Q3 2021 Revolution Medicines Inc Earnings Call

November 10, 2021

[music].

Good day, ladies and gentlemen, and welcome to the Revolution medicines third quarter fiscal 2021 financial results conference call and webcast.

Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q3 fiscal 2021 financial results conference call and webcast. At this time, all participants are in listen-only mode. Following management prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star followed by the number one on your touch tone phone. Please be advised that today's conference call is being recorded. If anyone has a difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer for opening remarks. Peg, you may begin.

At this time all participants are in listen only mode. Following management's prepared remarks, we will hold a Q&A session.

Can I ask a question at that time. Please press the star followed by the number one when you touched on the phone.

Be advised that today's conference call is being recorded.

If anyone has had difficulty hearing the conference. Please press star zero for operator assistance.

I would now like to hand, the call and friendship to bag coin revolutions, Chief operating officer for opening remarks.

They began.

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 our Principal Accounting Officer. 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. 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, Evolutions, Chairman and Chief Executive Officer, Dr. Steve Kelsey The company 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 meaning 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.

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 and other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted on 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.

I encourage you to review the legal disclaimer slides presenting today as well as all of the Companys filings with the SEC concerning these and other matters.

During this presentation, we will be referring to a few slides from our corporate presentation.

Entire presentation, that's posted on our website immediately prior to this call.

With that I will turn the call over to Dr. Mark Goldsmith, Evolutions, Chairman and Chief Executive Officer.

Mark.

Good afternoon, and thank you for joining us.

Mark Goldsmith: Good afternoon, and thank you for joining us. We're very pleased to report that during this quarter, Revolution Medicines continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatments on behalf of patients with a wide range of RAS-addicted cancers, representing some 30% of all cancer patients. Our ambition is, first, to serve the significant unmet needs that remain for patients with KRAS G12C bearing tumors, despite first generation targeted inhibitors coming online. Second, to deliver first in class or best in class solutions to benefit even larger numbers of patients with cancers driven by other RAS variants beyond KRAS G12C. RevMed continues making excellent progress, reinforcing our belief that the company's innovative and integrated asset portfolio can drive rational, mechanism-based combination treatments for the benefit of patients with diverse RAS addicted cancers.

We're very pleased to report that during this quarter Revolution Medicine continued building momentum with our targeted therapeutics pipeline advancing our mission to improve treatments on behalf of patients with a wide range of brass addicted cancers, representing some 30% of all cancer patients.

Our ambition is first to serve the significant unmet needs that remain for patients with <unk> T 12 fee bearing tumors. Despite first generation targeted inhibitors coming online.

And second to deliver first in class or best in class solutions to benefit even larger numbers of patients with cancers, driven by other rats variants beyond the <unk> 12 fee.

<unk> continues making excellent progress reinforcing our belief that the company's innovative and integrated asset portfolio can drive rational mechanism based combination treatments for the benefit of patients with diverse rats addicted cancers.

Mark Goldsmith: Today, rather than providing a comprehensive overview of RevMed's entire pipeline, I would like to take you through a few highlights of several recent significant scientific presentations made by our R&D organization. As a reminder, represented on slide five of our November corporate slide deck, our primary R&D strategy is to advance our emerging RAS(ON) inhibitors to suppress RAS cancer drivers through innovative compounds with superior potential deriving from their unique mechanisms of action and highly differentiated chemical and pharmacologic profiles. I'll update you on these exciting programs momentarily. We also recognize that RAS addicted cancers are often supported and sustained by various cooperating proteins and cell regulatory pathways that limit the rate or durability of initial responses to targeted therapies.

Today, rather than providing a comprehensive overview of revenue its entire pipeline I would like to take you through a few highlights of several recent significant scientific presentations made by our R&D organization.

As a reminder, represented on slide five of our November corporate slide deck.

Our primary R&D strategy is to advance our emerging Ras on inhibitors to suppress Ras cancer drivers through innovative compounds with superior potential deriving from their unique mechanisms of action and highly differentiated chemical and pharmacologic profiles I'll update you on these exciting programs.

Momentarily.

We also recognize that Ras addicted cancers are often supported and sustained by various cooperating proteins.

Cell regulatory pathways that limit the rate or durability of initial responses to targeted therapies to defeat. These oncogenic contributors. We are advancing our collection of high quality targeted Ras companion inhibitors to deploy in combination with targeted Ras inhibitors in order to enhance.

Mark Goldsmith: To defeat these oncogenic contributors, we are advancing our collection of high quality targeted RAS companion inhibitors to deploy in combination with targeted RAS inhibitors in order to enhance clinical benefit. I'll touch on progress we've made in this part of our portfolio as well. RMC-6291 is our potent oral and selective tri-complex inhibitor of KRAS G12C on with an exciting preclinical profile designed to address persistent unmet needs for patients with cancers driven by KRAS G12C. Shown in slide eight is RMC-6291's high potency and selectivity for KRAS G12C tumor cells and its favorable comparison to leading members of the KRAS G12C off inhibitor class.

Clinical benefit I'll touch on progress we've made in this part of our portfolio as well.

RMC 60, 91 is our potent oral selective try complex inhibitor of <unk> 12 C on with an exciting preclinical profile designed to address persistent unmet needs for patients with cancers driven by <unk>.

Shown in slide eight is six to nine months high potency and selectivity for <unk> 12 see tumor cells.

And its favorable comparison to leading members of the <unk> inhibitor class.

Mark Goldsmith: As shown on slide 9, our scientists recently disclosed data from a mouse clinical trial that was run with 19 KRAS G12C-bearing non-small cell lung cancer models to compare the impact of RMC-6291 head to head in vivo with a representative of the KRAS G12C OFF inhibitor class. Consistent with findings we've reported in the past from previous experiments in individual tumor models, RMC-6291 performed very well in this larger survey, showing broad antitumor benefit evidenced by shrinking many tumors, inducing many regressions, including CRs, and demonstrating an overall response rate of 68% in this tumor set.

As shown on slide nine our scientists recently disclosed data from a mouse clinical trial that was run with 19, K Ras <unk> 12 C bearing non small cell lung cancer models to compare the impact of RMC 69, one head to head in vivo with a representative of the <unk> 12.

<unk> off inhibitor class.

Consistent with findings we've reported in the past from previous experiments and individual tumor models.

69, one performed very well in this larger survey showing broad antitumor benefit evidenced by shrinking many tumors.

<unk>, many regression, including Crs and demonstrating an overall response rate of 68% in this tumor setting.

The results of this study as shown on the previous slide in here on Slide 10 point to specific advantages in terms of rate.

Mark Goldsmith: The results of this study, as shown on the previous slide and here on slide 10, point to specific advantages in terms of rate, depth, and/or durability of response in the preclinical setting and establish an exciting best-in-class thesis for RMC-6291 that we look forward to testing in the clinic. Additional data were presented just this week that extended the evaluation of RMC-6291 into gastrointestinal cancers. Slide 11 shows a mouse clinical trial with 13 KRAS G12C-bearing colorectal cancers, demonstrating an objective response rate of 31% and disease control rate of 54%. Further, RMC-6291 showed compelling durability of effect and delayed resistance development. Overall, these findings provide a broad foundation for our best-in-class thesis for RMC-6291 that we expect to assess in the clinic.

And or durability of response in the preclinical setting.

And establish an exciting best in class thesis for RMC 60, 91 that we look forward to testing in the clinic.

Additional data were presented just this week that extended the evaluation of 69, one into gastrointestinal cancers.

Slide 11 shows a mouse clinical trial with 13, K recipe 12 fee bearing colorectal cancers.

Demonstrating an objective response rate of 31%.

And disease control rate of 54%.

Further 69, one showed compelling durability of effect and delayed resistance development.

Overall these findings provide a broad foundation for our best in class thesis for RMC 60, 91 that we expect to assess in the clinic.

Mark Goldsmith: The company remains on track to submit an Investigational New Drug or IND application for RMC-6291 in H1 2022. I'd also like to highlight recent findings with RMC-6236, our first-in-class oral RAS(ON) multi-selective inhibitor designed to treat cancers driven by a variety of KRAS mutations, including those that have emerged in patients following treatment with KRAS G12C OFF inhibitors. As shown on slide 15, our recently reported findings showed significant, broad, and durable activity of RMC-6236 in vivo against numerous RAS-addicted tumor models driven by diverse RAS or RAS pathway mutations. In particular, as shown on the right, RMC-6236 drove significant tumor shrinkage across multiple non-small cell lung cancer models with various mutations at the G12 position in KRAS, including G12D, G12V, and G12C.

The company remains on track to submit an investigational new drug or IND application for RMC $60 91 in the first half of 2022.

I'd also like to highlight recent findings with RMB 63, six our first in class oral Ras selective Ras multi on inhibitor.

Designed to treat cancers, driven by a variety of K Ras mutations, including those that have emerged in patients following treatment with <unk> <unk> off inhibitors.

As shown on slide 15, our recently reported findings showed significant broad and durable activity of arms to $63 six in vivo against numerous Ras addicted tumor models, driven by diverse rasp or Ras pathway mutations in particular as shown on the right 63 six.

Drove significant tumor shrinkage across multiple non small cell lung cancer models with various mutations at the G 12 position in K, Ras, including G 12, D. G 12, B and G 12 fee.

In addition, slide 16 shows a deeper dive specifically into the performance of 63 six in preclinical models of pancreatic cancer with mutations at K Ras position G 12.

Mark Goldsmith: In addition, slide 16 shows a deeper dive specifically into the performance of RMC-6236 in preclinical models of pancreatic cancer with mutations at KRAS position G12. This updated mouse clinical trial data set shows an objective response rate for RMC-6236 of 57% across tumors with G12V, G12D, or G12R mutations, with nearly complete disease control and sustained antitumor benefit. Likewise, data disclosed this week, as represented in slide 17, shows significant antitumor benefit of RMC-6236 across colorectal cancer models carrying either KRAS G12V or KRAS G12D in vivo, characterized by regressions, encouraging disease control, and highly durable antitumor effects. Overall, these data represent a very large and strong body of preclinical evidence that is a robust foundation for advancing RMC-6236 to the clinic.

This updated mouse clinical trial data set shows an objective response rate for RMC 63, six or 57% across tumors with <unk> b or G. <unk> are mutations with nearly complete disease control and sustained anti tumor benefit.

Likewise data disclosed this week as represented in slide 17 show significant anti tumor benefit of 63, six across colorectal cancer models carrying either <unk> or <unk> in vivo characterized by regression.

Encouraging disease control and highly durable antitumor effects.

Overall these data represent a very large and strong body of preclinical evidence that as a robust foundation for advancing RMC 60 362 the clinic.

Mark Goldsmith: The company remains on track to submit an IND for RMC-6236 in H1 2022 to enable clinical evaluation for patients with these common, serious, and poorly served cancers. In addition to progressing RMC-6291 and RMC-6236 through IND-enabling programs, our RAS innovation platform enables the generation of additional new mutant-selective inhibitors of diverse oncogenic RAS mutants. As examples on slide 23, which was initially disclosed last quarter, we described breakthrough work on crafting unprecedented potent RAS(ON) inhibitors that use highly mutant-selective covalent attachments to the KRAS G13C or KRAS G12D variants, respectively. Building on this important progress in drug discovery, recently we reported initial in vivo evaluation of two representative covalent KRAS G12D inhibitors labeled in slide 24 as RMC-036 and RMC-037.

The company remains on track to submit an IND for RMC 63, six in the first half of 2022 to enable clinical evaluation for patients with these common serious and poorly served cancers.

In addition to progressing $6 91, and $63 six through IND, enabling programs.

<unk> innovation platform.

<unk> enables the generation of additional new mutant selective inhibitors of diverse oncogenic Ras mutants.

As examples on slide 23, which was initially disclosed last quarter. We described breakthrough work on crafting unprecedented potent Ras on inhibitors that youth highly mutant selective covalent attachment to the K Ras G 13, C or <unk> 12, the variance respectively.

Building on this important progress in drug discovery.

Recently, we reported initial in vivo evaluation of two representative covalent <unk> inhibitors.

And slide 24, as our M O three six and RMB <unk> hundred seven.

Both compounds administered orally drove deep regressions in this K Ras <unk> dependent pancreatic cancer model, achieving crs and nearly all animals.

Mark Goldsmith: Both compounds administered orally drove deep regressions in this KRAS G12D-dependent pancreatic cancer model, achieving CRs in nearly all animals. With this momentum, we remain on track to select a third development candidate from our lead optimization pipeline to advance into development by the end of this year. We will likely provide an update on this at an investor conference in early Q1. We also expect additional mutant-selective RAS(ON) inhibitors to mature out of our ongoing RAS(ON) programs in the coming 12 to 24 months. The second key element of our R&D portfolio is developing targeted RAS companion inhibitors to counter other proteins and biochemical pathways that often cooperate with RAS mutants in driving or sustaining tumors.

With this momentum we remain on track to select a third development candidate from our lead optimization pipeline to advance into development by the end of this year.

We will likely provide an update on this at an Investor conference in early Q1.

We also expect additional mutant selective rason inhibitors to mature out of our ongoing Ras on programs in the coming 12 to 24 months.

The second key element of our R&D portfolio is developing targeted Ras companion inhibitors to counter other proteins and bio chemical pathways that often cooperate with Ras mutants and driving or sustaining tumors.

Mark Goldsmith: Today, I'll focus on certain aspects of our SHP2 inhibitor, RMC-4630, which we are developing in partnership with Sanofi, our global development and commercialization partner for SHP2 inhibitors. RMC-4630 is being evaluated in multiple combination studies with approved or late-stage drugs in development. Amgen's CodeBreaK 101c study continues evaluating RMC-4630 in combination with sotorasib across multiple KRAS G12C-bearing tumor types. To date, this combination has demonstrated acceptable tolerability. RMC-4630-03 is a new study we announced in August evaluating the efficacy, safety, tolerability, and pharmacokinetics of RMC-4630 in combination with sotorasib specifically in subjects with advanced lung cancer bearing the KRAS G12C mutation with or without additional mutations. Revolution Medicines is sponsoring the RMC-4630-03 study under its global partnership with Sanofi and conducting the trial in collaboration with Amgen.

Today I'll focus on certain aspects of our ship two inhibitor RMC 463, O, which we are developing in partnership with canopy, our global development and commercialization partner for ship two inhibitors.

RMC for six <unk> is being evaluated in multiple combination studies with approved or late stage drugs in development.

Amgen's code break one O. One C study continues to evaluating RMC 4630 in combination with soda wrapup across multiple K recipe will see bearing tumor types to date. This combination has demonstrated acceptable tolerability.

RMC 463, or three is a new study we announced in August evaluating the efficacy safety and Tolerability and pharmacokinetics of RMC 4630 in combination with soda rapid specifically in subjects with advanced lung cancer bearing the K Ras G <unk> mutation with or without.

Additional mutations.

Revolution medicines is sponsoring the RMC 463003 study under its global partnership with fantasy and conducting the trial in collaboration with Amgen.

Mark Goldsmith: This study is now recruiting. In addition, under its global partnership with RevMed, Sanofi plans to sponsor a combination study evaluating RMC-4630 in combination with Mirati's KRAS G12C inhibitor, adagrasib, to expand the evaluation of the potential benefit of adding this SHP2 inhibitor to the KRAS G12C OFF inhibitor class. We're also anticipating evaluating RMC-4630 in combination with RAS(ON) inhibitor assets from our own portfolio as these progress. Finally, the PCD16210 study sponsored by Sanofi continues evaluating RMC-4630 in combination with pembrolizumab, a PD-1 inhibitor, and Sanofi is planning an expansion cohort with this combination in first-line PD-L1-positive lung cancer.

This study is now recruiting.

In addition, under its global partnership with Revlimid Fanapt plans to sponsor a combination study evaluating <unk> in combination with Murata U K Ras G 12 P inhibitor at a grass it to expand the evaluation of the potential benefit of adding this ship two inhibitor inhibitor to the K Ras G <unk>.

Inhibitor class.

And we also anticipating evaluating 4630 in combination with Ras on inhibitor assets from our own portfolio as these progress.

Finally, the P. C D 16 to 10 studies sponsored by Safi.

<unk> is evaluating <unk> in combination with <unk> PD, one inhibitor and fantasy is planning an expansion cohort with this combination in first line PD lone positive lung cancer.

Mark Goldsmith: With these prepared comments, I have tried to convey the status of our development stage assets represented by exciting and robust new data sets that suggest large clinical opportunities ahead for us to address in a wide range of RAS-addicted cancers. Further, our pipeline continues to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, including multiple targeted RAS(ON) inhibitors and RAS companion inhibitors as we pursue 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 to report on our financial condition.

With these prepared comments I have tried to convey the status of our development stage assets represented by exciting and robust new datasets that suggest large clinical opportunities ahead for us to address a wide range of Ras addicted cancers.

Further our pipeline continues to grow with highly distinctive new assets deriving from a Ras cancer innovation engine, including multiple targeted rason inhibitors, and Ras companion inhibitors, as we pursue science driven strategies to outsmart Ras addicted cancers. Please take the opportunity to review the.

<unk> corporate slide deck that you can download from our Investor Relations website.

I'll now turn to Jack Anders to report on our financial condition.

Thank you Mark and good afternoon, everyone.

Jack Anders: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $609 million in cash equivalents, and investments. Turning to revenue, the company recorded a non-cash, non-recurring GAAP accounting adjustment that reduced collaboration revenue by $8.5 million during the quarter. This non-cash adjustment is a result of adding the RMC-4630-03 study and deprioritizing the RMC-4630-02 study under our Sanofi collaboration. As a result of these events, we revised our estimates of the accounting transaction price and percentage of work performed to date under the collaboration. These revised estimates resulted in a cumulative catch-up accounting adjustment that negatively affected revenue by $8.5 million. Total revenue, including the effect of this non-cash revenue adjustment, was $1.1 million for the quarter.

We ended the quarter with $609 million in cash cash equivalents and investments.

Turning to revenue the company recorded a noncash nonrecurring GAAP accounting adjustment that reduced collaboration revenue by $8 5 million during the quarter.

This noncash adjustment.

As a result of adding the RMC 463 O <unk> III study and prioritizing the RMC 463002 study under our Sanofi collaboration.

As a result of these events, we revised our estimates of the accounting transaction price and percentage of work performed to date under the collaboration.

These revised estimates resulted in a cumulative catch up.

Accounting adjustment that negatively affected revenue by $8 5 million.

Total revenue, including the effect of this noncash revenue adjustment was $1 1 million for the quarter.

Total operating expenses for the quarter increased to $54 3 million.

Jack Anders: Total operating expenses for the quarter increased to $54.3 million, largely driven by research and development expenses, which were 46.5 million. Net loss for the quarter was $52.9 million or $0.72 per share. With regards to financial guidance, we continue to expect full-year GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million. With that, I'll turn the call back over to Mark.

Largely driven by research and development expenses, which were 40 $46 5 million.

Net loss for the quarter was $52 9 million or <unk> 72 per share.

With regards to financial guidance, we continue to expect full year GAAP net loss to be between 170 and $119 million.

Which includes estimated noncash stock based compensation expense of approximately $20 million.

And with that I will turn the call back over to Mark.

Thank you Jack.

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

Rowing set of exciting product assets and a strong balance sheet.

We are proud of the tireless commitment to patients by our organization and are grateful to our patients and their families and our many partners who work with us for providing Rev. Med with the opportunity to advance our unique pipeline of Ras on inhibitors in Ras companion inhibitors, which we believe may transform the treatment of Ras addicted cancers in the future.

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, sir. As a reminder to all participants, if you have a question, please press star one on your telephone keypad. Again, it's star one on your telephone keypad. Please stand by while we compile the Q&A roster. Your first question is from the line of Michael Schmidt with Guggenheim. Your line is open.

Thank you Sir as a reminder to all participants if you have a question. Please press star one on your telephone keypad again star one on your telephone keypad. Please standby will compile the Q&A roster.

Yes.

Your first question is from the line of Michael Schmidt with Guggenheim. Your line is open.

Michael Schmidt: Hey, guys. Thanks for taking my questions. I just had a couple ones. Maybe first on your RAS(ON) inhibitors. My question there was if you could remind us perhaps what the KRAS wild type inhibition is of your pan-RAS, pan-KRAS inhibitor relative to the mutation selective inhibitors. Related to that, how you envision clinical development next year of RMC-6236 relative to the selective inhibitors like RMC-6291 or the G12D inhibitor that you mentioned.

Hey, guys. Thanks for taking my questions I just had a couple of ones maybe first on your K Ras inhibitor My question there.

You could remind us perhaps.

What the.

The K Ras wild type and ambition.

It is of your Pan RAF Pan <unk> inhibitor relative to the mean patient selective inhibitors and related to that how you innovation.

Clinical development next year off.

RMC 62, 36 relative to the selective inhibitors like $6 91, or <unk> inhibitor that you mentioned.

Yeah.

Mark Goldsmith: Hi, Michael. Thanks very much for your question, or your questions. First, with regard to the RAS multi-inhibitor RMC-6236, it is active on wild type, and there's really not a differentiation on mutants versus wild type, so it is a multi-RAS inhibitor. As you know from previous conversations, we view this as a strength and a feature of the molecule in that we know that multiple forms of wild type RAS can contribute even to tumors that are driven primarily by a mutant form of RAS. The ability to suppress both of those does offer a potential therapeutic benefit, added benefit. As you point out, or as you're implying, it also carries with it some liability in terms of the degree to which you can suppress RAS in normal tissues and still be tolerated.

Hi, Michael Thanks, very much for your question.

Your question Sir.

With regard to the last multi inhibitor RMB 63, six is active on wild type.

And there's really not a differentiation on mutant versus wild type. So it is a multi RAF inhibitor.

And as you know from.

These conversations we view this as a <unk>.

Strength in a feature of the molecule in that.

We know that multiple forms of wild type Ras.

Can contribute even consumers that are driven primarily by a mutant form of Ras and so the ability to suppress both of those does offer a potential therapeutic.

Benefit out of the benefit, but as you pointed out or as you're implying it also carries with it some liability in terms of the degree to which you can suppress that in normal tissues and still be tolerated. So.

Mark Goldsmith: I think we'll be operating with some sort of ceiling, but in the evidence that we've generated so far, including evidence that I just described and is covered in the new corporate deck, across many different model systems, we've seen quite dramatic antitumor effects at tolerable doses. I think that's gonna be the name of the game, is to find the right dose and schedule in the clinic to maximize antitumor benefit without incurring intolerability. Your second question is about our clinical strategy for RMC-6236. It's a terrific question. It's about a month or two too early.

I think we will be operating with some sort of feeling but in the evidence that we've generated so far including evidence that I've just described and its covered in the new corporate deck.

Across many different model systems, we've seen quite dramatic antitumor effects.

At tolerable doses. So I think that's going to be the name of the game is to find find the right dose and schedule in the clinic to maximize.

One benefit without.

Incurring in Tolerability.

Your second question is about our clinical strategy pharmacy 63, so it's a terrific question it's about <unk>.

Too early.

Mark Goldsmith: I think we'll talk about that as we enter 2022, and as we're really ramping up the activities around the submission of the IND and then moving into clinic, and we will try to share some sort of overview about how we'll approach both RMC-6291 and RMC-6236 in the H1 of 2022.

I think we'll talk about that as we enter 2022 and as we're really ramping up the activities around.

And of the IMD and moving into the clinic.

We will try to share.

Some sort of overview about how we will approach.

69, one and RMB 63, six in the first half of 2022.

Okay makes sense and then the follow up on the ship to program 46 30.

Michael Schmidt: Okay, makes sense. Then the follow-up on the SHP2 program, RMC-4630, regarding the pembrolizumab combination study. It looks like, as you said, Sanofi is advancing into an expansion cohort in lung cancer. Any visibility on when you or Sanofi might be able to disclose data from that arm of the study?

Regarding the <unk> lithium app combination study it looks like as he said Santa Fe is advancing into an expansion cohort in lung cancer.

Any visibility on when you are saying if he might be able to disclose data from that arm.

This study.

Well as you pointed out <unk> is sponsoring that and so they have the right to make that determination and we will know about it we're in close contact with them, but we can't communicate anything about that so you've gotta go directly to equity.

Mark Goldsmith: Well, as you point out, Sanofi is sponsoring that, and so they have the right to make that determination, and we will know about it since we're in close contact with them, but we can't communicate anything about that. You've got to go directly to Sanofi. As you rightly indicated, you know, they are activating that expansion and we're looking forward to seeing how that goes.

But as he.

As you rightly indicated they are they are activating that expansion.

And where we're looking forward to seeing how that goes.

Michael Schmidt: Okay. Just one more. Not sure if you can answer, but on the trial collaboration around Mirati's KRAS inhibitor, I guess in addition to Amgen, is that really just to, you know, hedge your bets more or less and cover any of the KRAS inhibitors out there, or is there more to it, to also adding that to the trial lineup?

Okay, and then just one more I'm not sure if you can answer but on the on that trial collaboration around the varieties K Ras inhibitor I guess in addition to Amgen is that.

Really just to hedge hedge your bets more or less and cover any of the chaos inhibitors out there or is there more to it to also adding that to the to the trial.

Up.

Mark Goldsmith: Yeah. We've always anticipated that players with RAS(ON) inhibitors would try to access a wide range of potential companion inhibitors. You know, there are differences between all these different molecules that are floating around, and so it makes sense if you own an important RAS inhibitor asset that you would make sure to keep open all potential lines of combination and to evaluate them. I think this very much fulfills our expectation that the leading RAS inhibitors will look for a leading SHP2 inhibitor to combine with. In our view, RMC-4630 is a leading SHP2 inhibitor, and I think this suggests that others think so as well.

Yeah.

We've always anticipated that.

Players with <unk> inhibitors would try to access.

A wide range of potential companion inhibitors.

There are differences between all these different molecules that are floating around.

And so it makes sense, if you own an important Ras inhibitor asset that you would make sure.

To keep open all potential lines of combination and to evaluate them. So I think that's very much football fulfills our expectation after leading RAF inhibitors will look for a leading ship two inhibitor to combine with <unk> 4630, as a leading ship two inhibitor and I think.

This suggests that other thing think so as well.

Mark Goldsmith: You know, practically speaking, from our perspective, what it will do is to help expand the range of RAS inhibitors that the SHP2 inhibitor can be combined with and to build a broader data set. Of course, the Amgen study and the 03 study that we've announced will likely get to the sort of fundamental answer to the question earlier than the adagrasib data. We're excited to see adagrasib pulled into this as well, and it's just lots of parties dancing with lots of other parties, and it'll all sort itself out down the line.

Practically speaking from our perspective, what it will do is to help expand.

The range of Paas inhibitors that are the ships inhibitor can be combined with and to build a broader dataset.

But of course, the Amgen study and the <unk>.

<unk> study that we announced.

We'll likely get to that sort of a fundamental.

Answer to the question earlier than the classic data, but we're excited to see how aggressive are pulled into this as well and there's just lots of parties dancing with lots of other parties and it'll all sorts itself out online.

Okay, great. Thanks for taking my questions.

Michael Schmidt: Okay, great. Thanks for taking my question.

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

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

Hi, guys. Thanks for taking my questions can you talk about how you're thinking about a dose escalation strategy with Iraq on inhibitors as you prepare to enter the clinic next year had received any sort of regulatory input on this and how might that inform how soon we could see initial proof of concept.

Jonathan Chang: Hi, guys. Thanks for taking my questions. Can you talk about how you're thinking about a dose escalation strategy with the RAS(ON) inhibitors as you prepare to enter the clinic next year? Have you received any sort of regulatory input on this, and how might that inform how soon we could see initial proof of concept data from those programs?

Data from those programs.

Mark Goldsmith: Thank you, Jonathan. Nice to talk with you, and thanks for your questions. As I mentioned, in the early part of 2022, we'll start to lay out more information about how we'll approach the development, the clinical development of RMC-6291 and RMC-6236. I'm not sure that there's something specific on the question of dosing and dose escalation that you're trying to ask about. Is there something kind of narrower that you can clarify?

Yeah. So I think thank you Jonathan nice to talk with you and thanks for your question.

As I mentioned in the.

Early part of 2022, we'll start to lay out more information about how we will approach the development the clinical development of pharmacy, 69, and one and RMB 63 six.

Not sure that there is something.

Specific on the question of dosing and dose escalation that youre trying to ask about is there is there something kind of narrow or that you could clarify.

Jonathan Chang: Any more sort of granular thoughts on, you know, I guess just trying to back out when we might see initial efficacy data from those programs?

A more sort of granular thoughts on an on.

Jonathan Chang: Any more sort of granular thoughts on, you know, I guess just trying to back out when we might see initial efficacy data from those programs?

I guess, just trying to back out when we might see.

And this show.

You could see data from those programs.

Mark Goldsmith: It's really a timing question. It's a good question. I'd say hold that, you're again a couple of months ahead of us in terms of the question that you're asking, but we'll try to be forthcoming on that, on that point, in the early part of 2022 as we lay out the overall strategy for development.

Okay. So it's really a timing question.

A good question I'd say hold that.

Again, a couple of months ahead of us in terms of the question that you're asking but we'll try to be.

Forthcoming on that on that point.

And the early part of 2022 as we lay out the overall strategy for development.

Understood and then just maybe one last question for me.

Jonathan Chang: Understood. Just maybe one last question from me. Can you discuss the considerations for choosing your next RAS(ON) development candidate? Thank you.

Can you discuss the considerations for choosing your next draft on development candidate. Thank you.

Right well you know our process here reflects the fact that we have multiple programs running in parallel.

Mark Goldsmith: Right. Well, you know, our process here reflects the fact that we have multiple programs running in parallel. We sort of select some to talk about, but we certainly don't talk about all the things going on. It's a very leveraged drug discovery process, meaning that each of the programs is learning from each of the other programs. As soon as one thing advances, we gain knowledge that gets fed into all the other programs. There's just sort of a constant shuffling going on, particularly in lead optimization, where you're trying to optimize against a variety of different parameters. It's always hard to predict on a given day, you know, when those parameters will all come together in the optimal molecule.

We sort of select some to talk about but we certainly don't talk about all the things going on.

It's a very leverage.

The discovery process, meaning that.

Each of the programs is learning from each of the other programs. So as soon as one thing advance as we gain knowledge that gets fed into all the other programs and they are just sort of a constant shuffling going on particularly in lead optimization, where you're trying to optimize against a variety of different parameters, it's always hard to predict on a given day.

When those parameters will all come together in the optimal molecule and so we don't really make a decision about the molecule until we make a decision until we have all the data and it's up to the team.

Mark Goldsmith: We don't really make a decision about a molecule until we make a decision, till we have all the data, and it's up to the teams to determine the pace of that, based on those data packages that are brought forward. To a large degree, it's driven really by, you know, if you will, a bit of an internal competition, but really a set of standards that each program has to meet. When it meets those standards, the packages get presented, and we make a decision about whether to move something forward or not. So far, we've not made decisions where we've decided to sort of hold one thing back and move something else forward.

The pace of that.

Mark Goldsmith: We've just been fortunate to be able to advance the molecules that are being proposed to advance, and it just happened to be RMC-6291 and RMC-6236, which were proposed on the very same day last year and accepted on the very same day. There isn't sort of a hyper strategy to prioritize in terms of advancing molecules. That's not to say that there isn't a strategy around which targets we prioritize in the discovery process. We of course can't work on 36 targets simultaneously. We work on a smaller number than that. There is some prioritization that's going on there. At the end of the day, it's just when the data packages become available, and we evaluate them quite quickly and make a determination about whether something qualifies to advance.

And that's going on there.

But at the end of the day, it's just when the data package to become available and reevaluate them quite quickly, making determination about whether it's something qualifies two events.

Got it thanks for taking the questions.

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

Your next question is from the line of Eric Joseph with J P. Morgan Your line is open.

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

Hi, good afternoon.

Eric Joseph: Hi, good afternoon, and thanks for taking the questions. Maybe just to follow up on Jonathan's, I'm wondering whether from your dose range finding studies or pre-IND work with RMC-6291, whether you can sort of talk a little about sort of the anticipated dosing interval or PK profile, whether you anticipate any having to evaluate intermittent dosing when the phase 1 gets underway. Following up on the Sanofi or Mirati collaboration, do you have a sense of how much of the focal indications in their phase 1/2 study might overlap with your RMC-4630-03 trial or with Amgen's CodeBreaK 101c?

And the question.

Did you just to follow up on Jonathan.

I'm wondering whether from your dose for AG dose range, finding studies or do you work with 62 91.

Whether you can sort of.

Talk a little of that sort of the anticipated dosing interval or pique profile.

Whether you anticipate any.

To evaluate intermittent dosing.

When the phase when it gets underway and then.

Following up on the.

<unk> collaboration do you have.

A a sense of how us of the vocal indications in their face went to study my overlap with your Oh through trial for with and James Coburn, what I want to.

Okay.

Mark Goldsmith: Okay. Hi, nice to talk to you. Thanks for your questions. With regard to RMC-6291, Steve, do you wanna comment? The question was about, are we planning daily dosing versus intermittent dosing, and how are we learning-

Hi, nice to talk to you thanks for your questions.

With regard to sponsor 60 911 comment the question was about.

Ah refining daily dosing versus intermittent dosing and how will everyone.

Have we learned ankle for RMC six to nine water RMC 69, one that was the question if I show up.

Steve Kelsey: For RMC-6291.

Mark Goldsmith: For RMC-6291, that was the question, if I heard it.

Steve Kelsey: Yeah, sure. I think what we're learning from the current information coming in, particularly from the sotorasib and adagrasib programs, is that you need to really continuously cover the mutant G12C for as long as you and as hard as you possibly can. In that respect, it is unlikely that some form of intermittent dosing schedule will be deployed with RMC-6291, which has at least as good selectivity against G12C, the mutant G12C, as it is against wild-type RAS. We're not anticipating having to deploy an intermittent dosing strategy with RMC-6291, or indeed with any of our, you know, truly mutant-selective RAS(ON) inhibitors that we bring forward to the pipeline behind RMC-6291.

I think the what we're learning from the.

Current information coming in particularly from <unk> the amount of progressive.

Programs is in need to ranting continuously cover.

S G 12 C.

For as long as you and as hard as you, possibly can and so.

In that respect.

It is unlikely that some form of intermittent dosing schedule.

Will be deployed with IMC 69, one which has at least as good selectivity against do 12 C. J told C. As announcements wildfire brass. So we're not anticipating having to deploy an intermittent dosing strategy without an 6291 or indeed with any of them.

Truly select to brass on inhibitors that will bring forward feel <unk> arms.

6291, it's a strategy that I think was very well for.

Steve Kelsey: It's a strategy that I think works very well for inhibitors that inhibit wild-type RAS pathway signaling. I'm not sure that it's either necessary, or even desirable for the mutant-selective RAS(ON) inhibitors.

Four inhibitors inhibit while Thai.

Rasp halfway signalling.

I'm not sure that it's either necessary or even desirable for the selected brass on inhibitors.

Okay that makes sense.

Eric Joseph: Okay, that makes sense. From the PK profiling work that you've done, do you have a sense of whether you have coverage for once daily dosing versus twice daily?

From.

The PK profiling work that you've done do you have a sense of whether.

You have coverage for once daily doses versus twice daily.

Steve Kelsey: The PK profile of RMC-6291?

The PK profile of RMC six to nine one.

Eric Joseph: Correct.

Correct.

Yes, it's very difficult to to predict I mean, we've run the usual.

Steve Kelsey: Yeah. It's really difficult to predict that. I mean, we've run the usual sort of allometric scaling and what have you. We're still waiting for some data to come in. So it's not complete yet. You know, the default I suspect will be once daily dosing, but once we get to begin the clinic, we'll have to revisit that and see whether that's still the best thing to do. I mean, you know, we have quite a lot of flexibility there. But for now, I think it would be safe to assume that that's a good starting position. We of course reserve the right to change our mind as information becomes available to us in the clinic.

Sort of Allometric scaling and what have you was still waiting for some.

Data to come in so it's not completely is not complete yet.

The default I suspect will base once daily dosing, but once you get some began to play that will have to revisit happened. So you are still the best thing to do I mean.

We have we have quite a lot of flexibility that but.

For now I think it would be safe to assume that that's a good starting position at but we of course reserved the right to change our mind as as information becomes available to us and the planet.

Understood.

Eric Joseph: Understood. Just coming back to the Sanofi Mirati collaboration, yeah, if you just kinda talk about what's complementary to the Lumakras combination with RMC-4630 versus potentially redundant.

And just coming back to the.

Sanofi variety of collaboration.

Yeah, you just kind of talk about what's complimentary too.

The lunar crash combinations with RMC, 46, 30 versus potentially redundant.

Yes, if I might just add something almost the issued CD versus.

Mark Goldsmith: Yeah, if I might just add something on the issue of QD versus BID dosing on RMC-6291, just to return to that briefly. That is just keeping in mind that the RAS, the dynamics of inhibiting RAS(ON) versus the dynamics of inhibiting RAS(OFF) may be very different. I know, Eric, you and I have talked about that in the past, that you know, we have this immediate and complete cessation of RAS signaling from KRAS G12C when we hit it with a RAS(ON) inhibitor, as opposed to the requirement for sustained accumulation of RAS(OFF) in the compound bound form, which is required for RAS(OFF) inhibitors to work.

AIG dosing on a C 69, one just to return to that briefly.

And that is just keeping in mind at the rafts the dynamics of into being rason.

Versus the dynamics of inhibiting Ras off may be very different and I know.

Eric.

Talk about that in the past that.

We have this immediate and complete cessation of Ras signaling from <unk>, when we hit it with a rash on inhibitor as opposed to the requirement for sustained accumulation of Ras off.

In the in the compound bound form which is required harass off inhibitors were so it's really it's not really an apples to apples comparison, if you started thinking about prepare dime for.

Mark Goldsmith: It's not really an apples to apples comparison if you're sort of thinking about the paradigm for adagrasib and sotorasib and the other RAS(OFF) inhibitors versus RMC-6291. It's a different paradigm. Nonetheless, I think Steve's answer was very clear about what we believe is the default assumption here, and if we're informed otherwise in the clinic, we'll react to it. I think with regard to CodeBreaK 101 and-

At a graphic and so there after the the other rosoff inhibitors vs. On two six to nine let us a different paradigm.

Nonetheless, I think Steve's answer was very clear about.

What we believe is the default assumption here and if we're informed otherwise the clinic will react.

React to it.

I think with regard to co break 101 and.

Steve Kelsey: It's Mirati.

Mark Goldsmith: Mirati. Well, he's asking sort of both questions, so maybe you could comment on Steve. You know, kind of part A was how does it differ versus how is it complementary to CodeBreaK 101c? Then the second question was, what about the adagrasib combination?

Alright, well is that feature to both questions. So maybe you could comment or a C.

The party was how does that differ versus how does the complimentary to Quebec, one O. One C. And then the second question was what about Africa.

Steve Kelsey: Yes. The RMC-4630-03 study, which is the combination study with sotorasib, was deliberately designed to be different, but yet complementary to the lung cancer component of CodeBreaK 101c. It is different. We've learned from some of the, you know, the public data with regards to how to divide up the cohorts. As you know, I mean, there are essentially two predefined cohorts in that study. One which is essentially restricted to patients who have G12C mutations and co-mutations in other genes that might alter the response to either sotorasib or even RMC-4630. So that allows us to evaluate those arms separately. There are some other subtle differences as well, like which may become important.

Yes.

The the RMC 463 study, which is the combination study with <unk> as well.

Was deliberately designed to be different but yet complementary to the lung cancer component cause break.

101 C.

It is different we've learned from some of the the public data with regards to hide to divide up the cohorts.

As you know running.

Essentially too predefined cohorts in that study.

One which is a sudden chili restricted to patients who have G. Chelsea mutations and kind of mutations in.

In the genes that might also the response to this addressable or even RMC 463.

So the lines us to evaluate in his arms separately. There are some other subtle differences as well, which which may become important firstly the number of lines across therapy is restricted in <unk> study, which is not in co bright 101 C. And then the probably the the more obvious operational differences.

Steve Kelsey: Firstly, the number of lines of prior therapy is restricted in the 03 study, which is not in CodeBreaK 101c. Then, probably the more obvious operational difference is that the lung cancer arm of CodeBreaK 101c is restricted to the United States, whereas the 03 study will enroll a substantial portion of patients outside the United States. I don't think that's gonna make any difference to the ultimate evaluation or availability of the data set. The Mirati combination is, we see it as hugely complementary. Which is, firstly, as Mark said, it's inevitable, because RMC-4630 is a companion inhibitor for all RAS inhibitors and adagrasib is one of those RAS inhibitors.

The lung cancer, so could break 101 C.

Is restricted to the United States Wednesday entry study will involve substantial portion patient types of the United States I don't think that's going to make any difference to the ultimate.

Ultimate evaluation on a brand new abilities of the <unk>.

The morality combination is we see it is hugely complimentary we say firstly Mark said it's inevitable.

Because RMC for six shows a companion inhibitor for all rats inhibitors.

I prefer acid is one of those last inhibitors.

Steve Kelsey: It's complementary, and it's both enabling as well, because at the very least, safety data from that study will enable us, if we wish, to move very quickly into more advanced trials, should that become desirable in combination with adagrasib. I think it's all part of the rich tapestry of using RMC-4630 as a companion for RAS inhibition. I think we're very focused right now on G12C because of course, those are the two, the more obvious clinical RAS inhibitors inhibit G12C. This of course is gonna become incredibly important later as we get inhibitors against RAS mutations that are not G12C. We very much hope to be first into the clinic with those at some future date.

It's complementary and despite the neighboring as well because at the very least safety data from that study.

And Abel us if we wish to move very quickly into more advanced trials.

Sure.

Come desirable with in combination with it.

Nebraska.

I think it's it's all all the rich tapestry of using IMC force experience a companion for rat.

Ras inhibition I think with very focused right now on <unk> because of course those are the two.

The more obvious clinical rash inhibitors inhibit G 12 C. But this of course is going to become.

Incredibly important later once we get inhibitors. It interacts mutations that will not be 12 C.

And.

We very much hope the first into the climate with those at some future date.

Eric Joseph: Okay, great. Thanks for the questions.

Okay, Great darkness.

Your next question is from the line of Mark Crammed with Cowen and company in line as healthy.

Operator: Your next question is from the line of Marc Frahm with Cowen and Company. Your line is open.

Marc Frahm: Hey, guys. Thanks for taking my questions. Maybe Steve, on your last comment about kind of safety read across from trials and that that's very much an ongoing process. Are you able to update the CodeBreaK trial? Has it now selected a recommended phase 2 dose or with that target dose of 200 mg QD day one, day two, or is that still not quite finalized yet? Then related to that, is in the 03 trial because the recommended phase 2 dose hadn't been selected when you were opening that up, there's a safety run-in period.

Hi, Thanks for taking my questions.

Maybe she was on your last comment.

Comment about safety read across from trials and that that's very much an on going process.

Are you able to update it to Quebec Kubrick trial has it now selected a recommended face Judas or.

With that target dose of 200 milligrams day, one day, two or is that still.

Quite finalized yet and they're related to that is in the three trial.

Because of the recommended tasty just hadn't been selected when you were opening that up there's a safety running period have that safety running period been completed on your end.

Steve Kelsey: Has that safety run-in period been completed on your end? Or are you able to skip it given the evolving safety data within CodeBreaK?

Marc Frahm: Has that safety run-in period been completed on your end? Or are you able to skip it given the evolving safety data within CodeBreaK?

Or are you able to skip it given the evolving safety data within could break.

Mark Goldsmith: Hi, Mark. Thanks for your question. With regard to Lumakras, as you know, we're not the sponsor of that CodeBreaK 101c study, so that disclosure needs to come, driven by Amgen, so we don't have any update on that. With regard to the 03 study, you know, we just started that. We announced the study in August, and we just, you know, today are now indicating that it's actively recruiting. It would be fantastic if we could tell you that we had already recruited and dosed enough patients to have selected a dose or to complete the dose run-in, but that wouldn't be true. I can't say so.

Hi, Mark Thanks for your question.

So with regards to learn the craft.

As you know we're not the sponsor of that could break 100. Once this study so.

Closure needs to come driven by by Amgen. So we don't have any update on that.

And then with regard to the free study.

We just started that we announced the study in August and we just today are now indicating that it actively recruiting.

It would be fantastic if we could tell you that we had already recruited and dosed enough patients.

To have selected of those are the completion of those running but that wouldn't be true.

So I can't say so.

Mark Goldsmith: You know, I think we'll be informed by the selection of that dose when Amgen is able to disclose. If they do not disclose the dose publicly while we're dosing in the run-in, we'll dose at 140 milligrams, and then we'll bump up to 200 milligrams. I think we're still in the same paradigm that we were in, you know, a few weeks ago or a couple of months ago. We'll update you when we are able to give you a material update on this.

But.

I think we will be will be will be informed.

By the selection of that those when Amgen.

Is able to disclose.

If there if they do not disclose the dose.

Obviously, while we're dosing in the run it will go said 140 milligrams and then we will bump up to 200 milligrams. So.

I think we're still on the same paradigm that we were in.

A few weeks ago or a couple of months ago.

And we will update you when there's when we are able to give you a material update on that.

Okay. That's helpful. And then just in terms of the guidance to from the three trial to.

Marc Frahm: Okay. That's helpful. Then just in terms of the guidance from the O3 trial to potentially disclosing results the H2 of next year, is that in your mind likely to be just kind of the data from that safety run-in period, or should we think broader than that?

Potentially disclosing results the back half of next year is that your mind likely to be just kind of at the data from that safety runnin period or.

Shall we think broader than that.

Yeah.

Mark Goldsmith: Oh, yeah, that's a good question. I mean, what we intended to communicate was that our ambition, our aspiration is to have high-level findings from the activity of the combination, antitumor activity by the end of next year. Obviously, that depends on how quickly we ramp up enrollment. But I don't think it's really strictly gonna be driven by that short run-in. I think it's driven by the desire to have a larger number of patients, which is really the whole purpose of that study, is to get to that kind of range of N equals 46, split between the cohort without mutations and the cohort with mutations. They're not necessarily split evenly, but split between those two. So that's the kind of data we're really looking for.

Yeah. That's a good question I mean, what we intended to communicate.

Was that our ambition our aspiration is to have.

High level findings from the activity of the combination antitumor activity by the end of next year, obviously that depends on how quickly we wrap up.

Enrollment, but I don't think it's really strictly going to be driven by that short run. It I think it is driven by the desire to have a larger number of patients which is really the whole purpose of that studies to get to that.

Kind of range of an equal 46 slipped.

Split between the cohort without communications in the court with mutations not necessary.

Not necessarily split evenly split between those two so that's the kind of data we're really looking for I think they run into us as.

Mark Goldsmith: I think the run-in to us is a relatively modest, kind of early piece, but we hope to generate, you know, more substantial data, throughout the year. Of course, everything depends upon enrollment and, you know, it's very hard to predict exactly enrollment rates before you've enrolled patients. Our best guess is by the end of 2022 we'll be in a position to share something.

A relatively modest kind of early piece.

But we hope to generate more substantial date of the.

The year, but of course that are independent upon enrollment then it's very hard to predict exactly enrollment rates.

Before he's enrolled patients so our best guesses by the end of twice I'm sure we'll be in a position.

Alright, Thank you very helpful.

Marc Frahm: All right. Thank you. Very helpful.

Six.

Mark Goldsmith: Thanks.

Your next question is from the line of Chris Super Tiny and Goldman Sachs. Your line is open.

Operator: Your next question is from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Thank you very much and apologies in advance.

Chris Shibutani: Thank you very much, and apologies in advance. I'm hopefully there won't be too much background noise. I'm at a train station. Mark and Steve, there were two questions that I had, one on the colorectal cancer opportunity. I believe this is some new data that you're sharing preclinically in terms of RMC-6291 and RMC-6236. I'm curious to know how you're thinking about the opportunity set and the strategy, particularly in view of clinical data that's been unfolding, particularly for instance, with the EGFR combinations that are ongoing. What's your view on the opportunity? What's your strategy looking like?

Hopefully there won't be too much background noise in a train station.

Steve There were two questions that I had one.

Colorectal cancer opportunities I believe this is some new data that you're sharing preclinically 62916236.

Curious to know how you're thinking about the opportunity set in the strategy.

Italy and Hugh clinic.

Clinical data that's been unfolding.

Particularly since with it and GFR combination that are ongoing what's your view any opportunities such a strategy.

Yes, Thanks, Chris Chris.

Mark Goldsmith: Yeah, thanks Chris. Appreciate your going to the trouble calling in despite being on the road. Thank you so much. Colorectal cancer, Steve, I think you probably will wanna comment about this.

Appreciate your going to the trouble of crawling into sight being on the road. Thank you so much.

Colorectal cancer, Steve I think you probably will want to comment on about this.

Steve Kelsey: Yeah.

And yes, the recent data.

Mark Goldsmith: In light of recent data.

Steve Kelsey: Yeah. I mean, firstly, Chris, you know, as you know, just under half the colorectal cancer is RAS mutant, and it's a really nasty disease to have. In the context of, you know, serving an unmet medical need, it's a really high priority for us. We are encouraged by the RMC-6291 data in RAS mutant colorectal cancer. You know, whether or not RMC-6291 as a single agent has enough punch there to really do justice to patients, we'll wait and see. I think what you're angling at is ultimately, you know, that we are prospectively planning to combine RMC-6291 with companion inhibitors in colorectal cancer.

Firstly, Chris.

As you know.

Just under half the current cancelled raspy mask.

And.

It's really nasty disease to have so in the context of serving an unmet medical need is a really high priority for us.

We are encouraged by the 69, one day to in the last few colorectal cancer.

And whether or not.

69, one as a single agent has on a hunch that too so really do justice to patients will wait and see but I think what you're angling at is ultimately.

We prospectively planning to combine RMC 69, one with companion inhibitors in colorectal cancer.

Steve Kelsey: You know, we have a number of those in our portfolio, but we're certainly not afraid to do a clinical trial in combination with one of the EGFR, anti-EGFR antibodies if it comes to that. You know, we expect RMC-6291 to have a reasonably clean selectivity profile, so we don't anticipate there being overlapping toxicities with EGFR inhibitors, and that's a completely legitimate path forwards for G12C mutant colorectal cancer. Now of course, the big unmet medical need in colorectal cancer is in the other G12 mutations because most RAS mutant colorectal cancer is either a G12D mutation or a G12V mutation. I think that's where the impact of the RMC-6236 data comes in.

And.

We have a number of those in our portfolio, but we're certainly not afraid to to a clinical trial in combination with one of the Egypt Anted GFR antibodies.

If it comes to that.

A very.

We expect RMC 69, one to have a reasonably clean selectivity profile. So we don't anticipate that the.

Overlapping toxicities with Egfr as it was an absolutely completely legitimate.

Half Fords four G 12 C.

Covenant will come so now of course, the big on that medical need and colorectal cancer is in the other G 12 mutations because most most perhaps newton correct and cancer of others utility Mutational G. Toby mutation on I think that's where the the impacts of the RMC 63, six nights it comes and we've seen very impressive.

Steve Kelsey: You know, we've seen very impressive responses in RAS mutant colorectal and pancreatic cancer with single agent RMC-6236. We have no hesitation in testing RMC-6236 as a single agent in RAS mutant colon cancer once we get to that point. Because RMC-6236 has RAS wild-type activity, it does restrict the combinations that we may be able to use a little bit. Nevertheless, you know, there is a very active combination preclinical program ongoing, which we haven't disclosed yet and will do in due course. I think in general, what you can expect to see is pretty much what we have already observed with the KRAS off inhibitors, which is there'll be some single-agent testing.

Responses in Ras mutant Carteret planned pancreatic cancer was single agent RMC 63, six and we have no hesitation in in testing RMC 63, six as a single agent and wraps me in Pelham cancel once we once we get that <unk>.

<unk>.

Because RMC 63, six has rats, while type activity it does restrict the.

The combinations that we may be able to use a little bit, but nevertheless, there.

There is a very active combination preclinical program ongoing which we haven't disclosed yet and will do in due course, but.

I think in general what you can expect to see is.

Pretty much what we we've already observed.

The care as often as soon as witches there'll be some simulation testing if it packs a punch then that'll be great and then the combinations will will move forward to try to optimize on the clinical benefit.

Steve Kelsey: If it packs a punch, then that'll be great, and then the combinations will move forward to try to optimize on the clinical benefit.

Okay.

Chris Shibutani: Great.

Mark Goldsmith: Dr. Ab-

Chris Shibutani: A second question, if I may, one on strategy. Oh, I'm sorry, Mark, but did you wanna add some comments, please do.

And if I had a question if I may one on strategy, Oh, I'm, sorry, Mark or did you want to add some comments.

Yeah, I was just going to build on six six good comments there.

Mark Goldsmith: Yeah. I was just gonna build on Steve's good comments there. You know, there probably is also an advantage to RMC-6236 in its wild-type anti-RAS activity, which I had alluded to earlier with Michael's question, and I think that could come into play in colorectal cancer and where we know that other forms of RAS do step in and contribute. That's, I think, quite well established now. We're quite excited about the datasets in colorectal cancer for RMC-6291 and RMC-6236, and appreciate your highlighting that, and I think there's real opportunity there.

There probably is also an advantage to 63, six and it's wild type.

Empty rasp activity, which I alluded to earlier with.

Michael's question, and I think that could come into play and colorectal cancer.

Where we know that other forms of grass you step in and contribute that's I think quite well established now so we're quite excited about the datasets and colorectal cancer for 69, one in 63, six and I. Appreciate your we're highlighting that and I think there's a real opportunity there.

Great and then if I could follow with a strategic question.

Chris Shibutani: Great. If I could follow with a strategic question. You guys have. It's really strategy and capacity. In the past, you've done a number of partnerships, including with Amgen and Sanofi, for instance. There's pros and cons of doing these approaches. Maybe somebody else gets to pay the bill, but then they also have control, perhaps better, of communication, particularly with shareholders or, pacing and whatnot. As you sit here in November 2021, the RAS(ON) portfolio certainly seems to be, you know, coming into its own. Some of the earlier questions also were trying to contemplate how much you guys felt you could do on your own versus do with others. If you did a partnership, what's the most important priority for you?

I have.

It's really strict strategy and capacity so in the past you've done a number of partnerships, including with Amgen panic feed line.

There's pros and cons and doing this approaches maybe somebody else gets to pay the bill, but then they also have control, perhaps better communication contributing to shareholders.

Pacing and whatnot.

As you sit here in November of 21, the rash on portfolio certainly seems to be.

Coming into its all and some of the earlier question also what kind of contemplate how much you guys do.

Do on your own.

If you get a partnership what's the most important priority for Ya.

Chris Shibutani: Are you thinking now that you're gonna go it alone for a while as we, for instance, head into that notorious competitive conference in January? Thanks.

Or are you thinking now that you're going to go out alone for awhile actually.

His head into that Newport as competitive occupancy January thanks.

Mark Goldsmith: Great set of comments, Chris. I appreciate everything you said and agree with it all. As to our posture, I think we are fundamentally viewing the RAS(ON) inhibitor opportunity as being a RevMed opportunity. I think, you know, we're leaders there. We're pumping out these molecules at an astonishing rate and high-quality molecules, and the preclinical data are continuing to kind of affirm the commitment for us because of the kinds of success we're seeing. We're not particularly anxious to get into the complexities of partnerships around these assets. If we do it would be very narrow. You know, I could imagine a single asset in a partnership, but I don't think it's necessarily likely that we would do it, but I can imagine it.

Great Great set of comments, Chris I appreciate everything you said and agree with agree with at all.

As to our posture I think we are fundamentally viewing.

The RAF on inhibitor opportunity as being a RESNET opportunity I think where leaders there were pumping out these molecules at an astonishing rate and a high quality molecules in the preclinical data are continuing to kind of a firm.

The commitment for us because of the tons of success. We are seeing so we are not.

Particularly anxious.

Get into the complexities of partnerships around these assets if we do it it would be very narrow.

Imagine a single asset.

Partnership, but I don't I don't think it's necessarily likely that we will do it but I can imagine it.

Mark Goldsmith: You know, I think a big feature here, and you alluded to this in your remarks, is that it does actually take extra bandwidth for us to enter partnerships. It can complicate our own, you know, strategic activities because we have to now make decisions in concert with somebody else's strategic vision, which almost inevitably is not the same as ours. That's just the nature of two companies. They will have different views. There is a certain amount of heat that just gets generated that we have to support just in doing a partnership. At some point, you then wonder whether or not the net benefit is there. At the same time, we are expanding our programs.

And.

But I think the big feature here you alluded to this in your remarks is that it does actually take extra bandwidth for us to enter partnerships that can.

Complicate our own.

Strategic activities, because we have to now make decisions in concert with somebody else's strategic vision, which.

Almost inevitably is not the same as ours. That's just the nature of two companies that will have different views and so there is a certain amount of.

He said just gets generated that we have to support just been doing a partnership and so at some point you then wonder whether or not the net benefit is there but.

At the same time.

Are expanding our programs with two more compound going into the clinic, but we'll have.

Mark Goldsmith: We have two more compounds going into the clinic, so we'll have, you know, 4 in the clinic in 2022. I expect there will be more after that. Our pipeline is getting very big, costly, and as we talk about the combinations which spin off of that, you know, add another level of complexity. There is always gonna be a voracious appetite for supporting that with personnel and, you know, things that cost money. We'll see. I would say our default assumption is that there would not be a partnership anytime soon, but there has been significant interest inbound, and we'll see if we can design something that's optimized for us rather than for somebody else.

Four in the clinic in 2022.

And I expect there will be more after that and so our pipeline is getting very big.

Costly and as we talk about combinations, which spin off of that add another level of complexity. So there is always going to be.

A voracious appetite.

Or.

For supporting that with personnel and things that cost money. So.

But I would say are the false assumption is that they would not be a partnership.

Anytime soon but there has been significant interests inbound and we'll see if we can design something that's.

Optimize for us rather than for somebody else.

Great. Thank you both for your thoughtfulness and candor opposite.

Chris Shibutani: Great. Thank you both for your thoughtfulness and candor. Talk to you soon.

And your last question is from the line of Ben Bernanke.

Operator: Your last question is from the line of Ben Burnett with Stifel. Your line is open.

Stifel. Your line is open.

Ben Burnett: Hey, thank you very much. I was wondering if you could just offer maybe just a little bit more color on some of the strategies that you might be able to employ with regards to the RAS multi RMC-6236, just what you could employ clinically to optimize the therapeutic window, if needed. And then I have a quick follow-up.

Okay. Thank you very much.

I was wondering if you could just offer maybe you're just a little bit more color on some of the strategies that you might be able to employ with regards to their <expletive> multi.

RMC 63, six is just what you could employ clinically to optimize it therapeutic window.

If if needed and then I have a quick follow up.

Mark Goldsmith: Maybe Steve wants to comment on that.

She wants to come out on that for 63 six yes.

Steve Kelsey: For 6236? Yeah. I mean, we've tried hard to message this, because of the initial wave of concerns that we had over anything that hits wild-type RAS being toxic. There are a number of ways that we are going around optimizing the therapeutic index around RMC-6236. The first and most obvious is that we think it's inherent in the fact that tumors with RAS mutations are addicted to mutant RAS, that there will be a therapeutic index. Because I think and I think that the more information we see from sotorasib and adagrasib, that becomes increasingly clear. You know, tumors with mutant RAS seem to be highly dependent on it, and if you switch that off, then they tend to implode to at least some extent.

We've tried hard to.

So the message this.

Because of the initial way even concerns that we had over anything that Haiti hits wild tight rasping toxic there are a number of.

A number of ways that we.

Going around.

Optimizing the therapeutic again next Rumsey 63, six the first and most obvious is that we think is inherent in the fact that tumors with Ras mutations are addicted to Newton rash that will be a therapy begin next because I think I think the more information you see from <unk>.

The Doctor said that that becomes increasingly clear.

<unk> with with new rap seems to be highly dependent on it any of you switch that off and then they tend to implode to at least to some extent. So we do expect the tumor to suffer more underexposed dorms 63, six in normal tissue.

Steve Kelsey: We do expect the tumor to suffer more under exposure to RMC-6236 than normal tissue. There are, as we've alluded to, in some of our previous disclosures, certain recent disclosures, ways of scheduling RMC-6236 that can improve the therapeutic index. I think this gets back to this concept of intermittent dosing. I think it's important to point out RMC-6236 is a very unique molecule in as much as the pharmacokinetics in tumors seems to be different from the pharmacokinetics in normal tissue. I think that has something to do with the binding of RMC-6236 to the intracellular chaperone cyclophilin A, which on a net basis across tumors seems to be more abundant than in normal tissue counterparts.

They're all as we've alluded to.

In some of our previous disclosures recent.

Recent disclosures ways of scheduling RMC 63, six with can improve the therapeutic index I think it gets back to this concept of intermittent dosing way, but I think it's important to point in time RMC 63, six is a very unique molecule.

In as much as the.

The pharmacokinetics and chairman it seems to be different from the pharmacokinetics in normal tissue and I think that has something to do with.

The binding of RMC 60, 362, the intracellular chaperone site to fill in a way.

Which on a net basis across tumors seems to be more abundant.

In normal tissue counterparts. So.

Steve Kelsey: What you see is a sort of residence time of RMC-6236 in tumors, which greatly outstrips the residence time in normal tissue. What that ultimately results in is that the intermittent dosing that may be deployed in the clinic actually only results in intermittent inhibition of RAS in normal tissues and not intermittent dosing of RAS in tumor tissue, which ultimately creates quite a significant therapeutic index because the dynamics of RAS within tumors and the way that the RAS pathway signaling is inhibited diverge very dramatically with quite subtle changes in the intracellular exposure. On top of that, I think, you know, we can harness the immune system. We've already disclosed some data on how RMC-6236 significantly changes the tumor microenvironment in a way that would favor the antitumor effect versus any inhibition on normal tissue.

What you see is so residents time of RMC 63, six and tumors, which greatly outstrips the resident assigned the normal tissue and what that ultimately results. In is is the intermittent dosing that may be deployed in the clinic actually only results and submit.

Inhibition of rats in normal tissues are not internet.

Dosing of rash in tune of tissue, which ultimately creates a quite a significant therapy again next because the the.

The the dynamics of were has within tumors in the way the rash properly signaling is inhibited.

Diverged very dramatically with quite subtle changes in the intercellular exposure.

So on top of that I think we can honest immune system we.

Already disclosed some data on how RMC 63, six significantly changes the tumor microenvironment in a way that would favor the <unk>.

Antitumor effect versus any inhibition on normal tissue and then ultimately if if.

Steve Kelsey: Then ultimately, you know, if we need to preferentially enhance the antitumor activity of RMC-6236, we can combine it with something that has a selective antitumor effect and something which even potentially has a synergistic effect. There are a number of things that we're testing right now in that respect. I think the direction in which we're heading, we're confident that we will achieve a therapeutic index around RMC-6236. That clearly the fact, the nature of that, how it's manifested, is gonna vary probably from patient to patient and from patient population to patient population. There are a number of strings we can pull, and we're pulling on all of them.

We need to preferentially enhance the antitumor activity of RMC 63, six we can combine it with something that has a selective that's true.

Perfect and somebody which potentially has a synergistic effect to narrow a number of things that were testing right now in that respect. So I think the direction in which we're heading we're confident that we will achieve therapeutic index Rumsey 6236.

And.

That clearly the nature about high was manifest is going to vary probably from patient patient from patient populations patient population, but.

There are a number of strings, we can pull them with pulling all of them.

Okay, that's super helpful fascinating.

Ben Burnett: Okay. That's super helpful. Fascinating. Just one other quick question. What is the relevant potency of KRAS inhibition between RMC-6236, the multi-RAS inhibitor, with the KRAS G12C specific inhibitor? I guess what's motivating that. You showed some preclinical data of the multi-RAS inhibitor that looks like it was done at a lower dose than the KRAS G12C inhibitor. I think 25 mg/kg versus 200 mg/kg. I guess I was just wondering, is the multi-RAS inhibitor more potent than the KRAS G12C? If not, could you just comment on the choice of dose for those assays?

Just one other quick question is there.

What like what are the relevant potency.

K rising inhibition between the 6236, the multi rather inhibitor with the G 12 C specific inhibitor and I guess, what's motivating that.

You show some preclinical data.

Of the multi rouse inhibitor that looks like it was done at a lower dose to the <unk> better I think I think 25 mixed per K versus 200 mixed per keg and so I guess I was just wondering if the multi inhibitor more potent than that you talk seen if not I guess could you just comment on the choice of dose for those those assays.

Oh.

Yeah the.

Steve Kelsey: Yeah. The potency as measured in the classical in vitro systems against G12C is not terribly different between RMC-6291 and RMC-6236. In the context of, you know, how you might deploy RMC-6236, there is still some possibility that it would have utility in patients who have tumors harboring the G12C mutation. It's not entirely how we will develop RMC-6236 in patients with G12C mutations, as opposed to the other G12 mutations or indeed the other KRAS mutations. As Mark said, we'll go into that in a bit more detail in the early part of next year.

The <unk> C as manager of the and the sort of in the classical in vitro systems against do 12 C is not terribly different between RMC 69, one in RMC 63 six.

In the context of.

How you might deploy RMC 63 six.

Still some.

Possibility, but it would have a utility in patients who have children's harboring. The G 12 seed mutation, it's not in time.

How we will develop RMC 60, 316 patients who <unk> mutations as opposed to the other.

12 mutations or indeed, the other K Ras mutations that has not said we will go into more detail.

In the early part of next year.

Steve Kelsey: With regards the dosing paradigm, I mean, right now we are dosing RMC-6236 in our preclinical models at a dosing schedule which is well-tolerated and which has profound antitumor activity against all of the RAS mutations that we've shown you in the slide deck today. It is quite possible that some of the antitumor activity that we are seeing with RMC-6236 is due to the inhibition of feedback through wild-type RAS. It is not completely restricted to its profound inhibition of the mutant RAS. It's very hard to compare RMC-6236 and RMC-6291. They're very complementary compounds, and in fact, you know, in the long-term strategy, it is quite possible that RMC-6236 could be a very useful companion inhibitor for a RAS mutant selective inhibitor like RMC-6291.

With regards the dosing paradigm I mean right now we are dosing RMC 63, six and all preclinical models.

A dosing schedule, which is well tolerated.

And which has profound antitumor activity against all of the Ras mutations that we show you.

In the slide deck today.

It is quite possible that the some of the antitumor activity that we are seeing with RMC 63, six is due to the inhibition I'll feedback for awhile tight rash is not it is not.

Bleakley restricted to is profound inhibition of the rash and so it's very hard to compare RMC 60, 369, 69, one they're very complimentary sometimes and in fact.

And in the long term strategy. It is quite possible that RMC 63, six could be a very useful companion inhibitor for a Ross.

Selective inhibitor like RMC 69, one so I don't think.

Steve Kelsey: I don't think, you know, we see these as very complementary compounds marching forwards together. For all we know, they may well be useful in combination in G12C mutant tumors.

We wanted we see these is very complimentary compilers marching forwards together and for all we know they they may well be useful in combination G toasting treatments.

And if I could add to that I think that's really well put Steve with regard to the queue 12 fee and as you mentioned earlier mentioned earlier that contest extends to other meat slices inhibitors of other targets and we just shared with you today recently data for example on our oral highly selective.

Mark Goldsmith: If I could add to that, I think that's really well put, Steve, with regard to G12C. As you mentioned earlier, as Steve mentioned earlier, that concept extends to other mutant selective inhibitors of other targets. We just shared with you, today and recently data, for example, on our oral highly mutant selective KRAS G12D inhibitor, which is coming, just behind RMC-6236. We really don't see those as mutually exclusive. They could end up converging. It's quite a remarkable, bit of biology that's going on here, and we're trying to create a master clinical toolkit, if you will, of compounds that are, that have, special features. Sometimes those features are particularly useful for killing tumors. If we can put them together in the optimal way, we'll have the greatest, impact for patients.

<unk> 12, D inhibitor, which is coming just behind RMC 63, six and we really don't see those as mutually exclusive.

Could end up converging.

It's quite a remarkable a biology, that's going on here, we're trying to create a master clinical.

Clinical toolkit, if you will of compounds that are that.

That have a special features sometimes those features are particularly useful fulfilling tumors and if we can put them together in the optimal way, we will have the greatest impact for patients.

Interesting. Thank you.

Ben Burnett: Interesting. Thank you.

As I see no further questions at this time that concludes the question and answer session for the call I Dunno Hanneken things back to Doctor Martin Goldsmith for final call.

Operator: As I see no further questions at this time, that concludes the question and answer session for the call, and I'll hand the conference back to Dr. Mark Goldsmith for final comments.

Well, thank you operator, and thank you to everyone for participating today. We appreciate your continued support of Revolution medicines.

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

This concludes today's conference call. Thank you for joining you may not disconnecting safe and well.

Operator: This concludes today's conference call. Thank you for joining. You may now disconnect. Stay safe and well.

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