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 Tumor Volume (mm Tumor Volume (mm 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 Receptor positive Tumor Burden

Time

Target ligand dependent ERα Activity Target ligand- independent ERα Activity • SERDs – selective • Aromatase Inhibitors (letrozole) – block degraders () synthesis of • ERα Antagonists () – 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 Xenogra 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 (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 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 in EU

25 Timelines refer to the expected dates of first filing; 1 approved in JP since 2011, in EU 2012; 2approved in US since 2013 Neuroscience: Nav1.7

Voltage-gated sodium channel for pain indications

26 Why are we interested in treating pain?

• Pain is a significant medical issue • 20% of individuals experience pain (majority moderate-severe) • There is a substantial unmet medical need for novel pain drugs • Only 25% of people with pain achieve adequate relief with current therapy • Driven primarily by insufficient efficacy & narrow safety margins that limit dose • Clinical studies are primarily dominated by reformulated or next generation opioids with similar liabilities to current therapy • There is a huge opportunity for novel pain drugs with new mechanisms of action

27 Nav1.7 Function: Voltage gated sodium channel that drives pain signaling

Nav1.7 Pain sensing receptors begin - to depolarize + - the nerve + Signal + propagates Nav1.7 senses the down the nerve change in polarization and then opens Na+ ++ --

-- ++ - 65 mV + 40 mV Closed state Open state

--

28 ++ Inactivated state Nav1.7: Pain target identified from experiment of nature

Nav1.7 Biology • Voltage-gated Na+ channel (generation of action potential) • Expressed in pain-sensing nerve fibers

• Selectivity relative to other Nav channels will be important for optimal safety profile

Nav1.7 Human Genetics • Loss-of-function mutations in Nav1.7 results in Congenital Indifference to Pain (CIP) • Recessive disorder; no pain from birth • Defective olfaction (anosmia); Otherwise physiologically normal • Activating mutations cause spontaneous pain syndromes (IEM- Ashlyn Blocker- inherited erythromelalgia, PEPD- paroxysmal extreme pain CIP patient with complete loss of disorder; SFN- small fiber neuropathy) function of both Nav1.7 alleles 29

Nav1.7 knockout mice show reduced pain behavior • Acute, inflammatory, and neuropathic pain models

Based on this promising biology, Genentech is collaborating with Xenon Pharmaceuticals to discover selective and orally available Nav1.7 inhibitors Collaboration Structure

• Upfront payment, research funding • Eligible for milestone payments that could reach $650MM • Royalties

• Exclusive license to all collaboration compounds • Helped discover human • Exclusive access to know- • Consider Nav1.7 to be best genetic evidence implicating how and proprietary novel, biologically validated Nav1.7 as compelling pain research technologies pain target target • Pain is re-emerging area, • Deep expertise in pain and looking to leverage partner’s ion channels know-how

• Compelling early stage inhibitor molecules Integrated collaboration maximizes PTS for first-in-class and/or best-in-class compound for high-priority, highly- competitive target COLLABORATION TO PURSUE EMERGING BIOLOGY

30 Summary

• 50% of the Genentech portfolio reflects partnering activities

• Blend of internal and external innovation drives pipeline growth

• Advancing leadership in Oncology through new Pathways, Combination trials and Cancer Immunotherapy

• Positioned well to deliver innovative and differentiated therapies to improve patient’s lives

31 Q&A