Table 10: Summary of Subject Disposition, Cubist-sponsored Phase 1 Studies
`(Population: All Subjects Treated)
`Sincle Dose
`
`Multi ule Dose
`
`Total
`
`E-“E-E-
`
`—m
`
`Adverse events - Cubist-sponsored Phase 1 studies
`Similar proportions of subjects in the daptomycin and comparator treatment
`groups experienced at least one AE during the Cubist-sponsored Phase I studies
`(62/240 [25.8%] daptomycin; 32/109 [29.4%] comparator). No single AE
`occurred in more than 5% of the daptomycin subjects, while injection site pain
`occurred in 5.5% (6/109) and headache occurred in 5.5% (6/109) of subjects in
`the comparator groups. The majority of ABS were mild (53/240 or 22.1% in the
`daptomycin-treated subjects, 30/109 or 27.5% in the comparator-treated subjects)
`or moderate (13/240 or 5.4% in the daptomycin-treated subjects, 4/109 or 3.7% in
`the comparator-treated subjects) in intensity. Marked AEs occurred in 2/240
`(<1%) of daptomycin-treated patients and no comparator-treated patients. Four
`AEs that were judged to be marked in intensity by the investigator were reported
`in three daptomycin subjects. These included facial palsy and syncope in two
`daptomycin subjects and diarrhea and vomiting in a third daptomycin subject.
`In
`single dose daptomycin studies 14.9% (18/121) of subjects experienced I or more
`AEs; no AE occurred in more than 5% of subjects.
`In multiple dose studies, 37%
`(44/119) of daptomycin-treated subjects experienced one or more ABS, and the
`most commonly occurring AEs (>5%) were injection site pain (7/119, 5.9%),
`injection site edema (6/119, 5%), increased blood creatine phosphokinase (6/119,
`5%), and headache (6/119, 5%). Table 11 below gives the frequencies of all AEs
`in Cubist-sponsored Phase I studies.
`
`12
`
`

`

`l::::
`
`Table 11: Adverse Events in Cubist-sponsored Phase 1 Studies (Population: All
`Sub'ects Treated
`
`ystem Organ Class/
`referred Term
`
`
`
`-
`-
`
`1 Least One AE
`
`dministration site conditions
`
`Single-Dose
`
`Multiple-Dose
`
`Total Clinical
`Pharmacolocv Studies
`
`Da-tomvcin
`
`‘=121
`N %)
`
`N=17 mm
`
`1 (0.8) “mu—Imm-
`1 (0.8)
`6 (5.0M"
`1 (0.8) mum-mm-
`
`--IGE---_-
`
`mum-m
`
`
`
`Elli!- -
`0 (0.0)m
`0 (0.0)
`0 (0.0)m
`0 0-0
`
`n'ectionsiteedema
`
`- dalaise
`
`0 (0.0 _-__M-
`0(00)
`0(00)
`6(5.0)
`3(3.3
`3(2.8)
`0(0.0)
`0(00
`6(55
`3 (1.3
`o (0.0
`3 (2.5
`.
`o (0.0
`0 (00
`m—_--lm--lml
`
`niection site crun'tus
`
`. mam-W
`IE=mm0 0-0
`
`mum—"MIKE!!-
`(mum—mmm
`mum-Ima-
`_—--—IIGE--lm-m-
`
`'nfection NOS
`
`'
`
`n‘u 'and -oisonin2 mum-mumm-
`WWW-mm-
`'—-—_-—-—--
`l-lood creatine phosphokinase
`l (0.8)
`2 (1.8)
`increased
`
`-
`
`.-"'\
`
`13
`
`

`

`oisorders
`
`issue and bone disorders
`Anhralzia
`
`
`
`mum-ma-
`Rack uain m
`. mum-m5-
`
`I ervoussvstem disorders
`
`II izziness (excludin veni 0)
`
`Mu
`
`m-
`0(0.0)
`0(00 “moral-[mumm-
`l 0-8 --IGE-_--—-
`
`I mesmesiaoramos
`.nsomniaNF—C
`
`l’ eproductive system and
`reast disorders
`
`- mmmmmm.
`-m-mll-lm-mm-
`mutual-IM-
`moron—m-
`l (0.4)
`0 (0.0)
`
`
`
`Ilvsmenorrhea —M-Im-
`
`- menu-Imam..-
`
`1(0.8)
`"MIKE!!-
`inus tain
`_--_-_—-Im-
`neczina
`ore lhroat NOS mum-Irm-
`’heezine mum-mumm-
`kin&subcutaneous
`l(O.8)
`l(0.8)
`2(0.8)
`issue disorders
`
`'
`
`ellulitis WEED-mm-
`llermatitisNOS
`0(0.0>
`1(0.8 "metal-“mumm-
`0(00 ”mm-Km-
`zemascbonheic
`_Mmm-mm--lm-
`
`_==mm-mm--Im-mm-mmn
`0(0.0 mill-MIKE-
`MUM-m-
`I—W-Im-
`
`u'ocedures
`“mm-mum-
`
`\nenension NOS mam-“mm.”—
`:
`Note: Subjects reponing more than one adverse event within a system organ class (SOC) are counted only once in the total hue for that SOC.
`Subjects reporting more than one adverse event coded to the same preferred term are counted only once in the line for that preferred ten-n.
`
`

`

`::
`
`Drug related adverse events - Cubist-sponsored Phase 1 studies
`In the Cubist sponsored Phase 1 studies, 29/240 (12.1%) of subjects who received
`daptomycin experienced at least one AE that was considered possibly or probably
`related to study treatment. Of subjects in the comparator groups, 6/109 (5.5%)
`experienced at least one adverse event that was considered possibly or probably
`related to study treatment.
`In both groups the Nervous System Disorders System
`Organ Class (SOC) were the most commonly reported AEs.
`In the daptomycin
`group, 11/240 subjects (4.6%) experienced AEs within this SOC compared with
`3/109 subject (2.8%) in the comparator group. As demonstrated in Table 12
`below, the most frequently reported drug-related ABS by preferred term were
`headache, increased CPK, and vomiting.
`
`Table 12: Drug-Related Adverse Events Occurring in 21% of Subjects by
`System Organ Class and Preferred Term, Cubist-sponsored Phase 1 Studies
`
`(Po ulation: All Sub'ects Treated
`
`
`
`
`System/Organ
`
`
`Daptomycin Comparator
`Comparator
`Daptomycin
`
`
`N=109
`N= 92
`N=121
`
`
`N M)
`N 0%)
`
`
`
`10 (8.3) Total Number of Subjects with
`
`at Least one Related AB
`
`
`Multiple Dose
`
`Single Dose
`
`3. Includes events assessed as probably or possibly related l0 study treatment. The highest relationship (probable > possible
`> unrelated) is tabulated
`
`Adverse events leading to discontinuation - Cubist-sponsored Phase 1 studies
`1n
`the Cubist-sponsored
`clinical
`pharmacology
`studies,
`seven
`subjects
`discontinued study medication due to AE’s:
`5/240 (2.1%) in the daptomycin
`group and 2/109 (1.8%) in the comparator group. Six of the seven AEs causing
`discontinuation were considered probably or possibly related to study medication.
`One subject (study DAP-OO—OZ) in the control group (placebo) was discontinued
`from the study because ofa mild rash with mild pruritus starting on Day 1; these
`events were considered to be possibly related to study medication. A second
`subject (study DAP-MDRl-01-03; dose = loading dose of4 mg/kg, then 3 mg/kg
`on days 3, 5, 7, 11, and 13) discontinued prematurely due to elevated CPK
`concentrations after five doses of daptomycin (total daptomycin dose = 1767 mg).
`Maximum serum CPK was 4498 U/L on d10 and decreased to 649 U/L by d5P.
`A third subject (study DAP-QTNC-01-06; dose of 6 mg/kg q24h for a planned 14
`days) discontinued the study on Day 9 of daptomycin treatment due to facial palsy
`considered unrelated to the study medication.
`In the same study, two daptomycin-
`treated subjects and one placebo-treated subject discontinued the study due to
`_, “v
`
`15
`
`

`

`elevated CPK. concentrations considered probably related to study drug. One of
`the daptomycin-treated subjects had a maximum serum CPK (asymptomatic) of
`'1940 U/L on dl4, which returned to normal by d25. The second daptomycin-
`treated subject had a maximum serum CPK (asymptomatic) of 1593 U/L on d7,
`which returned to normal by le. The placebo-treated subject had a maximum
`serum CPK (asymptomatic) of ll,430 U/L on d14 which returned to normal by
`d28. All CPK isoenzymes in these patients were MM. One subject (study DAP-
`00-04) discontinued study medication due to severe diarrhea after receiving a
`single dose of 346 mg (4 mg/kg) daptomycin; the diarrhea was considered to be
`probably related to study drug.
`
`Medical Officer Comment
`the Cubist-sponsored clinical
`The
`elevations
`in
`serum CPK noted in
`pharmacology trials are fairly typical of this AE due to daptomycin. Serum CPK
`elevations were noted after approximately one week of treatment and no
`symptoms were present. ‘ Resolution over several days is often seen. Of note,
`however, is that the doses at which CPK elevations were noted are consistent with
`
`those used in the pivotal phase 111 trials.
`
`Serious adverse events - Cubist—sponsored Phase 1 studies
`There were three SAEs in the Cubist-sponsored clinical pharmacology studies.
`One subject (Study DAP-QNTC-Ol-06) developed right-sided facial numbness
`and weakness after receiving daptomycin 6 mg/kg q24h for 9 days; the day of
`symptom onset was between day 9 and 14. The diagnosis was Bell's palsy, the
`patient was treated with steroids, and the symptoms improved by follow-up at 6
`months. The investigator considered the Bell's palsy to be unrelated to the study
`drug. The second subject (Study DAP—OO-O4) developed diarrhea, nausea, and
`vomiting approximately two hours after a single dose of daptomycin 4 mg/kg.
`His gastrointestinal
`symptoms resolved over
`the following 24 hours with
`symptomatic therapy, and were judged probably related to study treatment by the
`investigator. A third subject (Study DAP-OO-04) developed nausea and vomiting
`approximately two hours after
`the infusion of daptomycin 4 mg/kg. His
`symptoms
`resolved over
`the following 12 hours with no treatment;
`the
`investigator considered the SAE to be probably related to study treatment.
`
`Deaths - Cubist-sponsored Phase 1 studies
`No deaths occurred during the Cubist-sponsored clinical pharmacology studies.
`
`Lillv-sponsored Phase I studies
`Demographics
`The Lilly Phase I studies enrolled 362 subjects who received daptomycin. These
`human pharmacology studies included single- and multiple-dose safety and
`phannacokinetic studies in healthy subjects. Multiple-dose studies examined
`various doses and regimens up to 4 mg/kg q12h for 14 days. Also included are in
`viva protein binding studies; a metabolism and excretion study using radiolabeled
`
`16
`
`

`

`::
`
`daptomycin, a study in subjects with various degrees of renal impairment, and
`drug interaction studies with tobramycin and amikacin.
`
`Demographic data was unavailable for studies BSB-MC-AVAD (39 patients) and
`B8B—MC—AVAL (6 patients). Limited demographic data was available for study
`B8B-EW-0001 (12 patients) and the studies conducted in Japan (5 studies, 6
`patients each).
`In the single-dose studies conducted in the US, where the data was
`available, the mean age was 31.6 years (range 19 to 46 years), in 35 males and 12
`females. All of the subjects were Caucasian (race data was unavailable for studies
`BSB—EW-OOO] and BSB-MC-AVAL).
`In the studies conducted in Japan (B8B-
`XO-lOOl, BBB-X04002, B8B-XO-1003, B8B-XO-1004 and B8B-XO-1005),
`the mean ages of the subjects were 28.5, 28.5, 34.3, 34.3, and 30.8 years,
`respectively. Subjects in the three repeat dose studies (B8B—LC-AVAB, B8B-LC~
`AVA], B8B-MC-AVAP and BSB-LC-AVAK) had a mean age of 33.9 years (24
`to 49 years) reported in 34 males. All but three of the subjects (two blacks and
`one with the race distinction of "other") were Caucasian. Subject demographics
`of Lilly-sponsored single-dose clinical pharmacology studies are shown in Table
`13.
`
`Table 13: Summary of Subject Demographics for the Lilly—sponsored Single-dose
`Da tomvcin Phase 1 Studies
`
`tud)‘ Number
`
`BSB-LC—
`AYAA
`
`BSB—LC-
`AVAC
`
`m— =5
`
`
`
`
`BSB-LC-
`AVAF
`
`
`
`
`
`
`
`
`BSB-LC-
`AVAJ
`
`B8B-LC— BBB MC-
`AVAK
`AVAL
`=6
`
`B8B-EVV
`000]
`
`31.7
`25-41
`
`29.0
`23 35
`
`N/A
`19-46
`
`25 5
`20 33
`
`/A
`
`“—-
`--
`
`
`3 9
`
`3 /
`
`N
`
`A
`
`N
`
`/A
`
`N/A
`
`69.0
`65-73
`
`
`
`73.0
`67-79
`
`70.0
`61 76
`
`74 3
`54-86
`
`I\=6
`
`
`
`
`
`
`
`'
`
`I eight (in.)
`can
`I' ange
`Veight (kg)
`can
`I' ange
`N 'A=Not available
`
`39.5
`32-46
`
`31.2
`25-36
`
`32.7
`28-37
`
`— 5
`
`5
`O
`
`68.0
`64-72
`
`65.8
`64-68
`
`70.2
`69-72
`
`71.8
`61-88
`
`69.2
`67-72
`
`72.0
`56-87
`
`With the exception of 12 women enrolled in Studies BSB-MC-AVAL and B8B-
`EW-OOOl, all of the subjects were male and all were Caucasian; race data is
`unavailable for these 2 studies BSB-MC-AVAL and BBB-EW-OOOI. Subjects in
`these studies ranged in age from 19 to 46 years. Subject demographics of Lilly-
`sponsored repeated-dose Clinical pharmacology studies are shown in Table 14.
`
`ll
`
`17
`
`

`

`
`
`the Lilly-sponsored
`
`Table 14: Summary of Subject Demographics for
`Repeated-dose Daptomycin Phase 1 Studies
` Study .Number
`BBB-LC-AVAB
`BSB-LC-AVAI BSB-MC-AVAK BSB-MC-AVA'
`
`’ariable
`
`
`
`
`
`
`
`
`
`ace
`
`
`Caucasian
`
`Black
`
`
`
`a. Ofthc 6 subjects enrolled in BBB-MC-AVAK. only 5 were dosed during the repeated dose regimen
`b. weight in pounds
`
`All subjects in the repeated-dose studies were male and the majority were
`Caucasian. The mean subject age was approximately 32 years in studies BBB—LC-
`AVAB and BSB-LC-AVAI and was slightly younger, 30 years, in study BBB-LC-
`AVAK, and slightly older, 38 years,
`in study B8B-MC-AVAP.
`Subject
`demographics of Lilly-sponsored clinical pharmacology studies conducted in
`Japan are shown in Table 15.
`
`Table 15: Summary of Subject Demographics for
`Daptomycin Phase I Studies Conducted in Japan
`
`
`Study Number
`‘BSB-XO BBB-XO-- BSB-JE
`‘
`1002
`1003
`1004
`1005
`
` ’ariable
`
`
`N'A = N0! available
`
`0001
`
`
`
`
`
`BBB-JE
`0002
`
`
`
`
`
`
`66.7
`
`
`
`the Lilly-sponsored
`
`Adverse events - Lilly-sponsored Phase I
`AEs seen in the Lilly-sponsored Phase 1 studies included headache, abdominal
`pain and pain and bruising at the venipuncture site. Daptomycin, administered
`intravenously at doses up to 6 mg/kg; was well-tolerated in the single-dose studies
`in healthy men and a small number of women. All AEs that occurred during these
`studies are summarized in Table 16.
`
`1-;
`
`l8
`
`

`

`C::::
`
`Table 16: Adverse Events in Lillv-s-onsored Da tomvcin Sinaie-dose Phase 1 Studies
`
`tud)‘ .Number
`
`'BB-LC-
`
`'B8B-LC-
`- VAC
`
`'
`
` - VAA
`
`Ilaptorfiycin
`,IO,25
`0,75 mg IV
`
`II aplomyci II aptomyci II aptomyci II aptomyci ll aptomycin II aplomyci
`I ngg IV 1 mg/kg,
`
`=' =6 lea-1mm-
`
`Number of Sub'ects
`
`%
`
`- dverse Event
`
`eastoneAE
`
`vstem disorders
`
`nemia
`
`I (0.0) M“
`1 (16.7
`Swellingoffiehleveli106.7)
`
`00.0
`
`aisorders
`
`I(0-0 Emu-MM-
`_-1 16.7
`bdominal -ain
`- Emu-m0-
`um-
`um M-
`I(0.0 mum-mm-
`-I-I(0.0) l—l-M-
`_
`
`eneral disorders an I
`
`-
`
`
`
`
`
`EE-MM-
`
`onditions
`
`-I(0.0)W
`_I(00 mam-m-
`_-I(00)
`-
`IIIOOI
`
`
`l MEN-Elm-
`
`Elm-MEIE-
`
`
`
`(
`.
`' min-mm-
`=§El 20-0 ”MI-I-m-
`
`nfestations
`
`nfection
`
`.
`
`(0.0
`(0.0
`(0.0) _1 16.7
`(0.0)
`(0.0
`II (20.0 “WW
`
`InvestieaIions
`
`I 00)
`
`-I-I(0.0)
`
`(00 num-
`
`on nective tissue and
`I(0.0
`I
`16.7
`I
`16.7
`1
`I 0.0)
`I(0.0
`I(0.0
`I
`onedisorders
`II “3—3010-2100-
`WWW—mm-
`
`'
`oisorders
`II 0.0
`
`I 0-0
`
`INI-
`_~
`“(Dom—106.7
`(0.0) n. (0.0
`_ __..,.,
`
`

`

`_1(l6.7)
`
`.
`
`
`
`
`
`,
`- A .0
`K3 1.
`a
`
`
`
`
`'
`(0.0)
`Io 0.0) __<00)
`
`
`
`
`1
`
`I
`
`—-1(16.7)
`
`issue disorders
`
`
`o 0.0 “MM-
`
`
`I_v<0.0) Im-
`a. AEs listed here may have occurred during multiple dosing with 3 mg‘kg daptomycin
`.
`
`Headache was the most frequently noted AE among subjects in the single-dose
`studies. In several cases, IV infiltration occurred resulting in inflammation or
`edema. Mild gastrointestinal disturbances were also noted. These events were not
`dose-related and did not persist.
`
`studies are
`AEs that occurred in the Lilly-sponsored repeat-dose Phase I
`summarized in Table 17 below. Note that in the Lilly study report for study BSB-
`LC-AVAK, no distinction was made between AEs which occurred during single
`versus multiple dosing. Therefore, the AEs for this study are presented with the
`single-dose studies only (see Table 16 above). One of the five subjects who
`received daptomycin 3 mg/kg q]2h in study BSB-MCAVAP had elevations in
`alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate
`dehydrogenase. None of the other subjects in this dose group had any AEs
`reported. Among the subjects in the 4 mg/kg q] 2h group, 2/5 subjects experienced
`marked elevations in CPK levels with accompanying symptoms of muscle
`weakness and pain. These events led to early termination of this study. The other
`3 subjects in the 4 mg/kg group had normal CPK levels and had no symptoms of
`muscle pain or' weakness.
`.
`
`APPEARS TH!S ‘r’s'AY
`
`0N ORlGll-lAL
`
`20
`
`

`

`C:::
`
`Table 17: Adverse Events in Lilly—sponsored Daptomycin Repeated-dose
`Phase 1 Studies
`tudy Number
`
`
`
`
`mg/kg or
`
`- mg/kg q12h
`I
`'=]0
`
`
`
`
`
`
`
`
`
`
` Number of Subjects (%)
`:
`'o. ofSub'ecls with at least one AE
`
`EMM-
`
`ar nain
`ve disorders
`
`mam-mm.—
`
`
`
`
`
`éedness Iefi exe
`
`astroimestinal disorders
`
`"mm—-
`
`'
`
`- bdominal min
`Iliarrhea
`
`II 's-oesia M
`ooxhaehe M
`eneral disorders and administrationsit-—
`
`4 (40.0)
`
`4 80.0
`
`2 (20.0)
`
`onditions
`
`.—..
`
`_
`
`duscle weakness
`
`l’ain exuaciion siie
`'ain vem‘ mnemre site
`
`1 (10.0
`
`mum-
`__-_--—
`"Lewealions
`—--—-KGE-
`Alanine aminotransferase increased M
`
`aclate dehvdro- enase increased
`I\Iusculoskeletal, connective tissue and
`
`
`
`1 (10.0)
`
`0 (0.0
`0 (0.0)
`
`2 (20.0)
`
`mum-.-
`“mm—ma-
`
`'er\'ous svstem disorders Ml eadache
`
`m- 2 (400
`
`nsomnia
`
`Emman-
`
`esn’s disorder _-_-
`I' espiratory, thoracic and mediastinal
`0 (0.0)
`. isorders
`E_—--—-ME-
`M-
`
`i——_—
`’asodilation '
`
`“,
`_~.‘.
`
`21
`
`

`

`I
`
`.
`
`I
`
`Table 18 below summarizes the AEs that occurred in subjects enrolled in the
`Phase I studies conducted in Japan.
`
`tudy Number
`
`Table 18: Incidence of Adverse Events in Lilly-sponsored Daptomycin Phase 1
`Studies Conducted in Ja an
`BBB-X0
`B8B—XO‘ BSB-XO' BSB-XO
`
`
`100]
`1002
`
`
`
`h—6
`N=6
`‘
`dverse event _ Number ofSub'ects %
`_-I—
`-o.ofSubjectswith
`0(0.0)
`0(0.0)
`0(0.0)
`0(0.0)
`0(o.0)
`7(26.9)
`0(0.0)
`east oneAE
`
`BSB-XO
`1005
`l\=6
`
`888- JE BSB- JE
`0001
`0002
`N=26
`N=10
`
`'lGastrointestinal
`ldisorders
`' Stomamis
`:m-estiations
`Activatedpanial
`
`roloneed
`
`isorders
`
`0(o.0)
`
`0(0.0)
`
`0(o.0)
`
`0(0.0) "W
`-
`
`
`
`0(0.0)
`
`O(0.0)
`
`O(0.0)
`
`III-I-
`
`O(0.0)
`
`0(0.0)
`
`4(40.0)
`
`0(0.0)
`0(0.0)
`orom MIME]
`
`l cadache M
`
`ubcutaneous tissue
`isorders
`
`EL".
`
`0(0-0)
`
`o 0.0 “mu—limo]
`
`_
`Medical Oflicer Comment
`No AEs were reported in five of the seven Phase 1 studies conducted in Japan,
`consistent with the overall lower AE rate often reported from non-US sites.
`Headache was the most common AE reported, noted in 6/26 (23.1 %) subjects in
`study B8B-J5000]. 0] more concern are the 4/10 (40%) patients from study
`BSB-JEOOOZ who had prolongation of activated partial thromboplastin time
`(aPTT). Prolongation in aPTT was observed in one subject on the ninth day of60
`mg daptomycin and in 3/5 subjects at 120 mg daptomycin, according to the
`original study report, although the dose given is 60 mgfor 7 days, 120 mg for 7
`das (presumably sequentially).
`
`However, the clinical significance of the prolongation in aPYT is unclear, since
`this is not an AE 0f daptomycin predicted from the preclinical trials, nor has
`prolongation in aPTT been a significant finding in subsequent clinical trials.
`In
`addition, these doses are lower than the 4 mg/kg q24h proposed for use in the
`submitted indication ofc5551.
`
`22
`
`

`

`Drug related adverse events - Lilly-sponsored Phase 1 studies
`Information on study drug causality does not appear to have been systematically
`collectedin the Lilly-sponsored Phase 1 studies, and this information is not
`contained in the study reports or 185 (either Cubist or Lilly).
`
`AE leading to discontinuation- Lilly-sponsored Phase 1 studies
`In study BSB-MC—AVAP, two subjects of five who received daptomycin were
`discontinued from the study after elevations of serum CPK. The first subject
`developed symptoms of bilateral forearm pain and stiffness after 6 of the planned
`14 days of daptomycin 4 mg/kg q12h. His maximum serum CPK was 20,812 U/L
`with isoenzyme pattern MM; his symptoms resolved by 2 months post-therapy.
`The second subject developed symptoms of bilateral forearm pain and weakness
`after 11 of the planned 14 days of daptomycin 4 mg/kg q12h. Serum CPK was
`elevated to a maximum of >10,000 U/L. Symptoms resolved and serum CPK
`returned to normal when checked at 2 weeks post-therapy.
`
`Serious adverse events - Lilly-sponsored Phase 1 studies
`In study BSB--MC-AVAD, one male subject (age unknown) with chronic renal
`failure on hemodialysis received a single dose of daptomycin 2 mg/kg. Four days
`later, he developed bloody stools and a drop in hemoglobin. The patient was
`described as
`fluid overloaded during dialysis.
`No lesion was
`found by
`sigmoidoscopy and his anemia was corrected. The investigator felt
`that
`the
`bleeding was not related to study drug.
`
`Deaths - Lilly-sponsored Phase 1 studies
`No deaths occurred during the Lilly-sponsored clinical pharmacology studies.
`
`Cubist-sponsored Phase ”/1“ studies
`Demographics
`Cubist conducted two Phase 11 studies; a third study was discontinued due to slow
`enrollment, and the data is included here for purposes of this safety review. DAP-
`BAC-9803, is an open-label, Phase 11, dose-ranging trial in patients with culture-
`confrrmed Gram-positive bacterernia or presumed bacteremia.
`The study
`compared three doses of daptomycin (4 mg/kg q24h, 6 mg/kg q24h, or 3 mg/kg
`q12h with a 6 mg/kg loading dose) with standard therapy (vancomycin 1 g every
`12 hours or nafcillin or oxacillin 4—12 g daily in equally divided doses) and
`enrollment was three:one daptomycinzcomparator. The second Phase I] study,
`DAP-RRC-9804, is an open—label, non-comparative, multicenter study utilizing
`three dose regimens of daptomycin in hospitalized patients with bacteremia (4
`mg/kg q24h, 6 mg/kg q24h, 3 mg/kg q12h following a 6 mg/kg loading dose),
`c5551 (4 mg/kg q24h), lower respiratory tract infections (LRTI) (6 mg/kg q24h),
`intra—abdominal
`infections (1A1) (6 mg/kg q24h), or complicated urinary tract
`infections (UTl) (4 mg/kg q24h potentially adjusted according to MIC level)
`caused by Gram-positive pathogens that were resistant to vancomycin or whose
`infection was otherwise refractory to currently available therapy or for whom
`
`23
`
`

`

`
`
`currently available therapy was contraindicated. Study DAP-RRC-9804 was
`terminated due to slow enrollment.
`Study DAP-00-03 was an open-label,
`microbiologist-blinded, Phase II] study comparing daptomycin at a dosage of4
`mg/kg q24h with ciprofloxacin 400 mg in patients with UTls caused primarily by
`Gram-positive pathogens. The subject demographics of Cubist-sponsored clinical
`pharmacology studies are shown in Table 19.
`
`Table 19: Demographic Characteristics, Cubist-sponsored Phase “/1“ Studies
`
`(Poulation: All Patients Treated
`
`I
`haracteristic
`ll AP-BAC-9803
`II AP—
`00-03
`
`' C 9804
`
`> 1
`
`otal Other Studies
`
`
`
`
`
`—I_ll-ll-lI-ll-ll-I N=ss
`gee-rs) _W
`
`_———_—mm
`
`“Hill—W
`_————_mm
`_—_——MI
`
`"I %
`—— 6(8.1
`m—_ 46(62.2)10(29.4) H (32.4)
`_22<29.7
`
`
`
`
`
`
`
`-_ 10(13.5
`
`
`
`
`
`
`
`6 ( 47.)) 103 ( 57.2) 28 ( 48.3
`38 ( 52.8)
`_ 47 < 63.5)
`8 < 52.9)
`
`_--l_-
`
`
`
`
`(%
`
`
`
`aucaéian —_150(67'.6)-—133 97.I)_-l
`—18(24-3
`0(0.0)
`23
`12.8
`_-l-I-I—m l
`2.9
`0(o.0)
`
`
`
`—-l—--_ O ( 0.0)
`
`
`
`
`
`
`Patients in these studies ranged in age from 18 to 91 years of age with a mean of
`57.0 years in the daptomycin-treated patients and 60.9 years in patients treated
`with comparator. Comparator patients included equal numbers of patients <65 and
`>65 years of age, while 63.9% of the daptomycin patients were <65 years of age.
`A total of 65 patients who received daptomycin and 29 patients who received
`comparator were age 65 or older; 26 daptomycin patients and 13 comparator
`patients were age 75 or older. There was a greater percentage of males treated
`with daptomycin (57.2%) than with comparator (48.3%). Caucasians accounted
`for 81.7% and 86.2% of the patients who received daptomycin and comparator,
`respectively.
`
`Disposition - Cubist-sponsored Phase ll/lll studies
`Most patients in the Cubist-sponsored Phase ll/IIl studies completed treatment as
`planned.
`In DAP-BAC-9803 and DAP-RRC-9804, 74.3% and 55.6% of patients
`completed therapy, respectively.
`In DAP-BAC-9803, the most common reason
`for premature discontinuation was "Adverse Event" in the daptomycin group
`(8/74; 10.8%).
`in DAP-RRC-9804,
`the most common reason for premature
`L. :32.
`
`24
`
`

`

`
`
`the
`discontinuation was "Adverse Event" in the daptomycin group (18.1%);
`discontinuation rate due to clinical failure was 12.5%. Patient disposition for the
`Cubist Phase 11/111 studies is given in Table 20 below.
`
`Table 20: Summary of Patient Disposition, Cubist-sponsored Phase 11/111 Studies
` Po . ulation: All Patients Treated
`
`Decision
`
`Prematurely
`Discontinued
`Thera '
`Adverse Event
`Clinical
`
`(Symptomatic)
`Failure
`Patient‘s
`
`Overall adverse events - Cubist-sponsored Phase 11/111 studies
`For Study DAP-BAC—9803, a total of 66/74 (89.2%) patients in the daptomycin
`group and 19/24 (79.2%) in the comparator group reported at least one AE during
`the study. This; high rate of AES is consistent with the critically ill status of the
`patients; the majority of events were assessed by the investigators as unrelated to
`study treatment. The most frequently reported AEs in DAP-BAC-9803 were
`nausea reported in 14/74 (18.9%) patients in the daptomycin group and
`constipation reported in 7/24 (29.2%) patients in the comparator group. Other
`AEs reported in more than 10% of patients in either study arm were diarrhea and
`nausea in the daptomycin group and nausea, agitation, cardiac failure congestive,
`insomnia, and dizziness in the comparator group. The majority ofAEs were rated
`by the investigator as mild to moderate in severity.
`
`In Study DAP-RCC~9804, AEs were most commonly reported in the SOC of
`gastrointestinal disorders.
`The most
`frequently reported AEs were nausea
`(16.7%), diarrhea (15.3%), and vomiting (15.3%). AEs by SOC were more
`common in the dialysis group.
`
`Medical Oflicer Comment
`The mostfiequently reported A55 in these two studies are consistent with the AE
`profile derived fiom the preclinical and Phase 1 studies of daptomycin.
`The
`relatively high AE rate seen in both of these studies is not surprising considering _
`the serious underlying illness ofthe patients in these two Phase 11 studies.
`..
`-~..._,
`h -_ _,
`
`25
`
`

`

`For Study DAP-00-03, there was a significantly lower incidence of AEs in the
`daptomycin group than in the comparator group. A total of4/34 (1 1.8%) patients
`in the daptomycin group and 13/34 (38.2%) in the ciprofloxacin group reported at
`least one AE during the study. There were significantly fewer patients 6/34
`(2.9%) in the daptomycin group than in the ciprofloxacin group 6/34 (17.6%) who
`reported at
`least one AB in the SOC of gastrointestinal disorders. The most
`frequently reported AE was diarrhea occun'ing in 5/34 (14.7%) patients in the
`ciprofloxacin group. Table 21 below shows AEs by SOC including events
`reported in >2% of patients in any study group in Cubist-sponsored Phase Il/llI
`studies.
`‘
`
`Table 21: Adverse Events by System Organ Class Including the Most Commonly
`Reported Events (22% of Patients in any study group), Cubist-sponsored Phase
`”/1“ Studies Po-ulation: All Patients Treated
`
`w:.. O 5V 2 =
`: N
`N=34
`
`ystem Organ Class/ Preferred Term DAP-BAC-9803
`
`II aptomycin
`II
`'-
`\Ia.
`
`omparator
`u
`NA
`'
`
`otal Number ofPatients with at Least
`
`One AE
`
`l: lood'and lymphatic system
`. isorders
`- nemia NOS
`ardiac disorders
`I: radvcardia NOS
`ardiac arrest
`
`
`crdiac failure congestive
`
`
`ardio-res irato ' arrest
`
`
`jdocarditis NOS
`ulmonarv edema NOS
`
`
`
`%
`(89.2)
`
`(13.5)
`
`A N
`
`0\
`
`AAAAPr."—.~~31:5'VV
`
`(1.4)
`(48.6)
`
`AVDLI‘ AU!A
`
`10
`
`La)
`
`\1
`
`%
`
`(8.3)
`
`
`
`A“AQA9°89N994.5wLi’s-hN333
`
`(6.9)
`
`AAA/«GA5".h'l‘J'PNNOxbow-NoeVV
`
`2'» .5
`
`-03
`
`lC
`
`II AP-RRC-
`:804
`; N
`v.. O E I 2 3
`.
`omparator
`'=34
`. '=72)
`‘- “III
`%
`n %
`“(11.8)
`E 13
`(38.2)
`“H I
`an I.
`III nu (2.9
`“I! n
`.- “n n
`.- “n n
`.- um-
`I!
`.- ““ n
`n I.“ n
`(4-2) .- (5-6 n n
`achvcardiaNOS
`
`
`
`
`l-l-mnn
`astrointestinal disorders
`“mum-nu
`- bdominal -ain NOS
`l “nun-Inn
`-
`' bdominal ain u er
`n-I “nu-Inn
`onin-ation
`um mil-nu
`I- IaUhea nos
`_nn “II-Inn“!-
`,
`'mouth
`2
`n-mnnnn
`unmannn
`n-l-nnnn
`u—munnn
`"- nil-nun“
`_—mm “manna
`I.“ (8.3 "mu-nun"
`_-Iml mill-“nun
`eneraldisorders and
`(40.5)
`(41.7)
`(36.1) - (2.9) .-
`“nun-nun
`“II-nun“
`ln‘ection sitee 'thema n (5-4) “n““nnn
`ll
`
`4 dministration site conditions
`
`2 ON
`
`

`

`.
`
`
`.nflnmmwsmakmasmmmmmmsImUmmnememm.mwkNchEaumn..mn
`.mmmm...H.IMSS.1ToUdWCw.md%amm\0amUMW&
`
`
`
`.mEAmamddm."rmmfmevmnmmmmmef.fixk.\\\.Wnnaa.€.fle.m0v<v.£n009EEEW
`hr.“.191.1n.6.1-;Ihn0m..xd6156.l03..\.dC.|a1DD“nS
`
`
`mmohmmmm.macmmawmwwmmmruammMORbmkimmammmmmmmmwmm
`
`1e2k.nsmdmsasdndOcrindanadmnarbnnamhmeawfln6Nlyed?rvWrrC
`
`6at:rw3ncaNlnnnemd0mrmimls(XOEdC2r...dd
`
`si1sniiOrt.xbcasdcasas.nNnndlonu
`
`
`
`
`nnuflflmm“9J6.mmMONW.P.pn..N.-mIMdmnm.Mdammmm3MMHmmm.m.m.“.marummgS
`
`
`.ma.hddugo.msmegeumnxmemammoedsc.mw..-axis
`
`
`
`.I.LIIPPIIIIOPs...BRIIIONA.ll...DI...u:..OPPR
`
`dvowuronr05...nCBSmuok.eewRNemNsosmmamaflea mn.061e9eraduSC.1Ba.nmo..Na.“0..h.t.mCSnd.eSSS.mam.uLawn.neOn0USast.nddxoermadSa.mcernN.h...N.moeeCNSMd)0awnanrhflfi
`
`
`
`19:0adnidntaaeamronsfivhroei.miseantn0n.ltio
`
`
`
`
`811291IIZHZIZISHISZ21N459010245
`
`
`J4.47.5474.47.74.74.J.44.7.7.4.1.4.5.7..J4.
`
`
`(((((((((((((((((((((((((((
`
`5
`
`
`
`.)\Ix)x;\II
`
`
`
`31186J1]2J3A0446”282n2412((((x(2(.((
`
`n3
`
`7.22(((
`
`.1.
`
`85
`
`89.
`
`\l)
`
`II.
`
`
`2323332M3223.“232.2.2.2.27.22.2356.362.9.
`\I\I)\Ix)\r)()4555077ml
`..........8.844co84”a“0&88M6o(o\4414(4M“(804(“(211(a
`
`
`
`
`
`
`
`1..L.........5....41.......258.5.625L18((6M6045UMZMZ2003USWUM442((MUM((Q(M(124(Q(aM
`
`
`
`4462682662888876.46636222586329.269.500.26.4582.4.0.36.2.
`
`27
`
`
`

`

`
`
`
`
`—--Innnn
`
`“nun-nu
`“nu—mun
`I'Ieural effusion
`
`2
`(2.7 n“_ (4.2 mu“
`l'uesirato
`failure (excluding neonatal
`Winn-nun“
`
`ckjn & subcutaneous tissue disorders
`20 -----l-lnnn
`ermatitis NOS mum-nun“
`
`I rvthemaNEC
`"mu“ 3
`4-2 “nun
`
`Will-“nun '
`mun-[Inn
`
`
`Ile\'iceblocka-e mm- (2.8 “nun
`’asculardisorders
`16
`(21.6 m,“ l
`(2.9 --l
`
`I
`\ enension NOS MW.-
`
`-otension NOS
`_--lmlunnu
`
`
`
`
`
`
`
`
`
`
`Note: Patients reponing more than one adverse event within a system organ class (SOC) are counted only once in the total line for that
`SOC. Patients repomng more than on: adverse event coded to the same preferred term are counted only once in the line for that
`preferred term.
`
`
`
`
`
`Drug related adverse events - Cubist-sponsored Phase ll/lll studies
`Table 22 below contains a summary of drug-related AEs by SOC class which
`occurred in the Cubist-sponsored Phase 11/11] studies. The most common AB in
`the daptomycin arms by SOC for both Phase II studies was gastrointestinal
`disorders in 9/74 (12.2%) and 14/72 (19.4%) patients for studies DAP-BAC—9803
`and DAP—BAC-9804, respectively. Drug-related elevations in serum CPK were
`seen in 3/74 (4.1%) and 4/72 (5.6%) patients in studies DAP-BAC-9803 and DAP-
`BAC—9804, respectively. No drug-related AEs were reported in study DAP-00-03
`in the daptomycin group.
`
`28
`
`

`

`
`
`
`otal Number ofPatients with at Least
`
`ne Related AE -‘
`
`Table 22: Drug-Related Adverse Events Occurring in More than One Patient by
`System Organ Class and Preferred Term, Cubist—sponsored Phase 11/)“ Studies
`(P0 ulation: All Patients Treated
`System Organ Class/ Preferred Term
`
`DAP-BAC—9803
`
`DAP-RRC-
`9804
`
`DAP-OO-03
`
`Daptomycin
`ll
`\lA
`7
`'
`
`Comparator
`.- 1=24
`
`Daptomycin
`N=72
`
`'=34
`
`=34
`
`“KW-Inn“
`(37.8) (36.1) 5 (14.7)“
`nm-lmmuun
`--lm-nnunnnn
`nmmnnnnn
`Win-nun
`“nun-munuu
`I- (M) nun-“nun
`'mouth
`ll
`—--lnnnunnnn
`”mnnmnnnn
`Winn-nun“
`eneral disorders and administration
`(6.8) ---.-nn
`niection site -ain mum-“nun“
`mum-Inna
`ralcandidiasis
`.- 1-4) nmnunnnn
`‘n‘na
`'tract infection NOS
`“nun-mnunn
`"asinitis
`--lnm-nunnnn
`nvesri-ations mun-“nun
`l'lood alkaline phosphatase NOS
`(2.
`) "n“ "In" -
`-lood creatine hos hokinase increased “mu“nnnnn
`I
`iver function tests NOS abnormal
`2
`(2.7) nn-mnnnn
`- lusculoskeletal, connective tissue and
`(2.7) n“_ (4.2) “In"
`one disorders
`tuscle weakness NOS
`Il-nn-l-Innnn
`‘ervoussvstem disorders
`l- (5.4 mun-nun“
`l eadacheNOS
`.
`2
`2.7) “nun-unnu-
`insomnia NEC
`“tannin-nun“
`kin & subcutaneous tissue disorders --'“-_-_ 11.1)m
`ennatitisNOS
`I.
`“II—(2.8 nun-u
`l'ruritus NOS mum-nun“
`I‘ ash macular
`unnn— 28) “nun
`-
`obable > possible > unrelated) is
`lneludcs events assessed as probably or possibly related to study treatment. The highest relationship (p
`tabulated.
`
`
`
`
`. ite conditions
`
`'ncreased
`
`'
`
`Adverse events leading to treatment discontinuation - Cubist-sponsored Phase
`11/“! studies
`
`Table 23 contains data on patients from the Cubist Phase Il/lll studies who were
`discontinued from either study due to an AB.
`
`29
`
`

`

`Table 23: Listing of Daptomyein Treated Patients with Adverse Events Leading to
`Withdrawal, Cubist-sponsored Phase “/1“ Studies (Population: All Patients
`Treated
`
`Patient lD
`
`Age
`(yrs)
`.
`
`. Sex
`-
`
`Total Duration'Adwrse Event Leading to
`Dose
`of Rx
`tudy Drug Stoppage
`mas
`(days
`
`Day" Relationship
`
`u AP-BAC-9803
`
`_—
`I.—
`latieue
`24
`6085
`Male
`Il—
`- -_l useleweaknessNOS
`ll—
`
`Male
`
` 4 Endocardlllswos
`8835 lood ressure increased “—
`Male
`- -_lll—
`_m Male IE! 2
`les-iralo
`failure
`“—
`
`3
`[Res-irate
`failure
`_u Female
`1080
`“—
`
`W“
`W“
`ll50 n_-—
`II A P-RRC-9804
`
`_-_--_II—
`—-—-_5__II—
`I—__--£—_II
`_-_-_—-_
`_-___3_II_
`
`Male
`
`2868
`
`048400002 mus—_—
`Female ——_.—u—
`Female --_n—
`- Small intestinal obstructionNOS “—
`Male
`7010
`35
`cutemyeloid leukemia
`.—
`
`0045400005
`
`048400007
`
`048400009
`
`Female
`
`825
`
`aeravated
`
`043400011
`048400013
`MEMO”
`
`Male mun—ll—
`-—Female 10
`e-sisNOS
`Male “_n—
`- ——a-_n—
`—- —_;——n
`Male _nloodereallnem-oshokmase “_-
`
`Female -_—n
`74
`‘ Day relative lo the last dose of study medication
`Note: Patient 0048400002 was dual enrolled under the patient number 0048400004
`
`1n the Cubist-sponsored Phase ll/lII studies, a total of 23 patients (21 patients in
`the daptomycin group and 2 patients in the comparator group) were discontinued
`from study treatment due to AEs.
`In study DAP-BAC-9803, ten patients were
`discontinued from study treatment due to AEs, including 8/74 (10.8%) patients in
`the daptomycin group. Discontinuations due to AEs occurred in 5/24 (20.8%)
`patients in the daptomycin 4 mg/kg q24h group, 1/26 (3.8%) patients in ,the
`daptomycin 6 mg/kg q24h group, 2/24 (8.3%) patients in the daptomycin 3 mg/kg
`q12h group, and in 2/24 (8.3%) patients i