Genentech Research & Early Development Founders Research Centers 1 & 2 Founders Research Centers 1 & 2 Andrew Chan, M.D., Ph.D. Senior Vice President, Research Biology September 2017
gred focus areas Discovering new biologies and applying them broadly Oncology Discover and develop novel therapies and transformative combinations: Molecular oncology Cancer immunology Focus on high unmet need indications: Respiratory: asthma, COPD, IPF Rheumatology: RA, SLE, scleroderma Gastroenterology: UC, CD Opportunistic: wound healing, CSU Personalized cancer vaccine, T-cell dependent bispecific antibody platform Immunology BTK inhibitor Ophthalmology Focus on age-related macular degeneration Today s highlights Neuroscience Focus on: Alzheimer s disease Parkinson s disease Amyotrophic lateral sclerosis Moderate to severe pain Infectious disease Focus on difficult-to-treat bacterial and viral infections: Influenza Methicillin-resistant Staph. aureus ATB-resistant, gram-negative bacteria COPD=Chronic obstructive pulmonary disease; IPF=Idiopathic pulmonary fibrosis; RA=Rheumatoid arthritis; SLE=Systemic lupus erythematosus; UC=Ulcerative colitis; CD=Crohn's disease; CSU=Chronic spontaneous urticaria; ATB=Antibiotic 2
gred leads the industry in scientific publications Sustained record of cutting-edge scientific discoveries Past 7 Year Average ~400 Publications/yr ~16 in Cell, Nature and Science/yr 600 Total Cell, Nature, Science 120 Key Benefits 500 100 400 80 Progress science Recruit top talent 300 200 100 0 489 443 444 375 395 398 320 202 18 20 18 25 10 14 7 6 2010 2011 2012 2013 2014 2015 2016 2017* 60 40 20 0 External recognition for scientists Engage investigators interest to enhance collaboration *As of Aug 2017, including articles, reviews, books and conference 3
The cancer immunity cycle Oncology meets immunology 3 T cell priming and activation Lymph node Blood vessel 4 T cell trafficking 5 T cell infiltration 2 6 Cancer antigen uptake and presentation Personalized Cancer Vaccine (P1) 1 Cancer antigen release Tumor 7 Killing of cancer cells Tumor antigen recognition by T cells Checkpoint Inhibitors Source: Adapted from Chen & Mellman, Immunity 39(1):1-10 4
Personalized cancer vaccine Overcoming potential priming defects in the tumor Tumor biopsy Mutation identification Vaccine design Vaccine synthesis RNA backbone Neoantigen 1 Neoantigen 2 Neoantigen n Neoantigen n+1 4 weeks Fully individualized vaccine (mrna-based approach) On demand-production (highly iterated and reproducible with low failure rate) Suitable for potentially all tumor indications, also with low incidences No negative thymic selection of high-affinity TCRs against mutated epitopes Induction of immune responses with high tumor specificity TCR=T-cell receptor; PCV=Personalized cancer vaccine; PCV in collaboration with BioNTech Sahin et al., Nature 547:222-229 5
Immunogenic responses against neoantigens Initial monitoring data from melanoma patients 13 patients with stage III and IV melanoma Screening TAA RNA vaccination Neo-epitope discovery and vaccine manufacturing Days of vaccination, dose: 500 or 1,000 mg 1 4 8 11 15 22 29 43 8 neo-epitope RNA vaccinations * * * * * * * * Immune monitoring Up to 12 vaccinations in continued treatment PCV induces T cell immunity Reduction of recurrent metastatic events post-vaccination Neoepitopes T cells 32% 68% 26% 17% 57% P < 0.0001 de novo pre-formed CD4 CD8 CD4 & CD8 PCV=Personalized cancer vaccine; PCV in collaboration with BioNTech Sahin, U., et al, Nature 2017; 547:222-229 6
PCV may benefit all immunological phenotypes Inducing immunity in patients who have none Immune Desert Immune Excluded Inflamed Vaccine well tolerated Ongoing Phase 1b trial Ph1 trial in combination with Tecentriq expected 2H 2017 PCV=Personalized cancer vaccine; PCV in collaboration with BioNTech 7
TDB Abs bypass cancer immunity cycle steps 1-3 Anti-CD3 arm activates T-cell killing of target cell T cell Tumor T-cell Dependent Bispecific Antibody T Cell CD3 CD3 TDB CD3 Tumor Ag Tumor Ag Tumor cell TDB=T-cell dependent bispecific antibody Dead tumor cell 8
Splenic B cells (10 6 ) CD20 + B cell (number/gm spleen) CD20+ B cell Count (/g) PC (% of CD45-CD20-) TDBs for hematologic cancers CD20 TDB in Phase 1 in NHL and CLL ongoing CD3 CD20 CD3 FcRH5 CD20 TDB for B cell lymphoma and leukemias Ongoing Phase 1b trial Combination with atezolizumab planned FcRH5 TDB for multiple myeloma Published in Cancer Cell (Li, J., et al, Cancer Cell 31: 383 395, 2017) hucd3 hucd20 mouse Spleen-CD20+ B Cell Count Cyno splenic B cells (D7) 8*10 8 10 7 Depletion of PCs in BM at D10 Cyno plasma cells (D10) 3.0 6*10 6 10 7 2.0 P = 0.01 4*10 4 10 7 2*10 2 10 7 1.0 Control Antibody Rituxan CD20-TDB 0 mg/kg 0 1 mg/kg 1 2 mg/kg 2 4 mg/kg 4 FcRH5-TDB (mg/kg) FcRH5.TDB (IV Inf.) TDB=T-cell dependent bispecific antibody 1) Sun, L., et al, Sci Transl Med. 2015; 7(287):287ra70; 2) Li, J., et al, Cancer Cell. 2017; 31(3):383-395 0 0.0 0 2 4 FcRH5-TDB (mg/kg) 0 mg/kg 2 mg/kg 4 mg/kg anti-fcrh5/cd3 TDB (IV Inf.) 9
TDBs for HER2-positive breast cancer Novel MOA for a HER2-directed therapy CD3 HER2 Single agent activity in several models with durable complete responses (tumor regression observed at 0.05 mg/kg) Lack of killing HER-2 low expressing HT55 cells provides opportunity for therapeutic index Regression of T-DM1 insensitive tumors (not shown here) 1000 HT55 + T cells HT55 cells alone KPL4 Tumor HT55 Tumor HER2 HER2 Tumor size mm 3 500 KPL4 cells alone KPL4 + T cells 0 0 5 10 15 HER2-TDB (0.05 mg/kg) TDB=T-cell dependent bispecific antibody; MOA=Mechanism of action Junttila, T., et al, Cancer Res. 2014;74(19):5561-71 10
gred s TDB pipeline targets Best in disease T-cell recruiting therapy CD20 FcRH5 HER2 B-cell malignancies Multiple Myeloma Breast cancer Others to follow Colorectal cancer, ovarian cancer, prostate cancer, small cell lung cancer Off-the-shelf therapeutic Predictable PK/PD to aid drug development Predictable half-life TDB=T-cell dependent bispecific antibody 11
BTK small molecule inhibitor for immunology GDC-0853: highly potent, selective & reversible BCR FcgRIIIA FcgRI FceRI TLR 2,4 E-selectin a b g BTK I YPO4 T A M YPO4 BTK BTK BTK BTK BTK I YPO4 T A YPO4 M CD40 TLR 8,9 Rheumatoid arthritis (N=580) Phase 2 (cohort 1): GDC-0853 vs adalimumab in DMARD-IR patients (including dose ranging) Phase 2 (cohort 2): GDC-0853 vs MTX in TNF-IR patients BTK BTK Systemic lupus erythematosus (N=240) Phase 2: GDC-0853 vs placebo in moderate to severe SLE patients Chronic spontaneous urticaria (N=45) Phase 2: GDC-0853 vs placebo Data expected in 2018 BTK=Bruton s tyrosine kinase; DMARD=Disease-modifying antirheumatic drug; TNF=Tumour necrosis factor; DMARD-/TNF-IR=Insufficient response to DMARD/TNF; SLE=Systemic lupus erythematosus 12
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