New Drug Application NDA 21-572/S-008 Cubicin

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New Drug Application NDA 21-572/S-008 Cubicin
(daptomycin for injection)

• Microbiology Increased Daptomycin MICs During
  Therapy
• Peter Coderre, PhD, MBA
• CDER, DAIOP
• Anti-Infective Drugs Advisory Committee Meeting
• Rockville, Maryland
• March 6, 2006

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Increased Daptomycin MICs

• Increasing daptomycin MICs documented in vitro,
  in vivo, in the literature and during this
  clinical trial
• Currently S. aureus isolates with a MIC
  1 mg/ml are considered susceptible to daptomycin
• Breakpoints for intermediate and resistant
  isolates have yet to be established

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Increased Daptomycin MICs

• What are the implications of increasing
  daptomycin MICs during treatment with daptomycin
  for infective endocarditis and bacteremia?
• In patients with persistent or relapsing
  bacteremia, S. aureus demonstrated increasing
  daptomycin MICs ( 1 mg/ml) during or after
  therapy with the drug.

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Changes in MICs for Relapsing or Persistent
Bacteremia Patients
MIC gt1 gt 2 steps MRSA MSSA
daptomycin arm (N20) 9/20 (45.0) 9/20 (45.0) 12/20 (60.0) 11/20 (55.0)
comparator arm (N10) 1/10 (10.0) 0/10 (0) 8/10 (80.0) 2/10 (20.0)

3 patients had both MSSA and MRSA FDA Analysis
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Distribution of Terminal MICs for Daptomycin
Treated Patients (ITT) by Clinical Outcome
MIC (mg/ml)
0.12 0.25 0.5 1 2 4
clinical success (N53) 1 (1.9) 36 (67.9) 14 (26.4) 2 (3.8) 0 (0) 0 (0)
clinical failure (N59) 1 (1.7) 34 (57.6) 15 (25.4) 3 (5.1) 5 (8.5) 1 (1.7)
total (N112) 2 (1.8) 70 (62.5) 29 (25.9) 5 (4.4) 5 (4.5) 1 (0.9)
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Clinical Failures in Daptomycin Arm with
Increased Daptomycin MICs
Case Final Diagnosis Organism Baseline High MIC Step
MIC MIC Increase
009-212 complicated bacteremia MRSA 0.25 2 3
010-152 complicated RIE MSSA 0.25 4 4
015-105 complicated bacteremia Both 0.25 2 -
017-037 left IE Both 0.25 2 -
027-183 left IE MRSA 0.5 2 2
324-136 complicated bacteremia MRSA 0.5 2 2
300-111 left IE MRSA 0.25 1 2
300-246 left IE MRSA 0.25 1 2
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Frequency of Increased MICs and
Non-Susceptibility/Resistance to Daptomycin or
Vancomycin in Patients during Therapy
N, ? N, ? N, developed N, developed
Dapto MIC Vanco MIC DaptoNS VancoR
IEAC successes
daptomycin (N53) 17 (32.1) 12 (22.6) 0 (0) 0 (0)
comparator (N48) 11 (22.9) 13 (27.1) 1 (2.1) 0 (0)
IEAC failures
daptomycin (N67) 23 (34.3) 16 (24.2) 6 (9.0) 0 (0.0)
comparator (N65) 12 (18.5) 17 (26.2) 0 (0.0) 0 (0.0)
determination of MICs not done for one patient
determination of MICs not done for two
patients one or more dilution increase
contains non-evaluable patients as failures
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Overview of Isolates with Treatment Associated
Decreases in Daptomycin Susceptibility Following
Commercial Availability
Isolate/N Source Daptomycin MIC (mg/ml)
S.aureus blood 0.25 1
S.aureus 0.25 4
S.aureus--5 blood 0.5 4
S.aureus 0.5 4
S.aureus blood 1 2--4
S.aureus 0.5 8
MRSA 0.25 1.5
E. faecium urine/blood 4 32
E. faecium blood 4 gt 32
VRE blood 4
VRE 8
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Recent Literature Reporting Clinical Failures
with Daptomycin Treatment
Organism Condition Source Dose Highest Reference
(mg/kg) MIC (mg/ml)
MRSA bacteremia blood 4 2 Mangili et al., 2005
MRSA osteomyelitis blood 6 4 Hayden et al., 2005
MRSA bacteremia blood 8 4 Skiest, 2006
MRSA bacteremia blood 6 4 Marty et al., 2006
E. faecium bacteremia blood 6 gt32 Sabol et al., 2005
E. faecium fever blood none 4 Lesho et al., 2006
E. faecalis (VRE) bacteremia blood 16 Munoz-Price, et al., 2005
E. faecalis (VRE) febrile neutropenia blood ?? ?? Long et al., 2005
400 mg q48h
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Surveillance Data
Species Study/Year N Daptomycin MIC Distribution n () MIC (mg/ml) Daptomycin MIC Distribution n () MIC (mg/ml) Daptomycin MIC Distribution n () MIC (mg/ml) Daptomycin MIC Distribution n () MIC (mg/ml)
0.12 0.25 0.5 1 2
MSSA 2000-1 1601 304 (18.9) 1165 (72.7) 131 (8.2) 1 (0.1) 0 (0)
2002 1547 83 (5.4) 1140 (73.7) 319 (20.6) 3 (0.2) 2 (0.1)
2003 2894 229 (7.9) 2371 (81.9) 285 (9.9) 8 (0.3) 1 (lt0.1)
2003-4 3284 70 (2.1) 1891 (57.6) 1297 (39.5) 25 (0.8) 1 (lt0.1)
MRSA 2000-1 639 51 (7.9) 396 (61.9) 187 (29.3) 5 (0.8) 0 (0)
2002 1076 20 (1.9) 655 (60.9) 388 (36.1) 13 (1.2) 0 (0)
2003 1468 40 (2.7) 963 (65.6) 452 (30.8) 13 (0.9) 0 (0)
2003-4 1976 10 (0.5) 878 (44.4) 1047 (52.9) 40 (2.0) 1 (lt0.1)
Source Table 2.7.2-24, NDA 21-572 SN008
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S. aureus MIC Distributions 2004-2005 (2004 n
317 2005 n 359)
99.1
96.7

100
90
80
70
60
of Total
50
40
30
20
0.9
3.3
10
0
2004 2005
2004 2005
lt 1 (mg/ml)
gt 1 (mg/ml)
MIC Group
Source Focus Technologies
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In Vivo Evidence

• Sponsor data from rabbits, mice, rats for
  bacteremia, endocarditis, fibrin clot, etc.
• In rabbit model, daptomycin more efficacious than
  vancomycin, however, diminished susceptibility
  developed during therapy due to selection by
  sub-inhibitory concentrations of daptomycin in
  vegetations
• Silverman et al. (2001) extensive clinical use
  required to establish if resistance will be a
  major clinical problem

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In Vitro Evidence

• Spontaneous mutations rare no known transferable
  elements
• Liebowitz et al. (1988) stable resistant
  organisms after multiple passages in increasing
  daptomycin and after chemical mutagenesis
  isolates 16X higher than parental isolates
• Kaatz et al. (1990) DaptoR mutants were VanS,
  AmpS but cross-resistance to Nisin

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In Vivo Evidence--Biofilms

• Evidence for pathogenesis of biofilms in IE is
  strong
• 60 of daptomycin penetrates vegetation but 90
  is protein bound therefore, expect lt 60
  penetration
• Vegetations manifest biofilm-like antibiotic
  resistance that cannot be completely explained by
  poor penetration of antimicrobials
• Composition of the valve biofilm has direct
  bearing on clinical outcomes
• Results demonstrate association between biofilm
  composition and clinical manifestationsIE can be
  manipulated by targeting biofilm development

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Summary

• On therapy (endocarditis) increasing daptomycin
  MICs particularly among persisting or relapsing
  bacteremia
• On therapy (all-comers) increasing daptomycin
  MICs among clinical failures
• Surveillance data increasing daptomycin MICs
  over time more reports in literature (2005-6)
  showing daptomycin resistance
• In vivo rabbit model, daptomycin more
  efficacious than vancomycin but diminished
  daptomycin susceptibility during therapy
• In vitro bacteria develop resistance at
  sub-inhibitory concentrations cross-resistance
  to nisin, but not vancomycin or ampicillin
  biofilmssubinhibitory concentrations?