New concept – no traditional combination LODOZ contains Bisoprolol and Hydrochlorothiazide in subtherapeutic dosages: - Bisoprolol 2.5 mg (= half / quarter of the usual dosage) - Hydrochlorothiazide 6.25 mg (half / quarter of the usual dosage) Advantages:excellent efficacy, low dose-related adverse events FDA approved as first-line antihypertensive and side effects comparable to placebo Further dosages: LODOZ 5 and LODOZ 10

Study (reference) (total n=1.839) Additional characteristics Objectives... additional Comparitors End point Multifactorial trial (FRISHMAN et al., 1994) (n=512) placebo-controlled All: safety, efficacy and... dose response Bisoprolol (0, 2.5, 10 or 40 mg) + HCTZ (0, 6.25 or 25 mg) placebo Response / control Confirmatory trial (FRISHMAN et al., 1995) (n=547) placebo-controlled Bisoprolol 5 + HCTZ 6.25 Bisoprolol 5 HCTZ 25 placebo Comparative trial (PRISANT et al., 1995) (n=218) dose-escalation side-effect profile, quality of life Bisoprolol (2.5, 5, 10 mg) + HCTZ 6.25 Enalapril (5, 10, 20 mg) Amlodipine (2.5, 5, 10 mg) Response Comparative trial (NEUTEL et al., 1996) (n=323) placebo-controlled, dose-escalation side-effect profile, quality of life Bisoprolol (2.5, 5, 10 mg) + HCTZ 6.25 Enalapril (5, 10 mg q.d., 10, 20 mg b.i.d.) Amlodipine (2.5, 5, 10 mg) placebo Response / control Comparative trial (BENETOS et al., 2000) (n=164) double-blind, controlled quality of life 24 hr ABPM Bisoprolol HCTZ 6.25 Amlodipine 5 mg Comparative trial (PAPADEMETRIOU et al., 1998) (n=75) placebo-controlled, dose-escalation Exercise tolerance, 24 hr ABPM Bisoprolol (2.5, 5, 10 mg) + HCTZ 6.25 Losartan (50, 100 or 50 + HCTZ (12.5 mg)) placebo FRISHMAN et al., Arch Intern Med. 1994; 154: PRISANT et al., Am Heart J. 1995; 130: PAPADEMETRIOU et al., Cardiovasc Rev Rep.; December 1996 FRISHMAN et al., J Clin Pharmacol. 1995; 35: NEUTEL et al., Cardiovasc Rev Rep. 1996; 17:33-45 BENETOS et al., A, Heart J 2000; 140:e14 Pivotal clinical trials with LODOZ (all randomized, double-blind, parallel-group studies)

Response rates under LODOZ up to 84 % Response defined as a sitting diastolic blood pressure of ≤ 90 mm Hg and/or a decrease from baseline of ≥10 mm Hg, measured 24 hours after dosing. Response rates (from several trials) (1) FRISHMAN et al., Arch Intern Med. 1994; 154: (3) NEUTEL et al., Cardiovas. Rev Rep. 1996; 17:33-45 (5) PAPADEMETRIOU et al., Cardiovasc Rev Rep. Dec (2) FRISHMAN et al., J Clin Pharmacol. 1995; 35: (4) PRISANT et al., Am Heart J. 1995; 130: LODOZ 2.5 LODOZ 5 LODOZ 10 LODOZ Placebo Bisoprolol 10 + HCTZ 25 HCTZ 25 (1) 100% 80% 60% 40% 20% 0% (2) (1) (3)(4)(5)(1) (trial no.)

Response/control rates of LODOZ vs. Amlodipine, Enalapril and Losartan Response defined as sitting DBP of ≤90 mm Hg and/or a decrease from baseline of ≥10 mm Hg, measured 24 hours after dosing. Control defined as sitting DBP ≤90 mm Hg. Response rates NEUTEL et al., 1996 PRISANT et al., 1995 PRISANT et al., 1998 PAPADEMETRIOU et al., 1998 LODOZ Amlodipine Enalapril Placebo LODOZ Amlodipine Enalapril LODOZ Amlodipine Enalapril Placebo LODOZ Losartan / + Losartan + HCTZ Pla- cebo NEUTEL et al., Cardiovasc Rev Rep. 1996; 17: 33-45PRISANT et al., Am Heart J 1995; 130: PRISANT et al., Am J Ther. 1998; 5: PAPADEMETRIOU et al., Cardiovasc Rev Rep (Dec) Control rates 100% 80% 60% 40% 20% 0% *LODOZ significant vs. Amlodipine, Enalapril and placebo. *LODOZ and Amlodipine significant vs. Enalapril. *LODOZ significant vs. Enalapril and placebo. Combined analysis. *LODOZ significant vs. Losarten/Losarten + HCTZ and placebo.

Reduction in diastolic blood pressure under LODOZ vs. Bisoprolol, HCTZ and placebo Reduction from baseline diastolic blood pressure (mm Hg) LODOZ LODOZ 2.5 Placebo Bisoprolol 10 Bisoprolol 2.5 HCTZ 25 FRISHMAN et al., Arch Intern Med. 1994; 154: FRISHMAN et al., J Clin Pharmacol. 1995; 35: Reductions increased significantly with higher dosing of LODOZ. Results for LODOZ were significant vs. Bisoprolol and HCTZ alone in the resp. Dosage. LODOZ 5LODOZ 40 Bisoprolol HCTZ LODOZ 10 HCTZ 6.25 Bisoprolol 40

Reduction in systolic blood pressure under LODOZ vs. Bisoprolol, HCTZ and placebo Reduction from baseline systolic blood pressure (mm Hg)* LODOZ Placebo Bisoprolol 10, 40 Bisoprolol 2.5 HCTZ 25 FRISHMAN et al., Arch Intern Med. 1994; 154: FRISHMAN et al., J Clin Pharmacol. 1995; 35: *Results for LODOZ were significant vs. Bisoprolol and HCTZ alone in the resp. dosage. HCTZ 6.25 LODOZ 2.5LODOZ 5LODOZ 40 Bisoprolol25 HCTZ LODOZ 10

Diarrhea Bradycardia Dizziness Asthenia Edema Headache LODOZPlacebo 40% 35% 30% 25% 20% 15% 10% 5% 0% Incidence of adverse events (NEUTEL et al., 1996) Incidence and character of adverse events under LODOZ compared to placebo Total rate of patients with at least one adverse event Total rate of patients with at least one adverse event Rash Cough Diarrhea Dyspepsia Nausea Dizziness Asthenia Edema Headache 29% 27%

Incidence of adverse events under LODOZ vs. Amlodipine, Enalapril, ACE Inhibitors and placebo PRISANT et al., 1998 (combined analysis) LODOZ Amlodipine Enalapril Placebo Losartan/Losartan + HCTZ Placebo ACE Inhibitors PRISANT et al., Am J Ther. 1998; 5: FRISHMAN et al., ZIAC National Hypertension Trial Report, 1996 PAPADEMETRIOU et al., Cardiovasc Rev Rep (Dec) 50% 40% 30% 20% 10% 0% PAPADEMETRIOU et al., 1998 FRISHMAN, 1996 Rate of patients with at least one adverse event

Heart rate reduction under LODOZ vs. other treatments NEUTEL et al., 1996 Cardiovasc Rev Rep.; 17:33-45 Change from baseline sitting heart rate (beats/min) LODOZ Enalapril Placebo LODOZ Amlodipine LODOZ Placebo *LODOZ significant vs. comparitors BENETOS et al., 2000 Am Heart J.; 140:e14 PAPADEMETRIOU et al., 1998 Cardiovasc Rev Rep.; Dec. Losartan Amlodipine

Extent of quality of life under LODOZ vs. Amlodipine and Enalapril General Well-Being Index Zung Self-Rating Depression Scale Vital Sign Quality of Life Baseline Improvement Decline LODOZAmlodipineEnalapril *significant vs. enalapril * * Change in mean scores of 3 quality-of-life measures (WEIR, 1996) WEIR et al., Amer J Hyperten. 1996; 9: *LODOZ significant vs. Enalapril

20% 15% 10% 5% 0% LODOZ Amlodipine Enalapril Placebo LODOZ Amlodipine Enalapril Placebo LODOZ Amlodipine Enalapril Placebo Discontinuation due to adverse events Discontinuation due to lack of Efficacy* Discontinuation due to other reasons 42% *(blood pressure not controlled)NEUTEL et al., Cardiovasc Rev Rep. 1996; 17:33-45 Discontinuation rates (NEUTEL, 1996) Discontinuation rates under LODOZ vs. Amlodipine, Enalapril and placebo

Efficacy of LODOZ vs. Losartan/Losartan + HCTZ SBP, DBP and heart rate reduction after a treatment of up to 12 weeks mm Hg Losartan Systolic BPDiastolic BP heart rate PAPADEMETRIOU et al., 1998 Cardiovasc Rev Rep.; Dec. LODOZ vs. Losartan *p=0.0346; **p=0.0001; ***p= * ** *** LODOZ Losartan Placebo LODOZ beats per min LosartanPlacebo

LODOZ 2.5 in elderly patients with systolic hypertension Supine blood pressure reduction (mm Hg) Supine heart rate reduction (beats/min) *p<0.01 vs. baseline and p< vs. Amlodipine All reductions significant vs. baseline; p< Systolic BPDiastolic BP LODOZ Amlodipine LODOZ LODOZ - 7.6* BENETOS et al., 2000 Am Heart J.; 140:e14 Amlodipine

High efficacy Control of hypertension in up to 84% of patients Effective in a broad range of patients regardless of age, race or gender Recommended by the JNC VI and other guidelines Approved by the FDA as first-line treatment of hypertension Characteristics of LODOZ at a glance Multi-active mode of action Additive antihypertensive efficacy Blood pressure reduction via different mechanisms Metabolically neutral Low rate of adverse events Low-dose drug Specifically developed to minimize dose-related side effects Side-effect profile comparable to placebo Improved compliance Improvement in quality of life Once-daily dosage (consistent 24 hour-efficacy) Low discontinuation rates