1. 1 Role of Candesartan

2. Antagonist: AT 1 receptor interaction Losartan Candesartan Rapid dissociation Slow dissociation Lower affinity High affinity Re-association and prolonged antagonism Insurmountable antagonism Surmountable antagonism R R Morsing P, Vauquelin G. Cell Biochem Biophys 2001; 35(1): 89–102.

3. Chemical Structures of Angiotensin II Receptor Blockers Olmesartan CO 2 H N N C OH CH 3 H3CH3CH3CH3C NNN NH N O CO 2 H Valsartan EXP 3174 N N CO 2 H CI N N N NH Irbesartan O N N Candesartan N OCH 2 CH 3 N CO 2 H N N N NH N N N NH N N N NH

4. Insurmountable and Surmountable Antagonism: Relation to Duration of Binding telmisartan olmesartan candesartan EXP 3174 valsartan irbesartan losartan 0120 Dissociation t 1/2 0 100 Insurmountability (%) 80 10080 60 40 6040 20 20 Van Liefde et al 2009

5. Candesartan: selected properties Specific blockade of the effects of angiotensin II through selective AT 1 receptor blockade Induces dose-dependent reduction in DBP response to exogenous angiotensin II The antihypertensive effect persists for more than 24 hours; this long duration of action appears to be related to a slow dissociation rate from the AT 1 receptor Has placebo-like tolerability in hypertension clinical trials Easthope SE, Jarvis B. Drugs 2002; 62: 1253–1287.

6. Years 1 and 2 Years 3 and 4 Qualification Period Placebo Life style counseling Candesartan (16mg) Placebo At Visit 1:< 159/85-99 mm Hg or 130-159/ < 99 mm Hg Avg. of 3 Visits:< 139/85-89 mm Hg or 130-139/ < 89 mm Hg The TROPHY Study

7. TROPHY Study: ARB in Prehypertension 100 80 60 40 20 0 Cumulative Incidence (%) 01234 Placebo Candesartan Study Year Julius NEJM 2006; 354 : 1685-97

8. Long-lasting AT 1 -receptor blockade in isolated rat vessels Morsing P, et al. Hypertension 1999; 33(6): 1406–1413. Time (min) Response to angiotensin II (%) Vehicle (n=37) Irbesartan 50 nM (n=9) Candesartan 1 nM (n=12) EXP-3174 1 nM (n=9) Losartan 30 nM (n=11) 0 20 40 60 80 100 120 -300306090120150180 Antagonist

9. Meta-analysis based on USA New Drug Application evaluation reports * x-axis is extended to the highest recommended dose in the EU at the time of meta-analysis Elmfeldt D, et al. Blood Press 2002; 11: 293–301. Losartan Irbesartan Valsartan Candesartan 00000000 25 75 80 4 50 150 160 8 75 225 240 12 100 300 320 16 0 –1–1 –2–2 –3–3 –4–4 –5–5 –6–6 –7–7 –8–8 –9–9 –10 Reduction in DBP (mmHg) Losartan Irbesartan Valsartan Candesartan Dose (mg) *

10. Mean change from baseline to week 8 in SBP Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.

11. Mean change from baseline to week 8 in DBP Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.

12. The CLAIM study: candesartan vs. losartan Bakris G, et al. J Clin Hypertens (Greenwich) 2001; 3(1): 16-21. TROUGH CandesartanLosartan 0 –4–4 –8–8 –12 –16 Mean change from baseline (mm Hg) * * 0 –4–4 –8–8 –12 –16 48 hours POST-DOSE ** p<0.0001 compared with losartan * p<0.001 compared with losartan ** Mean change from baseline (mm Hg) DBP SBP

13. Belcher G, et al. J Hum Hyper 1997; 11: S85–S89. Candesartan: adverse events in hypertension trials Candesartan (n=1388) Placebo (n=573) Headache Respiratory infection Back pain Dizziness Nausea Cough % of patients reporting adverse events 11432156710980

14. Candesartan: tolerability in hypertension trials Belcher G, et al. J Hum Hyper 1997; 11: S85–S89. Withdrawals due to adverse events (%) n=573 Placebo n=311 4 mg n=537 8 mg n=303 16 mg 2.41.62.21.6 0 1 2 3 4 5 Candesartan

15. Real Life study: CVD Risk 0 5 10 15 20 25 30 35 Candesartan Losartan 06121824303642485460667278849096 Cumulative incidence (%) Time (months) Primary composite endpoint 6771581245483913318825912090173814581169 923715526385259183 95 73296291486040913385274222421875158013021021 794592436257152 78 Number at risk Los. Can. Adjusted risk reduction 14.4% p=0.0062 Unadjusted risk reduction 20.6% p<0.0001

16. Real Lifestudy: Risk of Separate Endpoints B ArrhythmiasA Heart failureC Peripheral artery disease D Chronic ischemic heart disease F Stroke 0 2 4 6 8 10 12 06 1824303642485460667278849096 Candesartan Losartan Cumulative incidence (%) Time (months) 67715902466640573347276122521887160213171044 820611456314221126 73296385497542303529287523721998169314091113 878664496301175 89 Number at risk Los. Can. Adjusted risk reduction 35.9% p=0.0004 Unadjusted risk reduction 41.9% p<0.0001 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715909466640533337274522351874159113001041 814598439301212115 73296380496842163515285523511977167713901097 867654488294169 90 Number at risk Los. Can. Adjusted risk reduction 20.0% p=0.0330 Unadjusted risk reduction 26.7% p=0.0029 Candesartan Losartan 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715932469640873376278822731907161913311063 834624460320 225126 73296400498342443541288323822009170614241128 892677507307 179 91 Number at risk Los. Can. Adjusted risk reduction 38.8% p=0.0140 Unadjusted risk reduction 44.1% p=0.0035 Candesartan Losartan 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715903465940443335274122341872157712861021 798590431297208113 73296378495042053502284423451968167013841091 854644480290172 89 Number at risk Los. Can. Adjusted risk reduction 14.3% p=0.1400 Unadjusted risk reduction 19.6% p=0.0350 E Myocardial infarction 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715921468640793364278222721904161013181047 822612452312221123 73296387497242313516285823621992168814061113 876661494299175 91 Number at risk Los. Can. Adjusted risk reduction 7.0% p=0.5600 Unadjusted risk reduction 15.5% p=0.1800 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative Incidence (%) Time (months) 67715916468140643361276922511887159813091047 819609448307217118 73296374496342203515285923621991169114081113 877662489295172 89 Number at risk Los. Can. Adjusted risk reduction 5.2% p=0.6400 Unadjusted risk reduction 12.0% p=0.2600

17. CHARM- added CHARM- preserved CHARM study programme Three component trials comparing candesartan with placebo in patients with symptomatic heart failure CHARM- alternative Primary outcome for overall programme: all-cause death Primary outcome for each trial: CV death or CHF hospitalisation Pfeffer MA, et al. Lancet 2003; 362(9386): 759–766. n=2028 LVEF  40% ACE inhibitor intolerant n=2548 LVEF  40% ACE inhibitor treated n=3025 LVEF >40% ACE inhibitor treated/not treated

18. CV death and CHF hospitalisation in the CHARM studies Proportion with cardiovascular death or hospital admission for CHF (%) 0 10 20 30 40 50 yrs3.50123 yrs Placebo Candesartan Proportion with cardiovascular death or hospital admission for CHF (%) HR 0.77 (95% CI 0.67–0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 CHARM-Alternative 0 10 20 30 40 50 yrs3.50123 10 Placebo Candesartan HR 0.85 (95% CI 0.75–0.96), p=0.011 Adjusted HR 0.85, p=0.010 CHARM-Added Placebo Candesartan HR 0.84 (95% CI 0.77–0.91), p<0.0001 Adjusted HR 0.82, p<0.0001 CHARM-Overall Proportion with cardiovascular death or hospital admission for CHF (%) 0 10 20 30 40 50 yrs3.50123 0 10 20 30 40 50 yrs3.50123 Placebo Candesartan CHARM-Preserved Proportion with cardiovascular death or hospital admission for CHF (%) HR 0.89 (95% CI 0.77–1.03), p=0.118 Adjusted HR 0.86, p=0.051 3.McMurray JJ et al, Lancet 2003; 362(9386): 767–771 4.Pfeffer MA et al; Lancet 2003; 362(9386): 759–766. 1.Yusuf S, Pfeffer MA, Swedberg K, et al. Lancet 2003; 362(9386): 777–781. 2.Granger CB, McMurray JJ, Yusuf S, et al. Lancet 2003; 362(9386): 772–776.

19. CHARM-Overall: new diagnosis of diabetes Yusuf S, et al. Circulation 2005; 112(1): 48–53. Hazard ratio=0.78; 95% CI: 0.64–0.96 01.02.03.03.5 Time (years) 0 2 4 6 8 p=0.020 12 10 202 (7.4%) 163 (6.0%) Candesartan 2715256523951662 Placebo 2721250123041622 Proportion of patients (%) Candesartan Control

20. Comparing Candesartan with other antihypertensive agents ReferenceTreatmentsResponse rate (%)Comparative efficacy Himmelmann et al. 2001 1 Candesartan 8–16 mg od Enalapril 10–20 mg od 58 50 Candesartan > enalapril Malmqvist et al. 2000 1 Candesartan 8–16 mg od Enalapril 10–20 mg od HCTZ 12.5–25 60 51 43 Candesartan > enalapril Candesartan > HCTZ Andersson et al. 1998 2 Candesartan 8–16 mg od Losartan 50 mg od Placebo – Candesartan 16 mg > losartan Candesartan 8 mg = losartan Bakris et al. 2001 1 Candesartan 16–32 mg od Losartan 50–100 mg od 62 54 Candesartan 32 mg > losartan 100 mg Vidt et al. 2001 1 Candesartan 16–32 mg od Losartan 50–100 mg od 59 52 Candesartan 32 mg > losartan 100 mg Gradman et al. 1999 1 Candesartan 16–32 mg od Losartan 50–100 mg od 64 54 Candesartan 16–32 mg > losartan 50– 100 mg Lacourciere & Asmar 1999 1 Candesartan 8–16 mg od Losartan 50–100 mg od –Candesartan 16 mg > losartan 100 mg Farsang et al. 2001 1 Candesartan 8 mg od Amlodipine 5 mg od44 Candesartan = amlodipine Kloner et al. 2001 1 Candesartan 16–32 mg od Amlodipine 5–10 mg od 79 87 Candesartan = amlodipine 1.Adapted from Easthope SE, Jarvis B. Drugs 2002; 62: 1253–1287. 2.Adapted from McClellan KJ, Goa KL. Drugs 1998; 56: 847–869.