Q4 2023 Revolution Medicines Inc Earnings Call
Operator: Good day, and thank you for standing by. Welcome to Revolution Medicine's fourth quarter and full year 2023 conference call. At this time, all participants are in a listen-only mode.
Good day and thank you for standing by welcome to Revolution medicines fourth quarter and full year 2023 conference call. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask a question. During the session you will need to press Star. One wondering your telephone you will then hear and automate.
Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1-1 on your telephone. You will then hear an automated message advising that your hand is raised.
It must be advising their heinous race to withdraw your question. Please press star one again, please be advised that today's conference is being recorded I would now like to hand, the conference over to your first speaker today, Aaron Grace Senior director of corporate Communications.
Operator: To withdraw your question, please press star 1-1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Erin Grace, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
Communications and Investor Relations. Please go ahead.
Yeah.
Thank you and welcome everyone to the fourth quarter and full year 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith Revolution, medicines, Chairman and Chief Executive Officer, and Jack Anders Our Chief Financial Officer, Dr. Wei Lin, our Chief Medical Officer will join us for the Q&A portion of today's call.
Erin Grace: Thank you and welcome everyone to the fourth quarter and full year 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's chairman and chief executive officer, and Jack Anders, our chief financial officer. Dr. Wei Lin, our chief medical officer, will join us for the Q&A portion of today's call. Before we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statement.
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As we begin I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward looking statements within the meaning of the private Securities Litigation Reform Act. These statements are subject to a number of assumptions risks and uncertainties actual results may differ materially from these statements and <unk>.
Except as required by law the company undertakes no obligation to revise or update any forward looking statements I encourage you to review the legal disclaimer in our corporate presentation and our earnings press release as well as all of the Companys filings with the SEC concerning these and other matters with that I will turn the call over to Dr. Mark Goldsmith Revolution medicines chairman.
Erin Grace: I encourage you to review the legal disclaimer in our corporate presentation and our earnings press release, as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Thanks, Aaron. Good afternoon, everyone, and thank you for joining us.
<unk> and Chief Executive Officer Mark.
Thanks, Darren good.
Good afternoon, everyone and thank you for joining us.
Dr. Mark Goldsmith: We will keep our prepared remarks brief today in light of the corporate presentation we provided at the JP Morgan Healthcare Conference in January. Today, I'll review highlights of our company progress and lay out several important 2024 milestones for our pioneering RASON inhibitor pipeline, and Jack Anders will provide highlights of our financial results. 2023 was a transformative year for revolution medicine. First, we disclosed the preliminary clinical profiles of two unprecedented targeted RAS-on inhibitors, RMC6236, a RAS-on multiselective inhibitor, and RMC6291, a RAS-on G12C selective inhibitor, as evaluated in phase 1, 1B trials in patients with RAS-mutated cancer.
We will keep our prepared remarks brief today in light of the corporate presentation. We provided at the Jpmorgan Healthcare conference in January.
I'll review highlights of our company progress.
Hey out several important 2024 milestones for our pioneering rason inhibitor pipeline and Jack Anders who will provide highlights of our financial results.
2023 was a transformative year for Revolution medicines.
We disclosed the preliminary clinical profiles of two unprecedented targeted rason inhibitors, RMC 63, six <unk> on multi selective inhibitor and RMC 69, one <unk> selective inhibitor as evaluated in phase <unk> trials in patients with Ras.
<unk> mutated cancers.
Initial safety Tolerability and anti tumor activity data reported at the Triple meeting and ESMO Congress showed that both investigational drugs have highly differentiated clinical profiles, suggesting substantial promise for patients and supporting their continued development.
Dr. Mark Goldsmith: Initial safety, tolerability, and anti-tumor activity data reported at the TRIPLE meeting and the ESMO Congress showed that both investigational drugs have highly differentiated clinical profiles, suggesting substantial promise for patients and supporting their continued development. We also announced in September that we had dosed our first patient in the Phase 1, 1B trial of RMC9805, an oral and covalent G12 D-selective inhibitor, our third distinguished grass-on inhibitor As I'll summarize momentarily, this important progress with our first wave of RAS-on inhibitors provides significant momentum heading into this year's plans and we believe serves as validation of the RAS-on inhibitor platform and deep pipeline more broadly. Second, we ended 2023 with a particularly strong balance sheet bolstered by the EQRX acquisition that fuels our ambitious plans aiming to maximize clinical impact and drive shareholder value.
We also announced in September that we had dosed our first patient in the phase <unk> trial.
RMC, nine 805, and oral and covalent <unk> selective inhibitor or third distinguished <unk> inhibitor in clinical development.
I'll summarize momentarily this important progress with our first wave of rasp inhibitors provide significant momentum heading into this year's plans and we believe serves as validation of the Ras on inhibitor platform and deep pipeline more broadly.
Second we ended 2023 with a particularly strong balance sheet.
All stirred by the <unk> acquisition that fuels, our ambitious plans aiming to maximize clinical impact and drive shareholder value.
With a strong pipeline and financial position, we have three strategic priorities for 2024.
First building on strong clinical momentum with our boldest and most mature investigational drug with broad potential our highest priority in 2024 is to propel single agent RMC 63, six into its first pivotal trials.
We are currently working toward the goal of launching randomized controlled trials against standard of care chemotherapy for patients with Ras mutated non small cell lung cancer or pancreatic ductal adenocarcinoma and we expect that these efforts will command the largest share of our resources this year.
Dr. Mark Goldsmith: With a strong pipeline and financial position, we have three strategic priorities for 2024. First, building on strong clinical momentum with our boldest and most mature investigational drug with broad potential, our highest priority in 2024 is to propel single agent RMC6236 into its first pivotal trial. We are currently working toward the goal of launching randomized controlled trials against standard of care chemotherapy for patients with RAS mutated non-small cell lung cancer or pancreatic ductal adenocarcinoma, and we expect that these efforts will command the largest share of our resources this year.
Encouragingly at the Jpmorgan conference, we disclosed that with ongoing follow ups since ESMO. The RMC $63. Six safety profile has remained relatively stable, including at 300 milligrams per day with relatively few dose interruptions or discontinuation.
In the non small cell lung cancer cohort, we reported favorable trends for aggregate objective response rate across doses into the low to mid $40 range and that we're trending even higher in the 300 milligram cohort.
And the pancreatic ductal adenocarcinoma cohort, we reported favorable trends for aggregate <unk> into the mid twenties and that we're trending even higher in the 300 milligram cohort.
We are now focused on the 300 milligram dose and below for both lung and pancreatic cancer and continue to follow these patients as we develop a more mature data set to determined progression free survival or PFS.
Dr. Mark Goldsmith: Encouragingly, at the J.P. Morgan Conference, we disclosed that, with ongoing follow-up since ESMO, the RMC6236 safety profile had remained relatively stable, including at 300 mg per day, with relatively few dose interruptions or discontinuations. In a non-small cell lung cancer cohort, we reported favorable trends for aggregate objective response rate across doses into the low to mid 40s range and that were trending even higher in the 300 In the pancreatic ductal adenocarcinoma cohort, we reported favorable trends for aggregate ORR into the mid-20s, and that was trending even higher in the 300 milligram cohort.
We've begun preparing our regulatory packages for dose selection and monotherapy pivotal trials that we plan to initiate in the second half of 2024.
Beyond advancing into late stage development in second line lung and pancreatic cancers, our second strategic priority for 2024 is to expand the reach of RMB 63 six.
We've begun evaluating the impact of single agent <unk> hundred six in patients with tumors harboring Ras mutations beyond the 12 X mutations that had been the focus of the dose escalation.
Mainly <unk> and <unk> 60 onex mutations.
Likewise, we're studying 63 six in patients with tumor types beyond lung and pancreatic cancer, including colorectal cancer melanoma and gynecologic cancers.
We anticipate disclosing initial clinical PK safety, Tolerability and activity data from the genotype and tumor type cohorts in the second or third quarter of 2024.
In addition, we've initiated combination drug cohorts to examine options for reaching into first line treatment settings. For example, we've begun evaluating RMC 63, six in combination with the checkpoint inhibitor combination that is likely required for advancing into first line treatment for lung cancer.
Dr. Mark Goldsmith: We are now focused on the 300 milligram dose and below for both lung and pancreatic cancer and continue to follow these patients as we develop a more mature data set to determine progression-free survival, or PFS. We've begun preparing our regulatory packages for dose selection and monotherapy pivotal trials that we plan to initiate in the second half of 2024. Beyond advancing into late-stage development in second-line lung and pancreatic cancers, our second strategic priority for 2024 is to expand the reach of RMC6236. We've begun evaluating the impact of single agent 6236 in patients with tumors harboring RAS mutations beyond the G12X mutations that had been the focus of the dose escalation, mainly G13X and Q61X mutations. Likewise, we're setting 6236 in patients with tumor types beyond lung and pancreatic cancer, including colorectal cancer, melanoma, and gynecologic cancers.
We anticipate disclosing initial data in the second half of 2024 with the staff establishing safety of these combinations is the main focus.
Our third priority for the year is to qualify our Ras on mutant selective inhibitors for late stage development RMC 60, 91, RG 12, <unk> selective inhibitor and RMC 985, RG 12, <unk> selective inhibitor.
At the Triple meeting in October we reported preliminary results with RMC 60, 91, monotherapy supporting clinically meaningful differentiation at doses that were generally well tolerated.
Just on dose optimization work that has been completed further study of RMC 69, one as a single agent continues at 200 milligrams PID.
As the major next step for RMC 69, one we have initiated our first rason inhibitor doublet trial with RMC 63, six in patients with advanced K Ras <unk> mutated cancers.
Patients are currently being treated in the dose escalation portion of the trial.
And we anticipate disclosing initial clinical PK safety Tolerability and activity data in the second half of 2024.
We've also begun treating patients with RMC 691, and a checkpoint inhibitor to assess the safety of this combination.
For our <unk> selective inhibitor RMC nine 805, we shared at the Jpmorgan conference that oral bio availability of <unk> hundred five has been confirmed in patients we've seen pharmacokinetics consistent with expectations from our preclinical data.
Dr. Mark Goldsmith: We anticipate disclosing initial clinical PK, safety, tolerability, and activity data from the genotype and tumor type cohorts in the second or third quarter of 2024. In addition, we've initiated combination drug cohorts to examine options for reaching into first-line treatment settings. For example, we've begun evaluating RMC6236 in combination with a checkpoint inhibitor, a combination that is likely required for advancing into first-line treatment for lung cancer. We anticipate disclosing initial data in the second half of 2024, with establishing the safety of these combinations as the main focus. Our third priority for the year is to qualify our RAS-on mutant selective inhibitors for late-stage development, RMC6291, our G12C selective inhibitor, and RMC9805, our G12D selective inhibitor. At the triple meeting in October, we reported preliminary results with RMC6291 monotherapy supporting clinically meaningful differentiation at doses that were generally well tolerated. Based on dose optimization work that has been completed, further study of RMC6291 as a single agent continues at 200 milligrams BID. As a major next step for RMC6291, we have initiated our first RAS-on inhibitor doublet trial with RMC6236 in patients with advanced KRAS G12C mutated cancers.
<unk> dose dependent increases in plasma exposure on once daily dosing.
With clear several dose levels with good Tolerability and no dose limiting toxicities have been reported thus far.
We anticipate disclosing initial safety and activity data in the second half of 2024.
Finally, these ambitious clinical development priorities for advancing our first wave of rasp inhibitors are made possible by our strong balance sheet, which now includes approximately $1 1 billion of cash from the acquisition of <unk> that closed in November.
With our compelling pipeline innovation engine and financial position, we aim to continue building and solidifying our position as an industry leader in developing targeted medicines for patients living with Ras addictive cancers for many years to come.
I'd like to now turn the call over to Jack Anders Our Chief Financial Officer to provide the fourth quarter and full year financial update Jeff.
Thank you Mark.
We are pleased to strengthen our balance sheet with the acquisition of <unk>, which added approximately $1 1 billion in net cash proceeds after estimated post closing wind down and transition costs.
We ended the year with $1 85 billion in cash and investments, which is expected to fund planned operations into 2027 based on our current operating plan.
Q4, and full year 2023 financial results included $26 9 million and operating expenses associated with the wind down at <unk>.
Which primarily consisted of nonrecurring accounting charges associated with employee related termination expenses and stock based compensation.
<unk>, resulting from the acceleration of equity awards in conjunction with the closing of the transaction.
These were mostly onetime accounting charges specific to the close of the transaction in 2023 and are not expected to repeat in 2024.
Collaboration revenue was zero point $7 million for the fourth quarter of 2023 compared to $15 3 million for the prior year quarter.
Dr. Mark Goldsmith: Patients are currently being treated in the dose escalation portion of the trial, and we anticipate disclosing initial clinical PK, safety, tolerability, and activity data in the second half of 2024. We've also begun treating patients with RMC6291 and a checkpoint inhibitor to assess the safety of this common drug. For our G12D-selective inhibitor, RMC9805, we shared at the J.P. Morgan Conference that oral bioavailability of RMC9805 has been confirmed in patients. Additionally, we've seen pharmacokinetics consistent with expectations from our preclinical data, including dose-dependent increases in plasma exposure on once-daily doses.
$11 6 million for full year 2023, compared to $35 4 million for the prior year.
Decrease in revenue was due to the termination of the Companys collaboration agreement with Sanofi in 2023.
Total operating expenses for the fourth quarter of 2023 increased to $180 7 million largely driven by R&D expenses, which totaled $148 5 million.
Total operating expenses for full year 2023 increased to $498 8 million with R&D expenses, increasing to $423 1 million.
As noted earlier, our Q4 and full year 2023 operating expenses included $26 9 million and expenses associated with the wind down of <unk> <unk>.
Mainly an increase in total operating expenses for Q4 and full year 2023 was primarily due to an increase in clinical supply manufacturing and clinical trial expenses for our ongoing clinical development programs.
Dr. Mark Goldsmith: We've cleared several dose levels with good tolerability, and no dose-limiting toxicities have been reported thus far; we anticipate disclosing initial safety and activity data in the second half of 2024. Finally, these ambitious clinical development priorities for advancing our first wave of Rason inhibitors are made possible by our strong balance sheet, which now includes approximately 1.1 billion of cash from the acquisition of eQRX that closed in November. With our compelling pipeline, innovation engine, and financial position, we aim to continue building and solidifying our position as an industry leader in developing targeted medicines for patients living with RAS-addictive cancers for many years to come. I'd like to now turn the call over to Jack Anders, our Chief Financial Officer, to provide the fourth quarter and full year financial update. Jack?
Increase in personnel related expenses related to additional head count.
And an increase in stock based compensation expense.
Net loss for the fourth quarter of 2023 was $161 5 million or $1 14 per share.
For the full year net loss was $436 4 million or $3 86 per share.
Turning to financial guidance for 2024, we expect full year GAAP net loss to be between $480 and $520 million, which includes estimated noncash stock based compensation expense.
$70 million to $80 million.
The increase in expected GAAP net loss for 2024 as a result of increased expenses associated with the progression of our ongoing clinical development programs.
I'll now turn the call back over to Mark.
Thank you Jack.
Jack Anders: Thank you, Mark. We are pleased to strengthen our balance sheet with the acquisition of EQRF, which added approximately $1.1 billion in net cash proceeds after estimated post-closing wind-down and transition costs. We ended the year with $1.85 billion in cash and investments, which is expected to fund planned operations into 2027 based on our current operating plan. Q4 and full year 2023 financial results included $26.9 million in operating expenses associated with the wind-down of EQRF, which primarily consisted of non-recurring accounting charges associated with employee-related termination expenses and stock-based compensation expense resulting from the acceleration of eQRX equity awards in conjunction These were mostly one-time accounting charges specific to the close of the transaction in 2023 and are not expected to repeat in 2024. Collaboration revenue was $0.7 million for the fourth quarter of 2023, compared to $15.3 million for the prior year quarter, and $11.6 million for the full year 2023 compared to $35.4 million for the prior year. The decrease in revenue was due to the termination of the company's collaboration agreement with Sanofi in 2023.
In summary in 2024, we at <unk> have ambitious plans to deliver on clear priorities for our pioneering rasp inhibitor portfolio building on tremendous momentum coming out of 2023 and enabled by our strong balance sheet and a highly talented and motivated team.
We remain committed to discovering developing and delivering innovative targeted therapies for patients living with Ras addicted cancers on behalf of our organization I'd like to extend our deep appreciation to our patients clinical investigators scientific and business collaborators advisors and shareholders. This concludes our prepared remark.
For today and I'll now turn the call over to the operator for the Q&A session. Thank.
Thank you.
As a reminder to ask a question you will need to press star one on your telephone to withdraw your question. Please press star one again, please wait for your name to be announced we ask that you.
Please limit your questions to one and one follow up until all have had a chance to ask a question after which we'll be able to answer any additional questions from you as time permits. Please standby, while we compile the Q&A roster one moment for your first question.
Our first question comes from the line of Marc Frahm with TD Cowen. Your line is now open.
Hi, Dan This is Ernie Rodriguez for core Mark Congrats on all the progress and thanks for taking our question.
My question is on on the combinations with <unk>.
Hambro for six to nine 1% to three six would you like to see on on on those on that early data in the combination for you to feel comfortable to make a decision to move those combinations into pivotal development.
Okay.
Hi, Ernie Thanks, very much for your question.
Really what we're looking for is to validate.
Safety as you know the biggest challenge so far.
And your first line has been up.
For the rest of inhibitors has been combined and.
Kind of toxicity signals.
Jack Anders: Total operating expenses for the fourth quarter of 2023 increased to $180.7 million, largely driven by R&D expenses, which totaled $148.5 million. Total operating expenses for the full year 2023 increased to $498.8 million, with R&D expenses increasing to $423.1 million. As noted earlier, our Q4 and full year 2023 operating expenses included $26.9 million in expenses associated with the winding down of EQRX. The remaining increase in total operating expenses for Q4 and full year 2023 was primarily due to an increase in clinical supply manufacturing and clinical trial expenses for our ongoing clinical development program, an increase in personnel-related expenses related to additional headcount, and an increase in stock-based compensation. The net loss for the fourth quarter of 2023 was $161.5 million, or $1.14 per share. For the full year, the net loss was $436.4 million, or $3.86 per share.
Well, we have early reason to believe that.
This is less likely to happen with either $63 six or 69 one.
To the earlier compounds.
We just have to evaluate it and so that's really the main thing we will be looking for is establishing a safety profile that can support.
Sure.
The first one.
Thank you.
And then just a quick one.
Can you remind me.
You've mentioned before.
The.
Central or how you're thinking about the potential for combining 990 805 with $6 36.
Sure. We haven't said much about that other than what you've said in the six to nine one plus 63 six combination to me.
Sort of a key test case.
And as those combined are comfortably as we have seen pre clinically is that carries through into patients and it will certainly be encouraging with regard to combining other view selective inhibitors with 63, six and of course that would be would be early on that list.
Got it. Thank you thanks again for taking my questions.
Thank you one moment for our next question. Our next question comes from the line of Michael Schmidt with Guggenheim Partners. Your line is now open.
Hey, good afternoon, thanks for taking my questions.
Yes, Mark.
I appreciate some of the maturing phase one data for 636, I think you make comments on how the data has been <unk>.
Improving our changing all the time now but just.
I'm just curious if you could comment a bit more on how much more data do you need to support initiation of a phase III in order to fulfill our.
Dr. Mark Goldsmith: Turning to financial guidance for 2024, we expect full-year gap net loss to be between $480 and $520 million, which includes estimated non-cash stock-based compensation expenses of $7 to 80 million. The increase in expected gap net loss for 2024 is a result of increased expenses associated with the progression of our ongoing clinical development program. I'll now turn the call back over to Mark. In summary, in 2024, we at RevMed have ambitious plans to deliver on clear priorities for our pioneering Rasson inhibitor portfolio, building on tremendous momentum coming out of 2023 and enabled by a strong balance sheet and a highly talented and motivated team. We remain committed to discovering, developing, and delivering innovative, targeted therapies for patients living with RAS-dedicated cancer.
Project Optimus requirements before launching the pivotal studies as a monotherapy. Thanks so much.
Thank you Michael appreciate the question.
Right. So the update that we provided in January that you're referring to has to do with response rates and that information is helpful for guiding.
Dose selection.
And of course, we are incorporating an updated information into our into our analysis into packages for the FDA. So thats really for dose selection I think.
Moving into the pivotal trials for actually making the go decision on those we're looking for.
Sure.
PFS.
Assessments or estimate that can come from more mature.
This ratio, which obviously, we're developing now.
And that really leads to finalization of a trial design with statistical power and so on and accompanying all that of course is FDA input.
I think those are the key elements for making a final go decision associated with each of those trials.
Okay. Thanks, and then.
You've highlighted a number of.
Some data disclosed this in the second half of this year, including additional monotherapy and then also early combination data from all three of your programs.
Dr. Mark Goldsmith: On behalf of our organization, I'd like to extend our deep appreciation to our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Thank you. As a reminder, to ask a question, you'll need to press star 11 on your telephone. To withdraw your question, please press star 11 again. Please wait for your name to be announced.
Could you just help us understand the sequence of events.
I'll come at the same time is there some of the data might come before we seek to see how the data could you help us understand the cadence of data disclosed in the second half a bit better.
I wish I knew.
That would be able to tell you.
We have some ideas about how things might roll out, but I think it's too early to really set out of schedule. We're not we're not engineering it for a particular property.
The clear disclosure methodology, just as information becomes available and as it becomes appropriate to dispose. It will do so I think clearly what people are most.
Anxious to hear about is the timing does it go decision and timing.
Operator: We ask that you please limit your questions to one and one follow-up until all have had a chance to ask a question, after which we'll be able to answer any additional questions from you as time permits. Please stand by while we compile the Q&A roster. One moment for our first question. The first question comes from the line of Mark Fromm with P.D. Cowan.
Details about the final plan for those pivotal trials. So that's clearly what we would highlight.
That's the most important events in the second half of the year, but it is it is also true there will be other information coming out as we outlined in the milestones.
Great well, thanks, so much and congrats on the progress.
Thank you.
<unk>.
One moment for our next question. Our next question comes from the line of Eric Joseph with Jpmorgan. Your line is now open.
Yes, good evening, thanks for taking the questions.
Maybe just following up on Mike's question regarding.
Regulatory bias.
Operator: Your line is now open. Hi Tim, this is Ernie Rodriguez from Cormark. Congratulations on all the progress and thanks for taking our questions. A question on the combinations with Pembroke for 62916236.
And the Finalization of the pivotal studies.
Is.
Visibility on sort of activity in the.
The context of <unk> 12.
<unk> 261 mutations.
Needed at all to sort of get buy in on the nested efficacy analysis as part of the proposed design.
And then I have a follow up to that question.
Okay. Thanks, Eric Thanks for joining us today.
Operator: What would you like to see in that early data in the combinations for you to feel comfortable to make a decision to move those combinations into pivotal development? Hi Ernie, thanks very much for your question. Primarily, what we're looking for is civility.
Clearly where we are.
Trying to make decisions and collaboration ultimately with the FDA about what you include in that final trial design and to the extent that we have any activity information that can guide it will.
We'll include that information and conversations with the FDA. We do of course have preclinical data that suggests.
Dr. Mark Goldsmith: Safe, as you know, the biggest challenge so far. First Line has been, for all the rest, inhibitors have been combined with Patatoxicity. And while we have early reason to believe that it is less likely to happen with either 6236 or 6291. Compared to the earlier compounds, that's something we just have to evaluate. And so that's really the main thing we'll be looking for, establishing a safety profile that can support. Thank you. That's helpful. And then just a quick one.
It supports the notion that really all forms.
Forms of Ras certainly all that we've ever tested.
So some degree of sensitivity to pharmacy 63, six and the elevation of the <unk> X population you might recall came out of a large cell lines panel shows statistically greater.
Sensitivity of the <unk> 12 X population of tumor lines.
636 than the others, but did not distinguish them is yes versus no. It was more quantitative signal.
Dr. Mark Goldsmith: Do you remember if you mentioned before that I don't remember the potential or how you think about the potential for combining 9805 with 6336? Sure, we haven't said much about that other than we consider the 6291 plus 6236 combination to be sort of a key test case. And if those combined comfortably, as we have seen pre-clinically, if that carries through into patients, then it will certainly be encouraging with regard to combining other mutant-selective inhibitors with 6236, and of course, 9805 would be early on that.
Highlighted them and therefore, we prioritize them in the in the dose escalation study. So the bulk of the data that we have is around the <unk>.
But we are working together additional information that extends into these other genotypes as you've alluded to.
The extent that we can include that in our final determination of whats the whats the best design, we'll certainly discuss that with the FDA as well.
Okay, Great and maybe just a follow up on.
<unk> combination studies with 63 six.
Specifically can you talk about what the gating steps are to starting a.
Frontline pancreatic combination study.
With chemo.
There are particular chemo regimen, you're looking to combine with.
Between either full ferredoxin.
Jim Jeff Paclitaxel.
Operator: Thank you. Thanks again for taking our, Thank you. One moment for our next question. Our next question comes from the line of Michael Schmidt with Guggenheim Partners. Your line is now open. Hey, good afternoon.
And.
Yes.
Beyond adequate Tolerability is there an efficacy signal that you'd want to see.
And a combination study.
We're pursuing the frontline opportunity.
Yes. Thanks for that question I really appreciate your enthusiasm youre moving us to first of all.
Terrific.
Michael Schmidt: Thanks for taking my questions. Mark, we really appreciate the maturing phase one data for 6236. I think you made comments on how the data has been improving or changing over time now. But I'm just curious if you could comment a bit more on, you know, how much more data do you need to support the initiation of phase three and also to fulfill project optimist requirements before launching the studies as a model therapy? Thank you, Michael.
There is I think growing interest in the first line space with RPC six to $3 six given given what investigators have experienced so far maybe.
Lynn <unk>, our Chief Medical Officer, who is joining us today can comment on.
What we're looking for to help us make the decision about about launching in designing and launching such a trial.
How do you do that.
Hi, Andy I think you did mention the two current regimens that are currently on this kind of care one is.
Fair enough, yes, there is.
Tim Brackney and both are why why clinical use so.
We would be exploring the combination with both of these regimens.
Dr. Mark Goldsmith: I appreciate that question. Right, so the update that we provided in January that you're referring to had to do with response rate, and that information is helpful for guiding dose selection. And, of course, we're incorporating that updated information into our analyses and into packages for the FDA. So that's really for dose selection. I think for moving into the pivotal trials, for actually making the go decisions on those, we're looking for a mature PFS. Assessment or estimate that can come from more mature observations, which obviously we're developing now, and that really leads to the finalization of a trial design with statistical power and so on.
In early Phase study.
Does that in fact for those are Tim Brackney to late response rate and a 30.
30% range and then Opex I'll.
I'll turn ochsner, 30% to 40% range so.
Thats really be superior to either warranties.
Enable us going forward.
I would say obviously that's at the response rate.
Ultimately, we'd like to provide a survival benefit PFS.
Okay.
Okay, great. Thanks, again for taking the question.
Thank you.
And our next question comes from the line of Jonathan Chang with Leerink Partners. Your line is now open.
Hi, guys. Thanks for taking my questions.
First question with an enviable cash balance about 185 billion can you discuss your high level thought process around how we spend that capital effectively within the context of all the moving parts in your pipeline.
Dr. Mark Goldsmith: And accompanying all that, of course, is FDA. So I think those are the key elements for making a final go decision, each of those. Okay, thanks. And then you highlighted a number of potential data disclosures in the second half of this year, including additional model therapy options and then also early combination data from all three of your programs. Can you just help us understand the sequence of events? You know, will this all come at the same time?
And then second question on RMC 636, what is your latest thinking on what the development path for <unk> in second line pancreatic cancer could look like with the phase III highway endpoint of that study be OS or PFS.
Thanks, Jonathan.
I think on the first question, which was capital allocation.
Given all the competing opportunities that we have.
I think we've been pretty clear about this that our number one strategic priority.
To advance $63 six into pivotal trials in second line pancreatic and lung cancer.
Dr. Mark Goldsmith: Is there some of the data that might come before we see other data? Could you help us understand the cadence of data disclosure in the second half a bit better? I wish I knew.
No question that from our bandwidth perspective, and even direct spending that supports it.
The allocation of capital is.
As made accordingly, so that's going to take the lion's share of our of our effort.
Dr. Mark Goldsmith: I'd be able to tell you. You know, we have some ideas about how things might roll out, but I think it's too early to really set out a schedule. We're not, we're not engineering it for a particular... Particular Disclosure Methodology, just as the information becomes available, appropriate to dispose of, will do so. I think clearly what people are most anxious to hear about is the timing, a go decision, and timing and details about the final plan for those pivotal trials. So that's clearly what we would highlight. War and events in the second half of the year, but it is also true there will be other information coming out as we outline them.
So then beyond that.
We've identified these two additional corporate priorities for 2024, which is expand the reach of $63 six that you've heard the various ways in which we're doing that.
That requires a certain amount of capital in a certain amount of bandwidth in them.
<unk>, our <unk> selective inhibitor 69, one and $90 five to advance into late stage development that requires a certain amount of capital too.
So those are clearly kind of ring fence.
And and elevated priority for 2024.
It doesn't account for the entire bedroom question of course, because we have programs that go beyond those assets.
Operator: Great. Well, thanks so much and congratulations on the progress. Thank you. One moment for our next question. Our next question comes from the line of Eric Joseph with J.P. Morgan. Your line is now open. Good evening.
Those are earlier stage programs either defined.
I'll, let stage assets of which we have several that we've identified and talked about and then we have a robust discovery effort.
Bridges.
Here's a accumulated know how to build out second later generation.
Eric William Joseph: Thanks for taking the questions. Maybe just following up on Mike's question regarding regulatory buy-in and the finalization of the pivotal studies, is visibility on sort of activity in the context of G12X and Q61 mutations needed at all to sort of get buy-in on the nested efficacy analysis as part of your proposed design? And then I have a follow-up to that question. Okay, thanks, Eric. Thanks for joining us today.
And so on.
So.
We're going to continue to allocate according to those priorities, but we are thinking about not just the near term. So when we're making these investments in 2024, we have to meet our 2024 goals, but we also are trying to build.
Our our strategy, our dataset and our asset.
Cool.
Sustained.
And protect the franchise once we are able to create a commercial franchise from the first from the earliest.
Assets that move forward, so lots of things to invest in.
It seems like we have a lot of capital today at some point it won't feel like that much capital but.
Dr. Mark Goldsmith: You know, clearly, we're trying to make decisions in collaboration, ultimately, with the FDA about what to include in that final trial design, and to the extent that we have any activity information that can guide it, we will include that information in our conversations with the FDA. We do, of course, have preclinical data that suggests and that supports the notion that really all mutant forms of RAS, certainly all that we've ever tested, showed some degree of sensitivity to Rmc6236. And the elevation of the G12x population, you might recall, came out of a large cell-line panel that showed statistically greater sensitivity of the G12X population of tumor lines to 6236 than the others but did not distinguish them as yes versus no. It was more a quantitative signal that highlighted them, and therefore, we prioritized them, in the Dust Escalation Study.
We're managing according to various strategic plan.
Understood.
And then just on that 636.
<unk> path in pancreatic cancer.
636, monotherapy second line pancreatic cancer clinical trial design phase III exact.
Exactly exactly.
What is your latest thinking on what that primary endpoint.
Look like thank you.
Well I think yes, I think we can clarify what we've stated so far and then anything else that adjust that based on conversations with the FDA, we will update in the second half of the year, but I think weighted whalen.
Oh strip them out.
Right.
The endpoint in front of me. We're looking at is that really go to endpoint of PFS and overall survival.
Thank you one moment our next question please.
Our next question comes from the line of Ellie Merle with UBS. Your line is now open.
Hey, guys. Thanks, so much for taking my question.
Just heading into the <unk>.
Keira will come back later this year, that's what would you consider good data from those from that 60 366 to nine one combo and what are your thoughts on from this initial data.
Okay. Thanks for joining us and thanks for your question, yes, the RASK doublet.
Dr. Wei Lin: So the bulk of the data that we have is around the G12x group, but we are working to gather additional information that extends into these other genotypes, as you alluded to, and to the extent that we can include that in our final determination of what's the best design, we'll certainly discuss that with the FDA. Okay, great. And maybe just a follow-up on plant combination studies with 6236, specifically, can you talk about what the steps are to starting a frontline pancreatic combination study with chemo? Is there a particular chemo regimen you're looking to combine with, you know, between either Fulfuradox or Gemfaclitaxel? And, Beyond Adequate Tolerability, is there an efficacy signal that you'd want to see in a combination setting to warrant pursuit of a frontline opportunity?
It's really kind of another differentiating angle of <unk> portfolio of strategy I think at the moment, we're really the only organization exited attempt such a combination and the preclinical data.
Strongly supported.
And do support evaluating 6300 60 combination was 69, one <unk> cancers.
What we don't know is exactly how that will play out translation rate in humans. We know in the animal models, which are generally relatively short term models and don't have the same evolution characteristics.
True human cancer heterogeneous unit cancer.
We know what that looks like and it can look like increased depth of response increased durability of response.
Or increased frequency response really everything you can measure you can see in the preclinical studies, but it's very hard to try to tie a direct line from those into.
Dr. Wei Lin: You know, thanks for that question. I really appreciate your enthusiasm. You're moving us to the first line.
Into the humans studies so.
A fair amount of this will be keeping our eyes wide open and looking for early signals that we then bought it.
Dr. Wei Lin: Terrific. You know, there is, I think, growing interest in the first line space with RPC-6236 given what investigators have experienced so far. Maybe Dr. Lin, our Chief Medical Officer who's joining us today, can comment on what we're looking for to help us make the decision about launching and designing and launching such a trial. I think you did mention the two current regiments that are currently the Santa Clara. One is the other, and both are white and white.
Wanted to chase down and have to validate further but I do think the very first question is simply as a safe combination safe and tolerated and the two comp the two components of that seem to be safe and well tolerated to date, but putting the two together, we just need to verify.
<unk>.
Doesn't create any.
Kind of interactions or other modifications that could compromise the strategy going forward and then after that we.
We will be thinking about and looking for the clinical activity signal.
And then just alluded to whether it's frequency response depth of response or durability.
Great. Thanks, so much and just a quick follow up I guess.
Which indications should we expect data on the expansion cohorts from 16, three facts and the data update later this year.
Dr. Wei Lin: We would be exploring the combination with both of these strategies in the past. So that's really superior to either one of them. WikiVidi.com, of Persons.
And then more broadly I'd ask CRC cohort what are you looking to see to make that go no go decision on <unk>.
Dr. Wei Lin: Obviously, that's just a response rate in all communities we'd like to provide a survival benefit in here. Okay, great. Thanks again for taking the question. Thank you. And our next question comes from the line of Jonathan Chang with Lerig Partners. Your line is now open.
Longer term for a potential pivotal study start there. Thanks.
Okay. Thank you managed to Sweden.
The third question that nicely.
<unk>.
So in terms of the data that we've committed to communicating later this year, let's just start with the pivotal trials. There are two separate trials on a contemplation here, okay, great at cancer and lung cancer, and so theres a dataset associated with each of those and I think those are hit those would be sort of headline.
Operator: Hi guys, thanks for taking my question. First question, with an end-to-end urine cap balance of about $1.85 billion, can you discuss your high-level thought process around how one spends that capital effectively within the context of all the moving parts in your pipeline? And then, second question, on RMC6236, what is your latest thinking on what a development path forward in second-line pancreatic cancer could look like? Would the primary endpoint of that study be OS or PFS? Thank you. Thanks, Jonathan.
Datasets to come out later in the year.
As we announced plans go forward plans.
But then I think you were asking about going beyond pancreatic cancer and lung cancer.
Yes.
Expansion cohorts.
Spansion cohorts that go beyond pancreatic and lung cancer.
We've indicated that there are several different directions for those one is different genotypes.
Genotypes beyond 12 X and we've indicated will provide some preliminary view of that sometime in the mid year range. I think we said Q2 to Q3 timeframe.
The second is tumor types beyond.
Jonathan Chang: I think on the first question, which was capital allocation, given all the competing opportunities that we have, I think we've been pretty clear about this, that our number one strategic priority is to advance 6236 into pivotal trials in second-line pancreatic and lung cancer, and there's no question that from our bandwidth perspective and, you know, even direct spending that supports it, the allocation of capital is made accordingly. So that's going to take the lion's share of our effort in America. And beyond that, we've identified these two additional corporate priorities for 2024, which is to expand the reach of 6236, and you've heard the various ways in which we're doing that, and that requires a certain amount of capital and a certain amount of bandwidth, and then qualify our mutant-selective inhibitors, 6291 and 9805 That requires a certain amount of capital.
Lung and pancreatic cancer and that includes colorectal cancer and we've indicated will provide some information on that.
Second half of the year.
And then third is combinations that help us too.
Begin to enable optionality for going into first line and the 669, one combination. We just spoke about and then combinations of $63 six with Pembroke 69, one with Pembroke and then.
I alluded to a few other things that one would consider for ultimately moving into first line, particularly in pancreatic cancer.
With chemotherapy. So there's a wide range of things that are going to happen a good number of those we could read out in the second half of this year.
Great. Thanks.
Yes, as you have did you want to follow up on that.
Thank you.
Our next question comes from the line of Amy <unk> with Needham <unk> Company. Your line is now open.
Hi, Good evening. Thanks for taking my question a quick one follow up on a question John.
Feedback data that you'll be presenting from the ongoing study data for <unk> in second line.
Could you tell us what you see as the bar in terms of PFS that you would like to see.
And with regards to your program or what you're pursuing and plus nine.
Developing strategics in second line or you are planning to initiate a pivotal study there.
What is the.
Clinical rationale the hypothesis in terms of what would be the right.
Dr. Mark Goldsmith: So those are clearly kind of a ring fence and elevated in priority for 2024. That doesn't account for the entire budget, of course, because we have programs that go beyond those assets. Those are earlier stage programs, either defined development stage assets of which we have several that we've identified and talked about. And then we have a robust discovery effort that leverages, you know, years of accumulated know-how to build out second, you know, later generation grants and so on. So, you know, we're going to continue to allocate according to those priorities, but we are thinking about not just the near term. So when we're making these investments in 2024, we have to meet our 2024 goals, but we also are trying to build our strategy, our data set, and our asset pool that would sustain and protect a franchise once we're able to create a commercial franchise from the first, from the earliest assets that move forward So there are lots of things to invest in.
Combination partner with 10 barrel plus minus chemo, whether it would be 66 to nine one.
If you could sort of share your thinking there that'd be helpful. Thanks.
Let me comment on the first question that I might ask you to repeat the second question because I'm not sure that I completely track.
Your question was in second line feedback what is the bar that would compel us to move forward from a PFS perspective.
That's why we're asking.
Yes.
Really specified a particular number of course, we have our own internal benchmarks, but we've not publicly discuss.
Those go no go decisions, but we're clearly looking to be superior to second line chemotherapy and we know what median PFS is in virtually every second line study thats ever been done it's really around three to three and half months adverse.
In true second line patients keep in mind, our population is not truly second line our population for the second third and potentially even some beyond that people had multiple different <unk>.
Previous treatments, so our population probably isn't quite perform as well as the second appear second line population would perform but nonetheless, we've said what we're trying to do with our current patient population.
Be superior to the well accepted benchmark for second line, but how much superior I think it's a question that goes beyond where we are.
Dr. Wei Lin: It seems like we have a lot of capital today; at some point, it won't feel like that much capital, but we're managing according to a very strategic plan. Understand and then just on the six two three six development path in pancreatic cancer, 6236 Monotherapy Second Line Pancreatic Cancer Clinical Trial Design Space Reaches Out Yeah, exactly, exactly. And what is your latest thinking on what that primary end point could look like? Well, I think, yes, I think we can clarify what we've stated so far, and then anything else that adjusts that based on conversations with the FDA will be updated in the second half of the year. But I think only Lynn can comment.
Comment on today.
If you want to repeat your second question then we can figure out who's the best person to comment on that sure.
Just from a mechanistic perspective.
I can understand it.
<unk> as a monotherapy.
Makes sense and second line.
The standard logic behind exploring.
Combination of that with timberland plus nine.
Why would someone suite with six to nine months of <unk> in first line and then move this expertise.
Good luck.
Just hypothetically.
So your question is in pancreatic cancer.
If you received RMC 63, 6% as part of our first flight regimen.
Why would you continue why would you repeat $63 six as part of our second line regimen does that is that what youre asking.
Well why would you stock with 291, which is more positive.
Dr. Wei Lin: I think that an end point probably we're looking at is really going to be the end point of PFS. Survivor. Thank you. One moment for our next question. Our next question comes from the line of Ellie Merrill with UBS. Your line is now open.
First line treatment and then move to <unk> statistics that you brought up.
Oh, okay.
Now I understand so we're talking about in <unk> cancers, specifically talking about the rock and Youre talking about lung cancer and your question was if we combined 63, 6% with 69, one in first line now.
Operator: Hey guys, thanks so much for taking my question. Just heading into the initial KRAS combo data later this year, I guess what would you consider good data from this, from the 6236, 6291 combo, and what are you focused on from this initial data? Okay, thanks for joining us and thanks for your question. Yeah, the rafts double it, and it's really kind of another differentiating angle of RevMed's portfolio and strategy. Moment was really the only organization that could attempt such a combination, and the preclinical data was strongly supported.
And I'll call. It gets so maybe you can interpret the question I can answer it.
Let me take your question. So I think what I'm hearing you say is that if we were able to succeed in developing 691, plus timber where 69, one plus tamblyn chemo and that becomes the new standard of care for Tchiakovsky patients in first line lung.
Why with patients get 63, six second line is that your question.
Yeah, Yeah, that's helpful. Thanks.
Yeah. So.
Alright, great.
Got it thank you.
Yes, I'll take a stab at I mean, that's certainly one area, we could keep all using our 691 sure truly phase III, chairman plus either timber mono for the PEO and high or Campbell of chemo four four for all occasions.
There is another scenario, what we could be developing 69, one plus 63 six slipped hambro.
Dr. Mark Goldsmith: Support, evaluating 6236 in combination with 6291 in G12c cancer. What we don't know is exactly how that will play out translationally in humans. We know in the animal models, which are generally relatively short-term models and don't have the same evolution characteristics as a true human cancer, heterogeneous human cancer, we know what that looks like, and it can look like increased death of response and increased durability of response or increased frequency of response, so really everything you can measure you can see in the preclinical studies, but it's very hard to try to tie a direct line from those into the human studies.
Kiki both ranked that'd be another option just wanted to put that out there, but let's take the when you put on the table, which is 691 plus Tamara was six to nine months plus <unk> plus chemo if that became the standard of care in first line.
We.
We still do believe that there can be central rationale.
For 2636 through Maine is an option in the second line setting and.
And the reason is the following I think.
It really has to do with.
The way that topic.
Raskin tumor caves in developing resistance against any tchiakovsky inhibitor.
Well I think that from sort of assets aircraft with Andy Your asset I think one really emerging.
Number 180, 90% of those tumors behaviorally from key trustee mutation don't lose it number two the vast majority FTE resistant mutation involve some type of either another brac mutation or another mutation.
Dr. Mark Goldsmith: So I think a fair amount of this will be keeping our eyes wide open and looking for early signals that we then want to chase down and have to validate further. But I do think the very first question is simply, is this a safe combination? Is it safe and tolerated?
In the Ras pathway to reactivate.
<unk> pathway, so what we call it <unk> rescue mechanism, so rescuing or reactivating the rat seem to be the predominant mechanism enhance it goes along.
Dr. Mark Goldsmith: And the two components of that... seem to be safe and well-tolerated to date, but putting the two together, we just need to verify first that that doesn't create any drug-drug interactions or other manifestations that could compromise the strategy going forward. And then after that... Foundation, the Academy Awards, and other funds. Clinical Activities signal, that I just alluded to, whether it's... Frequency of Response, Depth of Response, or, Right. And just a quick follow-up, I guess, which indications should we expect data on in the expansion cohorts from 6.2.3.6 and the data update later this year? And then more broadly, I guess, in the CRC cohort, what are you looking to see to make a go, no-go decision, thinking longer term for a potential pivotal study start there? Thank you. Okay, I think you managed to squeeze in at least a third question in. Nicely done.
Hallmarks. We described these tumors as rapid a decade I think the fact that youre seeing today.
They are really relying on trained the consumer pathway.
RAF and hence the broad spectrum activity up 636 involving not only other RAF mutations that can potentially cover so if I.
<unk> <unk> mutation to bypass that you'd see that six months or three 6% remain active.
And Furthermore, even if a patient were to activate a receptor tyrosine kinase like Egfr and the cyclical a wild type Ras that 600 <unk> also cover so there are so many.
Resistant mutations that are well characterized for the current XI how theaters.
Potentially $600.
Three six can be active against so I think it's still.
Provided rationale obviously, we need to generate better support that for 46% to 36 remains a standard of care in the sack line say even.
Even if it takes two not one SAP itself as a first line treatment of choice.
Dr. Mark Goldsmith: So in terms of the data that we've committed to communicating later this year, let's just start with the pivotal trials. There are two separate trials under consideration here, pancreatic cancer and lung cancer. And so there's a data set associated with each of those.
So you got yourself a very scholarly.
Good answer thanks.
I just wanted to circle back.
Hello.
Yes, if I could just go back to the first thing that we said that was really important might've caught me a little bit quickly, which is that although we're testing 69, one plus tempo.
We're also evaluating 63 six plus Pam grow. We're also evaluating 69, plus 63, six and all three of those are way of Triangulating potentially on a triplet combination of 69, one plus 636, plus PEMCO, which would be.
Dr. Mark Goldsmith: And I think those would be headline data sets to come out later in the year, as we announce plans, move, you know, go forward with plans. And I think you were asking about going beyond pancreatic cancer and lung cancer and expansion cohorts that go beyond pancreatic and lung cancer. We've indicated that there are several different directions for those. One is different RAS genotypes beyond G12AX, and we've indicated we'll provide some preliminary views of that sometime in the mid-year range. The second is tumor types beyond lung and pancreatic cancer, and that includes colorectal cancer. It provides some information on that in the second half of the year.
<unk> set a chemo free regimen.
First slide we don't it's not the only outcome of that stuff the only possible outcome, but that would be one way in which all of those get rationalized one shouldn't assume today.
We will or will not move forward with the doublet of a PD one plus.
Let's see one of those agents, we will see we'll let the data tell us what makes sense to do.
That makes sense. Thanks.
Thank you.
One moment for our next question.
Our next question comes from the line of Alec Stranahan with Bank of America. Your line is now open.
Hey, guys. This is John on for Alex Thanks for taking my question.
Just a quick one from us in terms of second half data updates.
Dr. Mark Goldsmith: And then third, combinations that help us to begin to enable optionality for going into the first line and the 6236-6291 combination we just spoke about, and then combinations of 6236 with PEMBRO 6291. Pembroke and then Wei alluded to a few other things that one would consider for ultimately moving into first line, particularly in pancreatic cancer, with chemotherapy, so there's a wide range of things that are going to happen, and a good number of those we could read out in the second half. Great, thanks. Yes, did you have, would you want to follow up on that?
What could be the venue that we would be expecting would it be like a low.
Comprehends, where should we just expect a okay.
Okay.
The press release, so like Investor day, any color on that that'd be great. If you can share.
Thanks, John hard to answer that question because theres, so many different datasets.
We've listed there that could come out of the second half of the year.
Although our preference is to disclose such information in the context of peer reviewed.
Medical conferences, it's not always up to us it just depends on the timing and availability often these things require abstracts that are submitted long ahead of when we might have the information. So we'll pick a forum for each of the disclosures that.
To make sure that we're not holding on to data.
Investors need to know about.
Okay. Thank you for color.
Thank you.
One moment for our next question.
Dr. Mark Goldsmith: Thank you. Our next question comes from the line of Amy Faddea with Needham & Company. Your line is now open. Hi, good evening.
And our next question comes from the line of Jay Olson with Oppenheimer. Your line is now open.
Oh, Hey, congrats on the progress and thank you for taking the question as you look ahead to the potential for multiple pivotal trials can you just talk about how youre thinking about partnering opportunities both in the U S and outside the U S.
Operator: Thanks for taking my question. I've got one follow-up and a question just on the PDAC data that you'll be presenting from the ongoing study data this year and the second time. Could you tell us what the bar in terms of PFS is that you would like to see? And with regard to your program or what you're pursuing in First Line, you're developing 6236 in second line, or at least, you know, you're planning to initiate a pivotal study there. What is the, you know, clinical rationale or the hypothesis in terms of what would be the right choice?
Hi, Jay Thanks for joining us and thanks for your question.
I think again, we've been pretty consistent about this which is that.
In the U S. We really believe this is a serious opportunity for <unk> to build its own franchise.
And to use the <unk> portfolio to create a very strong and leading franchise. So I don't think we're particularly keen on.
Sharing any of that with a partner and I don't think there's any reason to do so at least as we see things today.
Amy Faddea: Combination partner with Pembro plus minus chemo, whether it would be 6236 or 6291, if you could sort of share your thinking there, that would be helpful. Thanks.
Outside the U S. It's pretty clear that we don't have much opportunity there thats a much more complex.
Context in which to think about commercializing we can't do development outside of the U S. We already do development outside the U S. But doing pivotal late stage global development typically it takes a real appreciation of that to us is a different country settings in different geographies. So that can be done that can be enhanced by working.
Dr. Mark Goldsmith: Let me comment on the first question, and then I might ask you to repeat the second question because I'm not sure that I completely transcribed it. Your question was, in second line PDAC, what is the bar that would compel us to move forward from a PFS perspective? That's right.
With a partner that already has that infrastructure and then of course commercialization per se is not something that we have any near term plan to pursue.
On our own so I think it's pretty clear that the ex.
Ex U S partner or partners could be in the offing for us at some point in the future.
We're open to that possibility.
Dr. Mark Goldsmith: Yeah, I don't think we've really specified a particular number. Of course, we have our own internal benchmarks, but we've not publicly discussed those no-go, no-go decisions, but we're clearly looking to be superior to second-line chemotherapy, and we know what the median PFS is in virtually every second-line study that's ever been done. You know, it's really around three to three and a half months at best in true second-line patients. But keep in mind, our population is not truly second-line.
And.
When the right opportunity presents itself and it makes sense for us to do it.
Sure we would do so.
Super helpful. Thank you very much and if I could ask one follow up as you look ahead to the potential tumor agnostic setting for $6. Three six can you just talk about the regulatory path.
We're thinking about there.
Dr Wei Lantus.
Yes.
Yes happy to address that.
We already presented publicly.
On activity in non small cell lung cancer as fast.
Pancreatic cancer. So those are probably going to be serve as an anchor and our approach of tissue agnostic right now we're actually growing patient. Please.
Dr. Mark Goldsmith: Our population includes second, third, potentially even some beyond that, people who've had multiple... Previous Treatment. So our population probably isn't going to perform as well as the peer second-line population would perform. But nonetheless, we've said what we're trying to do with our current patient population is to be superior to the well-accepted benchmark for second-line therapy. But how much superior, I think, is a question that goes beyond what we've come in on today.
Colorectal cancer.
Melanoma is thoughts on iconic market cancers that swath of a solid tumor.
And obviously to be very much static driven but that's our aspiration given the broad accurate we've seen frequently at this.
This molecule could potentially help.
As many as 30% of patients with solid tumor, which brought mutation so we sit by.
Test that hypothesis to the fullest and that would drive our decision about how much of a tissue mask as Fox.
Okay, great. Thanks, again for taking the questions.
Thank you.
As a reminder to ask a question you will need to press star one one and please wait for your name to be announced.
Dr. Mark Goldsmith: If you want to repeat your second question, then we can figure out who's the best person. Sure. You know, just from a mechanistic perspective, I can understand if fiscal 3-6 as a monotherapy makes sense in the second line; I understand the logic behind exploring a combination of that with PEMRO in the first line. But why would someone treat with 6291 plus PEMRO in the first line and then move to 6236 in the second line? Just hypothetic.
Our next question comes from the line of Laura.
Gas from Raymond James Your line is now open.
Hey, guys. Thanks for taking the questions and look forward to seeing all these data later in the year.
Just one for me.
I'm curious since you're running.
At the same time, the Panorama trial and then.
Ross lots of clinical trials.
The bathroom trial investigators on how they make the decision on whether to enroll patients on our pan Roswell or reflect the trial.
SMA that you probably have some trials going on at the same location. It was curious have you got any insight there.
Yes, I'll just make a general comment.
Amy Faddea: Ah, so your question is, in pancreatic cancer, if you received RMC-6236 as part of a first-line regimen, why would you continue to receive it? Why would you repeat 6236 as part of a second-line regimen? Is that, is that what you're asking? Well, or why would you start with 6291, which is more targeted as a first-line treatment and then move to 6236, which is broader? Ah, okay.
And most of the indications we're talking about the need for these compounds is so high.
We can possibly support in these early stage clinical trials, where the where the size of the trial.
Just is inherently limited.
So I.
I don't think there's really any sort of near term issue associated with that but maybe maybe way it wants to comment further about when youre into pivotal trials.
That effect.
Any.
Yes, I think the bigger pumps.
Should we expect fairly well.
So far in terms of Ah.
Queen patients.
Dr. Wei Lin: Now I understand, so we're talking about a KRAS G12C cancer, specifically lung cancer. And your question was, if we combine 6236 with 6291 in the first line. No, I'm not following it.
We're addressing I think since really highlighted.
This is <unk>.
The situation is the biggest driver in all of oncology and egg bite.
But this really.
Unlocks huge unmet need.
All the patients coming in interest in our trial this reflection of that.
Okay very helpful. Thank you very much.
Dr. Wei Lin: So maybe you can interpret the question, and you can answer it. Or, let me interpret your question. So, I think what I'm hearing you saying is, if we were able to succeed in developing 6291 plus Pembro, where 6291 plus Pembro and chemo would become a new center of care for T12C patients in the first line lung. Why would patients get 6236, the second line? Is that your question? Yeah, yeah, that's helpful. Thanks. Yeah, I'll take a stab at that. I mean, that's certainly one scenario we could devolve into using a 6291 purely based regimen plus either PEMBRO mono for the p-hormone high or PEMBRO for the p-hormone low, for Keybo. That would be another option.
Thank you.
One moment Sir final question. Please.
Our final question comes from the line of Ben Burnett with Stifel. Your line is now open.
Hi, This is Kelly read on for Ben Burnett. Thanks for taking our questions. I. Just had one quick question about RMB 62, 36, I was wondering if you could give us any additional color on how the confirmed response rates for non small cell lung and feedback.
Our trending post ESMO. Thank you.
Yes, Thanks for your question.
As we mentioned in January and reiterated here.
We see favorable trends in the response rates.
Youre asking specifically about confirmation.
Generally what I can say is that most responses to confirm most of the responses that have been confirmed previously have been subsequently confirmed except in those instances where somebody progressed in the interim or had to come off of drug and will never have the opportunity to to confirm so.
Dr. Wei Lin: I just want to put that out there. But let's take what you put on the table, which is 691 plus PEMBRO plus CHEMO. If that became the standard care in first line, I think we still do believe that there could be sensitive rationales for 6236 to remain as an option in the second line setting. And the reason is the following. I think it really has to do with the way that a RAS-resistant tumor behaves in developing resistance against any G12C inhibitor. I think there's a wealth of data from psoriasis, atograssis, and deviriasis. I think one really emerging sign is that, number one, 89% of those tumors retain original G12C mutations. They don't want to lose it.
Are these due to confirm I'm not going to able to give you specific.
Confirmed rates today in part because these are all ongoing trials. So what happens is you.
We're always enrolling new patients and getting unconfirmed responses, while we're being asked about what's the confirmed response rate. So I would say you'll have to hang on and wait until later in the year when will we will try to.
Give more precise information.
Okay. Thank you very much.
Thank you.
I'm currently showing no further questions in the queue at this time I'd like to hand, the conference back over to Dr. Michael Smith for closing comments.
Well. Thank you operator, and thank you everyone for participating today and for your continued support of Revolution medicines.
Dr. Wei Lin: And number two, the vast majority of the resistant mutation involves some type of either another RAS mutation or another mutation in the RAS pathway to reactivate the RAS pathway. So this is what we call a RAS rescue mechanism. So rescuing or reactivating the RAS seems to be the predominant mechanism, and hence it goes along, I think, with how Mark is describing these tumors as RAS-addicted. I think the fact that they're addicted means that they are really reliant on turning the tumor pathway back on in RAS, and hence the broad spectrum activity of 6236 involving not only other RAS mutations that can potentially cover, so And furthermore, even if a patient were to activate a resectricizing kinase like HFR, and the signal goes to a wild-type RAS, that 6236 can also cover. So there are so many resistant mutations that are well-characterized for the current G12D inhibitors that, potentially, 6236 can be active against. So I think it still provides rationale.
This concludes today's conference call. Thank you for your participation you may now disconnect everyone have a wonderful day.
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Dr. Wei Lin: Obviously, we need to generate clinical data to support that for 6236 to remain the standard of care in the second line setting, even if 6291 establishes itself as a first line. So you got yourself a very scholarly lead answer. Thank you. I just want to circle back to the first thing. Yeah, if I could just go back to the first thing that Wei said, that was really important.
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Dr. Mark Goldsmith: It might have gone by a little bit quickly, which is that although we're testing 6291 plus Pembroke, we're also evaluating 6236 plus Pembroke. We're also evaluating 6291 plus 6236, and all three of those are a way of triangulating potentially on a triplet combination of 6291 plus 6236 plus PEMRO, which would be, as Wayne said, a chemo-free regimen for FirstLine. But it's not the only outcome of that. It's not the only possible outcome, but that would be one way in which all those things get rationalized.
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Dr. Mark Goldsmith: One shouldn't assume today that we will or would not move forward with the doublet of a PD-1 plus. See, we'll let the data tell us what makes sense.
Dr. Mark Goldsmith: Thanks. Thank you. One moment for our next question. Our next question comes from the line of Alex Stranahan with Bank of America. Your line is now open. Hey guys, this is John on Mom4Alec.
Operator: Thanks for taking our question. Just a quick one from us. In terms of second half data updates, what could be the venue that we would be expecting? Would it be at like a medical conference or should we just be expecting one? Like a press release or like yesterday, so any color on that would be great if you could share it.
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John: Thanks, John. It's hard to answer that question because there are so many different data sets that we've listed there that could come out in the second half of the year, although our preference is to disclose such information in the context of peer review. Medical Conference. It's not always up to us; it just depends on the timing and availability. Often, these things require abstracts that are submitted long ahead of when we might have the information.
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Dr. Mark Goldsmith: So we'll pick a forum for each of the disclosures that suits it to make sure that we're not holding on to data that investors need to know about. Okay, thank you for the call. Thank you. One moment for our next question. And our next question comes from the line of Jay Olson with Oppenheimer. Your line is now open.
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Operator: Oh hey, congratulations on the progress and thank you for taking the question. As you look ahead to the potential for multiple pivotal trials, can you just talk about how you're thinking about partnering opportunities both in the U.S. and outside the U.S.? Hi Jay.
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Jay Olson: Thanks for joining us, and thanks for your question. I think, again, we've been pretty consistent about this, which is that in the U.S., we really believe this is a serious opportunity for RedMed to build its own franchise and to use the RAS portfolio to create a very strong and leading franchise. So I don't think we're particularly keen on sharing any of that with a partner, and I don't think there's any point in doing so, at least as we see things today.
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Dr. Mark Goldsmith: Outside the U.S., it's pretty clear that we don't have much opportunity there. That's a much more complex context in which to think about commercializing. We can't do development outside the U.S. We already do development outside the U.S., but doing pivotal, late-stage global development typically takes a real appreciation of the nuances in different country settings and, you know, different geographies.
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Dr. Mark Goldsmith: So that can be done, that can be enhanced by working with a partner that already has that infrastructure, and then, of course, commercialization per se is not something that we have any near-term plan to pursue on our own. So I think it's pretty clear that an ex-U.S. partner or partners could be in the offing for us at some point in the future. We're open to that possibility, and when the right opportunity presents itself, and it makes sense for us to do it, Show. Super helpful, thank you very much. And if I could ask one follow-up question, as you look ahead to the potential tumor agnostic setting for 6236, can you just talk about the regulatory path that you were thinking about there? Dr. Wayland is prominent and fabulous.
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Dr. Wei Lin: Yeah, I have to address that. I think we have already presented activity in non-small cell lung cancer as well as pancreatic cancer. So those are probably going to be served as anchors in our approach to tissue agnostic. Right now, we're actually rolling patients, Cancer, melanoma, as well as chronic spondylitis, as well as other diseases, and obviously, it could be very data-driven, but it's our aspiration, given the broad activity we've seen pre-monthly, that this molecule could potentially help. As many as 30% of patients were followed to murder. Wrap.
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Dr. Wei Lin: We'd certainly like to test that hypothesis to the fullest, and then that will drive our decision about how much the tissue needs to be removed. Okay, great. Thanks again for taking the time to answer the question. Thank you. As a reminder, to ask a question, you'll need to press star one one and please wait for your name to be announced. Our next question comes from the line of Laura Prendergast from Raymond James. Your line is now open. Hey guys, thanks for taking the questions and I look forward to seeing all these data updates later in the year. Oh, just one for me. I'm curious, since you're running, you know, at the same time, this pan-RAS trial and then RAS-selective clinical trials, have you gotten any feedback from trial investigators on, you know, how they make the decision to enroll patients in a pan-RAS trial or a RAS-selective trial? You know, assuming that you probably have some trials going on at the same location. I'm just curious if you've gotten any insight there.
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Operator: Yeah, I'll just make a general comment. In most of the indications we're talking about, the need for these compounds is so high that there are more patients that we can possibly support in these early stage clinical trials where the size of the trial is just inherent. So I don't think there's really any sort of near-term issue associated with that, but maybe Wei wants to comment further about when you're into pivotal trials and how it might add a thing.
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Laura Prendergast: Yeah, I think that should reflect fairly well, we're correct, really highlights, and you, whose situation is the biggest driver in all of oncology, and then fire, have made me proud, and really unlocks a huge... Pacific. Interest in our trial. This would touch so many people.
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Dr. Mark Goldsmith: Great, very helpful. Thank you very much. Thank you. One moment for our final question, please. Our final question comes from the line of Ben Burnett with Stiefel. Your line is now open. Hi, this is Kaylee Brizion on behalf of Ben Burnett.
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Operator: Thanks for taking our questions. I just had one quick question about RMC 6236. I was wondering if you could give us any additional color on how the confirmed response rates for non-small cell lung cancer and PDACs are trending post-ESMO. Thank you. Yeah, thanks for your question. You know, we, as we mentioned in January and reiterated here, we've seen favorable trends in the response rates. You're asking specifically about confirmation, and I think generally what I can say is that most responses to confirm most of the responses that have been unconfirmed previously have been subsequently confirmed. Except in those instances where somebody progressed in the interim, or had to come off of a drug, and we'll never have the opportunity to confirm.
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Kaylee Brizion: So, most of these do do confirm. I'm not gonna be able to give you specifics. Confirmed rates today, in part, because these are all ongoing trials. And so what happens is you're always enrolling new patients and getting unconfirmed responses while we're being asked about what the confirmed response rate is. So, I say, you'll have to hang on and wait until later in the year when we'll try to. I'll give you more precise information.
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Dr. Mark Goldsmith: Okay, thank you very much. Thank you. I'm currently showing no further questions in the queue at this time.
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Thank you.
Please go ahead.
Operator: I'd like to hand the conference back over to Dr. Mark Goldsmith for closing comments. Thank you, Operator, and thank you, everyone, for participating today and for your continued support of Revolution Medicine. This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.
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