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

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. Staphylococcus aureus Bacteremia Henry F. Chambers, M.D. Professor of Medicine, UCSF Chief of Infectious Diseases San Francisco General Hospital

3. Case 1 • 38 y/o man, new CHF, alcoholic cardiomyopathy, Hct = 13 (normal 40-45) • Given PRBCs, diuretics, afterload reducers • HD 6: upper + lower endoscopy • Post-procedure T = 39oC, blood cultures taken • HD 7: afebrile but BC x2 = GPC in clusters; R forearm former IV site red, tender, indurated • Vancomycin administered • HD 8: BC isolate = MSSA; f/u BC sterile

4. Management Issues • What is the risk of a poor outcome? • What antibiotic should be used? • What is the duration of therapy?

5. What is the risk of a poor outcome? Complications in catheter-associated SAB Raad, CID 14:75, 1992

6. What is the risk of a poor outcome? Complication

7. Independent Predictors of Complicated SAB Fowler, Arch Intern Med 163:2066, 2003

8. What is the risk of a poor outcome? 1 point each for skin findings, fever > 72h, community onset 4 points for positive blood culture @ 48-96h Fowler, Arch Intern Med 163:2066, 2003

9. Predictors of Poor Outcome for Staphylococcus aureus Bacteremia • Septic shock • Persistent focus of infection • Secondary focus of infection • Prolonged bacteremia on therapy (>48-72h) • Elderly patient (age > 60 years) • MRSA • Use of vancomycin instead of a b-lactam • Duration of treatment < 10-14 days

10. Criteria for Antimicrobial Therapy of Staphylococcus aureus Bacteremia • Bactericidal activity • Non-toxic, well-tolerated • Parenteral administration, at least initially • Convenient dosing

11. What antibiotic should be used? “If the focus of infection has been promptly removed with rapid documented resolution of the bacteremia (< 3 days), 2 weeks of antibiotic therapy with a penicillinase-resistant penicillin, first-generation cephalosporin, or glycopeptideis likely to be enough…..Under no circumstances should patients simply have the catheter removed without antibiotic treatment .” Antimicrobial Therapy and Vaccines, 2nd Ed., 2002, page 641

12. What antibiotic should be used? Fowler, CID 27:478-86, 1998

13. What antibiotic should be used?

14. What is the duration of therapy? 7-10 or fewer days? • Associated with high relapse, complication rates 10-14 days? • Standard recommended duration 4-6 weeks? • For endocarditis, osteomyelitis, complicated SAB

15. What was done? • PICC placed • Ceftriaxone 2g IV q24h for 14 days • Home infusion therapy arranged

16. Case 2 • 44 y/o man, homeless, IVDU with fever and back pain, non-localizing exam • Vancomycin administered • 3/3 BC positive MRSA • TTE negative, MRI spine negative • Fever persists during first week • 1/3 BC + MRSA 72h after admission

17. What is the risk of a poor outcome? Complications in community-onset SAB Jensen, Arch Intern Med 162: 27, 2003

18. Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

19. Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

20. Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

21. Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

22. What antibiotic should be used?

23. What was done? • PICC placed • Methadone maintenance • Vancomycin ~1g q12h IV for 6 weeks • Trough serum concentrations of ~15 mg/ml

24. What happened? • Patient returned 3 mo later complaining of back pain • Afebrile, normal exam • Blood cultures negative • MRI: T10-T11 osteomyelitis, discitis • Bone biopsy culture: MRSA

25. What was done? • PICC placed • Methadone maintenance • Vancomycin ~1g q12h IV for 6 weeks • Trough serum concentrations or ~15 mg/ml

26. Management Issues • Is this a vancomcyin failure? • Is so, why did it fail? • What is the risk of a poor outcome now? • What antibiotic(s) should be used now? • What is the duration of therapy?

27. “State of the Art” Treatment of Staphylococcus aureus Bacteremia • Current armamentarium is inadequate for • Out patient treatment • MRSA • Patients who fail or cannot tolerate therapy • Physicians often must rely on • Drugs not approved for treatment of complicated staphylococcal infections • Drugs of unknown or poorly documented efficacy • Second-line agents • Combinations of agents of uncertain benefit

28. CUBICIN® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis David Mantus, Ph.D. Vice President, Regulatory AffairsCubist Pharmaceuticals Adjunct Assistant ProfessorMassachusetts College of Pharmacy

29. Adjudication Committee Member and Affiliation

30. Experts Available for Questions and Answers

31. What is Daptomycin? • Cyclic lipopeptide natural product • Approved (IV, 4 mg/kg q24h) for complicated skin and skin structure infections, including MRSA • US 2003 • Israel 2004 • Argentina 2005 • EU 2006

32. Post-licensure Experience • 150,000+ patients treated • No new toxicities • ~1/3 of doses delivered in outpatient setting • Potency vs. S. aureus maintained • Microbiologic surveillance studies demonstrate> 99.9% of isolates are daptomycin susceptible • ~25% of use is for bacteremia (off-label) • ~50% of this use at the 4 mg/kg dose approved for skin, NOT the 6 mg/kg dose studied in S. aureus bacteremia

33. Rationale for Daptomycin in S. aureus Bacteremia and Endocarditis • Rapidly bactericidal in vitro and in vivo • Potency against MRSA and MSSA • Proven clinical efficacy in skin (MRSA and MSSA) • Proven efficacy in animal models of S. aureus endocarditis at 6 mg/kg human equivalent dose • Potential for outpatient treatment • Monotherapy • Once-daily

34. Continuous Dialogue with FDA on Development • Study design (2001-2002) • Open-label • Comparators • Enrollment of all patients with S. aureus • Data Safety Monitoring Board • Study assessments and analyses (2004-2005) • Adjudication Committee • Primary endpoints • Statistical Analysis Plan agreed upon prior to unblinding • Study results (2005) • sNDA filed • Priority review granted

35. S. aureus Bacteremia and EndocarditisSupplemental Indication and Dose • Proposed Indication • Staphylococcus aureus bacteremia (SAB) including those with known or suspected endocarditis (SAIE) caused by methicillin-susceptible and methicillin-resistant strains • Proposed Dose • 6 mg/kg monotherapy administered as a 30-minute intravenous (IV) infusion once per day for a minimum duration of 2 to 6 weeks, depending on theclinical condition

36. Agenda Introduction David Mantus, Ph.D.V.P. Regulatory AffairsCubist Pharmaceuticals Efficacy Helen Boucher, M.D.Assistant Professor of MedicineDir. Infectious Diseases Fellowship ProgramDiv. of Infectious Diseases and Geographic MedicineTufts University-NEMC Microbiology Jeff Alder, Ph.D.V.P. Drug Discovery & EvaluationCubistPharmaceuticals Safety Gloria Vigliani, M.D.V.P. Medical StrategyCubist Pharmaceuticals Conclusions G. Ralph Corey, M.D.Professor of Internal Medicine & Infectious DiseaseDuke University Medical Center

37. Overall Findings Daptomycin 6 mg/kg once daily: • Effective in the treatment of S. aureus bacteremia and endocarditis • Response higher in MRSA • Well tolerated for extended treatment durations • Less nephrotoxic than standard-of-care agents • Provides a much needed option for treatment of patients with S. aureus bacteremia including those with known or suspected endocarditis