1. Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosis ALBION

2. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Background and Rationale  Optimal and rapid platelet inhibition in ACS: crucial in the context of urgent care  Clopidogrel (300 mg LD) has been shown to be of clinical benefit in the treatment of ACS 1  A LD of 300 mg administered early is of proven clinical benefit 2,3  Ex vivo measurements of platelet aggregation suggest that a higher loading dose can shorten the time to reach the plateau of antiplatelet efficacy 4,5  Q: What is the effect of higher loading doses on the pharmacokinetics and pharmacodynamics of clopidogrel ? 1.Yusuf S et al. NEJM 2001;345(7):494-502 2.Steinhubl Set al., JAMA 2002; 2411-2420 3. Mehta S. R. Lancet, 2001, 358(9281), 527-533 4 Müller I et al. Heart 2001; 85: 92-93 5. Seyfarth HJ et al. Am Heart J2002; 143:118-123

3. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Study Design *ASA=250-500 mg on admission, then  100 mg/day plus other standard care n=35 LMWH and ASA* Clopidogrel 300 mg LD then 75 mg qd Randomized, open-label trial with blind centralized laboratory assessment in patients aged 18  85 years with UA/NSTEMI (onset < 48 h) Clinical follow-up at 30 days R Clopidogrel 600 mg LD then 75 mg qd Clopidogrel 900 mg LD then 75 mg qd n=34 D2 0234562411/2 Sampling Time Hours post-LD LD

4. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Inclusion criteria  Age 18  85 years  UA/NSTEMI within 48 hours  Planned treatment with clopidogrel Major exclusion criteria  Intention of angiography within 24 hours  Contraindication to the use of clopidogrel or ASA  BP > 180/ 100mmHg despite therapy  Platelet count < 100 000/ mm 3  Neutrophil count < 1800/ mm 3  Severe risk of bleeding  Patients treated with a thienopyridine, dipyridamole, NSAID, cilostazol, GPIIb/IIIa inhibitor within the previous 10 days before randomization or planned to receive any of these products within the 24 h post-randomization  Evolving cancer  NYHA class IV heart failure  Venous status incompatible with an indwelling catheter Inclusion/Exclusion Criteria

5. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Primary:  Platelet aggregation induced by 5 µM/L ADP (T0  T24) Secondary:  Platelet aggregation induced by 20 µM/L ADP (T0  T24)  Flow cytometry (T0  T24): PAC1, anti-P selectin, VASP  Inflammation markers (T0, T6, T24) : hsCRP, wWF Ag, PAI-1 Ag, sCD40-L  Myonecrosis markers (T0, T6, T24): Troponin I, CK  MACE* at Day 30  Safety Evaluation Criteria MACE: Major Adverse Cardiac Events

6. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Baseline Characteristics 300 mg LD (n = 35) 600 mg LD (n = 34) 900 mg LD (n = 34) Males (%)77 Age (years, mean)606364 Symptoms onset (%)  < 24H   24H and < 48H 80 20 76 24 79 21 Previous MI (%)111218 Previous PCI&CABG (%)232441 Hypertension (%)536063 Diabetes (%)331323 Current smoking (%)332737 Hypercholesterolemia (%)475760 Admission ECG (%)   ST (transient)   ST  LBBB 6 23 0 9 30 0 6 44 6 Positive TnI (%)293224

7. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Patients Invasive Management 300 mg LD (n = 35) 600 mg LD (n = 34) 900 mg LD (n = 34) Coronary Angiography (%)979488 PCI (%)547153 CABG (%)603 *No statistically significant differences between groups

8. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Primary Endpoint: Faster Onset of Action and Higher Level of Platelet Inhibition  p< 0.05 vs. 300 mg LD Shortened time to reach the highest level of inhibition of the 300 mg LD

9. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Secondary Endpoint: Faster Onset of Action and Higher Level of Platelet Inhibition  p< 0.05 vs. 300 mg LD

10. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. AUC Inhibition: Baseline to 24 hours Areas Under the IPA* - Time Curves 0 1 2 3 4 5 6 5 µM/L ADP 300mg 600mg 900mg p < 0.05 20 µM/L ADP IPA: Inhibition of Platelet Aggregation

11. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Flow Cytometry  p< 0.05 vs. 300 mg LD

12. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Flow cytometry (cont.)  p< 0.05 vs. 300 mg LD

13. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. VASP : MFI (PGE 1 +ADP) at 6 and 24 Hours p < 0.05 VASP= Vasodilator-Stimulated Phosphoprotein MFI = Median Fluorescence Intensity p < 0.05

14. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. VASP Index at 6 and 24 Hours p < 0.05 VASP Index = [(MFI PGE1 – MFI PGE1 +ADP )/ MFI PGE1 ] X 100 p < 0.05

15. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. No statistically significant differences between the three LDs at 6 and 24 hours Inflammatory Markers –hs CRP –von Willebrand factor Ag –PAI-1 Ag –sCD40-L Myonecrosis Markers: CK and Troponin-I Inflammatory and Myonecrosis Markers

16. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Patients with Increasing Troponin-I at Day 2 p = NS Increasing Troponin defined as: either within normal range at Day 1 and > normal range at Day 2 or, > normal range on Day 1 and increased by  30% at Day 2

17. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Major Adverse Cardiac Events 300 mg n = 35 600 mg n = 34 900 mg n = 34 Death (n) Non-fatal MI*(n) Unplanned PCI (n) Hospitalization for recurrent angina (n) 01120112 02000200 00000000 TOTAL – n (%)4 (11.4)2 (5.9)0 * New Q wave or CK > 3 times the ULN

18. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Safety 300 mg n = 35 600 mg n = 34 900 mg n = 34 Bleeding* Day 1- Discharge (n)  Severe  Moderate  Mild TOTAL 0 1 10 11 0 10 0 1 13 14 * GUSTO Classification

19. FOR INTERNAL USE ONLY. NOT FOR SALES PRESENTATIONS ALBION Montalescot G. EuroPCR- May 2005. Summary In patients with NSTE-ACS, ALBION has shown that 600 and 900 mg LDs compared to the conventional 300-mg LD provided:  More rapid and higher levels of IPA during the first 24 h  Greater reductions in some markers of platelet activation (PAC-1 and VASP) during the first 24 hours  No statistically significant differences in various inflammatory and myonecrosis markers  Potential favorable trends on troponin release and ischemic events  Comparable safety profiles IPA: Inhibition of Platelet Aggregation