NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
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`Page 52 of l 14
`.
`
`Primary Efficacy Outcome
`The Clinical Success rates for the pooled MITT population from Studies 9801 and 9901
`were 75.8% in_the daptomycin group and 76.2% in the comparator group (95% CI: -5.7,
`5.0) (see Table 40). The results indicate that daptomycin at 4 mg/kg q24h for 7 to 14 days
`is clinically and statistically non-inferior to the comparator agents for the treatment of
`cSSSI.
`'
`
`Table 40: Primary efficacy endpoint: Sponsor-Defined Clinical Outcome, Primary
`Comparative cSSSl Studies (MITT population)
`-
`
`Pooled c855] 9801 + 9901
`
`Daptomycin
`(N=422)
`
`Comparator '
`(N=467)
`
`'
`
`%
`n
`°/o'
`n
`Clinical Response
`(76.2%)
`356
`(75.8%)
`320
`Clinical Success
`(41.8%)
`195
`(41.0%)
`173
`Cure
`(34.5%)
`161
`(34.8%)
`147
`Clinical Improvement
`(23.8%)
`111
`(24.2%)
`102
`Clinical Failure
`(14.1%)
`66
`(15.2%)
`64
`Clinical Failure
`(9.6%)
`45
`(9.0%)
`38
`Nonevaluable
`a. Vancomycin 1 g q12h or semi-synthetic penicillin (oxacillin, nafcillin. cloxacillin, or flucloxacillin) 4 to 14 grams
`daily in equal divided doses.
`13.
`95% confidence interval around the difference in success rate (Comparator Daptomycin) using the normal
`approximation to the binomial distribution. For combined protocols. the confidence interval is calculated stratifying on
`protocol.
`
`95% C1”
`(-5.7, 5.0)
`
`Clinical Success Rates by Pathogen
`_ Clinical Success rates by pathogen for the ME population (Table 41) were similar to those
`of the MlTT population (Table 42) when these rates for daptomycin were assessed against
`all comparators. Tables showing data for clinical success rates for both populations
`comparing daptomycin to either semi-synthetic penicillins or vancomycin are not shown
`here but can be found in Microbiology Section 8.6.10 as tables 8-16, 8-17, 10-59, and 10-
`60.
`
`Table'41: Sponsor Defined Clinical Success Rates by Pathogen (ME population:
`Daptomycin arm versus Comparator arm) for comparative cSSSl studies at test-of-
`cure'
`‘
`' Daptomycin
`-
`Pathogen”
`Comparator‘
`222/265
`(83.8%)
`Staphylococcus aureus (all)
`240/285
`(84.2%)
`176/208
`(84.6%)
`Staphylococci: aureus (MSSA)‘
`185/216
`(85.6%)
`21/30
`(70.0%)
`Staphylococcus aureus (MRSA)6
`27/39
`(69.2%)
`80/87
`(92.0%)
`Streptococcus pyogenes
`82/94
`(87.2%)
`24/28
`(85.7%)
`Streptococcus agalactiae
`22/31
`(71.0%)
`9/10
`(90.0%)
`Streptococcus abtsga/actiae equisimilis
`9/1 1
`(81.8%)
`15/22
`(68.2%)
`Viridans Streptococci Group
`27/32
`(84.4%)
`27/39
`(69.2%)
`Enterococcusfaecalis (all)
`41/54
`(75.9%)
`25/36
`(69.4%)
`Enterococcusfaecalis (VSE)d
`39/52
`(75.0%)
`Based on the Sponsor-Defined Clinical Outcome.
`Only pathogens for which an indication is being sought are shown.
`Semi-synthetic penicillin (oxacillin, nafcillin, cloxacillin, or flucloxacillin).
`Susceptibility determinations were made only for Central Lab isolates.
`Seven subjects in the pooled MEpopulation were initially treated with semi-synthetic penicillins and had MRSA
`-~‘—.-
`
`95% C1‘
`(-5.8, 6.7)
`(-5.9, 7.9)
`(-23.1, 21.6)
`(-13.7, 4.3)
`('-35.7, 6.2)
`(-38.2, 21.8)
`(-7.5, 39.8)
`(-1 2.1, 25.5)
`(-l3.9, 25.0)
`
`_
`
`.
`
`9999‘.»
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`'
`
`Page 53 of 1 14
`
`isolated as a baseline pathogen. Six of these subjects were then switched to vancomycin: five ofthese were clinical
`successes. The remaining subject was continued on semi-synthetic penicillin and was a clinical success.
`
`Table 42: Clinical Success Rates by Pathogen, Primary Comparative cSSSl Studies:
`Pooled Analysis (MlTT population)
`
`Pathogenh
`
`Staphylococcus aureus (all)
`Staphylococcus aureus (MSSA)'
`Staphylococcus aureus (MRSA)'
`Streptococcus pyogenes
`Streptococcus agalactt'ae
`Streptococcus ajsgalacliae equist'milt's
`Viridans Streptococci Group
`Enterococcusfaecalis (all)
`Emerococcusfaecalis (VSE)'
`
`Daptomycin
`n/N
`(%)
`'
`223/299
`(74.6%)
`177/227
`(78.0%) .
`21/39
`(53.8%)
`81/92
`(88.0%)
`24/30
`(80.0%)
`9/13
`(69.2%)
`15/23
`(65.2%)
`27/45
`(60.0%)
`25/41
`(61.0%)
`
`'
`
`'
`
`i
`
`Comparator‘
`an
`(%)
`241/320 (75.3%)
`185/237 (78.1%)
`27/46
`(58.7%)
`82/103 (79.6%)
`23/39
`(59.0%)
`9/ 12
`(75.0%)
`27/32
`(84.4%)
`42/61
`(68.9%)
`40/56
`(71.4%)
`
`95% Cl“
`
`(-6.2, 7.7)
`(-7.6, 7.8)
`(-16.7, 26.4)
`(-18.9, 2.0)
`(-42.5, 0.5)
`(-30.0, 41.6)
`(-4.5, 42.8)
`(-10.0, 27.7)
`(-9.0, 29.9)
`
`Based on the Sponsor-Defined Clinical Outcome.
`a.
`b. Only pathogens for which an indication is being sought are shown.
`c.
`Semi-synthetic penicillin (oxaeillin. nafcillin, cloxacillin. or flucloxacillin) or vancomycin.
`d.
`95% confidence interval around the difi’erence in success rate (Comparator Daptomycin) using the normal
`approximation to the binomial distribution. For combined protocols, the Cl. is calculated stratifying on protocol.
`e. Restricted to lnfecting Pathogens with susceptibility testing performed at the Central Laboratory
`
`Reviewer ’5 comments: In both populations, the clinical success rates for
`daptomycin and comparators were very similar for Staphylococcus aureus
`including MSSA and MSRA. Daptomycin was less effective (35% lower clinical
`success rate) than semi-synthetic penicillins against MRSA.
`
`Overall, clinical success rates of daptomycin for the treatment of Streptococcus
`pyogenes, Streptococcus agalactiae and Streptococcus a'ysgalactiae equisir’tilis
`were rather superior (25% higher clinical success rate) to comparators. However,
`clinical success rates of daptomycin for the treatment of viridans streptococci were
`lower overall to comparators. Daptomycin seemed more successful against viridans
`\
`streptococci than semi-synthetic penicillins.
`
`Overall", clinical success rates of daptomycin for the treatment of Enterococcus
`faecalis, including VSE, were lower than comparators. This was due to the
`observationthat clinical success rates of daptomycin were superior to vancomycin
`but inferior to that for semi-synthetic penicillins.
`
`Pathogen Eradication Rates
`Pathogen eradication rates by pathogen and treatment group for the pooled ME population
`is shown in Table 43 and for the MITI‘ population in Table 44. Pathogen eradication rates
`were comparable for the two populations. Additional data for pathogen eradication rates for
`both populations comparing daptomycin to either semi—synthetic penicillins or vancomycin
`are not shown here but can be found in Microbiology Section 8.6.] as Tables 8-19, 8-20,
`10-62, and 10-63.
`._-~_.,
`.2-‘.,
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 54 of114
`
`Table 43: Eradication Rates By Pathogen and Treatment Group For The Primary
`Comparative cSSSl Studies: Pooled Analysis (ME population)
`
`Pathogen'
`
`‘
`
`'
`
`Staphylococcus aureus (all)
`Staphylococcus aureus (MSSA)d
`Staphvlococcus aureus (MRSA)°
`Streptococcus pyogenes
`Streptococcus agalactiae
`Streptococcus dj’sgalactiae equisimr'lis
`Viridans Streptococci Group
`Enterococcusfaecalis (all)
`Enterococcusfaecalis (VSE)‘
`
`antomycin
`nN
`(%)
`186/265
`(70.2%)
`148/208
`(71.2%)
`15/30
`(50.0%)
`77/87
`(88.5%)
`22/28
`(78.6%)
`9/1 0
`(90.0%)
`17/25
`(68.0%)
`25/39
`(64.1%)
`23/36
`(63.9%)
`
`‘
`
`Comparators”
`nN
`(%)
`211/285
`(74.0%)
`161/216
`(74.5%)
`23/39
`(59.0%)
`74/94
`(78.7%)
`19/31
`(61.3%)
`9/11
`(81.8%)
`28/38
`(73.7%)
`35/54
`(64.8%)
`33/52
`(63.5%)
`
`95% Cl'
`
`(-3.8,11.5)
`(-5.3.12.0)
`(-15.1,33.1)
`(-20.6,l.1)
`(-40.7,6.1)
`(-38.2,21.8)
`(-17.8,29.2)
`(-19.4,20.8)
`(-21.3,20.4)
`
`a. Only pathogens for which an indication is being sought are shown.
`b.
`Semi-synthetic penicillin (oxacillin, nafcillin, eloxacillin. or flucloxacillin) or vancomycin.
`C.
`95% confidence interval around the difference in success rate (Comparator Daptomycin) using the normal
`approximation to the binomial distribution. For combined protocols, the Cl. is calculated stratifying on protocol.
`(1. Restricted to lnfecting Pathogens with susceptibility testing performed at the Central Laboratory.
`
`Table 44: Eradication Rates By Pathogen and Treatment Group for the Primary
`Comparative cSSSl Studies: Pooled Analysis (MITT population)
`
`Pathogen'
`.
`Staphylococcus aureus (all)
`Staphylococcus aureus (MSSA) d
`Staphylococcus aureus (MRSA)'’
`Streptococcus pyogenes
`Streptococcus agalactiae
`Streptococcus dysgalactiae equisimilis
`Viridans Streptococci Group
`Enterococcusfaecalis (all)
`Enterococcusfaecalis (VSE) ‘
`
`Daptomycin
`
`n/N
`186/299
`148/227
`15/39
`77/92
`22/30
`9/13
`17/26
`25/45
`23/41
`
`'
`
`(%)
`(62.2%)
`(65.2%)
`(38.5%)
`(83.7%)
`(73.3%)
`(69.2%)
`(65.4%)
`(55.6%)
`(56.1%)
`
`Comparator”
`n/N
`(%)
`21 1/320
`(65.9%)
`161/237
`(67.9%)
`23/46
`(50.0%)
`74/103
`(71.8%)
`19/39
`(48.7%)
`9/ 12
`(75.0%)
`28/38
`(73.7%)
`35/61
`(57.4%)
`33/56
`(58.9%)
`
`95% Cl‘
`
`(-4.0,1 1.4)
`(-6.0,1 1.5)
`(-9.9,33.0)
`(-23.6,—0.l)
`(—47.4,-l .9)
`' (-30.0,41.6)
`(~15.2,31.8)
`(-17.7,21.3)
`(-17.5,23.2)
`
`a. Only pathogens for which an indication is being sought are shown.
`b.
`Semi-synthetic penicillin (oxacillirt nafcillin, eloxacillin, or flucloxacillin) or vancomycin.
`C.
`95% confidence interval around the difTerence in success rate (Comparator Daptomycin) using the normal approximation to
`the binomial distribution. For combined protocols. the Cl. is calculated stratifying on protocol.
`(1. Restricted to Infecting Pathogens with susceptibility testing performed at the Central Laboratory.
`
`Reviewer ’5 comments: In the ME population, the pathogen eradication rates for
`daptomycin and comparator were similar for Staphylococcus aureus however,
`daptomycin was less effective (9% lower pathogen eradication rate) comparator
`against MRSA. 1n the MITT population, the pathogen eradication rate among
`MRSA was significantly lower (1 1.5%) for daptomycin versus comparator.
`
`Overall, pathogen eradication rates of daptomycin for the treatment of
`Streptococcus pyogenes and Streptococcusagaiactiae were significantly superior to
`comparators. Daptomycin had higher eradication rates in both the ME and MITT
`.. “.,
`populations (9.8% and 11.9% higher, respectively) against Streptococcus pyogenes.
`
`

`

`NDA No. 21—572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`‘
`
`Page 55 of l 14
`_
`
`Again, daptomycin had higher eradication rates in both the ME and MlTT
`populations (17.3% and 24.6% higher, respectively) against Streptococcus
`ago/actiae. However, pathogen eradication rates of daptomycin for the treatment of
`viridans streptococci and Streptococcus dysgalactiae equisimilis were lower overall
`to comparators. Eradication rates in both the ME and MITT populations were -
`lower for daptomycin versus comparators (5.7% and 8.3% lower, respectively)
`against viridans streptococci. However, against Streptococcus a’ysgalactiae
`equisimilis, the eradication rate in the ME population was 8.2% higher against
`comparator while the eradication rate in the MITT population was 5.8% lower for
`daptomycin versus comparators. The disagreement in eradication rates between the
`two populations is odd but may be partially explained by particularly low numbers
`of isolates.
`
`Overall, pathogen eradication rates of daptomycin for the treatment of Enterococcus
`faecalis, including VSE, were similar to comparators. This was due to the
`observation that pathogen eradication rates of daptomycin were somewhat superior
`to vancomycin but somewhat inferior to that of semi-synthetic penicillins.
`
`Clinical success rates and pathogen eradication rates of daptomycin versus comparators
`for the various pathogens paralleled one another with two exceptions. First, pathogen
`eradication rates for daptomycin versus comparators was somewhat lower for MRSA
`than clinical success rates. Thus it seems, daptomycin may have a similar clinical
`success rate for the treatment of MRSA as compared to comparators but the drug will not
`be as effective in eradicating the pathogen as the comparator drugs. The second
`exception is that daptomycin has a comparable rate of eradicating E. faecalis as do the
`comparator drugs despite the fact that the comparator drugs seem to be more successful
`clinically.
`
`a
`
`Overall, compared to subjects infected with a single pathogen, subjects infected with two
`pathogens had lower success rates (see Table 45); the clinical success rates for those
`subjects were similar for daptomycin (70.1%) and comparator (67.5%). The most prevalent
`combination of dual infecting pathogens was S. pyogenes and S. aureus, which was found
`in 48 subjects in each treatment group in the pooled MIT—1' population‘(see Table 10-64 of
`the Microbiology Section). Among these subjects, the clinical success rates were higher in
`the daptomycin group than in comparator, (81.3% vs. 68.8%, respectively); the individual
`pathogen eradication rates against S. aureus were 66.7% and 54.2%, respectively, and
`against S. pyogenes, 77.1% and 62.5%.
`
`Table 45: Clinical Success Rates‘ by Number of Infecting Gram-Positive Pathogens at
`Baseline, Primary Comparative cSSSl Studies: Pooled analysis. (MITT population)
`
`Number of lnfecting Gram-Positive
`Pathogens at Baseline
`One Pathogen
`Two Pathogens
`Three Pathogens
`All MITT Subjects
`
`-. “a
`“' “‘ "
`
`"
`
`Daptomycin
`n/N
`250/322
`68/97
`2/3
`320/422
`
`(%)
`(77.6)
`(70.1)
`(66.7)
`(75.8)
`
`Comparator’
`n/N
`(%)
`269/342
`(78.7)
`79/117
`(67.5)
`8/8
`(100.0)
`356/467
`(76.2)
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 56 of l 14
`‘
`
`a. Using Sponsor~Defined Clinical Outcome
`b.
`Semi-synthetic penicillin (oxacillin. nafcillin, cloxacillin, or flucloxacillin) or vancomycin.
`
`The overall in vitro daptomycin susceptibility of all pathogens from the MITI' populations
`of trials DAP-SST-980] and DAP-SST-9901 is shown in Table 46. Overall, the two trials
`yielded Mleo and MIC9o values that were within one doubling dilution. The maximum
`MlC values in DAP-SST~9901 for E. faecalis (MIC = 8 pg/ml), and S. aureusMRSA
`(MIC = 2 ug/ml) were more than one doubling'dilution higher than the corresponding
`combined M1C9o values of 2 and 0.5 ug/ml, respectively.
`
`Table 46: In vitro susceptibility to daptomycin of Infecting Pathogens at Baseline,
`Primary Comparative cSSSl Studies' (MITT population)
`
`Pathogen”
`
`-
`
`Enterococcusfaecalis (V SE)
`DAP-SST-9801
`DAP-SST—990]
`Combined
`Staphylococcus aureus (MRSA)
`DAP-SST—980]
`DAP-SST—990l
`
`Combined
`Staphylococcus aureus (MSSA)
`DAP-SST-980]
`DAP-SST-9901
`Combined
`Staphylococcus aureus (total)
`DAP-SST-980]
`
`DAP-SST-9901
`Combined
`Streptococcus agalactiae
`DAP-SST~9801
`DAP-SST~9901
`Combined
`Streptococcus absgalactiae equisimilt's
`DAP—SST~9801
`DAP-SST4990l
`Combined.
`_
`Streptococcus pyogenes
`DAP-SST-9801
`DAP-SST-9901
`Combined
`Viridans Streptococci Groupc
`DAP-SST-9801
`DAP-SST—9901
`Combined
`
`N
`
`54
`43
`97
`
`69
`16
`
`85
`
`200
`264
`464
`
`269
`
`280
`549
`
`37
`27
`64
`
`l3
`l0
`23
`
`6]
`1 l4
`175
`
`29
`28
`57
`
`Daptomycin Susceptibility (pg/ml.)
`Minimum Maximum
`Mleo
`
`Mle
`
`l
`2
`l
`
`0.25
`0.5
`
`- 0.25
`
`0.25
`0.25
`0.25
`
`0.25
`
`0.25
`0.25
`
`0.25
`0.25
`0.25
`
`=0.03
`0.06
`0.06
`'
`=0.03
`=0.03
`=0.03
`
`0.5
`0.5
`0.5
`
`‘
`
`'
`
`,
`
`2
`2
`2
`
`0.5
`1
`
`0.5
`
`0.5
`0.25
`0.5
`
`0.5
`
`0.25
`0.5
`-
`0.25
`0.25
`0.25
`
`0.06
`0.06
`0.06
`
`0.06
`0.06
`0.06
`
`0.5
`1
`1
`
`.
`
`I.
`
`i
`
`~
`
`'
`
`'
`
`‘
`'
`
`Restricted to lnfecting Pathogens with susceptibility testing performed at the Central Laboratory.
`:1
`b. Only pathogens for which an indication is being sought are shown; all geographic regions combined.
`c.
`Three isolates were not tested by the Central Lab for susceptibility to daptomycin and are not included in this
`_hv
`analysis.
`.7 M..—
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 57_of I I4
`
`A summary of clinical success and pathogen eradication rates by daptomycin MIC value
`for staphylolcocci, streptococci and Enterococcusfaecalis can be found in Tables 8-23, 8-
`24, 8-25 and 8-26 ofth‘e Microbiology Section 8.6.14. These data are visually reflected in
`Figures 6, 8 and 10, which can found below.
`
`The listing of daptomycin MIC values with clinical success and pathogen eradication for
`all S aweus in the ME pOpulation at TOCis shownin Table 8-23 and Figure 6. The
`daptomycin MIC values ranged from 0.12 to 0.5 11ngin the daptomycin--treated subjects,
`and from 0.12 to 2 ug/ml in the comparator treated subjects. The Applicant states that
`“There was no correlation in the clinical success rate or pathogen eradication rate
`compared to MIC value for S. aureus (see Figure 6)”. Figure 7 shows that the distribution
`of S. aureus MIC values for the daptomycin pooled treatment group isolates was similar to
`distribution for the combined SECURE surveillance isolates from skin.
`
`Reviewer ’5 comments: In fact, there seemed to be a trend as the clinical success
`rate and pathogen eradication rate increased compared to MIC value. MICs for both
`MSSA and MRSA were restricted to a range of 3 dilutions. Most isolates in both
`
`the clinical and surveillance studies demonstrated a MIC of 0.25uyml.
`
`Figure 6: Bar chart' of percentage of clinical success and pathogen eradication at
`each daptomycin MIC for Staphylococcus aureus (total) from comparative cSSSI
`studies (ME subpopulation; Central Lab isolates; daptomycin-treated subjects)
`
`quill-nllMIC
`I“rt-JInw-m-Pull-‘9'“
`
`
`|E:lc1n~m _Ma.a l
`'11:: number tum: cut bx mam IL: numb: o: nit-jam I I): MIC (for chain] umber lb: mice-11mins l Ih: MIC afar pathogen flute-I
`
`~ M-P
`._ H.,
`
`

`

`NDA No. 2l-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 58 of I 14
`
`Figure 7': Bar chart ofpercentage of isolates at each daptomycin MIC for
`Staphylococcus aureus (total) from comparative cSSSl studies 8and isolates isolated
`from skin or skin structures from the SECURE surveillance studies
`
`ItI.IIH:-I.“IC 8b883
`
`t,_-.“m
`V".,.4'-.ug‘-man...u:l.u,rmv;.'4__y_-+;;;;I__;-.__
`
`
`
`< 410':
`
`us
`
`no
`
`on
`
`0.:
`
`1
`
`2
`
`a
`
`9
`
`Inc own : 0mm
`
`5
`
`AH Harlan palms I'm: when; m the HT whpowlmm n 1!};th
`
`[:1 wsccune: n-eoo — muses: n-so
`
`' The listing of daptomycin MIC values with clinical success and pathogen eradication for
`individual baseline Streptococcus spp. in the ME population at TOC is shown in Table
`47 and the grouping of all baseline Streptococcus spp. into a single group is shown in Table
`8-25. The daptomycin MIC values ranged from =0.03 to 10 ug/ml in the daptomycin and
`comparator treated subjects. There was no correlation in the clinical success rate or
`pathogen eradication rate compared to MIC value'for Streptococcus spp. (see Figure 8).
`The majority of the isolates were S. pyogenes, which had a narrow M'IC range (0.03 to 0.06
`ug/ml). The broadest MIC range was observed in the vin'dans Streptococci group with a
`MIC range from 0.06 to 1 ug/ml. S. pyogenes was the most common streptococcal baseline
`pathogen. The distribution of MIC values in the combined SECURE surveillance studies
`for S. pyogenes and all of the Streptococcus spp. from skin or all sources were similar to
`the MIC values obtained in DAP-SST-9801 and DAP-SST-9901 (see Figure 9).
`
`Reviewer ’5 comments: It should be noted that according to the data in Figure 9,
`more clinical isolates have lower MIC values than the surveillance isolates.
`
`_-...—,
`
`

`

`NDA No. 21-572 '
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 5901‘ 1 14
`
`Table 47: Clinical Success RatesII and Pathogen Eradication Rates For Streptococcus Spp.
`by Daptomycin MIC of Infecting Pathogen at Baseline, Primary Comparative cSSSI
`Studies: Pooled Analysis (ME population)
`
`Baseline
`Infecting
`Pathogenh
`
`Streptococcus
`aga/actiae
`
`Streptococcus
`djsgalactiae
`equisimi/i:
`
`Daptomycin
`MIC '
`(jig/m1)
`
`Comparator‘
`Daptomycin
`Clinical
`Pathogen
`Clinical
`Pathogen
`‘
`Success
`.: Eradication
`Success
`Eradication
`n/N
`(%) .
`a n/N
`(%)
`n/N
`n/N
`(%)
`l/ 1
`(100.0%)
`0/1
`(0.0%)
`—
`———
`-—
`0.06
`8/9
`(88.9%)
`6/9
`(66.7%)
`8/ l 0
`7/ l 0
`(70.0%)
`0.12
`13/15
`12/15
`(80.0%) 13/19
`(68.4%)
`13/19
`(68.4%)
`0.25
`1/1
`1/1
`(100.0%)
`-—
`—
`—-
`-—-—
`0.5
`4/4
`4/4
`(100.0%)
`4/4
`(100.0%)
`4/4
`' (100.0%)
`50.03
`5/5
`5/5
`(100.0%)
`3/5
`(60.0%)
`3/5
`(60.0%)
`0.06
`0.12 . —
`-—
`—-
`—-
`~-
`—-
`~—
`0.25
`--
`-—
`-—
`——
`-—-
`—-
`--
`
`(%)
`——
`(80.0%)
`(86.7%)
`(100.0%)
`(100.0%)
`(100.0%).
`- .
`—
`
`Streptococcus
`pyogenes
`Viridans
`Streptococci
`Group6
`
`'
`
`-—-
`57/64
`13/15
`0/1
`—
`3/5
`2/4
`7/10
`3/3
`
`1/1
`—
`(89.1%) 67/75
`(86.7%)
`8/10
`(0.0%)
`2/2
`--
`-—
`(60.0%)
`-——
`(50.0%)
`7/9
`(70.0%) 10/12
`(100.0%)
`6/7
`
`(100.0%)
`(89.3%)
`(80.0%)
`(100.0%)
`---
`-—
`(77.8%)
`(83.3%)
`(85.7%)
`
`1/1
`60/75
`7/10
`2/2
`0/1
`1/1
`5/11
`12/14
`6/7
`
`(100.0%)
`(80.0%)
`(70.0%)
`(100.0%)
`(0.0%)
`(100.0%)
`(45.5%)
`(85.7%)
`(85.7%)
`
`——
`-—
`0.5
`(92.2%)
`59/64
`50.03
`(93.3%)
`14/15
`0.06
`—
`—
`NDf
`—
`——
`0.06
`(60.0%)
`3/5
`0.12
`(33.3%)
`1/3
`0.25
`(66.7%)
`6/9
`0.5
`(100.0%)
`3/3
`1
`a. Using Sponsor—Defined Clinical Outcome
`b. Only Streptococcus spp. for which an indication is being sought are shown in this table; restricted to isolates .
`with susceptibility testing performed at the central laboratory.
`c.
`Semi-synthetic penicillin (oxacillin, nafcillin, cloxacillin, or flucloxacillin) or vancomycin.
`.d.
`For the Viridans Streptococei Group, Some subjects had two different Viridans Streptococci Group species at Baseline.
`N represents the number of subjects at each MIC; each pathogen is shown in the Pathogen Eradication column. The subject 5
`Clinical Outcome is shown only once, assigned to the Baseline pathogen that is the least susceptible to daptomycin.
`e. ND, Not determined; the isolates were received by the Central Lab, but the daptomycin Mle were ibt determined.
`
`Figure 8. Bar chart ' of percentage of clinical success and pathogen eradication at
`each daptomycin MIC for all Streptococci species b“ from comparative cSSSI studies
`(ME subpopulation; Central Lab isolates; daptomycin- treated subjects)
`\
`
`8‘8
`
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`
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`1
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 60 of114
`_
`
`Figure 9: Bar chart of percentage of isolates at each daptomycin MIC for all
`Streptococci species " from comparative cSSSI studies b"and isolates isolated from
`skin or skin structures from the SECURE surveillance studies
`
`1'dI-vlll-uwe 3
`
`
`
`
`
`The listing ofdaptomycin MIC values with clinical success and pathogen eradication for all E.
`faecalis in the ME population at TOC is shown in Table 8-26 of the Microbiology Section. The
`daptomycin MIC values ranged from 0.5 to 2 ug/ml in the daptomycin-treated subjects, and from
`0.12 to 8 ug/ml in the comparator treated subjects. There was no correlation in the clinical
`success rate or pathogen eradication rate compared to MIC value -for E. faecalis (see Figure 10).
`For the daptomycin treated subjects, the E. faecalis MIC values were distributed nearly equally
`over three values (0.5 to 2 pg/ml). The daptomycin clinical success ranged from 58.3% to
`84.6%, and the pathogen eradication was from 58.3% to.69.2%. In both cases, the highest
`success rates were obtained against the E. faecalis with the highest MIC value (2 ug/ml). The
`range of E. faecalis MIC values in the daptomycin-treated arm of DAV-SST-98OI and DAP-
`SST-99OI was slightly narrower than the MIC values produced in the combined SECURE
`studies, but the"overall distribution was similar (see Figure 11).
`
`A series of tables containing data examining the correlation of daptomycin zone sizes with
`clinical success and pathogen eradication has been provided by the Applicant and can be
`found in Microbiology Section 8.6.15. These tables include Tables 8-27, 8-28, 8-29, 8-30,
`10-90 and 10-91.
`
`_ “"—
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 6] ofll4
`~
`
`Figure 10. Bar chart ' of percentage of clinical success and pathogen eradication at
`each daptomycin MIC for Enterococcusfaecalis from comparative cSSSl studies (ME
`subpopulation; Central Lab isolates; daptomycin-treated subjects)
`
`
`
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`Figure 11: Bar chart of percentage of isolates at each daptomycin MIC for
`Enterococcusfaecalis from comparative cSSSl studies ‘ and isolates isolated from skin
`or skin structures from the SECURE surveillance studies
`0
`
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`
`I
`
`

`

`NDA No. 21572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 63 of l 14
`
`A summary of daptomycin zone sizes correlated with clinical success rates and pathogen
`eradication rates for MRSA and MSSA in the ME population at TOC can be found in Table
`8-27. The zone sizes andclinical success for all S. aureus combined are also displayed in
`Table 10-90. The zone sizes ranged from 16 mm to 25 mm in the daptomycin treated
`subjects, and from 17 mm to 26 mm in the comparator treated subjects. For MRSA, the
`daptomycin zone size was from 17 mm to 24 mm. The most prevalent zone sizes for
`MRSA were 19, 20, and 21 mm (22/30, 73% isolates). The clinical sucCess rate ranged
`from 57.1% to 87.5% for these three zones, while the pathogen eradication rateranged
`from 42.9% to 75.0%. The clinical success rates were 100% and 50% for the 2 smallest
`zones (17 and 18 mm, respectively), while the pathogen wadication rates were 100% and
`25%, respectively. There was not a clear pattern of zone versus clinical outcome for
`MRSA.
`
`For S aureus MSSA, the most prevalent zone sizes were also 19, 20, and 21 mm (166/208,
`80% of isolates). The clinical success rates ranged from 85.3% to 86.8% and the pathogen
`eradication rates ranged from 66.7% to 73.7% for MSSA ofthese three zone sizes. For the
`next three smaller zone sizes (16 - 18 mm), the clinical success rates were 75.0% to 100%
`(14/18, 78% overall), and the pathogen eradication rates were 69.2% to 100%( 13/18, 72%
`overall). There was not a clear pattern of zone size versus clinical outcome for MSSA.
`Similar results were obtained with the combined results of MSSA and MRSA (see Table
`10-90). The distribution of zone sizes was similar between the combined FOCUS
`Surveillance studies and clinical studies DAP-SST-9801 and'DAP—SST~9901 (see Table
`10-38 and Figure 10-27).
`
`The listing of daptomycin zone sizes correlated with clinical success rates and pathogen
`eradication rates for S. agalactiae and S. pyogenes in the ME population at TOC is shown
`in Table 828. The S. ago/actiae zone sizes ranged from 16 mm to 22 mm and the S.
`pyogenes zones ranged from 18 mm to 26 mm for daptomycin treated subjects. For both S.
`ago/actiae and S. pyogenes, the clinical success and pathogen eradication rates were high
`for daptomycin treated subjects across all zone sizes. The one zone listing with a lower
`pathogen eradication rate was S. aga/actiae 17 mm zone with a pathogen eradication rate
`of 40% (2/5). This result appeared to be an aberration, as the daptomycin treated pathogen
`eradication rates were higher for S. ago/acriae in the zones immediately larger (18 mm)
`and smaller (16mm). S. pyogenes was the most common Streptococcus spp. in trials 9801
`and 9901, and daptomycin produced a high clinical success and pathogen eradication rate
`across all zone sizes. The zone size distribution was similar for the combined SECURE
`, Surveillance studies and trials DAP-SST-9801 and DAP~SST-9901 for S. pyogenes (see
`Figure 10—32,Table lO-45 and Table 10-46) and S. agaiactiae (see Figure 10-34, and Table
`10-48).
`
`The listing of daptomycin zone sizes with clinical success rates and pathogen eradication
`rates for S. dysgalacn'ae subsp. Equisimilis (S. ajrsgalacriae) and viridans streptococci
`group in the ME population at TOC is shown in Table 10-91 and Table 8-29. The S.
`dysgalactiae zone sizes ranged from 19 mm to 26 mm, and the viridans streptococci group
`zones ranged from 16 mm to 28 mm for daptomycin treated subjects. For S. dysgalactiae,
`the clinical success and pathogen eradication rates were 100% for daptomycin treated
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`.
`
`Page 64 of l 14
`
`subjects across all zone sizes. For the viridans streptococci group, the zone distribution was
`relatively large and the resulting N for any given zone was =3. The clinical success and
`pathogen eradication rates were 7/11 (64%) and 8/ 12 (67%), respectively, against viridans
`streptococci group with zone sizes =21 mm (the median value). The clinical success and
`pathogen eradication rates were 6/9 and 7/10-(700/0), respectively, for viridans streptococci
`group with zone sizes =22 mm. Thus, there appeared to be no pattern of viridans
`streptococci zone size and clinical success or pathogen eradication. The zone size
`distribution was similar for the combined SECURE Surveillance studies and trials DAP-
`
`SST-9801 and DAP-SST-9901 for S. dysgalactiae equisimilis (see Figure 10-36, and Table
`10-50) and the viridans streptococci group (see Figure 10-38, and Table 10-52).
`
`A summary of the daptomycin-treated subjects who were therapeutic failures was
`examined for any trend or pattern corresponding to pathogen or MIC value. There was
`no apparent pattern of clinical failure, microbiologic failure and overall therapeutic
`failure with daptomycin MIC for S. aureus, the streptococci, or E. faecalis.
`
`The correlation of daptomyéin MIC results, zone size, and clinical outcome for daptomycin
`treated subjects is shown in the following scattergrams. The scattergrams are presented for
`S. aureus, the streptococci (combined) and E. faecalis. For each pathogen group, sets of
`two scattergrams are presented. The first shows the MIC and zone correlation for the
`clinical isolates from studies DAP-SST-9801 and DAP—SST-9901 combined. The second
`
`graph in each series shows the baseline infecting pathogens from therapeutic failures. The
`third graph in each series shows the baseline infecting pathogens from therapeutic failures.
`Therapeutic failures are defined as subjects who were sponsor- defined clinical failures or
`microbiological failures at TOC. Note that not all scattergrams are shown here and the
`reader is referred to Microbiology Section 8.6.17 for these scattergrams.
`
`The scattergrams for S. aureus (Figures 12, 13, and 14) and the breakout of MRSA and
`MSSA (Figures 15, 16, 17, 18, 19, and 20) with proposed breakpoint MIC and zone sizes
`are provided. The MIC zone susceptibility for all S. aureus in the two clinical trials (see
`Figure 13), and the clinical failures (Figure 14) show the correlations. The S. aureus in the
`clinical trials are representative of the isolates encountered in the larger surveillance
`studies. The SECURE studies did report a small number ofS. aureus isolates with MIC
`values of l ug/ml, while none were encountered in the clinical trials. For the S. aureus
`from the two clinical trials (see Figure 8-8), there was a narrow MIC zone range from 0.12
`to 0.5 jig/ml: with the majority of the isolates at MIC = 0.25 ug/ml. There was a similar
`narrow distribution of zone sizes from 16 - 25 mm in these isolates. The distribution of S.
`
`aureus MIC and zone sizes for isolates that were therapeutic failures (Figure 14) was very
`similar to the overall MIC/zone distribution of S. aureus from the clinical studies. There
`
`was no clear correlation between MIC/zone distribution and therapeutic failure for S.
`aureus in the clinical trials. With the proposed zone and MIC susceptibility criteria, there
`was a minor error rate of 0.04% in the combined SECURE surveillance set ofisolates and
`no errors in the cSSSI set of isolates.
`
`

`

`NDA No. 21-572
`Cubicin
`CubisI Phannaceuticals, Inc.
`
`-
`
`Page 65 of114
`-
`
`Figure 12: Scattergram of daptomycin zone size versus MIC for Staphylococcus
`aureus isolated from skin or skin structures from the SECURE surveillance studies
`
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`Figure 13. Scattergram of daptomycin zone size versus MlC for Staphylococcus
`aureus (total) from the comparative cSSSl studies (Baseline pathogens; ME
`subpopulation; Central Lab isolates; daptomycin- treated subjects)
`
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`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 66 of 1 l4
`_
`
`Figure 14. Scattergram of daptomycin zone size versus MIC for Staphylococcus
`aureus (total) from the comparative cSSSI studies (Baseline pathogens; ME
`subpopulation; Central Lab isolates; daptomycin- treated subjects who were
`therapeutic failures) '
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`Figure 15: Scattergram of daptomycin zone size versus MIC for Staphylococcus
`aureus (MRSA) isolated from skin or skin structures from