CUBICIN

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

• Anti-Infective Drugs Advisory Committee Meeting
• March 6, 2006

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Staphylococcus aureus Bacteremia

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

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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

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Management Issues

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

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What is the risk of a poor outcome?
Complications in catheter-associated SAB
Raad, CID 1475, 1992
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What is the risk of a poor outcome?
Complication
Study Rate Types
Fowler, N 314 (CID 40695, 2005) 13 Endocarditis, arthritis, osteomyelitis
Thomas, N 276 (Int Med J 35319, 2005) 9 death 6 early 4 late Endocarditis, arthritis, thrombosis, pneumonia, epidural asbcess
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Independent Predictors of Complicated SAB
Fowler, Arch Intern Med 1632066, 2003
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What is the risk of a poor outcome?
1 point each for skin findings, fever gt 72h,
community onset 4 points for positive blood
culture _at_ 48-96h
Fowler, Arch Intern Med 1632066, 2003
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Predictors of Poor Outcome for Staphylococcus
aureus Bacteremia

• Septic shock
• Persistent focus of infection
• Secondary focus of infection
• Prolonged bacteremia on therapy (gt48-72h)
• Elderly patient (age gt 60 years)
• MRSA
• Use of vancomycin instead of a b-lactam
• Duration of treatment lt 10-14 days

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Criteria for Antimicrobial Therapy of
Staphylococcus aureus Bacteremia

• Bactericidal activity
• Non-toxic, well-tolerated
• Parenteral administration, at least initially
• Convenient dosing

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What antibiotic should be used?
If the focus of infection has been promptly
removed with rapid documented resolution of the
bacteremia (lt 3 days), 2 weeks of antibiotic
therapy with a penicillinase-resistant
penicillin, first-generation cephalosporin, or
glycopeptide is 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
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What antibiotic should be used?
Fowler, CID 27478-86, 1998
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What antibiotic should be used?
Regimen Pros Cons
Nafcillin or oxacillin 2 g q4h IV Highly effective Poorly tolerated, inconvenient
Cefazolin 2 g q8h IV Effective Inconvenient
Vancomycin 1 g q12h IV Well tolerated, convenient Less effective than b-lactams
Dicloxacillin or cephalexin 1 g qid PO Convenient (oral) Unknown efficacy, GI side effects, qid dosing
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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

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What was done?

• PICC placed
• Ceftriaxone 2g IV q24h for 14 days
• Home infusion therapy arranged

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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

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What is the risk of a poor outcome?
Complications in community-onset SAB
Jensen, Arch Intern Med 162 27, 2003
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Independent Predictors of Complicated SAB
Fowler, et al, Arch Intern Med 1632066, 2003
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Independent Predictors of Complicated SAB
Fowler, et al, Arch Intern Med 1632066, 2003
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Independent Predictors of Complicated SAB
Fowler, et al, Arch Intern Med 1632066, 2003
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Independent Predictors of Complicated SAB
Fowler, et al, Arch Intern Med 1632066, 2003
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What antibiotic should be used?
Regimen Pros Cons
Nafcillin or oxacillin 2 g q4h IV Highly effective Poorly tolerated, inconvenient
Cefazolin 2 g q8h IV Effective Inconvenient
Vancomycin 1 g q12h IV Well tolerated, convenient Less effective than b-lactams
Dicloxacillin or cephalexin 1 g qid PO Convenient (oral) Unknown efficacy, GI side effects, qid dosing
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What was done?

• PICC placed
• Methadone maintenance
• Vancomycin 1g q12h IV for 6 weeks
• Trough serum concentrations of 15 mg/ml

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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

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What was done?

• PICC placed
• Methadone maintenance
• Vancomycin 1g q12h IV for 6 weeks
• Trough serum concentrations or 15 mg/ml

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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?

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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

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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

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Adjudication Committee Member and Affiliation
Elias Abrutyn, M.D.Associate Provost and Associate Dean for Faculty Affairs, and Interim Chief, Infectious Disease Drexel University
G. Ralph Corey, M.D.Professor of Internal Medicine Infectious DiseaseDuke University Medical Center
Sara Cosgrove, M.D.Assistant Professor, Dept of Medicine, Div of Infectious DiseaseJohns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health
Vance G. Fowler, M.D.Associate Professor of MedicineDuke University Medical Center
Adolf W. Karchmer, M.D.Professor of Medicine, Chief, Division of Infectious Diseases Beth Israel Deaconess Medical Center
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Experts Available for Questions and Answers
Christopher H. Cabell, M.D., M.H.S., F.A.C.C. Assistant Professor of Medicine Division of Cardiology Duke University School of Medicine
Henry F. Chip Chambers, M.D.Professor of MedicineUniversity of California - San FranciscoChief, Division of Infectious DiseasesSan Francisco General Hospital
George Drusano, M.D.Professor of Medicine and PharmacologyAlbany Medical CollegeCo-directorOrdway Research Institute
Donald Levine, M.D.Professor of MedicineChief, General/Internal MedicineWayne State University
Albert Sheldon, Jr., Ph.D.PresidentAntibiotic and Antiseptic Consultants, Inc.
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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

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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 demonstrategt
  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

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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

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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

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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

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