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Download5 MB Genentech: Pipeline with focus on Partnering James Sabry, MD, PhD Senior Vice President of Genentech Partnering Roche Group Unique diversity of approaches Independent centers for research Academia & Worldwide execution industry and early development Global Product gRED Development Over 150 pRED Manufacturing partners Chugai Commercialisation Roche Diagnostics 2 gRED Portfolio 33 molecules from Early Development to Phase 2 (18 with Collaborators) Early Devt (16) Phase 1 (10) Phase 2 (7) Pinatuzumab vedotin NME Anti-MUC16 ADC (Anti-CD22 ADC) Anti-STEAP1 ADC NME Anti-NaPi ADC NME ChK-1 inh (GDC-0575) Anti-HER3 EGFR DAF NME ERK inh (GDC-0994) Ipatasertib (GDC-0068) NME ADC NME Quilizumab (Anti-M1 prime) NME ADC NME Crenezumab (Anti-Aβ) Anti-OX40 NME Anti-FluA NME SERD (GDC-0810) NME Anti-IL17 NME NME NME NME NME NME Oncology! Immunology! NME Neuroscience ! NME Ophthalmology ! Legend:! Metabolism! Collaborator(s)! Infectious Diseases! 3 Source: Roche Q3 2014 Investors Update, October 15, 2014. Phase based on FPI. Genentech Portfolio Strategy gRED’s focus is to:! ! 1." Remain the leader in Oncology! 2." Continue to deliver diagnostic-based therapies in Immunology & Ophthalmology! 3." Make significant advances in Neuroscience, Infectious Diseases, and other key areas! R&D highlights:! ! •" Robust portfolio of large molecules and small molecules! •" Advances in antibody engineering! •" Personalized Health Care: right medicine for the right patient! 4 Expanding Our Leadership in Oncology Future:! Immunotherapy (anti-PDL1, anti-ox40, IDO, NMEs)! Leading in further outcome Combinations! improvements " Antibody Drug Conjugates (ADCs)! New pathways (PI3K, SERDs, apoptosis) ! Present: HER2! Heme ! Anti-" Transformative angiogenesis! Pathway! Franchise! approaches" ! Herceptin®# Rituxan®/ Avastin! ®! ® ® Kadcyla # MabThera # ! Perjeta®! Gazyva®/ GazyvaroTM! Bcl-2! ADCs! 5 Outline: Project Highlights •" Oncology: -" Cancer Immunotherapies -" Seragon ARN-810 -" HER2 Therapies: Herceptin, Perjeta, Kadcyla •" Neuroscience: Nav1.7 6 Cancer Immunotherapies anti-PD-L1 (MPDL3280A), anti-OX40, NLG919 IDO Inhibitor 7 The Cancer Immunity Cycle: Immunosuppression is the rate limiting step to effective anti-tumor immunity Immuno- suppression 8 Chen & Mellman (2013) Immunity Targeting immunosuppression by blocking the PD-L1/PD-1 pathway “Adaptive expression” •" PD-1/PD-L1 interaction inhibits T cell of PD-L1 activation, attenuates target killing: prevents overstimulation of T cells or tumor- during acute virus infection infiltrating IFNγ-mediated immune cells up-regulation of tumor PD-L1 • " A large percentage of tumors also up- PD-L1/PD-1 inhibits regulate PD-L1 and evade killing by T tumor cell killing cells Shp-2 MAPK! PI3K •" Blocking PD-1 binding restores effector pathways! T cell activity 9 Rapid and Sustained Response in an NSCLC Patient Treated With MPDL3280A Monotherapy Baseline Post C2 (Week 6) Post C12 (Week 36) 64-year-old male with squamous NSCLC s/p R lobectomy; cisplatin + gemcitabine, docetaxel, erlotinib; PD-L1 positive 10 Hospital Universitario Vall d´Hebron (Cruz/Tabernero). Herbst et al. MPDL3280A Anti-PDL1 Phase I ASCO 2013 PD-L1 positive kidney cancer patient with a rapid response to MPDL3280A Biomarkers*at*baseline:* Baseline After 4 weeks Baseline PD-L1PD-L1 CD8 Biomarkers*at*week*4*post*C1D1:* On- Tx PD&L1$ CD8$ 51-year-old male with RCC s/p L nephrectomy, sunitinib, XRT T9, temsirolimus Carolina BioOncology Institute (Powderly) 11 Cho et al., J Clin Oncol. 31, 2013 (suppl; abstr 4505) Using patient data to understand cancer immunity and find new targets Anti-PDL1 Phase I data urothelial bladder cancer Progressive Disease (PD) • Why do many patients not respond? Stable disease (SD) • What combinations will promote PRs & CRs? Monotherapy durable responses (PR/CR) • What are the drivers of single agent response? Awarded FDA Breakthrough Status, May 2014 12 Powles et al (2014) Nature, in press T cell-directed Therapeutics: Multiple Possibilities Safety issues Clinical validation 13 Mellman et al (2011) Nature! Anti-OX40 can induce durable responses and immunity as a single agent: Pre-clinical efficacy and durability of response Primary Tumor Challenge Re-challenge CT26 Secondary ) ) 2000 3 3 Control EMT6 Secondary 3000 Anti-mouse OX40 EMT6 Primary 1500 2000 1000 1000 500 0 0 (mm Volume Tumor Tumor Volume (mm Volume Tumor 0 10 20 30 40 50 0 10 20 30 day day Treatment No Treatment Recently initiated enrollment in the Phase 1 clinical trial GO29313 14 http://clinicaltrials.gov/show/NCT02219724 gRED recently licensed new cancer immunotherapy molecule, NLG919 IDO Inhibitor IDO (indoleamine di-oxygenase) is induced by IFNg and acts with PD-L1 to suppress effector T cells Adaptive expression of PD-L1 Adaptive expression of IDO IDO IFNγ-mediated IFN -mediated γ up-regulation of up-regulation of tumor IDO tumor PD-L1 Inhibition of effector T cell function Shp-2 Shp-2 MAPK! MAPK! PI3K PI3K pathways! pathways! 15 Georgia Hatzivassiliou, Yichin Liu IDO mediates T cell suppression by reducing extracellular tryptophan and increasing kynurenine Dendritic Tumor cells Macrophages cells IDO* IFNg activates Free tryptophan IDO Kynurenine expression high low arylhydrocarbon mTOR ñ Uncharged Tryptophanol-tRNA receptor suppressive GCN2 kinase cytokines FoxP3 Promote translation Stress response Suppress Enhance T effectors T reg *TDO (tryptophan dioxygenase) is a 16 second related target to IDO Seragon: ARN-810 17 Targeting Estrogen Receptor positive Breast Cancer Tumor Burden Time Target ligand dependent ERα Activity Target ligand- independent ERα Activity •" SERDs – selective estrogen receptor •" Aromatase Inhibitors (letrozole) – block degraders (fulvestrant) synthesis of estrogens •" ERα Antagonists (tamoxifen) – compete with estrogens for binding to Erα •" SERDs – selective estrogen receptor degraders Seragon ARN-810 is an ER modulator with a dual mechanism of action: blocks the activation of ERα and induces the degradation of ERα by the proteosome 18 ARN-810 Demonstrates Tumor Regressions in Tamoxifen Sensitive and Tamoxifen Resistant Breast Cancer Models Tamoxifen-Resistant Breast Cancer Xenogra5 Study vehicle tamoxifen ARN-810 Chronic daily dosing of ARN-810 in ER+ Not all SERM/SERDs are created equally. xenograft model In tamoxifen-resistant xenografts: •" Tumor regression followed by long durable response •" ARN-810 at 100 mg/kg QD regress all tumors •" Study followed out to 1 yr •" Modest effect of Fulvestrant (SERD) and pipendoxifene (SERM Wyeth terminated post Median TTP for ARN-810 >1yr Phase I) Chronic dosing of Tamoxifen •" No effect for Arzoxifene (SERM Lilly failed in19 mBC •" Emergence of resistance @ approx. 70 days Phase 3) Identification of mutations in ERa in patients with acquired resistance to endocrine therapies •" Estimate that ~22% of ER+ patients acquire activating mutations in ERa •" ERa LBD mutations are ligand independent and constitutively active •" ARN-810, an orally administered, selective ER antagonist/degrader (SERD) is in Phase 1 (FPI April 2013) •" SRN-927, a next generation SERD from different chemical series, is in Early Development 20 Robinson et al 2013; Toy et al 2013; Merenbakh-Lamin et al 2013; Jeselsohn et al 2014 Oesterreich, S., Davidson, N. E. (2013). Nature Genetics, 45(12), 1415–1416 Cross-talk between ERα and PI3K pathways offer strong rationale for combination Letrozole Androstenedione Estrogen Testosterone Aromatase Plasma PIP PIP membrane P 2 P 3 P P P PTEN Tamoxifen PDK1 PI3K Cytoplasm ER P AKT P ER GDC-0032 P P ER ER ARN-810 ER P P Nucleus ER ER ER ER Response Element Response Proliferaon, Element growth, and 21 survival HER2 Therapies: Herceptin, Perjeta, Kadcyla 22 Continuing to raise the efficacy bar in HER2-positive metastatic breast cancer 25 PFS *? 20 PFS 18.5 Kadcyla/ PERJETA 15 PERJETA / (Months) PFS 12.4 Herceptin / Docetaxel PFS 10 Herceptin/ Docetaxel PFS 6.7 Median 5 PFS 2.5 Herceptin Paclitaxel Paclitaxel CLEOPATRA MARIANNE 0 Commitment to HER2 + mBC patients •" *Illustrative. MARIANNE trial ongoing, results are not yet available. 23 CLEOPATRA: Perjeta + Herceptin Overall survival (OS) final analysis (Feb 2014) • First-line treatment with pertuzumab, trastuzumab, and docetaxel significantly improved OS for patients with HER2-positive MBC compared with placebo, trastuzumab, and docetaxel • The 56.5-month median OS is unprecedented in this indication and confirms the pertuzumab regimen as first-line standard of care for patients with HER2-positive MBC 1.0 Ptz + T + D: median 56.5 months Δ 15.7 0.9 Pla + T + D: median 40.8 months months 0.8 0.7 HR 0.68 95% CI = 0.56, 0.84 0.6 p = 0.0002 0.5 0.4 0.3 0.2 Randomised treatment Proportion event-free Proportion 0.1 Ptz + T + D Pla + T + D 0.0 0 10 20 30 40 50 60 70 80 24 Month Median follow-up of 50 months (range 0–70 months) at final analysis Improving standard of care in HER2-positive breast cancer in all lines of treatment Biosimilars launch (EU) 2nd line mBC Xeloda + lapatinib Kadcyla (EMILIA) 1st line Herceptin Herceptin & Perjeta + chemo Kadcyla & Perjeta (MARIANNE) mBC + chemo (CLEOPATRA) Adjuvant Herceptin + Herceptin sc + chemo Herceptin & Perjeta Kadcyla & Perjeta BC chemo (HannaH) + chemo (APHINITY) + chemo (KAITLIN) Neoadjuvant Herceptin + chemo Herceptin + Perjeta + chemo Kadcyla & Perjeta (KRISTINE) BC (NOAH)1 (Neosphere, Tryphaena)2 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Established standard of care Potential new standard of care Potential future standard of care NEOSPHERE study filed for neoadjuvant breast cancer indication
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