# Presentation: 529900

## Daptomycin Safety Review

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

## Overview	

- SAE’s
- Infection-related
- Renal Toxicity
- CPK analysis

## SAE’s

## Infection-Related SAE’s

## Infection-Related SAE’s

## Infection-related SAE’s	

- Daptomycin (n=6)
*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 (n=0)

- Gram-negative infection-related SAE’s by PT

## Renal Toxicity

## 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

## 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**

## 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%)

## 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

## Contingency Table Graph – Distribution by Age and Treatment Duration

- Total n = 116

- Total n = 120

## Contingency Table Graph – Distribution by Age and Treatment Duration

- Total n = 116

- Total n = 120

## Contingency Table Graph – Renal Toxicity by Age and Treatment Duration

- 11/26 (42.3%)

- 5/27 (18.5%)

- 5/38 (13.2%)

- 4/25 (16%)

- 4/32 (12.5%)

- 6/47 (12.7%)

- 3/11 (27.3%)

- 4/30
- (13.3%)

- Total n = 120

- Total n = 116

## 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%)

## CPK Analysis using Central Lab Data

## CPK > 500 by Treatment Group and HMG- CoA Reductase Inhib Exposure

| Rates of CPK Elevations to Above  > 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 > 500  with prior concomitant treatment with a statin | 0/1 (0.0) | 4/9 (44) |

## Conclusion	

- SAE’s
- Greater number of infection-related SAE’s 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

## END