I'll spend the next few minutes briefly recapping four drug candidates that constitute our development-stage RAS(ON) inhibitor portfolio directed against RAS variants that are the primary drivers of RAS-addicted cancers. Dr. Steve Kelsey, our President of R&D, will then highlight recent updates on our clinical-stage RAS companion inhibitors RMC-4630, SHP2, and RMC-5552, and TORC1. Our first RAS(ON) inhibitor, RMC-6236, is an innovative and exciting drug candidate, a first-in-class RAS(ON) multi-selective inhibitor with potentially very broad utility across many RAS cancer variants. As shown on Slide 12, initially, we are particularly interested in the more than 130,000 new pancreatic, colorectal, and/or lung cancer patients in the US each year, with tumors bearing one of various mutations at amino acid 12 in KRAS, the dominant hotspot for KRAS cancer mutations. We refer to these collectively as G12X mutations.

Mark Goldsmith: I'll spend the next few minutes briefly recapping four drug candidates that constitute our development stage RAS inhibitor portfolio directed against RAS variants that are the primary drivers of RAS-addicted cancers. Dr. Steve Kelsey, our president of R&D, will then highlight recent updates on our clinical stage GRAS companion inhibitors, RMC4630, SHIP2, and RMC5552, mTORC1. Our first RAS-on inhibitor, RMC6236, is an innovative and exciting drug candidate, a first-in-class RAS multi-on inhibitor with potentially very broad utility across many RAS cancer variants.

I'll spend the next few minutes briefly recapping for drug candidates that constitute our development stage Ras inhibitor portfolio directed against Rasbury instead of the primary drivers of breast cancers.

Dr. Steve <unk>, our president of R&D will then highlight recent updates on our clinical stage Ras companion inhibitors RMC for sure.

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Our first rasp inhibitor RMC 63, six is an innovative and exciting drug candidate.

First in class ramps, multi <unk> inhibitor with potentially very broad utility across many.

Cancer variance.

Mark Goldsmith: As shown on slide 12, initially, we are particularly interested in the more than 130,000 new pancreatic, colorectal, and lung cancer patients in the U.S. each year, with tumors bearing one of various mutations at amino acid 12 and KRAS, the dominant hotspot for KRAS cancer mutations. We refer to these collectively as G12X mutations.

As shown on slide 12.

Initially we are particularly interested in the more than 130000.

New pancreatic colorectal and lung cancer patients in the U S. Each year with tumors bearing one of various mutations that amino acid 12 kilograms dominant hotspot two <unk> cancer mutations.

We refer to these collectively in K 12 X mutations.

Mark Goldsmith: RMC-6236 has demonstrated strong single-agent activity across numerous cancer models with such G12X driver mutations derived from non-small cell lung, pancreatic, and colorectal cancer patients. We believe this compound has the potential to be the first RAS targeted therapy for many patients still reliant upon chemotherapy, including those with tumors bearing KRAS G12D or KRAS G12V mutations. This compound is in the late stages of IND preparation, and we are on track to submit an IND in the coming months and then to begin single-agent dose escalation with an initial focus on patients with various tumors carrying KRAS G12X mutations. During dose escalation, we plan to deploy a dynamic below MTD expansion strategy to help us both find the right dose and schedule and discover the most sensitive tumor types as efficiently as possible. The next compound, RMC-6291, is our first mutant selective inhibitor planned to enter the clinic.

Mark Goldsmith: RMC6236 has demonstrated strong single-agent activity across numerous cancer models with such G12x driver mutations derived from non-small-cell lung, pancreatic, and colorectal cancer patients. We believe this compound has the potential to be the first RAS-targeted therapy for many patients still reliant upon chemotherapy, including those with tumors bearing KRAS G12D or KRAS G12V mutations. This compound is in the late stages of IND preparation, and we are on track to submit an IND in the coming months and then begin single-agent dose escalation with an initial focus on patients with various tumors carrying KRAS G12X mutations.

<unk> 66 has demonstrated strong single agent activity across numerous cancer models with such <unk> 12 X strong reputations July for non small cell lung pancreatic and colorectal cancer patients.

We believe this compound has the potential to be the first <unk> targeted therapy for many patients still reliant upon chemotherapy, including those with tumors bearing <unk>.

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This is Comcast in the late stages of R&D preparation and we are on track to submit a 90 in the coming months and then to begin single agent dose escalation with an initial focus on patients with various tumors carrying K rasp 12 X mutations.

Mark Goldsmith: During dose escalation, we plan to deploy a dynamic below-NPD expansion strategy to help us both find the right dose and schedule and discover the most sensitive tumor types as efficiently as possible. The next compound, RMC6291, is our first mutant-selective inhibitor planned to enter the clinic, this one focused specifically on the KRAS G12C target.

The dose escalation, we plan to deploy a dynamic below MPD expansion strategy to help us find the right dose and schedule and discover the most sensitive tumor types as efficiently as possible.

The next compound RMC 691 is our first selective inhibitor plans to enter the clinic. This one focused specifically on the <unk> target.

Mark Goldsmith: This one focused specifically on the KRAS G12C target. RMC-6291 is differentiated from first-generation KRAS G12C off inhibitors, which sequester the KRAS G12C off form by its mechanism of directly inhibiting the KRAS G12C on or active protein form. We believe direct inhibition of the on form of RAS cancer variants offers important biological advantages that could translate into meaningful increases in patient benefit relative to KRAS G12C off inhibitors. Based on extensive preclinical characterization showing compelling response rates, depth, and durability, we believe RMC-6291 has best-in-class potential for treating KRAS G12C cancers, addressing approximately 29,000 new US patients per year, primarily with lung or colorectal cancers. As with the 6236 compound, as shown in slide 16, we expect to submit an IND for RMC-6291 in H1 of this year, followed by beginning single-agent dose escalation in patients with various tumors carrying KRAS G12C mutations.

Mark Goldsmith: RC6291 is differentiated from first-generation KRAS-G12C-off inhibitors, which sequester the KRAS-G12C-off form, by its mechanism of directly inhibiting the KRAS-G12C-on, or active, protein form. We believe direct inhibition of the ON form of RAS cancer variants offers important biological advantages that could translate into meaningful increases in patient benefit relative to KRAS-G12C- Based on extensive preclinical characterization, showing compelling response rates, depth, and durability, we believe RMC6291 has best-in-class potential for treating KRAS G12C cancers, addressing approximately 29,000 new U.S. patients per year, primarily with lung or colorectal cancer.

RMC 69 months differentiated from first generation <unk> inhibitors, which sequester the key West Street will see off form.

<unk> mechanism of directly inhibiting <unk> on or active <unk>.

We believe direct inhibition of the on form of breast cancer bearings offers important biological advantages that could translate into meaningful increases in patient benefit relative to UK rescue totally off inhibitors.

Just on extensive preclinical characterization showing compelling response rate depth and durability. We believe RMC 69, one has best in class potential for treating <unk> cancers, addressing approximately 29000 U S patients per year, primarily with lung and colorectal cancer.

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As with the $63 six compound as shown on slide 16, we expect to submit an IND for RMC <unk> 91 in the first half of this year.

Mark Goldsmith: As with the 6236 compound, as shown in slide 16, we expect to submit an IND for RMC6291 in the first half of this year, followed by initiating single-agent dose escalation patients with various tumors carrying KRAS G12C mutations. Likewise, we plan to deploy a dynamic below-NTD expansion strategy to help us both find the right dose and obtain anti-tumor activity data in select populations as efficiently as

Followed by beginning single agent dose escalation in patients with various tumors carry <unk> mutations likewise, we plan to deploy a dynamic below NCD expansion strategy to help us find the right dose and obtain antitumor activity data in select populations as efficiently as possible.

Mark Goldsmith: Likewise, we plan to deploy a dynamic below-MTD expansion strategy to help us both find the right dose and obtain anti-tumor activity data in select populations as efficiently as possible. Our overall ambition is to demonstrate clinical superiority to the first-generation KRAS G12C off inhibitors. In addition to progressing RMC-6236 and RMC-6291 through IND submission, as expected in H1 of this year, we recently announced two new RAS(ON) inhibitors from our RAS innovation platform that have advanced into IND-enabling development. The first is RMC-9805, summarized on slide 17, a remarkable mutant-selective inhibitor of the KRAS G12D cancer driver. It's highly potent and benefits from what we believe to be the first-ever highly selective covalent engagement of the oncogenic aspartic acid in this clinically important RAS variant.

Mark Goldsmith: Our overall ambition is to demonstrate clinical superiority to the first-generation KRAS G12C off-inhibitors. In addition to progressing 6.236 and 6.291 through IND submission, as expected in the first half of this year, we've recently announced two new RASON inhibitors from our RAS Innovation Platform that have advanced into IND-enabling development. The first is RMC9805, summarized on slide 17, a remarkable mutant-selective inhibitor of the KRAS G12D cancer drug. It is highly potent and benefits from what we believe to be the first ever highly selective covalent engagement of the oncogenic aspartic acid in this clinically important RAS variant.

Our overall ambition is to demonstrate clinical superiority to the first generation <unk> inhibitors.

In addition to progressing 63, six and 691 through IND submission is expected in the first half of this year, we recently announced two new rasp inhibitors from our ramps innovation platform that have advanced into R&D, enabling development.

The first is RMC nine eight <unk> summarized on slide 17.

Remarkable Newton selective inhibitor of the <unk> 12 D cancer driver.

It's highly potent and benefits from what we believe to be the first ever highly selective covalent engagement of the oncogenic aspartic acid and is clinically important rents variant.

Mark Goldsmith: Indeed, it appears to be the first drug candidate ever to deploy this sort of selective target binding mechanism directed against an aspartate-containing disease target. Like our other development-stage assets, it is also orally bioavailable, promoting effective target coverage in cancer cells. We recently showed that RMC-9805 drives deep and durable anti-tumor responses as a single agent in preclinical KRAS G12D pancreatic and colorectal cancer models in vivo. We aim to file an IND for this highly innovative compound in H1 2023. Our second new development candidate is RMC-8839, summarized on slide 20, an exciting mutant-selective inhibitor of the KRAS G13C cancer variant that forms a selective bond with the oncogenic cysteine in this RAS target that has not been previously drugged.

It appears to be the first drug candidate ever to deploy this sort of selective target binding mechanism directed against an aspartate containing disease target.

Like our other development stage assets. It is also orally bio available promoting effective target coverage in cancer cells. We recently show that our RMC nine 805 drive deep and durable antitumor responses as a single agent in preclinical <unk> pancreatic and colorectal cancer models and <unk>.

Hello.

We aim to following IND for this highly innovative compound in the first half of 2023.

Our second New development candidate is RMC 83, nine summarized on slide 20, and exciting mutant selective inhibitor of the <unk> <unk> cancer bearing.

Mark Goldsmith: Our second new development candidate is RMC8839, summarized in slide 20, an exciting mutant-selective inhibitor of the KRAS G13C cancer variant that forms a selective bond with the oncogenic cysteine in this RAS target that has not been previously drugged. Like our other development stage RAS-on inhibitors, RMC8839 exhibits attractive potency, selectivity, and oral bioavailability, and was shown recently to drive significant anti-tumor responses as a single agent in preclinical KRAS G13C lung cancer models in vivo. We aim to file an IMD for this novel compound in the second half of 2023.

It forms the selective bond with the oncogenic <unk> in this range target that has not been previously drugs.

Mark Goldsmith: Like our other development-stage RAS(ON) inhibitors, RMC-8839 exhibits attractive potency, selectivity, and oral bioavailability, and was shown recently to drive significant anti-tumor responses as a single agent in preclinical KRAS G13C lung cancer models in vivo. We aim to file an IND for this novel compound in H2 2023. Beyond these four groundbreaking development-stage RAS(ON) inhibitors, I mentioned earlier that our strategy also includes developing specific RAS companion inhibitors, as illustrated on slide 24, targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers and, in some instances, confer drug resistance. We believe that combining best-in-class RAS inhibitors with best-in-class companion inhibitors offers the greatest chance to deliver the best clinical outcomes. In that context, Dr. Kelsey will review briefly two clinical-stage assets that are designed to support combination treatment approaches.

Like our other development stage Ras inhibitors, RMC 83, nine exhibits attractive potency selectivity and oral bio availability.

And we've shown recently to drive significant antitumor responses as a single agent in preclinical <unk> <unk> lung cancer models in vivo.

And to file an IND for this novel compound.

The second half of 2023.

Beyond these four a groundbreaking development stage Ras inhibitors I mentioned earlier that our strategy also includes developing specific Ras companion inhibitors as it is.

Mark Goldsmith: Beyond these four groundbreaking development stage RAS-on inhibitors, I mentioned earlier that our strategy also includes developing specific RAS companion inhibitors, as illustrated on slide 24, targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-indicated cancers and, in some instances, confer drug resistance. We believe that combining best-in-class grasp inhibitors with best-in-class companion inhibitors offers the greatest chance to In that context, Dr. Kelsey will briefly review two clinical stage assets that are designed to support combination treatment approaches.

Illustrated on slide 24.

Targeted drugs that suppress cooperating targets and pathways known to work in coordination with Ras cancer drivers to sustained rapid ticket cancers and in some instances conferred drug resistance.

We believe that combining best in class Rasp inhibitors with best in class Companion inhibitors offers the greatest chance to deliver the best clinical outcomes.

In that context, Dr. Kalsi will review briefly two clinical stage assets that are designed to support combination treatment approaches Steve.

Mark Goldsmith: Steve?

Steve Kelsey: Thanks, Mark. RMC-4630 is our potent selective and oral inhibitor of SHP2, a convergent signaling node that contributes to RAS-addicted cancers and is believed to mediate some types of resistance to RAS inhibition. We developed an innovative intermittent dosing regimen that is designed to maximize dose intensity without compromising safety and tolerability, and in doing so, have demonstrated that RMC-4630 is clinically active as a single agent in RAS-addicted cancers. We are now primarily focused on evaluating RMC-4630 as a companion inhibitor in combination with RAS inhibitors. Currently, only KRAS G12C inhibitors are in clinical development and available as partners for RMC-4630. The ongoing and planned RMC-4630 clinical program is summarized in slide 25. Amgen continues its initial evaluation of dosing of RMC-4630 in combination with sotorasib in second-line and beyond treatment of various KRAS G12C tumors in the CodeBreaK 101 trial, which is predominantly US-based.

Thanks Mel.

Steve Kelsey: Thanks, Mel. RMC4630 is our potent, selective, and oral inhibitor of SHIP2, a convergent signaling node that contributes to RAS-addicted cancer and is believed to mediate some types of resistance to Rassinovich. We developed an innovative intermittent dosing regimen that is designed to maximize dose intensity without compromising safety and tolerability, and in doing so, we have demonstrated that RMC4630 is clinically active as a single agent in RAS-infected cancer. We are now primarily focused on evaluating RMC463A as a companion inhibitor in combination with Ras inhibitors.

RMC for <unk> trio is a potent selective oral inhibitor of ship to.

Convergence signaling known contributes to ratchet it cancels and is believed to mediate some types of resistance to <unk> inhibition.

We developed an innovative intermittent dosing regimen that is designed to maximize dose intensity without compromising safety and tolerability.

And in doing so have demonstrated that RMC for <unk> is clinically active as a single agent <unk>.

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We are now primarily focused on evaluating RMC 463, I was a companion inhibitor in combination with <unk> inhibitors.

Steve Kelsey: Currently, only KRAS G12C inhibitors are in clinical development and available as partners for RMC4630. The ongoing and planned RMC 4630 clinical program is summarized in slide 25. Amgen continues its initial evaluation of dosing of RMC463 in combination with soteracid in second-line and beyond treatment of various KRS-CH4C tumors in the COBRATE-101 trial, which is predominantly U.S.-based. And recently, Amgen announced its intention to disclose initial dose escalation data from the C-arm of this study, which includes RMC4630, in the second half of this year.

Currently only <unk> inhibitors are in clinical development on available as partners for RMC for six trio.

The ongoing and planned RMC for six clinical program as summarized in slide 25.

Amgen continues its initial evaluation of dosing.

RMC for <unk> in combination with <unk> in second line and beyond treatment of various Kols, Chelsea tumors and the co break 101 trial, which is predominantly U S based.

Steve Kelsey: Recently, Amgen announced its intention to disclose initial dose escalation data from the C arm of this study, which includes RMC-4630, in H2 of this year. We have recently initiated a new global phase 2 study of RMC-4630 plus sotorasib, specifically in KRAS G12C lung cancer patients who have not previously received a KRAS G12C inhibitor, and we are actively recruiting patients. We announced in January that the first patient has been treated and enrollment is ongoing. Amgen is supporting this trial with clinical supply of sotorasib for both our US and ex-US study sites. Our goal is to complete enrollment in this study and communicate our preliminary evaluation of the available data in 2022. Sanofi, our global partner for development and commercialization of RMC-4630, is the sponsor of another study with Mirati of adagrasib plus RMC-4630 in lung cancer patients that is currently in preparation to begin.

And recently Amgen announced its intention to disclose initial dose escalation data from the C arm of this study which includes RMC for trio.

In the second half of this year.

Steve Kelsey: We have recently initiated a new global phase 2 study of RMC4630 plus soteracid, specifically in KRAS G12C lung cancer patients who have not previously received a KRAS G12C inhibitor, and we are actively recruiting patients. We announced in January that the first patient has been treated, and enrolment is ongoing.

We have recently initiated a new global phase two study of RMC for <unk> plus <unk>.

Specifically in <unk> lung cancer patients, who have not previously received a <unk> inhibitor.

Actively recruiting patients we announced in January the first patient has been treated and enrollment is ongoing.

Steve Kelsey: Amgen is supporting this trial with clinical supply of sulfur acid for both our U.S. and ex-U.S. study sites. Our goal is to complete enrollment in this study and communicate our preliminary evaluation of the available data in 2022. Sanofi, our global partner for development and commercialization of RMC4630, is the sponsor of another study with Merati of adagracid plus RMC4630 in lung cancer patients that is currently in preparation to begin. And in their study, they demonstrated that RMC4630 can be combined with pembrolizumab without unacceptable toxicity.

Amgen is supporting this trial with clinical supply of <unk> for both our U S and ex U S study sites.

Our goal is to complete enrollment in this study and communicates our preliminary evaluation of the available days in 2022.

Sanofi all global partner for development and commercialization of RMC for <unk> trio is the sponsor of another study with morale Tse of AD aggressive plus RMC for <unk> in lung cancer patients that is currently in preparation to begin.

Steve Kelsey: In their study, Sanofi have demonstrated that RMC-4630 can be combined with pembrolizumab without unacceptable toxicity, and they are now studying that combination as a first-line treatment for patients with PD-L1 positive lung cancer. Moving to slide 26 and regarding our near-term clinical priorities for RMC-4630, our aim is to complete the evaluation of RMC-4630 as a RAS companion inhibitor in KRAS G12C non-small cell lung cancer. In addition, we intend to pursue a registration study if this is appropriate and supported by the data and expand the combination strategy to additional KRAS G12C tumor types and perhaps even additional KRAS G12C inhibitors. Looking at slide 27, clinical data recently published suggests that the majority of RAS mutant non-small cell lung cancer escaping on or after treatment with a KRAS G12C inhibitor have no identifiable genomic resistance mechanism.

And in that study Sanofi have demonstrated that RMC for <unk> can be combined with <unk> without unacceptable toxicity and they are now studying that combination as a first line treatment for patients with PDL, one positive lung cancer.

Steve Kelsey: And they are now studying that combination as a first-line treatment for patients with PD-L1 positive lung cancer. Moving to slide 26, and regarding our near-term clinical priorities for RMC4630, our aim is to complete the evaluation of RMC4630 as a RAS companion inhibitor in KRAS G12C non-small cell lung cancer. In addition, we intend to pursue a registration study if this is appropriate and supported by the data and expand the combination strategy to additional KRAS G12C tumor types and perhaps even additional KRAS G12C inhibitors.

Moving to slide 26, and regarding our near term clinical priorities for RMC for <unk> trio.

Our aim is to complete the evaluation of RMC for <unk> trio is a Ras companion inhibitor in <unk> non small cell lung cancer and.

In addition, we intend to pursue a registration study if this is appropriate and supported by the data and expand the combination strategy to additional <unk> and perhaps even additional <unk> inhibitors.

Looking at slide 27.

Steve Kelsey: Looking at slide 27, clinical data recently published suggests that the majority of RAS mutant non-small cell lung cancers escaping on or after treatment with a KRAS-GTLC inhibitor have no identifiable genomic resistance mechanism. Many studies have shown that adaptive resistance may occur due to hyperactive receptor tyrosine kinase signals that signal through Ship Two. Combining RMC4630 with a KRAS-G12C inhibitor is, therefore, an example of a strategy to inhibit the primary RAS cancer driver while also suppressing RAS pathway resistance mechanisms that we now understand frequently limit the single-agent activity of the first-generation KRAS-G12C- Now there's no reason to believe that these emergent resistance mechanisms will be specific to KRAS G12C mutations.

Clinical data recently published suggests the majority of Ras mutant non small cell lung cancer escape thing on or after treatment with a <unk> inhibitor have no identifiable genomic resistance mechanism.

Steve Kelsey: Many studies have shown that adaptive resistance may occur due to hyperactive receptor tyrosine kinase signaling that signal through SHP2. Combining RMC-4630 with a KRAS G12C inhibitor is, therefore, an example of a strategy to inhibit the primary RAS cancer driver while also suppressing RAS pathway resistance mechanisms that we now know or understand frequently limit the single-agent activity of the first-generation KRAS G12C off inhibitors. Now, there's no reason to believe that these emergent resistance mechanisms will be specific to KRAS G12C mutations. As suggested on slide 27, RMC-4630 may be similarly useful for countering RAS pathway resistance mechanisms that emerge with RAS mutant selective inhibitors directed to other RAS variants, such as with RMC-9805 in KRAS G12D mutant cancers.

Many studies have shown that adaptive resistance may occur due to high proactive receptor tyrosine kinase signaling that signal through ship too.

Combining RMC for <unk> with a <unk> inhibitor is therefore, an example of a strategy to inhibit the primary RASK counts to drive.

Ill also suppressing Ras pathway resistance mechanisms, but we now know or understand frequently amendment. The simulation type two the first generation <unk> totally off inhibitors.

There's no reason to believe that these emergent resistance mechanisms will be specific to <unk> 12 see mutations.

Steve Kelsey: As suggested on slide 27, RNC4630 may be similarly useful for countering RAS pathway resistance mechanisms that emerge with RAS mutant-selective inhibitors directed to other RAS variants, such as with RMC 9805 in KRAS G12D mutant cancer. Slide 27 also outlines two other complementary strategies that may be pursued in parallel to SHIP-2 inhibitor combinations and to address other mechanisms of RAS inhibitor resistance, such as increased flux through wild-type RAS or acquisition of other RAS mutations beyond G12C.

As suggested on slide 27, RMC for <unk> may be similarly useful for country Ras pathway resistance mechanisms that will emerge with Ras mutant selective inhibitors directed to other rasp areas such as with RMC 98, five in <unk> two dee.

Kansas.

Steve Kelsey: Slide 27 also outlines two other complementary strategies that may be pursued in parallel to SHP2 inhibitor combinations and to address other mechanisms of RAS inhibitor resistance, such as increased flux through wild-type RAS or acquisition of other RAS mutations beyond G12C. In some clinical contexts, patients may gain maximal clinical benefit from the broad activity of our RAS multi inhibitor, RMC-6236, which, in preclinical experiments, has shown three separate effects in a single drug candidate. Firstly, deep and durable suppression of the primary RAS mutant cancer driver, inhibition of additional escape RAS mutations beyond the primary RAS mutant cancer driver, and inhibition of cooperating wild-type RAS proteins in cancer cells.

Slide 27, all sight lines to other complementary strategies that may be pursued in parallel to ship two inhibitor combinations and to address other mechanisms of Ras inhibitor resistance, such as increased flux through wild type virus or acquisition of other Ras mutations beyond.

<unk>.

And some clinical context patients may gain maximal clinical benefit from the broad activity of our RASK multi inhibitor RMC 63 six.

Steve Kelsey: In some clinical contexts, patients may gain maximal clinical benefit from the broad activity of our RAS multi-inhibitor, RMC6236, which, in preclinical experiments, has shown three separate effects in a single drug candidate. Firstly, deep and durable suppression of the primary RAS mutant cancer driver, inhibition of additional escape RAS mutations beyond the primary RAS mutant cancer driver, and inhibition of cooperating wild-type RAS proteins in cancer cells.

Which in preclinical experiments have shown three separate effects and a single drug candidate firstly deep and durable suppression of the primary Ras mutant accounts the driver.

Inhibition of additional escape Ras mutations beyond the primary Ras mutant cancer driver and in addition of cooperates a wild type Ras proteins in cancer cells.

Steve Kelsey: In other contexts, a mutant-selective RAS(ON) inhibitor such as RMC-9805 may be optimized by using RMC-6236 as a companion inhibitor, an approach that combines highly selective suppression of the particular cancer driver with direct inhibition of RAS co-mutations that cooperate to sustain these cancers. Ultimately, we anticipate that each of these three combination treatment strategies will need to be evaluated in parallel but will ultimately prove to be optimal in biomarker-defined specific patient subsets. I'd also like to highlight here RMC-5552, our innovative, potent, and selective inhibitor of mTORC1 that may also prove to be useful as a RAS companion inhibitor in certain situations. As shown in slide 28, RMC-5552 has a unique pharmacologic profile. It is distinct from mTOR active site inhibitors as it is selective for mTORC1 over mTORC2, thereby avoiding mTORC2-mediated toxicities.

In other context of mutants.

Steve Kelsey: In other contexts, a mutant-selective RAS-on inhibitor, such as RMC9805, may be optimized by using RMC6236 as a companion inhibitor, an approach that combines highly-selective suppression of the particular cancer driver with direct inhibition of RASK mutations that cooperate to sustain these cancers. Ultimately, we anticipate that each of these three combination treatment strategies will need to be evaluated in parallel, but will ultimately prove I'd also like to highlight RMC 5552, an innovative, potent, and selective inhibitor of mTORC1 that may also prove to be useful as a RAS companion inhibitor in certain situations, as shown in slide 28.

Selective <unk> inhibitors, such as RMC in RNA side might be optimized by using RMC 63, six as a companion inhibits up on.

An approach that combines highly selective suppression of the particular accounts that driver.

With direct inhibition of <unk> mutations that cooperate to sustain these ounces.

Ultimately, we anticipate that each of these three combination treatment strategies will need to be evaluated in parallel but will ultimately prove to be optimal and biomarker defined specific patient subsets.

I'd also like to highlight here RMC 5552.

Innovative potent and selective inhibitor of <unk>, but may also proved to be useful as a brass companion inhibitor in certain situations.

As slow as shown in slide 28.

Steve Kelsey: RMC 5552 has a unique pharmacologic profile. It is distinct from mTOR active site inhibitors as it is selective for mTORC1 over mTORC2, thereby avoiding mTORC2-mediated toxicities. Also, unlike raffaelogues, it is able to inhibit phosphorylation of both substrates of unsolved one.

RMC $5 $55 two has a unique pharmacologic profile.

It is distinct from <unk> active sites inhibitors.

As it is selective for <unk> over and talk to thereby avoiding <unk> mediated toxicities.

Steve Kelsey: Also, unlike rapalogs, it is able to inhibit phosphorylation of both substrates of mTORC1. We believe, based on extensive preclinical studies, that RMC-5552 has the potential to deliver clinical benefit to patients with tumors bearing mutations in the mTOR pathway. As RAS mutations and co-mutations in the mTOR pathway are relatively common in epithelial tumors, RMC-5552 could become an important companion inhibitor for our RAS(ON) inhibitor portfolio. In 2021, we began treating patients in the dose escalation portion of the initial phase 1 single-agent clinical trial, and the initial results are summarized in slide 29. They are encouraging in that they show clear evidence of anti-tumor activity at a dose that has acceptable safety and tolerability. So far, the compound has been well tolerated at doses up through 6 mg weekly.

Also unlike rafa logs it is able to inhibited phosphorylation of both substrates it until <unk>.

Steve Kelsey: We believe, based on extensive preclinical studies, that RMC5552 has the potential to deliver clinical benefit to patients with tumors bearing mutations in the mTOR pathway, as RAS mutations and co-mutations in the mTOR pathway are relatively common in epithelial tumors. RMC5552 could become an important companion inhibitor for our Rasson inhibitor portfolio. In 2021, we began treating patients in the dose escalation portion of the initial Phase 1 single-agent clinical trial, and the initial results are summarized in slide 29.

We believe based on extensive preclinical studies that RMC 505.

<unk> has the potential to deliver clinical benefit to patients with tumors bearing mutations in the <unk> pathway.

As Ras mutations and <unk> mutations in until possibly a relatively common and epithelium chambers.

RMC thought <unk> could become an important companion inhibitor for a <unk> inhibitor portfolio.

In 2021.

We began treating patients in the dose escalation portion of the initial phase one single agent clinical trial.

And the initial results are summarized in slide 29.

Steve Kelsey: They are encouraging in that they show clear evidence of anti-tumour activity at a dose that has acceptable safety and tolerability. So far, the compound has been well tolerated at doses up through six milligrams weekly. Preliminary assessments suggest that mucositis is the dose-limiting toxicity of iodine, which we believe is an on-target biological effect. Four patients have been treated at six milligrams IV weekly and were invaluable for efficacy as of the 7th of January, 2022, all with tumors carrying mutations associated with hyperactive mTOR1 signaling.

They are encouraging in that they showed clear evidence of anti tumor activity.

The dose that has acceptable safety and tolerability.

So far the compounds has been well tolerated at doses up through six milligrams weekly.

Steve Kelsey: Preliminary assessments suggest that mucositis is the dose-limiting toxicity at higher doses, which we believe is an on-target biological effect. 4 patients have been treated at 6 mg IV weekly and were evaluable for efficacy as of 7 January 2022, all with tumors carrying mutations associated with hyperactive mTORC1 signaling. 3 of these patients have experienced a best response to stable disease, and one patient with a head and neck cancer, and PTEN loss of function mutation has exhibited a confirmed partial response based on a 63% reduction of tumor volume from baseline. This patient had a single dose of 12 mg followed by 6 mg weekly and continues on treatment.

Preliminary assessment suggests that mucositis is with dose limiting toxicity at high doses, which we believe is an on target biological effect.

Four patients have been treated six milligrams IV weekly and were Evaluable for efficacy.

As of the 17th of January 2022.

All with tumors carrying mutations associated with hyperactive and $12 6 million.

Three of these patients have experienced a best response or stable disease.

Steve Kelsey: Three of these patients have experienced a best response to stable disease, and one patient with head and neck cancer and a P10 loss of function mutation has exhibited a confirmed partial response based on a 63% reduction of tumor volume from baseline.

And one patient with a head and neck cancer and <unk> loss of function mutation is.

<unk> had a confirmed partial response based on a 63% reduction of tumor volume from baseline.

Steve Kelsey: This patient had a single dose of 12mg, followed by 6mg weekly, and continues on treatment. We hope to complete the single-agent dose escalation for RMC5552 this year in order to be able to select a recommended Phase II dose and start to study RNC5552 in selected expansion cohorts and ultimately aim to initiate testing of combinations with our RAS-on inhibitors in patients that have co-activation of the RAS and N-TOR pathway. Now, we'll turn it back to Mark. Thank you, Steve.

This patient had a single dose 12 milligrams, followed by six milligrams weekly and continues on treatment.

Steve Kelsey: We hope to complete the single-agent dose escalation for RMC-5552 this year in order to be able to select a recommended phase 2 dose and start to study RMC-5552 in selected expansion cohorts and ultimately aim to initiate testing of combinations with our RAS(ON) inhibitors in patients that have co-activation of the RAS and mTOR pathways. Now I'll turn it back to Mark.

We hope to complete the single agent dose escalation for RMC 505 to this year in order to be able to select a recommended phase II dose.

And start to study <unk> hundred 552 in selected expansion cohorts and ultimately aim to initiate testing of combinations with our <unk> inhibitors in patients that have co activation of the <unk> and Tor complex.

Now I'll turn it back to Mark.

Mark Goldsmith: Thank you, Steve. With these prepared comments, we have briefly summarized the status of six development stage assets, which are supported by exciting, robust, and growing data sets that suggest large clinical opportunities we may be able to serve for patients with a wide range of RAS-addicted cancers. Further, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our science-driven strategies to outsmart RAS-addicted cancers. Please take the opportunity to review the full corporate slide deck that you can download from our investor relations website. I'll now turn to Jack Anders, our Senior Vice President for finance, to report on our financial condition. Jack?

Thank you Steve.

Mark Goldsmith: With these prepared comments, we have briefly summarized the status of six development stage assets, which are supported by exciting, robust, and growing data sets that suggest large clinical opportunities we may be able to serve for patients with a wide range of RAS-addicted cancers. In addition, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our science-driven strategies to outsmart RAS-addicted cancers.

With these prepared comments, we have briefly summarize the status of six development stage assets, which are supported by exciting robust and growing datasets.

Suggest large clinical opportunities, we may be able to serve for patients with a wide range of brass addicted cancers.

Further we expect that our pipeline will continue to grow with highly distinctive new assets deriving from a Ras cancer innovation engine, which should expand our science driven strategies to outsmart Ras addicted cancers. Please take the opportunity to review the full corporate slide deck that you can download from our Investor Relations website.

Mark Goldsmith: Please take the opportunity to review the full corporate slide deck that you can download from our Investor Relations website. I'll now turn to Jack Anders, our Senior Vice President for Finance, to report on our financial condition. Thank you, Mark. As shown on slide 33, we ended the year with $577 million in cash and investments. Revenue from our collaboration agreement with Sanofi was $9.5 million for the fourth quarter of 2021 and $29.5 million for the second quarter of 2021, a total of $2.4 million for the full year.

<unk>.

I'll now turn to Jack Anders Senior Vice President for Finance to report on our financial condition Jack.

Jack Anders: The decrease in revenue for the full year of 2021 compared to 2020 was primarily driven by a non-cash, non-recurring revenue adjustment in the third quarter of 2021, resulting from a change in accounting, under our agreement with Sanofi, and to a lesser extent, Lower Reimbursed Manufacturer. Total operating expenses for the fourth quarter of 2021 increased to $62 million, largely driven by R&D expenditure, totaling $54, total operating expenses for the full year of 2021.

Jack Anders: Thank you, Mark. As shown on slide 33, we ended the year with $577 million in cash and investments. Revenue from our collaboration agreement with Sanofi was $9.5 million for Q4 2021 and $29.4 million for the full year. The decrease in revenue for the full year of 2021 compared to 2020 was primarily driven by a non-cash, non-recurring revenue adjustment in Q3 2021, resulting from a change in accounting estimate under our agreement with Sanofi and, to a lesser extent, lower reimbursed manufacturing costs. Total operating expenses for Q4 2021 increased to $62 million, largely driven by R&D expenses, which totaled $54 million. Total operating expenses for the full year of 2021 increased to $217 million, with R&D expenses increasing to $187 million.

Thank you Mark.

As shown on slide 33, we ended the year with $577 million in cash and investments.

Revenue from our collaboration agreement with Sanofi with $9 5 million for the fourth quarter of 2021 and $29.

$4 million for the full year.

The decrease in revenue for the full year of 2021 compared to 2020 was primarily driven by a noncash nonrecurring revenue adjustment in the third quarter of 2021, resulting from a change in accounting estimate under the agreement under our agreement with Sanofi and to a lesser extent lower reimbursed manufacturing costs.

Total operating expenses for the fourth quarter of 2021 increased to $62 million larger.

Largely driven by R&D expenses, which totaled $54 million.

Total operating expenses for the full year of 2021 increased to $217 million with R&D expenses, increasing to $187 million.

Jack Anders: Christ at 217. R&D, increasing to 187; the increase in total operating expenses in 2021 was due to the expansion of the company's preclinical research portfolio and increase in headcount. Christian Stark, B.S. Net loss for the fourth quarter of 2021 was $53 million, or $0.71. For the full year of 2021, net loss was $187 million.

Jack Anders: The increase in total operating expenses in 2021 was due to the expansion of the company's preclinical research portfolio, an increase in headcount, and an increase in stock-based compensation. Net loss for Q4 of 2021 was $53 million or $0.71 per share. For the full year of 2021, net loss was $187 million or $2.57 per share. With regards to financial guidance for 2022, we expect full year 2022 GAAP net loss to be between $260 and 290 million, which includes estimated non-cash stock-based compensation expense of $35 to 40 million. The increase in expected net loss for 2022 is a result of increased expenses as we expand and advance our research and development programs. With that, I'll now turn the call back over to Mark.

The increase in total operating expenses in 2021 was due to the expansion of the company's preclinical research portfolio and increase in head count and an increase in stock based compensation.

Net loss for the fourth quarter of 2021 was $53 million or <unk> 71 per share.

For the full year of 2021, net loss with $187 million or $2 57 per share.

With regards to financial guidance for 2022, we expect full year 2022, GAAP net loss to be between 260 and $290 million.

Mark Goldsmith: $52.57. With regard to financial guidance for 2022, we expect full year 2022 gap net loss to be between $260,000 and $290,000, which includes estimated non-cash, stock-based compensation. 35 to 40 minutes. The increase in expected net loss for 2022 is a result of increased..., as we expand and advance our research and development. And with that, I'll now turn the call back over to Mark. Thank you, Jack.

Which includes an estimated noncash stock based compensation expense of $35 million to $40 million.

The increase in expected net loss for 2022 as a result of increased expenses as we expand and advance our research and development programs.

And with that I'll now turn the call back over to Mark.

Mark Goldsmith: Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to our patients, their families, and the many partners who work with us for providing Revolution Medicines with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

Thank you Jack.

Mark Goldsmith: We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to our patients and their families and the many partners who work with us for providing Revolution Medicine with the opportunity to advance our unique pipeline of RAS-on inhibitors and RAS-companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Operator?

We believe that Revlimid is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy a growing set of exciting product assets and a strong balance sheet.

We're proud of the tireless commitment to patient as part of our organization and are grateful to our patients and their families and the many partners who work with us for providing dilution medicines with the opportunity to advance our unique pipeline of <unk> inhibitors, <unk> inhibitors, which we believe may transform the treatment of brass addicted cancers.

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: Thank you. As a reminder, to ask a question, please press the star key followed by 1 on your touchtone phone. To withdraw your question, press the pound key. Please stand by as we compile the Q&A roster. Our first question comes from Jonathan Chang with SVB Leerink. Your line is open.

Operator: Thank you. As a reminder, to ask a question, please press the * key followed by 1 on your touchtone phone. To withdraw your question, press the pound key. Please stand by as we compile the Q&A roster. Our first question comes from Jonathan Chang with SVB Leerink. Your line is open.

Thank you as a reminder to ask a question. Please press the star can you followed by one on your Touchstone phone. So I'm sorry. Your question press the pound key.

Operator: Thank you. As a reminder, to ask a question, please press the star key followed by 1 on your touchtone phone. To withdraw your question, press the pound key.

Operator: Please stand by as we compile the Q&A roster. Our first question comes from Jonathan Chang with SCV Larynx. Your line is open.

Please standby as we compile the Q&A roster.

Our first question comes from Jonathan Chang with SBB Leerink. Your line is open.

Jonathan Chang: Hi, guys. Thanks for taking my questions. First question, approximately how many addressable second-line non-small cell lung cancer KRAS G12C patients are there in the US? Amgen is saying it's around 7,000. Is that consistent with your views?

Hi, guys. Thanks for taking my questions.

Jonathan Chang: Hi guys, thanks for taking my questions. First question: approximate how many addressable second-line non-small cell lung cancer, KRAS G12C patients are there in the U.S.? So Amgen is saying it's around 7,000. Is that consistent with your... Hey, Jonathan. This is Mark Goldsmith.

Last question.

How many addressable second line non small cell lung cancer K Ras <unk> half the patients are there in the U S.

And Genesis, saying, it's around 7000 is that consistent with your views.

Yeah.

Mark Goldsmith: Hey, thanks, Jonathan. This is Mark Goldsmith. Appreciate the question. It's actually a fairly complex question, and we're aware of the subtleties and the discussion going on around that right now with regard to Amgen's comments on that. I'd suggest that's something we could discuss with you offline and that that's probably the better place to do it at this time.

Okay. Thanks, Jonathan This is mark Goldsmith I appreciate the question, it's actually a fairly complex question and.

Mark Goldsmith: I appreciate the question. It's actually a fairly complex question, and we're aware of the subtleties and the discussion going on around that right now with regard to Amgen's comments on that. I'd suggest that's something we could discuss with you offline and that that's probably the better place to do it at this time.

We're aware of the subtleties in the.

Discussion going on around that right now with regard to amgen's comments on that.

I would suggest that something we could discuss with you offline and thats, probably the better place to do it at this time.

Jonathan Chang: Got it. On the second question on RMC-5552, how does targeting just mTORC1 compare to targeting both mTORC1 and 2? And how does 5552 overcome potential resistance mechanisms encountered by existing mTORC1 inhibitors? Thank you.

Got it.

Steve Kelsey: Got it. On the second question, about RMC5552, how does targeting just mTORC1 compare to targeting both mTORC1 and 2? And how does 5552 overcome potential resistance mechanisms encountered by existing mTORC1 inhibitors? Thank you. Thank you very much.

On the second question on RMC five five.

Two.

How does targeting just end torque one compare to targeting both <unk>, one and two and how does 555 to overcome potential resistance mechanisms and countered by existing and talk one inhibitors. Thank you.

Mark Goldsmith: Thanks very much. Steve, would you like to take this question?

Steve Kelsey: Steve, would you like to take this question? Sure. Thank you. The first..., question, the first part of your question, I think is best addressed in the clinical data that's available for the dual mTORP1 and mTORP2 inhibitors. When we set out to develop RNC5552, we were specifically going after the substrate of mTORP1, which is 4-ABP1, which is critical for the cat-dependent translation of certain oncogenes, such as MEK, for instance, but a bunch of others as well.

Thanks, very much Steve would you like to take this question.

Steve Kelsey: Sure. Yeah, the first part of your question, I think, is best addressed in the clinical data that's available for the dual mTORC1, mTORC2 inhibitors. When we set out to develop RMC-5552, we were specifically going after the substrate of mTORC1, which is 4E-BP1, which is critical for cap-dependent translation of certain oncogenes such as MYC, for instance, but a bunch of others as well. The challenge with the mTORC1, 2 inhibitors, the dual inhibitors, is specifically that the inhibition of mTORC2 confers toxicity. The problem with the mTORC2-mediated toxicity is that you can't dose high enough to inhibit the 4E-BP1 substrate. You can only inhibit the S6 kinase substrate. That's been shown very clearly by AstraZeneca in a series of sort of PD-driven clinical evaluations that they did.

Steve Kelsey: Sure. , the first part of your question, I think, is best addressed in the clinical data that's available for the dual mTORC1, mTORC2 inhibitors. When we set out to develop RMC-5552, we were specifically going after the substrate of mTORC1, which is 4E-BP1, which is critical for cap-dependent translation of certain oncogenes such as MYC, for instance, but a bunch of others as well. The challenge with the mTORC1, 2 inhibitors, the dual inhibitors, is specifically that the inhibition of mTORC2 confers toxicity. The problem with the mTORC2-mediated toxicity is that you can't dose high enough to inhibit the 4E-BP1 substrate. You can only inhibit the S6 kinase substrate. That's been shown very clearly by AstraZeneca in a series of sort of PD-driven clinical evaluations that they did.

Sure.

Yes.

The first.

Question. The first part of your question I think is best addressed in the.

The clinical data that's available for the dual until one of them took two inhibitors.

We set out to develop <unk>, 5%.

Two we will specifically going after the.

The substrate to them until one which is for ABP, one which is critical for.

Translation of certain oncogene, such as MC for instance, but a bunch of others as well.

Steve Kelsey: The challenge with the mTORP1,2 inhibitors, the dual inhibitors..., is specifically that the inhibition of TORC2 confers toxicity, and the problem with the TORC2 mediated toxicity is that you can't dose high enough to inhibit the 4-ABP1 substrate. You can only inhibit the S6 kinase substrate, and that's been shown very clearly by AstraZeneca in a series of sort of PD-driven clinical evaluations that they did.

The challenge with the <unk>.

One two and have the dual inhibitors.

Is it specifically that the inhibition of talk to confirm toxicity.

The problem with the <unk> mediated toxicity.

Is that you can dose high enough to inhibit the <unk> substrate, you can only inhibit <unk> kinase substrate and that's been shown very clearly <unk> is it sort of.

Steve Kelsey: So I think that's essentially the uniqueness of its selectivity for the inhibition of mTORP1 selectively is that you don't have the mTORP2 mediated toxicity, and you can inhibit both substrates of mTORP1, which is both the S6 kinase and the 4-ABP1, and we think the 4-ABP1 is really critical to inhibit in order to get a therapeutic effect. I think that that sort of addresses part two of your question as well because rapalogues don't inhibit 4-ABP1, either conventional rapamycin or rapamycin derivatives like everolimus. They just don't inhibit 4-ABP1. There are some complex sort of mechanistic reasons why that's the case, but essentially, I think 5.5.2 is unique in its ability to inhibit phosphor 4-ABP1. I got it.

PD driven clinical evaluations that they did so I think that's the third.

Steve Kelsey: I think that's essentially the uniqueness of its selectivity of the inhibition of mTORC1 selectively is that you don't have the mTORC2-mediated toxicity, and you can inhibit both substrates of TORC1, which is both the S6 kinase and the 4E-BP1. We think the 4E-BP1 is really critical to inhibit in order to get a therapeutic effect. I think that sort of addresses part two of your question as well because rapalogs don't inhibit 4E-BP1 either, conventional rapamycin or rapamycin derivatives like everolimus. They just don't inhibit 4E-BP1. There are some complex sort of mechanistic reasons why that's the case. Essentially, I think 5552 is unique in its ability to inhibit phosphorylated 4E-BP1.

Essentially the uniqueness of.

Selectivity of inhibit <unk>.

Inhibition of them.

<unk> selectively is that you don't have the end until two mediated toxicity and you can inhibit both substrates.

<unk>, which is both the <unk> and we think for BP. One is really critical to inhibit when do we get a therapeutic effect.

I think that.

That.

Sort of addresses part two of your question as well because <unk> doesn't inhibit for edp, one either conventional rapamycin erythromycin derivatives luck overlying lets say they just don't inhibit plentiful and there are some complex sort of mechanistic reasons why that's the case, but.

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

Operator: Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is open.

Michael Schmidt: Thanks for taking the question. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is open. Hey, good afternoon.

[Analyst] (Guggenheim Securities): Hey, good afternoon. This is Yiwen for Michael. Thanks for taking our questions. You now have a suite of KRAS inhibitors. Just curious, besides the KRAS selectivity, how different are these compounds in their pharmacokinetics? And would the potential difference in PK make one of them better be used for certain histology or tumor types or at a certain specific setting?

Yige Guo: This is Yige Alper and Michael. Thanks for taking our questions. You now have a suite of KRAS inhibitors. Just curious, besides the KRAS selectivity, how different are these compounds in their pharmacokinetics? And would the potential difference in PK make one of them better for certain histology or tumor types or at a certain specific setting? This is Marc.

In our questions.

You know have a suite of.

K Ras inhibitors.

Just curious besides the Trs selectivity E. How different are these compounds in their farmer cool kinetics and the wood wood the potential difference in PK make one of them better be used for certain histology or tumor types or at a certain specific setting.

Mark Goldsmith: This is Mark. Thanks for your question. Just to clarify, are you asking for comparing the kinetics of RAS on inhibitors in our collection with RAS off inhibitors, KRAS G12C RAS off inhibitors, or are you asking about differences even within our own portfolio?

Marc Frahm: Thanks for your question. Just to clarify, are you asking about comparing the kinetics of RAS-on inhibitors in our collection with RAS-off inhibitors, KRAS-G12C RAS-off inhibitors, or are you asking about differences, even within our own portfolio? Sorry, this is for your own inhibitors, and mine were inhibitors, among our compounds. You're asking? That's right. OK. Steve, do you want to take us from your pen?

This is mark Thanks for your question just to clarify are you asking for comparing the kinetics of rash on inhibitors in our collection with Rosoff inhibitors K rescue 12 C. Rosoff inhibitors or are you asking about differences even within our own portfolio.

[Analyst] (Guggenheim Securities): Sorry. This is for your own inhibitors, among your inhibitors.

Sorry.

This is this is for your own inhibitors among or hepatitis.

Mark Goldsmith: Among our compounds, you're asking?

Among among our compounds you are asking that's right.

[Analyst] (Guggenheim Securities): That's right.

Mark Goldsmith: Okay. Steve, do you want to take some of that?

Okay.

Steve you ought to fix me with that.

Steve Kelsey: Yeah. I think the first thing to say is that the pharmacokinetics of our RAS(ON) inhibitors is quite complex because it's a multi-compartmental model. Basically, you've got the plasma. You've got the entry into the tissue, the potential interaction of the molecule with intracellular cyclophilin A, which is in abundance. It's in excess. That does sort of things to the actual tissue pharmacokinetics, which varies from tissue to tissue and from drug to drug. Obviously, you've got the binding to the target, which is not just driven by the affinity for cyclophilin A and the affinity for KRAS, but it's also driven quite significantly by whether the warhead is a covalent binding warhead or not a covalent binding warhead. Fundamentally, I think I can simplify this by saying there are really two sets of differences across our range of inhibitors.

Steve Kelsey: . I think the first thing to say is that the pharmacokinetics of our RAS(ON) inhibitors is quite complex because it's a multi-compartmental model. Basically, you've got the plasma. You've got the entry into the tissue, the potential interaction of the molecule with intracellular cyclophilin A, which is in abundance. It's in excess. That does sort of things to the actual tissue pharmacokinetics, which varies from tissue to tissue and from drug to drug. Obviously, you've got the binding to the target, which is not just driven by the affinity for cyclophilin A and the affinity for KRAS, but it's also driven quite significantly by whether the warhead is a covalent binding warhead or not a covalent binding warhead. Fundamentally, I think I can simplify this by saying there are really two sets of differences across our range of inhibitors.

Steve Kelsey: Yeah, I think the first thing to say is that the pharmacokinetics of our RAS-on inhibitors is quite complex because it's a multi-compartmental model. Basically, you've got the plasma, you've got the entry into the tissue, the potential interaction of the molecule with intracellular cyclophilin A, which is in abundance, it's in excess, and that does sorts of things to the actual tissue pharmacokinetics, which vary from tissue to tissue and from drug to drug.

Yeah, I think the first the first thing to say is that the the connected the pharmacokinetics of our rason inhibitors is quite complex because it's a multi called compartmental model you've you've got.

Basically you've got a plasma.

You've got the the entry into the tissue the potential interaction of the molecule with intracellular Cyclacillin, a which is which is in abundance Susan access and that does that does sort of things to the to the actual tissue pharmacokinetics was where you can tissue <unk> tissue and from drug to drug and then obviously you got.

Steve Kelsey: And then obviously, you've got the binding to the target, which is not just driven by the affinity of cyclophilin A and the affinity for KRAS, but it's also driven quite significantly by whether the warhead is a covalent-binding warhead or not a covalent-binding warhead. So, fundamentally, I think I can simplify this by saying there are really two sets of differences across our range of inhibitors. The first is affinity for cyclophilin A.

Binding to the target, which is not just driven by.

The the Affinitive such termini in the affinity for K rest of this whole so driven quite quite significantly by whether the warhead is a copayment binding warheads will knock Havana binding morehead so.

Fundamentally I think.

I can simplify this by saying they're really too.

Two sets of differences between across our our range of inhibitors. The first is affinity for slight to fit in a.

Steve Kelsey: The first is affinity for cyclophilin A. That does have a significant impact on the intracellular retention time and the effective intracellular potency. The second thing is whether or not the warhead is covalent or not covalent. Of the four compounds that Mark described, three of them have a covalent warhead. The 12C, 13C, and 12D all have a covalent warhead, which means essentially, once they're bound, they're effectively irreversibly bound. RMC-6236 does not have a covalent warhead. Its inhibition is non-covalent, but that is very tightly bound to cyclophilin A. That compound's very tightly bound to cyclophilin A. So it stays within tumor cells considerably longer than it does within normal tissue. We've shown data for that in several scientific meetings.

Steve Kelsey: That does have a significant impact on the intracellular retention time and the effective intracellular potency. And the second thing is whether or not the warhead is covalent or not covalent. Of the four compounds that Mark described, three of them have a covalent warhead. The two for the 12C, 13C, and 12D all have a covalent warhead, which means essentially once they're binded, they're effectively irreversibly bound. RMC6236 does not have a covalent warhead. Instead, its inhibition is non-covalent, but it is very tightly bound to cyclophilin. That compound is very tightly bound to cyclophilin A, so it stays within tumor cells considerably longer than it does with normal tissues.

That does have a significant impact on the intracellular.

Retention time on the effective intracellular potency and the second thing is whether or not the warhead is kind of dialogue noncovalent of the three com times, but not described.

Sorry, all the full come hasn't not described three of them have a prevailing warhead.

Two four the 12 <unk> 12 D. All have one which means essentially once that bond.

Two new year with those will be banned.

RMC 6236 does not have.

Morehead, it's inhibitions noncovalent, but that is very tightly bank decided to submit compounds very topic bombs. So tonight. So it stays within chew the cells considerably longer than it does or the normal tissue and we've shown data for the several scientific meeting so.

Steve Kelsey: And we've shown data for that at several scientific meetings. So, you know, at the end of the day, it's very hard for us to predict what's going to be best. We're going to evaluate this during our clinical programs, but I think it's safe to say that we have a range of optionality here, and we can exploit it in the interest of the best combination.

Steve Kelsey: At the end of the day, it's very hard for us to predict what's going to be best. We're going to evaluate this during our clinical programs. I think it's safe to say that we have a range of optionality here, and we can exploit it in the interest of the best combinations.

At the end of the day, it's very hard for us to predict what's going to be best we're going to.

Levada witnessed during all clinical programs, but I think it's safe to say that we have a range of functionality here and we can exploit it for.

In the interest of the best combinations.

[Analyst] (Guggenheim Securities): Got it. That's super interesting. Thank you.

Got it at Super interesting. Thank you.

Operator: Our next question comes from Eric Joseph with J.P. Morgan. Your line is open.

Our next question comes from Eric Joseph J P. Morgan Your line is open.

Eric Joseph: That's super interesting. Thank you. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open. Hi, this is Sean on behalf of Eric.

[Analyst] (J.P. Morgan): Oh, hi. Yeah, this is Sean for Eric. Thanks for taking our questions. So looking ahead into the preliminary data readout from the RMC-4630-03 study, wondering if you could frame expectations there in terms of number of patients and plans to follow up. Are you targeting any particular medical or scientific conferences for our presentation? Thanks.

Shayan Hussain: Oh, hi. , this is Sean for Eric. Thanks for taking our questions. So looking ahead into the preliminary data readout from the RMC-4630-03 study, wondering if you could frame expectations there in terms of number of patients and plans to follow up. Are you targeting any particular medical or scientific conferences for our presentation? Thanks.

Alright that is a strong for Eric thanks for taking our questions. So.

Sean: Thanks for taking our questions. So looking ahead to the preliminary data readout from the 4630, Zero, and O3 studies. Wondering if you could frame expectations there in terms of number of patients and lines of follow-up? And are you targeting any particular medical or scientific conferences for a presentation? Thanks.

Looking ahead into the preliminary data read out from the 46 30.

And also are you studying wondering if you could frame expectations. There in terms of finding nemo patients and trying to follow up on.

Are you targeting on your particular dramatic authenticate compensate for our presentation. Thanks.

Mark Goldsmith: Steve, do you want to address the question of numbers and outcome measures?

Steve Kelsey: Steve, do you want to address the question of numbers and outcome measures? Yeah, sure. I think it's, you know, we've said previously, and I think you could probably read it on clinicaltrials.gov, that the RMC 463003 study, which is the one that we're sponsoring, is the only one actually that we're able to really talk to in detail about the two other studies. One is being sponsored by Amgen, and one is being sponsored by Sumafi. So really, you know, those questions would have to be addressed to those companies.

Steve do you want to do you want to address the question of of numbers and.

Outcome measures yes.

Steve Kelsey: Yeah, sure. I think what we've said previously, and I think you could probably read it on ClinicalTrials.gov, that the RMC-4630-03 study, which is the one that we're sponsoring, it's the only one actually that we're able to really talk to in detail. The two other studies, one is being sponsored by Amgen, one's been sponsored by Sanofi. Really, those questions would have to be addressed to those companies. For RMC-4630, we're planning to treat up to 46 patients. They will be retrospectively stratified by whether or not they have a co-mutation in either STK11 or KEAP1. The way that the data's falling out right now, we expect it rather to be about a 2 to 1 split. We expect maybe somewhere in the region of 30 patients will not have a co-mutation in STK11 or KEAP1, and about 15 will do.

Steve Kelsey: , sure. I think what we've said previously, and I think you could probably read it on ClinicalTrials.gov, that the RMC-4630-03 study, which is the one that we're sponsoring, it's the only one actually that we're able to really talk to in detail. The two other studies, one is being sponsored by Amgen, one's been sponsored by Sanofi. Really, those questions would have to be addressed to those companies. For RMC-4630, we're planning to treat up to 46 patients. They will be retrospectively stratified by whether or not they have a co-mutation in either STK11 or KEAP1. The way that the data's falling out right now, we expect it rather to be about a 2 to 1 split. We expect maybe somewhere in the region of 30 patients will not have a co-mutation in STK11 or KEAP1, and about 15 will do.

Yeah sure I think it's.

We.

We've said previously, but I think you could probably read it.

Charles Dot Gov.

The RMC for <unk>, which is the one that we're sponsoring is the only one I actually that we're able to really talk to in detail.

The two other studies one is being sponsored by Amgen was been dumped sponge by Sanofi So really the.

[laughter].

Those questions would have to be addressed to those companies, but for arms equal 631.

Steve Kelsey: But for RNC4630, you know, we're planning to treat up to 46 patients. We do expect they will be retrospectively stratified by whether or not they have a co-mutation in either STK11 or KEEP1. And the way that the data is falling out right now, we're expecting that to be about a two to one split, so we expect maybe somewhere in the region of 30 patients will not have a co-mutation in STK11 or KEEP1, and about 15 will do.

Planning to trade up to 46 patients.

We do it they will be retrospectively stratified by whether or not they have a co mutation and neither SDK level will keep one.

And the way that the basis falling at right now we suggest we expected and that'll be about a two to one split so we expect maybe somewhere in the region of 30 patients will not have okay mutation of this Taylor will keep wondering about 15 will do.

Steve Kelsey: Of course, the primary outcome measure for efficacy will be overall response rate by RECIST. We're basically comparing against a historical overall response rate in that patient population that's derived from the sotorasib approval, the label, which gave them a response rate around 36%. If you take out the STK11 and KEAP1 mutant patients, it goes up a little bit. Maybe it bumps up to maybe sort of 40%, 41%. That will be the reference efficacy number.

Steve Kelsey: And of course, the primary outcome measure for efficacy will be overall response rate by RESSIS. So, you know, we're basically comparing against a historical overall response rate in that patient population that's derived from the soteracid approval and label, which gave them a response rate around 36%. If you take out the STK11 and KEEP1 mutant patients, it goes up a little bit, maybe it bumps up to maybe sort of a low 40, 41%. And that will be the reference number; that will be the reference efficacy number. Yeah, that's helpful. Thank you.

The course of the primary outcome measure for for efficacy will be overly response rate by wrestlers so.

We're basically comparing against a historical overall response rate and that patient population was derived from the.

Such a acid approval of the label, which which gave him a sponsor around 36%.

If you take out the SDK them keep one mute in patients with it goes up a little bit maybe bumps up to maybe soda no footman 40, 41% and that will be the that would be the reference that'll be the reference <unk>.

[Analyst] (J.P. Morgan): Yeah, that's very helpful. Thank you.

Shayan Hussain: , that's very helpful. Thank you.

Yeah, that's very helpful. Thank you.

Mark Goldsmith: Yeah. Just to address the second part of your question, this is Mark again, as to what forum we might present results in. We're not expecting to have these observations put together in a form that we could talk about until towards the end of the year. It's not likely that there's going to be a scientific forum that's perfectly available to us at exactly the right time. We may have to make some sort of disclosure outside of that context and then follow it up with a more detailed disclosure at a subsequent scientific meeting. That's something we're still sort of working through. Until we have much better visibility on enrollment pace and the timing of those data, we really can't get more specific than that.

Mark Goldsmith: . Just to address the second part of your question, this is Mark again, as to what forum we might present results in. We're not expecting to have these observations put together in a form that we could talk about until towards the end of the year. It's not likely that there's going to be a scientific forum that's perfectly available to us at exactly the right time. We may have to make some sort of disclosure outside of that context and then follow it up with a more detailed disclosure at a subsequent scientific meeting. That's something we're still sort of working through. Until we have much better visibility on enrollment pace and the timing of those data, we really can't get more specific than that.

Yes, I am just to address the second part of your question. This is mark again is.

Mark Goldsmith: Yeah, and just to address the second part of your question, this is Mark again, as to what forum we might present the results. You know, we're not expecting to have these observations put together in a form that we can talk about until towards the end of the year. And so it's not likely that there's going to be a scientific forum that's perfectly available to us at exactly the right time. So we may have to make some sort of disclosure outside of that context and then follow it up with a more detailed disclosure at a subsequent scientific meeting. But that's something we're still sort of working through.

As to what forum, we might present results in.

We're not expecting to have these observations put together in a form that we could talk about until towards the end of the year.

And so.

It's not likely that there's going to be a scientific form that's perfectly available to us at exactly the right time.

So we may have to make some sort of disclosure outside of that context, and then followed up with a more detailed disclosure at a subsequent scientific meeting.

But that's something we're still sort of working through and until we have much better visibility on enrollment pace and the timing of those data, we really can't get more specific from that.

Marc Frahm: And until we have much better visibility on enrollment pace and the timing of those data, we really can't get more specific than that. Our next question comes from Marc Frahm with Cohen and Company. Your line is open.

Operator: Our next question comes from Marc Frahm with Cowen & Company. Your line is open.

Our next question comes from Mark Fram, What's Cowen and company airline that's open.

Marc Frahm: But thanks for taking my questions. Maybe just start with the design of the 6236 and 6291 trials that you're getting close to opening. When you talk about having below-MTD expansion cohorts and starting those kind of early, will those be really just very broad enrollment expansion cohorts across all sorts of mutations and tumor types to really just kind of backfill the overall experience, or are you already going to be kind of subdividing patients into either by their mutation or by tumor type? Hi Mark.

Marc Frahm: Thanks for taking my questions. Maybe just to start with the design of the RMC-6236 and RMC-6291 trials that you're getting close to opening up. When you talk about having below-MTD expansion cohorts and starting those kind of early, will those be really just very broad enrollment expansion cohorts across all sorts of mutations and tumor types to really just kind of backfill the overall experience, or are you already going to be kind of subdividing patients either by their mutation or by tumor type?

Thanks for taking my questions, maybe sister with the design of the 63, six and 69, one the trials that you're getting close to opening up.

When you talked about having below MTV.

Expansion cohorts and starting those kind of early will those be really just very broad enrollment expansion cohorts across all sorts of mutations in and tumor types to really just kind of backfill. The overall experience or are you already going to be.

Subdividing patients into either either by their mutation or by two other type.

Mark Goldsmith: Hi, Mark. Thanks for joining us. Thanks for your question. Yes, I think it's going to come down a little bit to the word dynamic and how that gets deployed. Maybe Steve can comment on our below-MTD dynamic expansion plans.

Hi, Mark Thanks for joining us thanks for your question.

Marc Frahm: Thanks for joining us. Thanks for your question. Yes, I think it's going to come down a little bit to the word dynamic and how that gets deployed. Maybe Steve can comment on our below MTD dynamic expansion plan. Yeah, it might be.

Yes, I think it's going to come down a little bit to the word dynamic.

And how that give support may be Steve can comment on or below entity.

Dynamic expansion plans.

Steve Kelsey: Yeah, Mark. The below-MTD expansions have a number of utilities, but the primary utility is to increase the sort of database for safety tolerability so that we can make much more informed decisions about the optimal dose to take into any phase 2 expansion. In that context, the specific tumor types or mutations are not so relevant because they don't really drive the tolerability profile. Having said that, at the end of the day, firstly, we do refine the types of patients that we like. We would want to enroll as we start if we start picking up an efficacy signal, we'll start refining the types of patients that we want to enroll. For instance, for RMC-6291, it's pretty obvious that the dynamic goes in two dimensions.

Steve Kelsey: , Mark. The below-MTD expansions have a number of utilities, but the primary utility is to increase the sort of database for safety tolerability so that we can make much more informed decisions about the optimal dose to take into any phase 2 expansion. In that context, the specific tumor types or mutations are not so relevant because they don't really drive the tolerability profile. Having said that, at the end of the day, firstly, we do refine the types of patients that we like. We would want to enroll as we start if we start picking up an efficacy signal, we'll start refining the types of patients that we want to enroll. For instance, for RMC-6291, it's pretty obvious that the dynamic goes in two dimensions.

Yes.

<unk>.

Steve Kelsey: The below-end 2D expansions have a number of..., a number of utilities, but the primary utility is to increase the sort of database for safety and tolerability so that we can make much more informed decisions about the optimal dose to take into any Phase 2 expansion. In that context, you know, the specific tumor types or mutations are not so relevant because they don't really drive the tolerability profile. Having said that, you know, at the end of the day, firstly, we do refine the types of patients that we like and that we would want to enroll as we start. If we start picking up an efficacy signal, we'll start refining the types of patients that we want to enroll. For instance, for 6291, it's pretty obvious that the dynamic goes in two dimensions.

The below NTT expansions.

Have a number of.

A number of utilities, but the primary utility is to increase the.

Database for safety Tolerability search so that we can make much more informed decisions by the optimal dose to take into any place to expansion.

In that context.

Ossific.

Schumer types all mutations.

I'm not so relevant because they don't really drive tolerability profile, having said that at the end of the day.

Firstly, we do refine the types of patients that we like we would want to enroll as we start if we start picking up on that because he signal will start refining the types of patients that we wanted to load.

Steve Kelsey: One is whether or not they have or haven't received a KRAS inhibitor previously, and the second is whether or not they've got lung cancer or colon cancer. For IMC 6236, it's a little bit more complex than that, but we do refine it as the dose increases and as we get more information. But really, you know, this is in part because we started doing this for SHIP-2 back in 2018.

For instance was 69, one is pretty obvious.

The dynamic as in two dimensions, one is whether or not they have or haven't received a K Ross and that which was previously and the second is whether or not we bought lung cancer or colon cancer.

Steve Kelsey: One is whether or not they have or haven't received a KRAS inhibitor previously, and the second is whether or not they've got lung cancer or colon cancer. For RMC-6236, it's a little bit more complex than that. We do refine it as the dose increases and as we get more and more information. Really, this is in part although we started doing this for SHP2 back in 2018. Now, of course, it's taken on a whole new dimension with this FDA Project Optimus type thing where they want us to spend more time and energy really drilling down on the best phase 2 dose for expansion. I think it contributes significantly to the best selection of the recommended phase 2 dose to take forwards. That's essentially why we're doing it.

6236 is a little bit more a little bit more complex than that but we do refiner as the dose.

Base increases and as we get more information, but but really this is this as in Paul.

Although we we started doing this for <expletive> to back in 2018.

Steve Kelsey: But now, of course, it's taken on a whole new dimension with this FDA project optimist type thing where, you know, they want us to spend more time and energy really drilling down on the best phase two dose for expansion. I think it contributes significantly to the best selection of the recommended phase two dose to take forward, so that's essentially what we're doing. Okay, thanks, that's helpful. And then just thinking through, you know, obviously those agents have...

But now of course has taken on a whole new dimension with this FDA.

Project Optimus type thing where.

They want us to spend more time and energy.

Really draining down on the best place to those three expansion I think it contribute significantly to the best selection, mostly of the recommended phase two dose to take forward.

Essentially.

Marc Frahm: Okay. Thanks. That's helpful. Then just thinking through obviously, those agents have potential as monotherapies, but also a big part of your overall strategy is a combination approach. What do you need to see from, I guess, the monotherapy trials before you would start the combination approaches? I guess related to that is, what do you need to see additive efficacy in the sotorasib combo for 4630 to pursue 4630 combos with your own RAS inhibitors, or are there subtleties to the different mutations that kind of make them an independent decision?

Thanks, that's helpful. And then just thinking through obviously those agents have some have potentials monotherapies, but could also be part of your overall strategy combination of person what do you need to see from.

Marc Frahm: Some have potential as monotherapies, but a big part of your overall strategy is a combination approach. So what do you need to see from the monotherapy trials before you start the combination approaches? And I guess related to that is... Do you need to see additive efficacy in the soda-acid combo for 4630 to pursue 4630 combos with your own RAS inhibitors, or are there subtleties to the different mutations that kind of make them an independent disease?

The.

Mono therapy trials before you would start the combination of purchase I guess related to that is.

What do you need do you need to see additive efficacy and the soda rapid combo for.

For 4630 to pursue 4630 combos with your own.

Inhibitors.

Or their subtleties to the different mutations that kind of make them an independent decisions.

Mark Goldsmith: Yeah, Mark, if I could just add one more point to the discussion on the first question that you asked, which is Steve emphasized gathering safety data and dose selection and primarily using the expansions below MTD to help build that dataset. Now, I think we should also acknowledge, though, in the context of 6236, where we're evaluating multiple genotypes as well as histotypes, we may begin to see some evidence about which tumor types or which genotypes are responding during that dose escalation. That could be another opportunity for us to expand some of that early information to help us really clarify whether we're seeing a particular signal in a particular context. That would be a secondary objective from the below-MTD expansions.

Mark Goldsmith: , Mark, if I could just add one more point to the discussion on the first question that you asked, which is Steve emphasized gathering safety data and dose selection and primarily using the expansions below MTD to help build that dataset. Now, I think we should also acknowledge, though, in the context of 6236, where we're evaluating multiple genotypes as well as histotypes, we may begin to see some evidence about which tumor types or which genotypes are responding during that dose escalation. That could be another opportunity for us to expand some of that early information to help us really clarify whether we're seeing a particular signal in a particular context. That would be a secondary objective from the below-MTD expansions.

Marc Frahm: Yeah, Marc, if I could just add one more point to the discussion on the first question that you asked, which is Steve emphasized gathering safety data and dose selection and primarily using the Future, as well as histotypes, we may begin to see some evidence about which tumor types or which genotypes are responding during that dose escalation, and that could be another opportunity for us to expand some of that early information to help us really clarify whether we're So that would be a secondary objective from the below-MTD expansions.

Yeah, Mark if I could just add one more point to the discussion on the first question that you asked which is.

Steve emphasized gathering safety data and dose selection and primarily using the.

The.

Expansion slow MTBE to help build that datasets.

Think we should also acknowledge so in the context of 6236, where we're evaluating multiple genotypes.

As well assisted types, we may begin to see some evidence about which which tumor types or which genotypes are responding.

During during that dose escalation and that could be another opportunity for us to expand some of that early information to help us further clarify whether we're seeing.

A particular signal in a particular.

Context, so that would be a secondary.

<unk>.

After the expansion.

Mark Goldsmith: With regard to your second question, do we need to see combinatorial activity in either our 03 study or the CodeBreaK 101C study before we would combine 4630 with I think you mean specifically with our G12C inhibitor or with any of our RAS inhibitors?

Marc Frahm: And then with regard to your second question, do we need to see activity of combinatorial activity in either our O3 study or the Code Break 101 C study before we would combine 4630 with, I think you mean specifically with our G12 C inhibitor or with any of our grass inhibitors? But actually, both.

And then with regard to your second question do we need to see activity combinatoria activity in the either or <unk> study or the Quebec wanted once C study before we would combine <unk> with I think you mean, specifically with Archie 12, C inhibitor or with any of our assets.

Marc Frahm: Both, actually.

But both actually.

Mark Goldsmith: Yeah. I don't want to draw sort of a hard line in the sand, but we do expect that we're going to see. We project that we should see activity in combination with sotorasib and that that's a very nice dataset for us to build on. If RMC-4630 is combinatorial, is additive with sotorasib, then there would be no real reason to believe it shouldn't be additive with our KRAS G12C inhibitors, so just starting with G12C. If it isn't, I think we'd really want to understand why it isn't. That could influence the decision about whether we would still combine it with RMC-6291 or not. I think that relationship largely probably holds for the other RAS mutant inhibitors as well. The biology does differ across different genotypes.

Mark Goldsmith: . I don't want to draw sort of a hard line in the sand, but we do expect that we're going to see. We project that we should see activity in combination with sotorasib and that that's a very nice dataset for us to build on. If RMC-4630 is combinatorial, is additive with sotorasib, then there would be no real reason to believe it shouldn't be additive with our KRAS G12C inhibitors, so just starting with G12C. If it isn't, I think we'd really want to understand why it isn't. That could influence the decision about whether we would still combine it with RMC-6291 or not. I think that relationship largely probably holds for the other RAS mutant inhibitors as well. The biology does differ across different genotypes.

Yeah.

Mark Goldsmith: Yeah. You know, I don't want to draw a sort of hard line in the sand, but we do expect that we're going to see, we project that we should see activity in combination with sodoracib and that that's a very nice data set for us to build on. And if RMC4630 is combinatorial, is additive, So, if it's with soda acid, then there would be no real reason to believe it shouldn't be additive with our KRS-G12C inhibitors, so just starting with G12C.

I don't want to draw a sort of a hard line in the sand, but we do expect that we're going to see we we project that we should see.

Activity in combination with soda rather than that that's.

A very nice.

Data set for us to build on and if RMC forces trios is combinatorial is additive.

With soda rather than there would be no real reason to believe it shouldn't be additive with our our <unk> inhibitor. So just starting with with <unk> and if it isn't I think we would really want to understand why it isn't and that could influence the decision about whether we the silk combined it with RMC 69, one.

Mark Goldsmith: And if it isn't, I think we'd really want to understand why it isn't, and that could influence the decision about whether we would still combine it with RMC6291 or not. I think that relationship largely probably holds for the other RAS mutant inhibitors as well. But the biology does differ across different genotypes. Some are more likely to be sensitive to the modulating effects of signaling through SHIP2, or RTKs, and some may be less likely to be sensitive.

Not.

I think that relationship largely probably holds for the other Ras mutant inhibitors as well, but the biology does differ across different genotypes.

Mark Goldsmith: Some are more likely to be sensitive to the modulating effects of signaling through SHP2, through RTKs, and some may be less likely to be sensitive. It's not necessarily the case that every genotype should be treated in the same way. Still, largely, I think we're looking for clear evidence of combinatorial activity in the combination of the Amgen and RevMed studies with sotorasib and RMC-4630.

Some are more likely to be sensitive to the modulating effects of signaling cruise ship to who arkie caves and some may be less likely to be sensitive and so.

Mark Goldsmith: And so it's not necessarily the case that every genotype should be treated, you know, in the same way, but still, largely, I think we're looking for clear evidence of combinatorial activity in the combination of the Amgen and RevMed studies with photographs of an RMT4630. It's probably also worth mentioning, Mark, that... It's not just the genotypes that differ, but also the histotypes differ very considerably as well. I mean, the mechanisms of escape that are emerging from in colon cancer with psoriasis are out of grasp of a very different from the mechanism state emerging from lung cancer.

Not necessarily the case that every genotype should be treated.

The same way, but still largely I think we're looking for clear evidence of Combinatoria activity.

The combination of the Amgen in reference studies with photographs of an RMC 463.

Steve Kelsey: It's probably also worth mentioning, Mark, that it's not just the genotypes that differ, but also the histotypes differ very considerably as well. I mean, the mechanisms of escape that are emerging in colon cancer with sotorasib and adagrasib are very different from the mechanisms of escape emerging in lung cancer. I think we have optionality. We have to pay attention to the histotype, the genotype. also, we also have other companion inhibitors beyond RMC-4630. I think we have a lot of confidence in RMC-4630 because of the sheer weight of mechanistic data that's available for it. at the end of the day, we have others to go with as well. somehow, we have to figure out which is the best one for any individual patient.

So it's probably also worth mentioning.

It's not just the the the genotype.

But also has two times did the very considerably as well I mean, the mechanisms of escape.

That are emerging from.

<unk> kind of a sort of wood wood. So the rest of it autographed with a very different from the mechanism escaping emerging wood.

Steve Kelsey: So I think we have optionality, you know, we have to pay attention to the histotype, the genotype, and also, you know, we also have other companion inhibitors beyond RMC4630. I think we have a lot of confidence in RMC4630 because of the sheer weight of mechanistic data that's available for it, but at the end of the day, you know, we have others to go with as well.

With an unconscious. So I think we have optionality we have.

We have to pay attention to the history type genotype and also.

We also have other companion and I'm just beyond arms equals three of them I think we we have a lot of confidence and arm simple six through because of the sheer weight of of mechanistic.

Date, so that's available for it but we.

At the end of the day, we have others to go with as well and we have to somehow we have to figure out which is the best one trying again.

Steve Kelsey: And we have to somehow figure out which is the best one for any given individual. Okay, thank you. As a reminder, to ask a question, please press star then 1. Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open. Hi all, this is CJ on for Chris tonight.

Sure.

Marc Frahm: Okay. Thank you.

Okay. Thank you.

Operator: Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

As a reminder to ask a question. Please press Star then one.

Operator: Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

Our next question comes from Chris to be tiny with Goldman Sachs. Your line is open.

[Analyst] (Goldman Sachs): Hi all. This is C.J. on for Chris tonight. Thanks for taking the question. I think we've talked about a lot of different topics so far. One of interest that has come up a lot lately in the KRAS space is handwringing about the potential for accelerated pathways for new novel molecules, particularly in the G12C space. Curious, as you potentially advance 4630 to a registrational trial, first timing of that, would that be next year potentially? Is there potential for 4630 to follow an accelerated pathway, or would this need to be more of a traditional pathway if that definition of unmet need has potentially been filled? Presumably for your pipeline RAS inhibitors, both the multi and other mutations, potential for accelerated approval may be available for those as well. Could you comment there? Thank you.

C.J. MacDonald: Hi all. This is C.J. on for Chris tonight. Thanks for taking the question. I think we've talked about a lot of different topics so far. One of interest that has come up a lot lately in the KRAS space is handwringing about the potential for accelerated pathways for new novel molecules, particularly in the G12C space. Curious, as you potentially advance 4630 to a registrational trial, first timing of that, would that be next year potentially? Is there potential for 4630 to follow an accelerated pathway, or would this need to be more of a traditional pathway if that definition of unmet need has potentially been filled? Presumably for your pipeline RAS inhibitors, both the multi and other mutations, potential for accelerated approval may be available for those as well. Could you comment there? Thank you.

Hello. This is CJR for Christmas and thanks for taking the question.

Chris Shibutani: Thanks for taking the question. We've talked about a lot of different topics so far. One of the things of interest that has come up a lot lately in the KRES space is hand-wringing about the potential for accelerated pathways for A New Novel Molecule. I'm curious, as you potentially advance 4630 to a registrational trial, the first timing of that, would that be next year, potentially? And is there potential for 4630 to follow an accelerated pathway? Or would this need to be more of a traditional pathway, if that definition of unmet need has potentially been filled?

I think we've talked about a lot of different topics. So far one of interest that has come up a lot lately and the <unk> spaces handwringing about the potential for accelerated pathways for.

CJ: and then presumably for your pipeline graph inhibitors. Both the multi and other mutations potential for accelerated approval may be available for those as well. Could you comment there?

New novel molecules.

Particularly energy told C statements curious as you potentially advance 46 32 Registrational trial.

First timing of that would that be next year potentially and is there potential for 46 30 to file an accelerated pathway or this made too.

Be more of a traditional pathway if that definition of unmet need is potentially be filled.

And then presumably for your pipeline.

Grass inhibitors.

And put the multi and other mutations potential for accelerated approval maybe available for those as well could you comment there. Thank you.

Mark Goldsmith: Yeah. Thanks very much, C.J. Those are great questions, and they're sort of hot topics that are actively discussed within RevMed and with regard to 4630, of course, with our partner Sanofi. We don't have definitive answers, but it's probably the case that you have to separate KRAS G12C sotorasib combination from the others given that that's a space in which there's already one approved treatment, and there will be a second undoubtedly later this year. Whereas all the other mutants, there are no, and there won't be any approved therapies anytime in the near future. I think those are a lot easier to think about because they're unprecedented at that point. They're unserved by targeted therapies. All options, I think, would be still open there. We'll have Steve comment on that. I think that one's an easier one.

Mark Goldsmith: . Thanks very much, C.J. Those are great questions, and they're sort of hot topics that are actively discussed within RevMed and with regard to 4630, of course, with our partner Sanofi. We don't have definitive answers, but it's probably the case that you have to separate KRAS G12C sotorasib combination from the others given that that's a space in which there's already one approved treatment, and there will be a second undoubtedly later this year. Whereas all the other mutants, there are no, and there won't be any approved therapies anytime in the near future. I think those are a lot easier to think about because they're unprecedented at that point. They're unserved by targeted therapies. All options, I think, would be still open there. We'll have Steve comment on that. I think that one's an easier one.

Mark Goldsmith: Yeah, thanks very much, CJ. Those are great questions, and they're sort of hot topics that are actively, actively discussed within ResMed and, and with regard to 4630, of course, with our partner Sanofi. So we don't have definitive answers. But it's probably the case that you have to separate KRAS G12C, SodaRacid combination from the others given that That's a space in which there's already one approved treatment and there will be a second undoubtedly later this year, whereas all the other mutants, there are no, and there won't be any approved therapies any time in the near future.

Yeah. Thanks, very much C. J those are great questions of their sort of hot topics that are actively actively discussed within RESNET and and with regard to 406 trio of course with our partner Santa fee.

So we don't have definitive answers.

But it's probably the case that you have to separate Hey, rescue 12 C.

Acid combination from the others given that.

That's a space in which there is already one approved treatment and there will be a seconds undoubtedly later this year.

Whereas all the other mutants there are no and there won't be any approved therapies anytime in the near future. So I think.

Mark Goldsmith: So I think those are a lot easier to think about because they're unprecedented at that point, they're unserved by targeted therapies, and so all options, I think, would still be open there. We'll have Steve comment on that. I think that one's an easier one. With KRAS G12c, it's a little bit more complex, and it might be that there are several different options and that the question to be decided is strategically which option or options to pursue rather than just whether they exist. Steve, do you want to give any more color to that?

Those are a lot easier to think about because they are they are unprecedented at that point that are unserved by targeted therapies and so all options I think would be still open there will have Steve comment on that I think that once an easier one.

Mark Goldsmith: With KRAS G12C, it's a little bit more complex, and it might be that there are several different options and that the question to be decided is strategically which option or options to pursue rather than just do they exist. Steve, do you want to give any more color to that?

<unk> 12, see it's a little bit more complex and it might be that there are several different options and that the question to be decided as strategically which option or options to pursue rather than.

Do they exist.

Steve do you want to do.

Steve Kelsey: Well, I think the only two bits of color I would add to that is firstly, C.J., don't confuse accelerated approval with rapid approval. There are plenty of ways of getting to market relatively quickly without necessarily having to invoke the Subpart H of 21 CFR, which is the accelerated approval option. As you pointed out, there were already preexisting issues with accelerated approval even before the recent sort of controversies around how long it takes to get the confirmatory trials done and whether or not the Alzheimer's drug should have got it in the first place, all that sort of stuff. We are currently looking at a whole load of options both for accelerated approval within the US, and also a rapid approval globally.

You have any more color.

Steve Kelsey: Well, I think the only two bits of color I would add to that are... Firstly, CJ, don't confuse accelerated approval with rapid approval. There are plenty of ways of getting to market relatively quickly without necessarily having to invoke subpart H of CFR 21, which is the accelerated approval option. There are, as you pointed out, there were already pre-existing issues with accelerated approval, even before the recent sort of controversy controversies around how long it takes to get the confirmatory trials done and whether or not the Alzheimer's drug should have got it in the first place, all that sort of stuff, but we are currently looking at a whole load of options both for accelerated approval within the U.S. and also for rapid approval globally.

I think the only the only two.

Two bits of color I would add to that is.

Firstly, CJ duncombe shoes accelerated approval with rapid approval there are plenty of ways of getting to market relatively quickly.

Without necessarily having to invoke.

The Saint Paul Agency, or 21, which is the accelerated approval option narrow but.

Calling tonight.

Already preexisting issues with accelerated approval.

Even before the recent so control control the seas around how long it takes to get that comes from the tree, Charles done and whether or not the.

Outside of this drug should have got it in the first place all that sort of stuff but.

We are.

Currently looking at a whole load of options for.

Both for accelerated approval within the U S and also a rapid approval globally and.

Steve Kelsey: Obviously, at the end of the day, the options available to us, to some extent, and the speed at which we get there will depend on the strength of the phase 2 data that we see in the 3 trials that we're running, certainly for RMC-4630. I don't think the situation has changed for the RAS inhibitors, particularly outside of G12C. I think that if the data is compelling, then it's very hard for the Food and Drug Administration to deny patients access to it under the accelerated approval banner. I think they will obviously require confirmatory trials to be done, and of course, we're very happy to do them. All that remains to us remains an option.

Steve Kelsey: And obviously, at the end of the day, the options available to us, to some extent, and the speed at which we get there will depend on the strength of the Phase II data that we see in the three trials that we're running. So, certainly for 4630.

Obviously at the end of the day the options available to us to some extent the speed with which we get will depend on the strength.

To date, so that we see.

And the three channels that were running so certainly.

631.

Steve Kelsey: I don't think the situation has changed for the RAS inhibitors, particularly outside the GTOC. I don't think the situation has changed. I think that if the data is compelling, then it's very hard for the Food and Drug Administration to deny patients access to it under the accelerated approval banner. I think, you know, they will obviously require confirmatory trials to be done, and of course, we're very happy to do them.

I didn't think the situation has changed for the rash inhibitors, particularly.

Particularly outside of <unk> out of the situation has changed I think that if you if if if the data is compelling.

Then it is very hard for the food and drug administration to deny patients access to the.

Under the et cetera has to prove who.

I think they will obviously.

Require comes from the two trials can be done in the course without having to do it.

Steve Kelsey: But, you know, all that remains to us remains an option. I think, in principle, the RAS mutant remains. The precedent that was set by Sotiris will remain true for the other RAS mutations as well. Great, thank you. And our final question comes from Ben Burnett with CIFL. Your line is open.

All that remains to us remains an option, but I think in principle, the Ras mutant space remains.

Steve Kelsey: I think in principle, the RAS mutant space remains the precedent that was set by sotorasib will remain true for the other RAS mutants as well.

The precedent that was set by so tourists will remain true for the other last week mutations as well.

[Analyst] (J.P. Morgan): Great. Thank you.

Shayan Hussain: Great. Thank you.

Great. Thank you.

Operator: Our final question comes from Ben Burnett with Stifel. Your line is open.

And our final question Thompson, then Burnett, but Sniffle your line is open.

[Analyst] (Stifel): Good afternoon. This is Neil on for Ben. Your KRAS G12D inhibitor will be administered orally. Can you talk to the bioavailability and target coverage you've seen preclinically and any early thoughts you may have around dose levels or dosing frequency?

Neil Stone: Good afternoon. This is Neil on for Ben. Your KRAS G12D inhibitor will be administered orally. Can you talk to the bioavailability and target coverage you've seen preclinically and any early thoughts you may have around dose levels or dosing frequency?

Good afternoon. This is neil on for prevent.

Ben Burnett: Good afternoon. This is Neil. I'm on behalf of Ben.

You are chaos equal the inhibitor will be it will be administered orally can you talk to the bio availability and target covered you've seen pre pre clinically and any early thoughts you may have around.

Neil: Your KRAS G12D inhibitor will be administered orally. Can you talk about the bioavailability and target coverage you've seen pre-clinically and any early thoughts you may have around dose levels or dosing frequency? Yeah, thanks for your interest and for your question.

Dose levels or dosing frequency.

Mark Goldsmith: Yeah. Thanks for your interest and for your question. We actually put out, I think, in this corporate deck and in the investor deck in January, data that shows very good pharmacodynamic effects in vivo over an extended period of time with RMC-9805. I think it shows suppression of the pathway out to well beyond 24 hours with just a single dose. It also shows the pharmacokinetics associated with that. Of course, this is in a mouse xenotransplant context. That was dosed at 100 mg/kg, sort of a convenient kind of conventional dose for that purpose. I don't think we showed a dose response per se in that particular experiment. That gives you a sense that at least in that context, a single dose can provide not only very rapid and deep effects but quite sustained effects.

Mark Goldsmith: . Thanks for your interest and for your question. We actually put out, I think, in this corporate deck and in the investor deck in January, data that shows very good pharmacodynamic effects in vivo over an extended period of time with RMC-9805. I think it shows suppression of the pathway out to well beyond 24 hours with just a single dose. It also shows the pharmacokinetics associated with that. Of course, this is in a mouse xenotransplant context. That was dosed at 100 mg/kg, sort of a convenient kind of conventional dose for that purpose. I don't think we showed a dose response per se in that particular experiment. That gives you a sense that at least in that context, a single dose can provide not only very rapid and deep effects but quite sustained effects.

Yeah. Thanks for your interest in for your question.

We actually put out I think in this corporate deck and an investor day in January .

Mark Goldsmith: We actually put out, I think, in this corporate deck and in the investor deck in January data that shows very good pharmacodynamic effects in vivo over an extended period of time with ARMC9805. I think it shows suppression of the pathway out to well beyond 24 hours with just a single dose. And it also shows the pharmacokinetics associated with that. But, of course, this is in a mouse, in a transplant context. So, and that was dosed at 100 mg per kilogram, sort of a convenient kind of conventional dose for that purpose.

Data that shows very good pharmacodynamic effects.

Bo over an extended period of time with RMC 95, I think it shows suppression of halfway out too well beyond 24 hours with just a single dose.

And we.

And it also shows the pharmacokinetics associated with that of course. This is in a in a mouse xenotransplant context.

So.

And that was dose at 100 mix per kilogram.

Sort of a convenient kind of conventional dose for that purpose I don't think we showed a dose response per se.

Mark Goldsmith: I don't think we showed a dose response per se in that particular experiment. So that gives you a sense that, at least in that context, a single dose can provide not only very rapid and deep effects but quite sustained effects. And what that will translate into people will depend a lot on what pharmacokinetics we see in people. And although we have modeling around that based on multiple preclinical species, that simply is going to be a projection.

Particular experiment.

So that gives you a sense that.

At least in that context, a single dose can provide.

Not only very rapid in deep effects, but quite sustained effects.

Mark Goldsmith: What that will translate into people will depend a lot on what pharmacokinetics we see in people. Although we have modeling around that based on multiple preclinical species, that simply is going to be projection. I think until we're in the clinic and establish the actual PK and PK variability, which is always an important parameter as well, I don't think we can answer the question. In an ideal world, we'll be dosing once a day, and we'll be dosing in the ballpark of or less than the current doses that are used for KRAS G12C inhibitors. That's very, very hard to say today.

What that will translate into people will depend a lot on.

Pharmacokinetics, we see in people and although we have modeling around that based on multiple preclinical species.

That simply is going to be projection and I think until we're in the clinic and establish the actual PK and pique variability.

Mark Goldsmith: And I think until we're in the clinic and establish the actual PK and PK variability, which is always an important parameter as well, I don't think we can answer the question. You know, in an ideal world, we'd be dosing once a day, and we'd be dosing in the ballpark of or less than the current doses that are used for KRAS G12C inhibitors, but, you know, that's very, very hard to say today.

Which is always important parameter as well I don't think we can answer the question.

In an ideal world.

It will be dosing once a day and will be dosing.

In the in the ballpark of or less them.

The current doses that are used for curiosity 12 inhibitors.

Right.

It's very very hard to say today.

[Analyst] (J.P. Morgan): Great. Thank you.

Shayan Hussain: Great. Thank you.

Great. Thank you.

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

As there are no more questions in the queue I was kind of a call back over deductible Smith was closing remark.

Mark Goldsmith: Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for closing remarks. Thank you, operator. And thank you to everyone, including our analysts who asked questions, for participating today and for your continued support of Revolution Medicine. This concludes the program. You may now disconnect. Everyone, have a great day.

Mark Goldsmith: Thank you, operator. Thank you to everyone, including our analysts, who asked questions for participating today and for your continued support of Revolution Medicines.

Thank you operator, and thank you to everyone, including our analysts who ask questions for participating today and for your continued support of Revolution medicines.

Operator: This concludes the program. You may now disconnect. Everyone, have a great day.

This concludes the program you may now disconnect everyone have a great day.

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