Erasca, Inc. · NASDAQ:ERAS
Erasca — Investor Presentation (January 2023)
63 slides from Erasca's investor presentation, Jan 9, 2023
Slide 1: On a Journey to Erase Cancer: Erasca Corporate Presentation
On a Journey to Erase Cancer Erasca Corporate Presentation January 2023 Exhibit 99.1
Slide 2: Forward-looking statements
We caution you that this presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, research and development plan
Slide 3: Our name is our mission: to erase cancer
Our name is our mission: to erase cancer CNS = central nervous system 1 Number of patients alive and free of cancer or free from cancer progression 2-yrs after starting an Erasca regimen, as measured by disease-free survival (adjuvant setting) and progression-free survival (metastatic setting) 2 Una
Slide 4: SAB includes world's leading experts in the RAS/MAPK pathway
SAB includes world’s leading experts in the RAS/MAPK pathway Erasca co-founder. World expert in RAS who pioneered development of approaches to inhibit KRAS G12C (RAS-GDP) and active states of RAS (RAS-GTP) World expert in ERK, having studied nearly every ERK inhibitor that has been or is being devel
Slide 5: Blue ocean and red ocean opportunities by RAS/MAPK alteration
* Post-Osimertinib resistant population shown for EGFRm NSCLC except for SCLC transformation ** Co-occurring activating MAPK pathway alterations exclude EGFR overexpression Source: SEER database (2020), ECIS database (2020), GLOBOCAN database (2020), The AACR Project GENIE Consortium version 8.1 (20
Slide 6: Our singular focus is on the RAS/MAPK pathway
Our singular focus is on the RAS/MAPK pathway P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF Nodes targeted by Erasca Target upstream and downstream RAS/MAPK nodes with single agents and clamp on
Slide 7: Erasca pipeline by program and phase
Program/ Company Target Modality Indication Discovery IND-enabling Phase 1 Phase 2 Phase 3 Erase Cancer Strategy Worldwide Rights Naporafenib BRAF/CRAF Pan-RAS Q61X tissue agnostic ❶ NRASm melanoma ❶ NF1 LOF, pan-RAS G13R, KRAS G12C, BRAF Class 2/3 solid tumors ❶ ERAS-007*ǂ ERK1/2 RAS/MAPK altered t
Slide 8: Our pipeline targets every node of the RAS/MAPK pathway
Our pipeline targets every node of the RAS/MAPK pathway Note: MAPKlamp = ERAS-007 in combination with ERAS-601 and/or other agents P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-9 ERAS-601 naporafenib ERAS-
Slide 9: Clinical development plan generates multiple ways to win for patients
Erasca’s clinical development plan generates multiple ways to win for patients Indication Benchmark Regimen tested Erasca trial(s) HERKULES-2 Sub-study 11 EGFRm NSCLC post-osi ERAS-007 + osimertinib ORR 29%, mDOR 4.2 mos. HERKULES-3 Sub-study 13 BRAFm CRC EC-naïve ERAS-007 + encorafenib + cetuximab
Slide 10: Clinical-stage programs could address up to 1.7 million patients annually
Erasca’s clinical-stage programs could address unmet needs in up to 1.7 million patients annually in the US and Europe SEACRAFT-3/HERKULES-1: BRAF Class 2/3 * Addressable patient population, US and Europe (’000s; numbers may not add up due to rounding) ERAS-801 Naporafenib Napo + ERAS-007 or ERAS-60
Slide 11: Naporafenib could address approximately 500k patients in US and Europe
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF Erasca’s naporafenib pan-RAFi could address unmet needs in approximately 500k patients in the US and Europe ERK BRAF CRAF naporafenib Addressable Patien
Slide 12: Naporafenib is a potent and selective inhibitor of BRAF and CRAF
Naporafenib is a potent and selective inhibitor of BRAF and CRAF with sub-nanomolar IC50 potency and most advanced pan-RAFi in development Source: Monaco K-A, Delach S, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. 2021. PMID:
Slide 13: Naporafenib dosed in many patients, establishing safety and preliminary PoC
Naporafenib has been dosed in more than 500 patients to date, establishing its safety, tolerability, and preliminary PoC in multiple indications Source: Novartis Non-Confidential Materials; PoC = proof-of concept P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK P
Slide 14: Preliminary clinical PoC in NRAS Q61X melanoma and KRAS Q61X NSCLC
Preliminary clinical PoC in NRAS Q61X melanoma and KRAS Q61X NSCLC supports development in RAS Q61X tissue agnostic solid tumors (SEACRAFT-1) Strong antitumor activity, with confirmed ORR = 44% 15 out of 16 patients had confirmed codon Q61X melanoma (1 patient had no data) Source: LXH254X2102 Ph 1b
Slide 15: Standard of care post-IO for NRASm melanoma is chemotherapy
Current standard of care post-IO for NRASm metastatic melanoma is chemotherapy with 7% ORR and 1.5m PFS 1 NEMO trial (Lancet Oncol (2017) 18: 435-445.); IO = immuno-oncology Front line Second line plus IO mono or combo Ex: nivolumab, pembrolizumab, nivolumab + ipilimumab Post-IO therapy is predomina
Slide 16: NRASm melanoma: naporafenib + trametinib showed strong anti-tumor activity
Phase 1 in NRASm melanoma: naporafenib 200mg BID + trametinib 1mg QD showed strong anti-tumor activity De Braud et al AACR 2022 (Trial LXH254X2102, NCT02974725). ^ NEMO trial initially limited to 1 prior therapy later amended to allow more than 1 line. Range not available. * 95% confidence interval.
Slide 17: Case Study: Partial response in NRASm melanoma
Case Study: Partial response with naporafenib 200mg BID + trametinib 1mg QD in a patient with NRASm melanoma Source: Novartis Non-Confidential Materials On treatment Pre-treatment
Slide 18: Naporafenib and trametinib exhibited durable time on treatment
Phase 1 in NRASm melanoma: naporafenib and trametinib exhibited durable time on treatment De Braud et al AACR 2022 (Trial LXH254X2102, NCT02974725) * Median PFS was calculated based on two RDEs: napo 200mg BID + trame 1.0mg QD and napo 400mg BID + trame 0.5mg QD Responses observed in patients with n
Slide 19: Clinical activity reproducible across Phase 1 and Phase 2 studies
Clinical activity of naporafenib + trametinib in NRASm melanoma at the likely Recommended Dose was reproducible across Phase 1 and Phase 2 studies *De Braud et al AACR 2022 # Lebbe et al ESMO 2022 Total of 13/39 responses 33.3% ORR Study/Indication Data Cutoff Naporafenib (200 mg BID) + trametinib (
Slide 20: Patients remaining on treatment show potential for PFS benefit
Phase 2 in NRASm melanoma: Analysis of pts who remain on treatment show potential for naporafenib + trametinib to demonstrate PFS benefit Duration of Exposure (months) for naporafenib 200 mg BID + trametinib 1 mg QD 9/24 patients remain on treatment as of data cutoff 1 of these has already delayed p
Slide 21: Patients with SD could contribute to PFS benefit vs. SOC
Patients with SD at, or on track, for delayed progression > 4 months could contribute to PFS benefit vs. SOC Ph 2 patients continuing on treatment on naporafenib + trametinib = potential for confirmation of Ph 1 DOR and PFS advantage in SEACRAFT-2 *includes unconfirmed responses 24 enrolled 15 off t
Slide 22: Naporafenib + trametinib favorable and manageable safety profile
Naporafenib + trametinib demonstrated a favorable and manageable safety profile Phase 1 data in NRASm melanoma from De Braud et al AACR 2022
Slide 23: Proposed pivotal and Phase 2 trial designs
Single-Arm Phase 2 Trial (SEACRAFT-1) Randomized Phase 3 Trial (SEACRAFT-2) naporafenib + trametinib TBD (e.g., dacarbazine, physician’s choice) Metastatic Melanoma Post-IO NRASm (Q61X and non-Q61X) R Study Endpoints PFS, OS (dual primary) ORR, DOR (secondary) 1:1 Solid Tumors (Age 12+) Post-availab
Slide 24: SEACRAFT-3: Naporafenib could combine with rest of our pipeline
SEACRAFT-3: Naporafenib could combine synergistically with the rest of our pipeline P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF trametinib Target Tumor Types NF1 LOF Tissue Agnostic RAS G13R Tissue Agno
Slide 25: ERAS-007 and ERAS-601 could address over 1.1 million patients
ERAS-007 ERKi and ERAS-601 SHP2i could address unmet needs in over 1.1 million patients in the US and Europe P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-601 ERAS-007 BRAF Class II/III Solid 55,000 TOTAL
Slide 26: ERAS-007 is the most potent ERK inhibitor in development
We believe ERAS-007 is the most potent ERK inhibitor in development, with a uniquely longer target residence time Assay Type Assay ERAS-007 IC50 (nM) Biochemical ERK1 2 ERK2 2 Cell-based mechanistic (HT-29) pRSK 7 ERAS-007 was designed to be a potent, selective, reversible, oral inhibitor of ERK1/2
Slide 27: ERAS-601 is a potential best-in-class SHP2 inhibitor
We believe ERAS-601 is a potential best-in-class SHP2 inhibitor that demonstrates high potency and selectivity against SHP2 Compound Biochemical SHP2 inhibition IC50 (nM) ERAS-601 4.6 Cell Line Cancer Type IC50 (nM) ERAS-601 RMC-45501 HCC44 NSCLC 48 95 MIA PaCa-2 Pancreatic 6 17 NCI-H1373 NSCLC 64 4
Slide 28: ERAS-007 + EC in BRAFm CRC: in vivo combination activity
ERAS-007 + EC in BRAFm CRC: ERAS-007 showed strong in vivo combination activity in BRAF V600E CRC ERAS-007 60 mpk QD dose showed similar activity to 30 mpk BID, either as a mono or combo Tx with encor. +/- cetux. ERAS-007 combinations were generally well tolerated across the tested models as demonst
Slide 29: ERAS-601 + cetuximab in triple wildtype CRC and HPV-negative HNSCC
ERAS-601 + cetuximab in triple wildtype CRC and HPV-negative HNSCC: Combo demonstrated significantly greater tumor inhibition vs. cetuximab alone in both models Combination was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) ERAS-601 was dosed orally and cetuximab was dosed int
Slide 30: ERAS-007 + ERAS-601 MAPKlamp in BRAF Class 3 and NF1 LoF
ERAS-007 + ERAS-601 MAPKlamp in BRAF Class 3 and NF1 loss of function: Combination showed consistent activity in both models MAPKlamp combination showed activity in both models and was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) ERAS-007 and ERAS-601 were dosed orally and c
Slide 31: Best overall response in BRAF-driven Blue Ocean Indications
* Unconfirmed partial responses indicated with an asterisk NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly monotherapy dose intensity between 12
Slide 32: Duration of treatment in BRAF-driven Blue Ocean Indications
Duration of Treatment Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly m
Slide 33: FLAGSHP-1 Case Study: Single agent ERAS-601 response
Per RECIST 1.1: ≥30% = objective response Tumor assessment (5) (Jan 4, 2022): patient had radiologic progressive disease (PD) due to a new lesion Peri-Esophageal lesion, shrinkage in non-target lesions also noted (not shown) Diagnosis Stage III/IV endometrial cancer, metastatic disease, BRAF Class 3
Slide 34: Likely recommended dose of ERAS-007 well tolerated
Likely recommended dose of ERAS-007 for combinations was well tolerated *includes uniocular blindness (one patient in 250mg QW cohort), chorioretinopathy, papilloedema, retinal detachment, retinal oedema, retinopathy, serous retinal detachment, subretinal fluid, vision blurred, visual impairment, an
Slide 35: ERAS-601 QD and BID regimens well tolerated
ERAS-601 QD and BID regimens were well tolerated with acceptable safety profile * Includes thrombocytopenia and platelet count decrease Source: ENA 2022 System Organ Class/ Preferred Term QD (20-80 mg) N=15 QD MTD (40 mg) N=3 BID (20 and 40 mg) N=13 BID MTD (40 mg) N=9 QD + BID N=28 ALL Gr ≥ 3 ALL G
Slide 36: ERAS-801 EGFRi could address 37k patients in US and EU
ERAS-801 EGFRi could address high unmet need in 37k patients in US and EU P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-801 Glioblastoma multiforme 37,000 TOTAL 37,000 Addressable Patient Pop. Tumor Type N
Slide 37: Poor activity of legacy EGFRi in GBM
Poor activity of legacy EGFRi in GBM due to minimal activity against GBM-specific EGFR alterations and poor CNS penetration TCGA Cell, 2013 Therapy (brain penetration %) Clinical Trial Results: NSCLC/BrCa Clinical Trial Results: GBM Erlotinib (8%) Recurrent NSCLC: Improved PFS and OS vs. chemo (Ph 3
Slide 38: ERAS-801 designed to inhibit EGFR in GBM with high brain penetration
ERAS-801, a potent EGFRvIII/wt inhibitor with a Kp,uu over 4-fold higher than approved EGFR inhibitors, was specifically designed to inhibit EGFR in GBM 1 Kp,uu is a measure of the ratio of unbound brain concentration to unbound plasma concentration Kim M, et al. Brain Distribution of a Panel of Epi
Slide 39: ERAS-801 survival benefit in multiple glioma PDX models
ERAS-801 shows significant survival benefit in multiple glioma PDX models harboring a variety of EGFR alterations
Slide 40: ERAS-801 improves outcomes of >90% of EGFR altered GBM PDXs
ERAS-801 improves outcomes of >90% of EGFR mutant and/or amplified GBM PDXs across a diverse range tested EGFR mut and/or amplified EGFR All models Significant survival benefit
Slide 41: All of Erasca's 2022 milestones achieved on or ahead of schedule
All of Erasca’s 2022 milestones were achieved on or ahead of schedule 1 ERAS-007 (oral ERK1/2 inhibitor) and ERAS-601 (oral SHP2 inhibitor) together comprise our first innovative MAPKlamp Program Mechanism Trial Name Indication 2022 milestone guidance Status ERAS-007 and/or ERAS-601 (MAPKlamp1) ERK1
Slide 42: Anticipated key milestones and clinical trial readouts
Anticipated key milestones and clinical trial readouts 1 ERAS-007 (oral ERK1/2 inhibitor) and ERAS-601 (oral SHP2 inhibitor) together comprise our first innovative MAPKlamp 2 Triple wildtype CRC is KRASwt, NRASwt, and BRAFwt 3 FPD = first patient dose 4 Data to include preliminary combination safety
Slide 43: Compelling investment thesis
Compelling investment thesis Experienced team with track record of serial successes Seasoned drug developers who have advanced multiple programs from discovery to IND to global approvals World-class Scientific Advisory Board Leading pioneers in KRAS (Shokat, UCSF), SHP2 (Blacklow, HMS), ERK (Corcora
Slide 44: Thank You!
ERASCA- Thank You!
Slide 45: Naporafenib: Potential first-in-class pan-RAF inhibitor
Naporafenib: Potential first-in-class pan-RAF inhibitor Company Program Stage naporafenib Ph 2 tovarafenib Ph 2 Lead indication in pediatric low-grade glioma; novel-novel belvarafenib Ph 1b FORE-8394 Ph 1 lifirafenib Ph 1 BGB-3245 Ph 1 Combo w/ mirdametinib starting 2023 KIN-2787 Ph 1 Unclear whethe
Slide 46: Focused development plan for naporafenib
Erasca is well positioned to advance naporafenib through a focused development plan that leverages RAS/MAPK pipeline synergies Top Priority Potential RASm opportunities to address unmet needs for ~1.9m patients WW Ungate potential opportunities in other RASm indications if well tolerated combination
Slide 47: ERAS-007: Potential best-in-class ERK1/2 inhibitor
ERAS-007: Potential best-in-class ERK1/2 inhibitor in a field marked by attrition Company Program Stage ulixertinib Ph 2 (combo w/ HCQ, palbo) Safety concerns (disfiguring rash); CoM patent through 2025 ERAS-007 Ph 2 (multiple combos) ASTX029 Ph 2 (combo w/ internal SHP2) temuterkib Ph 1 Reported mo
Slide 48: Scientific rationale: triple blockade of BRAF, EGFR and ERK in BRAFm CRC
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERK Scientific rationale: Triple blockade of BRAF, EGFR and ERK in BRAFm CRC SHP2 ERK inhibition may overcome treatment-induced resistance to BRAF/EGFR inhib
Slide 49: ERAS-007 blocked MAPK feedback reactivation in BRAF V600E CRC cell lines
BRAF V600E CRC Cell Lines MEKi combination ERKi combinations Binimetinib 1 µM + Encorafenib 0.1 µM ERAS-007 0.1 µM + Encorafenib 0.1 µM LY3214996 1 µM + Encorafenib 0.1 µM Ravoxertinib 1 µM + Encorafenib 0.1 µM RKO HT29 MAPK Feedback Reactivation No Reactivation Reactivation Reactivation Source: Unp
Slide 50: HERKULES and SU2C clinical trial series: ERAS-007 master protocols
HERKULES and SU2C clinical trial series – ERAS-007 master protocols Indication Agent(s) Tissue Agnostic Regimen ERAS-007 Indication Exploring safety & PK of various intermittent dosing schedules for combinations Regimen Indication Lung Cancer EGFR-mutant NSCLC KRAS G12C-mutant NSCLC ERAS-007 + osime
Slide 51: ERAS-007 Phase 1: responses in RAS and RAF altered tumors
Four responses seen in patients with: BRAF V600E thyroid CA (180mg) BRAF K601E NSCLC (120mg) HRAS salivary gland CA (250mg) BRAF rearranged melanoma (250mg) ERAS-007 Phase 1: Responses observed in patients with RAS and RAF alterations in diverse tumor types with single agent QW schedule Source: ASN0
Slide 52: ERAS-007 swimmer plot demonstrated encouraging duration of treatment
ERAS-007 swimmer plot demonstrated encouraging duration of treatment Melanoma BRAF (mutation not available) 7110-011 Prostate Ca BRAF K601E 7110-013 Melanoma NRAS Q61 any 7106-004 Prostate Ca BRAF 7104-007 Oropharynx ACC BRAF D594N 7110-012 NSCLC BRAF 6466V 7104-006 CRC KRAS G13 any 7101-007 Salivar
Slide 53: Sept. 2022 R&D Day highlights
Sept. 2022 R&D Day highlights*: MAPKlamp has potential to meaningfully impact BRAF Class II and III patients ERAS-007 and ERAS-601 are active drugs – monotherapy responses 23% (6/26) of patients with RAS/MAPK-altered non-CRC solid tumors and 44% (4/9) with BRAF-driven non-CRC solid tumors responded
Slide 54: Best overall response in RAS/MAPK-altered Blue Ocean Indications
Best overall response with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy * Unconfirmed partial responses indicated with an asterisk. NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where
Slide 55: Duration of treatment in 15 RAS/MAPK-altered Blue Ocean Indications
Duration of treatment observed with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy Efficacy-Evaluable Patients Thyroid, BRAF V600E Ovarian, KRAS G12C Saliv. Gland, HRAS Q61 Endometrial, BRAF D594G Pancreatic, KRAS G12V Melanoma, BRAF rearr. Ampullary, KRAS
Slide 56: HERKULES-1 Case Study: Single agent ERAS-007 response
Per RECIST 1.1: ≥30% = objective response Diagnosis Stage II pancreatic cancer, metastatic disease, KRAS G12V, initially diagnosed in January 2018 Sites of Metastases Lung, lymph nodes Prior Therapy Surgery, adjuvant radiation, gemcitabine/ capecitabine (#1); 5FU/oxaliplatin/irinotecan (#2); gemcita
Slide 57: Maximize time above IC90 while maintaining Cmin near IC50
Goal is to maximize the time above IC90 to improve cancer cell killing, while maintaining Cmin near or below IC50 to give normal cells a treatment break (i.e., extend time below IC50) Dosing Regimen Cmax, ng/mL Cmin, ng/mL T>IC90 T<IC50 250 mg QW 425 3 ~2/7 ~1/7 50 mg BID-QW 103 3 ~2/7 ~1/7 80 mg BI
Slide 58: ERAS-601: Potential best-in-class SHP2i
ERAS-601: Potential best-in-class SHP2i, favorable profile for combination Company Program Stage TNO155 Ph 3 Observed LVEF decrease may pose combo challenges RMC-4630 Ph 2 Observed anemia does not improve with intermittent dosing JAB-3312 Ph 2 ERAS-601 Ph 1b RG6433 Ph 1 In-licensed from Relay Therap
Slide 59: Scientific rationale: dual inhibition of EGFR and SHP2
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERK Scientific rationale: Dual inhibition of EGFR and SHP2 in triple wildtype CRC and HPV-negative head and neck squamous cell carcinoma (HNSCC) SHP2 EGFR-dr
Slide 60: ERAS-007 and ERAS-601 use different target coverage strategies
ERAS-007 and ERAS-601 use different target coverage strategies that seek to achieve optimal efficacy and safety ERAS-007: 50-125mg BID-QW dosing provided high target coverage (C>IC90) for maximum activity, followed by lower PK coverage (C<IC50) for MAPK pathway recovery to alleviate target driven to
Slide 61: Treatment-related AEs of ERAS-601 and ERAS-007
ERAS-601 ERAS-007 Treatment-related AEs in Preferred Terms 20 and 40 mg BID (N=13) 50-125mg BID-QW (N=23) System Organ Class / Preferred Term All Grade Gr ≥ 3 All Grade Gr ≥ 3 Hematologic Thrombocytopenia* 3 (23.1%) 2 (15.4%) 0 0 Anemia 3 (23.1%) 1 (7.7%) 1 (4.3%) 1 (4.3%) Cardiovascular Hypertensio
Slide 62: Dr. Kevan Shokat at UCSF turned KRAS from undruggable to druggable
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR EGFR/ FLT3 Other RTKS MYC GEF ERK Dr. Kevan Shokat at UCSF turned KRAS from undruggable to druggable RAS-GDP RAS-GDP Source: Ostrem J., et al. K-Ras(G12C) inhibitors allosterically control G
Slide 63: Promising CNS-penetrant KRAS G12Ci pre-candidates
Parameter 34901 3691 3599 3537 3788 Reference compounds2 Mouse AUCpo/D (hr*kg*ng/mL/mg) 693 597 1,333 535 326 102 - 637 Rat braintotal / plasmatotal (%) 52% 13% 66% 68% 11% 1 - 6% Rat brain concentration (ng / g) 156 32 176 290 91 6 - 36 P-gp substrate ratio3 1.5 4.1 2.7 8.3 4.0 30.94 Human LM metab