# Presentation: 858641

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

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

## DAPTOMYCIN TOXICODYNAMICS  Time to CPK Elevation 

**Log-rank test, stratification on  C****MIN**** CPK breakpoint:**
- Chi-Sq statistic: 22.380 with 1 df
- Significance level: p << 5 X10-4

- DAPTOMYCIN TOXICODYNAMICS  ***Time to CPK Elevation ***

- * When CMIN was evaluated as a continuous variable using Cox proportional hazards regression, it was also significant, p = 0.02.

## RISK ASSESSMENT  Dose and Probability of CPK Abnormalities

| Dose
(mg/kg) | P (CMIN ≥25.7 mg/L) |  P (↑CPK) |
| --- | --- | --- |
| 4 | 3.7% 370/9999 | 3.7% |
| 6 | 7.3% (730/9999) | 6.0% |
| 8 | 15.9% (1585/9999) | 9.3% |
| 10 | 24.5% (2448/9999) | 12.8% |
| 12 | 32.8% (3279/9999) | 16.1% |

- RISK ASSESSMENT  ***Dose and Probability of CPK Abnormalities***

- From the cSSI study (CID 2004:38:1673), overall CPK elevations = 2.8%; daptomycin treatment emergent drug related CPK elevations = 2.1 %; 1.4% of troughs exceeded 25.7 mg/L

## Success by Pathogen-specific Therapy vs Comparator Agent (ITT AC)

**Success by****Pathogen-specific Therapy**

**Success by ****Comparator Agent**

**20 45**

**33 74**

**3470**

**33 74**

**2860**

**20 45**

**1444**

## Success in Patients with Septic Pulmonary Emboli (ITT) 

| 
Risk Factor  | DaptomycinN = 120n/N (%) | ComparatorN = 115n/N (%) |
| --- | --- | --- |
| Septic pulmonary emboli | 6/10 (60.0) | 6/13 (46.2) |
| RIE | 6/10 (60.0) | 6/9 (66.7) |
| MSSA | 3/6 (50.0) | 3/5 (60.0) |
| MRSA | 3/4 (75.0) | 3/4 (75.0) |
| LIE | 0 | 0/3* |
| cBAC-MSSA | 0 | 0/1 |

*** MRSA in 2 and MSSA in 1 comparator patients**

## Adjudication Committee Success in Patients who Completed Therapy (ITT EOT/TOC)

**Success Rate  %**

## Investigator Success in Patients who Completed Therapy (ITT EOT/TOC)

**Success Rate  %**

## Duke Criteria Underestimate Endocarditis

** **

|  | Definite  IE |  | Possible IE | Not IE |
| --- | --- | --- | --- | --- |
| Entry Dx | LIE | RIE |  |  |
|  | 12 | 25 | 144 | 54 |
| Final Dx | LIE | RIE | cBAC | uBAC |
|  | 18 | 35 | 121 | 61 |

**16 cases (6 LIE, 10 RIE) of *****S. aureus***** IE (7%) ****Diagnosed On-study**

## Vancomycin Pharmacokinetic Summary

**53/115 comparator patients received vancomycin**
**44 (83.0%) had trough levels reported**
**Mean vancomycin trough levels = 14.1 μg/mL**

## Complicated Bacteremia with Bone and Joint Infections

| 
 | DaptomycinN = 21 | ComparatorN = 11 |
| --- | --- | --- |
| Pts with Bone and Joint Infections | n (%) | n (%) |
| No. who received intervention prior to or during treatment | 11 (52.4) | 9 (81.8) |
|     Success at End of Therapy | 10 (47.6) | 3 (27.3) |
|     Success at Test of Cure | 8 (38.1) | 2 (18.2) |

## Adjudication Committee Success  All Randomized Patients (ITT EOT, TOC AC)

|  | Daptomycin
N = 124
% | Comparator
N = 122
% |     Differences In Success Rates (95% CI) |
| --- | --- | --- | --- |
| End of Therapy |  |  |  |
| Success | 59.7 | 58.2 | 1.5% (-10.8, 13.8) |
| Test Of Cure |  |  |  |
| Success | 42.7 | 39.3 | 3.4% (-8.9, 15.7) |

## Follow-up of Patients with Emergence of Reduced Susceptibility to Daptomycin and Failure due to Persisting/Relapsing S. aureus

| PtID | BaselinePathogen | FinalDx | Clinical Summary | Dur Tx | Intervention | Follow-up
  Therapy        Outcome |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 037 | MRSA | LIE | Mitral/aortic IE, pulmonary edema | 7 | No surgery | Vanco, mino | Made DNR, Died |
| 183 | MRSA | LIE | Mitral IE, stroke | 8 | No surgery | Vanco, cefepime | MOFS, Died |
| 152 | MSSA | cRIE | Tricuspid IE, large pulmonary emboli/ cavities, prob SC osteo, tunnel infection | 20 | PICC removed D18 after AE redness at exit site x 11 days; exit cx + MSSA | Oxacillin, gent | Comp abx d40P |
| 212 | MRSA | cBAC | IV port infection, ? septic thrombphlebitis | 14 | Port removed D2, pocket inadequately debrided | Vanco | Comp abx d28P |
| 105 | MRSA | cBAC | Septic arthritis | 23 | Knee asp D2, synovectomy D5, D20P when relapse diagnosed | Vanco, CTX | Comp abx d66P |
| 136 | MRSA | cBAC | Undiagnosed retroperitoneal abscess | 35 | Abscess dx’d day 31, CT drainage attempted D32 | Linezolid, Vanco | Comp abx d60P |

## Post-marketing Reports of CPK Elevation* (> 150,000 Patients Treated)

| AE Reported | Number of Reports |
| --- | --- |
| CPK elevation | 61 |
| CPK elevation with rhabdomyolysis | 14 |

***Data through 11 December 2005; reference Periodic Safety Update Reports 1 through 9**

## Rhabdomyolysis Case Definition

***Adapted from “ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins” (Pasternak et al, *****J Am Col Cardiology***** 2002;40(3):567-572) ******“Controlled Comparison of Amikacin and Gentamicin” (Smith et al, *****NEJM***** 1977;296(7):349-353. **

| Criteria | Required |
| --- | --- |
| *Marked CPK elevation (typically substantially >10X ULN) | + |
| **Creatinine elevation within 2 weeks of onset of symptoms or CPK elevation:
 0.5 mg/dL if  3.0 mg/dL
 1.0 mg/dL if > 3.0 mg/dL | + |
| Elevated urinary myoglobin
OR
Elevated serum myoglobin
OR
Brown urine | +/- |

## Postmarketing Reports of Rhabdomyolysis 

| Age
Sex | Dose (mg/kg) | Hx | Statin | Onset | CPK Max (U/L) | Creat
BL mg/dL | Creat
Max
mg/dL | Myo-globin | Symptoms |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 71
M | 6 | DM | N | 15 | 3,965 | 1.3 | 1.8 | Unk | Muscle weakness and myalgia,  |
| 72
M | 3.7 | DM
CRF | Y | 10 | 6,698 | unk | 2.2 to 2.6 | Urine
 and 
serum | Weakness and pain, rechallenge positive |
| 52*
M | 6.4 | Hep C
ITP | Held | 10 | 20,771 | 0.8 | 1.4 | Unk | Generalized weakness and pain |
| 65M | 4 | DM CRI  CHF CAD | N | 4 | 23,035 | 1.7 | 4.7 | Unk | Dyspnea, lethargy; elevated BNP cTnI,CK-MB |
| 53**F | 6 | DM | N | 10 | 21,243 | 0.9 | 2.7 | Urine | Generalized muscular weakness |

***Echevarria K, Datta P, Cadena J *****et al*****. *****J Antimicrob Chemother***** 2005; 55: 599–600******Kazory A, Dibadj K. Weiner ID. *****J Antimicrob Chemother***** advance access 12 Jan 2006**

## Shifts in CrCl from Baseline to Worst Value

|  | Creatinine Clearance on Study |  |  |
| --- | --- | --- | --- |
| Baseline CLcr 
(mL/min) | 50 - 80 | 30 - < 50 | < 30 |
| Daptomycin (N = 120) |  |  |  |
| > 80 | 11  | 3 | 1 |
| 50 - 80 |  | 5  | 2 |
| 30 - < 50 |  |  | 1  |
| Comparator (N =116) |  |  |  |
| > 80 | 23 | 3 | 1  |
| 50 - 80 |  | 14 | 4 |
| 30 - < 50 |  |  | 7  |

**Note:  Both central and local laboratory data are utilized; if both results were available on a given day, the central laboratory result was used in the analysis**

## Safety and Efficacy With and Without Gentamicin

| 

 |  | Comparator without GentamicinN = 8n (%) | Comparatorwith GentamicinN = 108n (%) |
| --- | --- | --- | --- |
| Renal Impairment AE(Safety population) |  | 0 (0) | 21 (19.4) |
| Success at TOC(ITT population) |  | 2 (25.0) | 46 (42.6) |

***Patient with LIE**

## Safety and Efficacy With and Without Gentamicin

***Patient with LIE**

| 

 | Daptomycin with GentamicinN = 1*n (%) | Comparator without GentamicinN = 8n (%) | Comparatorwith GentamicinN = 108n (%) |
| --- | --- | --- | --- |
| Renal Impairment AE(Safety population) | 1 (100) | 0 (0) | 21 (19.4) |
| Success at TOC(ITT population) | 1 (100) | 2 (25.0) | 46 (42.6) |

## CPK Adverse Events Across Dose and Study

| Study, Dose | Daptomycin | Comparator |
| --- | --- | --- |
| cSSSI, 4 mg/kg	Any event	DC due to event | 15/534 (2.8%)1/534 (<1%) | 10/558 (1.8%)0 |
| SAB/IE, 6 mg/kg	Any event	DC due to event | 8/120 (6.7%)3/120 (2.5%) | 1/116 (<1%)0 |
| Other studies, 6 mg/kg	Any event	DC due to event | 14/249 (5.0%)6/279 (2.2%) | 4/160 (2.5%)2/160 (1.3%) |

## IVPD Model: MRSA in Stationary Phase

**Simulated endocardial vegetations in an *****in vitro *****pharmacodynamic model**
**MRSA strain at high inoculum (5 x 10****9**** CFU / SEV)**
**Daptomycin exhibited rapid bactericidal activity against stationary phase MRSA**

**LaPlante AAC 2004**

- Gentamicin

## 200 CA-MRSA 

|  | MIC (μg/mL) |  |  | % Susceptible | MBC (μg/mL) |
| --- | --- | --- | --- | --- | --- |
|  | 50% | 90% | Range |  | Range |
| Daptomycin | 0.25 | 0.5 | 0.06-1 | 100 | 0.06-1 |
| Teicoplanin | 0.5 | 1.0 | 0.13-2 | 100 | 0.13-4 |
| Vancomycin | 1 | 2 | 0.13-2 | 100 | 0.13-8 |

**All CA-MRSA were SCC*****mec***** type IV**
**78% of CA-MRSA strains carried PVL **

**Tsuji ICAAC 2005**

## S. aureus with Defined Virulence Factors 

|  | MIC (μg/mL)  |  |  |
| --- | --- | --- | --- |
|  Antimicrobial Agent  | Range  | MIC50 | MIC90  |
| Daptomycin | 0.12 - 0.5 | 0.25 | 0.5 |
| Oxacillin |  0.06 - >8 | 0.25 | 4 |
| Vancomycin |  0.25 - 1 | 0.5 | 0.5 |

**Daptomycin is active against *****S. aureus *****with defined virulence factors (n = 42), including:**
**Accessory gene regulator (*****agr*****) 1 to 4**
**Hemolysins**
**Panton Valentine leukocidin (PVL)**
**Toxic shock syndrome toxin-1 (TSST-1)**
**Enterotoxins **

**Thorne GM, *****et al*****.  Poster TH-11, ISSSI 2004.***** ***

## In Vitro SEV Model

**Huang JAC 2006**

## 14C-Daptomycin Penetration into Cardiac Vegetations

**14****C-daptomycin diffuses into cardiac vegetations**
**Daptomycin homogeneously distributes throughout all the vegetations examined**
**Diffusion within the vegetations was consistent between ****all vegetations**

**Caron et al, AAC 1992**

## Baseline and Post-baseline Isolates

**3 Log****10**** Reduction = Bactericidal**

**Daptomycin (8**** μg/mL)**** was bactericidal *****in vitro***** against all isolates after 4 hours**

**152**

**Patient Number (Daptomycin-treated)**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

** ****Log****10**** Reduction at 4 Hours**

**212**

**105**

**037**

**183**

**136**

**172**