1. 1 Review of Efficacy Data New Drug Application NDA 21-572/S-008 Cubicin® (daptomycin for injection) Alfred Sorbello, DO Medical Officer FDA, CDER Center for Drug Evaluation and Research Anti-Infective Drugs Advisory Committee March 6, 2006

2. 2 Overview All-comers Endocarditis Mortality Data

3. 3 All-comers

4. 4 Study Population: All-comers Pathogen-driven target population ≥1 positive blood culture for S. aureus Statistically powered for an all-comers analysis Risk factors: infection within 30 days of enrollment (74%) surgery within 30 days of enrollment (36%) Final diagnosis assessments Blinded, retrospective Incorporate central echocardiography No systematic assessment for metastatic foci

5. 5 FDA: Post-Hoc Analysis of Potential Portals of Entry (ITT)

6. 6 Sponsor Efficacy Data: IEAC Success Rates in All-comers and Final Diagnosis Subgroups Total N Daptomycin (n/N,%) Comparator (n/N,%) All-comers (ITT)23553/120 (44.2)*48/115 (41.7)* Final Diagnosis Subgroups Complicated Bacteremia12126/60 (43.3)23/61 (37.7) Uncomplicated Bacteremia6118/32 (56.3)16/29 (55.2) Right IE358/19 (42.1)7/16 (43.8) Left IE181/9 (11.1)2/9 (22.2) *95% CI for difference in success rates: 2.4% (-10.2, 15.1)

7. 7 Compilation of IEAC Reasons for Failure*: All-comers IEAC Reasons for FailureDaptomycin N = 58 Comparator N = 53 Total N= 111 Microbiologic Failure282351 Clinical Failure211435 PRSA191130 PENS191534 Death13 26 Adverse Event91625 Missing Blood Culture91221 Other437 Total122107229 * at EOT and TOC for All-comers in the ITT population PRSA = persisting and relapsing S. aureus infection; PENS = potentially effective non-study medication

8. 8 FDA: Microbiologic Failures in All-comers due to PRSA *persistent knee infection; † persistent urinary tract infection Daptomycin n=21 Comparator n=11 Oxacillin Susceptibility MRSA129 MSSA92 Clinical Subgroups Total Endocarditis85 Complicated RIE13 Uncomplicated RIE30 Left IE42 Total Bacteremia125 Complicated125 Uncomplicated00 Other Persistent Infections1*1†1†

9. 9 Increasing MICs to Daptomycin and Vancomycin during Study Drug Treatment n IEAC Outcome at TOC SuccessFailure Comparator N=96 Vancomycin MIC=2321 Daptomycin MIC ≥2000 Increased MICs to both drugs110 Total Subjects431 Daptomycin N=113 Vancomycin MIC=2312 Daptomycin MIC ≥2404 Increased MICs to both drugs202 Total Subjects918

10. 10 All-comers: Summary Heterogeneity of all-comers population Small size of clinical subgroups PRSA accounted for more failures among daptomycin-treated subjects Bacteremia Endocarditis Increasing MICs to daptomycin observed during daptomycin treatment was associated with failure at primary efficacy endpoint (TOC)

11. 11 S. aureus Endocarditis

12. 12 Sponsor Efficacy Data: S. aureus endocarditis ITT (N = 53)PP (N = 33) Daptomycin n = 28 Comparator n = 25 Daptomycin n = 19 Comparator n = 14 Left IE1/9 (11)2/9 (22)1/7 (14.2)2/6 (33.3) Total RIE8/19 (42)7/16 (43.8)6/12 (50)4/8 (50) Uncomplicated RIE 3/6 (50)1/4 (25)1/2 (50)0/2 (0) Complicated RIE 5/13 (38.5)6/12 (50)5/10 (50)4/6 (66.7)

13. 13 Echocardiography 53 patients (ITT) (35 RIE, 18 LIE) 34 positive Central echo (17 RIE, 17 LIE) 10 pos Central echo had negative Local echo (8 LIE, 2 RIE) 18 negative Central echo (17 RIE, 1 LIE) 8 neg Central echo had positive Local echo (8 RIE) 1 patient: no echo (1 RIE)

14. 14 IEAC Success Rates at TOC by Echocardiographic Findings IE Population (ITT)NComparatorDaptomycin All subjects with IEAC Final Diagnosis of endocarditis 539/25 (36)9/28 (32.1) All subjects with pos Central echo plus all pos Local echo 429/24 (37.5)6/18 (33.3) All subjects with positive Central echo (regardless of Local echo) 347/20 (35)4/14 (28.6) All subjects with Positive Local echo (regardless of Central echo) 327/19 (36.8)6/13 (46.1)

15. 15 Mortality

16. 16 All-Cause Mortality Data DaptomycinComparator N=120N=116 Deaths up to day 42P15 (12.5)13 (11.2) Bacteremia12 (10)8 (6.9) Endocarditis3 (2.5)5 (4.3) All deaths (to end of study)18 (15)19 (16.4) Bacteremia15 (12.5)11 (9.5) Endocarditis3 (2.5)8 (6.9)

17. 17 Increasing MICs to Daptomycin and Vancomycin during Study Drug Treatment, PRSA, and Mortality nPRSADeath Comparator N=96 Vancomycin MIC=2300 Daptomycin MIC ≥2000 Increased MICs to both drugs100 Total Subjects400 Daptomycin N=113 Vancomycin MIC=2301 Daptomycin MIC ≥2441 Increased MICs to both drugs221 Total Subjects963 PRSA = persisting/relapsing S. aureus

18. 18 Crude Mortality Rate* DaptomycinComparator Relative Risk of Death All deaths to end of study All-cause MR15.0%16.4% Proportionate MR associated with PRSA 44.4%36.8% MR associated with PRSA 6.66%6.02%1.10 95% CI (0.41, 2.95) *Mortality Rate from PRSA = (all-cause mortality rate) X (proportionate mortality rate); MR = mortality rate

19. 19 Overall Summary

20. 20 Summary All-comers Study was powered to demonstrate efficacy based on all subjects having ≥1 positive blood culture for S. aureus Generalizability of efficacy performance from all-comers population to endocarditis subgroup was problematic Pathophysiology Adjunctive treatment Prognosis Heterogeneous nature of all-comers population warranted further characterization Overall point estimates for success were low

21. 21 Summary Endocarditis Small subpopulation of all-comers Insufficient power to permit statistically meaningful inferences Difficult to establish the specificity of the diagnosis Low efficacy rates in both treatment groups

22. 22 Summary PRSA was more frequent among failures in the daptomycin group Bacteremia Endocarditis Irrespective of oxacillin susceptibility Increasing MICs to daptomycin during daptomycin therapy Increased likelihood of failure at primary efficacy endpoint (TOC) Associated with PRSA and subsequent death

23. 23 FDA: All Subjects with Increasing Daptomycin MICs during Study treatment Case ID #Study GroupBaseline Pathogen IEAC Final DiagnosisIEAC Outcome at TOC Study Day Daptomycin MIC ≥ 2 004-193ComparatorMRSAComplicated RIESuccessDay 11 009-212 § DaptomycinMRSAComplicated bacteremia FailureDay 09P 010-152 § DaptomycinMSSAComplicated RIEFailureDay 18 015-105 § DaptomycinMRSAComplicated bacteremia FailureDay 20P 017-037* § DaptomycinMRSALeft IEFailureDay 4 027-183* § DaptomycinMRSALeft IEFailureDay 7 088-172DaptomycinMSSAComplicated bacteremia SuccessDay 13 324-136 § DaptomycinMRSAComplicated bacteremia FailureDay 7 *Death; § PRSA infection