Q4 2022 Revolution Medicines Inc Earnings Call

Speaker 2: The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1-1.

Speaker 2: The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1-1.

Operator: Good day, and thank you for standing by. Welcome to Revolution Medicine's Q4 and year-end 2020 earnings conference call. At this time, all participants are on the list in only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press Star 1-1 on your telephone. You will then hear an automated message advising that your hand has been read. To withdraw your question, please press Saur-1-1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Peghorn's Chief Operating Officer. Please go ahead.

Speaker 3: Good day and thank you for standing by. Welcome to the Revolution Medicine Q4 year-end 2022 earnings conference call. At this time, all 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 the session, you will need to press star 1-1 when you're T ?

Margaret A. Horn: Thank you and welcome everyone to the fourth quarter and full year 2022 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's chairman and chief executive officer, Dr. Steve Kelsey, the company's president of research and development, and Jack Anders, our chief financial officer.

Speaker 3: Please go ahead.

Speaker 4: Thank you and welcome everyone to the fourth quarter in full year 2022 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's president of research and development, and Jack Anders are Chief Financial Officer. Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's president of research and development, and Jack Anders.

Margaret A. Horn: As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

Speaker 4: 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.

Speaker 4: 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.

Margaret A. Horn: I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings release, press release, as well as all of the company's filings with the SEC concerning these and other matters. During this presentation, we will be referring to a number of slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I'll hand this call over to Dr. Mark Goldsmith, Revolution Medicine Chairman and Chief Executive Officer. Mark?

Speaker 4: I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release.

Speaker 4: as well as all of the company's filings with the FCC concerning these and other matters.

Speaker 4: During this presentation, we will be referring to a number of slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call.

Speaker 4: With that, I'll come call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark.

Mark A. Goldsmith: Good afternoon, and thank you for joining us.

Mark A. Goldsmith: Today I'll provide an update on our company progress. Steve Kelsey will provide additional information about our RMC 6236 clinical program, and Jack Anders will provide highlights of our financial results. Revolution Medicines is advancing our pipeline of groundbreaking RAS-on inhibitors and RAS companion inhibitors on behalf of patients with a wide range of RAS-addicted cancers, setting up an exciting and data-rich year. We have advanced the first two drug candidates from this highly innovative Rasson inhibitor portfolio into clinical development.

Speaker 5: Good afternoon and thank you for joining us. Today I'll provide an update on our company progress. Steve Kelsey will provide additional information about our RMC 6236 clinical program. And Jack Anders will provide highlights of our financial results.

Speaker 5: Revolution Medicines is advancing our pipeline of groundbreaking RAS-on inhibitors and RAS-companion inhibitors on behalf of patients with a wide range of RAS-addicted cancers setting up an exciting and data-rich year.

Speaker 5: We have advanced into clinical development the first two drug candidates from this highly innovative RAS-ON inhibitor portfolio.

Mark A. Goldsmith: RMC 6236 is a groundbreaking RAS inhibitor with the potential to treat all or nearly all RAS cancer patients due to its highly differentiated mechanism of action, facilitating broad activity across major RAS variants. RMC 6291 is the vanguard of our mutant selective RAS-on inhibitor portfolio, which also includes our oral and covalent K-RASG12D inhibitor, expected to enter the clinic mid-year, and a second wave of inhibitors designed to treat a range of RAS mutant cancers.

Speaker 5: RMC-6236 is a groundbreaking RAS inhibitor with the potential to treat all or nearly all RAS cancer patients due to its highly differentiated mechanism of action facilitating broad activity across major RAS variants. RMC-6291 is the Vanguard.

Speaker 5: of our mutant selective Ras-on inhibitor portfolio, which also includes our oral and covalent KRAS G12D inhibitor expected to enter the clinic mid-year, and a second wave of inhibitors designed to treat a range of Ras mutant cancers.

Mark A. Goldsmith: Together, the two phase one programs will provide key insights into the potential of each exciting drug candidate and initial information to validate our tri-complex RAS-on inhibitor platform as a whole. RMC 6236 and 6291 have been well behaved so far in the dose escalation portions of the RMC 6236-001 and RMC 6291 clinical studies, respectively. Both compounds have shown oral bioavailability, leading to increasing exposure levels with increasing dose, consistent with our preclinical projection. Additionally, they've both been generally well tolerated.

Speaker 5: Together, the two Phase I programs will provide key insights into the potential of each exciting drug candidate and initial information to validate our Tricomplex RAS-on inhibitor platform as a whole.

Speaker 5: RMC6236 and 6291 have been well behaved so far in the dose escalation portions of the RMC6236-001 and RMC6291-001 clinical studies respectively.

Speaker 5: Both compounds have exhibited oral bioavailability, leading to increasing exposure levels with increasing dose, consistent with our preclinical projections.

Mark A. Goldsmith: We've cleared several dose levels for each compound with a once daily dosing schedule, and we have not yet reached a maximal tolerated dose or defined a recommended phase two dose for either. Today we'll expand further on the findings related to RMC 6236 in particular. Meanwhile, Steve Kelsey will share with you additional information coming from the RMC 6236-001 trial. You'll hear about initial pharmacokinetic, molecular, and radiographic findings from the early stages of this study, supporting our belief that we are dosing this compound in a pharmacologically active range and observing anti-tumor activity consistent with clinical benefit with acceptable safety and tolerability.

Speaker 5: They've both been generally well tolerated.

Speaker 5: We've cleared several dose levels for each compound with a once daily dosing schedule, and we have not yet reached a maximal tolerated dose or defined a recommended phase two dose for either compound.

Speaker 5: Today, we will expand further on the findings related to RMC 6236 in particular.

Speaker 5: Momentarily, Steve Kelsey will share with you additional information coming from the RMC 6236-001 trial.

Speaker 5: You'll hear about initial pharmacokinetics, molecular and radiographic findings from the early stages of this study supporting our belief that we are dosing this compound in a pharmacologically active range and observing antitumor activity consistent with clinical benefit with acceptable safety and tolerability.

Mark A. Goldsmith: Although the data Steve will describe today are early, we believe these findings are quite encouraging for RMC6236 itself as a drug candidate. However, they are insufficient to define the full profile and potential of 6236, including response rates or long-term durability in any tumor type, which will require more data in time. Nevertheless, we feel these data are important as they significantly de-risk key aspects of our broad portfolio of multiple clinical and pre-clinical RAS-on inhibitors that all share a number of fundamental properties. Let me offer additional context by reminding you of some key elements regarding the compound RMC 6236.

Speaker 5: Although the data Steve will describe today are early, we believe these findings are quite encouraging for RMC 6236 itself as a drug candidate.

Speaker 5: They are insufficient to define the full profile and potential of 6236, including response rates for long-term durability in any tumor type, which will require more data and time.

Speaker 5: Nevertheless, we feel these data are important as they significantly de-risk key aspects of our broad portfolio of multiple clinical and pre-clinical RAS-on inhibitors that all share a number of fundamental properties.

Speaker 5: Let me offer additional context by reminding you of some key elements regarding the compound RMC6236.

Mark A. Goldsmith: Our description of 6236 as a RAS multi-on inhibitor has three components. It is designed to bind selectively to rass proteins. It binds to and inhibits all or nearly all forms of RAS, including every known oncogenic mutant and wild type form we've tested, and it binds RAS exclusively in the on or activated state, in contrast to first-generation K-RAS G-12C inhibitors that bind RAS in the off-state. 6236 shows high potency in cellular assays, inhibiting Ras signaling typically at low nanomolar to sub-nanamolar concentrations and frequently driving deep and sustained RAS pathway suppression in RAS-dependent tumor cells, and we've shown extensive preclinical evidence that 6236 induces deep and sustained regressions in diverse in vivo cancer models representing multiple tumor types and multiple RAS mutant genotypes, especially K-RAS G A RAS inhibitor profile that is, to our knowledge, unprecedented.

Speaker 5: Our description of 6-3-3-6 as a RAS multi-on inhibitor has three components.

Speaker 5: It is designed to bind selectively to RAS proteins. It binds to and inhibits all or nearly all forms of RAS, including every known oncogenic mutant and wild-type form we've tested. And it binds RAS exclusively in the on- or activated state, in contrast to first-generation KRAS G12C inhibitors that bind RAS in the off-state.

Speaker 5: 6236 shows high potency in cellular assays, inhibiting RAS signaling, typically at low nanomolar to sub-nanomolar concentrations, and frequently driving deep and sustained RAS pathway suppression in RAS-dependent tumor cells.

Speaker 5: And we've shown extensive preclinical evidence that 6236 induces deep and sustained regressions in diverse in vivo cancer models representing multiple tumor types and multiple Ras mutant genotypes, especially KRAS G12X mutants.

Mark A. Goldsmith: Overall, the design of RMC6 is a RAS multi-on inhibitor that not only chemically and pharmacologically breaks new ground in the field but also serves the bold, biological goal of leveraging its ability to inhibit all or nearly all forms of RAS, including both the primary mutant RAS driver and normal or wild-type RAS forms, to maximally suppress RAS signaling overall in cancer cells that are addicted to RAS. A fundamental question being evaluated in the RMC 6236-001 clinical trial is whether 6236, with this biological profile, can be dosed in patients at levels that deliver clinical antitumor impact without causing, also, unacceptable effects on normal tissues due to the compound's intentional activity against wild-type forms of rass that would also be anticipated in normal cells.

Speaker 5: A RAS inhibitor profile that is, to our knowledge, unprecedented.

Speaker 5: Overall, the design of RMT626 is a RAS multi-on inhibitor, not only chemically and pharmacologically breaks new ground in the field, but also serves the bold, biological goal of leveraging its ability to inhibit all or nearly all forms of RAS.

Speaker 5: including both the primary mutant grass driver and normal or wild type grass forms.

Speaker 5: to maximally suppress RAS signaling overall in cancer cells that are addicted to RAS. A fundamental question being evaluated in the RMC 6236-001 clinical trial is whether 6236 with this biological profile can be dosed in patients at levels that deliver clinical anti-tumor impact.

Speaker 5: without also causing unacceptable effects on normal tissues due to the compound's intentional activity against wild-type forms of RAS that would also be anticipated in normal cells.

Mark A. Goldsmith: The extensive preclinical evidence of dramatic antitumor activity and multiple animal models came from studies at dose levels that did not induce concomitant intolerability, and the RM6-236-001 clinical study is a first test of these aspirations for this drug candidate in patients. Steve Kelsey, our president of R&D, will present our first report of clinical experience with a RASO and inhibitor, RMC 6236.

Speaker 5: The extensive preclinical evidence of dramatic anti-tumor activity in multiple animal models came from studies at those levels that did not induce concomitant intolerability. And the RMC626001 clinical study is a first test of these aspirations for this drug candidate in patients.

Speaker 5: Steve Kelsey, our President of R&D, will present our first report of clinical experience with a RAS-ON inhibitor, RMC6236. Steve? Thank you, Steve.

Speaker 5: Thank you Mark. As we stated previously based on extensive pre-clinical studies of RMC6236.

Stephen M. Kelsey: Thank you, Mark. As we've stated previously, based on extensive pre-clinical studies of RMC 63-6, our working assumption is that the on-target effects of inhibiting wild-tack rats in normal tissues will ultimately determine the maximum tolerated dose in people. We have consistently represented that we believe rass-mediated toxicities will be predictable, manageable, manageable, monitorable, and reversible. We have also presented preclinical data suggesting that the slower clearance of RMC 6236 from tumors compared with normal tissues may enhance the therapeutic index for RMC 6236 and contribute to achieving meaningful antitumour activity at tolerated exposure.

Speaker 6: Our working assumption is that the on-target effects of inhibiting wild-fat rats in normal tissues will ultimately determine the maximum tolerated dose in people.

Speaker 6: We have consistently represented that we believe RAS mediated toxicities will be predictable, manageable, monitorable, and reversible. We have also presented pre-clinical data suggesting that the slower clearance of RMC636 from tumors compared with normal tissues.

Speaker 6: may enhance the therapeutic index for RMC6236 and contribute to achieving meaningful anti-tumor activity for tolerated exposures. Meaningful clinical activity includes both reduction in tumor size and durable inhibition of tumor growth, represented most frequently as progression-free survival in clinical trials.

Speaker 6: In the clinical program to date, patients have been treated in five dose cohorts ranging from 10 milligrams daily to 120 milligrams daily.

Stephen M. Kelsey: Meaningful clinical activity includes both reduction in tumor size and durable inhibition of tumor growth, represented most frequently as progression-free survival in clinical trials. In the clinical program to date, patients have been treated in five dose cohorts, ranging from 10 milligrams daily to 120 milligrams daily, to calibrate you based on measured drug exposures in these patients.

Speaker 6: to calibrate you based on measured drug exposures in these patients.

Speaker 6: The 10 and 20 milligram doses fall at the lowest end of exposures we evaluated pre-clinically and were associated with some degree of tumor growth in the vision and xenograft models.

Speaker 6: Drug exposures seen in patients treated at 40, 80 and 120 milligrams daily are similar to those associated with more significant anti-tumor effects in pre-clinical studies.

Stephen M. Kelsey: The 10 and 20 milligram doses fall at the lowest end of exposures we evaluated preclinically and were associated with some degree of tumor growth in the vision of Xenograph model. However, drug exposures seen in patients treated at 40, 80, and 120 milligrams daily are similar to those associated with more significant antitumor effects in preclinical studies. These included dose-dependent tumor regressions and delay in time to tumor growth in in vivo studies of several Rast Newton cancer models.

Speaker 6: These included dose-dependent tumor regressions and delay in time to tumor growth in in vivo studies of several Ras mutant cancer models.

Speaker 6: But with these doses in patients, we haven't yet reached exposure levels achieved at the dose we studied the most pre-clinically. The battery is 25 milligrams per kilogram daily.

Speaker 6: 36 patients have been evaluated for initial safety and tolerability in the clinical trial so far.

Speaker 6: as shown in the table of drug-related adverse events on slide 11.

Speaker 6: Treatment across all dose cohorts has been generally well tolerated.

Stephen M. Kelsey: But with these doses in patients, we haven't yet reached exposure levels achieved at the dose we studied most preclinically, that is, 25 milligrams per kilogram daily. 36 patients have been evaluated for initial safety and tolerability in the clinical trial so far, as shown in the table of drug-related adverse events on slide 11. Treatment across all dose cohorts has been generally well tolerated, although some patients have exhibited predicted on-target normal tissue effects, presumably due to inhibition of wild-type rats.

Speaker 6: Some patients have exhibited predicted on target normal tissue effects, presumably due to inhibition of wild type RAS.

Speaker 6: These are primarily grade one or two skin rashes.

Speaker 6: similar to those observed with EGFR inhibitors.

Speaker 6: and a range of mild to moderate severity gastrointestinal toxicities, usually nausea or diarrhoea. The frequency and severity seem to be dose dependent and thus far have been manageable with standard supportive care.

Speaker 6: One patient required a brief dose hole to skin rash and resume dosing at reduced dose.

Stephen M. Kelsey: These are primarily grade one or two skin rushes, similar to those observed with EGFR inhibitors, and a range of mild to moderate severity gastrointestinal toxicities, usually nausea or diarrhea. The frequency and severity seem to be dose-dependent, and thus far, have been manageable with standard supportive care. One patient required a brief dose hold for skin rash and resumed dosing at a reduced dose. Skin RAS and gastrointestinal toxicity are recognized consequences of suppressing rash signaling in normal tissues, based on a wide experience in the field with other drugs and drug candidates, including EGFR, MEC, and SHIF2 inhibitors. Skin rash has historically been viewed as a biomarker of pharmacologic activity for some of these drugs.

Speaker 6: Skin ras and gastrointestinal toxicity are recognized consequences of suppressing ras signaling in normal tissues based on a wide experience in the field with other drugs and drug candidates including EGFR, MEK, ERK and SHP2 inhibitors.

Speaker 6: Skin rash has been historically viewed as a biomarker of pharmacological activity by some of these drugs. Therefore, the clinical findings further support our belief based on PK data that we are achieving exposures of RMC6236 in patients that are in an active range without inducing unacceptable toxicity.

Speaker 6: Among all 36 patients evaluated so far, one related serious adverse event has been observed.

Speaker 6: This patient with metastatic pancreatic cancer and a KRAS G12B mutation.

Speaker 6: Enter the study with extensive abdominal disease, including a large and deeply invasive tuna implant in the cirrhosa wall of the large intestine.

Stephen M. Kelsey: Therefore, the clinical findings further support our belief based on PK data that we are achieving exposures of RMC-636 in patients that are in an active range without inducing unacceptable toxicity. Among all 36 patients evaluated so far, one related, serious adverse event has been observed; this patient with metastatic pancreatic cancer and a Keras G12B mutation entered the study with extensive abdominal disease, including a large and deeply invasive tumor implant in the serosal wall of the large intestine.

Speaker 6: About one week into treatment at 80 milligrams daily, the patient experienced an unfortunate bowel perforation that occurred at the invasive tumor site, accompanied by radiographic evidence of tumor reduction at that location and other metastatic sites.

Speaker 6: No evidence or clinical symptoms of colitis or colomic ulceration were seen preceding the event or observed on subsequent imaging.

Speaker 6: based on abdominal CT scans.

Speaker 6: and the opinions of the clinical investigators, we believe that this event is likely attributable to shrinkage of the tumor by RMC6236 in the heavily infiltrated bowel wall, even within this short treatment period.

Stephen M. Kelsey: About one week into treatment at 80 milligrams daily, the patient experienced an unfortunate bowel perforation that occurred at the invasive tumor site, accompanied by radiographic evidence of tumor reduction at that location and other metastatic sites. No evidence or clinical symptoms of colitis or cholomic ulceration were seen preceding the event or observed on subsequent images; based on an abdominal CT scan, and the opinions of the clinical investigators, we believe that this event is likely attributable to shrinkage of the tumor by RMC 6236 in the heavily infiltrated bowel wall, even within this short treatment period, rather than to a direct toxic effect of RMC-6-2336 on Similar events attributed to tumor shrinkage in the bowel wall have occasionally been described on treatment with DRAP inhibitors and with chemotherapy.

Speaker 6: rather than to a direct toxic effect of RMC6236 on the normal barrel wall.

Speaker 6: Similar events attributed to tumor shrinkage in the bowel wall have been occasionally described on treatment with BRAF inhibitors and with chemotherapy.

Speaker 6: We have treated patients with RMC6236 in a higher dose cohort, 120 milligrams, without observing additional serious adverse events so far and expect to continue dose escalating even further towards a recommended phase 2 dose.

Speaker 6: Let me provide some information on the anti-tumor activity we have seen in the study.

Speaker 6: Consistent with study eligibility criteria, patients with a range of tumor types in which K-RAS G12X mutations are common have been enrolled, including major epithelial cancers such as non-small cell lung cancer, pancreatic, colorectal.

Speaker 6: and other tumours including ovarian cancer, appendiceal and bile duct cancers. The KRAS mutations in those tumours cover the range of KRAS G12 mutations, G12D, VASR, with D being the most heavily represented so far. This is consistent with the epidemiology of RAS mutations in human cancer.

Stephen M. Kelsey: We have treated patients with RMC 6236 in a higher dose cohort, 120 milligrams, without observing additional serious adverse events so far, and we expect to continue dose escalating even further towards a recommended phase two dose. Let me provide some information on the anti-tumor activity we have seen in the study. Consistent with study eligibility criteria, patients with a range of tumor types in which Keras G12x mutations are common have been enrolled, including major epithelial cancers such as non-small cell lung cancer, pancreatic, colorectal, and other tumors, including ovarian cancer, appendicele, and bile duct cancer.

Speaker 6: and 20 milligram dose levels, radiographic imaging showed either stable disease with some tumour reduction or disease progression as the best responses.

Speaker 6: Interestingly, in several patients at these lower dose levels, we have measured significant reductions in tumor variant alleles in CTDNA. For instance, in one patient with a KRAS G12V non-solar cell lung cancer, treatment at 20 milligrams daily was associated with initial stable disease.

Stephen M. Kelsey: The K-RAS mutations in those tumors cover the range of K-RASG-G-12 mutations, G-12 D, V, A, S, and R, with D being the most heavily represented so far. This is consistent with the epidemiology of RAS mutations in humans.

Speaker 6: and 100% clearance of all RAS mutant alleles and all other concurrent tumor variant alleles. These earliest signs were consistent with our expectations at these low dose levels and were encouraging.

Stephen M. Kelsey: Patients enrolled in this study had been previously treated with a standard of care and or other regimens, with an overall median of three prior therapies, as is typical for an oncology dose escalation phase one study. At the 10 milligram and 20 milligram dose levels, radiographic imaging showed either stable disease with some tumor reduction or disease progression as the best response. Interestingly, in several patients at these lower dose levels, we have measured significant reductions in tumor variant alleles in CTDNA.

Speaker 6: We'd like to show you more detail regarding early and preliminary treatment related activity at the 40, 80 and 120 milligram dose levels.

Speaker 6: We're focusing on non-small cell lung cancer and pancreatic cancer, since those are the two histologies most likely to be sensitive to a RAS inhibitor monotherapy based on the G12c experience. We will report on other tumour types including colorectal cancer in future updates.

Speaker 6: The waterfall plot of tumor volumes on slide 12 shows our experience so far with the nine pancreatic cancer patients and three non-solar cell lung cancer patients that have been treated at 40 milligrams daily or higher and are efficacy available. All 12 of these patients have exhibited stable disease or better.

Stephen M. Kelsey: For instance, in one patient with KRAS G12V non-sul cell lung cancer, treatment at 20 milligrams daily was associated with initial stable disease and 100% clearance of all RAS mutant allials and all other concurrent tumor variants. These early signs were consistent with our expectations at these low-dose levels and were encouraging.

Stephen M. Kelsey: We'd like to show you more detail regarding early and preliminary treatment-related activity at the 40, 80, and 120 milligram best levels. We're focusing on non-small lung cancer and pancreatic cancer, since those are the two histologies most likely to be sensitive to a RAS inhibitor monotherapy based on the G12C experience, we will report on other tumotites, including colorectal cancer in future, The waterfall plot of tumor volumes on slide 12 shows our experience so far with the nine pancreatic cancer patients and three non-sol cell lung cancer patients that have been treated at 40 milligrams daily or higher and our efficacy are valuable.

Speaker 6: to partial response on first restaging scan and was subsequently confirmed with a follow-up scan.

Speaker 6: One pancreatic cancer patient with a KRAS G12 demutation also achieved a thus far unconfirmed partial response, a case study I will describe more fully in a moment. Even at this early stage with short follow-up,

Speaker 6: small patient numbers and doses below the anticipated recommended phase 2 dose. We believe that these data compare favorably with chemotherapy regimens for advanced pancreatic cancer where disease control rates rarely exceed 60% and the response rates are low.

Speaker 6: The durability of disease control is of high importance for conferring clinical benefits and ultimately regulatory approval, particularly in advanced pancreatic cancer.

Stephen M. Kelsey: All 12 of these patients have exhibited stable disease or better as their best response and remain on study from approximately 1 and a half to 4.5 months, as of the data cutoff date. 10 of 12 patients have shown some degree of tumor volume reduction by race. One patient with Keras G12D non-small cell lung cancer achieved a partial response on the first re-staging scan and was subsequently confirmed with a follow-up scan. One pancreatic cancer patient with a KRAS G12 demutation has also achieved a thus far unconfirmed partial response, a case study I will describe more fully in a moment.

Speaker 6: follow-up continues on all of these patients as we've noted. In some cases, children has continued to reduce in size beyond the first response of all the ocean.

Speaker 6: Let me now describe for you a particular case that is still ongoing and requires further data collection while the patient's treatment continues, but even at this stage provides a view into the therapeutic potential of RMC6236.

Speaker 6: As described on slide 13, this patient is a 76-year-old male with metastatic pancreatic cancer harboring the KRAS G12D allele and associated gene copy number loss in tumor suppressor genes for CDKN2A and N2B, as well as the associated putative tumor suppressor cortexes.

Stephen M. Kelsey: Even at this early stage with short follow-up, small patient numbers, and doses below the anticipated recommended phase two dose, we believe that these data compare favorably with chemotherapy regimens for advanced pancreatic cancer, where disease control rates rarely exceed 60% and the response rates are low. The durability of disease control is of high importance for conferring clinical benefits and ultimately regulatory approval, particularly in advanced pancreatic cancer. Follow-up continues on all of these patients, as we've noted.

Speaker 6: After both neo-adjuvant and post-surgical adjuvant chemotherapy, he developed metastatic disease in the lungs and progressed following the third course of chemotherapy.

Speaker 6: He received RMC6236 at 80 milligrams daily, which, as noted earlier, we project to be in the mid-range for anti-tumor activity and is below the anticipated recommended phase to those.

Speaker 6: The patient is tolerating the drug well.

Speaker 6: At baseline, the patient had three distinct lesions, one in the right lung and two in the left lung, that are being followed radiographically. These lesions are identified on the upper row of the three CT images on slide 14.

Stephen M. Kelsey: In some cases, tumours continue to reduce in size beyond the first response about it. Let me now describe for you a particular case that is still ongoing and requires further data collection while the patient's treatment continues. But even at this stage provides a view into the therapeutic potential of RMC 6236. As described on slide 13, this patient is a 76-year-old male with metastatic pancreatic cancer harboring the KRAS G12D allele and associated gene copy number loss in tumor suppressor genes to CDK N2A and N2B, as well as the associated putative tumor suppressure N2B, After both neoadjuvant and post-surgical adjuvant chemotherapy, he developed metastatic disease in the lungs and progressed following the third course of chemotherapy.

Speaker 6: All three lesions underwent significant reduction over 12 weeks of therapy. At six weeks, all three tumor lesions were reduced in size, with an overall 17% reduction in tumor size by assets.

Speaker 6: On the 12-week scans shown in the second row of CT scans, target lesion 1 has disappeared and target lesion 2 is considerably reduced.

Speaker 6: The single non-target lesion is barely detectable. In addition, the density of the residual tumor has changed.

Speaker 6: RESCIST quantifies response by measuring only the unidimensional longest axis for each target lesion and does not consider density or three-dimensional volume. As the first target lesion has been assigned a minimum measurement of 5 mm, this patient has formally achieved a 70% tumor reduction.

Stephen M. Kelsey: He received RM6-236 at 80 milligrams daily, which, as noted earlier, we project to be in the mid-range for anti-tumour activity and is below the anticipated recommended pasteur dose. The patient is tolerating the drug well. At baseline, the patient had three distinct lesions, one in the right lung and two in the left lung that are being followed radiographically. These lesions are identified in the upper row of the three CT images on slide 14.

Speaker 6: and a clear partial response by resist, even though volumetrically, the reduction in tumor burden appears greater. He continues on study, and the partial response needs to be confirmed with a follow-up scan. We must emphasize that it is too early to project the frequency or durability of responses.

Speaker 6: or comparative results across genotypes and genotypes.

Speaker 6: The numbers are small, the dose levels are likely to be below the recommended phase 2 dose and follow-up is short.

Speaker 6: Nevertheless, the totality of data across these 12 patients...

Speaker 6: reinforces our growing conviction about the potential for RMC6236 to exhibit promising clinical anti-tumor activity in patients with advanced RAS mutant tumors at doses that are well tolerated. And now I will turn the call back to Mark. Thank you, Steve.

Stephen M. Kelsey: All three lesions underwent significant reduction over 12 weeks of therapy. At six weeks, all three tumor lesions were reduced in size, with an overall 17% reduction in tumor size by RASI. On the 12-week scans, shown in the second row of CT scans, Target Lesion 1 has disappeared, and Target Lesion 2 is considerably reduced. The single non-target lesion is barely detected.

Speaker 5: The collection of data just presented is, to our knowledge, the first-ever clinical data to be presented on any inhibitor designed to target the on state of RAS.

Stephen M. Kelsey: In addition, the density of the residual tumor has changed. Refs quantifies response by measuring only the unidimensional longest axis for each target lesion and does not consider density or three-dimensional volume, as the first target lesion has been assigned the minimum measurements of 5mm. This patient has formally achieved a 70% tumor reduction and a clear partial response by resist, even though volumetrically, the reduction in tumor burden appears greater. He continues to study, and the partial response needs to be confirmed with a follow-up scan. However, we must emphasize that it is too early to project the frequency or durability of responses or comparative results across tunotypes and genotypes.

Speaker 5: Any RAS targeted therapy used to treat a patient with a tumor bearing the KRAS G12D mutation

Speaker 5: or any oral RAS-ON inhibitor used to treat a patient with lung or pancreatic cancer bearing KRAS G12D or various other non-G12C mutations.

Speaker 5: While initial data from the patients described today are quite encouraging overall in terms of tolerability and anti-tumor activity in multiple tumor types with multiple RAS genotypes, and the case report shows a dramatic effect in KRAS G12D pancreatic cancer at a tolerated dose, we will need additional data to project response rates.

Mark A. Goldsmith: The numbers are small, the dose levels are likely to be below the recommended phase two dose, and follow-up is short. Nevertheless, the totality of data across these 12 patients reinforces our growing conviction about the potential for RMC-636 to exhibit promising clinical anti-tumour activity in patients with advanced rast mutant tumors at doses that are well tolerated.

Speaker 5: or durability in pancreatic lung or other cancers and across different grass mutations at the recommended phase two dose of schedule.

Speaker 5: We show these early data today to illustrate what may be possible with a RAS-ON inhibitor, as represented by the boldest compound in our collection, with arguably the greatest a priori therapeutic index risk profile.

Speaker 5: and we will continue to develop more clinical information. These findings are quite encouraging about the ability of a rationally designed tricomplex Rasson inhibitor to be taken orally, for it to exhibit drug-like pharmacokinetics, and for the tricomplex mechanism of action to drive inhibition of Rasson proteins and confer promising anti-tumor benefit in patients.

Mark A. Goldsmith: The collection of data just presented is, to our knowledge, the first ever clinical data to be presented on any inhibitor designed to target the on state of RAS, any RAS targeted therapy used to treat a patient with a tumor bearing the K-RAS G12D mutation, or any oral rasson inhibitor used to treat a patient with lung or pancreatic cancer bearing K-Ras G12D or various other non-G12C mutations While initial data from the patients described today are quite encouraging overall in terms of tolerability and anti-tumor activity in multiple tumor types with multiple RAS genotypes, and the case report shows a dramatic effect in K-RASG-12D pancreatic cancer at a tolerated dose, we will need additional data to project response rates or durability in pancreatic lung or other cancers and across different RAS mutations at the recommended phase two dose of schedule.

Speaker 5: without being accompanied by extraordinary toxicities. We confirm our intention to provide a more detailed public update on 6-2-3-6-mid-year, including further follow-up from patients described today, and information we expect to collect from additional patients in the dose escalation phase of the study.

Speaker 5: Let's briefly touch on RMC6291, our mutant selective KRAS G12C on-intimitor, for which we also have some early experience that allows us to build on the earlier comments about general drug-like behavior and tolerability.

Mark A. Goldsmith: We show these early data today to illustrate what may be possible with a RAS-on inhibitor, as represented by the boldest compound in our collection with arguably the greatest a priori therapeutic index risk profile, and we will continue to develop more clinical information. These findings are quite encouraging about the ability of a rationally designed, tricomplex rasson inhibitor to be taken orally, for it to exhibit drug-like pharmacokinetics, and for the tri-complex mechanism of action to drive inhibition of rasson proteins and confer promising antitumor benefits in patients without being accompanied by extraordinary toxicities.

Speaker 5: Based on initial PK, molecular data, that is CT DNA, and radiographic imaging data, that is serial CT scans, we believe that we are also dosing this compound in a pharmacologically active range and, so far, with acceptable safety tolerability. We plan to provide a more substantive update in the second half of this year.

Mark A. Goldsmith: We confirm our intention to provide a more detailed public update on 6236 mid-year, including further follow-up from patients described today and information we expect to collect from additional patients in the dose escalation phase of the study. Let's briefly touch on RMC 6291, our mutant selective KRAS G12C on inhibitor, for which we also have some early experience that allows us to build on the earlier comments about general drug-like behavior and toler Based on initial PK, molecular data, that is, CT DNA, and radiographic imaging data, that is, serial CT scans, we believe that we are also dosing this compound in a pharmacologically active range and so far with acceptable safety tolerability. We plan to provide a more substantive update in the second half of this year.

Speaker 5: or our RAS on inhibitors more broadly.

Speaker 5: Of course, much more information is needed for more definitive conclusions to be drawn about each individual drug candidate, which we expect will be forthcoming over time, but we believe the information we've shared, intended to represent our experience with two RAS-on inhibitors so far.

Speaker 5: increases the probability of success for these two assets and may well read through to other assets we are developing. Next up in our RAS-ON inhibitor collection is our mutant-selective inhibitor of KRAS-G12D, the most common RAS variant causing human cancer, RMC9805.

Speaker 5: This compound that we introduced last year is administered orally, engages the on form of KRAS G12D, and executes a covalent attachment selectively to the oncogenic aspartic acid. IND enabling work remains on track toward our goal.

Mark A. Goldsmith: Based on the aggregate early evidence from the 6236 program, as updated here, and initial experience with 6291, I will summarized briefly. We believe these findings serve as growing validation of the distinctive chemistry, pharmacology, and biology, and therapeutic vision for our RAS-on inhibitors more broadly. Of course, much more information is needed for more definitive conclusions to be drawn about each individual drug candidate, which we expect will be forthcoming over time, but we believe the information we've shared, intended to represent our experience with two RAS-on inhibitors so far, increases the probability of success for these two assets and may well read through to other assets we are developing.

Speaker 5: of beginning clinical evaluation of this exciting compound in mid-2023. Last month we also introduced a new RAS-on inhibitor drug candidate.

Speaker 5: RMCO708 is an oral mutant selective non-covalent inhibitor of K-RASQ-61H.

Speaker 5: It has now entered development to prepare it for clinical evaluation after the first wave of RAS on-inhibitor drug candidates, that is 6236, 6291, and 9805. It represents the fifth drug candidate we've disclosed in our portfolio of RAS on-inhibitors. We have now described both RAS multi- and non-inhibitors.

Speaker 5: and mutant selective drug candidates directed to each of the three common mutation hotspots and RAS proteins. Finally, let me provide brief updates on two clinical stage RAS companion inhibitors in our portfolio. RMC 4630, our shift to inhibitor.

Mark A. Goldsmith: Next up in our RAS-on inhibitor collection is our mutant selective inhibitor of K-RAS G12D, the most common RAS variant causing human cancer, RMC 9805. This compound that we introduced last year is administered orally, engages the on form of KRAF G12D, and executes a covalent attachment selectively to the oncogenic aspartic acid.

Speaker 5: continues under study in patients with KRAS G12C, non-small cell lung cancer, in combination with sotiracib, in our global phase two trial, RMC4630-03. The study is fully enrolled now, and we continue to expect to read out top line results in the second half of 23.

Mark A. Goldsmith: I&D enabling work remains on track toward our goal of beginning clinical evaluation of this exciting compound in mid-20203. Last month, we also introduced a new RAS-on inhibitor drug candidate. RMC 0708 is an oral, mutant-selective, non-covalent inhibitor of KRAQ61H.

Speaker 5: And RMC5552, our MTORC-1 selective inhibitor, continues under study as model therapy in patients with tumors, carrying mutations associated with hyperactivation of MTORC-1 signaling.

Mark A. Goldsmith: It has now entered development to prepare it for clinical evaluation after the first wave of RAS-on inhibitor drug candidates, that is, 6236, 6291, and 9805. It represents the fifth drug candidate we've disclosed in our portfolio of RAS-on inhibitors. We have now described both RAS multi and mutant-selected drug candidates directed to each of the three common mutation hotspots in RAS proteins. Finally, let me provide brief updates on two clinical stage RAS companion inhibitors in our portfolio.

Speaker 5: We expect to provide a more detailed update from this study later this year, and our aim is to bring it together with one or more RAS-ON inhibitors to test as combination treatment in patients with tumors harboring both RAS mutations and mTORC1 pathway activation.

Speaker 5: Now, I'll shift to our corporate progress and comment on our priorities for 2023.

Speaker 5: With a strong balance sheet, we entered this year with an explicit focus on the timely execution of the multiple development stage activities currently underway with our highest priority being to deliver on important clinical milestones in the year. We continue deploying our development resources primarily.

Mark A. Goldsmith: RMC 4630, our SHIP2 inhibitor, continues to be studied in patients with KRAS G12C non-small cell lung cancer in combination with soda acid in our global phase two trial, RMC 4630-O3. The study is fully enrolled now, and we continue to expect to read out top-line results in the second half of 23. And RMC 5552, our mtork 1 selective inhibitor, continues to be studied as monotherapy in patients with tumors carrying mutations associated with hyperactivation of the mtork 1 signal.

Speaker 5: to ensure we meet the goals of our first three most advanced RAS-ON inhibitors, RMC6236, 6291, and 9805, and two clinical-stage RAS companion inhibitors, RMC4630 and 5552.

Speaker 5: While interim in nature, we at ResMed view the information shared today as quite important and impactful on our own assessments of technical probabilities of success.

Speaker 5: With greater confidence that our innovation engine is delivering assets that deserve to be progressed and can earn the right to be deployed on behalf of patients.

Speaker 5: Part of management's bandwidth is now directed toward defining the paths and steps we need to take now and over the next several years to ensure that we can maximize the value of these exciting product candidates and others in our growing portfolio.

Mark A. Goldsmith: We expect to provide a more detailed update from this study later this year, and our aim is to bring it together with one or more RAS-on inhibitors to test as combination treatment in patients with tumors harboring both RAS mutations and M-TorK-1 pathway activation. Now, I'll shift to our corporate progress and comment on our priorities for 2023. With a strong balance sheet, we entered this year with an excellent explicit focus on the timely execution of the multiple development stage activities currently underway, with our highest priority being to deliver on important clinical milestones during the year.

Speaker 5: Building on this momentum, I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack.

Speaker 5: this momentum I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack? Thank you, Mark.

As shown on slide 34, we ended the year with $645 million in cash and investments.

which is expected to fund planned operations through 2024 based on our current operating plan. Revenue from our collaboration agreement on shift to inhibitors with Sanofi was $15.3 million in the fourth quarter of 2022 compared to $9.5 million in the fourth quarter of 2021.

The increase in revenue was due to a $7.6 million non-cash adjustment related to the acceleration of revenue, resulting from the termination of the Sanofi agreement, which has an effective date in June 2023.

As a result of the termination of the agreement, we adjusted our estimates of the accounting transaction price and estimated percentage of completion of work performed to date, which resulted in a cumulative catch-up adjustment that increased collaboration revenue in the quarter.

Mark A. Goldsmith: We continue deploying our development resources primarily to ensure we meet the goals of our first three most advanced RAS-on inhibitors, RMC 6236, 6291, and 9805, and two clinical stage RAS companion inhibitors, RMC-4630 and 555-2. While interim in nature, we at ResMed view the information shared today as quite important and impactful on our own assessments of the technical probabilities of success, with greater confidence that our innovation engine is delivering assets that deserve to be progressed and can earn the right to be deployed on behalf of patients. Part of management's bandwidth is now directed toward defining the paths and steps we need to take now and over the next several years to ensure that we can maximize the value of these Building on this momentum, I'll now turn to Jack Anders, our chief financial officer, to provide a financial update. Jack?

Collaboration Revenue for full year 2022 with 35.4 million.

Total operating expenses for the fourth quarter of 2022 increased to $77 million, largely driven by R&D expenses, which totaled $66.1 million.

Total operating expenses for full year 2022 increased to $293.7 million with R&D expenses increasing to $253.1 million.

The increase in total operating expenses in 2022 was primarily due to the advancement of RMC6236 and RMC6291 into clinical trials.

in stock-based compensation.

Net loss for the fourth quarter of 2022 was $56.5 million or $0.63 per share.

For full year 2022, net loss was $248.7 million or $3.08 per share.

We have to turn into financial guidance for 2023. We expect full-year gap net loss to be between $335 and $365 at million, which includes estimated non-cash stock-based compensation expense of 40.

to $50 million. The increase in expected gap net loss for 2023 is a result of increased expenses associated with the advancement of our RAS On portfolio and a decrease in expected collaboration revenue.

And with that, I'll now turn the call back over to Mark. Thank you, Jack. We are highly encouraged with the progress of our rich development pipeline, particularly by the body of clinical evidence developed so far that provides initial validation of our RASO on a Twitter platform and is subscribed here.

Jack Anders: Thank you, Mark. As shown on slide 34, we ended the year with $645 million in cash investment, which is expected to fund planned operations through 2024 on our current revenue from our collaboration agreement on ship to inhibitors with Sinovian. 13.3, fourth quarter of 2022 compared to 9.5, fourth quarter of 2021. The increase in revenue was due to a 7.6 million non-cash adjustment related to the acceleration of revenue resulting from the termination of the Sanofi Agreement, which has an effective date of June 2020.

Promising early evidence that RMC 6236 can be dose in patients to induce significant anti-tumor activity without unacceptable side effects.

We look forward to sharing further information on our collection of exciting clinical and preclinical assets throughout the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors and shareholders, and of course the tireless efforts of ResMed employees in pursuit of our mission to outsmart RAS-addicted cancer. This concludes our prepared remarks for today.

And I'll now turn the call over to the operator for the question and answer session. As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced.

Jack Anders: As a result of the termination of the agreement, we adjusted our estimates of the accounting transaction price and estimated percentage of completion of work performed, resulting in a cumulative catch-up adjustment that increased collaboration revenue in the quarter Collaboration revenue for full year 2022 increased by 35.4. Total operating revenue for the fourth quarter of 2022 increased to $77, largely driven by R&D expenses, which totaled 66.1. Total Operating Expenses for full year 2022

To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

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

Hi, guys. This is Hasselkoshid on for Jonathan. Wanted to ask, so you reported on those 12 patients who were treated at 40 mgs and above with lung cancer and pancreatic cancer. What's the denominator on that number, like how many patients were treated there, as in like how many were excluded for being non-valuable or how many were excluded for having another tumor type?

Jack Anders: R&D. 153, the increase in total operating expenses was primarily due to the advancement of RMC 6236 and R&C 6291, as well as an increase in personnel-related expenses related to additional research expenses associated with the company research portfolio and an increase, Doc Pace, net loss for the fourth quarter of 2020. 56.5 million. 63 cents. For full year 2022, the net loss was $248.7 million, or $3 to financial guidance. We expect full-year gap net losses to be between 335 and 365. Blue's estimated non-cash stock-based compensation expense of 40 to 50 increased an expected gap net loss with the advancement of our Rath-on portfolio and a decrease in expected collaboration revenue.

I see if you want to comment on it. Sure. Okay.

We didn't report on the patient's treatment at 10 and 20, basically because there's really, there's no evidence from the pre-tropical models that we're gonna be anywhere near the exposure's required to.

to see anything worth reporting, to be honest with you. The actual data is restricted largely to reductions in CT DNA. And we haven't reported on colorectal cancer patients at all because it's completely different disease. And there is no precedent right now for a rat in a or a rat in the

Mark A. Goldsmith: And with that, I'll call back over. Thank you, Jack. We are highly encouraged by the progress of our rich development pipeline, particularly by the body of clinical evidence developed so far that provides initial validation of our RASO on inhibitor platform and is described here, promising early evidence that RMC 6236 can be dosed in patients to induce significant anti-tumor activity without unacceptable side effects. We look forward to sharing further information on our collection of exciting clinical and preclinical assets during the year.

you to putting together a more comprehensive strategy for the treatment of patients with rasputin colorectal cancer and RMC636. So essentially the data that we're showing you right now is the data that we're showing you and all of the rest of the data will be in the most vulnerable aspect in the middle of the year.

Hey, guys. Thanks for taking my questions. So, it sounds like the pre-chemical data has been pre-predictive as it relates to dosing ranges and, you know, some of the dose response, et cetera. Based on that, I guess, Mark, what is your prediction of the entity?

Mark A. Goldsmith: We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders, and, of course, the tireless efforts of RedMed employees in pursuit of our mission to outsmart rass-addicted cancer. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the question and answer session.

Operator: As a reminder, to ask a question, please press Star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press Star 1-1 again. Please stand by while we compile the Q&A roster. Our first question comes from Jonathan Chang with SBB Securities. Your line is now open.

of the experiment right now.

So, you know, we're clearly below what's likely to be a recommended phase two dose, but I think

Unknown Executive: Hi guys, this is Hesukashidon for Jonathan. I wanted to ask you to report on those 12 patients who were treated at 40 migs and above with lung cancer and pancreatic.

My sense is from all the discussions we've had internally that it's the sort of thing that you'll know when you see it. I don't know if Steve wants to add any more color to it, but I would just want to confirm. I think that the preclinical data have been very predictive of what we've seen in humans. We tried to convey that sort of in a soft way back in January , but now we're providing.

Unknown Executive: cancer, What's the denominator on that number, like how many patients were treated there, as in, how many were excluded for being non-invaluable or how many were excluded for having another tumor?

concrete data to support that statement. In order? No, I mean other other than that as you can see from the adverse vent table that we've included the Holar velocity profile right now, even though our 120 milligrams table is pretty benign.

Unknown Executive: were excluded for being non-imvaluble, or how many were excluded for having another Kim or

Unknown Executive: We didn't report on the patients treated at 10, 20, basically because there was really no evidence from the preclinical models that we were going to be anywhere near the exposure required to see anything worth reporting, to be honest with your feet. The actual data is restricted largely to reductions in CTDNA, and we haven't reported on the co-orectin cancer patients at all because it's a completely different disease, and there is no precedent right now for a rat inhibitor being effective as a single agent in Bratheaton and Coal Reckin cancer.

I think Mark is correct in that at some point we are going to be hitting wild type ratinol tissue to the point which will make the compound or the dose intolerable but it's really hard to predict how high

how high we can go there. If, you know, just to be clear, I mean, the... we dose nice.

at 25 milligrams per kilogram daily, routinely. And that's because if we increased to 40 milligrams per kilogram daily, we saw some intolerability.

Unknown Executive: So it is quite likely that we will compile information on the choleraic cancer patients as it reaches a critical mass with a view to putting together a more comprehensive strategy for the treatment of patients with Rasput and Colorado Episansans, R&C-6036. So essentially, the data that we're showing you right now is the data that we're showing you, and all of the rest of the data will be in a more formal update in the middle of the year.

Right now, we're doing something way below the mirror in equivalent of 25 mix.

So we think that's a reasonable amount of headroom. That's a go, but it's very difficult to say exactly how much.

Yeah, but it sounds like you have some additional upside on the dosing. And then I guess when you think about, you know, read through of this data to your mutant selective TRS inhibitors, where I guess one would expect less.

Operator: Please stand by for our next question. Our next question comes from Michael Schmidt with Gudenheim Partners. Your line is now open.

Unknown Executive: Hey guys, thanks for taking my questions.

Unknown Executive: So it sounds like the pre-conical data has been pre-predictive as it relates to dosing ranges and, you know, some of the dose response, etc. Based on that, I guess, Mark, what is your prediction, what the MTC might be in this study and how much more room to increase dose do you think you'll have in the phase one study here? Yeah, hi, Michael, thanks for the question.

on target toxicities. You know, how should we think about that, you know, in terms of the dosing ranges? And I guess, you know, how much wider would one expect the therapeutic index to be as it relates to that? Yeah, well, we thought it.

Unknown Executive: You know, I think we just don't know how steep the curve will be in humans. I think that's the point of the experiment right now. So, you know, we're clearly below what's likely to be a recommended phase two dose, but I think, from all the discussions we've had internally, that it's the sort of thing that you'll know when you see it. I don't know if Steve wants to add any more color to it, but I would just want to confirm.

meaning ultimately the issue isn't therapeutic indexes. How high can you dose and what's the absolute impact at that dose level?

Unknown Executive: I think that the preclinical data have been very predictive of what we've seen in humans. And we tried to convey that sort of in a soft way, you know, back in January, but now we're providing concrete data to support that statement. No, I mean, other than that, as you can see from the adverse vent table that we've included, the polarity profile right now, even at 120 milligrams sale, is pretty benign.

But it will all converge around 1.0 as you have talked about before because that's the point of MPD.

But I think just to go back to the big picture, we're obviously quite encouraged by a significant level of anti-tumor activity that we've seen at, as Steve described, a very well tolerated dose range. starff Meinl and what's happened in the last five years.

And over this below the 25-minute perturbation that we use that are standard dosing advice.

Unknown Executive: I think Mark is correct in that at some point, we are going to be hitting, while type rat in all the tishins, a point which will make the compound or the dose intolerable, but it's really hard to predict how high we can go there. You know, just to be clear, I mean, the We dose nicely at 25 milligrams per kilogram daily. And that's because if we increased to 14 milligrams per gram daily, we saw some intolerability.

It's not below dose levels that we know should have anti-tumor activity, so it's actually quite consistent with our collection of pre-clinical data. So we're quite encouraged about it, but I think the least selective inhibitors one would expect to have much more flexibility around dosing.

Unknown Executive: Right now, you know, we're dosing way below the equivalent of the varying equivalent of 25 minutes a kilogram daily, so we think that's a reasonable amount of hebrun left to go, but it's very difficult to say exactly how much.

Unknown Executive: Yeah, but so it sounds like you have some additional upside on the dosing. And then, I guess, when we think about, you know, reading through this data to your mutant selective KERS inhibitors, where, I guess, one would expect less on target toxicities, you know, how should you think about that, you know, in terms of the dosing ranges and, I guess, you know, how much wider would one expect the therapeutic index to be as it relates to that?

our calculation around that risk profile.

Yeah, great. And then could you, when looking at the waterfall chart on slide 12, could you just comment on the response kinetics? Did they all, did, did you see these responses early at the first scan? Did they happen later? Did they deepen all the time?

you think about that. Yeah, well, the information there is a role across the bottom that it says mostly scan, and that was designed to give you the information of what the bar represents. And you'll see that it varies from the Mark cycle three day one, which would be the first.

Unknown Executive: How much wider would one expect the therapeutic index to be as it relates to that? Yeah, well, we fully expect the therapeutic index to be wider with the Mute Selective Indimitator by definition. If it's not wider, if they're having wild-type grass effects, then they're not being selective.

post treatment scan and others are at cycle 5 day 1. I think the case that Steve described is pretty informative there where on the first scan which was in cycle 3 day 1, it was an aggregate 17% to volume reduction fire-resist criteria.

Unknown Executive: So, you know, there will be a wider therapeutic index. I think, as we talked about before, ultimately, the issue isn't the therapeutic index. It's how high you can dose and what the absolute impact is at those levels.

Although the scan looked a little more impressive than that, that's what it was. But by cycle 5 day 1, you know, it's pretty clear that the tumor is nearly obliterated across all three of those lesions and so that score is resist.

Unknown Executive: But it will all converge around 1.0, as you have talked about before, because that's the point of NPD, you know, dosing. But I think just to go back to the big picture, we're obviously quite encouraged by the significant level of anti-tumor activity that we've seen at, as Steve described, a very well-tolerated dose range. And although this is below the 25 minutes per gig that we use, it's standard dosing and bias, it's not below those levels that we know should have anti-tumber activity, so it's actually quite consistent with our collection of people in the data. So we're quite encouraged about it.

You know in the 70% range is probably in terms of tumor content is far more than a 70% reduction You know, that's that's what we have that's what we're seeing so far As we get to higher doses possibly it will take fewer cycles to see that who knows but it might also just be the kinetics of the generalers That's the sort of thing. We need more information on being able to get a more precise answer right Just in terms of the study contact going

Unknown Executive: But I think the needs of selective inhibitors, one would expect to be, have much more flexibility around dosing. And when we think of RMC6236, it's sort of the highest risk molecule from that perspective. And today's information, you know, in our views, substantially lowers our calculation around that risk.

finger on the scale if you will. And clearly we're showing you some information that we think is exciting and the investigators think is exciting. So I would imagine you'll see more of some of these patients.

Unknown Executive: Yeah, great. And then, could you, when I'm looking at the waterfall chart on slide 12, could you just comment on the response kinetics? You know, did you all see these, you know, responses early on in the first scan, you know, did they happen later? Did they deepen all the time?

in the back fills. There's always this tension, and I know you and I have also talked about this before, this tension between wanting to sample across...

because that's important information too versus wanting to get a deeper dataset in a smaller number of tumor types and genotypes. I think in a sense it's sort of playing out the way epidemiology would predict. So we end up with a larger dataset with Q12D and pancreatic cancer, not surprisingly.

Unknown Executive: Yeah, well, there is a box across the bottom that says the most recent scan, and that was designed to give you information on what the bar represents, and you'll see that it varies. Some of them are in cycle three, day one, which would be the first post-treatment scan, and others are at cycle five, day one. I think the case that Steve described is pretty informative here, where on the first scan, which would have been cycle three day one, it was an aggregate 17% tumor volume reduction by resist criteria.

But we'll continue to involve patients across these, especially with some enrichment by the investigators. Yeah, all right, don't make sense. All right, well, thank you for taking my questions and congrats on the data update today.

can be involved in patients across these potentially with some enrichment by the investigators. Yeah, all right. That makes sense. All right. Well, thank you for taking my questions and congrats on the data update today. And I'll end it now, and should see you.

Please stand by for our next question. Our next question comes from Mark Fram with Cohen. Your line is now open. Thanks for taking my questions and congrats on the data and seeing that 63.6 is active in the clinic.

Unknown Executive: Although the scan was a little more impressive than that, that's what it was, but by cycle five, day one, you know, it's pretty clear that the tumor is nearly obliterated across all three of those lesions, and so those scores are in the 70% range, and probably similar content is far more than a 70% reduction.

Just to follow up on one of the earlier questions to start, Steve, I think there's 20 patients dosed at 40 milligrams and above in the AE table, and then there's 12 in the waterfall plot. Can you just explain those incremental eight patients? It sounds like maybe a few of them are colorectal cancer patients that you just don't have enough to do.

Unknown Executive: You know, that's what we have. That's what we're seeing so far. As we get to higher doses, possibly it will take fewer cycles to see that. Who knows? But it might also just be the kinetics of the Jimers. That's the sort of thing we need more information on to be able to get a more site-specific answer.

to talk about monotherapy with and then are there more patients who are just on study but haven't been scanned yet versus people who may have dropped out before the first scan? Yes, there are far more patients on study that have not yet been evaluated for efficacy than there are patients with colorectal cancer in study.

Unknown Executive: Just in terms of the study conduct going forward, do you plan to enrich for certain tumor types, perhaps lung cancer and PDAQ, or are you still continuing with the autopsy?

Unknown Executive: continuing with the all-comers approach. Well, I think as we've described it publicly, and I think we'll say with this, is that the backfill patients really give us the greatest opportunity to put a finger on the scale, if you will. And clearly, we're showing some information that meetings are exciting, and the investigators think is exciting.

I was deliberately vague about the other histotypes, but that's because we will provide an update later in the year which addresses that. But the reality is that the discrepancy is due to the speed at which this study is enrolling and the fact that patients have to be on study for six weeks before they get their first scan. So if you enroll a whole bunch of patients within the last six weeks, they are...

Unknown Executive: So I would imagine you'll see more of some of these patients, you know, in the back fills. There's always this tension, and I know you and I've also talked about this before; there's a tension between wanting to sample across tumor types and genotypes, because that's important information too, versus wanting to get a deeper data set in a smaller number of tumor types and genotypes. I think in a sense it's sort of playing out that we could get what epidemiology would predict. And so we end up with a larger data set with G12 and pancreatic cancer, not surprisingly. But we'll continue involving patients across these, eventually with some enrichment by endocratitis.

Maybe just to the point of the preclinical modeling being pretty predictive. I guess one, given the exposures you're seeing so far, I guess, what dose level do you think might be equivalent to that 25 milligrams you tested mostly? And then also related to that, certain time preclinically that...

Unknown Executive: Yeah, all right, that makes sense. All right, well, thank you for taking my questions and congrats on the data updates. Thank you.

Operator: Please stand by for our next question. Our next question comes from Mark Fram with Cohen. Your line is now open. Hi, thanks for keeping that questions and congratulations on the data, you know, seeing that 60-6.

G12D alterations might be maybe modestly more sensitive than the other alterations and make sense that they would start responding first? Or do you think this is just kind of the noise in the system of seeing a lot of different tumor types and a lot of different mutations?

Unknown Executive: Thanks for taking my questions and congratulations on the data and, you know, seeing that 60-36 is active in the clinic. Maybe just to follow up on one of the earlier questions to start, Steve, I think there are 20 patients dosed at 40 milligrams and above in the AE table, and then there are 12 in the waterfall plot. Can you just explain those incremental A patients? It sounds like maybe a few of them are colorectal cancer patients that, you know, you just don't have enough to talk about monotherapy with.

Yeah, one second question, not so much. I mean, would we, I think we share data on the G12X versus non-G12X in various presentations, not necessarily corporate, but at some of the scientific meetings, we'd give it a further breakdown.

without any doubt the G12X.

without any doubt, the G12 acts as a group showed.

Unknown Executive: And then, you know, are there more patients who are just on study but haven't been scanned yet versus people who may have dropped out before the first? Yeah, there's far more patients on study that have not yet been evaluated for efficacy, that are patients with no recollection counseling in study. You know, I was a little, deliberately vague about these other histotypes, but that's because we will, you know, we will provide an update later in the year which stresses that, but the reality is that the discrepancies are due to the speed at which the study is rolling and the fact that patients have to be on study for six weeks before they get that first scan.

enrichment for sensitivity, higher sensitivity on average. But then you start to get into fairly small numbers trying to compare D to B to A to S. You know in some cases we only have a couple models of one particular gene type or another. So I don't think we can say that today. I don't think we would conclude that D is more sensitive.

in the waterfall. It's just not enough.

or 8 out of 12 are D in the waterfall plot and 3 are B and 1 is A. So it's just really no way to determine sensitivity from that yet. We need to collect more information.

Your first question was what dose will we get to? What dose will we get to? Yeah, or how does it match up? What dose? Given the exposures, you've got a fair amount of clinical exposure data now to start building the human model, not just the extrapolation from animals. Based on that, can we get to the next question?

Unknown Executive: So if you know a whole bunch of patients within the last six weeks, they are available for safety, but not privacy. Yeah, well, that's the key point, Mark, is that they're on the table for adverse events, or they're considered as part of that calculation once they start experiencing them, but they need to be on study for six weeks before you get an OK. Thanks, that's helpful.

Where does that 25 milgram animal this fall on the pretty is that you know 240 is it 400 milligrams Higher than other 20 I think is what we should it's what we can share today What will you guys make it's not you know, it's not 10 miles away

Unknown Executive: And then maybe just to the point of the preclinical modeling being pretty predictive, I guess, one, given the exposures you're seeing so far, what dose level do you think might be equivalent to that 25 milligrams you tested mostly? And then also, kind of related to that, is there any sign preclinically that G12D alterations might be, you know, maybe modestly more sensitive than the other? Does it make sense that they would start responding first, or do you think this is just kind of the noise in the system of seeing a lot of different tumor types and a lot of different, Yeah. On the second question, not so much.

But I think we'd rather give that to you in the context of showing PK curves and by then we'll have more information. It just seems you know potentially misleading to sort of give you a projection that's not showing you the data with it. So that equals things where we are.

Okay, that's very helpful and then completely understand your. Points in your prepared remarks about, you know, it's pretty early to just too early to be talking about specific response rates and efficacy and individual tumor types or genotypes. Do you think you'll be in a position to start saying that for some types of genotypes in the middle of the year at that update? We hope so.

Unknown Executive: I mean, when we, I think we share data on the G12X versus non-G-12X in various presentations, not necessarily corporate, but at some of the scientific meetings, we'd give it a further breakdown. And without any doubt, the G12X, as a group, showed enrichment for higher sensitivity on average. But then you start to give them fairly small numbers, trying to compare d to B to A to F. You know, in some cases, we only have a couple models of one particular genetic type or another.

You know, I mean that's an ambition, that's a hope. You know, of course it's a matter of opinion, but adjusting 10 out of 12 patients.

That 40 milligrams above showing some degree of timber volume reduction was some clear evidence that we're time on drug.

you know, gives you a greater chance at actually hitting a PR threshold is quite encouraging, but I just, it's hard to say and I feel like anything we say here probably will not be rewarded with anything positive. So in the spirit of

Unknown Executive: So I don't think we can say that today, and I don't think we would conclude that D is more sensitive in the waterfall, it's just not enough, you know, nine out of the, or sorry, data 12 RD in the waterfall plot, and three are B, and one is A. So there's just really no way to determine sensitivity from that yet. We need to collect more information. Your first question was, what kind of place will we get?

Don't break in, not to break into jail. I think we'll just stay with where we are. Okay, fair enough. Thank you and congrats again. Please stand by for our next question. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.

Unknown Executive: What happens when we get to, yeah, or how does it? What does, you know, given the exposures? You've got a fair amount of clinical exposure data now to start building the kind of human model, not just the extrapolation from animals, you know, but based on that kind of, where does that 25 milligram animal fall on? Is that, you know, 240, is it 400 milligrams? Higher than the other 20, I think is what we should, it's what we can share today. We'll give you that information. It's not, you know; it's not 10 miles away. But I think we'd rather give that to you in the context of showing PK curves, and by then, we'll have more information.

Hi, good evening. Thanks for taking the questions.

On the 20 milligram cohort with it being larger than the others, I just want to confirm that that's the result of backfilling and that there wasn't necessarily some kind of safety event that triggered further expansion of that cohort. And then maybe just second the pages.

sort of state where you are right now in terms of further enrollment of the 120 milligram cohort. And if you do in fact proceed through further dose escalation, would you kind of move through 40 milligram increments as well? So Steve.

Unknown Executive: It just seems so.

Unknown Executive: Okay, that's very helpful. And then I completely understand your point.

Unknown Executive: points in your prepared remarks about, you know, it's pretty early to be talking about, you know, specific response rates and efficacy and, you know, individual tumor types or genotypes. Do you think you'll be in a position to start saying that for some tumor types and genotypes?

study at that dose level. And so six of the patients were in a food effect study. We don't have the results yet from the food effect study, but the patients have been enrolled at that dose level and have been evaluated for safety, which is why the denominator for that dose level is...

Unknown Executive: position to start saying that for some tumor types and genotypes in the middle of the year at that update.

Unknown Executive: I hope so, you know, I mean, that's an ambition; that's a hope. Of course, it's a matter of opinion, but I don't see, you know, 10 out of 12 patients at 40 milligrams above showing some degree of Tumberthal reduction and some clear evidence that more time on drugs gives you a greater chance at actually hitting a PR threshold. That's quite encouraging, but I just, it's hard to say, and I feel like anything we say here probably will not be rewarded with anything positive So in the spirit of not breaking in, not to break into jail, I think we'll just stay with where we are. Okay, fair enough, thank you, and congrats again. Please stand by.

dose that all. And that dose that will, by the way, is determined by a conversation between us as the sponsor and the investigators. So I'm not really in a position at the moment to tell you what that dose that will be.

But it will be some sort of similar increment, 160 or 180 something in that range.

Operator: Please stand by for our next question. Our next question comes from Eric Joseph with J.P. Morgan. Your line is now open.

Okay, got it. And I guess if we're just trying to prepare ourselves for the scope of the readout that you're planning for midyear, I guess any sort of rough guidance in terms of additional patients you would expect to have accrued to the trial and I guess

Unknown Executive: Hi, good evening; thanks for taking the questions.

Unknown Executive: On the 20 milligram cohort, with it being larger than the others, I just want to confirm that that was a result of backfilling and that there wasn't necessarily some kind of safety event that triggered further expansion of that cohort. And then maybe, secondly, can you just sort of state where you are right now in terms of further enrollment in the 120 milligram cohort? And if you do, in fact, proceed through further dose escalation, which you kind of move through, you know, 40 milligram increments as well. So Steve, you get, you know, the first question.

additional follow-up that you want to have for the evaluation predictions that you're describing here today. Well, they're clearly going to be additional follow-up on all these patients. I mean, you'll get more information on whether or not, well, firstly, as a bunch of patients, there's a bunch of patients that have been enrolled that haven't yet been evaluated for XC, so we'll have that.

there will be more durability data hopefully the patients that are currently on study. You know, as Mark said, the investigators are beginning to lean in to the selection of patients of this study and it's highly biased towards nosebleed so long cancer and pancreatic cancer. And the epidemiology of that means that around half of them are going to have a key 12-D mutation.

Unknown Executive: Eric, it's a combination of two things. One is, there were a few patients that were backfilled after the escalation to 40 milligrams, but we also built in a food effect study at that dose level. And so six of the patients were in a food effect study. We don't have the results yet from the food effect study, but the patients have been enrolled at that dose level and have been evaluated for safety, which is why the denominator for that dose level is somewhat larger.

and probably a third of them are going to have a G12E mutation and the rest will be a scaptering of other things. So I would expect that to be substantially larger database for a dominant limit. We focused on pancreatic cancer and lung cancer with G12E and G12E being the major mutational forms that we report on.

Unknown Executive: The 120 milligram dose level is fully enrolled, and it'll read out. We'll know shortly whether or not we can escalate to the next dose level. And that dose level, by the way, is determined by a conversation between us as the sponsor and the investigators. So I'm not really in a position at the moment to tell you what that dose level will be, but it will be some sort of similar increment, 160 or 180, something in that range.

Yeah, I would just say, Eric, we have discretion about...

when we do this mid-year update, mid-year isn't the date or a time, it's just kind of a time of year. It's a season. And so, you know, obviously we're giving you some information now, which wasn't that they were contemplated previously. So we're going to collect some more information. We're going to try to...

Unknown Executive: Okay, got it. And I guess if we're

try to make the next update, you know, meaningful update, incremental to this. But there's no sort of prescribed formula, which is why asking is more about what we'll have. We'll have more patients and we'll have more follow-up, that's for sure. So, Mark, with that comment, I take it that you're not necessarily targeting presentation at one of the major scientific meetings. Perhaps there's some expectation that you guys would like to present at ASCO.

Unknown Executive: Just trying to prepare ourselves for the scope of the readout that you're planning for mid-year.

Unknown Executive: I guess any

Unknown Executive: sort of rough guidance in terms of additional

Unknown Executive: Patients you would expect to have accrued for the trial and, I guess, additional follow-up that you want to have.

Unknown Executive: that you'd want to have for the valuable patients that you're describing here today. Well, there's clearly going to be additional bars on all these patients.

Well, as I pointed out previously, we did not link this specifically to a scientific meeting or not. We left that unspoken. If we do do a scientific meeting, we may still have a corporate session. If we don't do it at a scientific meeting, we'll probably still have a corporate session and then do a scientific meeting after that. But it's true.

Unknown Executive: I mean, you'll get more information on whether or not, well, firstly, there are a bunch of patients that have been enrolled that haven't yet been evaluated for efficacy, so we'll have that. There will be more durability data, hopefully, for the patients that are currently on study. You know, as Mark said, the investigators are beginning to lean in to the selection of patients for this study, and it's heavily biased towards normal soul lung cancer and pancreatic cancer and the epidemic cancer.

All of the above are in play here. Okay, great. Understood. Thanks for taking the questions, Anthony. Congrats here. Please stand by for our next question.

Our next question comes from Chris Shubabtani with Goldman Sachs. Your line is now open.

Unknown Executive: That means that around half of them are going to have a key 12d mutation, and probably a third of them are going to have a G12 B mutation, and the rest will be a scattering of other things. So I would expect there to be a substantially larger database predominantly focused on pancreatic cancer and lung cancer, with G12 D and G12 B being the major mutational forms that we report on.

Hi, everyone. This is Charlie on for Chris. Thank you so much for taking our questions and congratulations on the data thus far. Just real quick from us, regarding the 120 meg dose cohort, just wondering if you can give us a sense of how long these patients have been at this dose level and being dose at this level. I understand that it's probably at a lower, on the lower end of the range of duration of.

Unknown Executive: Yeah, I just say, Eric, we have discretion about when we do this mid-year update. You know, mid-year isn't a date or a time; it's just kind of a time of year, it's a season. And so, you know, obviously, we're giving you some information now, which wasn't necessarily contemplated previously. So we're going to collect some more information. We're going to try to make the next update, you know, a meaningful update, incremental to this. But they still sort of prescribe a formula, which is,

subsequent cycles. Thank you very much.

Let me address the second question first because it's a more concrete question for which we actually have data.

Let me address the second question first because it's a more concrete question for which we actually have things on.

Unknown Executive: Mark, with that comment, I take that you're not necessarily targeting presentation at one of the major scientific meetings. Perhaps there's some expectation that you guys would look to present and ask. Well, I

Giorace the time to onset of rash is between one week and two weeks into dosing depending on the dose being used. So the higher doses it tends to start sooner but not usually before one week of dosing has been completed.

Unknown Executive: Well, as I pointed out previously, we could not link this specifically to a scientific meeting or not. We left that unspoken. If we do a scientific meeting, we may still have a corporate session, and if we don't do it at a sign-in meeting, we'll probably sell the corporate session and then do a sign-in meeting after that. So it's sort of all of the above in play here.

The severity does not increase over time. In fact, if anything, I would say it's the same or improves.

Unknown Executive: Okay, great. Understood. Thanks for taking the question, guys. Congratulations. Please stand by.

We have had reports of patients whose rash has...

Operator: Please stand by for our next question. Our next question comes from Chris Shububtani with Goldman Sachs. Your line is now open.

got better with just persistent dosing and we have reports of patients who brash, remains unchanged and is easily manageable with premium.

Unknown Executive: Hi, everyone. This is Charlie on for Chris.

Unknown Executive: Thank you so much for taking our questions and congratulations on the data thus far. Just real quick from us, regarding the 120-Mig dose cohort, just wondering if you can give us a sense of how long these patients have been at this dose level and how much they have been taking at this level. I understand that it's probably at the lower end of the range of duration of therapy that you guys gave us some color on there, but just trying to get a sense of how long they've been on this drug.

you know, just like putting up with Uncle Coop. You know, these rashes are very much like EGFR associated rashes in that they don't, they occur in different parts of the body in different people. Sometimes it's just the face, sometimes it's just the arms or the trunk.

But nobody seems to think that it's terribly, you know, terribly debilitating. We've actually only had one patient who...

Unknown Executive: And also, if you can give us some sense of the kinetics with the appearance of adverse events such as rash, like how long does it typically take for the rash to show up? And is there the potential for the severity of rash to increase over time in subsequent cycles? Thank you very much. Let me address the second question first because it's a more concrete question for which we actually have data.

I had to stop for a couple of days and then restart and that wasn't actually because of rash it turns out it was because of

an associated vertical itch that was associated with, that seemed to accompany the rash.

I think, you know, it's, that's pretty much all I can tell you at the moment. And then in terms of the duration of 120 milligrams, I think the only thing we can tell you is that the three patients who are on that waterfall plot, you can see that the bar that's shown there is associated with the first scan. Thank you so much.

Unknown Executive: The time to onset of rash is between one week and two weeks into dosing, depending on the dose being used. So the higher doses tend to start sooner, but not usually before one week of dosing has been completed. Severity does not increase over time. In fact, if anything, it either stays the same or improves.

Understood. That makes sense. Thank you. If I could just sneak in one more, just based on the safety profile that you're seeing thus far, are you still considering the potential for intermittent dosing in the future, or has this given you more confidence for the potential for just the once daily? Thank you so much for taking our questions.

Unknown Executive: We have had reports of patients whose rash has got better with just persistent dosing, and we have reports of patients whose rash remains unchanged and is easily manageable with cream, and you know, just like putting up with the local crew. You know, these rashes are very much like EGFR-related rashes in that they occur in different parts of the body in different people. Sometimes it's just the face; sometimes it's just the arms or the trauma.

Yeah, thank you Charlie, appreciate it. I think we're very much where we were, you know, in January when we commented on this that we're feeling quite encouraged by the once daily dosing. All of the data we're showing you here is based on once daily dosing. We've gotten away with it quite well with very good tolerability and...

Unknown Executive: But nobody seems to think that it's terribly, you know, it's terribly debilitating. We've actually only had one patient who had to stop for a couple of days and then restart. And that wasn't actually because of the rash, it turns out; it was because of an associated vertical itch that was associated with, that seemed to accompany the rash.

Unknown Executive: I think, you know, it's, That's pretty much all I can tell you at the moment. And then, in terms of the duration of 120 milligrams, I think the only thing we can tell you is about the three patients who are on that waterfall plot. You can see that the bar that's shown there is associated with the first scan. Got it. Thank you so much. And if I could just speak one,

test an intermittent dosing schedule is not our highest priority at the moment. And to the extent that we can...

move forward with monotherapy on a daily basis. We want to do that, but we would want to determine at some point whether we're leaving anything on the table in terms of potential clinical benefit. But so far doesn't appear to be so. Please stand by for.

Unknown Executive: Yeah, understood. That makes sense. Thank you. And if I could just speak in one more, just based on the safety profile that you're seeing thus far, are you still considering the potential for intermittent dosing in the future, or has this given you more confidence about the potential for just once daily? Thank you so much for taking our question. Yeah, thank you, Charlie. I appreciate it.

that stopped you from doing it in the itch, but then it was restarted. Can you comment if were they restarted at the original dose? And also how long did they pause dosing?

Unknown Executive: I think we're very much where we were, you know, in January when we commented on this, that we're feeling quite encouraged by the once daily dosing. All of the data we're showing you here is based on once daily dosing. We've gotten away with it quite well, with a very good tolerability and safety profile and clear evidence of anti-tumor activity. So it doesn't look to us as if intermittent dosing and is on a critical path to defining our first recommended phase two dose to schedule for monotherapy.

I think, I think, I'm just going to remember it, so forgive me, is what I say subsequently turns out to be slightly inaccurate. But my recollection is it was only for a couple of days that they actually stopped dosing. And then when they restarted, they started at the most level below.

Unknown Executive: With that said, we also began in January, and I think we'll stand by this. We're likely to test an intermittent dosing schedule. It's not our highest priority at the moment, and to the extent that we can move forward with monotherapy on a daily basis, we want to do that, but we would want to determine at some point whether we're leaving anything on the table.

in the adverse event table overall? The median duration of, it's really short. I mean, the median is really short. I would have thought, right, again, it's.

We haven't actually formally calculated it, but I would be surprised if it was in excess of a couple of months.

Operator: Please stand by for our next question. Our next question comes from Ben Burnett with Feeful. Your line is now open.

Okay, okay. Let's try to answer it correctly. Yes, we have it. No, we haven't, no, it's really uncalibrated, but it's really short. And I think the, you know, the data that we're showing you is deliberately a very preliminary snapshot of what we're seeing, not something that we can necessarily play will persist over time.

Unknown Executive: Hey, thank you very much. I wanted to ask about the patient you just mentioned. So the one patient that stopped treatment due to an itch, but then it was restarted. Can you comment, were they restarted at the original dose, and also how long did they pause the dose?

Unknown Executive: I think, I think, I'm just going for a memory event, so forgive me if what I say subsequent concerns is actually slightly inaccurate, but my recollection is it was only for a couple of days that they actually stopped dosing, and then when they restarted, they started at a dose level below the one that they had originally been on, and that patient remains on.

That's helpful. Okay. But you know it is.

It's also fair to say that it's 40 to 120 milligrams of fruit with pancreatic or lung cancer.

is afforded 120 milligrams of proof with pancreatic or lung cancer. They're all

still on. So yeah, all the patients that have been evaluated for efficacy are all on study. The long-term cancer patients that we evaluated are still on study. Okay, that's great. And then I also wanted to ask, going back to that intermittent dosing conversation, you know, is there

Unknown Executive: Okay, okay, that's helpful, thank you. And then just going back to, so the, can you please go on with the median follow-up time in the adverse event table overall?

Can you frame the level of toxicity that's tolerable? And is it likely to be different in different indications? Like, could there be a scenario wherein you may have intermittent dosing for CRC or for certain tumor types but not others?

Unknown Executive: the median duration of It's really short. I mean, the median is really short.

Unknown Executive: I would have thought, right, again, it's. We haven't actually fallen and calculated it, but I would be surprised if it was in excess of a couple of months. Okay, okay. It's straight forward to the record. We have calculated. Yeah, we haven't, no, we haven't calculated it, but it's really short. I think the, you know, the data that we're showing you is deliberately a very preliminary snapshot of what we're seeing and not something that we can necessarily play will persist over time.

Not so much because of differences in tolerability, but there could be differences in sensitivity across tumor types. And so if it somehow, I think that was really the point about not wanting to leave activity on the table. I think that's the point about not wanting to leave activity on the table.

Just realized the metaphor is you want to leave it all out on the field that you don't want to leave anything on the table to make those two metaphors.

You know, so what can imagine that there may be some benefits in some settings?

to if you can achieve a higher dose intensity for particular tumor types or there's particular combination in which that's particularly logical to do, but I mean we're out really over our speed for my third metaphor just to say anything like that at the moment because

Unknown Executive: That's helpful. Okay. You know, and I just wanted to

Unknown Executive: Parents say that in the 40 to 120 milligrams group, with Dinkranicured Lung Answer, they're all still on. Oh yeah, no, all the patients that have been evaluated for advocacy are all on study. The lung and pancreatic patients that we evaluated are still all on study.

It's just not what we're experiencing. By the way, pre-clinically, as you know, the vast majority of what we showed was on with daily dosing, admittedly in a mouse with different particle kinetics, but nonetheless, we had targeted coverage for 24 hours a day and we were able to do it. So what's happening in humans seems to reflect that, at least within the limits of what we can detect so far. Interesting. Okay. Thank you.

Unknown Executive: Okay, that's great. And then I also wanted to ask, going back to that intermittent dosing conversation,

Unknown Executive: You know, is there, can you frame the level of toxicity that's tolerable?

Unknown Executive: and is it likely to be different in different indications like

Unknown Executive: Could there be a scenario wherein you may have intermittent dosing for CRC or for, you know,

Unknown Executive: or C or for certain tumor types but not others.

Unknown Executive: Not so much because of differences in tolerability, but there could be differences in sensitivity across tumor types, and so if it somehow, I think that was really the point about not wanting to lead activity on the table. Realize the metaphor is you want to leave it all out on the field, but you don't want to leave anything on the table to mix those two metaphors. You know, so I imagine that there may be some benefits in some settings if you can achieve a higher dose intensity for particular tumor types or if there's a particular combination in which that's particularly logical to do so.

And frequently, the empty tuber activity, even at the best optimized should do with their schedule and dose.

just didn't work in the same league as SRR-C6236. There just needs to be no question that a kidney raft is far different from a kidney something of streamed or downstream rafts.

Unknown Executive: But, I mean, we're really overseas from my third metaphor, just to say anything like that at the moment, because it's just not what we're experiencing. And, by the way, preclinically, as you know, the vast majority of what we showed was daily dosing, admittedly in a mouse with different pharmacokinetics, but nonetheless, we had target coverage for 24 hours a day, and we were

I see. Okay. So it's like the guiding light here. Is that just is it really like a PK and are you achieving the concentration threshold that are needed or is it really about efficacy?

I think the guiding light here is how much efficacy can we get at a tolerated dose? And so far we're encouraged by the efficacy signal we're seeing so far at a tolerated dose. I mean the PKC not to make the decision for us, it's going to be the clinical outermost. Yeah, okay. Okay. Yeah.

I think the guiding light here is how much efficacy can we get at a tolerated dose. So far we're encouraged by the efficacy signal we're seeing so far at tolerated doses. The PKs often make a decision for us. It's going to be the clinical outcomes. Yep. Okay. Okay. Thanks so much. Thanks.

Unknown Executive: Interesting, okay, okay, thank you. I think this does contrast with, you know, and I think it does contrast. Maybe you have one other bit of color.

Please stand by for our next question. Our next question comes from Alex Ranahan with Bank of America. Your line is now open. Hey guys, thanks for taking our questions. Congrats to you as well on your initial responses. Interesting that the two PRs are.

Unknown Executive: does contrast with, you know, and I think it does contrast, maybe we have one other bit of color here, where amongst the groups that I've spent here studying a shift two inhibitor, it does contrast significantly with the shift to inhibitor experience, where inhumans really get the kinds of overall dose to intentional

Unknown Executive: I see. Okay, so the guiding light here is, is it really like the PK and are you achieving the, um, the, the concentration thresholds that are needed, um, or is it really about efficacy? I think the guiding light here is how much efficacy we can achieve.

Could you give us a sense of the G12X makeup for the other 10 patients in the FQC group? Was it entirely G12D and G12C or something else? Well, there's no G12C patients in this study. The right nine of those patients are all being...

Unknown Executive: I think the guiding light here is how much efficacy can we get at a tolerated dose.

channeled into a K-RUSG-TOTC in the study, R-1691. The patients in the group overall really cover the full range of K-RUSG-12.

Unknown Executive: Yep, okay. Okay. Thanks so much. I appreciate it. Please.

Operator: Please stand by for our next question. Our next question comes from Alex Branahan with Bank of America. Your line is now open.

mutations and the ones on the walls are indicated. So you can see that there are really only three types here, G12V, G12V and G12A.

Unknown Executive: Hey guys, thanks for taking our questions. Congratulations on me as well on your initiative.

Unknown Executive: and congrats to me as well on your initial responses. It is interesting that the two PRs are G12D. Could you give us a sense of how the G12X made up for the other 10 patients in the FQ group? Was it entirely G12D and G12C or something else? Well, there are no G12C patients in this study, and right now, those patients are all being channeled into our K-RAS Gat C study, RMS. The patients in the room overall really cover the full range of p12 mutations, and the ones on the waterfall are indicated, so you can see that there are really only three types here, G12V, G12D, and G12A.

And if I'm counting correctly here, there are one, two, three, four, five, six, eight of the 12 have G12D mutations. So that just, I think, is completely consistent with the epidemiology of the ARS mutations in these particular histopires. Got it.

That's helpful. And just to follow up, thinking through the balance of safety, efficacy, you know, you said your goal is to maximize responses, but would this be through the lens of taking this forward as a monotherapy or would you take a hit on efficacy at a lower dose if safety is good with an eye towards combinations, since I know you've shown.

Unknown Executive: And if I'm counting correctly here, there are one, two, three, four, five, six, eight of the 12 G12 D mutations. And that just, I think, is completely consistent with the epidemiology of the Aeros mutations in these particular patients. Got it, got it, that's helpful. And just to follow up, thinking through the balance of safety and efficacy, you know, you said your goal is to maximize responses. But would this be through the lens as a key?

in the past of preclinical data combining 6236 with the MPPT-1? Yeah, that's a great question, but I don't think we're there yet. I just don't think that we know enough about the tolerability profile or what's going to be post-limiting.

to know whether either you know to know what level of Toxicity we would be prepared to tolerate as a single agent or indeed in combination with anything. So it's really too early I would say it's a very reasonable question, but it's just one which we don't have an answer to right now because as you know toxicity is not all created equal. You know I mean

Unknown Executive: speaking this forward as a monotherapy, or would you take a hit on efficacy at a lower dose of safety is good with an eye towards combinations since I know you've shown in the past?

Unknown Executive: in the past, some pre-coding code and code data combining 626 with the NPPD one. Yeah, that's a great question, but I don't think we're there yet. Yeah, I just don't think that we know enough about the tolerability profile or what's going to be dose-limiting to know whether either or to know at what level of toxicity we would be prepared to tolerate as a simulation or indeed in combination So it's really too early.

Unknown Executive: It's a very reasonable question, but it's just one to which we don't have an answer right now. Because, as you know, toxicity is not all created equal. You know, I mean, some toxicities are very well managed and easily tolerated, and some are absolutely horrible and unpleasant and are going to be clearly decimated. We're just gonna have to keep escalating those and following these patients and see what happens. With a view to maximizing the dose for response, that's not actually the primary or the main driver here; the main driver is durability.

The main driver is durability. We're looking for durability because there are only two approvable endpoints that are going to make people prescribe this drug. One of them is progression through survival and the other is overall survival. A response rate per se without either of those two things.

Unknown Executive: We're looking for durability because there are only two approvable endpoints that are going to make people prescribe this drug. One of them is progression-free survival, and the other is overall survival. A response rate per se without either of those two things is not particularly helpful for patients. And so we're really looking not just for sooner, shrinking, but the durability of And I think that's just one small point.

is not particularly helpful for patients. So we're really looking for, we're really looking not just for shouldn't be strengthening but for your ability of that.

And I thought that just one small point, you know, one small point, you know, on the combinations, we've shown data that 6236 can combine with, for example, 6291 effectively at a dose lower than the dose that we typically use for model therapies studies in the mouse.

Unknown Executive: Yeah, one small point. You know, on the combinations, we've shown data that 626 can combine with, for example, 6291, effectively, kind of those lower than the just dose that we typically use for model therapy studies in the mouse. So we have a lot of flexibility in the combination realm, and so determining the recommended phase two dose for monotherapy doesn't necessarily dictate the limits of what we might do in combinations where we may lower the dose. In fact, that sure, a combination study will start with a lower dose. Okay, okay, that makes sense. And just on the duration versus ORR point,

So we have a lot of flexibility in the combination realm. And so determining the recommended phase two dose for monotherapy doesn't necessarily dictate.

the limits of what we're going to do in combinations where we may lower the dose. In fact, I'm sure the combination study will start with a lower dose.

Okay, that makes sense. And just on the duration versus ORR point, it sounds like the mid-year update, the median follow-up is just not going to be long enough to get to that.

duration question and it's going to be more about just the gross responses, correct? I can't answer that because we don't really know but you know again no all 12 of these patients are still on study.

duration question and it's going to be more about just the the gross responses correct? I can't answer that because we don't really know but you know again no all 12 of these patients are still on study and

Unknown Executive: It sounds like the mid-year update, you know, the median follow-ups are just not going to be long enough to get to that duration question, and it's going to be more about just the

Unknown Executive: That duration question, and it's going to be more about just the gross responses, correct? I can't answer that because we don't really know. But, you know, again, no, all 12 of these patients are still on study. You know, when pancreatic second line cancer comes, one doesn't have the weight, he wants to find out whether or not you've got a drug defective treatment. So I think one has to really talk about individual indications in order to know what the reference, you know, the benchmark is for that particular indication. Okay. Okay, one last quick one, if I may, just on the differences between 6236 and 19805 as it relates to the binding.

You know, in pancreatic second-line cancer, one doesn't have to wait 18 months to find out whether or not you've got a drug that's active to prepare for your stay of care.

So I think one has to really talk about individual indications in order to know what the reference you know the benchmark is for that particular indication.

individual indications in order to know what the reference, you know, the benchmark is for that particular indication. Okay.

Okay, one last quick one, if I may. Just on the differences between 6236 and 9805 as it relates to the binding to G12D, you know, whether it's covalent inhibition or another aspect that you think could result in different clinical profiles beyond just the therapeutic window that was mentioned before. Right. Right.

Well, you know, it has the differentiated feature that it is selected for G12V. It forms a covalent, but selective bond with the G12V Ras, and hence is basically irreversible. Rc6236 is non-covalent, and it's reversible. So its binding will go up and down with whatever the plasma levels are or where the intracellular concentrations are at that minute in time.

Unknown Executive: D12D, you know, whether it's Kavilan inhibition or another aspect that you think could result in different clinical profiles beyond just the therapeutic window that was mentioned before. Right, well, you know, it has

Unknown Executive: Right, well, you know, it has the differentiating feature that is selected for G12D; it forms a covalent but selective bond with the G12 V brass, and hence is basically irreversible. Pharmacy 6236 is non-covalence, and so, and it's reversible. So its binding will go up and down with where the plasma levels are or the intracellular concentrations are at that minute in time. But the trade-off is you capture the activity against a wider range of rass proteins that might be part of the overall oxygen supply for a RASC tumor cell.

But the trade-off is you capture the bacteria against a wider range of RAS proteins that might be part of the overall ocogenes addiction for For a RAS tumor cell so there are trade-offs between those and I think it's just really yet to be determined Which of those is more favorable obviously overlaid on top of that is tolerability. How much dose can you get etc?

Unknown Executive: So there are trade-offs between those, and I think it's sort of just really yet to be determined which of those is more favorable. Obviously, what we're looking at on top of that is tolerability, how much dose you can get, et cetera. But I just think it's too early to be making projections about, you know, which is better. You know, I tend to think that RR6-236 may be the mother of all RASD emitters, but for us to be effective in treating all RAss cancers, we were probably going to need a whole family of RAssol inhibitors. And that's why we sign our portfolio the way we do.

But I just think it's too early to be making projections about which is better. I tend to think that pharmacist 6236 may be the mother of all ras inhibitors, but for us to be effective in treating.

All right, answers were probably going to need a whole family of grass-on-tivers. And that's probably the signer for clothing when we did.

all RAS cancers, we're probably going to need a whole family of RAS-all inhibitors. And that's why we signed our portfolio the way we did. OK. Thanks, and congrats again on the progress.

Thank you. Please stand by for our next question. Our next question comes from Amy Fadia with Needham. Your line is now open. Your line is now open.

Unknown Executive: Okay, thanks, and congrats again on the progress.

Operator: Please stand by for our next question. Our next question comes from Amy Fadio. With Needham, your line is now open.

Thank you for taking the question and the data. My first question is just around how to interpret the evolution of response with duration of treatment. How do you interpret the evolution of response with duration of treatment?

Unknown Executive: Thank you for taking the question and data. My first question is just around how to interpret the evolution of response with duration of treatment. If I'm reading the chart on slide 12 correctly, some of the patients who were Someone in the chart are cycles seven, day one on stable disease. But then there are the last two patients in that chart, which are cycles five, and they seem to have shown a response rate, um, I'm just trying to understand.

If I'm reading the chart on slide 12 correctly, some of the patients who were…

So the chart are cycle 7, day 1 on stable disease.

But then there are last occasions in that chart, which are cycle 5, and they seem to have shown a response rate. I'm just trying to understand so for those people.

Unknown Executive: So, for those cases, Cytsev and clearly wore on treatment longer. Is that a fair way to look at it? Overall, is this just too short of a duration for us to really interpret responses over time? Well, we definitely need more data, and we need more time on study to collect those data, but you're right, so lung cancer

I haven't clearly wore on treatment longer. Is that a fair way to look at it? And you know overall is this just too short of a duration for us to really interpret...

You know, responses over time. Well, we definitely need more data. And we need more time on study to, to let those say that, but you're right. So that lung cancer patient, which shows cycle seven day one.

Unknown Executive: Well, we definitely need more data, and we need more time in the study to process those data, but you're right, so that lung cancer patient who shows some

Unknown Executive: If I'm interpreting this correctly, but if we're talking about the same age, has stable disease with some tumor-bolic reduction, but not a PR. We don't know if they'll go on to shape the PR. We're not trying to imply that they will or won't. We don't know, but we'll have to follow them. So I don't know how else to comment on it. Yeah, I don't know.

That means that patient has been on long enough to have likely a third scan. That's what cycle seven would be. Cycle seven, day one would be a third scan. So that patient at 40 milligrams if I'm interpreting this correctly, if we're talking about the same patient.

has stable disease with some tuberbolic reduction but not a PR. We don't know if it will go on to shape a PR. We're not trying to imply that they will or won't. We don't know. We'll have to follow them.

So, I don't know how well Sue would comment on this. I think that directionally you are correct in inferring that whether a patient has a response by a resist is a function of both dose and time on treatment.

Unknown Executive: No, I mean, I think that you, you know, directionally, you are correct in inferring that whether a patient has a response by a resist is a function of both dose and time on treatment. Clearly, what this chart is beginning to, perhaps, indicate is that responses at 40 milligrams might be uncommon, which is why we escalated it to three times that dose level, where you are beginning to see, you know, racist responses We wait long enough, and as Mark said earlier, we don't know whether there is a dose at which the majority of responses will be seen at the first response valuation or not.

and clearly what this chart is beginning to perhaps indicate is that responses at 40 milligrams might be uncommon.

which is why we've just escalated to three times that dose level where we are beginning to see you know, restive responses if we wait long enough and as Mark said earlier, we don't know whether there is a dose at which the majority of responses will be seen as a first response evaluation or not. It's just not it's not clear to us whether increasing the dose changes for kinetics are...

Unknown Executive: It's just not clear to us whether increasing the dose changes the genetics of response. Again, I want to really emphasize here that these two diseases are diseases where chemotherapy induces responses, but it doesn't last very long. And that's what we're trying to solve.

Unknown Executive: We're trying to solve for the very short duration of response or benefit that patients get with cytotoxin chemotherapy. The median time to progression for patients with pancreatic cancer that have received prior therapy is three and a half months, and we're trying to solve for that. So it's really about how long it takes the tumor to get to 30% or 31% reduction isn't really the point. The point is how long do they stay on study before they progress again? And we would like to push that beyond three and a half months.

in cytotoxic chemotherapy. The median time to progression for patients with pancreatic cancer that have received prior therapy is three and a half months. And we're trying to solve for that. So it's really about how long it takes the tumor to get to 30% or 31% reduction. That isn't really the point. The point is how long do they stay on study before they progress again? And we would like to see that happen.

Unknown Executive: Yeah, okay, that's helpful. And just clarify for me, after how many cycles does a patient receive a scan?

to push that beyond three and a half months. Yep, okay, that's helpful. And just clarify for me, after how many cycles did a patient receive a scan? Is it out every two cycles?

three and a half months. Yep okay that's that's helpful and just clarify for me after how many cycles did a patient receive a scan? Is it every two cycles? Every two cycles.

Unknown Executive: Yeah, okay, got it, six cycles, and then that goes. I think it goes.

Unknown Executive: I think it goes to every three of them. Yeah, so cycle three, day one means they've completed two cycles. It's the day after that.

Yeah, okay. The first six cycles and then I think it goes to every three of them. Yeah, so cycle three day one means they completed two cycles. It's the day after they completed two cycles. Got it. Okay. Just with regards to safety, you know, you mentioned that you dosed up to 40 milligrams per gig in sort of the preclinical model before you started to see some safety. What type of safety emerged at that point?

Unknown Executive: Got it. Okay.

Unknown Executive: Just with regard to safety, you know, you mentioned that you dosed up to 40 milligrams per kig in sort of the pre-trial models before you started to see some safety. What type of safety emerged at that point? You know, what was it, and then maybe, you know, what duration of treatment?

And then, what duration of treatment? Okay. So this is very species specific.

Unknown Executive: Okay, so this is very species specific. So, mice, we just see weight loss. The Tox species were mice and synomogous monkeys, and obviously, the monkey is a little bit more representative of what happened in humans.

So mice, we just see weight loss. The toxed species were mice and However, we saw sleep loss as disappeared after that easy rate, caused by severe viruses in mice and rabies and

Unknown Executive: And there we saw very clearly wild typegrass media toxicity, predominantly gastroid toxicity, and some suppression of myelo, you know, poised. Now, interestingly, in the human studies so far, we have seen some GI toxicity, it's not, it's a little bit diverse in terms of exactly which part of the GI tract is affected and how that manifests itself. So sometimes we've seen nausea, sometimes we've seen diarrhea, sometimes we've seen loss of acetype, for instance. It's a constellation of gastrointestinal effects that almost all of them have either been grade one or grade two and very easily manageable.

And obviously the monkey is a little bit more representative of what happens in humans. And there we saw very clearly wild-type rasps to toxicity, predominantly gastric to sialotoxicity and some suppression of myeloid hemopoiesis. Now interestingly, in the human study so far, we have seen some GI toxicity. It's a little bit diverse in terms of the...

exactly which part of the GI tract is affected and how that manifests itself. So sometimes we've seen nausea, sometimes we've seen diarrhea, sometimes we've seen loss of appetite for instance. It's a constellation of gastrointestinal effects that almost all of them have either been grade one or grade two and very easily manageable. But the predominant toxicity, the one that's coming through with increased frequency is skin rash.

Unknown Executive: But the predominant toxicity, the one that's coming through with increased frequency, is a skin rash, which we were not able to detect in the preclinical pox species largely because we're limited by what we can detect in those species. But it is interesting, the one organ in which we showed in our JPM organ presentation that it is the one organ where the clearance of the drug is slightly delayed compared with the other organs.

which we were not able to detect in the preclinical POC species, largely because we're limited by what we can detect in those species. But it is interesting the...

the one organ in which we showed, in our JT Morgan presentation, we showed that it is the one organ where the clearance of the drug is slightly delayed compared with the other organs. Nowhere near as much as Tumor by the way, but the clearance of the drug from skin is slower than from...

Unknown Executive: Nowhere near as much as tuna, by the way, but it is that the clearance of the drug from the skin is slower than from, for instance, the Pallonic epithelium or other organs in the body. So it may be that the tissue kinetics of 636 and contributes to the skin rack. And that makes the pattern of toxin. a little different in humans compared to come over the preclums.

for instance, colonic epithelium or other organs in the body. So it may be that the tissue kinetics of 63.6 are contributing to the skin rash, and that makes the pattern of toxicity a little different in humans compared to the preclinical species. Understood. Okay. Steve, remind me, I don't know if you mentioned exactly what dose the patient was on, the patient that had to...

Unknown Executive: Okay. Um, to remind me, I don't know if you mentioned exactly what dose the patient was on, the patient that had to, you know, pause the dose, and then we start at a lower dose.

Unknown Executive: I don't remember. I'll have to take that. I'll have to take that. I'll have to take out the lines.

you know, cause the dose and then restart at a lower dose? I don't remember. I'll have to take that off the site. I'm sorry. I don't remember. Okay. We have time for one more question. Is that right? From another speaker. I think there's one other person.

Unknown Executive: Sorry, I don't remember. Okay. Okay. I think it would be a good time for one more question. Is that right? Another speaker. I think there's one other

Operator: Please stand by. Please stand by for our next question. Our last question comes from Jay Olson with Oppenheimer. Your line is now open.

Please stand by for our next question.

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

Unknown Executive: Oh, hey, thank you for the update and for taking the questions. We had a couple on 6-2-36. What are you expecting to be the minimally effective dose? Is there any saturation of target occupancy that could lead to a plateau of efficacy, and at what dose would you see that plateau?

Oh, hey, thank you for the update and for taking the questions. We had a couple on 6236. What are you expecting to be the minimally effective dose? Is there any saturation of target occupancy that could lead to a plateau of efficacy and what dose would you see that plateau? And then...

Unknown Executive: And then since the AE table excluded events that occurred in fewer than four patients, can you just comment on what those AEs were and if any of them were grade three or four? Thank you. Well, it's easy. We should speak to the last answer on the second question. We haven't seen none.

Since the AE table excluded events that occurred and fewer than four patients can you just comment on what those AE's were and if any of them were grade three or four. Thank you.

Unknown Executive: Well, it's easy; we should be able to answer the second question. We haven't seen any grade three or grade four events other than that one bowel preparation that we described, which was a grade four, an E, and also a serious adverse event. But as we said, the bowel preparation was most likely due to the efficacy of the drug, not due to the toxicity of the drug on the gastrolystine repothelium. I got some sort of question about MAD.

Well, it's easy to answer the second question. We don't see no grade three or grade four events other than that one ballot preparation that we described, which was a grade four AE and also a serious adverse event. As we said, the

The cloud preparation was most likely due to the efficacy of the drug, not due to the toxicity of the drug on the gastroenostone record video. I don't have a question about NAD. There's no other, there is no faxato in our substance. We continue to see increases in efficacy up to the point where the drug becomes intolerable due to inhibition of wildfire breath. So there is no accident.

Unknown Executive: There's no, there is no plateau in our dose response. We continue to see increases in efficacy up to the point where the drug becomes intolerable due to inhibition of wild fibers. So there is no expectation of a plateau as we continue to dose escalate. And this is really important because this compound so far, everything we know about RMC-6-236 does not follow the paradigm for project opt-past. We continue to see increasing efficacy as we see increasing toxicity. They are absolutely related to each other, but we all see increased efficacy at doses that are tolerable, and that is incredibly important both for the platform and for the

They are absolutely related to each other, but we all see in efficacy that those are tolerable and that is incredibly important both for the platform and for the development of the compound.

Unknown Executive: Okay, great. Thanks for taking the question.

Mark A. Goldsmith: I would now like to turn the conference back to Mark Goldsmith, Chief Executive Officer, for closing remarks.

Thank you. I would now like to turn the conference back to Mark Goldsmith, Chief Executive Officer for closing remarks. Thank you, Operator. Thank you to everyone for participating today and for your continued support of Revolution Medicine. I can't read it well.

Operator: Thank you, Operator. Thank you to everyone for participating today and for your continued support of Revolution Medicine.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This concludes today's conference call. Thank you for participating. You may now disconnect.

The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1-1.

So.

Cigarette

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