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CUBICIN ® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis

CUBICIN ® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis. Anti-Infective Drugs Advisory Committee Meeting March 6, 2006. DAPTOMYCIN TOXICODYNAMICS Time to CPK Elevation . Log-rank test, stratification on C MIN CPK breakpoint:

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CUBICIN ® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis

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  1. CUBICIN® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis Anti-Infective Drugs Advisory Committee Meeting March 6, 2006

  2. DAPTOMYCIN TOXICODYNAMICS Time to CPK Elevation Log-rank test, stratification on CMIN CPK breakpoint: Chi-Sq statistic: 22.380 with 1 df Significance level: p << 5 X10-4 * When CMIN was evaluated as a continuous variable using Cox proportional hazards regression, it was also significant, p = 0.02.

  3. Monte Carlo simulation (9,999 iterations) utilized to estimate the probability of daptomycin trough concentrations being ≥25.7 mg/L RISK ASSESSMENT Dose and Probability of CPK Abnormalities From the cSSI study (CID 2004:38:1673), overall CPK elevations = 2.8%; daptomycin treatment emergent drug related CPK elevations = 2.1 %; 1.4% of troughs exceeded 25.7 mg/L

  4. Vancomycin SSP 14 43 Success by Pathogen-specific Therapy vs Comparator Agent (ITT AC) 20 45 20 45 1444 33 74 3470 33 74 2860 Success byPathogen-specific Therapy Success by Comparator Agent

  5. Success in Patients with Septic Pulmonary Emboli (ITT) * MRSA in 2 and MSSA in 1 comparator patients

  6. 50 80 4777 70 80 69 77 Adjudication Committee Success in Patients who Completed Therapy (ITT EOT/TOC) Success Rate %

  7. 64 80 5877 77 80 74 77 Investigator Success in Patients who Completed Therapy (ITT EOT/TOC) Success Rate %

  8. Duke Criteria Underestimate Endocarditis 16 cases (6 LIE, 10 RIE) of S. aureus IE (7%) Diagnosed On-study

  9. 53/115 comparator patients received vancomycin 44 (83.0%) had trough levels reported Mean vancomycin trough levels = 14.1 µg/mL Vancomycin Pharmacokinetic Summary

  10. Complicated Bacteremia with Bone and Joint Infections

  11. Adjudication Committee Success All Randomized Patients (ITT EOT, TOC AC)

  12. Follow-up of Patients with Emergence of Reduced Susceptibility to Daptomycin and Failure due to Persisting/Relapsing S. aureus

  13. Post-marketing Reports of CPK Elevation* (> 150,000 Patients Treated) *Data through 11 December 2005; reference Periodic Safety Update Reports 1 through 9

  14. Rhabdomyolysis Case Definition *Adapted from “ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins” (Pasternak et al, J Am Col Cardiology 2002;40(3):567-572) **“Controlled Comparison of Amikacin and Gentamicin” (Smith et al, NEJM 1977;296(7):349-353.

  15. Postmarketing Reports of Rhabdomyolysis *Echevarria K, Datta P, Cadena J et al. J Antimicrob Chemother 2005; 55: 599–600**Kazory A, Dibadj K. Weiner ID. J Antimicrob Chemother advance access 12 Jan 2006

  16. Shifts in CrCl from Baseline to Worst Value Note: Both central and local laboratory data are utilized; if both results were available on a given day, the central laboratory result was used in the analysis

  17. Safety and Efficacy With and Without Gentamicin *Patient with LIE

  18. Safety and Efficacy With and Without Gentamicin *Patient with LIE

  19. CPK Adverse Events Across Dose and Study

  20. 12 11 Growth Control 10 9 8 Linezolid 7 Linezolid/Gentamicin 6 Vancomycin 5 Vancomycin/Gentamicin 4 3 Daptomycin 2 Daptomycin/Gentamicin 1 0 8 16 24 32 40 48 56 64 72 hour IVPD Model: MRSA in Stationary Phase Gentamicin • Simulated endocardial vegetations in an in vitro pharmacodynamic model • MRSA strain at high inoculum (5 x 109 CFU / SEV) • Daptomycin exhibited rapid bactericidal activity against stationary phase MRSA LaPlante AAC 2004

  21. 200 CA-MRSA • All CA-MRSA were SCCmec type IV • 78% of CA-MRSA strains carried PVL Tsuji ICAAC 2005

  22. S. aureus with Defined Virulence Factors • Daptomycin is active against S. aureus with defined virulence factors (n = 42), including: • Accessory gene regulator (agr) 1 to 4 • Hemolysins • Panton Valentine leukocidin (PVL) • Toxic shock syndrome toxin-1 (TSST-1) • Enterotoxins Thorne GM, et al. Poster TH-11, ISSSI 2004.

  23. In Vitro SEV Model Huang JAC 2006

  24. 14C-Daptomycin Penetration into Cardiac Vegetations • 14C-daptomycin diffuses into cardiac vegetations • Daptomycin homogeneously distributes throughout all the vegetations examined • Diffusion within the vegetations was consistent between all vegetations Caron et al, AAC 1992

  25. Baseline Post-baseline Baseline and Post-baseline Isolates Patient Number (Daptomycin-treated) 152 212 105 037 183 136 172 0 -1 -2 3 Log10 Reduction = Bactericidal -3 Log10 Reduction at 4 Hours -4 -5 -6 -7 Daptomycin (8 µg/mL) was bactericidal in vitro against all isolates after 4 hours

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