Roche Holding Ltd · SIX:RO
Roche — Genentech — Technical Presentation (April 2022)
18 slides from Roche's technical presentation, Apr 11, 2022
Slide 1: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers
Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers Hans Purkey Genentech Inc., South San Francisco, CA New Drugs on the Horizon, April 11, 2022 AACR National Meeting 2022
Slide 2: Disclosure Information
Disclosure Information Hans Purkey I have the following relevant financial relationships to disclose: Employee of: Genentech, Inc. Stockholder in: Roche Holding AG
Slide 3: GDC-6036 Research Team
GDC-6036 Research Team Discovery Oncology Translational Oncology Chemistry Process Chemistry BCP Legal Marie Evangelista Mark Merchant Hans Purkey Haiming Zhang Nick Endres Kevin Clark Shervin Afghani Cecile de la Cruz Tim Heffron Carmela Molinaro Yevgeniy Izrayelit Rana Mroue Emily Chan Sushant Mal
Slide 4: Mutations in KRAS are the most common oncogenic driver mutations found in human cancer
Mutations in KRAS are the most common oncogenic driver mutations found in human cancer RAS mutation by isoform across tumor types KRAS codon 12 mutations by tumor type 17% G12D Head and neck squamous cell carcinoma 23% G12V 5% Lung adenocarcinoma 85% G12 G12C Pancreatic ductal 32% adenocarcinoma 86%
Slide 5: KRAS signaling in normal cells
RTK KRAS signaling in normal cells • KRAS is a signaling GTPase SHP2 that cycles between active GTP-bound and inactive GDP-bound states to KRAS Inactive Active KRAS regulate intracellular signaling in response to extracellular growth factors GTP GDP RTK • GTP-bound KRAS activates multiple downstream
Slide 6: Mutated KRAS in cancer
RTK Mutated KRAS in cancer • Oncogenic mutations in SHP2 KRAS, such as G12C, interfere with the transition from GTP-bound to GDP- KRAS Inactive Active KRAS G12C G12C bound states • Locking KRAS G12C in its GTP constantly active state RTK increases downstream GDP oncogenic signaling, resulting in unc
Slide 7: Genentech has a long history in the biology and targeting of RAS
Genentech has a long history in the biology and targeting of RAS Discovery of Genentech Genentech Kevan Shokat at KRAS & HRAS scientists discover scientists UCSF discovers the Adagrasib by Werner 2 different discover Switch II pocket enters Kirsten and activating inhibitors of RAS enabling mutant cl
Slide 8: Landmark discovery for selective targeting of KRAS G12C
Landmark discovery for selective targeting of KRAS G12C GDP-bound KRAS G12C structure, showing disordered Switch-II domain Disulfide-tethering screen identified fragments that targeted Cys12 identifying a novel pocket near Switch-II domain Ostrem JM, et al. 2013. Nature; 503: 543-551. 8
Slide 9: Covalent inhibitors of KRAS G12C irreversibly lock it in the inactive GDP-bound state
Covalent inhibitors of KRAS G12C irreversibly lock it in the inactive RTK GDP-bound state SHP2 KRAS Inactive Active KRAS G12C G12C GTP RTK GDP GDC- 6036 PI3K RAF MEK ERK AKT mTOR 9
Slide 10: New functionality improves KRAS G12C potency
New functionality improves KRAS G12C potency Reducing aromatic ring count 1* 2 HTRF IC50 = 190 nM HTRF IC50 = 450 nM Cell alk. EC50 = 1000 nM Cell alk. EC50 = 2800 nM 3 Improving Filling the interactions pocket 3 4 HTRF IC50 = 63 nM HTRF IC50 = 1.9 nM Cell alk. EC50 = 450 nM Cell alk. EC50 = 79 nM *
Slide 11: Discovery of GDC-6036
Discovery of GDC-6036 4 HTRF IC50 = 1.9 nM Reactivity & Cell alk. EC50 = 79 nM stability Cys. React T1/2 = 30 min Asp69 Tyr64 Glu62 Potency enhancement Lys16 Cys12GDP His95 GDC-6036 HTRF IC50 0.0029 nM Cell alk. EC50 = 0.52 nM X-ray co-crystal structure of KRAS G12C:GDC-6036 Cys. React T1/2 = 55 min
Slide 12: GDC-6036 is an exceptionally potent and selective covalent KRAS G12C inhibitor
GDC-6036 is an exceptionally potent and selective covalent KRAS G12C inhibitor GDC-6036 MW, TPSA, logD 622, 100, 2.3 Kinetic Solubility 130 mM G12C HTRF IC50 0.0029 nM G12C Kinact/Ki 710,000 (M*s)-1 HCC1171 Alkylation EC50 0.32 nM H358 Kinact/Ki 27,000 (M*s)-1 Median Cell Potency / Sel. 0.18 nM /16,
Slide 13: GDC-6036 is more potent and selective in vitro than other clinical KRAS G12C inhibitors
GDC-6036 is more potent and selective in vitro than other clinical KRAS G12C inhibitors HCC1171 Alkylation HCC1171 Alkylation GDC-6036 (nM) Sotorasib (nM) H358 kinact/KI Proliferation potency/selectivity GDC-6036 Sotorasib Adagrasib GDC-6036 Adagrasib Sotorasib 13 Do Not Post
Slide 14: GDC-6036 is more potent and selective in vitro than other clinical KRAS G12C inhibitors
GDC-6036 is more potent and selective in vitro than other clinical KRAS G12C inhibitors NCI-HCC1171 Median Cell KRAS G12C KRAS G12C Alkylation IC50 NCI-H358 Prolif IC50 (nM) / HTRF IC50 (nM) kinact/KI (M*s)-1 (nM) kinact/KI (M*s)-1 Selectivity GDC-6036 0.0029 710,000 0.32 27,000 0.18 / 16,000 X Soto
Slide 15: Anti-tumor efficacy of GDC-6036 in KRAS G12C-positive NSCLC tumor models
Anti-tumor efficacy of GDC-6036 in KRAS G12C-positive NSCLC tumor models NCI-H358 (higher sensitivity) NCI-H2122 (lower sensitivity) Regressions as low as 5 mg/kg QD Stasis achieved at 100 mg/kg Efficacy: Efficacy: ED50: 2 mg/kg ED50: 6.3 mg/kg ED90: 13 mg/kg ED90: 21 mg/kg All dosing, PO, QD All tr
Slide 16: PK/PD alkylation is consistent with xenograft efficacy
PK/PD alkylation is consistent with xenograft efficacy Efficacy: Efficacy: NCI-H358 ED50: 2 mg/kg NCI-H2122 ED50: 6.3 mg/kg ED90: 13 mg/kg ED90: 21 mg/kg G12C alkylation: G12C alkylation: ED50: 6.6 mg/kg ED50: 9.7 mg/kg ED90: 13 mg/kg ED90: 20 mg/kg • KRAS G12C alkylation/MAPK target gene modulation
Slide 17: Preclinical PK/PD modeling guides clinical dose projections
Preclinical PK/PD modeling of KRAS G12C mutant tumor models help guide clinical dose projections Xenograft 25 mg/kg Single Dose 0 Plasma Concentration (uM) KRAS G12C % Alkylation 1 H358 Alkylation Observed 0.1 H358 Alkylation Simulated 50 H2122 Alkylation Observed 0.01 H2122 Alkylation Simulated 0.0
Slide 18: Summary
Summary GDC-6036: • Irreversibly alkylates KRAS G12C and locks it in the inactive GDP-bound state KRAS G12C • Is more potent and more selective in vitro than sotorasib and adagrasib • Exhibits significant anti-tumor efficacy across KRAS G12C-positive models GDC- GDP 6036 • Currently is in Phase 1 cl