1. 1 Daptomycin Safety Review Chuck Cooper, M.D. Medical Officer Division of Anti-Infective and Ophthalmology Products March 6, 2006 Advisory Committee Meeting

2. 2 Overview SAE’s Infection-related Renal Toxicity CPK analysis

3. 3 SAE’s

4. 4 Infection-Related SAE’s

5. 5

6. 6 Infection-related SAE’s Daptomycin (n=6) Enterobacter aerogenes bacteremia (1) Urosepsis (1) Pseudomonas aeruginosa from blood and urine Bacteremia (1) Acinetobacter calcoaceticus Klebsiella Infection NOS (1) Klebsiella pneumoniae from blood Sepsis NOS (2) Burkholderia spp. in blood Klebsiella pneumoniae in blood Comparator (n=0) Gram-negative infection-related SAE’s by PT

7. 7 Renal Toxicity

8. 8 Limitations with Renal AE Reporting No standardization of renal adverse events open label trial expectation of renal toxicity in comparator arm but not in the study drug arm potential for comparator-treated patients to receive treatment for longer duration

9. 9 Examples of AE Reporting Inconsistencies Daptomycin-tx Pts No AE; Cr 0.9 - 2.2 ARF; no creats reported No AE; Cr 1.7 - 2.1 No AE; Cr 1.1 - 1.8 No AE; Cr 0.7 - 1.6 Comparator-tx Pts ARF; Cr 1.2 - 1.5 RF NOS; Cr 0.8 - 1.4 ARF; onset same day as enrollment; b/l creat 2.0 No AE; Cr 1.0 - 1.8 The disease under study has an expected rate of renal events, so standardization of renal adverse event reporting is critical

10. 10 Alternative Approach to Assessing Renal Toxicity Renal toxicity case definition used: Creatinine increase of 25% or more  While on therapy or within 30 days after last dose Creatinine increase to above ULN (1.5) Results: Comparator 25/116 (21.6%) Daptomycin 17/120 (14.2%)

11. 11 Renal Toxicity Analysis Problems with interpretation Treatment arms have differences with regard to age and treatment duration Patients 60 years and older who had longer duration of therapy (longer than the median of 14 days) had the highest rate of renal toxicity There were more of these patients in the comparator arm than the daptomycin arm

12. 12 Contingency Table Graph – Distribution by Age and Treatment Duration Total n = 116Total n = 120

13. 13 Contingency Table Graph – Distribution by Age and Treatment Duration Total n = 116Total n = 120

14. 14 Contingency Table Graph – Renal Toxicity by Age and Treatment Duration 11/26 (42.3%) 5/27 (18.5%) 5/38 (13.2%) 4/25 (16%) 4/32 (12.5%) 6/47 (12.7%) 3/11 (27.3%) 4/30 (13.3%) Total n = 120Total n = 116

15. 15 Results after Correcting for Age and Duration of Treatment Results: Comparator 25/116 (21.6%) Daptomycin 17/120 (14.2%) Comparator 20/116 (17.2%) Daptomycin 17/120 (14.2%)

16. 16 CPK Analysis using Central Lab Data

17. 17 CPK > 500 by Treatment Group and HMG- CoA Reductase Inhib Exposure Rates of CPK Elevations to Above > 500 by Treatment Group Comparator n/N (%) Daptomycin n/N (%) Overall Study1/116 (0.90)9/120 (7.5) Prior or Concomitant treatment with a Statin 0/20 (0.0)4/24 (16.7) Patients with CPK > 500 with prior concomitant treatment with a statin 0/1 (0.0)4/9 (44)

18. 18 Conclusion SAE’s Greater number of infection-related SAE’s were reported in the daptomycin arm This increase may be related to underlying disease process or propensity for gram-negative infections CPK Greater number of patients with increases to over 500 U/L from baseline Possible association with prior or concomitant treatment with HMG-Co A reductase inhibitors Renal Similar rates of percentage increase in creatinine from baseline

19. 19 END