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

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CUBICINCUBICIN®® (daptomycin for injection) (daptomycin for injection) for for S. aureusS. aureus Bacteremia Bacteremia

Including Those With Known or Including Those With Known or Suspected EndocarditisSuspected Endocarditis

Anti-Infective Drugs Anti-Infective Drugs Advisory Committee MeetingAdvisory Committee Meeting

March 6, 2006March 6, 2006

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Staphylococcus aureus Staphylococcus aureus Bacteremia Bacteremia

Henry F. Chambers, M.D.Henry F. Chambers, M.D.Professor of Medicine, UCSF Professor of Medicine, UCSF Chief of Infectious DiseasesChief of Infectious Diseases

San Francisco General HospitalSan Francisco General Hospital

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Case 1Case 1• 38 y/o man, new CHF, alcoholic cardiomyopathy, 38 y/o man, new CHF, alcoholic cardiomyopathy,

Hct = 13 Hct = 13 (normal 40-45)(normal 40-45)

• Given PRBCs, diuretics, afterload reducersGiven PRBCs, diuretics, afterload reducers

• HD 6: upper + lower endoscopy HD 6: upper + lower endoscopy

• Post-procedure T = 39Post-procedure T = 39ooC, blood cultures takenC, blood cultures taken

• HD 7: afebrile but BC x2 = GPC in clusters; HD 7: afebrile but BC x2 = GPC in clusters; R forearm former IV site red, tender, induratedR forearm former IV site red, tender, indurated

• Vancomycin administeredVancomycin administered

• HD 8: BC isolate = MSSA; f/u BC sterileHD 8: BC isolate = MSSA; f/u BC sterile

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Management IssuesManagement Issues

• What is the risk of a poor outcome?What is the risk of a poor outcome?

• What antibiotic should be used?What antibiotic should be used?

• What is the duration of therapy?What is the duration of therapy?

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Early

Late

None

Raad, CID 14:75, 1992

What is the risk of a poor outcome?

Complications in catheter-associated SAB

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Study Rate Types

Fowler, N = 314(CID 40:695, 2005)

13% Endocarditis, arthritis, osteomyelitis

Thomas, N= 276(Int Med J 35:319, 2005)

9% death6% early4% late

Endocarditis, arthritis, thrombosis, pneumonia, epidural asbcess

Complication


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Independent Predictors of Independent Predictors of Complicated SABComplicated SAB

Predictor Odds ratio Positive f/u blood culture

5.6

Community-onset 3.1

Persistent fever @ 72h 2.2

Skin lesions 2.0

Fowler, Arch Intern Med 163:2066, 2003

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What is the risk of a poor outcome?What is the risk of a poor outcome?

0

20

40

60

80

100P

rob

abili

ty, %

0 1 2 3 4 5

Score

1 point each for skin findings, fever > 72h, community onset4 points for positive blood culture @ 48-96h

Fowler, Arch Intern Med 163:2066, 2003

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Predictors of Poor Outcome for Predictors of Poor Outcome for Staphylococcus aureusStaphylococcus aureus Bacteremia Bacteremia

• Septic shockSeptic shock

• Persistent focus of infection Persistent focus of infection

• Secondary focus of infectionSecondary focus of infection

• Prolonged bacteremia on therapy (>48-72h)Prolonged bacteremia on therapy (>48-72h)

• Elderly patient (age Elderly patient (age >> 60 years) 60 years)

• MRSAMRSA

• Use of vancomycin instead of a Use of vancomycin instead of a -lactam -lactam

• Duration of treatment < 10-14 daysDuration of treatment < 10-14 days

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Criteria for Antimicrobial Therapy of Criteria for Antimicrobial Therapy of Staphylococcus aureusStaphylococcus aureus Bacteremia Bacteremia

1.1. Bactericidal activityBactericidal activity

2.2. Non-toxic, well-tolerated Non-toxic, well-tolerated

3.3. Parenteral administration, at least initiallyParenteral administration, at least initially

4.4. Convenient dosing Convenient dosing

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What antibiotic should be used?What antibiotic should be used?

Antimicrobial Therapy and Vaccines, 2nd Ed., 2002, page 641

“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 glycopeptide is likely to be enough…..Under no circumstances should patients simply have the catheter removed without antibiotic treatment .”

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What antibiotic should be used?What antibiotic should be used? -lactam

(n = 110) Vancomycin

(n = 133)

Cure 84% 62%*

Relapse 4% 20%

Death 6% 12%

Fowler, CID 27:478-86, 1998

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Regimen Pros Cons

Nafcillin or oxacillin2 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 -lactams

Dicloxacillin or cephalexin1 g qid PO

Convenient (oral)

Unknown efficacy, GI side effects,

qid dosing


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What is the duration of therapy?What is the duration of therapy?

7-10 or fewer days? 7-10 or fewer days? – Associated with high relapse, complication ratesAssociated with high relapse, complication rates

10-14 days?10-14 days?– Standard recommended durationStandard recommended duration

4-6 weeks? 4-6 weeks? – For endocarditis, osteomyelitis, complicated SABFor endocarditis, osteomyelitis, complicated SAB

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What was done?What was done?

• PICC placedPICC placed

• Ceftriaxone 2g IV q24h for 14 daysCeftriaxone 2g IV q24h for 14 days

• Home infusion therapy arrangedHome infusion therapy arranged

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Case 2Case 2

• 44 y/o man, homeless, IVDU with fever and back 44 y/o man, homeless, IVDU with fever and back pain, non-localizing exampain, non-localizing exam

• Vancomycin administeredVancomycin administered

• 3/3 BC positive MRSA 3/3 BC positive MRSA

• TTE negative, MRI spine negativeTTE negative, MRI spine negative

• Fever persists during first weekFever persists during first week

• 1/3 BC + MRSA 72h after admission1/3 BC + MRSA 72h after admission

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Endo

Osteo

Other

None

Jensen, Arch Intern Med 162: 27, 2003


Complications in community-onset SAB

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5.6

Community-onset 3.1


Skin lesions 2.0

Fowler, et al, Arch Intern Med 163:2066, 2003

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5.6

Community-onset 3.1


Skin lesions 2.0


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5.6

Community-onset 3.1


Skin lesions 2.0


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5.6

Community-onset 3.1


Skin lesions 2.0


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RegimenRegimen ProsPros ConsCons

Nafcillin or oxacillinNafcillin or oxacillin2 g q4h IV2 g q4h IV

Highly effectiveHighly effective Poorly tolerated, Poorly tolerated, inconvenientinconvenient

Cefazolin Cefazolin 2 g q8h IV2 g q8h IV

EffectiveEffective InconvenientInconvenient

Vancomycin Vancomycin 1 g q12h IV1 g q12h IV

Well tolerated, Well tolerated, convenientconvenient

Less effective Less effective than than -lactams-lactams

Dicloxacillin or Dicloxacillin or cephalexincephalexin1 g qid PO1 g qid PO

Convenient Convenient (oral) (oral)

Unknown efficacy, Unknown efficacy, GI side effects, GI side effects,

qid dosing qid dosing

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• Methadone maintenanceMethadone maintenance

• Vancomycin ~1g q12h IV for 6 weeksVancomycin ~1g q12h IV for 6 weeks

• Trough serum concentrations of ~15 Trough serum concentrations of ~15 g/mlg/ml

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What happened?What happened?

• Patient returned 3 mo later complaining of back Patient returned 3 mo later complaining of back painpain

• Afebrile, normal examAfebrile, normal exam

• Blood cultures negativeBlood cultures negative

• MRI: T10-T11 osteomyelitis, discitisMRI: T10-T11 osteomyelitis, discitis

• Bone biopsy culture: MRSABone biopsy culture: MRSA

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• Methadone maintenanceMethadone maintenance

• Vancomycin ~1g q12h IV for 6 weeksVancomycin ~1g q12h IV for 6 weeks

• Trough serum concentrations or ~15 Trough serum concentrations or ~15 g/mlg/ml

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Management IssuesManagement Issues

• Is this a vancomcyin failure?Is this a vancomcyin failure?

• Is so, why did it fail?Is so, why did it fail?

• What is the risk of a poor outcome now?What is the risk of a poor outcome now?

• What antibiotic(s) should be used now?What antibiotic(s) should be used now?

• What is the duration of therapy?What is the duration of therapy?

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““State of the Art” Treatment of State of the Art” Treatment of StaphylococcusStaphylococcus aureus Bacteremia aureus Bacteremia

• Current armamentarium is inadequate forCurrent armamentarium is inadequate for– Out patient treatmentOut patient treatment

– MRSAMRSA

– Patients who fail or cannot tolerate therapyPatients who fail or cannot tolerate therapy

• Physicians often must rely on Physicians often must rely on – Drugs not approved for treatment of complicated Drugs not approved for treatment of complicated

staphylococcal infections staphylococcal infections

– Drugs of unknown or poorly documented efficacy Drugs of unknown or poorly documented efficacy

– Second-line agentsSecond-line agents

– Combinations of agents of uncertain benefitCombinations of agents of uncertain benefit

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CUBICINCUBICIN®® (daptomycin for injection) (daptomycin for injection) for for S. aureusS. aureus Bacteremia Bacteremia

Including Those With Known or Including Those With Known or Suspected EndocarditisSuspected Endocarditis

David Mantus, Ph.D.David Mantus, Ph.D.Vice President, Regulatory AffairsVice President, Regulatory Affairs

Cubist PharmaceuticalsCubist Pharmaceuticals

Adjunct Assistant ProfessorAdjunct Assistant ProfessorMassachusetts College of PharmacyMassachusetts College of Pharmacy

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Adjudication Committee Member and AffiliationAdjudication 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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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.

Experts Available for Questions and AnswersExperts Available for Questions and Answers

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What is Daptomycin?What is Daptomycin?

• Cyclic lipopeptide Cyclic lipopeptide natural productnatural product

• Approved (IV, 4 mg/kg q24h) Approved (IV, 4 mg/kg q24h) for complicated skin and skin for complicated skin and skin structure infections, including structure infections, including MRSAMRSA– US US 20032003

– Israel Israel 20042004

– ArgentinaArgentina 20052005

– EUEU 20062006

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Post-licensure ExperiencePost-licensure Experience

• 150,000+ patients treated150,000+ patients treated– No new toxicitiesNo new toxicities

– ~1/3 of doses delivered in outpatient setting~1/3 of doses delivered in outpatient setting

• Potency vs. Potency vs. S. aureusS. aureus maintained maintained– Microbiologic surveillance studies demonstrateMicrobiologic surveillance studies demonstrate

> 99.9% of isolates are daptomycin susceptible> 99.9% of isolates are daptomycin susceptible

• ~25% of use is for bacteremia (off-label)~25% of use is for bacteremia (off-label)– ~50% of this use at the 4 mg/kg dose approved for skin, ~50% of this use at the 4 mg/kg dose approved for skin,

NOT the 6 mg/kg dose studied in NOT the 6 mg/kg dose studied in S. aureusS. aureus bacteremia bacteremia

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Rationale for Daptomycin in Rationale for Daptomycin in S. aureusS. aureus Bacteremia and Endocarditis Bacteremia and Endocarditis

• Rapidly bactericidal Rapidly bactericidal in vitroin vitro and and in vivoin vivo

• Potency against MRSA and MSSAPotency against MRSA and MSSA

• Proven clinical efficacy in skin (MRSA and MSSA)Proven clinical efficacy in skin (MRSA and MSSA)

• Proven efficacy in animal models of Proven efficacy in animal models of S. aureusS. aureus endocarditis at 6 mg/kg human equivalent doseendocarditis at 6 mg/kg human equivalent dose

• Potential for outpatient treatmentPotential for outpatient treatment– MonotherapyMonotherapy

– Once-dailyOnce-daily

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Continuous Dialogue with FDA on Development Continuous Dialogue with FDA on Development

• Study design (2001-2002)Study design (2001-2002)– Open-labelOpen-label

– ComparatorsComparators

– Enrollment of all patients with Enrollment of all patients with S. aureusS. aureus

– Data Safety Monitoring BoardData Safety Monitoring Board

• Study assessments and analyses (2004-2005)Study assessments and analyses (2004-2005)– Adjudication CommitteeAdjudication Committee

– Primary endpointsPrimary endpoints

– Statistical Analysis Plan agreed upon prior to unblindingStatistical Analysis Plan agreed upon prior to unblinding

• Study results (2005)Study results (2005)– sNDA filed sNDA filed

– Priority review grantedPriority review granted

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S. aureusS. aureus Bacteremia and Endocarditis Bacteremia and EndocarditisSupplemental Indication and DoseSupplemental Indication and Dose

• Proposed IndicationProposed Indication– Staphylococcus aureusStaphylococcus aureus bacteremia (SAB) including bacteremia (SAB) including

those with known or suspected endocarditis (SAIE) those with known or suspected endocarditis (SAIE) caused by methicillin-susceptible and caused by methicillin-susceptible and methicillin-resistant strainsmethicillin-resistant strains

• Proposed DoseProposed Dose– 6 mg/kg monotherapy administered as a 30-minute 6 mg/kg monotherapy administered as a 30-minute

intravenous (IV) infusion once per day for a minimum intravenous (IV) infusion once per day for a minimum duration of 2 to 6 weeks, depending on theduration of 2 to 6 weeks, depending on theclinical conditionclinical condition

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AgendaAgenda

G. Ralph Corey, M.D.G. Ralph Corey, M.D.Professor of Internal Medicine & Professor of Internal Medicine & Infectious DiseaseInfectious Disease Duke University Medical CenterDuke University Medical Center

ConclusionsConclusions

Gloria Vigliani, M.D.Gloria Vigliani, M.D.V.P. Medical StrategyV.P. Medical StrategyCubist PharmaceuticalsCubist Pharmaceuticals

SafetySafety

Jeff Alder, Ph.D.Jeff Alder, Ph.D.V.P. Drug Discovery & EvaluationV.P. Drug Discovery & EvaluationCubistCubist PharmaceuticalsPharmaceuticals

MicrobiologyMicrobiology

Helen Boucher, M.D.Helen Boucher, M.D.Assistant Professor of MedicineAssistant Professor of MedicineDir. Infectious Diseases Fellowship ProgramDir. Infectious Diseases Fellowship ProgramDiv. of Infectious Diseases and Geographic MedicineDiv. of Infectious Diseases and Geographic MedicineTufts University-NEMCTufts University-NEMC

EfficacyEfficacy

David Mantus, Ph.D.David Mantus, Ph.D.V.P. Regulatory AffairsV.P. Regulatory AffairsCubist PharmaceuticalsCubist Pharmaceuticals

IntroductionIntroduction

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Overall FindingsOverall Findings

Daptomycin 6 mg/kg once daily:Daptomycin 6 mg/kg once daily:

• Effective in the treatment of Effective in the treatment of S. aureusS. aureus bacteremia bacteremia and endocarditis and endocarditis – Response higher in MRSAResponse higher in MRSA

• Well tolerated for extended treatment durationsWell tolerated for extended treatment durations

• Less nephrotoxic than standard-of-care agentsLess nephrotoxic than standard-of-care agents

• Provides a much needed option for treatment of patients Provides a much needed option for treatment of patients with with S. aureusS. aureus bacteremia including those with known or bacteremia including those with known or suspected endocarditissuspected endocarditis

Documents

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