Day 2 Welcome Back !

1. 8.30 BIG 1-98 Issues 8.45 BIG 1-98 Syndicate 10.00 The Case for Switching ITA & ARNO/ABCSG 10.30 The Switch Call Video 11.00 Statistics for Non-Statisticians 11.15 ATAC Syndicate 12.15 Arimidex/Zoladex in pre-menopausal 12.30 Extended Adjuvant Data 1.00 Lunch 1.45 Differentiation Summary 2.00 Marketing Tools 2.20 Regional Marketing Syndicate 3.00 Quiz and Close Day 2 Welcome Back !

2. BIG 1-98 Issues

3. You are letrozole Product Manager at Novartis and you are very proud of your company pension, car and business card. You are slightly less happy about the latest data from BIG 1-98. You are also very aware of the concerns being expressed due to the safety profile. New legislation allows you to make a direct-to- customer or direct-to-doctor television advert. You can mention other brands, and you MUST mention the side effect profile of your own brand. In your teams, please make a 2 minute advert for letrozole to show to the group. Please be as creative as you can ! Syndicate

4. Expand the Brand

5. Positioning / Strategic Drivers Arimidex is the first choice endocrine therapy for post-menopausal women with breast cancer • Establish Arimidex as the standard of care for early breast cancer • Expand use of Arimidex across the early disease segments • Achieve strong positioning and differentiation relative to the other AI’s in early breast cancer • Leverage meaningful value propositions with key stakeholders

6. Life Cycle Claims • 2005/2006 Extended Adjuvant • Giving Arimidex to patients who have completed their 5 years of TMX significantly reduces their risk of recurrence • 2006/2007 Premenopausal • Arimidex/Zoladex combination is more effective then TMX and Zoladex in reducing BC recurrence in premenopausal women • 2009 DCIS/Prevention • Giving Arimidex to patients at risk from developing early breast cancer is more effective than giving tamoxifen or no treatment.

7. EXPAND ARIMIDEX – the SWITCH Opportunity • Patients already on tamoxifen: • Optimise ARNO/ABCSG/ITA data and prepare for new extended adjuvant data (ABCSG 6a)

8. The Switch Opportunity • Switch offers the best opportunity for a quick return • …… but there are risks to increasing the focus on switching patients • Establishing 5 years of Arimidex as the standard of care remains the priority

9. Living through the breast cancer experience - expand the brand Patients who have been on 5 years of tam Initial treatment Patients who have been on 2-3yrs of tam Remission Diagnosis Patients WANT to be on the best treatment Clinicians WANT to do the best for their patients A Key driver: Mobilise patients to demand Arimidex

10. Switch DataITA / ARNO/ABCSG

11. How do we position the switch data? • Switch message applies to patients ALREADY on tamoxifen Key messages: • We know from ATAC that tamoxifen is inferior to ‘Arimidex’ • use the best drug as early as possible because women will have their risk of recurrence significantly reduced if they are switched to ‘Arimidex’ • Need to target switch business effectively on customer-by-customer basis

12. Switch vs. sequence

13. 5 yrs’ initial adjuvant tamoxifen OR Adjuvant hormonal therapy 5 yrs’ initial adjuvant ‘Arimidex’ OR PROSPECTIVE DECISION FOLLOWED BY 2-3 yrs’ adjuvant ‘Arimidex’ START WITH 2-3 yrs’ adjuvant tamoxifen Surgery Newly diagnosed Radiotherapy Chemotherapy (if given) Newly diagnosed patients ? There are NO DATA for a strategy of PROSPECTIVELY sequencing adjuvant endocrine therapies In newly diagnosed patients SEQUENCING

14. Continue on adjuvant tamoxifen OR Clinician convinced by data Patient has suffered an AE Patient at increased risk of an AE Patient request Change to adjuvant ‘Arimidex’ Existing patients EVIDENCE BASED MEDICINE Switch NOT sequence For switch we DO have the data: ABSCG/ARNO ITA IES Already completed 2-3 yrs’ adjuvant tamoxifen SWITCH

15. Recurrence-free survival (%) ATAC and BIG 1-98 100 ABCSG8/ARNO IES and ITA 90 MA.17 80 * * 70 60 0 5 10 Years Aromatase Inhibitors in the adjuvant setting – reported trials These trials differ, not only in their design, but also in the characteristics of the enrolled patients due to differences in the timing of randomization *Denotes time frame when randomisation to an AI occurs EBCTCG Lancet 1998; 351:1451–1467

16. Do not confuse switch with sequence! • Switching trials onlyprovide evidence on the outcome of replacing tamoxifen with an AI in patients who have already been receiving tamoxifen for 2–3 years • They give no information on what happened on tamoxifen in the 2 yrs prior to randomization • It is not appropriate to extrapolate results from these studies and plan to use a sequencing strategy for newly-diagnosed patients who have yet to start adjuvant therapy: • Switching trials do not study the newly-diagnosed patient population • Switching trials do not account for patients who do not complete 2–3 years of tamoxifen due to relapse or withdrawal

17. This is not the perception in clinical practice! • Views of the Breast Cancer Summit Audience (based on key pad voting), Sitges 2005 • 41% would proactively sequence (initiate tamoxifen with the intention of switching)

18. ‘Arimidex’ Tamoxifen Smoothed hazard rates for recurrence (ITT* population) Patients selected out during First 2-3 years Note excess recurrences on tamoxifen This equates to ~ 60 more patients who recurred on tamoxifen in the first 2.5 years of the trial 3.0 Annualhazardrates(%) 2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 5 6 Follow-up time (years)

19. But look at the number of patients who will recur if started on tamoxifen first! Switching is superior to continuing on tamoxifen 5 yrs initial tamoxifen 2-3 yrs tamoxifen  ‘Arimidex’ 5 yrs initial ‘Arimidex’ 2-3 Y Switch Starts Don’t wait to start ‘Arimidex’ ! 100% % of patients without an event 5 Y 0 Treatment Period

20. Predefined adverse events/1000 patients first 2.5 years This equates to ~ 350 more predefined adverse events on tamoxifen in the first 2.5 years of the trial ‘Arimidex’ Tamoxifen Difference 15 Venous thromboembolic 18 33 8 Ischaemic cerebrovascular 8 16 Endometrial cancer 0 4 4 202 33 Vaginal bleeding 42 75 Vaginal discharge 27 113 86 Hot flushes 398 342 56 Musculoskeletal events 265 195 70 92 22 32 54 Fractures

21. Assumptions for modelling • Recurrences on tamoxifen • 2.5% per year for 5 years • 2% per year for next 5 years • Initial aromatase inhibitor use leads to 25% relative reduction    • Delayed aromatase inhibitor use leads to 40% relative reduction from time of use    • Relative benefits maintained out to 10 years 

22. 5 years AI Switch to AI at 2 years Extend with AI at 5 years It’s always better to start with an AI 5 years tamoxifen .25 .2 .15 .1 .05 0 0 2 4 6 8 10 Time (years)

23. Summary - Evidence based medicine • ATAC provides the only mature data comparing an AI with tamoxifen as initial adjuvant endocrine treatment • Based on the data from the ITA, ABCSG/ARNO, BIG 97-02 and MA-17 studies, it is reasonable to consider switching patients currently on tamoxifen to an AI after 2-3 years, or extending therapy for a further 5 years • There are no data for a strategy of prospectively sequencing adjuvant endocrine therapies in newly diagnosed patients. • ATAC data indicateit is even better to start treatment with 'Arimidex' than start with tamoxifen with the intention of switching to an AI Specifically, the higher rates of recurrence, adverse events, and treatment withdrawals associated with tamoxifen, and the substantial benefit of 'Arimidex' in the first 3 years, justify the approach of offering the most effective therapy at the earliest opportunity

24. Summary – Overcoming issues • Start is better than switch – best treatment first • Don’t start to switch – switch only those patients ALREADY on tamoxifen • Use ‘Arimidex’ to prevent: • Breast cancer recurrence • Life-threatening side effects • DON’T use tamoxifen to prevent or treat: • Bone/joint disorders • Lipids/cardiovascular events

25. Expand the Brand Syndicate We will watch the experts at work ! Members of the global team will act out a ‘Switch’ Call. We would like you to offer a critique of the call including data used, techniques used, objections raised and handled how would you do it better

26. Statistics for Non-Statisticians ……

27. We will divide into 2 groups. Group 1 – Using the ATAC data please describe how to the group which efficacy data you would present to a Tamoxifen die-hard to encourage then to use Arimidex first-line in EBC Group 2 – Please describe to the group how you would explain the tolerability profile of Arimidex to a tamoxifen die-hard. ATAC Syndicate

28. PremenopausalStrategyArimidex and Zoladex

29. Rationale for Zoladex + Arimidex

30. Pituitary gland Androgens Ovary Oestrogens Aromatase enzyme Adrenalglands Tumour growth

31. Pituitary gland Androgens Ovary Oestrogens Adrenalglands ZOLADEX ARIMIDEX Tumour regression

32. What do we know to date? We know that: • Combining an LHRHa and tamoxifen confers better efficacy than either agent alone in premenopausal patients with advanced disease • Arimidex offers superior efficacy to tamoxifen in postmenopausal patients with advanced disease • Tamoxifen is no longer the standard of care in the adjuvant treatment of breast cancer in postmenopausal patients

33. So… • If a younger woman is made effectively postmenopausal with an LHRHa • Should we treat her as a postmenopausal woman? • Can we achieve the benefit seen in ATAC?

34. Postmenopausal status • Postmenopausal women do not have functioning ovaries • Hospital reference intervals for oestradiol are: • Premenopausal levels: >200pmol/L • Postmenopausal levels : < 110pmol/L Postmenopausal status is NOT defined by age Forward et al 2004; BJC 90; 590-594

35. What data do we have?Advanced breast cancerEarly breast cancer

36. Disease progression* *Advanced disease Zoladex plus Arimidex: trial design • 16 premenopausal women Zoladex + tamoxifen Zoladex + Arimidex Forward et al 2004; BJC 90; 590-594

37. p<0.0001 Zoladex + Arimidex Oestradiol suppression with Zoladex + Arimidex p<0.0001 250 200 150 Mean serum oestradiol (pmol/L) 100 50 0 Baseline Zoladex + tamoxifen Forward et al 2004; BJC 90; 590-594

38. Zoladex + Arimidex: clinical effects Clinical result • objective response / static disease at 6 months in 12 (75%) patients • median duration of remission >17 months Forward DP et al. Br J Cancer 2004; 90: 590-4

39. Addition of Arimidex once postmenopausal E2 levels reached 300 250 200 150 100 50 0 Oestradiol (pg/ml) (n=7) 0 1 2 3 4 5 6 7 8 12 16 20 Time (weeks) 1 2 3 4 5 6 ‘Zoladex’ 3.6mg depot When should Arimidex be started? Postmenopausal threshold

40. Further Data • Adjuvant trials involving overian function suppression + AI • ABCSG12, PROMISE, SOFT, TEXT, PERCHE • Additional data in 1st line ABC • Data to come at ASCO • Cheung et al (abstract only) • 1st line ABC • Zoladex + Arimidex  60% CB rate • Steger et al (abstract only) • ABC 1st – 4th line • Zoladex + Faslodex  overall CB 45%

41. Why might this approach be acceptable? • Medically logical • We have some data • Supports current clinical thinking • KOL endorsed • Ongoing adjuvant trials

42. ‘Although limited, there are both endocrine and clinical data suggesting that AIs will be of value in premenopausal women being treated with OFS.’ ASCO Tech Assessment 2004 Recommendation for recurrent disease: ‘Ovarian ablation or suppression plus hormonal therapy as for postmenopausal women.’ NCCN Guidelines 2005 Who else thinks this is a good idea?

43. Focus Group Feedback – St Gallen • Zoladex + Arimidex concept is broadly accepted • Tam may be oestrogenic in patients treated with Zoladex • An AI may theoretically be superior • Some consideration of comparability of chemical vs natural menopause • Do endocrine difference impact on tumour and/or response to an AI • Very comfortable with idea of using combination in ABC • Provides further endocrine options and potential QoL benefits vs chemotherapy • Impact on disease control/life expectancy more important than potential concerns on side effects

44. Focus Group Feedback • In EBC wanted data • Bone effects, CV risk • Perceived benefit in addition to chemotherapy • Cost • BUT some doctors already using in selected patients (e.g. ER+/Her2+; ER+/PgR-)

45. By 2007… in Europe premenopausal women with ER+ disease will be treated with ovarian suppression plus an aromatase inhibitor Craig Jordan, St Gallen 2005

46. Extended Adjuvant DataMA17