Lacosamide
`N22-253
`
`Page 114 of 174
`
`— 12809
`PK Assessment
`Lacosamide and SPM 12809 in plasma
`Cmax, Cmaxmonn and CTrou_h and normalized
`Laborator
`tests, adverse events, ECGs
`
`
`
`
`Safet Assessment
`PD Assessment
`
`
`
`
`
`
`Pharmacokinetic Results:
`
`Pflar/Imcakt'lzetics oz lacosamia’e 1'11 glam/m:
`
`Descriptive statistics for Ctrough (predose) and Cmax (end of infusion) LCM plasma
`concentration on Day 2 (am and pm) by actual daily dose are presented in the following
`tables.
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`

`

`Lacosamide
`N22-253
`
`‘
`
`Page 115 of 174
`
`Descn'ptive statistics for Cgmgh {praéese} and Cam: (emi of infasion) LCM plasma
`cancentratian 1011121}; ‘2. by actuai daiiy dose and féme paint
`P-fipulation: Pharmamkinet’ic Set
`
`Concentrafiun in ggg‘EL
`
`
`
`133L013 Mean (SD)
`
`‘
`
`’
`
`*
`
`-
`
`Actual daily
`{lose}
`§nfusio=n
`durafionf
`
`Time paint
`
`LCM ZQflmgu‘day
`
`Day 2 am pit-adage
`{QM 21;)
`
`Day 2 ampesfdosg
`{Cm iv}
`
`Day 1 pm predms
`(cum; iv)
`
`' Day 2 pm pogtdose
`{meiv}
`
`Day'l am predoge
`{Cam i153
`
`Day? am posfdose
`{Cmiv’}
`
`Day 3 pm predma
`(cm; i?!)
`
`Day 2. pm pnstdoze
`{sziv}
`
`Day 2 am predme
`{ngl in!)
`
`Day 2' amposfdose
`{Cm iv}
`
`D33: 2 pm pxedose
`(Cm; iv)
`
`,
`
`Day 2 pm pogtdnse
`{me'iv}
`
` Adoa
`
`‘
`
`’
`
`=
`
`'
`
`»
`
`-
`
`13363 (9.5934?)
`
`5 3813 (£3.91 133)-
`
`2.6309 (11393?)-
`
`3338 {9.330863
`
`5.318681%?4)
`
`2.6333 {93‘30263
`
`.
`5.3055 (2.53599)
`
`£33925 (6.153 162:
`
`5.5 225 (2311???)
`
`_
`1.6059 (9.59912)
`
`.
`
`‘»
`
`5.97725 (£94803)
`
`
`
`elqgssodr539
`
`

`

`Lacosamide
`N22—25 3
`
`Page 116 of 174
`
`Descfigfive statistics far Chwgh {prfiéose} and CW; {em} of infasion) LCM plasma
`concentration on Bay 2 by actuai {may ($953 and time.- point
`Popzzlation: Phaz‘mncokinefic Set
`
`Actual daily
`£1959!
`infusion
`durafioni
`
`Time point
`
`LCM 3 fiflmyda};
`
`Ba}: 2 am preduse
`*1ng iv}
`
`Day 2 am puztdase
`{Cm iv}
`
`Day 2 pm madam
`{Cm iv)
`
`Day 2 pm pagtéose
`
`Day 2 1m predm‘e
`(Shady: WI!
`
`Day 2 am pastdase
`{Cmiv}
`
`Day ‘2 pm pastime
`{Cum-5 iv}
`
`Day 2. pm pastries:-
`{Cmifi
`
`Day 2 am gredaae
`(Ginny. it“)
`
`Day 2 am pes'tdose
`
`Day 2 pm pct-class»:
`(cm iv}
`
`Day 2 pm pmidose
`
`
`
`Concen'tmtiun in pgimL
`
`n>LOQ Mean (533)
`
`3.1659: {$361361}
`
`331325 {8.322173}
`
`3.6533 {figfigl’pj
`
`?.?133 {195341)
`
`3 3406 {6.965083
`
`2.7350 {$341101}
`
`”3.5313 {1336842)
`
`2.5075 {#3373233}
`
`6,9553 {3.61383)
`
`

`

`Lacosamide
`N22-253
`
`Page 117 of 174
`
`Bescfiijfive stafistics for C-Wugh {px‘edose} and Cm: (em: of'izifzzsion) LCM plasma
`concentration on Day ‘2 b}; actufi dafiy (12859 and time point.
`Pogulation: Pharmacakinefic Set
`
`Adan} dairy
`(lam;r
`Infusion
`duration!
`
`Concentration in [igfifiL
`
`Time point
`1§>LOQ Mean {SD}
`LCM manlgmy_
`—-—————
`Day 2 am pmduae
`{erng iv}
`
`4.35342 {1.49153}
`
`
`
`)
`
`Day 2 am pustdose
`{9mm}
`
`Day 2. pm predme
`{Cami fix)
`
`Day;2 pmposfiiose
`{mew}
`
`Day 2 amgrzdme
`(Cums-a if}
`
`Day-7 am pogtdnse.
`{Omit}
`
`' Day 2. pm predme
`
`Day? pm pogtfiose
`(Cm;1v}
`
`Dav-2 am predase
`(CW iv)
`
`Day 2 ampostdme
`{Cm‘iv}
`
`Day '2 pm pxedoeze
`{Swag iv}
`
`Day 2 pm postdose
`(Cum iv}
`
`-
`
`-
`
`9.3235 {2.46334}
`
`$.38ch {1.51039}
`
`9.4223 {2.137093
`
`'
`
`1.2664640990)
`
`.134:10
`
`£27883 (2.39032)
`
`12.2400
`
`3.955? {3.79375}
`
`3.=¥4ED
`
`.
`
`£67521 {3,3143%}
`
`18. E430
`
`

`

`Lacosamide
`N22-253
`
`\
`
`Page 118 of 174
`
`Besczipfive statistics far Ctmgh {predose} and Cm (£216 of infusion) LETM plasma
`concentration an Bay 2 by Miami daiiy (i959: and time paint
`Popalafion: Pharmamkinefic Set
`
`Actual dafiy
`dose!
`infusion
`(Eurafioni
`
`Concentration in 1%me
`
`Time point
`
`HL>L0Q Mean (SD)
`
`lCM 5IBfimg‘day—--——_—
`
`
`
`Da} 2 am yredme
`{Ctmgh if!)
`
`Day 2 am pnsndase
`{Cm iv}
`
`Day 2 pm prdGfie
`{Cvmgz 1V}
`
`Day7 pm 1305111933
`{£mij)
`
`Day“; am predose
`{5min N)
`
`Day 2 am pustdose
`
`Day? pm predma
`{8mg £17)
`
`Day 2 pm pogttiase
`
`Day-'2 am predage
`(EM iv)
`
`Day 2 am postdme
`(Cm iv}
`
`Day 2 pm pradma
`{0mg iv)
`
`Day 2 pm posténse
`{5mm-
`
`9.66013 {$331113}
`
`Qflififl
`
`F
`
`'
`
`§=633213 {3.31565}
`
`1133313
`
`1
`
`,
`
`6.3 563 (2.33900)
`
`'
`
`32.0567 (1.35644)
`
`

`

`Lacosamide
`N22-253
`
`'
`
`Page 119 of 174
`
`Destfipfive StflfiSfiCS for Cfmgh @wdose} and Cum: (end of infusion) LCM plasma
`conten'tmsfion on Day 2 by admit {may 121552 md fime point
`Pegulation: 13lxat‘macokiaetic Set
`
`Concentrating in ugn‘mL
`I
`
`8.1??3 {3.20534}
`
`15 .9343 {4.06895}
`
`3.46%? {2.18815}
`
`114130!)
`
`8336? {1.1539473
`
`13.0I25 {13.83792}
`
`Actual {Infly
`{1659? -
`Infusion
`éumfiom’
`
`Time point
`
`LCM. 1501311135133:
`
`Day 2 am Vedas:
`{ngt m
`
`Day 2 am pastdose
`(Emmi?)
`
`Day 2 pm 1312:1056
`{cw inst:
`
`Day ”2 pm pea-1131035
`{Cm1 iv}
`
`Day 2 am predwe
`{Cwmgt i?)
`
`Day 2 am postdose
`{Em iv}
`
`Day 2 pm grades:
`{Cm iv)
`
`D3312 pm pastdosa
`{Cm iv}
`
`Day 2 am madam
`{C‘lmgs 1‘33
`
`Day} am pustdsse
`(Cm iv)
`
`Day 2 pm predme
`{€31,151 iv)
`
`Day 2 pm postciose
`{Cm iv}
`
`m '3'
`
`9
`
`,mo.0
`
`9
`
`--
`
`pm 0’.
`
`M u
`
`w 01.
`
`W.‘M9]
`
`M a.
`
`m as
`
`w Ch
`
`.m[\JWWU)I“J
`
`b.)w4.4»?Wl
`
`

`

`Lacosamide
`N22-253
`
`Page 120 of 174
`
`Descriptive statistics for Cwugh {prairies-e} and Cum (end of .infzision) LCM plasma
`concentration on Day 2' by actual dafly 519-59 and time point
`Pepuilafion: Eimnnacokinefic Set
`
`.
`
`Cfoncentmfien in pgme
`
`.
`
`nhLOQ Mean (SD)
`
`-
`
`31.0925 {5982-57}
`
`.
`mass (533133}
`
`1164-53 {4.14554}
`
`
`
`Actual daiiy
`dose."
`Infusien
`duration}
`
`Time point
`
`LCM TOOmgfda}?
`
`Day 2 am predose
`{Caz-MEL iv)
`
`Day 2 am postdose
`(Cm iv}
`
`Day 2 pm predose
`’ (Cm; iv)
`
`Day 2 pm postdoae:
`(Cum iv}
`
`Day ‘3 am postdose
`{Cmiv
`
`Day 2 pm predose
`(QM? iv)
`
`Day 2 pm postdose
`(0mm
`
`LCM SQUmgjdaf
`—--————
`Defy-'2 empredose
`{Gama iv)
`
`.
`
`11.3225 (3.3?949}
`
`v
`
`,
`
`'
`
`2311023 {6.40992}
`
`10.9550 (3.§2139}
`
`10.96%
`
`-
`
`223325 {6.1324}
`
`22.7825
`
`iv=intravenoug LCM=§acosamideg LQQ=1iméit ofqnamificazion; fixinanimnm; Mafinaximmn;
`nk-LCIIQ=thB number cf subjects. with plasma levels above: the LOQ {0.59399‘3113; SD=s§andard deviation ‘
`a
`There. were. n9 subjects in the 36- and 10-minute infim'on mm groups who took LCM WGmgflay
`or LCM Sflmugz‘day.
`
`These Tables show that Lacosamide plasma concentrations (Ctrough, Cmax) were similar across
`all infusion duration (10, 15 and 30 minutes) groups within the daily dose groups of LCM
`200mg/day—600mg/day. Only subjects in the 15-minute infusion duration group received
`LCM 700mg/day-800mg/day. The LCM plasma concentrations (Ctrough, Cmax) increased
`proportionately as the actual daily dose increased.
`
`After normalization for body weight and actual individual dose, LCM plasma concentrations
`(Ctrough, Cmax) were comparable across LCM doses. The ratios of geometric means including
`90% confidence intervals (iv vs oral) of normalized Ctrough for the 30-, 15-, and 10-minute
`infusion duration groups are presented in the following table.
`
`

`

`Lacosamide
`N22-253
`
`Page 121 of 174
`
`Ratio of geometric means of normalized Ctrough (ug/mL x kg/mg) Population:
`
`Treatment
`
`Infusian
`duration
`(Cohort)
`
`30—minute
`
`(Cohort A1)
`
`Compariscn
`iv (fest) vs
`era} {reference}
`
`Katie
`{‘34:}
`
`90% CE
`
`Day 1 pm are vs Day 1 am pie
`
`95.4
`
`{?7,.0, 1182}
`
`{6-3.4 115.?)
`
`’
`
`i
`
`, Day 2 am pie vs Day 1 am pre
`
`Day 2 pm pie vs Day 1 am pm
`
`15—minute
`
`iv LCM 2’
`
`E Day 1 pm are vs Day 1 am pm
`
`(Cohort Bi
`
`and LCM
`
`Day 2 am pm vs Bay 1 am pre
`
`and B2)
`
`’ Day 2 pm pie vs Day 1 am pm
`
`10—mi11ute
`
`iv LCM 2’
`
`Day 1 pm 3313: vs. Day 1 am pre
`
`{Cohort C)
`
`era} LCM
`
`Day 2 3mm vs Day 1 am pre
`
`{75.0, 116.?)
`
`(3G3, 108.?)
`
`{79.3, 1 00.4)
`
`{82.3, 194.8)
`
`(T65, 97.8}
`
`{68.0, 126.2}
`
`(6?.8, 125.8}
`
`Day 2 pm pre vs Day 1 am pre
`C1=eanfideace interval; i¥=iatrm=encug LCM=1acaaamida
`a
`011E}; subjects with a valid Day 1 am Fred-nae. plasma value Marla valid prefioae value for Bay 1 pm
`Day 2 am, and Day 2 pm were inducted
`
`In general, the ratios of geometric means of normalized Ctrough were similar across the various
`infusion duration groups and time points. The ratio of geometric means 85-95%, indicating
`that normalized Ctrough plasma concentrations following iv LCM administration were
`comparable to normalized Ctrough plasma concentrations after oral LCM administration. The
`lower limit of the 90% confidence interval were more on the lower side for the 10 and 30
`
`minute infiisions, probably due to the smaller sample size compared to the 15 minute infiision.
`
`Lacosamide plasma concentration (mean iSD) versus time point for a, 15 minute infusion at
`the 300 mg/day dose is given below, showing similar Cmax and Ctrough between oral and iv
`Igur
`I
`LCM . Similar plots of different infusion grouepsland doses were available.
`Lacosamide Concentration (maaniSD) versus Timspoint by Infusion Duration and Actual Daily Dose
`Infusion Duration: 15—minute
`Actual Daily Dose: 300mg/day (N=1B)
`
`
`
`
`
`LacosamideConcantra‘llan(uglmL)
`
` |
`
`Duyl AM
`Day—l
`Cone. Oral Dfrcugh Oral
`
`|
`Day1 AM
`Cmax IV
`
`|
`Day1 PM
`Ctrough IV
`
`I
`Duyt PM
`(2me IV
`
`l
`Day2AN
`Cfmugh IV
`
`|
`DayZAM
`Cmax IV
`
`DnyZPM
`Clraugh IV
`
`DayZPM
`Cmax IV
`
`EOTP
`ctrough rVV
`
`Plasma concentrations for all doses by infusion duration is shown in the following Figures:
`
`Tlmepolnt
`
`
`
`
`
`Adogeiqgssodrsag
`
`

`

`Lacosamide
`N22-253
`
`Page 122 of 174
`
`..,_V .
`Mean Lacosamide Concenlraliqn versus Timepoini for all Adual Daily Dose: (mg/day) by Infusion Durafion
`'
`Infusion Duration: 30—minute
`
`
`
`
`LIB 200 (N: 5)
`000 300 (N: 3)
`000400 (N=12)
`-' $5? 500 (N: 5)
`AAA 600(N=11)
`
`
`
`as
`
`2k
`
`a
`
`.
`z
`
`3
`'
`
`A
`
`
`
`arses 500 (N: a)
`AAA 600 (N=17)
`
`#13”: 700 (N: 5)
`lo. 300 (N: 2)
`
`O
`
`.
`
`e
`
`a
`
`‘
`11
`
`0
`~¢
`0
`o
`a
`0
`:g
`"
`=1
`is
`A
`A
`g
`A
`o
`A
`0
`“
`o
`A
`8
`CI
`I:
`g
`Li
`8
`°
`0
`C‘
`o
`0
`D
`u
`8
`8
`D
`
`I
`I
`I
`‘
`“I—
`I
`I'— I
`'T—
`|
`I
`Day —1
`Day I AM
`Day 1AM
`Day1 PM
`Dayl PM
`Day 2 AM
`Day 2 AM
`Day 2 PM
`Day 2 PM
`EOTI’
`Cone. Oral
`(though Drol
`(Imux IV
`enough IV
`Cmax IV
`Enough IV
`Cmax IV
`Clmugh IV
`Cmax N
`Cimugn IV
`Timepoini
`. .3... v vu—
`Mean Lacosamide Conceniralion versus Timepoini for all Aciual Daily Doses (mg/day) by Infusion Durafion
`Infusion Duration: 15—minuia
`
`
`
`I IS 200 (N—17)
`000 300 (N=18)
`(>00 400 (N=26)
`
`34
`32
`so
`25
`E 25
`3 24
`f,
`22
`’2' 20
`E 18
`
`A g
`
`16
`E
`8 14
`
`g I2
`E
`IO
`°
`3
`8
`a
`5
`—I
`4
`2
`0
`
`54-
`32
`30
`28
`25
`24
`22
`20
`18
`16
`14
`12
`
`ONJAC!
`
`34
`32
`3O
`28
`26
`24
`22
`20
`18
`15
`14
`12
`
`CNJ‘O’
`
`
`
`
`
`LacosamlaeConcamraflon(pg/mL)
`
`
`
`
`
`LacosamrdeConcan‘lrallon(pg/mL)
`
`
`
`
`
`AdogquIssodIsag
`
`'
`
`1:
`’3
`35:
`9
`0
`U
`
`o
`
`A
`é
`a)?
`Q
`.»
`0
`a;
`a
`fl
`0
`g
`a:
`0
`A
`%
`A
`O
`A
`0
`A
`O
`V
`a
`8
`g
`I:
`3
`D
`2:
`D
`3
`u
`8
`8
`8
`8
`
`|
`—l— I
`—l—‘
`| —I
`7—“
`|
`Day —1
`. Day 1 AM
`Day I AM
`Day 1 PM
`Day 1 PM
`Day 2 AM
`Day 2 AM
`Day 2 PM
`Cone. Oral Cirough Dral
`Cmax IV
`Ctraugh IV
`Cmax IV
`Cfrough IV
`Cmax IV
`Clrough IV
`
`I
`Day 2 PM
`Cmax IV
`
`{300%bitO
`
`l
`EOTP
`cimugh Iv
`
`Timepoinl
`Mean Lacosamide Concenl’ralion versus Timepaini for all Adual Daily Dose: (mg/day) by Infusion Durafion
`Infusion Durul'ion: 1D—minuie
`
`
`
`
`
`
`200 (N: 2)
`I' I‘
`000 300 (N: 4)
`000 400 (N: 7)
`am“)? 500 (N: *4)
`
`AAA 500 (N: 3)
`
`A
`
`X
`
`5»
`
`'45
`
`A
`
`*1
`
`a.
`
`0
`
`0
`
`A
`A
`A
`.
`g
`O
`a2
`o
`3*
`O
`“k
`0
`III
`0
`o
`g
`a
`0
`CI
`0
`0
`El
`
`D
`I:
`D
`8
`I
`l
`l
`l
`I
`|
`|
`l
`Day —1
`Day 1 AM
`Day 1 AM
`Day 1 PM
`Day 1 PM
`Day 2 AM
`Day 2 AM
`Day 2 PM
`Cnnc. Oral Cirough Oral
`Cmux IV
`Cirnugh IV
`Cmax IV
`Cfrough IV
`Cmax IV
`Cmax IV
`
`
`
`GD
`
`<2
`,
`o
`
`A
`a:
`
`0
`8
`
`Day 2 PM
`Clmugh IV
`
`EOTP
`Cimugh IV
`
`The above figures also show that Cmax’s of a given dose are comparable across all infusion
`groups, as can be also seen from the mean data given in the previous Tables.
`
`

`

`Lacosamide
`N22-253
`
`Page 123 of 174
`
`The plasma concentration (Ctrough, Cmax) of SPM 12809 was similar across all infusions
`durations within the daily dose groups of LCM. The sponsor did not give summary Tables for
`the metabolite concentrations, but the individual Tables were reviewed. The concentrations of
`concomitant AEDs was also similar across all infusion groups.
`
`Sponsor’s conclusion on safety (to be reviewed by M0 as well):
`
`There were relatively few treatment-emergent AEs reported during the trial. In the 30-, 15-,
`and 10-minute infusion duration groups, 43%, 24%, and 35% of subjects, respectively,
`reported at least 1 treatment-emergent AE during the Treatment Phase. The frequency of ABS
`did not increase with more days of exposure nor with shorter infusion durations.
`
`Conclusions:
`
`In general plasma concentrations were similar between the oral and iv dosing and across all
`infusion groups, although the number of subjects in some of the dose and infusion groups are
`small.
`
`APPEMS TH IS WAY
`0N GREGH‘ML
`
`

`

`Lacosamide
`N22-253
`
`Page 124 of 174
`
`Study SP616: A multicenter, double-blind, double-dummy, randomized trial to
`investigate the safety, tolerability and pharmacokinetics of
`intravenous SPM 927 as replacement for oral SPM 927 in subjects
`with partial seizures with or without secondary generalization
`
`The safety aspects from this study will be reviewed by the Medical Officer. The sponsor also
`collected PK data in this study which will be reviewed by this reviewer.
`Objectives:
`'
`
`The objectives of this trial were to evaluate the safety, tolerability, and pharmacokinetics of
`SPM 927 when given as iv infusions compared with oral administration of the same dose
`strengths in subjects who were receiving oral SPM 927 in addition to 1 or 2 concomitant
`antiepileptic drugs (AEDs) for partial seizures with or without secondary generalization.
`
`The study design is as follows:
`
`
`Trial Site
`Seven (7) trial sites in the United States of America (USA) and
`Lithuania
`
`
`Study Design
`This was a multicenter, double-blind, double-dummy, randomized trial.
`A total of 60 subjects, who were participating in an open-label
`extension trial (SP615) of oral SPM 927, were enrolled. Subject had
`been on a stable dose of LCM and concomitant AED for at least 2
`weeks. The subjects were randomized in a 2:1 ratio to iv SPM 927 plus
`placebo tablets twice daily (bid) or iv placebo plus oral SPM 927 bid,
`respectively. Subjects were enrolled into 1 of 2 cohorts (A and B).
`
`
`
`The maximum duration of treatment in this trial was 3 days.
`calm A (an-arming Enfmioxk}
`Emir
`iv SPM i527 *9 paymefio hid
`(am)
`
`
`
`
`End 05%
`Pam'dpatim
`9W3
`
` iv placabe+ gm 317.8192? hid
`
`,
`_
`{133? i
`3 1 me
`Rm:
`
`{Fun
`
`./’“
`r/
`.2“
`,—.x
`
`w/T
`(Ax/r"
`
`we
`4 ’J/
`
`4’”!
`.
`j
`Cohort B (30-Mmula Infusion}
`
`hammer; mm
`(933-5 ‘2 and 3}
`iv SPM 5‘17 +pu§kxebo bid
`(F20)
`
`/‘ '
`
`~
`
`, 3’
`
`’
`
`\
`
`"
`
`{DEF 1}
`
`
`\
`/.r”
`
`
`iv placebo 2‘ pa 39M 92.? bid
`{$10)
`
`.
`,.
`$16sz
`«may 3
`
`
`
`StudLPopilation N=60_patients
`
`

`

`Lacosamide
`N22-253
`
`Page 125 of 174
`
`
`Age_:19-61 years (mean 41.7 years)
`Weight: 46.1-148.3 kg (mean 80.26 kg)
`Gender: 25 male and 35 females
`
`Treatment Group
`
`Race: 53 White, 6 Black, 1 Asian
`Cohort A= 60 min infusion: N=30
`CohortB=30 minute infusion: N=3O
`
`
`
`APPEARS THIS WAY
`ON ORlGlNAL
`
`

`

`Lacosarnide
`N22-253
`
`,
`
`Page 126 of 174
`
`
`
`
`Dosage and Administration
`
`On Day —1, oral SPM 927 tablets were administered in accordance with
`each subject’s SPM 927 dosage regimen in the open-label extension
`(SP615). A single infusion of iv placebo was administered in a single-
`blind fashion after admission procedures and screening assessments had
`been completed.
`
`
`
`
`
`
`
`
`
`
`
`During the Treatment Phase (Days 1 and 2), blinded trial medication (iv
`solution and oral tablets) was administered twice daily at 12-hour
`intervals, once in the morning and once in the evening. The oral trial
`medication was taken immediately prior to the start of iv infusion, with
`approximately 240mL (8 ounces) of water.
`
`On Day 3, oral SPM 927 tablet(s) were administered in the morning in
`accordance with each subject’s SPM 927 dosage regimen in the open-
`label extension (SP615). The tablet(s) were administered 12 hours after
`the start of the evening infusion on Day 2. The tablet(s) were taken with
`approximately 240mL (8 ounces) of water.
`a
`
`The dose of SPM 927 (100 to 300mg bid) was the same as the subject’s
`current daily dose in the open-label extension trial of oral SPM 927.
`End of Trial Phase assessments were performed the day after the
`Treatment Phase was completed, after which subjects continued in the
`open-label extension trial (SP615).
`
`Dietary regimen
`Throughout the trial, non-alcoholic and non-caffeinated beverages and
`non-quinine or nongrapefruit—containing beverages were served. The
`subjects were not allowed to consume alcohol during the trial.
`Breakfast, lunch, snacks, and evening meals were served under
`standardized conditions.
`
`IV formulation 10 mg/ml solution (200 mg in 20 m1 saline): batch
`WE12805
`
`Oral formulation: 50 and 100 mg tablets: batch: 231100
`
`50m_ SPM 927 , 232010 100m SPM 927}, and 231960 {placebo}
`Blood samples For LCM:
`Day -1: Pre-dose.
`Day 1: Pre—dose
`Day 2: Pre—dose and 0.5, 1, 1.5, 2, 4, 8, and 12 hours after the start of
`morning infusion of trial medication (8 samples per subject).
`Day 3: Pre—dose, before administration of oral SPM 927.
`
`
`
`
`
`Sampling: Blood
`
`‘
`
`
`
`
`
`Blood sample for concomitant AED:
`
`Da -1,1, 2 and 31predose
`
`none
`
`Feces
`none
`
`Analysis
`
`Method: LC/MS/MS method in plasma
`
`Lower Limits of Quantitation:
`
`Plasma
`
`

`

`Lacosamide
`N22-253
`
`Page 127 of 174
`
`
`
`
`Lacosamide
`10 ng/mL
`
`Plasma:
`
`
`
`Linear Range in plasma 10-10,000 ng /ml
`Quality control concentrations : 20, 500 and 4000 ng /ml
`
`
`Inter—day precision: < 3.4%CV for LCM
`
`
`Inter—day accuracy: -101.3-101 .6—101.9 for LCM
`
`
`
`
`
`
`Lacosamide in plasma
`AUC(0-12), Cmax, Cmin, tl/2, normalized parameter
`
`oarameter*Bod wei ht k- /dose m
`
`
`
`Safe Assessment
`Laborator
`tests, adverse events, ECGs
`
`
`
`PD Assessment
`None
`
`PK Assessment
`
`Pharmacokinetic Results:
`
`Pharmacokinetics of lacosamide in plasma:
`
`In total, 8 out of 60 subjects had invalid plasma concentration data due to reasons explained in
`the report. No PK parameters were calculated for n=7 of these subjects. As a result, the PK
`Set includes n=53 subjects out of n=60 subjects with concentration data.
`
`From Screening to End of Trial participation (Day —1, Day 1, Day 2, Day 3), subjects were
`maintained on a stable dose in accordance with current dosing from the open-label extension
`trial (SP615). Subjects entered the treatment phase (Day 1 and Day 2) under steady-state
`conditions. In both cohorts, all subjects received oral SPM 927 on Day —1. On Day 1 and Day
`2, subjects received iv SPM 927 plus placebo tablets bid or iv placebo plus SPM 927 tablets
`bid, respectively. On the morning of Day 3 (=End of Trial phase), a single dose of oral SPM
`927 was administered in accordance with each subjects’s dosage regimen in the extension
`trial. Steady-state plasma concentrations of SPM 927 were determined on Day —1, Day 1, Day
`2 and Day 3.
`
`Pharmacokinetic parameters AUC(0-12), Cmax, Cmin, and t1/2 were derived from concentration
`data of Day 2. For body weight- and dose-normalized AUC(0-12), Cmax, and Cmin, treatment
`ratios were calculated to compare the pharrnacokinetics of SPM 927 afier iv infusion over 60
`and 30 minUtes with the pharrnacokinetics of SPM 927 after oral treatment within each cohort
`as shown in the table below.
`
`

`

`Lacosamide
`N22-253
`
`-
`
`‘
`
`Page 128 of 174
`
`Normalized pharmacokinetic parameters on Day 2 and comparison between treatments
`(30- and 60-minute infusion vs oral)
`
`Treatment
`
`Comparison iva‘orai
`
`I
`
`i
`t "
`E’aélaggtei
`
`i
`
`L
`
`.
`
`{39%;th
`
`SPM 92.? 1.
`
`iv
`SPM 532.7 f
`
`91111 E'BO
`
`Geometric 11193131813
`
` 90% CI
`{itgz‘hi‘ikg’mg}
`
`AUC{0—12}mrm
`{iigz’niL’éhmkgfmgi
`
`menmm
`
`0mm...
`{agfhflfi‘kgfmg}
`
`“
`
`-
`
`3&9552158
`
`3113-22133
`
`100.5-
`
`041, £353)
`
`33.52—44.56
`{Ni=1 1)
`
`31.993213?
`{3:15)
`
`95.4
`
`{70.4, E294)
`
`33411-49
`{N=11)
`
`$.93i1f55
`{N=113
`
`4.42:1:133
`(32:15}
`
`1.90:1:i.60
`(2&1?)
`
`1.7212148
`9%”)
`
`$11.4
`
`{84.15, £45.?)
`
`$18.1
`
`{39.7. £55.15)
`
`92.?
`
`{62.7, i310}
`
`89.3
`
`(60.4. 132.0)
`
`Ci: confidence imam-“31; iv = intravenous; PBVO = jgiaceho; SD = standard deflation
`
`Cohort A: 60—minute in 31mm; Cohort B: 30-minute itrinfu'aion
`
`The bioavailability of SPM 927 after iv treatment for both the 60- (Cohort A) and the 30-
`minute infusion (Cohort B) was comparable to that after oral treatment. Ratios iv/oral for
`AUC(0-12)norm were 95-100%, although the 90% confidence intervals were outside the
`acceptable range.
`'
`
`Values of Cmax,norm were slightly elevated after iv treatment compared to oral treatment. This
`is reflected in ratios iv/oral of 11 1-1 18% for Cmax,norm.
`
`Values of Cmin,norm were slightly decreased after iv treatment which is reflected in ratios
`iv/oral of approximately 90%.
`
`The tmax was shorter afler iv administration of SPM 927 compared to oral administration.
`Thirteen out of 17 subjects receiving the 60-minute iv infusion reached tmax after 60-90
`minutes and 13 out of 15 subjects receiving the 30-minute iv infusion reached tmax after30
`minutes as expected. After oral administration of SPM 927, tmax was reached between 1.5 and
`4 hours after administration in the majority of subjects.
`
`From predose samples on Days 1, 2 and 3, trough plasma concentrations of SPM 927 were
`determined. Predose concentrations on Days 2 and 3 (=trough levels after iv or oral
`administration of SPM 927 on Days 1 and 2 [evening dose]) were compared with predose
`concentrations on Day 1 (=trough level after oral SPM 927) as shown in the table below.
`
`

`

`Lacosamide
`N22-253
`
`'
`
`Page 129 of 174
`
`(unit)
`
`N
`
`Ratio (‘24:)
`Day ZiDay 1 Day SfDay 1
`
`Comparison of trough plasma concentrations of SPM 927
`
`
`
`Parameter
`
`
`Treatment
`
`
`
`
`
`
`
`
`10
`Oral SPM 927 2’ iv PBO
`
`
`
`
`I?
`
`iv SPM 927 / oral PBO
`
`11
`
`
`Oral SPM 927 !' iv PBO
`
`
`
`iv SPM 927 f oral PBO
`
`iv = intravenous; PBO = 3313c ebo
`Cohort A: 60-minute iv infusion; Cohort B: 30-minute iv infusion
`
`In subjects who received iv treatment on Days 1 and 2, mean values of Ctrough on Days 2 and 3
`(=trough levels after iv SPM 927) were slightly lower compared with Day 1 (=trough level
`after oral SPM 927).
`
`In subjects continuing with oral SPM 927 on Days 1 and 2, mean values of Ctrough on Days 2
`and 3 may were slightly increased compared to Day 1. The increase was more pronounced for
`subjects receiving oral SPM 927 in Cohort B.
`
`Mean normalized SPM 927 plasma concentrations over time on Day 2 are graphically
`displayed below for Cohort A (60-minute iv infusion) and B (30-minute iv infusion),
`respectively.
`
`Mean SPM 927 plasma concentration versus time on Day 2
`normalized by body weight and dose (Cohort A: 60min infusion)
`
`W EV SPM 927/01'03 PBO N=f7
`”'"d’ Ora! SPM 927/IV PBO N:f0g
`
`
`
`"A“. N‘ .,..
`,.
`
`N“ ~. ~.. m u...
`
`
`“W... .‘W .,
`
`
`Y E
`
`w... by»...
`
`
`
`
`
`SPM92?Concentration(mg/mi.xkg/mg)
`
` 8
`
`1o
`
`{2
`
`Hours Post Dose
`
`

`

`Lacosamide
`N22—253
`
`Page 130 of 174
`
`Mean SPM 927 plasma concentration versus time on Day 2
`normalized by body weight and dose (Cohort B: 30min infusion)
`8
`“‘4’ Oral SPM 927/1V PBO N211
`W [V SPM 927/Oral P80 N215
`
`
`
`
`
`SPM927Concentration{[Lg/ml.atkg/mg)
`
`
`
`Hours Post 0053
`
`As seen in the figures above, maximum mean normalized plasma concentrations of SPM 927
`were higher and were reached earlier when SPM 927 was administered intravenously
`compared with oral administration. Maximum mean normalized plasma concentrations were
`reached at 30min after the 30—minute infusion, at 60min after the 60—minute infusion, and at 2
`hours after oral administration. Mean plasma concentrations of SPM 927 after 4, 8, and 12
`hours were slightly higher after oral SPM 927 compared with iv SPM 927.
`
`Effect of intravenous administration of SPM 927 on concomitant antiepileptic drugs
`
`Plasma concentrations of concomitant AEDs were determined on Day -1, Day 1, Day 2, and
`Day 3 simultaneously with the SPM 927 trough concentrations. For the most common
`concomitant AEDs, predose AED concentrations on Days 2 and 3 were compared with
`predose AED concentrations on Day 1 to investigate the effect of iv SPM 927 on the steady-
`state plasma concentrations of concomitant AEDs.
`
`Steady state plasma concentrations ofphenytoin (an inducer) and total valproic acid (an
`inhibitor) did not appear to be affected by administration of iv SPM 927.
`
`In general the plasma concentrations of all the concomitant AED after iv administration were
`comparable to that after oral administration, but there were less than 6 subjects in each group
`to make any conclusions on the AED concentration with iv administration.
`
`

`

`Lacosamide
`N22-253
`
`Page 131 of 174
`
`METABOLIC DIFFERENCES BETWEEN ORAL AND IV DOSING
`
`Study SP643: Randomized, open-label, 2-way crossover trial to investigate the
`pharmacokinetics and bioavailability of SPM 927 in poor and extensive
`metabolizers (CYP2C19)
`
`Objectives:
`
`The primary objective of this trial was to compare the pharmacokinetics and bioavailability of
`SPM 927 when given as intravenous solution or as oral tablet to four healthy Caucasian poor
`metabolizers (PM) (genotyped) compared to eight healthy Caucasian extensive metabolizers
`(EM).
`
`The secondary objective was to determine the safety and tolerability of SPM 927.
`The study design is as follows:
`
`
`
`Trial Site
`One Site in Germany
`
`
`StudLDesign
`This was an open—label, 2-way crossover trial in which healthy sub‘Ects
`Study Population
`N=12 Healthy subjects randomized (8 EMS and 4PMs) and N=ll valid
`for PK analysis
`-
`
`Age: EM: 26-42 years (mean 34.3years)
`PM: 25-44 years (mean 34.5years)
`Gender: All males
`
`
`
`
`
`Weight: EM: 58.2—84 kg (mean 68.9 kg)
`
`PM: 60.5-80 kg (mean 68.6 kg)
`Race: All White
`
`Treatment Group
`
`
`
`Treatment A: IV: a single dose of 200mg SPM 927 as SOmL
`intravenous infusion over 60min,
`
`Treatment B: Oral: a single dose of 200mg (2x100) SPM 927,
`followed by multiple doses of 200mg SPM 927 bid
`for 4 days, then 200mg on the last day.
`'
`
`Description of Invesfigational Product
`
`Total Dose/Treatment
`
`A (iv dose)
`
`200mg of SPM 927 in the morning
`
`200mg SPM 927
`
`B (p0 dose)
`
`on Day I: 200mg SPM 927 (morning)
`
`200mg SPM 927
`
`
`
`on Day 4 to 7: 2002113 SPM 927
`13 (p0 dose)
`(morning)
`
`
`
`
`
`
`
`
`
`
`plus 200mg SPM 927 (evening)
`
`400mg SPM 927
`
`8 (pa dose)
`
`on Day 8: .200 mg SPM 927 (morning)
`
`200mg SPM 927
`
`Dosage and Administration
`
`Vials containing 200mg SPM 927, administered as intravenous infusion
`(50mL over 60 minutes), batch number: WE12206 (Treatment A:
`040702);
`'
`
`Film-coated-tablets containing 100mg SPM 927, batch number: 223770
`(Treatment B: 050702).
`
`
`

`

`Lacosamide
`N22-253
`
`Page 132 of 174
`
`'
`
`Washout:
`
`Wash-Out Phase of at least 6 days between treatments
`
`Sampling: Blood
`
`For Lacosamide and its metabolite, SPM12809:
`Treatment A (iv treatment):
`
`Predose and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48,
`60, 72 hours post administration
`
`Treatment B (oral treatment):
`
`Day 1 to 4: Predose and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12,
`24, 36, 48, 60, 72 hours post administration
`
`Day 6 and 7: Before morning and evening dose
`
`Day 8 to 11: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, and
`72 hours post administration
`
`
`Feces
`
`Day 1 and Day 8: at 0 hours (predose voiding), 0-12 hours, and 12-24
`hours after res ective dose.
`none
`
`Analysis
`
`Method: LC/MS/MS method in plasma and urine
`
`
`
`Lower Limits of Quantitation:
`Plasma
`
`Lacosamide
`SPM 12809
`
`Plasma:
`
`100 ng/ml
`20 ng/ml
`
`Urine
`
`Spg/ml
`lug/m1
`
`Linear Range: 100-20,000 ng/ml in plasma for lacosamide and 20-4000
`ng/ml for SPM 12809
`Quality control concentrations 300, 1500, 15000 ng/ml for LCM and
`60, 300 and 3000 ng/ml for SPM12809
`Inter-day precision: <7.7 %CV for LCM and <9.1 for SPM12809
`Inter-day accuracy: -5.1to -7.0 % bias for LCM and 5.3 to 7.3% for
`SPM12809
`
`Urine:
`
`Linear Range: 5-500 ug/ml urine for lacosamide and 1-100 ug/ml
`for SPM 12809
`
`Quality control concentrations 15, 40, 400 ug/ml for LCM, 3,8, 80'
`ug/ml for SPM12809
`'
`Inter-day precision: <7.8 %CV for LCM and <10 for SPM12809
`Inter-day accuracy: -3.1 to -8.8 % bias for LCM and -13.8 to 7.5% for
`SPM12809
`
`
`PK Assessment
`
`Lacosamide and SPM 12809 in plasma
`Primary PK parameters were:
`
`- AUCg O-tz), F, Cmax t1/2 of lacosamide in plasma after SD;
`
`

`

`Lacosamide
`N22-253
`
`Page 133 of 174
`
`
`
`Cmax,ss, and T1/2 at steady state
`
`Secondary PK parameters were:
`' AUC(0_-oo), AUC (0-12),t1/2, tmax of lacosamide and M1
`
` Safety Assessment Laboratory tests, adverse events, ECGs
`
`PD Assessment None
`
`Method of genoflping:
`
`For the genotyping, ethylene diamine tetraacetic acid (EDTA) blood samples were collected
`and DNA was isolated using standard methods according to Miller et a1 (Nucleic Acids Res.
`1988 Feb 11;16(3):1215).
`Cytochrome P450 subgroup CYP2C19 determination was done using polymerase chain
`reaction and restriction analysis according to Sachse et al (Am J Hum Genet. Feb;60(2):284-
`95, 1997).
`
`For CYP2C19 (subfamily IIC [mephenytoin—4-hydroxilase] polypeptide 19; human genome
`gene locus: 10q24.1~q24.3; MIM [Mendelian inheritance in man] no. 124020), the wild-type
`allele and 1 mutated allele weredetermined. This covers 98% of alleles in the German
`population.
`
`_viw<m>
`
`Type Bf aifeie
`
`
`
`
`
`
`. Name of aliele
`
`
`
`
`
`
`
`
`
`(wt + wt)
`Intermediate metabolizer
`
`(heterozygous)
`Poor metabolizer
`
`
`a Phenmype fiequencies are based on previous deteiminatious of the aileles in the German popuizm'ou and represent
`expected frequencies. The fi‘equeney distaibuflxm can be difi‘erem in tithe: popuiztiom {age Blacks, Scandinavians).
`
`Genotyping identified 4 homozygous poor metabolizers (2 mutated alleles).
`The subjects included as extensive metabolizers were either heterozygous for the
`respective alleles (wild-type + mutated alleles) or homozygous (wild-type + wild-type
`alleles).
`
`Pharmacokinetic Results:
`
`Pharmacokinetics of lacosamide in plasma:
`
`The summary of pharrnacokinetic parameters (ranges) in the poor and extensive metabolizers
`are shown in the following Table:
`
`

`

`Lacosamide
`N22-253
`
`'
`
`Page 134 of 174
`
`Pharmacokinetic parameters of LCM after administration of 200mg LCM as single dose
`as well as after dosing at steady state in poor and extensive metabolizers (CYP2C19)
`
`Parameter
`
`Statistic
`
`Poor metabolizers
`
`Extensive metabolizers
`
`(unit)
`
`05:3}
`
`(N=8)
`
`Singie dose
`
`
`
`AUC(Q_§25 {ygfimfl‘h} Geometric
`AUC.;omyiugme‘i‘h) $3110)
`mefligme)
`
`95.84 (14.9)
`106.6 (3.3)
`101.? (4;?)
`9353(149)
`110.4(5.1}
`10386.4)
`
`5.504(152)
`6.882(142}
`5.730(86)
`
`96.87 (19.2)
`109.0 {19.4}
`6.209824)
`
`F63”
`
`14.40 {142)
`
`13.63 (9.1)
`
`1338618)
`
`101.4 (7.2)
`
`
`'
`
`sags-(24.7)
`
`46.3891}
`
`4533(132)
`
`
`
`Steady state
`
`AUCW (ygfmv‘h) Geometric
`“1321.1“.
`,
`
`
`NA
`98.63 {3.6)
`NA
`NA
`12.94 (7.6)
`NA
`
`W5.
`CV=coefficient of variation; F=absolme bioavailability: LCM=facosamide; NA=zlot applicatale
`
`<50)
`
`94.64 {15.5)
`12.51 {15.2)
`
`<1.
`
`mm
`
`For iv — Day 1, p0 - Day 1, and p0 — Day 8, t1/2 was marginally longer in PM accompanied
`by a slightly higher AUC. The difference however is very small (about 10 % or lower) and
`unlikely of clinical relevance.
`
`The AUCs were marginally higher after oral administration than after iv administration.
`
`The amounts of lacosamide excreted in the urine was higher (24-34% in the iv and oral
`groups) in the PMs compared to the EMS. In PMs, 50.3 % of the dose was recovered in the
`urine in form of unchanged SPM 927, whereas in EMs the urinary recovery was only 39.5%
`of the dose.
`
`The table also shows that the iv and oral PK parameters of SPM 927 on Day 1 were
`comparable.
`
`The absolute bioavailability (oral/iv) in terms of AUCO-tz Was 104.4% (90% CI 86-129%) in
`the PMs and 101.4% (90% CI 97-105%) in EMS. The larger confidence interval in the PMs
`could be due to the small sample size, hence these absolute bioavailabilities should be
`interpreted with caution.
`
`

`

`Lacosamide
`N22-253
`
`Page 135 of 174
`
`Pharmacokinetics of SPM 12909
`
`The pharmacokinetic parameters of the metabolite is summarized in the following Table:
`
`Pharmacokinetic parameters of SPM 12809 after administration of 200mg LCM on Day
`1 and at steady state in poor and extensive metabolizers (CYP2C19)
`
`
`
`
`
`Parameter
`
`Poor metabolizers
`
`Extensive metabolizers
`
`(n=3)
`
`iv — Day 1
`
`(n=8)
`
`was—12>
`
`243(161_363,n=6)
`
`mom)
`
`11*»me
`
`cm
`
`e
`
`um
`
`h h
`
`mum
`
`mumin
`
`CL
`
`cm
`
`wow-w)
`
`mm
`
`cm
`
`um
`
`um
`
`h
`h
`
`cm
`
`mum
`
`Aucss
`
`cm
`
`em
`
`mm
`
`W
`
`ug/mL
`
`cm
`
`mum
`
`“L : median, x : mean, geometric means listed in all other cases. Numbers in brackets are
`(ranges).
`
`
`
`
`
`
`
`

`

`Lacosamide
`N22-253
`
`,
`
`Page 136 of 174
`
`Although plasma concentrations of SPM 927 were found to be comparable (not more than
`10% difference) between PM and EM, there were noticeable differences (75-80% difference)
`between PM and EM with respect to AUCs of the metabolite SPM 12809.
`
`The ratio PM/EM of the parameters AUC(0-t,) or Ae of the main metabolite M1 is given in
`the tables below for iv and oral dosing.
`
`
`
`
`=3
`
`'
`
`_ h* _/mL
`Ratio
`PM/EM
`
`Difference
`
`
`
`
`PM-EM
`-76.31%
`
`SPM 927
`011.74
`SPM12909 _
`
`+ 6.15%
`1.06
`
`-80.88%
`
`
`SPM 927
`
`SPM12909
`
`'
`
`.
`
`.
`
`
`
`.
`
`.
`
`.
`
`.
`
`Difference
`PM-EM
`
`+ 10.01%
`
`This shows that the formation of SPM12909 or M1 is less in the poor metabolizers, although -
`the exposure to parent is comparable between the PMs and EMS. The metabolite is inactive,
`hence these differences may not be clinically relevant.
`
`Reviewer’s Note: The sponsor had noted a difference of -8.1% for M1, which was not
`correct.
`
`At steady—state total urinary recovery (arithmetic means) is compared in PM and EM in the
`following Table after oral dosing:
`
`
`
`: SPM 92.7
`
`
`
`
`Urinary recovery
`
`PM
`
`inns