Reviewer: BeLinda A. Ha cs Ph.D.
`
`‘NDA N0.
`
`
`
`fl“All
`
`Z 6 PEAR/M4CDi061770176701506'1”MVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NBA number:
`Review number:
`Sequence number/date/type of submission:
`Information to Sponsor:
`Sponsor and/or agent:
`'
`Manufacturer for drug substance:
`
`11(4)
`
`m4)
`
`‘
`
`13(4)
`
`——>
`
`1
`
`N ,- Sept. 28, 2007
`Yes ( ) No ( X )
`Schwarz BioSciences, Inc.
`/ /
`/ ,
`
`,/
`/
`
`/,
`/
`
`Reviewer name:
`Division name:
`HFD #:
`Review completion date:
`
`BeLinda A, Hayes, Ph.D.
`Anesthesia, Analgesia, and Rheumatology Products
`'
`170
`May 8,, 2008
`
`Drug:
`
`Trade name: Vimpa’tTM
`Generic name: Lacosamide
`
`Code name: SPM 927 (Schwarz BioSciences, Inc.), ADD 234937
`(NIH/Anticonvulsant Drug Development program), Harkoseride (Harris FRC
`code)
`Chemical name: (R)-2-Acetamidc-N-benzyl-3-methoxypropionamide
`CAS registry number: 175481-36-4
`»
`Molecular formula/molecular weight: C13H13N203/25030
`Structure:
`
`H
`
`HacYN
`
`O
`
`0
`
`x, 0
`
`CH
`
`
`
`10
`
`

`

`Reviewer: BeLinda A. Ha es PhD.
`NDA No.
`
`
`’— ’
`
`Relevant INDs/NDAs/DMFS:
`
`
`yINDs
`Status -
`Division
`>
`, Indication
`Sponsor
`
`
`57,939 Active Neurology Products
`Treatment of epilepsy
`05/19/1999
`Schwarz
`
`
`
`Biosciences
`
`
`
`A Schwarz
`Anesthesia, Analgesia and
`Treatment of
`
`Rheumatology Products
`neuropathic pain
`Biosciences
`
`68407
`Active Neurology Products
`Treatment of epilepsy
`10/16/2003
`Schwarz
`
`,
`Biosciences
`
`73,809 Hold
`Neurology Products
`Treatment of epilepsy
`11/23/2005
`Schwarz
`Biosciences
`
`
`
`
`31(4)
`
`11(4)
`
`
`
`
`DAs
`Product
`Status
`Division
`Indication ,
`.
`Sponsbr
`
`
`Division of
`22-253
`Lacosamide
`Pending
`Adjunctive Therapy
`09/28/2007
`Schwarz
`
`Neurology
`Tablets
`Treatment of Partial Onset
`Biosciences
`
`Products
`Seizures in Patients with
`
`
`EPJICPSL
`
`
`22-254
`Lacosamide
`Pending
`Division of
`Adjunctive Therapy
`09/28/2007
`Schwarz
`
`Injection
`Neurology
`Treatment of Partial Onset
`Biosciences
`
`Products
`'
`Seizures in Patients with
`
`E ilefiy
`
`
`
`
` r
`
`,___._._——~—————~
`
`"'5‘
`
`Lacosamide
`Tablets
`
`5—,
`
`
`
`
`
`
`
`
`Management of
`Division of
`Neuropathic Pain
`Anesthesia,
`
`Associated with Diabetic
`Analgesia and
`
`
`Peripheral Neuropathy
`Rheumatology
`
`
`Products
`
`
`
`
`-~ Schwarz
`Biosciences
`
`
`DMFS N2
`SLbiect ofDMF '
`
`Drug class: Anticonvulsant
`
`Intended clinical population: Management of neuropathic pain associated with diabetic
`peripheral neuropathy
`
`11
`
`

`

`0(4)
`
`0(4)
`
`
`
`Reviewer: BeLinda A. Ha es PhD. ‘ NDA No. ’ 7
`
`
`
`
`
`
`
`Clinical formulation: Lacosamide 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 300
`mg film-coated tablets. They are colored, oval, ' ӎ tablets of different size and are
`compositionally proportional formulations. The tablets are debossed with “SP” on one
`side and the tablet strength (“50”, “100”, “150”, “200”, “250”, “300”) on the other side.
`The composition of the film-coated tablets is described in the table below.
`
`
`Conlp_onent
`Function
`Tablet Stren th m lColor
`.
`7
`_l
`ISO/Salmon
`ZOO/Blue
`250/__,
`.300 ’—
`loll/Dark
`50/Pinkish
`
`Yellow
`
`V
`Amount (mgl
`Lacosamide
`
`
`Active
`50.0
`F1000
`‘l 150.0
`T2000
`‘l 250.0
`1300.0
`Ingredient
`
`Cellulose
`
`Microc
`stalline
`
`
`
`
`'
`
`
`
`Stearate
`
`/
`
`L.
`
`Total (lilm-
`7 126.00
`252.00
`378.00
`504.00
`coated tabletL
`
`[
`
`Route of administration: Oral
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`12
`
`

`

`
`
`Reviewer: BeLinda A. Ha es Ph.D. NDA N0. “=—
`
`Studies reviewed within this submission:
`
`
`Study Title
`Module/CTD _|
`
`
`
`
`Description
`
`»
`’
`.
`,
`PharmacOlogy
`'
`.v
`‘ f
`>
`>
`,
`13'
`
`Determination of the cytochrome P450 induction
`N2 N01-NS—4—2311
`
`
`Wntial of lacosamide in human hegtocytes.
` N9 1001020
`
`Pharmacologv Data Report
`
`, —l'
`>
`
`93(4)
`
`’7
`
`,,
`
`4.2.1.1/Primary
`”harmacodynamics
`
`N9 NOl-NS-4-2311
`_
`N9 'A6
`
`4.2.1 .3/Safety
`Pharmacology
`
`
`
`l3
`
`
`
`The profile of anticonvulsant activity and minimal
`tox1_ty of ADD 2340371n mice and rat.
`
`Report on in vitro carbonic anhydrase inhibition,
`change in heart rate and blood pressure in
`
`spontaneously hypertensive rats and
`saluresiskaluresis1n normal rats
`
`
`
`
`Neuroharmacol_og1c£profile (NPP!1n mice
`
`
`
`Neuronal vacuolization with SPM 927in rats
`
`
`Effect of SPM 927 on cloned hERG Channel
`
`
`
`ex uressed in mammalian cells.
`
` N2 20000377P
`SPM927: Evaluation of effect on cardiac action
`
`
`potential in isolated canine p_urkinje fibers.
`
` N9 A8
`
`The effects of ADD 234037 on the transmembrane
`
`
`
`otentials of isolated canine ventricular m oc tes.
`
`
`
` N9 E-Ol4-001
`Electrophysiological examination of activity of
`
`SPM 927 on the SCNSA—sodium channel expressed
`in CHO cells.
`
`
`
`
` N2 E-011119.TDA
`Effect of SPM 927 on the human cardiac lNa
`
`
`(hHNafiurrent expressed in mammalian cells.
`
` N2 SBOlDOl
`
`SPM 927: In vitro effect on lNa and ICa recorded
`
`
`from human myocytes.
`
`
`
`

`

`Reviewer: B'eLinda A. Hayes, PhD.
`
`NDA N0. —=—
`
`N4)
`
`M4)
`
`'
`
`
`
`N2 20000376P
`
`N2 20000378P
`
`N2 20000380P
`
`N2 20000381 P
`
`
`
`
`
`
`
`
`
`N2 " 15066/01 Examination of SPM 927 on L-type Ca2+ inward
`
`
`current in isolated ventricular myocytes from guinea
`
`
`
`
`4.2.1.3/Safety
`2340371n the 0 en-c—hest anesthetized do ;
`Pharmacology
`
`
`Cardiovascular (Hemodynamic) evaluation of ADD
`234037 in dos.
`
`
`
`Cardiovascular Evaluation of ADD 234037 in a
`
`d0_.
`
`
`
`
`Evaluation of haemodynamic effects and
`electrocardiogram following intravenous dosing1n
`
`
`the anaesthetized do-.
`Cardiovascular Evaluation of ADD 234037In non-
`human orimates.
`Behavioral Irwin Test and effect on body
`temperature following single oral administration on
`
`the rat.
`
`SPM 927: Evaluation of effect on intestinal transit
`
`
`in the rat followin;
`1e oral administration.
`
`
`
`SPM 927: Evaluation of interactions with
`
`
`neurotransmitters (Acetylcholine, histamine,
`
`
`serotonin) and barium chloride on isolated ileum of
`
`Evaluation of SPM 927 as a discriminative stimulus
`
`in a dru discrimination u'rocedure1n the rat.
`
`
`Evaluation of SPM 927 for abuse potential using an
`
`iv self-administration aradi _m in the rat.
`
`
`Evaluation of SPM 927 in the conditioned place
`
`oreference test in the rat.
`Pharmacok]net1cs/Tox1cokmet1cs '3
`._
`233 if
`SPM 927: A study of absorption, distribution,
`
`
`metabolism and excretion following oral
`
`
`
`administration to the mouse.
`
`Single dose pharmacokinetics of SPM 927 in CD®-
`
`
`1 mice.
`
`
`SPM 927: A'study of absorption, and excretion
`followin; oral administration to the rat.
`Bioavailability and excretion of [14C]ADD 234037
`
`
`
`
`le administration.
`in male bea le do s followin;
`'
`
`
`PM 927: A study of absorption, distribution,
`
`
`metabolism and excretion following oral and
`
`
`intravenous administration to the do_.
`
`N2 ——- 15654/02
`
`Pharmacokinetic study in male beagle dog after
`
`
`repeated (twice daily) oral administration of SPM
`
`
`927.
`
`
`SPM 927: A study of absorption, distribution,
`
`metabolism and excretion followin, oral
`
`
`
`
`
`N2 699/48
`
`
`
`N2 0699/46
`
`
`
`14
`
`N2 05.237/5
`
`N2 05.637/4
`
`N2 05.122/6
`
`
`,
`
`7
`_ 1
`N2 699/46
`
`’
`
`N2 18447/04
`
`N2 18772/05
`
`N2 133418/00
`
`N2 0699/023
`
`
`
`
`
`
`
`
`
`N2 699/47
`
`N2 F232
`
`
` 4.2.2.2/Absorption
`
`
`
`
`14-Day toxicokinetics study by oral administration
`of SPM 9271n CD®- 1 mice.
`
`Exposure of the mouse to SPM 927 after single
`intra - eritoneal administration
`
`[14C]--SPM 927: A study of absorption, metabolism
`and excretion following single and multiple oral
`administration to the rat.
`
`4.2.2.3/Distribution
`
`

`

`
`
`Reviewer: BeLinda A. Ha es Ph.D. NDA No. \
`
`mm
`
`— administration to the mouse.
`
`N9 F212
`Absorption, distribution, metabolism, and excretion
`
`of [l4C]-ADD 234037 in Sprague Dawley rats
`following either a single intravenous or oral
`administration.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SPM 927: A study of absorption, distribution,
`metabolism and excretion following oral and
`intravenous administration to the do.
`
`[14C]-SPM 927: A study of absorption, metabolism
`
`and excretion following single and multiple oral
`
`
`administration to the rat.
`
`[14C]-SPM 927: Placental transfer, lacteal secretion
`and transfer to sucklin neonates in the rat.
`
`[l4C]-SPM 927: In vitro binding to plasma proteins
`
`
`in mouse, rat, do ; and human.
`
`
`[l4C]-SPM 927: Quantitative whole-body
`
`autoradiography following oral and intravenous
`
`
`administration to the “imented rat.
`
`In vitro metabolism of ADD 234037 using liver
`microsomes from rat, do, monke and human.
`[l4C]-SPM 927: Metabolism in hepatocytes
`isolated from mouse, rat, rabbit, do 1 and man.
`Investigation of the metabolism of SPM 927 in
`different in vitro models.
`
`
`
`N 0699/48
`2
`
`N2 699/23
`
`N9 699/15
`
`N9 699/016
`
`2
`N 0699/17
`
`0
`
`N9 0699/25
`
`SPM 927: Metabolite profiling and identification in
`the mouse, rat and do.
`i
`Investigation of the Cytochrome P540 1A2 and 3A4
`induction of the compound SPM 927 in
`c cureserved human monoc tes.
`
`N9 BA 555-02
`
`4
`
`0
`
`4.2.2.4/Metabolism
`
`
`
`
`
`
`
`Determination of the cytochrome P450 induction
`otential of lacosamide in human he atoc tes.
`
`
`N9 Ml999—057
`An investigation of the potential for harkoseride to
`inhibit cytochrome P450 1A2, 2A6, 2C9, 2Cl9,
`
`2D6, 2E1, and 3A4 in cryopreserved human
`
`heatoc tes.
`
`N2 BA 481—03 and
`Interaction of the compounds SPM 927 and SPM
`
`
`BA 481-03-A1
`12809 (Dimethyl-SPM 927) with the cytochrome
`
`
`P450 isoforrns 1A2, 3A4, 2C9, 2C19 and 2D6.
`Inhibition of the cytochrome P450 isoforrns 1A1,
`2A6, 236, 2C8, 2E1 and 3A5 by SPM 927 and SPM
`12809.
`
`N2 865
`
`.
`
`.
`
`Transport of SPM 927 across Caco-2 monolayer —
`
`
`Investi ation of P- 1 co rotein involvement.
`
`
`
`
`
`4.2.2.6/Pharmacokinetic
`
`
`
`
`
`Dru Interactions
`
`
`
` Administration to CD-l Mice
`
`
`
`Administration to CD Rats
`
`Intravenous Administration to CD 1 Mice
`
`4.2.3.1/Single—Dose
`Toxicity
`
`
`
`
`
`
`No. 18566-0-800
`N9 "' 13123/00
`
`Acute IV Stud of ADD 234037 in Rats.
`13-week Subchronic Toxicny of SPM 927 by Oral
`Administration to CD—l Mice
`
`N2 148-235
`
`13-week Oral Gava_e Subchromc Toxici
`
`Stud of
`
`15
`
`0(4)
`
`
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No, ,3:
`
`
`
`M4)
`
`ADD 234037 in Rats.
`
`4.2.3.2/Repeat—Dose
`Toxicity
`
`
`
`
`6—Month Chronic Toxicity Study of SPM 927 by
`N2 13227/00
`
`Oral Administration to Spragye-Dawley Rats.
`lZ—Month Chronic Toxicity Study of SPM 927 by
`
`Oral Administration to Beagle Do_g_s.
`
`
`
`
`
`N2 13196/00
`
`Studiesn_ot reviewed within this submission: The studies below were reviewed by Dr.
`Ed Fisher for NDAs 22—253, 22-254,
`-—"‘“
`or not deemed pivotal for this
`indication.
`
`M4)
`
`16
`
`

`

`'
`
`I
`
`v Page(s) Withheld
`
`__/Trade Secret/Confideritial (b4)
`Draft Labelirig (b4) -
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`Reviewer: BeLinda A. Hayes, PhD.
`
`NDA No. 22-284
`
`“(4)
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`
`Lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, is a member of a series
`of functional amino acids. The pharmacology of lacosamide has been well characterized
`using various in vitro and in vivo models. Lacosamide (10-100 uM) did not significantly
`bind to any of the extensive number of receptors, channels or enzymes tested, including
`targets that other drugs with anti-epileptic and analgesic activity bind to. Also,
`lacosamide does not modulate the uptake of neurotransmitters, norepinephrine, serotonin,
`and dopamine into synaptomes. Lacosamide does not bind to GABA transporters or
`influence the activity of GABA tranasaminases.
`
`18
`
`

`

`Reviewer: BeLinda A. Hayes= PhD.
`
`NDA No. K
`
`11(4)
`
`Lacosamide appears to have a dual mode of action. Lacosamide selectively enhances
`slow inactivation of voltage-gated sodium channels without affecting fast inactivation
`and interacts with collapsin response mediator protein 2 (CRMP-Z). Lacosamide-induced
`enhancement of slow inactivation of voltage-gated sodium channels rediuces the number
`of sodium channels available and subsequently reduces the excitability of neurons. By
`enhancing slow inactivation of voltage-gated sodium channels, lacosamide attenuates the
`excitability of neuron characteristic of both neuropathic pain and epilepsy. Radioligand
`study with CRMP-Z expressed in Xenopus oocytes showed that lacosamide binds to
`CRMP-Z with a binding affinity of 5 uM. The diagram below was reproduced from the
`Sponsor’s submission and Beyreutheuther et a1. 2007.
`
`
`
`massing:
`aifiétznfiwéaanm ,
`.
`
`
`Repotarizatian
`
`Exmgiwa‘éfii *3 '
`”W???“s :
`
`
`
`Lnené aneaiheéins
`
`Resting.
`membrane
`antenna:
`
`fiaazingg
`attain g
`
`
`depolarization
`
`
`Specific mngnlntinn at
`Reguiafina of
`pathophystntngicat
`senium Warrant
`inngfiarm avariabfiafiy measmma hyperactivity
`
`Fit}. 2. Physiology of mirage-gated sodium channels‘ Depending on the membrane potential and the neumaml
`activity voltage-gated sodium channels are in diffemnt statesx At the resting potential. Sfldillnl channels are closed
`and can be opened by depolarization of the membrane potenfini allowing the flux of sodium ions into the cell.
`Within a few milliseconds the channeis close from”; the inside of the neuron anti go into the fast inactivated state
`{mm which they cannot be activated. When the membrane potential returns to its baseline the sodium channel
`gees back to its resting state. Under candi'tians of slight prolonged depolarization and repetitive neuronal activity
`the sodium channel can go into the slow inactivated state by closing the pare from the insider This process happens
`on a “Granada-minute time scam. Drugs can either block the open channei (tag, ioeni anaesthetics}, or enhance-
`fast inactivation {classical ant‘iconwlsams} or enhance slow inactivation {:flacnsam'ide)‘
`
`19
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No. \-
`
`at“)
`
`2.6.2.2 Primary pharmacodynamics
`
`Mechanism of action:
`
`To characterize the mechanism of action, the Sponsor conducted radioligand binding,
`electrophysiological and neurotransmitter release studies. A series of in vitro radioligand
`studies were'conducted to evaluate the binding selectivity of lacosamide (SPM 927), at a
`concentration of 10 uM, on a Wide range of receptors found in the CNS. Results
`demonstrated that lacosamide did not bind with high affinity (i.e., less than 20% to 10%
`displacement of binding) to any of the following receptors sites from rodents, bovine,
`guinea pigs or humans: adenosine, adrenergic (0h, (12, B], B2) benzodiazepine,
`cannabinoid, dopamine, GABAA, GABAB glutamate, glycine (strychnine-sensitive,
`strychnine-insensitive), histamine (H1, H2, H3), opioid (5, K, u), muscarinic, (M1, M2, M3,
`M4, M5) and SCI‘OtOl’lll’l (5HT1A, 5-HT2A, 5-HTzc, 5-HTlB, 5-HT3, 5-HT5A, 5-HT6, 5-HT7)
`receptors. The results from these binding studies are summarized in the table below.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`20
`
`

`

`
`
`Reviewer: BeLinda A. Ha es Ph.D. ' r" [1(4) NDA No.
`
`
`
` Lacosamide SPM 927
`
`bindin on various rece
`
`Screenin_ Assa of SPM 927 Lacosamide Bindin_
`
`Ligand
`Neutrotransmitter
`Species
`Tissue
`% inhibition of
`
`Concentration
`Recetor
`bindin_ at 10 M
`
`CHO cells
`Human
`DPCX(1)
`Adenosine A,
`< 10%
`
`
`recombinant
`
`
`Human
`recombinant
`
`~
`
`HEK 293
`cells
`
`CG821680 (6) '
`
`< 10%
`
` Adenosine AZA
`
`
`
`Adenosine A;
`
`Adenosine
`
`Human
`recombinant
`
`HEK 293
`cells
`
`AB—MECA (0.1)
`
`< 10%
`
`NECA (4.0)
`
`520%
`
`Study Report/Title
`
`N9 817003/ Study of SPM
`927 in various receptor
`
`binding and functional
`
`
`monoamine uptake assays
`
`(non-GLP, March 2001)
`
`
`
`
`N2 A2/ Thirty-seven
`receptor binding assays
`
`(non-GLP, March 1995)
`
`
`N9 817003/ Study of SPM
`
`
`927 in various receptor
`
`
`binding and functional
`
`monoamine uptake assays
`
`
`(non-GLP, March 2001)
`
`
`
`
`Rat
`Adrenergicuhnon— -- Prazosin (0.25)
`selective
`cortex
`Adrenergicabnon-
`RX821002(0.5)
`selective
`,
`cortex
`
`Adrenergicm
`
`Adrenergicm
`
`Adrener icu]
`Adrenergicuz
`
`Adrenergicm
`
`recombinant
`
`CGP 12177 (0.15)
`
`< 10%
`CGP 1277 (0.15)
`Sf9 cells
`Human
` recombinant
`Rat
`Forebrain
`Prazosin (0.50
`S 20%
`S 20%
`RX821002 (1.0)
`
`cortex
`
`cortex
`
`Cerebral
`cortex
`Heart
`
`W
`
`Flunitrazepam
`(0.4
`PK 11195 (0.2)
`
`< 10%
`
`<10%
`
`<10%
`
`S 20%
`
`14%
`
`<10%
`
`E 20%
`
`< 10%
`
`A _. 0%
`
`<10%
`
`< 10%
`/\ H
`0%
`
`<10%
`14%
`
`<10%
`
`<10%
`
`<10%
`
`S 20%
`S 20%
`
`
`
`
`
`
`
`
`
`
`
`
`Benzodiazepine,
`central
`Benzodiazepine,
`peripheral
`
`Rat
`
`'
`
`
`N9 A2/ Thirty—seven
`
`receptor binding assays
`
`(non-GLP, March 1995)
`
`
`
`
`
`
`N2 817003/ Study of SPM
`927 in various receptor
`
`binding and fiinctional
`monoamine uptake assays
`(non-GLP, March 2001
`
`N9 A2/ Thirty-seven
`
`receptor binding assays
`(non-GLP, March 1995
`
`
`N2 817003/ Study of SPM
`
`
`927 in various receptor
`
`
`binding and functional
`monoamine uptake assays
`(non-GLP, March 2001)
`
`N.) 817003/ Study of SPM
`
`927 in various receptor
`
`
`
`binding and functional
`
`monoamine uptake assays
`
`
`
`(non-GLP, March 2001)
`
`
`
`
`
`
`
`N2 Az/Thirty-seven
`receptor binding assays
`(non-GL1), March 1995
`
`
`
`
`
`Benzodiazepine,
`central
`
`Bovine
`'
`
`Cerebral
`cortex
`
`Flunitrazepam
`(1.0)
`
`Cannabinoid CB1
`
`Cannabinoid CB2
`
`Dopamine, D1
`
`Doamine,D1
`Dopamine, D2
`
`Human
`recombinant
`Human
`recombinant
`
`Human
`recombinant
`
`Human
`recombinant
`
`HEK 293
`cells
`HEK 293
`cells
`
`WIN 55212-2
`
`WIN 55212-2
`
`L cells
`
`SCH 23390 (0.3)
`
`CHO Cells
`
`SCH 23390 0-3
`Spiperone
`
`Snierone
`
`recombinant
`
`recombinant
`
`recombinant
`
`recombinant
`
`Dopamine, D2
`
`Rat
`
`Striatum
`
`21
`
`
`
`SCH23390 (0.5)
`Sulpiride (3.0)
`
`

`

`
`
` Reviewer: BeLinda A. Ha es Ph.D. NDA No. —/
`
`11(4)
`
`
`
`
`
`Screening Assay of SPM 927 Lacosamide Bindin cont.
`
`
`Neurotransmitte
`Species
`Tissue
`Ligand
`
`
`r Rece-tor
`Concentration
`
`
`Study Report/Title
`
`
`
`
`
`
`
`N2 817003/ Study of SPM selective
`927 in various receptor
`GABAA
`
`(non—GLP, March 2001)
`NQAZ/Thirty-seven
`receptor binding assays
`(non-GLP, March 1995)
`
`
`
`
`
`
`
`
`
`
`
`N9 817003/ Study of SPM
`927 in various receptor
`binding and functional
`monoamine uptake assays
`(non-GLP, March 2001)
`
`channel)
`
`(AMPA)
`
`Glutamate
`(NMDA Agonist
`Site)
`Glutamate (PCP)
`
`
`
`
`
`N2 A2/ Thirty-seven
`receptor binding assays
`(non-GLP, March 1995)
`
`Glutamate
`(NMDA
`Glutamate (KA)
`Glutamate v
`(AMPA
`Glutamate (PCP)
`Glutamate
`(MK-801)
`N2 817003/ Study of SPM Glycine,
`927 in various receptor
`Strychnine-
`binding and functional
`sensitive
`monoamine uptake assays
`Glycinie,
`
`
`
`
`
`-
`
`
`
`
`N2 A2/ Thirty—seven
`receptor binding assays
`(non-GLP, March 1995)
`
`
`N2 817003/ Study of SPM
`
`
`927 in various receptor
`binding and functional
`
`monoamine uptake assays
`(non—GLP, March 2001)
`
`
`N2 817003/ Study of SPM
`
`927 in various receptor
`binding and functional
`monoamine uptake assays
`(non-GLP, March 2001)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`927 in various receptor
`
`
`
`monoamine uptake assays
`(non-GLP, March 2001)
`
`insensitive
`
`Glycine,
`Strychnine-
`sensitive
`
`Glycinie,
`Strychnine-
`insensitive
`
`(central
`
`
`
`
`
`
`
`
`
`
`
`
`
`% inhibition of
`bindin at 10 M
`
`cortex
`Cerebral
`
`Muscimol (5.0)
`
`< 10%
`
`cortex
`Cerebral
`cortex
`Cerebral
`cortex
`
`Cortex
`Cerebral
`cortex
`
`Cerebral
`cortex
`
`GABA(5.0)
`
`GABA/isoguavacine
`(5.0
`
`Kainic acid (5.0)
`
`CGP 39653 (5.0)
`
`
`
`Cerebral
`cortex
`
`TCP (5.0)
`
`Forebrain
`
`CGP 39653 (1.0)
`
`'
`Forebrain
`
`Kainicacid<10.0)
`AMPA (5.0)
`'
`
`TCP(10.0
`Forebrain
`Forebrain MK-801 (2.60)
`
`10%
`
`< 10%
`
`S 20%
`
`E 20%
`
`Spinal
`Cord
`
`Strychnine (2)
`
`< 10%
`
`Cerebral
`
`MDL 105,519
`
`< 10%
`
`Strychnine (16.0)
`
`S 20%
`
`Glycine (10.0)
`
`S 20%
`
`Spinal
`Cord
`
`Cerebral
`cortex
`
`m m
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`Rat
`
`.
`
`V
`
`Cortex
`
`(0.5)
`
`‘
`
`recombinant
`
`cells
`
`recombinant
`
`cells
`
`M4, M5
`
`recombinant
`
`cells
`
`recombinant
`
`cella
`recombinant
`Nociceptin (0.20)
`HEK-293
`Human
`recombinant
`
`
`22
`
`

`

`
`
`NDA No. ~Reviewer: BeLinda A. Ha es Ph.D. ”(41
`
`
`
`
`
`
`
`
`
`
`N9 817003/ Study of SPM
`927 in various receptor
`binding and functional
`monoamine uptake assays
`(non-GL1), March 2001)
`
`Purinergic P2X
`
`Purinergic P2Y
`'
`
`
`
`
`
`Rat
`
`
`
`
`
`
`Rat
`
`urinary
`bladder
`
`Brain
`
`Serotonin 5-HT
`
`Rat
`
`Serotonin 5-HT1A
`
`Human
`recombinant
`
`Serotonin 5—HTlB
`
`Rat
`
`Cerebral
`Cortex
`CHO
`cells
`
`Cerebral
`
`
`
`N2 817003/ Study of SPM
`927 in various receptor
`binding and functional
`monoamine uptake assays
`(non-GLP, March 2001)
`
`
`
`
`
`
`
`
`
`
`
`N9 A2/ Thirty-seven
`
`
`receptor binding assays
`
`
`(non-GLP, March 1995)
`
`
`N9 817003/ Study of SPM
`
`
`927 in various receptor
`
`binding and fimctional
`
`
`monoamine uptake assays
`(non-GLP, March 2001)
`
`
`
`0L, B-MeATP (3.0)
`
`
`
`WW
`
`Serotonin (2.0)
`
`8-OH-DPAT (0.30)
`
`14%
`
`CYP (0.10)
`
`Ketanserin (2.0)
`
`< 10%
`
`Mesulergine (0.70)
`
`< 10%
`
`Serotonin 5-HT2A
`
`Serotonin 5-HT2C
`
`Serotonin 5 HT3
`
`Serotonin 5 HT”
`
`Serotonin 5—HT6
`
`Serotonin 5—HT7
`
`Serotonin 5-HT]
`
`Serotonin 5-HT]
`
`Human
`recombinant
`
`Human
`recombinant
`
`Human
`recombinant
`
`Human
`recombinant
`
`Human
`recombinant
`
`Human
`recombinant
`Rat
`
`Rat
`
`Rat
`
`
`
`
`
`cells
`
`000IIE00%
`
`cells
`
`HEK—293
`
`BRL 43694 (0.50)
`
`16%
`
`HEK—293
`
`HEK-293
`
`CHO
`cells
`
`LSD (1.0)
`
`LSD (2.0)
`
`LSD (4.0)
`
`Cerebral
`
`Serotonin (3.0)
`
`< 10%
`
`< 10%
`
`17%
`
`Cerebrak
`
`OOoo3:1('D(D><><
`
`Cerebral
`Cortex
`Cerebral
`Cortex
`Cerebral
`Cortex
`
`Ketanserin (1.0)
`
`S 20%
`
`
`
`
`
`
`
`
`
`
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`23
`
`

`

`.
`.
`Rev1ewer: BeLmda A. Hayes, PhD.
`
`_
`
`3(4)
`
`NDA No.
`
`
`
`The Sponsor submitted several pharmacology studies that used isolated receptors to
`evaluate the binding affinity of lacosamide and its metabolite SPM 12809 on
`neurotransmitter transporters. In vitro studies have indicated that lacosamide does not
`bind to transporters. At a concentration of 10 uM or 100 uM, no significant inhibition (<
`30%) of control specific binding occurred on the dopamine, norepinephrine, GABA, and
`serotonin transporters. The major metabolite SPM 12809 (100 uM), also did not display
`specific binding to these transporters. Consistent with the radioligand binding studies, in
`vitro studies using rat synaptosomes revealed that lacosamide (10 uM) did not inhibit
`neurotransmitter uptake mechanisms for dopamine, norepinephrine, serotonin, or GABA.
`Nor did lacosamide inhibit GABA transaminase.
`
`Lacosamide bindin to trans orters
`
`
`
`
` to transporters
`Effects of lacosamide 10 M on s-ecific radioligan bindin_
`
`
`
`
`Transporter
`Species
`% inhibition
`Study Report/Title
`Ligand
`
`
`
`
`
`
`(ConcentratigL
`of binding
`
`
`
`
`
`
`
`CHO cells
`GBR12935 (0.50)
`< 10%
`N9 817003/ Study of
`Dopamine
`Human
`recombinant
`SPM 927 in various
`
`
`
`receptor binding and
`
`
`functional monoamine
`
`
`uptake assays (non-GLP,
`
`
`
`March 2001)
`
`
` Rat
`Cerebral Cortex
`N9 817003/ Study of
`
`
`Norepinephrine
`
`Nisoxetine (1.0)
`
`
`
`SPM 927 in various
`Human
`MDCK cells
`
`
`Norepinephrine
`Nisoxetine (0.3)
`< 10%
`
`
`
`recombinant
`receptor binding and
`
`
`
`functional monoamine
`
`
`uptake assays (non-GLP,
`
`
`March 2001)
`
`
`
`
` Tissues
`
`% inhibition
`Ligand
`Transporter
`
`
`
`N9 817003/ Study of
`(Concentration)
`of binding
`
`
`SPM 927 in various
`
`
`receptor binding and
`
`functional monoamine
`
`uptake assays (non-GLP,
`
`
`March 2001)
`s natosomes
`
`
`
`
`
`
`
`
`Lacosamide SPM 927 and SPM 12809 bindin_ to neurotranmitter transorters
`
`
`
`
`
`
`'
`Effects of SPM 927 100 M and SPM 12809 100 M on s-ecific radioli_and bindin_ to transorters
`'
`1
`
`Study Report/Title
`Transporter
`Species
`Tissue
`Ligand
`% inhibition of
`
`
`
`
`
`Concentration
`bindin
`-
`Human
`Serotonin
`
`
`
`
`
`Imipramine (2.0)
`SPM 927: -5%
`HEK-293
`
`N9 10263/ In vivo
`recombinant
`cells
`
`
`
`
`SPM 12809: -1%
`
`pharmacology — Receptor
`
`
`Human
`HEK-293
`SPM 927: 28%
`binding assay with SPM 927
`Dopamine
`BTCP (4.0)
`
`
`
`
`
`
`
`recombinant
`cells
`and SPM 12809 (non-GLP,
`
`
`
`
`
`
`
`August 2005)
`SPM 12809: 29%
`
`
`
`
`Human
`HEK-293
`SPM 927: 16%
`
`Norephrine
`Nisoxetine (1 .0)
`
`
`
`
`recombinant
`cells
`
`
`
`N9 6065/ In Vitro
`
`
`
`GABA ( 10.0) +
`pharmacology — Study of SPM
`isoguvacine (10 uM) +
`
`
`
`927 (non-GLP, September
`baclofen (10 pM)
`
`2002
`‘
`
`
`
`s na-tosomes
`
`Striatum
`
`s naotosomes
`
`”15““sz
`
`
`
`24
`
`
`
`SPM 12809: 16%
`-7%
`
`

`

`
`
`Reviewer: BeLinda A. Ha es Ph.D. b“) NDA No. H
`
`
`
`
`
`
`
`
`The Sponsor has conducted several pharmacology studies to evaluate the effects of
`lacosamide on voltage-gated sodium channels and potassium conductance. Briefly, these
`studies showed that lacosamide modulates sodium channels by selectively enhancing
`sodium channel slow inactivation without effect on fast inactivation. These data are
`summarized in the following table.
`
`
`'Stud Ne/Title '
`
`
`Stud Assa
`‘
`Stu—dLOutcomes
`-
`N2 041012
`
`
`Radioligand binding assay: CRMP—2
`CRMP-2 transfected Xenopus oocytes possess a
`
`transfected Xenopus oocytes
`binding site for lacosamide with a Kd value ofM.
`
`
`
`Errington, 2006
`Cultured cortical neurons
`Lacosamide produced a significant reduction in the
`
`rate of incidence of both sIPSC (Control: 104.7 i
`
`5.3%, LCM:24.9 i 9.6%, P < 0.01, paired t test, n = 4)
`
`and sEPSC’s (Control: 127.5 in 16.9%,LCM: 46.1 i
`15.5%, P < 0.01, n = 4)
`
`
`Concentration-dependent reduction of number of
`
`s ontaneously arisin action otential
`ICSO = 61 M
`
`
`Rat cortical neurons
` Errington, 2006
`Lacosamide reduced firing induced by slow (epilepsy-
`
`
`
`like , bit not fast voltage
`
`
`
` Errington, 2006
`Mouse N1E-1 15 neuroblastoma cells
`Lacosamide did not show recovery from fast
`
`inactivation.
`
`
`
`
`
`
`Lacosamide in a concentration-dependent fashion
`enhanced the entry of voltage-gated sodium channels
`into the slow inactivated state and shifted V50 of
`steady state slow inactivation to more hyperpolarized
`potentials.
`
`
`
`
`
`
`
`Lacosamide did not affect recovery from slow
`
`. inactivation.
` Errington, 2006
`
`Xenopus oocytes expressing rat type 11
`
`At 320 uM, lacosamide shified the V50 of steady stated
`
`
`sodium channel (ct-subunit).
`slow inactivation from -43 mflcontrol) to -58 mV.
`
` F-993 8
`
`Chinese hamster ovary cells expressing
`Lacosamide enhanced the maximum probability and
`
`rat type 11 sodium channel (oz—subunit).
`shifted the V50 of steady state slow inactivation of
`
`sodium channels without the effect on fast
`
`
`inactivation.
`
`Lacosamide had no effect on fast or slow inactivation
`Xenopus oocytes expressing the a—subunit
`
`
`of the human skeletal sodium channel
`of NaV 1.4 up to 700 uM.
`
`isoform Nav 1.4
`
`
`
`
`Drug activity related to proposed indication:
`
`////
`
`0(4)
`
`25
`
`

`

`
`
` Reviewer: BeLinda A. Ha es PhD. NDA No —\
`
`[3(4)
`
`/// //
`
`2.6.2.3 Secondary pharmacodynamics
`
`Nonclinical studies have demonstrated that lacosamide is an effective anticonvulsant in
`
`various animal models of epilepsy. Lacosamide demonstrated effectiveness in the
`genetically susceptible Frings mouse, seizures induced in the maximal electroshock
`(MES) test in rats and mice or kindled seizures in the rat hippocampal kindling model of
`partial epilepsy and psychomotor seizures in the mouse 6 Hz model of partial seizures.
`Effective doses in the MES test (rats 4.5 mg/kg ip, mice 3.9 mg/kg ip) are in a range
`similar to that reported for other anticonvulsant drugs. Lacosamide at 4.5 mg/kg, i.e., the
`ED50 for the MES test, significantly elevated the seizure threshold in the intravenous
`pentylenetetrazole (PTZ) seizure test. It inhibited NMDA-induced seizures and was
`effective in the homocysteine model of epilepsy. Also, it attenuated kindling
`development in the amygdala kindling model of epileptogenesis.
`
`2.6.2.4 Safety pharmacology
`
`Neurological effects: The neurological effects of lacosamide (SPM 927, ADD 23407)
`were characterized in several studies. A summary of these studies is discussed below.
`
`Study Report N2 0200XH15.001 (non—GLP compliant). Neuropharmacological profile
`(NPP) in mice.
`'
`
`The neuropharmacological profile of lacosamide (10 mg/kg, i.p.) was characterized in
`CD—1 mice (n = 10). The mice were observed for noticeable neuropharmacological signs
`at 15, 30, and 45 minutes and 1, 2, 3, 4, and 24 hours after dosing. Body temperature was
`measured 60-minutes post-dosing. Lacosamide did not produce any apparent
`neuropharmacological signs or effects on body temperature.
`
`Study Report N2 D00.271/2/A (non-GLP compliant).
`
`The neurobehavioral effects of lacosamide were assessed in rodents in the modified Irwin
`
`test. Rats were dosed orally (gavage) with 25, 50 or 75 mg/kg of lacosamide. Battery of
`neurological parameters examined included: behavioral reactions, motor activity, central
`excitation, posture, muscle tone, reflexes and autonomic profile. Behavioral parameters
`were assessed immediately before and at l, 2, 3, 4, 6 and 24 hours after treatment.
`
`The motor effects of lacosamide were evaluated in mice and rats following oral and
`intraperitoneal administration in the rotarod test. For intraperitoneal administration male
`
`26
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No. /
`
`11(4)
`
`mice (n = 10/group) and rats (n= 10/group) were treated with a single of 0, 8 16, and 32
`mg/kg of lacosamide. The doses tested for oral administration were 0, 32, 64, and 128
`mg/kg. Motor coordination was measured by the number of animals falling off a rotating
`rod and the time to falling off the rod.
`
`Lacosamide impaired motor coordination in mice and rats following both intraperitoneal
`and oral routes of administration. A dose-dependent impairment in rotarod performance
`was observed in both species. At the highest dose (32 mg/kg) administered i.p., all mice
`fell off the rod compared to 1 out of 10 in the vehicle group. The time to falling was
`reduced from 162.9 d: 17.1 seconds in the vehicle group to 16.9 i 5.9 seconds in the high
`dose group. Compared to the vehicle group (5/ 10), the number of rats falling after the
`high—dose of lacosamide was 9/10; the time to fall was reduced from 123.9 :t 19.4
`seconds to 53.6 i219 seconds.
`
`Afier oral administration of lacosamide, a dose-dependent decrease in the time to fall off
`the rotator rod was noted. Significant impairment was observed in mice at a doses of 64
`(50.9 seconds vs 136.4 seconds for control) and 128 (28.3 seconds vs 136.4 seconds for
`control) mg/kg. In rats, a significant effect was observed at a dose of 128 mg/kg (59.4
`sec vs 140.8 seconds for control).
`
`The Irwin test was performed in mice and rats to evaluate the effects of lacosamide on
`behavior, physiological functions and signs of neurotoxicty following oral and
`intraperitoneal.administration. For intraperitoneal administration male mice (n =
`3/group) and rats (n= 3/group) were treated with a single dose of 4, 8, 16, 32, and 64
`mg/kg and 4, 8, 16, 32, 64 and 128 mg/kg of lacosamide, respectively. Rats were tested
`with lacosamide orally at doses of 8, 16, 32, 64, 128 and 256 mg/kg. As depicted in the
`Sponsor’s tables reproduced below, lacosamide produced qualitatively similar effects in
`both mice and rats. These effects included dose-dependent sedation with signs of
`sensorimotor deficit, abnormal gait, tremors (high dose) and hypothermia. No lethality
`was observed up to the highest doses tested.
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`27
`
`

`

`83(4) Reviewer: BeLinda A. Ha es Ph.D.
`
`NDA N0. —-—e
`
`Lacosamide effects on the primary observations of the Irwin Test in mice following
`intraperitonteal administration.
`
`
`
`
`
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