Roche Committed to Innovation

Transcription

1 Roche Committed to Innovation Jean-Jacques Garaud, M.D. Global Head of pharma. Research & Exploratory Development Roche Pharmaceuticals Exane BNP Paribas Healthcare Conference May 10, 2010, Paris 1

2 Roche: Focused on medically differentiated therapies Value Focus Pharma Dia MedTech OTC Generics Differentiation 2

3 Unique diversity of approaches Federation of >150 partners Autonomous centers Worldwide execution Genentech R&ED* Roche R&ED* Roche Dx Chugai Research Early Dev. Global Product Development Manufacturing Commercialisation Diversity Scale, Reach, Speed * R&ED = Research & Early Development 3

4 Roche pharma Research & Early Development Legacy Six transitions to late-stage over Dalcetrapib Aleglitazar Taspoglutide GA101 B-RAF antagonist Gly T-1 inhibitor 4

5 The pred mission Science and patients: our focus, our passion Deepen understanding of disease biology and the molecular basis of heterogeneity of diseases Deliver on individual patient needs through the implementation of PHC strategies Leverage technologies and capabilities to develop new compounds to Lifecycle Investment Point (LIP) 5

6 Three critical steps for innovation in drug discovery and early development We know what to target (Understanding disease, new pathways, Biomarkers, PHC) We have a powerful multiplier (Therapeutic Modalities) World-Class skills in Translational Medicine (PoM and PoC) Small Molecules Therapeutic Proteins RNA Interference Peptides Therapeutic stem cells 6

7 Strong progress in small molecule discovery Attrition for safety reasons dramatically reduced Outstanding medicinal chemistry capabilities + Industry-leading safety based attrition rates in Phase 0 and 1 Phase 0 Phase 1 % of projects terminated for safety reasons Source: internal analysis 7

8 MDM2 antagonist (RG7112) induces apoptosis Nutlins: a novel approach to cancer therapy p53 is a major tumor suppressor protein that induces apoptosis in tumors MDM2 naturally inhibits the activity of p53 Nutlins prevent MDM2 from inactivating p53 Nutlins represent a breakthrough in cancer drug research small molecule that specifically blocks the interaction between the two proteins Roche is the leader in the field RG7112 currently in late Phase 1 Companion diagnostics in co-development with Diagnostics (p53 chip & MDM2 expression) Xenografts model results L Vassilev et al. (2004) Science, 303, ; L Vassilev (2006) Trends in Molecular Medicine 13, ; Rosisnki, J., etal., Proc. Natl. Acad. Sci (2006); Xia M., etal., Cell Cycle (2008); Huang B, etal., Mol Cancer Res Sep;7(9):

9 Enhancing antibody performance drug NK or MØ bi-specific Antibodies Bi-specific antibody binds to two different targets in different cells drug Naked Antibodies Antibody inhibits or activates signaling Armed Antibodies Antibody specifies delivery of drug ADCC enhanced Antibody Antibody recruits immune effector cell and induces cytotoxicity bi-specific Antibodies Bi-specific antibody binds to two different targets and enhances specificity 9

10 T-DM1 HER2 suppression meets cytotoxic potency A novel anti-cancer agent Herceptin s biologic activity Targeted intracellular delivery of a potent cell-killing agent, DM1 Unprecedented efficacy in heavily pre-treated HER2+ mbc 33% ORR Single agent data indicates better tolerability than standard chemotherapy-containing regimens In collaboration with ImmunoGen 10

11 T-DM1 Changing paradigm in a broad clinical program HER2-positive Metastatic Breast Cancer Third-line Second-line First-line First-line Treatment Treatment Treatment Treatment Phase II Phase III EMILIA Randomised Phase II Preparing for Phase III Single ARM: T-DM1 ARM A: T-DM1 ARM B: Xeloda plus lapatinib ARM A: T-DM1 ARM B: Herceptin plus docetaxel ARM A: Herceptin plus taxane ARM B: T-DM1 ARM C: T-DM1 plus pertuzumab Potential US submission Potential submission 2012 Potential submission beyond Phase II 1L HER2+ mbc data submitted for presentation at In collaboration with ImmunoGen ESMO

12 Pertuzumab Redefining HER2 blockade in breast cancer Synergistic to Herceptin Phase II study of pertuzumab + Herceptin Clinical benefit rate 50% Important Upcoming Data Results: Phase II NeoSphere ASCO 2010 Phase III CLEOPATRA (2011) Neoadjuvant HER2-positive Breast Cancer Phase II NeoSphere ARM A: Herceptin plus docetaxel ARM B: Herceptin, docetaxel plus pertuzumab ARM C: Herceptin plus pertuzumab ARM D: Pertuzumab plus docetaxel First-line HER2-positive Metastatic Breast Cancer Phase III CLEOPATRA ARM A: Herceptin and docetaxel ARM B: Pertuzumab plus Herceptin and docetaxel 12

13 GA101: a glycoengineered, type II anti-cd20 antibody Enhanced ADCC and direct cell induction Type II epitope GA101 in patients with relapsed/refractory CD20+B-CLL Glycoengineered Mossner E., etal., Blood, Mar 2010 GA101 B-CLL data presented at ASH, December,

14 GA201 Anti-EGFR glycoengineered antibody for enhanced ADCC A potential breakthrough in cancer therapy opportunity to treat k-ras mutant tumors Will allow to demonstrate the utility of glycoengineering antibodies Roche could become the leader in ADCC enhanced antibody therapy GA201 vs. other EGFR Abs (NK92/FcgRIIIA-158F effector cells) Superior efficacy in CRC (kras mut liver met model in Scid-bg mice) ADCC (%) GA201 Cetuximab Fully human EGFR mab Survival % Cetuximab Vehicle GA Antibody Concentration (ng/ml) Study day Gerdes C., etal., Presentation at AACR Meeting, April 2009; Abstract Data on file, Roche Patient 1696 (kras WT, EGFR mut CRC): complete response after 12 cycles 14

15 Late-stage pipeline continues to build up Expanding into new therapeutic areas Number of NMEs Virology CNS Metabolic Inflammation Oncology 10 GlyT-1 inh aleglitazar taspoglutide dalcetrapib up to 13 HCV pol inh * ocrelizumab MS* GlyT-1 inh SGLT2 inh* aleglitazar taspoglutide dalcetrapib 4 ocrelizumab Hedgehog inh lebrikizumab * Hedgehog inh 2 taspoglutide dalcetrapib BRAF inhibitor T-DM1 BRAF inhibitor T-DM1 ocrelizumab ocrelizumab RG7159 (CLL) RG7159 (CLL, NHL) Actemra pertuzumab pertuzumab pertuzumab E * LIP or phase III decision pending 15

16 Metabolism/CV: High Unmet Need Remains > 65% of CV events not prevented despite wide use of statins 100% 80% 60% 40% 20% Major clinical trials aimed at reducing cardiovascular risk 0% 4S Lipid Care HPS WOSCOP AFCAPS/ TexCAPS % event not prevented % event prevented TNT 4S, The Lancet, Lipid, NEJM, Care, NEJM, HPS, The Lancet, 2002 WOSCOP, NEJM, AFCAPS/TexCAPS, JAMA, TNT, NEJM,

17 FRAMINGHAM: Low HDL-C is an independent factor of CAD risk even when LDL-C is low CAD Risk After 4 Years a (2.6) 160 (4.1) 220 (5.7) LDL-C, mg/dl (mmol/l) 25 (0.7) 45 (1.2) 65 (1.7) 85 (2.2) HDL-C is inversely correlated with CAD risk Correlation is independent of LDL-C HDL-C, mg/dl (mmol/l) a Men aged Castelli. Can J Cardiol. 1988;4(suppl A):5A 10A. CAD: coronary artery disease, HDL-C: high densitiy lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol 17

18 HDL removes cholesterol from atherosclerotic plaque CETP inhibition: next breakthrough in CV risk reduction? Hypothesis tested with CETP inhibition Increases HDL Promotes cholesterol efflux from macrophages in atherosclerotic plaque Promotes reverse cholesterol transport? Cardiovascular Morbidity and Mortality benefits LIVER LDL CETP Atherosclerosis Reverse Cholesterol Transport HDL Cholesterol Efflux Bile Excretion PLASMA PERIPHERAL TISSUE 18

19 Dalcetrapib and torcetrapib Different mechanisms of CETP inhibition dal HDL Dalcetrapib binds to CETP, inducing a conformational change of CETP 1 HDL generated is of normal composition CETP torcetrapib HDL Torcetrapib binding to CETP results in a high affinity complex of torcetrapib, HDL and CETP 2,3,4 HDL generated is different from physiological 1 Okamoto et al. Nature. 2000;406: ; 2 Niesor et al. Atheroslerosis. 2008;199:231; 3 Clark et al. J. Lipid Res. 2006;47: ; 4 Barter et al. N Engl J Med. 2007;357:

20 The true unmet medical need in type 2 diabetes is cardiovascular risk reduction Diabetes/CVD (n = 1148) Diabetes/No CVD (n = 569) Patients with acute coronary syndrome and diabetes: at highest risk of recurring CV events No Diabetes/CVD (n = 3503) No Diabetes/No CVD (n = 2796) RR=2.88 ( ) Patients with ACS and diabetes are characterized by atherogenic dyslipidemia: Triglycerides HDL Event rate RR=1.99 ( ) RR=1.71 ( ) small, dense LDL Apo-B 0.05 RR= Malmberg K et al. Circulation 2000;102: ; Results of the OASIS (Organisation to Assess Strategies for Ischemic Syndromes) Registry Months 20

21 Aleglitazar: Significant dose-dependent reduction in HbA1c and improvements in lipid profiles Triglycerides Placebo Aleglitazar Pioglitazone HDL-C Placebo Aleglitazar Pioglitazone μg 150 μg 300 μg 600 μg 45 mg 50 μg 150 μg 300 μg 600 μg 45 mg LS mean (SE) percent change from baseline triglycerides p= P< P< P< p=0.006 LS mean (SE) percent change from baseline HDL-C p=0.031 p< p< p< p=0.001 LDL-C Placebo Aleglitazar Pioglitazone HbA1c Placebo Aleglitazar Pioglitazone LS mean (SE) percent change from baseline LDL-C ?g 150?g 300?g 600?g p=0.08 p=0.003 p=0.012 Robert R Henry, et al., Lancet 2009:374: p< mg p=0.96 LS mean (SE) absolute change from baseline HbA1c (%) all P values vs. placebo 50 μg 150 μg 300 μg 600 μg p=0.048 p< p< p< mg p<

22 Aleglitazar development in patients with high CV risk Phase III CV outcomes study: recruitment started Q Design Double-blind, placebo-controlled study on top of standard of care Treatment duration: At least 2.5 years N = 6,000 Patients Type 2 diabetes (known and recently diagnosed) Hospitalized for acute coronary syndrome Screening/ placebo run-in period Treatment period Aleglitazar 150 µg or placebo Follow-up period Standard of care (diabetes and other cardiovascular risk factors) At least 2.5 years 4 weeks Primary endpoint Composite endpoint of reduction in cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke (MACE) 22

23 Schizophrenia, a devastating disease The clock stops when schizophrenia starts Average life expectancy ~20 years shorter Attributed to suicide and cardiovascular co-morbidities Patient faced with invalidility Loss of job, hobbies, friends Heavily dependent on support Poor insurance coverage in the US High burden for caregivers Isolation Loss of previous life, often job Depression and stress 23

24 Features of schizophrenia syndrome Heterogeneity requires specific treatment of symptoms Positive Symptoms Delusions Hallucinations Disorganized speech Catatonia Social Dysfunction Work Interpersonal relationships Self-care Primary Negative Symptoms Affective flattening Alogia Avolition Anhedonia Social withdrawal Cognitive Deficits Attention Memory Executive functions (eg, abstraction) Maguire GA. Am J Health-Syst Pharm. 2002;59:S4-S11. Comorbid Substance Abuse Mood Symptoms Depression Hopelessness Suicidality Anxiety Agitation Hostility Insomnia 24

25 GlyT-1 inh. phase II data in schizophrenia Primary endpoint: PANSS negative symptom factor score 0-1 Change from Baseline at Week Improvement Improvement * -7 p = p < 0.05 Placebo GlyT-1 Placebo GlyT-1 ITT Population Per-Protocol Population Three doses were tested in Phase II data shown is for the most effective dose 25

26 Strong late-stage portfolio of NMEs Limited risk due to rigorous proof of concept studies CHF 5 bn Peak sales CHF 2 bn dalcetrapib T-DM1 (early launch) aleglitazar ocrelizumab MS* GlyT-1 inh GA101 pertuzumab taspoglutide T-DM1 BRAF inh (Melanoma) Hedgehog inh (BCC) * Phase III go/no go decision pending 0% 50% 100% Probability of technical success 26

27 Changing the practice of medicine! Prevent blindness with Lucentis (AMD, RVO and DME) Better therapies for cancer (antibody drug conjugates, glycoengineered Abs- GA101, pertuzumab, BRAF and hedgehog inhibitors) New therapies for Schizophrenia and MS (GlyT-1 inh. and ocrelizumab) Improve outcomes in cardiovascular disease (taspoglutide, aleglitazar, dalcetrapib) Launch at least 6 new products (NMEs) by end Line extensions of existing products could be filed by end

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