Roche data & results at EULAR 2006 Conference call Amsterdam, The Netherlands and Basel, Switzerland Friday, June 23, 2006

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Darlene Booker
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1 We Innovate Healthcare 1 Roche data & results at EULAR 26 Conference call Amsterdam, The Netherlands and Basel, Switzerland Friday, June 23,

2 Forward-looking statements This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as believes, expects, anticipates, projects, intends, should, seeks, estimates, future or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 1 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. 3 Introduction Dr. Karl Mahler Head of Investor Relations, Roche 4 2

3 Conference call agenda Focus on rheumatoid arthritis patients with inadequate response to DMARDs Prof. Paul Emery, arc Professor of Rheumatology, Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds Teaching Hospitals Trust, UK Focus on rheumatoid arthritis patients with inadequate response to TNF inhibitors Prof. Edward Keystone, Professor of Medicine, University of Toronto, Canada Results from the clinical program for MabThera and Actemra in RA and Roche s emerging franchise in RA/autoimmune diseases Q&A Dr. Urs Schleuniger, Business Director, Hematology & Autoimmune Diseases, Roche 5 Sales of biologics in RA Strong growth outside the US Other 7% Canada 2% Top EU 16% RA 24 CHF 5bn US 75% Other 9% RA 25 CHF 7.7bn Canada 2% US 71% Top EU 18% 4 vs. 5 sales growth: US ~29 %, Canada ~31 %, Top 5 EU ~41 %, Others ~68 % Source: IMS PADDS, sales 25 in LC CHF; sales in RA estimated with US PDDA Verispan 6 3

4 Roche: Existing and future pillars of growth Oncology Xeloda MabThera Herceptin Avastin Tarceva R744 CERA Bondronat R1273 Omnitarg R1492 CAL CHU ANT 1 phase I compounds ON HAND Autoimmune MabThera Actemra R153 p38 kinase inh. R1594 Hum anti CD-2 4 phase I compounds PROMISING LATE STAGE Metabolic R144 R1438 R1658 (JTT-75) IPS 3 phase I compounds EMERGING MID-TERM Neurology 3 phase I compounds 4 phase compounds EARLY STAGE 7 Focus on rheumatoid arthritis patients with inadequate response to DMARDs Prof. Paul Emery arc Professor of Rheumatology, Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds Teaching Hospitals Trust, UK 8 4

Rituximab: a novel biological agent for RA Rituximab is a novel genetically engineered anti-cd2 therapeutic monoclonal antibody that selectively targets CD2+ B cells Shaw et al.

5 Rituximab: a novel biological agent for RA Rituximab is a novel genetically engineered anti-cd2 therapeutic monoclonal antibody that selectively targets CD2+ B cells Shaw et al. Ann Rheum Dis 23;62(Suppl. 2):55 59; Silverman & Weisman. Arthritis Rheum 23;48: Rituximab selectively targets CD2-positive B cells Antigen-independent phase Antigen-dependent phase Surrogate light chain IgM IgM IgD IgM, IgD, IgA, or IgE Secreted IgG, IgA, IgE, or IgM Stem cell CD19 CD2 Pro-B cell Pre-B cell Immature B cell Mature B cell Activated B cell Plasma cell Adapted from Sell et al. Immunology, Immunopathology, and Immunity. 6th ed. 21; Roitt et al. Immunology. 6th ed. 21; Tedder et al. J Immunol 1985;135:

6 Phase IIa: significant ACR responses at week 24 sustained up to week 48 Patients (%) MTX 24 Weeks 48 Weeks * Rituximab * Rituximab + CTX * * Rituximab + MTX * * MTX Rituximab * * Rituximab + CTX * Rituximab + MTX * * *p<.5, Fisher s exact test comparing the MTX group with each rituximab group. ACR = American College of Rheumatology Edwards et al. N Engl J Med 24;35: ACR2 ACR5 ACR7 11 DANCER study: Significant ACR responses at 24 weeks *** *** 54 *p=.29; ***p.1 vs placebo Patients (%) *** 34 *** 5 13 * 2 *** ACR2 ACR5 ACR7 Placebo (n=122) Rituximab 2 x 5 mg (n=123) Rituximab 2 x 1 mg (n=122) RF-positive patients, ITT population (n=367) Emery et al. Arthritis Rheum 26;54:

7 DANCER study: High efficacy endpoints associated with the high dose Patients/change (%) ACR ACRn 22 Good EULAR response DAS remission DAS low disease Placebo (n=122) Rituximab 2 x 5 mg (n=122) Rituximab 2 x 1 mg (n=121) Emery et al. Arthritis Rheum 26;54: DANCER study: iv glucocorticoid premedication reduces the incidence of acute infusion reaction Patients (%) Placebo DANCER study 1 st infusion 2 nd infusion 32 Rituximab 2 x 5 mg Rituximab 2 x 1 mg Placebo Rituximab 2 x 5 mg GC: placebo GC: iv GC: iv + po 8 9 Rituximab 2 x 1 mg Fleischmann et al. Arthritis Rheum 25;52:abstract

8 Open-label study of rituximab Repeated treatment courses: Patients with inadequate response to DMARDs (no prior TNF inhibitor exposure) 15 Study design Phase II Open-label extension study of rituximab treatment Course 1 of rituximab Course 2 of rituximab Phase IIa Placebo Rituximab 2 x 1 mg Rituximab 2 x 1 mg + cyclophosphamide Rituximab 2 x 1 mg + MTX The timing of the second treatment course was variable, depending on clinical need Phase IIb DANCER Rituximab 2 x 1 mg + MTX Placebo Rituximab 2 x 5 mg + MTX Rituximab 2 x 1 mg + MTX Rituximab 2 x 1 mg + MTX Long-term follow-up All patients in the open-label extension study received weekly methotrexate (1 25 mg) and methylprednisolone 1 mg IV on Days 1 and 15 plus oral prednisone 6 mg/day on Days 2 7 and 3 mg/day on Days

9 Eligibility criteria for additional treatment Patients had shown a defined improvement following a single course of rituximab given within the earlier, randomised, controlled rituximab clinical study 2% reduction in both SJC and TJC (at the same time) during any visit from Week 16 onwards SJC 8 (66 joint count) and TJC 8 (68 joint count) Patients had: Previously failed 1 5 DMARDs for lack of efficacy Inadequate clinical response to MTX at the time of enrolment Long standing, active RA, defined as 8 swollen and 8 tender joints Additional treatment courses were administered at the physician s discretion 17 Patients in clinical trials have received up to 4 treatment courses As of October 25, 57 patients had received 2 courses of rituximab 145 had an inadequate response to DMARDs without prior exposure to TNF inhibitors Of these, 99 patients reached 24 weeks of follow-up post-second course at the time of the data-cut Emery et al, EULAR 26 (Abstract No. OPO17) 18 9

10 Patient baseline disease characteristics show severe long-standing rheumatoid arthritis Patients who have reached 24 Weeks follow-up after 2 courses of rituximab (n=99) Age RA disease duration (mean, yr) Swollen joint count (mean, n) Tender joint count (mean, n) C-reactive protein (mean, mg/dl) Disease activity score (mean) Rheumatoid factor (n, %) Negative Positive (16%) 83 (84%) Emery et al, EULAR 26 (Abstract No. OPO17) 19 ACR scores further improved with repeated courses 8 73 Course 1 (n=99) Course 2 (n=99) Patients (%) ACR2 ACR5 ACR7 ACR2 ACR5 ACR7 Versus original pre-treatment baseline Emery et al, EULAR 26 (Abstract No. OPO17) Versus original course-specific baseline 2 1

11 Proportion of patients achieving low disease activity and remission further increased with repeated courses Patients (%) Course 1 (n=99) Course 2 (n=99) DAS28 low disease DAS28 remission DAS28 low disease DAS28 remission Versus original pre-treatment baseline Emery et al, EULAR 26 (Abstract No. OPO17) Versus original course-specific baseline 21 Safety all exposure population 22 11

12 More than 1,6 patient-years as of October 25 Duration of observation Total (any duration) >6 months >1 year >2 years >3 years Total exposure (patient-years) Patients (n) patient-years van Vollenhoven et al, EULAR 26 (Abstract No. SAT197) 23 The safety profile remained unchanged with repeated courses Patients (%) n=427 n= CTC Grade 4 CTC Grade 3 CTC Grade 2 n=255 n=315 CTC Grade 1 1 n=91 n= n=18 n= No Prior TNF Prior TNF No Prior TNF Prior TNF No Prior TNF Prior TNF No Prior TNF Prior TNF 1 st Course 2 nd Course 3 rd Course 4 th Course Emery et al, EULAR 26 (Abstract No. OPO17) 24 12

13 Acute infusion reactions reduced with subsequent courses First infusion Second infusion Patients (%) First course Second course Third course Fourth course Emery et al, EULAR 26 (Abstract No OPO17) 25 Infection rate consistent between treatment courses Course 1 (n=139) Course 2 (n=57) Course 3 (n=191) Patient years Infections (all infections) per 1 patient years Serious infections* per 1 patient yrs % confidence interval serious infections (3.961, 6.598) (2.93, 7.135) (2.37, ) *Reported as serious and/or requiring IV antibiotics Period of greatest risk is within the first 6 months Emery et al EULAR 26 (Abstract No. OPO17) 26 13

14 Rituximab - conclusions Rituximab is the only available selective B cell therapy for rheumatoid arthritis Rituximab provides sustained efficacy in controlling signs and symptoms of RA after only 2 x 1 mg infusions per treatment course Repeated courses of rituximab produced comparable or improved efficacy relative to original and course-specific baseline with no change in the safety profile 27 Focus on rheumatoid arthritis patients with inadequate response to TNF inhibitors Prof. Edward Keystone Professor of Medicine, University of Toronto, Canada 28 14

15 REFLEX: Study design Methotrexate (MTX) 3 months Screen/TNF and/or DMARD withdrawal period Screen Rituximab: 1 mg or placebo iv infusion Methylprednisolone: 1 mg iv before rituximab infusion Prednisone: 6 mg po Days 2 7, 3 mg po Days 8 14 Clinic visit Primary efficacy timepoint Randomisation Randomization Rituximab + MTX (Group A) n = 3 Placebo + MTX (Group B) n = 2 Day 1 Wk 2 Treatment period Wks 4, 8, 12, 16, 2 Wk 24 Long-term follow-up Wk 56 Rescue (Week 16) Group A: Standard of care Group B: Rituximab + MTX Potential for subsequent courses of rituximab in patients with 2% reduction in SJC and TJC from Week REFLEX: Study objectives Primary Endpoint: Proportion of patients with an ACR2 response at Week 24 Secondary and exploratory radiographic endpoints: Secondary: Change in modified Sharp radiographic total score, erosion score, and joint space narrowing score at Week 56 Exploratory: Change in modified Sharp radiographic total score, erosion score, and joint space narrowing score at Week

16 Baseline disease characteristics show longstanding severe rheumatoid arthritis Age (yr) Disease Duration (yr) SJC TJC Proportion Rheumatoid Factor (RF) Positive CRP (mg/dl) ESR (mm/h) DAS28 HAQ Total Genant-Modified Sharp Score All variables are mean values except % RF positive Cohen et al. Arthritis Rheum. 26 [in press] Placebo (n=29) % Rituximab (n=38) % Significant ACR responses at Week 24 Patients (%) p<.1 51 p< p< ACR2 ACR5 ACR7 Placebo (n=21) Rituximab (n=298) Cohen et al. Arthritis Rheum. 26 [in press] 32 16

17 Significant inhibition of radiographic progression at Week 56 p=.46 Mean change Placebo (n=184) p= Rituximab (n=273) p= Total Genant-modified Sharp score Primary Analysis: Radiographs within time window, linear extrapolation from Week 24 for missing values Keystone et al, EULAR 26 (Abstract No. OPO16) Joint space narrowing Erosion score 33 Significant higher proportion of patients with no erosive progression at Week 56 Patients (%) p= Placebo (n=184) Rituximab (n=273) p= No change in erosion score Missing values were imputed using linear extrapolation from baseline and Week 24 radiographs Keystone et al, EULAR 26 (Abstract No. OPO16) No change in Total Genant-modified Sharp score 34 17

18 Open-label study of rituximab Repeated treatment courses: Patients with inadequate response to TNF inhibitors 35 Median time interval was approximately 3 weeks Median time to repeated treatment courses (weeks) Prior TNF (n=82) Second course (C2) No prior TNF (n=5) Third course (C3) van Vollenhoven et al, EULAR 26 (Abstract No SAT197) 36 18

19 ACR scores further improved with repeated courses Patients (%) Week 24 post-course 1 (n=155) Week 24 post-course 2 (n=155) ACR2 ACR5 ACR7 Keystone et al, EULAR 26 (Abstract No.FRI125) 37 EULAR responses further improved with repeated courses st Course (n=158) 2nd Course (n=158) Moderate Good Low disease Remission Keystone et al, EULAR 26 (Abstract No. FRI125) 38 19

20 Further improvement in patients physical and mental health with repeated courses Mental component Physical component Initial treatment course (Course 1, n. 119) Repeat treatment course (Course 2, n. 119) Tak et al, EULAR 26 (Abstract No. SAT175) 39 Proportion of patients with Ig concentrations <LLN slightly increased with subsequent courses First course (n=139) Second course (n=57) Third course (n=191) Total Ig < LLN.1%.7% - IgG < LLN 1.4% 4.3% 5.9% IgM < LLN 1.3% 18.5% 23.5% Emery et al, EULAR 26 (Abstract No. OPO17) 4 2

21 Low IgM level is not associated with increased infection rate All exposure (n=27) Prior to Total IgM <LLN After Total IgM <LLN Total patient years Number of serious infections* Serious infections per 1 patient years 95% Confidence Interval 5.1 (2.6,1.2) 5.9 (3.4, 1.2) *Serious and/or those requiring IV antibiotics Emery et al, EULAR 26 (Abstract No. OPO17) 41 Safety of TNF inhibitors subsequent to rituximab therapy 78 patients received subsequent TNF inhibitor therapy Etanercept (n=23) Infliximab (n=23) Adalimumab (n=26) Multiple TNF inhibitors (n=7) Breedveld et al, EULAR 26 (Abstract No. THU26) 42 21

22 Subsequent use of TNF inhibitors is not associated with increased infection rate n=78 Total patient exposure (years) Number of serious infections Serious infections per 1 patient-years Serious infections per patient-year (95% CI) Before TNF inhibitor (1.7, 16.9) After TNF inhibitor (2.9, 2.3) Infection rate first anti-tnf exposure 6.4 per 1 patients/year BSR biological register ACR 25 Breedveld et al, EULAR 26 (Abstract No. THU26) 43 Rituximab - conclusions Rituximab is an important addition to the therapeutic armamentarium for RA Data from the REFLEX study provide the first indication that a B celltargeted therapy can inhibit radiographic progression These data also represent the first significant evidence of inhibition of radiographic progression in patients with an inadequate response to 1 or more TNF inhibitors 44 22

23 Rituximab conclusions cont d Repeated courses of rituximab treatment show similar or improved efficacy compared with the first course with no change in the safety profile In light of preliminary data the use of TNF inhibitors after rituximab exposure and the low IgM levels following repeated courses do not appear to be associated with increased infection rate Further studies on the effect of rituximab on Ig levels and the use of TNF inhibitors in rituximab exposed patients are ongoing 45 Results from the clinical program for MabThera and Actemra in RA and Roche s emerging franchise in RA/autoimmune diseases Dr. Urs Schleuniger Business Director, Hematology & Autoimmune Diseases, Roche 46 23

Summary: Roche s phase III program for MabThera in DMARD inadequate responders and MTX naïve patients Trial Treatment Sample Size Endpoints MTX-IR SERENE MTX + placebo vs. MTX + MabThera 1g vs.

24 Summary: Roche s phase III program for MabThera in DMARD inadequate responders and MTX naïve patients Trial Treatment Sample Size Endpoints MTX-IR SERENE MTX + placebo vs. MTX + MabThera 1g vs. MTX + MabThera 2g 495 Reduction in signs and symptoms MTX naïve (X-ray study) IMAGE MTX vs. MTX + MabThera 1g vs. MTX + MabThera 2g 852 Reduction in signs and symptoms Inhibition of structural joint damage Improvement in physical function MTX-IR Dose escalation MIRROR Rituximab 1g retx 1g vs. Rituximab 1g retx 2g vs. Rituximab 2g retx 2g 375 Effect of further courses and dose escalation EU Filing Actemra Japanese phase III results 48 24

25 Phase III in signs & symptoms Study design, Actemra monotherapy 6 pts MRA 8mg/kg/4W + MTX Placebo Pts on MTX 8 mg/wk for at least 8 wks Screening 24 wks 24 weeks Final Evaluation 6 pts MRA Placebo + MTX 8 mg/week Highest MTX recommended dose in Japan: 8 mg/week weeks MTX can be suspended or the dose reduced, depending on occurrence of AEs 49 Strong ACR scores Actemra shows consistent high efficacy % of patients MTX Actemra 8 mg/kg Full analysis set LOCF 8.3 p < (64) (61) (64) (61) (64) (61) ACR 2 ACR 5 ACR

26 Phase III in prevention of joints damage Study design; Actemra monotherapy Actemra 8 mg/kg/4 wks 15 patients W Any DMARDs 15 patients Interim Evaluation Final Evaluation W 51 Actemra substantially reduces joints damage Radiographic data, mean scores mean change from baseline Control Actemra Full analysis set p < (143) (157) (143) (157) (143) (157) TSS JSN ES TSS: Total Sharp Score; JSN: Joint Space Narrowing; ES: Erosion Score 52 26

27 Safety update Actemra well tolerated In general, Actemra is well tolerated To date, the occurrence of infections is within the expected rate for an immunosuppressant biologic agent No difference in liver function tests was observed between patients who received Actemra as monotherapy and the control group in both Phase III Japanese studies Increases in lipids occur during treatment with Actemra, as also observed during treatment with anti-tnfs. Increases in LDL are accompanied by increases in HDL, leading to a neutral impact on atherogenic index CRP, an important marker of CV risk, is favorably affected by Actemra treatment 53 Roche s phase III program for Actemra Five trials ongoing Treatment Sample Size Patient population Endpoints Actemra 4 mg + MTX Actemra 8mg + MTX MTX OPTION 63 MTX partial responders ACR 2 response at Wk 24 Actemra 4 mg + MTX Actemra 8 mg + MTX MTX LITHE 1 17 MTX partial responders ACR 2 at Wk 24 Sharp Score at Wk 52 Sharp Score at Wk 14 Physical function at Wk 14 Actemra 8 mg + DMARDs DMARDs TOWARD 1 2 DMARD partial responders ACR 2 response at Wk 24 Actemra 4 mg + MTX Actemra 8 mg + MTX MTX RADIATE 57 Anti-TNFα failures ACR 2 response at Wk24 Actemra 8 mg MTX AMBITION 55 MTX naive ACR 2 response at Wk 24 Filing

28 Actemra at EULAR Summary Actemra monotherapy is effective in controlling both signs and symptoms of RA and the progression of structural damage The effectiveness of Actemra is sustained over time Actemra is in general well tolerated The large phase III program being conducted in the US and Europe is expected to confirm the outstanding Japanese results Actemra, through its novel mechanism of action, might become soon a new option for patients suffering from RA 55 Roche in RA and Autoimmune Diseases Depth of portfolio and breadth of indications Phase I Phase II Phase III AI diseases RA Oral DMARDs Improved Biologics Phase I R1541 (IBD) R1295 (RA) R3421 (AI) BR3-FC (RA) GNE Phase II R153 (RA) R1594 (RA) MabThera (RRMS) GNE R1295 MabThera (RA DMARD) Actemra (RA) Actemra (sjia) CellCept (LN) Phase III R153 Ocrelizumab MabThera (PPMS) GNE MabThera (ANCA av) GNE MabThera (SLE) GNE MabThera (LN) GNE Actemra Filed/Approved MabThera (RA TNF) MabThera CellCept (MG) 56 28

29 Roche in RA and Autoimmune Diseases Roche is well placed to address high unmet need and capitalize from large growth opportunity Innovative pipeline with 2 first-in-class drugs in prelaunch/launch Large investment in development program (second only to oncology) Scientific and commercial collaboration with co-marketing partners Genentech and Chugai Strong corporate commitment to build up RA/Autoimmune franchise Roche poised to become a leader in RA 57 Q & A 58 29

30 We Innovate Healthcare 59 3

New Evidence reports on presentations given at ACR Improving Radiographic, Clinical, and Patient-Reported Outcomes with Rituximab

New Evidence reports on presentations given at ACR 2009 Improving Radiographic, Clinical, and Patient-Reported Outcomes with Rituximab From ACR 2009: Rituximab Rituximab in combination with methotrexate