Revolution Medicines Inc. Q1 2023 Earnings Call

May 8, 2023

[music].

Yeah.

Okay.

Good day and welcome to Revolution Medicines first quarter 2023 earnings conference call. At this time, all participations participants are in a listen only mode. After the speaker's presentation, there will be a question and answer session.

To ask a question. During this session you will need to press star one one on your telephone you will then hear an automated message advising that your hand is raised to withdraw your question simply press star one again.

Now we ask that each participant limit their questions to one initial question and one follow up question. After that we just simply ask that you rejoin the queue and we will address additional questions as time permits.

As a reminder, today's conference is being recorded.

I would now like to turn the conference over to your host Erin Graves Senior director of corporate Communications and Investor Relations Erin. Please go ahead.

Thank you and welcome everyone to the first quarter 2023 earnings call. Joining me on today's call are Dr. Goldsmith Revelation medicines, Chairman and Chief Executive Officer, Dr Speed, Kelsey, our president of R&D, and Jack Anders <unk>, Our Chief Financial Officer Tag Horn, our Chief <unk>.

Operating officer will also join us for the Q&A portion of today's call.

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

Actual results may differ materially from these statements and except as required by law. The company undertakes no obligation to revise or update any forward looking statements.

I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release as well as all of the Companys filings with the SEC concerning these and other matters.

During this call we will be referring to a few slides from our corporate presentation, which was posted to our website prior to this call.

With that I will turn the call over stocked at heart Goldsmith Revolution medicines, Chairman and Chief Executive Officer Mark.

Thanks Erinn.

It's good to be with you this afternoon and to provide an update on our first quarter 2023 earnings.

On today's call I'll provide a brief update on our company progress Dr. Kalsi will cover a few highlights of our R&D progress and Jack Anders will provide highlights of our financial results before we open the line for questions.

We're off to a strong start this year with two important steps that we shared in the first quarter.

First we communicated early findings from the phase one <unk> study of RMC 63, six our first in class Ras multi on inhibitor.

Which showed encouraging anti tumor activity safety and tolerability for patients with advanced solid tumors harboring a range of distinct <unk> 12, X mutations, particularly <unk> <unk> and <unk>.

While covering a relatively small sample size. This was an important update as it provided initial validation of the novel mechanism of action.

Potential clinical utility of RMC 63, six and also carried positive implications across our pioneering and deep portfolio of rasp inhibitors.

A second important step was a successful public equity offering in March which raised $345 billion of gross proceeds and further reinforced our strong financial position.

The additional capital is allowing us to consider additional near term and long term investments to strengthen clinical development of our first wave of Ras on inhibitors and to prepare our organization for the advancement of RMC 63, six through the hiring of additional senior leaders and staff.

I'll now turn to Dr. Steve Kelsey to review several clinical and preclinical highlights from the quarter Steve.

Thank you Mark.

Let me provide a few additional comments on our first wave of development stage Ras one drug candidates beginning.

Beginning with updates on dose escalation of RMC 63, six hour Ras multi <unk> inhibitor in the RMC 636001 trial.

First I am pleased to report an updates on the case, we highlighted in February .

Patients with previously treated metastatic pancreatic cancer harboring the <unk> mutation.

We reported that this patient had unconfirmed partial responses cycle five day, one on RMC 63, 6% to 80 milligrams daily.

The partial response was subsequently confirmed viruses with an 82% reduction in tumor measurements on cycle seven day one.

The <unk> scans are shown on slide 14 of the corporate deck and this patient continues on treatment.

Second we have escalated to dose level, three 160 milligrams daily and are now evaluating 220 milligrams daily while also continuing to backfill the 120 and 160 milligram dose levels.

We are encouraged that we continue to accumulate accumulate clinical evidence of anti tumor activity for RMC 63, six at doses that appear to be well tolerated.

We currently plan to provide additional updates on the program.

I'll support clinical updates this year.

These would be a combination of corporate disclosures and presentations at scientific meetings.

Beginning in Q3.

We expect to be able to provide a more detailed schedule of these updates in connection with our Q2 earnings release.

We will next discuss RMC 69, one hour mutant selective Kers G C.

EBITA.

At the recent.

The <unk> annual meeting, we presented new preclinical data and provided the first disclosure of the chemical structure of this drug candidate.

This is the first structure disclosure of a drug candidate from our pioneering <unk> inhibits a collection.

RMC 69, one exemplifies how we are able to bring favorable drug like properties, including potencies selectivity.

Higher availability to these beyond really the five macrocyclic campaigns.

We are continuing to dose escalate in the RMC 69 1001 study.

And are now focused on a twice daily dosing schedule to maximize continuous drug exposures.

RMC 60, 91 continues to be well tolerated and we have not yet reached the maximum tolerated dose all selected a recommended phase II dose we remain on track to provide an update in the second half of this year.

RMC 90, <unk> five hour mutant selective.

And covalent <unk> inhibitor remains on China can support with the goal of beginning clinical evaluation of this Brian breaking compounded mid 2023.

And we will shortly have our entire first wave of three rasp inhibitors under clinical evaluation.

As many lastly, epithelia achievements have a propensity to metastasized to the brain it.

It is important to define the potential activity of these rasp inhibitors against tumors have metastasized into the central nervous system.

This may become particularly important improvements in treatment of systemically visceral disease, allowing more cases involving the central nervous system to emerge.

Today, we highlight preclinical studies, demonstrating antitumor activity and intracranial choose by each of the three first wave <unk> inhibitors.

As shown on slide 21 of the corporate deck, we used a well validated intracranial xenograft model of human non small cell lung cancer carry the <unk> mutation. The <unk> 99 model in which an embedded luciferase gene enables nano.

<unk> phase that concentration of tumor size.

The graph on the far left of the slide shows the bioluminescence signal intensity of tumors in untreated animals and full validation adjacent so it is a group of animals treated with <unk> 100 milligrams per kilogram per day.

<unk> twice daily.

Showed a roughly 10 times lower signal representing significant tumor reduction.

This model and results match, those published by mere Aussie and important point since out aggressive was reported last year to display antitumor activity against brain metastasis in patients with <unk> lung cancer consistent with the preclinical results.

The next group in Orange shows the signal from implants at brain tumors treated with RMC 63, six at 25 milligrams per kilogram daily.

Showing encouraging antitumor impact, whether it's essentially indistinguishable from less aggressive.

And the next group in Blue.

It's nice treated with IMC 69, one at 100 milligrams per kilogram twice daily dose selected to be identical to the AD aggressive treatment regimen, where a greater anti tumor effect was observed.

And finally on the right is an analogous study of RMC 95 versus control in an intracranial model of pancreatic cancer carrying <unk> SG 12, D showing a profoundly reduce signal, indicating a significant antitumor effect by this compound as well.

Despite the limitations of these orthotropic models collectively these favorable preclinical results define a shed property of one three rasp inhibitors to potentially penetrate into central nervous system metastases.

<unk> not sure <unk> cancer agents this will be evaluated in subsequent clinical trials.

Finally, I'd like to provide a brief status update on our two clinical stage Ras companion inhibitors.

First our ship two inhibitor RMC for <unk> III.

The global Phase two RMC full six through three trial evaluating RMC for six trailing combination with <unk> for patients with <unk> non small cell lung cancer is fully enrolled and we remain on track to read our topline results in the second half of this year.

Second R&D talk one selective inhibitor RMC 5552 continues its evaluation as monotherapy in patients with tumors carrying mutations associated with hyper activation of until one signal.

With the goal of advancing into combination studies with <unk> inhibitors in select patients.

Previously we were focused on dose optimization in the six to eight milligrams a week range.

After observing dose limiting mucositis in patients treated at higher doses of side effect that is common with M Tor inhibitors.

Since then we have successfully piloted a revised prophylaxis strategy that appears to diminished both the frequency and severity of mucus sciences and has allowed dose escalation above eight milligrams per week.

We plan to provide a clinical update on RMC thoughts are far too at a scientific meeting in the second half of this year back to your model.

Thank you Steve.

In conjunction with the clinical momentum described above we have also continued building our organization with a particular emphasis on enhancing our late stage capabilities to support further progression of assets such as RMC 63 six.

Im, especially pleased to announce today several new executives who've joined the leadership group at RESNET and bring substantial experience and track records to our efforts.

Dr Wei Lin and oncologists with academic and industry experience has joined US as Chief Medical Officer, a significant leadership addition to Dr. Kelsey R&D organization.

After completing medical training at Harvard Medical School in the MD Anderson Cancer Center.

<unk> early stage and late stage cancer drug development programs during her career at Genentech, Nektar and Alaska and he now overseas clinical strategy and medical Affairs at Revolution medicines.

Alicia Gardner has joined as senior Vice President for commercial.

In her career at Genentech, Alicia held a variety of leadership roles across its oncology and hematology franchises, including lifecycle management commercial strategy and launch planning.

And we have also welcomed nisha brown as vice President of commercial development Zane Rogers as Vice President of regulatory Affairs, and Sriram, Naga and often as vice president of chemistry manufacturing and controls.

With these highlights of our recent R&D and organizational progress I'll now turn to Jack Anders our CFO to provide a financial update Jack.

Thank you Mark.

During the first quarter, we strengthened our balance sheet with the Upsized public offering of common stock raising gross proceeds of $345 million.

Net proceeds were approximately 324 million after deducting underwriting discounts commissions and estimated offering expenses.

Including the financing, our ending cash and investments balance as of March 31, 2023, with $909 8 million.

Which is now expected to fund planned operations into 2025.

Revenue from our collaboration agreement with Sanofi was $7.01 million in the first quarter of 2023.

Total operating expenses for the first quarter of 2023, or $82 2 million and increased by 25% over the prior year period.

The increase in operating expenses was largely due to R&D expenses related to the advancement of RMC 63, six and RMB 691 into clinical trials as.

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

Net loss for the first quarter of 2023, with $68 1 million or <unk> 72 per share.

We are updating our financial guidance for 2023, and now expect full year 2023, GAAP net loss to be between 360 and $400 million, which includes estimated noncash stock based compensation expense of $40 million to $50 million.

The increase in expected GAAP net loss as a result of increased investments to support and strengthen clinical advancement of our first wave of rasp inhibitors.

Including expanded clinical supply and additional senior leaders across late stage development manufacturing and commercial planning for RMC 6236.

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

Thank you Jack.

We are highly energized by the exciting pipeline and organizational progress. So far this year with ambitious plans to continue amplifying this momentum.

We look forward to sharing further clinical updates on our first wave of rasp inhibitors in Ras companion inhibitors in the second half of the year we.

We deeply appreciate the support of our patients clinical investigators scientific and business collaborators advisers and shareholders and the tireless efforts of our ref net employees in pursuit of our mission to outsmart Ras addicted cancers.

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

Thank you at this time, we will conduct a question and answer session. As a reminder to ask a question you will need to press star one on your telephone and wait for your name to be announced to withdraw your question simply press Star One again, we ask that each participant limb.

Their questions to one initial question and one follow up question and after that we will have participants rejoin the queue and we'll address additional questions as time permits.

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

Our first question comes from Mark from with TD Cowen Mark. Your line is open. Please go right ahead.

Mark Your line is open Mark from Okay, Yes.

Sorry.

Thanks for taking my questions and congrats on the progress that in a little bit of data update Steve.

He dropped in there.

Just looking forward to the additional.

Additional 63 six updates maybe to start off just can you give some context for the kind of patient numbers right now most of the data.

<unk> 12 D patients here in part from the epidemiology should we yes.

And the next updates to see.

You kind of get broadened out to two other mutations in <unk>.

Or is this really staying.

Given the epidemic genealogy, just very focused on <unk>, and then I'll probably have a follow up there.

Thanks Mark.

A question I.

I don't think we can really give you a lot more color on that right now obviously, we're still accumulating.

Accumulating data we're still following patients.

Who have been on study.

We are enrolling into escalation cohorts and then we're back filling.

At doses below the.

Escalation dose.

So, we'll certainly have a larger and as you know to a large degree we think that the patient population represented.

The epidemiology broadly, which is that <unk> is the most common mutation.

And that's.

That's what we're seeing in the study, but we are we are seeing additional genotypes.

In terms of histology.

Clearly, we continue to see most patients in the pancreatic cancer and non small cell lung cancer.

Tumor types.

But there are there are some others as well so it's hard to say from where we are today, we'll know better.

As we get closer to that.

Social point.

Okay. That's helpful and then.

Obviously, the net loss guidance implies a significant growth in expenses kind of here for the remainder of the year can you just kind of walk through what some of those priority trials are that you are looking to start.

The monotherapy expansion for.

It's a multi ras and maybe the Chelsea, but or is that really the combo work getting underway.

The priorities there.

Yes.

Yes, I don't think today, we're necessarily announcing new.

New studies I think it's more along the lines of plans that we've already had but the probability for those planned of course has gone up because of the progress.

And.

We do feel that there it is justified to increase our commitment to supply which will supply. Both this year and continue providing support into studies that extend into next year as well.

As well as expanding the personnel of the senior leadership that we talked about.

And so on.

Don't think its really today, a point for us to start disclosing the broader development plan around our RMC $63 six specifically.

Certainly expect that we are continuing mono therapy and expanding.

There and that priority as well that run in parallel to get into the combination studies, but no no specific update.

Today on that I think as we get later into the year and after we've unveiled.

More clinical data then I think it will be more appropriate to sort of combine that with projections about what's coming next.

Okay. Thank you.

Youre welcome.

Please standby for our next caller.

And our next question comes from the line of Eric Joseph with JP Morgan Eric. Your line is open go ahead.

For taking the questions just on the dose escalation update.

Now at $2 20.

Can you talk a little bit.

What you saw in terms of Tolerability at 160 that you're comfortable with widening the dosing interval in.

Okay, Steve Thanks.

Currently.

Alright.

Perhaps headroom to further dose escalate.

I think Steve.

We'll comment on that.

Sure.

The.

The Tolerability profile of RMC 63, six continues to be what.

What we consider favorable.

There have been no qualitative changes in the Tolerability profile of RMC $63 six since our last update.

Update.

Sure.

We feel comfortable in continuing to.

Dose escalate as we go.

Somewhat laboriously.

Wade through back in.

In February .

Even though rash is the most frequent toxicity remains the most frequent toxicity really is difficult to predict.

Similarly.

To become dose limiting we had previously.

Articulated I believe that we would expect on the basis mechanistic.

Studies and non clinical toxicity studies that may be Gi toxicity would ultimately become dose limiting but as of now that's not happening and so we're continuing to dose escalate is very difficult to Eric.

Where we're going to stop with this honestly cannot give you color on that.

They do even if.

Other than that.

The program continues.

Well.

Okay.

I don't know if you have visibility on this but just having highlighted the expectation of being at a medical conference in the third.

Third quarter I guess.

Should investors expect.

Sort of a meaningful difference from the.

As meaningful difference in the scope of data reading out sort.

Sort of mid year from what you might present at a medical meeting.

With this program.

Well I think I think what we're communicating Eric is that our mid year update will be a set of multiple updates, including corporate and scientific meeting presentations that begin in Q3, but I don't think we're going to be having.

Update next week, followed by an update.

That series that starts in Q3 I think those are all those are all part of the same the same series that will begin in Q3.

Got it okay. Thanks for clarifying appreciate it.

Yes.

Yes. Thank you.

Standby for our next caller.

And we have Michael Schmidt from Guggenheim Michael Your line is open. Please go ahead.

Hey, guys. Thanks for taking the questions.

Western on six to nine one.

Now there'll be seen a few more clinical data sets from other <unk>.

<unk> inhibitors at ACR.

I guess what are you looking for in the clinic for your program I guess what degree of.

No differentiation.

Either efficacy or safety argue.

We're looking for at a minimum relative to the others.

Rather comparable.

And then a follow up question on the the switch the tid dosing on the panel, but what drove that decision to move into twice daily.

Solid.

Once daily dosing.

Thank you.

Yeah, Hi, Michael Thanks for your questions.

I might just take both of those and Steve can add to it if there's if there's anything to add so that the question of <unk> dosing.

Really nothing specific drove it other than the fact that the PK and the daily dosing.

Turns out to be consistent with what we saw pre clinically and pre clinically we saw in that report at the half life of RMB 69, one.

In animals and now we've seen and people is shorter than a full 24 hour type of coverage for daily dosing.

We didn't really see much impact of that adverse impact of that preclinical impacted almost all of the preclinical data we reported were from <unk>.

Daily dosing.

So the preclinical differentiation that we reported was supported by that daily dosing, but nonetheless.

Humans, we want to have every opportunity to be successful here and.

There's really not a good argument for.

Going to staying at daily dosing.

Twice daily dosing will give us more continuous coverage and.

If theres a benefit that comes from that we'd like to have that on behalf of patients. So that's really all there is just nothing else from the clinic that.

That decision.

Yes.

And your first question was.

No I was asking about the degree of differentiation, you're sort of looking for in our planning relative to the other to talk about that but you can go fairly comparable so far.

Yes, well I think thats, the sort of the key points is that the entire wraps off inhibitor.

We will of drug candidates.

They look relatively similar and that's what we've expected based on the biology of inhibiting.

The the reserve pool of RASK in the off state.

And that you are always going to be chasing trying to get trying to get a leg up but without much biological.

Ability to do so so ultimately we'd like regimens that incorporate RMC 69, one.

To give us greater clinical benefit and as we've talked about in the past, we're not exactly sure whether that's going to be in higher response rates are greater durability of response.

And or.

Greater tolerability.

Those are all features that we have.

That we've seen pre clinically and any or all of those could be manifest in humans.

I think youre asking though.

How much of that do we need to see in monotherapy before we start.

Our combination studies since we've indicated.

Explicitly multiple times that our strategy around RMB 69, one.

Is to move it into combination studies as quickly as we can as a focus.

The long term plan on combinations, because I think the puck the puck has already moved past.

Monotherapy.

So we're trying to play where the puck is going to be in the future on behalf of patients and.

And the answer to that is we're not really prepared to define for you an answer to that we're going to move into combination studies as quickly as we can and we need to get sort of the basic profile.

In monotherapy, and we need to compare that to the benchmarks.

And how much of how much superiority or differentiation, we see relative to those benchmarks.

We just we don't know.

And we're not too concerned about it because we know mechanistically, it's going to be it is going to be differentiated qualitatively differentiated. So we're not we're not too hyped up about it.

Exactly what we see in a relatively small number of patients. So I think if we're in the ballpark of the benchmarks will be going into those combination studies.

We are vastly superior to way that one could draw such conclusions from a relatively small study that might allow us to continue on our monotherapy pathway, but.

We don't really anticipate that from a phase one dose escalation study.

Great. Thank you Mark.

Yes.

Standby for our next question.

Okay.

Chris Sheppard Tani joins us from Goldman Sachs. Chris. Your line is open go ahead.

Hi, good afternoon, everyone and thank you for taking our questions. This is Charlie on for Chris.

It's nice to see the CNS activity that we're seeing across the Ross that restaurant platform at this point. So I just wanted to get your take in terms of the potential for that inter cranial activity to translate into the human subjects. As we proceed in advance further into the clinic is there anything in particular that you would call out about the Tri complex mechanism of action that might influence the translator.

<unk> of that inter cranial activity that youre seeing in mouse model so far.

I don't think so I think the impact solves penetrating into CNS Mets.

Is going to be determined to a very large extent by the patient.

Population in which these drugs are being tested so ultimately.

As we get into earlier lines of therapy, as we have the opportunity to control the visceral disease more effectively than I think brain metastases are going to be an increasingly large part of the unmet medical need and that's when you will see the impacts of the two.

Friends Legibility so to speak.

Of compounds getting into CNS metastases with regards to the truck complex technology per se.

Particularly the selective compounds, which caused these regressions in these implanted tumors that highly selective full mutant Ras. So there is unlikely to see any translation into CNS space toxicity from any impacts in penetrating the normal CNS we.

Really don't have a very good handle on how much of the how much of these compounds got since non CNS all of the evaluations to date have been done in in tumors, specifically growing within the central nervous system and I think thats. The thats the message that we would like to convey at the moment.

Great. That's helpful. Thank you so much and then maybe just a quick one on 63 six with the profile that's still emerging.

Is there anything in particular in terms of combination partners that are you seeing a particular combination partner thats, maybe more or less likely to be combinable with $63. Six at this point or are you really seeing a relatively tolerable profile. Thus far that's leaving all potential combination partners on the table at this time.

Yes.

At this point everything everything is open obviously with the RASK multi inhibitor that is suppressing.

To some degree suppressing normal or wild type Ras in normal tissues, there would in principle be overlap with other inhibitors that also suppressed Ras signaling in normal tissues. So for example, a ship two inhibitor.

RMC 63, six they may be combinable with they may not be that you would worry more about that combination then you would about combining with something that's highly selective and has.

Non overlapping mechanistic mechanistic effect and an example of that might be PD one.

So 63 six.

Mystically targeting Ras and PD, one not mechanistically targeting you can imagine those Mike.

In principle be more combinable and pre clinically we have combined a lot of things.

Can see see impact in the preclinical models. So I just think it's hard to predict today.

Exactly what.

What will work out best but we do have some priorities and I've just given you some sort of guidance about how you might think about those priorities.

I really appreciate it thank you so much.

You bet.

Standby for our next caller.

Okay.

Alec Stranahan joins us from Bank of America, Alex Your line is open go ahead.

Hey, guys. This is John I'm on for Alex.

So just a quick one on 90 898 to five.

Obviously, we saw some preclinical data at ACR.

In terms of getting into the clinic at.

Dose the first patient in the our monotherapy dose escalation study.

It's kind of like patient baseline characteristics, we can expect and what tumor types are you going to go.

Go for in the study if you could shed some light on that thanks.

Well right now.

The plan for RMC 98, five is too I.

Identify a recommended phase two dose as expediently as possible and obviously convince ourselves that that's the right dose and persuade other constituencies.

We have the right dose.

Apart from an obvious restrictions for patients with tumors harboring <unk> mutation I don't think you're going to see a lot of difference from the RMC $63 six dose escalation frankly.

We know the the.

Historic types in which <unk> 12, the mutations predominate.

And we have enough experience now with $63 six to get a handle on the types of patients that we're going to get in the phase one study, they're going to be predominantly patients with lung cancer pancreatic cancer and colorectal cancer.

And I think that pretty much all we can say right now that there is nothing unusual about the phase one time for this compound.

Got it might be a real quick follow up.

It might be with that okay.

I don't know if slightly underlying it was a question about access to patients, which we sometimes get asked about.

There are 55000.

We estimate 55000, new U S.

<unk> D cancers, each year and given that even across multiple companies.

Studies that might be underway at the same time, you are talking about dozens.

Hundreds of patients I don't think theres going to be any impact of that would be.

Competition from from others to the extent that there is any.

Versus competition from around $63 six we will have plenty of access to patients with caris <unk> tumors.

Okay. Thank you and a quick follow up to that.

You mentioned that.

It's likely going to be.

One of the private patients recruited so given the complexity of colorectal cancer in general other than screening for the presence of <unk> are you also going to be screening important other mutations.

Well I think just to build on Steve's comments.

The first thing to do with the compound is the phase one dose escalation and that's not typically a time at which one.

Applied a whole bunch of restrictions.

That comes later after you've seen how it behaves and have a good sense of where you might prioritize so I think Steve mentioned it will be relatively few restrictions other than sort of conventional.

Criteria.

And then the inclusion as a curiosity towards the mutation, but I don't think we will be putting up.

Any other genetic.

Significantly other genetic restrictions.

Okay. Thank you thanks for the color.

Yes. Thank you.

And standby.

Our next question comes from Ben Burnett with Stifel.

Ben Please go ahead.

Hey, Thank you very much just wanted to build off an earlier question just about the regulatory path for the RASM multi RMC 63 six.

I realize it's early days, but could you give a sense for how many different sort of genetic variance of <unk> you would need to show data.

On to get a broad certain mutation agnostic label.

Hi, Ben No. We don't know it will just depend on how much activity. There is when we have more mature data set.

And then that will ultimately depend on conversation with the people who make that decision.

Okay, Alright got it thank you.

Yes.

Alright, please standby for our next question.

And Jay Olson joins us from Oppenheimer Jay Your line is open. Please go ahead.

Hey, Thanks for taking the question and congrats on all the progress.

Can you talk about any feedback you received from physicians following ACR and also is the brain penetrant property of your three molecules.

Design or is there a particular reason for the high CNS activity. Thank you.

So the first.

Sort of thinking about your second question, but remind me what the first question was could you state again.

Okay got from physicians following ACR. Thank you.

And are you asking about.

Are you asking about feedback on our programs are you asking about feedback on other things at ACR could you just clarify.

Feedback on the data you presented.

I think generally the feedback continues to be.

Very positive.

The heaters are quite enthusiastic we've said that previously.

We are not able to make available as many.

Investigational study slots as we'd like to be able to make available they're constrained just by the.

Escalation sort of paradigm.

And there is high demand and patients waiting and investigators waiting and we continue to receive feedback that so far the compound appears to be well tolerated.

Active and so there's quite a lot of excitement about six.

Six.

And then now I forgot the second question.

Oh was that by design center.

Central to the U S.

Yeah.

I think in a certain sense.

There are.

Physical chemical properties.

That the chemists at.

<unk>.

Have a have determined and also most importantly have figured out how to incorporate those properties into these compounds.

And those create more drug like molecules. So it is notable I think that all three of these have this property and all three are orally bio available which.

As somebody who's lived through the history of this debt was not universally accepted as a set of assumptions going into.

The discovery and development of these rason inhibitors based on Mac.

Macro cyclic large chemical backbones, but.

They now have been in doubt with these properties through pretty directed efforts. So I think we should acknowledge that the medicinal chemistry team with support by many others was able to do that whether or not they design them, specifically aiming to get them into the CNS.

Probably.

Maybe more of a philosophical question than anything else.

No.

I don't have to answer philosophical questions I guess.

Okay, great. Thank you and if I could maybe one follow up on <unk>. Three six can you just talk about the next data update and what sort of data you will have and what investors should expect to learn from that.

Yes.

Sure as we can.

Noted, we're following any patient who stays on on drugs. We continue following them. So we'll get a much better sense of durability in the course of treatment for those patients who have already been on drug.

And who remain on.

We're going to get a sense from backfill patients.

A deeper sense of Tolerability and a deeper sense of antitumor activity from those backfill patients might not have as much durability data from from those.

If theyre enrolled later in the game and then of course, we have escalation data.

It shows us.

Where we are on the Tolerability scale and get a better sense of how.

When and at what level will reach a recommended phase II dose or candidates for recommended phase two dose.

The tumor types are going to be as we talked about earlier.

What they are.

And the mutations are what the epidemiology dictate them to be and so.

Depending on how large the total said is that we will determine what's the absolute number of each of those.

Just the types in each of those genotypes just too hard to say today. So I think investors should be looking for a larger data set than what we've shown before with more information that's kind of deeper and broader.

And we will see whether the trends that we described earlier.

To what degree they continue to what degree if there are differences to what degree there are differences.

And we'll couple that with we hope.

Clarity about what comes next we've already given you in our body language that we are definitely looking beyond the phase one.

One <unk> dose escalation, we're definitely thinking about where where this compound needs to go and are scaling up our activities to support all of that but more detail when we have the data to support it.

Great. That's super helpful. Thank you so much for taking the questions and congrats again on all the progress.

Yes, Thanks, Jim.

And bringing on our next caller please standby.

Ami Fabio joins us from Needham Amit Your line is open.

Great. Thanks for taking my question.

With regard to RMB 600 feet thick.

Can you discuss where the 220 milligram doses.

Sure.

I don't think you tested in the preclinical models.

And how important is it.

To achieve a comparable.

Many of these people are ours.

You've been able to.

The clinical.

Got it.

And.

Maybe let me follow up.

Final question after that.

Okay. Thank you Amit I appreciate the questions.

Just to remind you how to selections made there's a dose selection committee, which is made up of all the investigators they review all the activity data.

Tolerability and safety data and a big package that they received before the meeting is called they look at that they look at the PK.

And if.

If we've cleared the DLT window then they proceed through dose escalation and they determined.

Of course with input from Revlimid.

How much to increase and they determined that 220 milligram.

Increased versus 160.

So just to make sure everybody understands how we arrive at those numbers.

With regard to what dose what exposure level will be at a 220 milligrams will know after we dose the patients.

And obtain their blood samples and determined PK.

So we don't know we can't no a priori, we have projections around that but but.

Rejections are projections, so I can't answer that question today.

And then your second second or third.

Hum.

Keep going up.

Yeah.

Think we've said in various ways more is always better.

That seems to be the case for most of these compounds.

Not just ours, but for most most anti.

Anti tumor drugs.

So we'd like to get up as high as we can within the bounds of our safety.

Safety and Tolerability.

And you're sort of asking a question that project Optimists, It's also asking and it's an equally difficult question to answer for project Optimists, which is how much is enough. We're not in that realm right now because as Steve pointed out which continues to be good tolerability. So we're not.

We're not in that zone, where we even have to be worrying about it but at some point there will be side effects.

It's just hard to conceive of that there won't be.

I'd effects and even more significant side effects that we've seen so far but we're pretty pleased with the exposures. We've had at the other dose levels up through 160.

It's.

We're above.

What we believe is the equivalent in mouse.

Exposure of 10 milligrams per kilogram, which was very much an active.

A dose level in the MISO exposure level in the mice and so we're well above that we've been we've been above it.

Sure.

We're a bit.

And but exactly where we are to 'twenty is hard to say.

Thank you.

I guess my follow up question.

Maybe just.

What do you.

Lines.

Do you think the clinical data.

Paul.

Kind of superiority to other.

Okay.

All of.

Wrap off traffic you saw in the preclinical dataset.

And then perhaps if you could.

In terms of time to <expletive>.

Relative to the data fabric you said at the last earnings call.

Do you expect.

Huntington Beach.

Beyond that timeframe.

Is that patient platforms.

Yes.

Okay. Thank you second follow up question. There was do we expect response rate to improve overtime as patients stay on.

On drug I think that's how I heard that question.

Right yes.

Yes, yes.

We made that statement.

Back at the end of February we did assert that and we said we stand by that assertion, we're continuing to accumulate evidence of anti tumor clinical activity.

But we stand by the assertion we've made previously and we will see over time, whether that holds as we go through.

We talked to escalate and when we recorded out.

With the data set we will have a from her answer as opposed to a preliminary answer at that point.

Thank you.

So on versus off.

RMB six increase probably not the best place to test.

On versus off because it is unique in its profile as far as we know for any compounds in the clinic or about to be in the clinic.

In that it is the.

Active against so many different phenotypes.

And so it's sort of stand it's sort of define a class of its own and it has to stand on its own and so it'll be compared more to standard of care in each of the.

Apologies.

RMB 69, one is one where ultimately the treatment regimen must still differentiation from.

Standard of care in standard of care at least in second line now includes our.

Our targeted <unk> 12 stay off inhibitor.

So but that is likely to come from us in the form ultimately.

Combination strategies.

What we've conveyed as our vision for the AMC 61 91 program.

And the combination we'd like to have the very best rasp inhibitor to that there is.

And we think RMC 69, one as a candidate to be the best.

Curiosity closely inhibitor in large part because of the mechanism, but that will be additive to whatever combination.

He has put together.

When tested in our phase two kind of context.

Understood. Thank you.

Youre welcome.

Okay standby for our last question.

And it comes from the line of Jonathan Chang with <unk> VP Securities Jonathan Youre on the air.

Hi, guys. Thanks for taking my question just one from me what do you see as the competition for RMC, Tennessee six thank you.

Thanks, Jonathan.

A good question.

Four.

For most of the indications the competition as standard of care.

That's what we that's what we're going up against.

For example for <unk> <unk> or any of the other <unk> mutations.

Aside from fee.

There aren't other compounds in the clinic today.

For <unk> D.

Obviously, there are some other compounds that have entered the clinic.

And so in principal those are competitive for that population.

The Gina <unk> genotype.

That's not a statement of my judgment about which compounded superior you just want to know what's on the list.

Those compounds that are in the clinic or about to be in the clinic.

Does that have to be competitive competition.

Okay.

Got it thanks for taking my question.

Youre welcome.

And that concludes our Q&A I would like to turn it now back to Dr. Mark Goldsmith, Chairman and Chief Executive Officer for closing remarks.

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

Thank you for your participation. This does conclude the program you may now disconnect.

[music].

As a reminder, today's conference is being recorded.

I would now like to turn the conference over to your host Erin Graves Senior director of corporate Communications and Investor Relations Erin. Please go ahead.

Thank you and welcome everyone to the first quarter 2023 earnings call. Joining me on today's call are Dr. Goldsmith Revelation medicines, Chairman and Chief Executive Officer, Dr Speed, Kelsey, our president of R&D, and Jack Anders Our Chief Financial Officer, Peg Horn, our chief <unk>.

Operating officer will also join us for the Q&A portion of today's call.

As we begin I would like to note that our presentation will include statements regarding our current beliefs of the company with respect to our business that constitute forward looking statements within the meaning of the private Securities Litigation Reform Act. These statements are subject to a number of assumptions risks and uncertainties actual results may differ materially from these statements and except as required by law.

The company undertakes no obligation to revise or update any forward looking statements I.

This call, we will be referring to a few slides from our corporate presentation, which was posted to our website prior to this call.

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

Thanks Erinn.

It's good to be with you. This afternoon to provide an update on our first quarter 2023 earnings.

We're off to a strong start this year with two important steps that we shared in the first quarter.

First we communicated early findings from the phase one <unk> study of RMC 63, six our first in class Ras multi on inhibitor.

Which showed encouraging antitumor activity safety and Tolerability for patients with advanced solid tumors harboring a range of distinct <unk> 12, X mutations, particularly <unk> and <unk>.

While covering a relatively small sample size. This was an important update as it provided initial validation of the novel mechanism of action.

Potential clinical utility of RMC 63, six and also carried positive implications across our pioneering and deep portfolio of <unk> inhibitors.

A second important step was a successful public equity offering in March which raised $345 million of gross proceeds and further reinforced our strong financial position.

I'll now turn to Dr. Steve Kelsey to review several clinical and preclinical highlights from the quarter Steve.

Thank you Mark.

Let me provide a few additional comments on our first wave of development stage Ras form drug candidates beginning with updates on dose escalation of RMC 63, six hour Ras multi <unk> inhibitor in the RMC six two to 36001 trial.

First I am pleased to report an update on the case, we highlighted in February of a patient with previously treated metastatic pancreatic cancer harboring the <unk> mutation.

We reported that this patient had an unconfirmed partial response cycle five day, one on RMC 63, 6% to 80 milligrams daily.

The partial response would subsequently confirmed viruses with an 82% reduction in tumor measurements on cycle seven day one.

The C. T scans are shown on slide 14 of the corporate deck and this patient continues on treatment.

Second we have escalated to dose level, three 160 milligrams daily and are now evaluating 220 milligrams daily while also continuing to backfill the 120 and 160 milligram dose levels.

We are encouraged that we continue to accumulate accumulate clinical evidence of anti tumor activity for RMC 63, six at doses that appear to be well tolerated.

We currently plan to provide additional updates on the program.

I'll support clinical updates this year please.

These will be a combination of corporate disclosures and presentations at scientific meetings.

Beginning in Q3.

We expect to be able to provide a more detailed schedule of these updates in connection with our Q2 earnings release.

We will next discuss RMC 69, one our selective <unk> inhibitor.

At the recent <unk>.

Annual meeting, we presented new preclinical data and provided the first disclosure of the chemical structure of this drug candidate.

This is the first structure disclosure of a drug candidate from our pioneering <unk> inhibits a collection.

RMC 69, one exemplifies how we are able to bring favorable drug like properties, including potencies selectivity and bioavailability to these beyond really five macrocyclic campaigns.

We are.

<unk> to dose escalate in the RMC 69, 1001 study.

And are now focused on a twice daily dosing schedule to maximize continuous drug exposures.

RMC 69, one continues to be well tolerated and we have not yet reached the maximum tolerated dose all selected our recommended phase II dose we remain on track to provide an update in the second half of this year.

RMC <unk> five hour mutant selective oral <unk> and <unk>.

Covalent <unk> inhibitor.

Inhibitor remains on track and support the goal of beginning clinical evaluation of this Brian breaking compounded mid 2023.

We will shortly have.

Our entire first wave of three rasp inhibitors underpinned the color valuation.

As many Ras mutant epithelium tumors have a propensity to metastasized to the brain it.

It is important to define the potential activity of these rasp inhibitors against tumors.

Test the size into the central nervous system.

This may become particularly important improvements in treatment of systemically visceral disease are liable cases involving the central nervous system to emerge.

Today, we highlight preclinical studies, demonstrating antitumor activity and intracranial choose by each of the three first wave <unk> inhibitors.

As shown on slide 21 of the corporate deck, we used a well validated intracranial xenograft model of human non small cell lung cancer carry the <unk> mutation the <unk> nine model in which an embedded luciferase gene enables <unk>.

Non invasive concentration of chamber size.

The graph on the far left of the slide shows the bioluminescence signal intensity of tumors in untreated animals.

And full validation adjacent to it as a group of animals treated with <unk> 100 milligrams per kilogram daily twice daily.

<unk> are roughly 10 times lower signal representing significant tumor reduction.

This model and results match, those published by morality and important point since out aggressive was reported last year to display anti tumor activity against brain metastasis in patients with <unk> lung cancer consistent with the preclinical results.

The next group in Orange shows the signal from implants at brain Shameless treated with RMC 63, six at 25 milligrams per kilogram daily.

Showing encouraging antitumor impact, whether it's essentially indistinguishable format.

Aggressive.

And the next group and Blue.

These mice treated with RMB 69, one at 100 milligrams per kilogram twice daily.

<unk> selected to be identical to the AD aggressive treatment regimen, where a greater anti tumor effect was observed.

And finally on the right is an analogous study of RMC 95 versus control in an intracranial model of pancreatic cancer carrying <unk> D showing a per finally reduce signal, indicating a significant antitumor effect by this compound as well.

Despite the limitations of these orthotropic models collectively these favorable preclinical results define a shed property of all three rasp inhibitors to potentially penetrate into central nervous system metastases, a prop C. Not sure bottom lines cancer agents this will be evaluated in <unk>.

Subsequent clinical trials.

Finally, I'd like to provide a brief status update on our two clinical stage rats companion inhibitors.

First our ship two inhibitor RMC for <unk> III.

The global Phase two RMC full six through <unk> three trial evaluating RMC for six trailing combination with sensor assay for patients with <unk> non small cell lung cancer is fully enrolled and we remain on track to read out top line results in the second half of this year.

Second R&D talk one selective inhibitor RMC 5552 continues its evaluation as monotherapy in patients with June is carrying mutations associated with hyper activation of until one signal.

With the goal of advancing into combination studies with <unk> inhibitors in select patients.

Previously, we will focused on dose optimization in the six to eight milligrams a week range.

You are observing dose limiting new decides this in patients treated at higher doses aside effect, which is common with M Tor inhibitors.

We plan to provide a clinical update on RMC thoughts up five two at a scientific meeting in the second half of this year.

Maximo.

Thank you Steve.

I'm, especially pleased to announce today several new executives who've joined the leadership group at Revlimid and bring substantial experience and track records to our efforts.

Dr Wei Lin and oncologists with academic and industry experience has joined US as Chief Medical Officer, a significant leadership addition to Dr. Calces R&D organization.

After completing medical training at Harvard Medical School in the MD Anderson Cancer Center Wade led early stage and late stage cancer drug development programs. During her career at Genentech, Nektar and <unk> and he now overseas clinical strategy and medical Affairs at Revolution medicines.

Gardner has joined as senior Vice President for commercial.

In her career at Genentech, Alicia held a variety of leadership roles across its oncology and hematology franchises, including lifecycle management commercial strategy and launch planning.

With these highlights of our recent R&D and organizational progress I'll now turn to Jack Anders our CFO to provide a financial update Jack.

Thank you Mark.

During the first quarter, we strengthened our balance sheet with the Upsized public offering of common stock raising gross proceeds of $345 million.

Net proceeds were approximately 324 million after deducting underwriting discounts commissions and estimated offering expenses.

Including the financing our ending cash and investments balance as of March 31, 2023 was $909 8 million.

Which is now expected to fund planned operations into 2025.

Revenue from our collaboration agreement with Sanofi was 7.0 million in the first quarter of 2023.

Total operating expenses for the first quarter of 2023 or $82 2 million, an increase by 25% over the prior year period.

The increase in operating expenses was largely due to R&D expenses related to the advancement of RMC 63, six and RMB six to nine one into clinical trials as.

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

Net loss for the first quarter of 2023 was $68 1 million or <unk> 72 per share.

The increase in expected GAAP net loss as a result of increased investments to support and strengthen clinical advancement of our first wave of rasp inhibitors.

Including expanded clinical supply and additional senior leaders across late stage development manufacturing and commercial planning for RMC 6236.

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

Thank you Jack.

We are highly energized by the exciting pipeline and organizational progress. So far this year with ambitious plans to continue amplifying this momentum.

We look forward to sharing further clinical updates on our first wave of rason inhibitors in Ras companion inhibitors in the second half of the year.

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 at this time, we will conduct a question and answer session. As a reminder to ask a question Youll need to press star one on your telephone and wait for your name to be announced to withdraw your question simply press Star One again, we ask that each participant.

Limit their questions to one initial question and one follow up question and after that we'll have participants rejoin the queue and we'll address additional questions as time permits.

Please standby while we.

Compile the Q&A roster.

Our first question comes from Mark from with TD Cowen Mark. Your line is open. Please go right ahead.

Okay.

Mark Your line is open Mark from Okay, Yes, sorry, thanks for taking my questions and congrats on the progress it in a little bit of data update Steve <unk> dropped in there.

Just looking forward to the <unk>.

Additional 63 six updates maybe to start off just can you give some context for the kind of patient numbers right now most of the data has been in <unk> <unk> patients in part from the epidemiology should we.

And the next updates to see.

You kind of get broadened out to other <unk>.

<unk> and <unk>.

Or is this really staying.

Given the epidemic Jimmy allergy, just very focused on <unk>, and then I'll probably have a follow up there.

Yes.

Thanks Mark.

Your question I.

I don't think we can really give you a lot more color around that right. Now obviously, we're still accumulating data we're still following patients.

Who have been on study.

We are enrolling into escalation cohorts and then we're back filling.

At doses below the escalate.

Escalation dose.

So, we'll certainly have a larger and as you know to a large degree we think that the patient population represented.

The epidemiology broadly, which is that <unk> is the most common mutation.

And that's what we're seeing in the study, but we are we are seeing additional genotypes.

In terms of histology.

Clearly, we continue to see most patients in the pancreatic cancer and non small cell lung cancer.

Tumor types.

But there are there are some others as well so it's hard to say from where we are today, we will know better.

As we get closer to that to that disclosure point.

Okay. Okay. That's helpful and then.

Obviously, the net loss guidance implies a significant growth in expenses kind of here over the remainder of the year can you just kind of walk through what some of those priority trials are that you are looking to start.

The monotherapy expansion for.

The multi ras and maybe the Chelsea, but or is that that's really the combo work getting underway.

The priorities there.

Yes.

Yes, I don't think today, we're necessarily announcing new.

New studies I think it's more along the lines of plans that we've already had but the probability for those planned of course has gone up because of the progress.

And.

We do feel that it is justified to increase our commitment to supply which will supply. Both this year and continue providing support into studies that extend into next year as well.

As well as expanding the personnel of the senior leadership that we talked about.

And so on.

Don't think its really today, a point for us to start disclosing the broader development plan around our RMC $63 six specifically.

Certainly expect that we are continuing mono therapy and expanding.

There and that priority as well that run in parallel to get into the combination studies, but no no specific update.

Today on that I think as we get later into the year and after we've unveiled.

More clinical data then I think it will be more appropriate to sort of combine that with projections about what's coming next.

Okay. Thank you.

Yes.

Youre welcome.

Please standby for our next caller.

And our next question comes from the line of Eric Joseph with Jpmorgan. Eric. Your line is open go ahead.

Thanks for taking the questions just.

Dose escalation update.

Now to 2000.

Can you talk a little bit.

What you saw in terms of Tolerability at 160 that you're comfortable with widening dose interval and I guess do you think.

Currently.

Great Alright.

Perhaps have room to further dose escalate.

I think Steve will comment on that.

Sure.

The.

The tolerability profile of RMC $63 six continues to be what.

What we consider favorable.

There have been no qualitative changes in the Tolerability profile of <unk> $63 six since our last update.

Update.

Sure.

We feel comfortable in continuing to.

Dose escalate as we can.

Somewhat laboriously.

Through back in.

In February .

Even though rash is the most frequent toxicity remains the most frequent toxicity really is difficult to predict.

Ultimately what is going to become dose limiting we had previously.

<unk> I believe that we would expect on the basis mechanistic.

Studies and non clinical toxicity studies that may be Gi toxicity, what ultimately become dose limiting but as of now.

Not happening and so we are continuing to dose escalate is very difficult to Eric.

Predict where we're going to stop with this.

Honestly cannot give you color on that I may do even.

Other than that.

The program continues.

Well.

Okay.

I don't know if you have visibility on this but just having highlighted the expectation of being at a medical conference.

Third quarter.

Yes.

Should investors expect.

Sort of a meaningful difference from the.

As meaningful difference in the scope of data reading out.

Sort of mid year from what you might present at a medical meeting.

With this program.

An update next week, followed by an update.

That series that starts in Q3 I think those are all those are all part of the same the same series that will begin in Q3.

Got it okay. Thanks for clarifying I appreciate you taking the questions.

Yes. Thank you.

Standby for our next caller.

And we have Michael Schmidt from Guggenheim Michael Your line is open. Please go ahead.

Hey, guys. Thanks for taking the questions.

Question on six to 901.

Now there'll be seen a few more clinical data sets from other <unk>.

<unk> inhibitors at ACR.

I guess what are you looking for in the clinic for your program I guess what degree of.

Differentiation.

Either on efficacy or safety argue.

We're looking for at a minimum relative to the others.

Rather comparable.

And then a follow up question on the the switch the Tid dosing help us understand what drove that decision to move into twice daily.

Solid.

Once daily dosing.

Thank you.

Yeah, Hi, Michael Thanks for your questions.

I might just take both of those and Steve can add to it if there's if there's anything to add.

The question of Tid dosing.

Really nothing specific drove it other than the fact that the PK and the daily dosing.

As it turns out to be consistent with what we saw pre clinically and pre clinically we saw in every ported that that the half life of RMC 60 91.

In animals and now we've seen and people is shorter than a full 24 hour type of coverage from daily dosing.

We didn't really see much impact of that adverse impact of that preclinical impact almost all of the preclinical data we reported were from.

Daily dosing and so the preclinical differentiation that we reported was supported by that daily dosing, but nonetheless in humans, we want to have every opportunity to be successful here and.

There's really not a good argument for.

Going to staying at daily dosing.

Twice daily dosing will give us more continuous coverage and.

If theres a benefit that comes from that we'd like to have that on behalf of patients. So that's really all there is just nothing else from the clinic that.

That decision.

Yes.

And your first question was.

No. So what I was thinking about the degree of differentiation, you're sort of looking for in our planning relative to the other <unk> inhibitors out there, but you know fairly comparable so far.

Yes, well I think thats, the sort of the key points is that the entire Ras off inhibitor.

We will of drug candidates.

They look relatively similar and that's what we've expected based on the biology of inhibiting.

The the reserve pool of RASK, that's in the off state.

And that you are always going to be chasing trying to get trying to get a leg up but without much biological.

Ability to do so so ultimately we'd like regimens that incorporate RMC 69, one.

To give us greater clinical benefit and as we've talked about in the past, we're not exactly sure whether that's going to be in higher response rates or greater durability of response.

And or.

Greater tolerability.

Those are all features that we have.

We've seen pre clinically and any or all of those could be manifest in humans.

I think youre asking though.

How much of that do we need to see in mono therapy before we start.

Our combination studies since we've indicated.

Explicitly multiple times that our strategy around RMB 69, one.

Is to move it into combination studies as quickly as we can as a focus.

The long term plan on combinations, because I think the puck the puck has already moved past.

Mono therapy.

So we're trying to play where the puck is going to be in the future on behalf of patients and.

And the answer to that is we're not really prepared to define for you an answer to that we're going to move into combination studies as quickly as we can and we need to get sort of the basic profile.

Monotherapy, and we need to compare that to the benchmarks.

And how much of how much superiority or differentiation, we see relative to those benchmarks.

We don't know.

And we're not too concerned about it because we know mechanistically, it's going to be it is going to be differentiated qualitatively differentiator. So we're not we're not.

Not too hyped up about exactly what we see in a relatively small number of patients. So I think if we're in the ballpark of the benchmarks will be going into those combination studies. If we are vastly superior to way that one could draw such conclusions from a relatively small study.

That might allow us to continue that in a monotherapy pathway, but.

We don't really anticipate that from a phase one dose escalation study.

Alright, Thank you Mark.

Yes.

Standby for our next question.

Okay.

Chris Sheppard Tani joins us from Goldman Sachs. Chris. Your line is open go ahead.

Hi, good afternoon, everyone and thank you for taking our questions. This is Charlie on for Chris.

It's nice to see the CNS activity that we're seeing across the Ross the Ras on platform at this point. So I just wanted to get your take in terms of the potential for that inter cranial activity to translate into the human subjects. As we proceed in advance further into the clinic is there anything in particular that you would call out about the Tri complex mechanism of action that might influence the translate ability.

<unk> of that intracranial activity that youre seeing in mouse model so far.

I don't think so I think the impact solves penetrating into CNS Mets.

<unk> going to be determined to a very large extent by the patient population in which these drugs are being tested so ultimately.

Friends Legibility so to speak.

Of compounds getting into CNS metastases with regards to the <unk> complex technology per se.

Particularly the selective compounds, which caused these regressions in these in plants of tumors that highly selective full mutant Ras. So there is unlikely to see any translation into CNS space toxicity from any impacts in penetrating the normal CNS we.

I don't see really don't have a very good handle on how much of the how much of these compounds get since northern CNS all of the evaluations to date has been done in <unk> in tumors, specifically growing within the central nervous system and I think that's the that's the message that we would like to convey at the moment.

Great. That's helpful. Thank you so much and then maybe just a quick one on 63 six with the profile that is still emerging.

Yes.

I think at this point everything everything is open obviously with the RASK multi inhibitor that is suppressing.

RMC 63, six they may be combinable with they may not be that you would worry more about that combination then you would about combining with something thats highly selective and has non overlapping mechanistic mechanistic effect and an example of that might be PD one.

So 63 six.

<unk> targeting Ras and PD, one not mechanistically targeting it you can imagine those Mike.

In principle be more combinable and pre clinically we have combined a lot of things and can see the impact in the preclinical models. So I just think it's hard to predict today.

Exactly what.

What will work out best but we do have some priorities and I've just given you some sort of guidance about how you might think about those priorities.

I really appreciate it thank you so much.

You bet.

Standby for our next caller.

Okay.

Alex Stranahan joins Us from Bank of America, Alex Your line is open go ahead.

Hey, guys.

John a mantra Alec.

So just a quick one on 90 898 to five.

Obviously, we saw some preclinical data at ACR.

In terms of getting into the clinic. Thank you.

Dose the first patient in our monotherapy dose escalation study.

What's the kind of like patient baseline characteristics, we can expect and what tumor types are you going to go.

Go for in the study if you could shed some light on that thanks.

Well right now.

Plan for RMC 98, five is two <unk>.

Identify a recommended phase two dose as expediently as possible and obviously convince ourselves that that's the right dose and persuade other constituencies.

We have the right dose so.

Apart from <unk>.

<unk> restriction for patients with tumors harboring <unk> mutation I don't think you're going to see a lot of difference from the RMC $63 six dose escalation frankly.

We know the.

The historic types in which KFC 12 D mutations predominate.

<unk>.

We have enough experience now with $63 six to get a handle on the types of patients that we're going to get in the phase. One study they are going to be predominantly patients with lung cancer pancreatic cancer and colorectal cancer.

And I think that pretty much all we can say right now that there is nothing unusual about the phase one plan for this compound.

Got it might be a real quick follow up.

It might be with that okay.

I don't know if slightly underlying it was a question about access to patients, which we sometimes get asked about.

55000.

55000, new use.

<unk> D cancers each year.

Given that even across multiple companies studies that might be underway at the same time you are talking about dozens.

Most hundreds of patients I don't think theres going to be any impact of that.

Their competition from from others to the extent that there is any.

Versus competition from around $63 six we will have plenty of access to patients with caris <unk> tumors.

Okay. Thank you and a quick follow up to that.

You mentioned that.

It's likely going to be.

One of the type of patients recruited so given the complexity of colorectal cancer in general other than screening for the presence of <unk> are you also going to be screening for the optimum of other mutations.

Well I think just to build on Steve.

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