Daptomycin Safety Review

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Daptomycin Safety Review

• Chuck Cooper, M.D.
• Medical Officer
• Division of Anti-Infective and Ophthalmology
  Products
• March 6, 2006 Advisory Committee Meeting

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Overview

• SAEs
• Infection-related
• Renal Toxicity
• CPK analysis

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SAEs
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Infection-Related SAEs
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Infection-Related SAEs
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Infection-related SAEs

• Gram-negative infection-related SAEs by PT

• Daptomycin (n6)
• Enterobacter aerogenes bacteremia (1)
• Urosepsis (1)
• Pseudomonas aeruginosa from blood and urine
• Bacteremia (1)
• Acinetobacter calcoaceticus
• Klebsiella Infection NOS (1)
• Klebsiella pneumoniae from blood
• Sepsis NOS (2)
• Burkholderia spp. in blood
• Klebsiella pneumoniae in blood

• Comparator (n0)

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Renal Toxicity
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Limitations with Renal AE Reporting

• No standardization of renal adverse events
• open label trial
• expectation of renal toxicity in comparator arm
  but not in the study drug arm
• potential for comparator-treated patients to
  receive treatment for longer duration

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Examples of AE Reporting Inconsistencies

• Daptomycin-tx Pts
• No AE Cr 0.9 - 2.2
• ARF no creats reported
• No AE Cr 1.7 - 2.1
• No AE Cr 1.1 - 1.8
• No AE Cr 0.7 - 1.6

• Comparator-tx Pts
• ARF Cr 1.2 - 1.5
• RF NOS Cr 0.8 - 1.4
• ARF onset same day as enrollment b/l creat 2.0
• No AE Cr 1.0 - 1.8

The disease under study has an expected rate of
renal events, so standardization of renal adverse
event reporting is critical
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Alternative Approach to Assessing Renal Toxicity

• Renal toxicity case definition used
• Creatinine increase of 25 or more
• While on therapy or within 30 days after last
  dose
• Creatinine increase to above ULN (1.5)
• Results
• Comparator 25/116 (21.6)
• Daptomycin 17/120 (14.2)

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Renal Toxicity Analysis

• Problems with interpretation
• Treatment arms have differences with regard to
  age and treatment duration
• Patients 60 years and older who had longer
  duration of therapy (longer than the median of 14
  days) had the highest rate of renal toxicity
• There were more of these patients in the
  comparator arm than the daptomycin arm

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Contingency Table Graph Distribution by Age and
Treatment Duration
Total n 116
Total n 120
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Contingency Table Graph Distribution by Age and
Treatment Duration
Total n 116
Total n 120
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Contingency Table Graph Renal Toxicity by Age
and Treatment Duration
Total n 120
Total n 116
11/26 (42.3)
5/27 (18.5)
3/11 (27.3)
4/30 (13.3)
4/32 (12.5)
6/47 (12.7)
5/38 (13.2)
4/25 (16)
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Results after Correcting for Age and Duration of
Treatment

• Results
• Comparator 25/116 (21.6)
• Daptomycin 17/120 (14.2)
• Comparator 20/116 (17.2)
• Daptomycin 17/120 (14.2)

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CPK Analysis using Central Lab Data
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CPK gt 500 by Treatment Group and HMG- CoA
Reductase Inhib Exposure
Rates of CPK Elevations to Above gt 500 by Treatment Group Rates of CPK Elevations to Above gt 500 by Treatment Group Rates of CPK Elevations to Above gt 500 by Treatment Group
Comparator n/N () Daptomycin n/N ()
Overall Study 1/116 (0.90) 9/120 (7.5)
Prior or Concomitant treatment with a Statin 0/20 (0.0) 4/24 (16.7)
Patients with CPK gt 500 with prior concomitant treatment with a statin 0/1 (0.0) 4/9 (44)
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Conclusion

• SAEs
• Greater number of infection-related SAEs were
  reported in the daptomycin arm
• This increase may be related to underlying
  disease process or propensity for gram-negative
  infections
• CPK
• Greater number of patients with increases to over
  500 U/L from baseline
• Possible association with prior or concomitant
  treatment with HMG-Co A reductase inhibitors
• Renal
• Similar rates of percentage increase in
  creatinine from baseline

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END