June 2010 Vol. 11 No.9
`
`rt opinion on pharmacotherapy.
`11, no. 9 (June 201 0)
`neral Collection
`EX52ML
`10-06-24 13:35:41
`
`on Pharmacotherapy
`
`EDITORIAL
`~ \ T;eatmen't ~rategies in urticari~ :;
`Luqi,ia· ~Fa~:n'iw~rcusMaurer & Torsten Zubcubier
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`Mtirial~ocorrcfH Fonto~ni, CesarAAraujcrNeto, StiniJraCSAtldrade, Rosa v Brim>· ..
`Adriana R>Matutino, Carofi~a c'$iiva]" Milena· C Santana: Mona lisa Nobre-Bastos,
`.
`Felipe (Jiiv_elr<J, Bruna B Barreio; _PabloM simtos;. LUcia Nobfat;·Maria-Regina A Cardoso;· :. .
`: •• ~
`: .•
`: <
`_,·
`· _
`·.
`·.
`·.··
`_
`·.·
`·CristianaMNascimento-Carvatho
`• Role of aspirin in the primary prevention of cardi.ovascular disease in diabetes mellitus: a meta-analysis
`~,
`NaveMYounis, Steven Williams, BasiiAmmori & Handrean Soran
`. ,;-
`REVIEWS
`Phamiacotherapy of neuroblastoma
`Rani E George, Lisa Differ & Mark L Bernstein
`Is there a role for anticoagulants in portal vein thrombosis management in cirrhotic patients?·
`Francesca· Rom ana Ponziani, Maria Assunta Zocco, Anna/isa Tortora.& Antonio Gasbarrini ..
`Transdermal menopausal hormone thenipy: delivery through skin changes the rules
`John E Buster
`Amyloidosis and POEMS syndrome
`Cheng E Chee, Angela Dispenzieri & Morie A Gertz
`Treating skin cancer with topical cream
`Giuseppe Micafi, Francesco Lacarrubba, Franco Dinotta, Doriana Massimino & Maria Rita Nasca
`Treating hypogonadism in younger males
`Anthony Yin & Ronald Swerdloff
`Evolving drugs in gastroesophageal reflux disease: pharmacologic treatment beyond proton pump
`inhibitors
`David A Johnson & Benjamin H Levy /II
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`'Gorti'e!P;. Kruin H •. DaVidson MH,scl'iwarz.~R
`Re~~f. Endocrine &Metabolic"
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`i Davidson MH
`·
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`! Oncologic
`Mon~emurro F, Tonini G, TheoharideSTC:
`
`ExP.ert
`Opinion on Pharmacotherapy
`
`Aims and scope
`Expert Opinion on Pharmacotherapy is a MEDLINE-indexed, peer-reviewed, international
`journal publishing review articles and original papers on newly approved/near to launch compounds,
`providing expert opinion on the likely impact of these new agents on existing pharmacotherapy of
`specific diseases.
`
`The Editors welcome:
`• Reviews covering new drugs/drug classes for specific diseases, from development Phase Ill to
`those that have been available to pharmacopoeia for up to 5 years, and their potential impact on
`future treatment strategies
`• Drug Evaluations reviewing the clinical and pharmacological data on a particular drug
`• Original Research papers reporting the results of clinical investigations on agents that are in
`Phase Ill and IV clinical trials and pharmacologically based studies with a strong link to
`clinical practice
`
`The audience consists of research and development, regulatory and marketing decision makers in
`the pharmaceutical industry and decision makers in healthcare provision.
`
`Editorial policy
`Articles published in Expert Opinion on Pharmacotherapy are commissioned by the
`Commissioning Editor in collaboration with the Editorial Board. Authors who wish to
`contribute should contact the Commissioning Editor. All reviews and drug evaluations are
`subject to anonymous peer-review.
`
`Editorial boards
`The Editorial Board is composed of senior scientists involved in drug research and
`development. The Board are responsible for selecting authors and topics for review to
`ensure comprehensive coverage of subjects in each therapeutic area.
`
`Citations
`Expert Opinion on Pharmacotherapy is indexed by:
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`Conditions of sale- Expert Opinion on Pharmacotherapy may be circulated only to those
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`Readers are reminded that, under internationally agreed copyright legislation,
`photocopying of copyright materials is prohibited other than on a limited basis for personal
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`Pharmacotherapy is a breach of the law and can lead to prosecution.
`Whilst every effort is made by the publishers and the advisory board to ensure that no
`inaccurate or misleading data, opinions or statements appear in this journal, they wish to
`make it clear that the data and opinions appearing herein are the responsibility of the
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`respective employees, officers and agents accept no liability whatsoever for the
`consequences of any inaccurate or misleading data, opinions or statements. Approved
`product information should always be reviewed prior to prescribing.
`
`2010 © lnforma UK Ltd ISSN 1465-6566
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2121 - 2/11
`
`

`
`Drug Evaluation
`
`Lacosamide: new adjunctive
`'treatment option for partial-onset
`seizures
`
`Steve S Chung
`Barrow Neurological Institute, St. joseph's Hospital and Medical Center, Department of Neurology,
`Phoenix, Arizona, USA
`
`Importance of the field: Epilepsy is one of the most common neurological
`disorders, affecting up to 2% of the population worldwide. Studies show
`that patients with refractory seizures have higher morbidity and mortality
`rates, as well as a poorer quality of life, than those with controlled seizures.
`Therefore, treatment that reduces the frequency of seizures may improve
`patients' quality of life. Lacosamide (LCM) is a recently approved anticonvul(cid:173)
`sant in Europe and the USA which offers new mechanisms of action and favor(cid:173)
`able safety profiles. Efficacy data have shown fast onset of anticonvulsant
`effects and significant reduction of partial-onset seizures as adjunctive
`therapy at LCM 200 and 400 mg/day, even in a severely refractory population.
`Areas covered in this review: This article reviews three pivotal clinical trials of
`LCM, including its efficacy and tolerability over 7 years. In addition, LCM's key
`pharmacodynamics and pharmacokinetics from a search of the literature are
`reviewed in detail. This article also includes recent publications on the safety
`and use of intravenous LCM solution for patients with epilepsy.
`What the reader will gain: This article provides comprehensive review of effi(cid:173)
`cacy and safety information of LCM along with comprehensive pharmacoki(cid:173)
`low protein
`netic information, which includes absolute bioavailability,
`binding, lack of hepatic enzyme induction or inhibition, and low potential
`for drug-drug interactions.
`Take home message: Considering the fact that more than 30% of epilepsy
`patients remain refractory despite various antiepileptic drugs, LCM may
`provide added benefit to patients with refractory seizures.
`
`Keywords: lacosamide, new anticonvulsant, partial seizures, slow inactivation, sodium channels,
`Vim par
`
`Expert Opin. Pharmacother. (2010) 11(9):1595-1602
`
`1. Introduction
`
`Epilepsy is one of the most common neurological disorders affecting up to 2% of
`the population worldwide, and almost 2 million people in the USA alone [1]. Treat(cid:173)
`ment of epilepsy often imposes an exposure to various antiepileptic drugs (AEDs)
`and requires long-term commitment and compliance from the patient [2]! Exdudirtg
`the small percentage of people who have undergone successful epilepsy surgery, the
`vast majority of patients are maintained through chronic medical management for
`appropriate seizure control. Despite the advent of new AEDs over the past 15 years,
`- 30% of epilepsy patients still experience recurrent seizures and many experience
`undesirable side effects [3,4]. Therefore, there are still unmet needs for the treatment
`of epilepsy and there remains a need to develop new AEDs that could reduce seizure
`frequency and severity as well as improve tolerability and safety.
`
`10.1517/14656566.2010.488639 © 2010 lnforma UK Ltd ISSN 1465-6566
`All rights reserved: reproduction in whole or in part not permitted
`
`1595
`
`intortna
`
`healthcare
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2121 - 3/11
`
`

`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Introduction
`
`Lacosamide
`
`Pharmacodynamics
`
`Pharmacokinetics and
`metabolism
`
`Clinical efficacy
`
`Safety and tolerability
`
`Regulatory affairs
`
`Conclusion
`
`Expert opinion
`
`Drug Evaluation
`
`Lacosamide: new adjunctive
`treatment option for partial-onset
`seizures
`
`Steve S Chung
`Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Department of Neurology,
`Phoenix, Arizona, USA
`
`Importance of the field: Epilepsy is one of the most common neurological
`disorders, affecting up to 2% of the population worldwide. Studies show
`that patients with refractory seizures have higher morbidity and mortality
`rates, as well as a poorer quality of life, than those with controlled seizures.
`Therefore, treatment that reduces the frequency of seizures may improve
`patients’ quality of life. Lacosamide (LCM) is a recently approved anticonvul-
`sant in Europe and the USA which offers new mechanisms of action and favor-
`able safety profiles. Efficacy data have shown fast onset of anticonvulsant
`effects and significant reduction of partial-onset seizures as adjunctive
`therapy at LCM 200 and 400 mg/day, even in a severely refractory population.
`Areas covered in this review: This article reviews three pivotal clinical trials of
`LCM, including its efficacy and tolerability over 7 years. In addition, LCM’s key
`pharmacodynamics and pharmacokinetics from a search of the literature are
`reviewed in detail. This article also includes recent publications on the safety
`and use of intravenous LCM solution for patients with epilepsy.
`What the reader will gain: This article provides comprehensive review of effi-
`cacy and safety information of LCM along with comprehensive pharmacoki-
`netic information, which includes absolute bioavailability,
`low protein
`binding, lack of hepatic enzyme induction or inhibition, and low potential
`for drug-drug interactions.
`Take home message: Considering the fact that more than 30% of epilepsy
`patients remain refractory despite various antiepileptic drugs, LCM may
`provide added benefit to patients with refractory seizures.
`
`Keywords: lacosamide, new anticonvulsant, partial seizures, slow inactivation, sodium channels,
`Vimpat
`
`Expert Opin. Pharmacother. (2010) 11(9):1595-1602
`
`1. Introduction
`
`Epilepsy is one of the most common neurological disorders affecting up to 2% of
`the population worldwide, and almost 2 million people in the USA alone [1]. Treat-
`ment of epilepsy often imposes an exposure to various antiepileptic drugs (AEDs)
`and requires long-term commitment and compliance from the patient [2]. Excluding
`the small percentage of people who have undergone successful epilepsy surgery, the
`vast majority of patients are maintained through chronic medical management for
`appropriate seizure control. Despite the advent of new AEDs over the past 15 years,
`~ 30% of epilepsy patients still experience recurrent seizures and many experience
`undesirable side effects [3,4]. Therefore, there are still unmet needs for the treatment
`of epilepsy and there remains a need to develop new AEDs that could reduce seizure
`frequency and severity as well as improve tolerability and safety.
`
`10.1517/14656566.2010.488639 © 2010 Informa UK Ltd ISSN 1465-6566
`All rights reserved: reproduction in whole or in part not permitted
`
`1595
`
`Expert Opin. Pharmacother. Downloaded from informahealthcare.com by NIH Pathology Lab on 03/10/14
`
`For personal use only.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2121 - 4/11
`
`

`
`ethosuximaide (250 mg/kg) [7]. However, LCM was inactive
`against
`clonic
`seizures
`induced by pentylenetetrazole
`~ 25 mg/kg), bicuculline (EC50 > 50 mg/kg) or picro-
`(EC50
`toxin (EC50 > 30 mg/kg) in rodents [7,8]. LCM was effective
`in a homocystein-cobalt-induced status epilepticus model,
`stopping limbic seizures induced by self-sustaining status
`epilepticus in rats within 15 min of administration and
`preventing their recurrence over the following 24 h [7].
`The precise mechanisms by which LCM exerts its antiepi-
`leptic effect in humans are not fully understood, but a new
`mode of action has been suggested. LCM selectively enhances
`slow inactivation of voltage-dependent
`sodium channels
`(VGSCs) without affecting fast inactivation, which may nor-
`malize neuronal firing thresholds (Table 1) [10]. VGSCs con-
`trol sodium ion influx across the cell membranes and can
`adopt different conformational states in response to changes
`in membrane potential. When depolarized from their resting
`state, VGSCs open to allow the influx of sodium ions into
`the cell, which then generate the action potential. Following
`depolarization, VGSCs change to a ‘fast inactivated state’
`over milliseconds before reverting back to the resting state.
`However, when neurons are firing rapidly and repetitively,
`VGSCs may undergo a ‘slow inactivated state’
`through
`structural or conformational rearrangement of the sodium
`channel pore, which develops over several seconds. Unlike
`other classical AEDs such as carbamazepine, phenytoin and
`lamotrigine, which act on fast inactivation of VGSCs, LCM
`selectively enhances the slow inactivated state of VGSCs,
`which promotes the inhibition of sustained repetitive firing
`of neurons [10]. In preclinical experiments, lacosamide has
`also been shown to bind to collapsin response mediator
`protein 2 (CRMP-2), which is involved in neuronal differen-
`tiation, regulation of gene expression, polarization and axonal
`outgrowth [7]. The role of CRMP-2 binding in seizure
`control is unknown at this time, but it may be a factor in
`the disease-modifying potential of LCM.
`
`4. Pharmacokinetics and metabolism
`
`LCM has a linear pharmacokinetic profile with high oral bio-
`availability [11]. Studies in healthy volunteers have demon-
`strated that LCM is rapidly and completely absorbed [12-14].
`The rate and extent of absorption are not affected by the pres-
`ence of food [12]. Following oral intake of LCM, peak serum
`concentrations occur within 1 -- 4 h, and the elimination
`half-life is ~ 13 h [6,12,15]. LCM has low plasma protein bind-
`ing (£ 15%) and the volume of distribution is ~ 0.6 liters/kg,
`which is similar to body water [14]. The pharmacokinetics of
`both oral and intravenous LCM are dose-proportional
`(up to 800 mg), with low intra- and inter-subject variability.
`Following twice-daily administration of oral LCM, steady-
`state plasma concentrations are reached after 3 days. The
`low protein binding of LCM minimizes the potential for
`displacement of other drugs [16] and, thus, low potential for
`drug--drug interactions. In addition, LCM has minimal
`
`Lacosamide
`
`Box 1. Drug summary.
`
`Lacosamide
`Launched
`Epilepsy, partial (focal, local)
`Voltage-gated sodium channel inhibitor
`Collapsin-response mediator
`protein 2 binding
`Alimentary, p.o.
`Parenteral, intravenous
`OCH3
`
`HN
`
`NH
`
`O
`
`Drug name
`Phase
`Indications
`Pharmacology
`description
`
`Route of
`administration
`Chemical
`structure
`
`Pivotal
`trial(s)
`
`O
`Phase II: SP667 (Ben-Manachem)
`Phase III: SP754 (Chung)
`Phase III: SP755 (Halasz)
`
`Pharmaprojects -- Copyright to Citeline Drug Intelligence (an
`Informa business).Readers are referred to Pipeline (http://informa-
`pipeline.citeline.com) and Citeline (http://informa.citeline.com).
`
`2. Lacosamide
`
`(R)-2-acetamido-N-benzyl-3-
`Lacosamide (LCM; Box 1),
`methoxypropionamide, previously known as harkoseride or
`SPM 927,
`is a functionalized amino acid with a novel
`anticonvulsant activity [5-7]. Its chemical structure is shown
`in Box 1. Based on the efficacy and therapeutic index observed
`in a range of animal models of epilepsy at the National Insti-
`tutes of Health (NIH) Anticonvulsant Screening Program,
`LCM was subsequently developed as an AED for both oral
`and intravenous use. LCM has been approved as an adjunctive
`treatment for partial-onset seizures in patients aged ‡ 16 years
`by the European Commission (August 2008) and in patients
`aged ‡ 17 years by the FDA (October 2008).
`
`3. Pharmacodynamics
`
`LCM has demonstrated potent anticonvulsant activity in a
`broad range of
`animal models of partial onset
`and
`pharmaco-resistant seizures, generalized tonic-clonic seizures,
`as well as status epilepticus. Intraperitoneal LCM was effective
`in preventing seizures in the 6-Hz psychomotor seizure model
`(ED50 9.99 mg/kg) and the audiogenic seizure model (ED50
`0.63 mg/kg). LCM 20 and 50 mg/kg completely prevented
`tonic convulsions
`induced by maximal electroconvulsive
`shock (MES), and 50 mg/kg provided partial protection
`against clonic convulsions induced by NMDA in mice [7,8].
`LCM has also been effective in amygdala and hippocampal
`the
`kindling models [8,9]. In hippocampal kindling rats,
`activity of LCM (25 mg/kg) was
`superior
`to that of
`maximally effective doses of phenytoin (150 mg/kg),
`carbamazepine (50 mg/kg), valproic acid (250 mg/kg) and
`
`1596
`
`Expert Opin. Pharmacother. (2010) 11(9)
`
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`
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`
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`RCT EX. 2121 - 5/11
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`

`
`Table 1. Main properties of lacosamide.
`
`Indications
`
`Approval status
`Mode of action
`
`Starting dose
`Therapeutic dose
`Dosing schedule
`Half-life (h)
`Time to Cmax (h)
`Oral bioavailability (%)
`Protein binding (%)
`
`Adjunctive therapy for
`partial seizures ($ 16 years)
`
`Approved by both EMEA and FDA
`Selective enhancement of
`slow inactivation of
`voltage-gated
`sodium channels
`100 mg/day
`200 -- 400 mg/day
`b.i.d.
`13
`1 -- 4
`~ 100
`< 15
`
`interaction with CYP-450 isoforms [17,18], making an effect on
`the metabolism of other drugs unlikely. Specific drug-
`interaction studies involving carbamazepine, valproic acid,
`omeprazole, metformin, digoxin and an oral contraceptive
`(ethinylestradiol and levonorgestrel) demonstrated no relevant
`interactions
`influence on the pharmacokinetics of
`these
`drugs or LCM [16,19]. However, in clinical efficacy and safety
`trials, LCM plasma concentration showed small reductions
`(15 -- 20%) when coadministered with carbamazepine,
`phenytoin or phenobarbital [17,18].
`LCM intravenous solution is typically administered over
`30 min and the Cmax is reached at the end of infusion. Studies
`in healthy volunteers demonstrate bioequivalence for Cmax
`and AUC for both the 30- and 60-min infusion durations [20].
`Infusion over 15 min was near bioequivalent, with a slightly
`higher Cmax and equivalence for AUC [21].
`Lacosamide is primarily eliminated renally as unchanged
`drug (> 40%) and an inactive metabolite, O-desmethyl
`metabolite (< 30%) [6,11,15]. In subjects with moderate hepatic
`impairment, LCM should be titrated with caution as
`an ~ 50 -- 60% higher plasma concentration of LCM has
`been seen. The recommended maximal dose of for patients
`with mild or moderate hepatic impairment is 300 mg/day
`[17,18]. For patients with severe renal
`impairment (creati-
`nine clearance of £ 30 ml/min) and in patients with end-
`stage renal disease, a maximum dose of 300 mg/day is
`recommended [17,18].
`
`5. Clinical efficacy
`
`Three pivotal studies (one Phase II and two Phase III studies)
`have been conducted to establish the efficacy and safety of
`LCM [22-24] (see Figure 1). The primary assessment of efficacy
`was based on the change in partial-onset seizure frequency and
`was evaluated in two ways: i) the change in seizure frequency
`per 28 days from baseline to the maintenance period; and
`ii) the proportion of patients who experienced a ‡ 50%
`reduction in seizure frequency from baseline to maintenance
`
`Chung
`
`period (50% responder rate). The primary efficacy analysis
`was conducted on the intent-to-treat (ITT) population, which
`is defined as all randomized patients who received at least
`one dose of
`the trial medication and had at
`least one
`post-baseline efficacy assessment.
`In the Phase II study [22], three doses of LCM (200,
`400 and 600 mg/day) were administered as adjunctive therapy
`for patients with partial epilepsy with or without secondary
`generalization (n = 418), with a starting dosage of 100 mg/day,
`followed by a weekly increase of 100 mg/day to the target
`dose. The titration phase was followed by a 12-week mainte-
`nance phase with an option for continued open-label treatment.
`Most patients in the study (84%) were taking two antiepileptic
`agents when LCM therapy was added, and the rest were taking
`one other agent when LCM was added. Despite treatment
`with one or two concomitant AEDs, the median seizure
`frequency per 28 days at baseline was 11 -- 13. Among the
`418 patients, 312 (75%) completed the trial and 106 (25%)
`discontinued prematurely (73, 17%, due to adverse effects).
`In the Phase II study, the 50% responder rates were 32.7%
`for 200 mg/day (p = 0.090, not statistically significant), 41.1%
`for 400 mg/day (p = 0.004) and 38.1% for 600 mg/day
`(p = 0.014), compared with 21.9% for the placebo group [22].
`Percentage reduction in seizure frequency per 28 days over
`placebo was 14.6% in the 200 mg/day group (p = 0.101),
`which did not
`reach statistical
`significance; but
`reached
`statistical
`significance for both the LCM 400 mg/day
`(28.4%, p = 0.002) and 600 mg/day (21.3%, p = 0.008)
`groups. The median change in percentage of seizure-free
`days was 3% in the placebo group, 6% in the LCM
`200 mg/day group, 12% in the LCM 400 mg/day group
`(p = 0.0036) and 12% in the LCM 600 mg/day group
`(p = 0.0004). Patients in the LCM 400 mg/day group experi-
`enced greater improvement in quality of life than the patients
`in the other treatment groups [22].
`Second study was one of two Phase III trials [23], which was
`conducted in Europe and Australia. This study evaluated
`LCM 200 and 400 mg/day doses compared with placebo in
`485 randomized patients. As in the Phase II study, patients
`with at least eight seizures and not more than a 21-day
`seizure-free period during an 8-week baseline assessment
`were randomized to placebo or LCM given twice daily.
`Lacosamide doses were titrated over 4 weeks and maintained
`for 12 weeks. The median percentage reduction in seizure fre-
`quency in the ITT population was 20.5% for placebo, 35.3%
`for LCM 200 mg/day (p = 0.02) and 36.4% for 400 mg/day
`(p = 0.03). The 50% responder rate for LCM 400 mg/day
`(40.5%) was significant (p = 0.01) over placebo (25.8%),
`but not for LCM 200 mg/day (35.0%).
`In the third study [24], which was another Phase III trial
`and conducted in the USA, evaluated LCM dosages of
`400 mg/day and 600 mg/day compared with placebo in a
`total of 405 randomized patients. The study design was simi-
`lar to the above studies: LCM was initiated at 100 mg/day and
`titrated in 100-mg increments per week until the target dose
`
`Expert Opin. Pharmacother. (2010) 11(9)
`
`1597
`
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`
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`
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`
`

`
`Lacosamide
`
`39‡ 40‡
`
`35.3*
`
`36.4*
`
`37.3‡
`
`37.8‡
`
`20.5
`
`20.8
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`26
`
`10
`
`Ben-Menachem
`(phase II)
`
`Halász (phase III)
`
`Chung (phase III)
`
`Placebo
`
`200 mg/day
`
`400 mg/day
`
`600 mg/day
`
`Figure 1. Efficacy of lacosamide: median percentage reduction in seizure frequency from baseline to maintenance phase
`(intention-to-treat population) [22-24].
`*p < 0.05 vs placebo.
`z
`p < 0.01 vs placebo.
`
`was met. One dose reduction (100 mg/day) was permitted at
`the end of
`titration (week 6)
`for patients experiencing
`intolerable adverse events. Patients who were unable to toler-
`ate trial medication earlier during titration and those unable
`to tolerate the reduced dose were to discontinue treatment.
`Following successful completion of titration, patients entered
`the 12-week maintenance period, during which no dose
`adjustments were allowed. Before the study, a total of
`82.1% of patients had been treated previously with four or
`more lifetime AEDs, including 48.3% who had been treated
`with seven or more AEDs in their lifetime. The median sei-
`zure frequency was 15.0 (placebo), 11.5 (LCM 400 mg/day)
`and 16.5 (LCM 600 mg/day) seizures per 28 days during
`the 8-week baseline period, despite treatment with one to
`three concomitant AEDs. Throughout the trial, 82.1% of
`patients were taking two to three concomitant AEDs, which
`most frequently included levetiracetam (39.1%) and lamotri-
`gine (36.1%). In addition to one to three concomitant AEDs,
`a total of 29.6% of patients were also using vagus nerve stim-
`ulation. Significant seizure improvement was observed in both
`LCM 400 mg/day and 600 mg/day groups. In the ITT pop-
`ulation, the median percentage reduction in seizure frequency
`per 28 days from baseline to maintenance was 20.8% for pla-
`cebo, 37.3% for LCM 400 mg/day and 37.8% for LCM
`600 mg/day. These reductions in seizure frequency were
`significant compared with placebo in both the lacosamide
`400 mg/day and 600 mg/day groups, with 21.6% (95% CI
`6.3 -- 34.5; p = 0.008) and 24.6% (95% CI 7.8 -- 38.3;
`p = 0.006) reductions over placebo. In addition, significant
`differences in the 50% responder rates from baseline to main-
`tenance were observed in both the 400 and 600 mg/day LCM
`groups (38.3 and 41.2%; p < 0.001 for both) compared with
`placebo (18.3%). Of 317 patients completing maintenance,
`nine were seizure-free throughout the 12-week maintenance
`
`period (placebo, 0%; LCM 400 mg/day, 2.5%; LCM
`600 mg/day, 8.1%) [24].
`One postmarketing experience has been reported recently
`which included 25 patients with medically refractory partial
`epilepsy (age 16 -- 74 years) [25]. All of them had at least a
`6-month follow-up evaluation, and LCM was initiated at
`100 mg/day with an initial target dose of 400 mg/day. In their
`study, a total of eight patients (32%) reported a > 50% seizure
`reduction and three patients (12%) had > 90% reduction in
`seizure frequency. Thirteen patients (52%) reported adverse
`effects from LCM, such as dizziness, fatigue, nausea and gait
`disturbance, mainly during the titration phase.
`
`6. Safety and tolerability
`
`Among patients randomized to LCM, treatment-emergent
`adverse events (TEAEs) with an incidence of at least 10%
`during the treatment period (both in titration and mainte-
`nance phases) included dizziness, nausea, diplopia, blurred
`In a
`(Table 2).
`vision, headache, vomiting and tremor
`Phase II study, dizziness was the most common TEAE, occur-
`ring in 10, 24, 26 and 55% of subjects during the trial for
`placebo and LCM 200, 400 and 600 mg/day, respectively [22].
`Headache was the second most common TEAE, but was not
`clearly dose-related (9, 11, 24 and 11% of subjects for placebo
`and LCM 200, 400 and 600 mg/day, respectively). All other
`TEAEs were dose-related and reported more often during
`titration than during the maintenance phase. Overall, discon-
`tinuation rates due to TEAEs were 8% in LCM 200 mg/day,
`17% in LCM 400 mg/day and 29% in LCM 600 mg/day,
`compared with 5% of placebo recipients [17,18]. According to
`the interim analysis of the long-term (up to 5.5 years) safety
`data of LCM, TEAEs were similar to those reported in the
`initial Phase II/III trials with an 11.1% discontinuation rate
`
`1598
`
`Expert Opin. Pharmacother. (2010) 11(9)
`
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`
`For personal use only.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2121 - 7/11
`
`

`
`Chung
`
`Table 2. Treatment-emergent adverse events leading to discontinuation of lacosamide during the treatment
`phase*.
`
`Placebo,
`n = 364(%)
`
`Lacosamide
`
`200 mg/day,
`n = 270
`(%)
`
`400 mg/day,
`n = 471
`(%)
`
`600 mg/day,
`n = 203
`(%)
`
`Total,
`n = 944
`(%)
`
`Any Event
`Dizziness
`Coordination abnormal
`Vomiting
`Diplopia
`Nausea
`Vertigo
`Blurred vision
`Convulsion
`
`*Data from Phase II and III trials.
`
`4.9
`0.5
`0
`0.3
`0.3
`0.3
`0
`0
`1.1
`
`8.1
`0.4
`0.4
`0.4
`1.5
`0.4
`1.1
`0.4
`0.7
`
`17.2
`4.2
`1.3
`2.3
`2.1
`1.7
`0.8
`0.6
`1.7
`
`28.6
`17.2
`5.4
`3.0
`2.0
`3.9
`2.5
`3.0
`0
`
`17.1
`5.9
`1.9
`1.9
`1.9
`1.8
`1.3
`1.1
`1.1
`
`somnolence
`[26]. The incidence of
`in LCM recipients
`during the treatment period was approximately 7% for
`placebo and 9% for the total LCM groups, and did not
`seem to be dose-related. The incidence of rash was low for
`patients randomized to LCM, similar to that reported with pla-
`cebo (3%). No rashes were serious and all were assessed as mild
`to moderate in intensity. LCM showed minimal effect on body
`weight: mean change from baseline in body weight after
`18 weeks of exposure in the Phase III study [24] was + 0.6 kg
`for the placebo group and + 0.1 kg and + 0.2 kg for the
`LCM 400 mg/day and 600 mg/day groups.
`Results of clinical laboratory tests and vital sign measure-
`ments across treatment groups did not identify any changes
`that seemed to be associated with LCM. Evaluation of ECG
`readings demonstrated little change from baseline to the end
`of maintenance in heart rate, QTc interval or QRS duration
`for placebo and LCM groups. A small increase in mean PR
`interval at the end of maintenance (1.4 -- 6.6-ms increase)
`was noted. There were no reports of adverse events associated
`with PR interval prolongation, and the degree of increase is
`considered to be similar to other AEDs, such as carbamaze-
`pine (8 -- 16-ms increase), lamotrigine (5-ms increase) and
`prebagalin (up to 5-ms increase) [27-30].
`The tolerability profile of short-term intravenous LCM was
`similar, and the injection-site pain was low. In a 2-day, ran-
`domized, double-blind, placebo-controlled study, patients
`(n = 60, aged 19 -- 61 years) previously treated with LCM
`were randomized to either oral LCM (plus placebo infusion)
`or 30- or 60-min intravenous LCM infusions (plus oral pla-
`cebo) [31]. The intravenous LCM dosage was the same as the
`previous oral dosage (range 200 -- 600 mg/day). TEAEs
`associated with intravenous LCM were mild or moderate in
`intensity and included dizziness, headache, back pain and
`somnolence. Infusion-site-related pain was infrequent (0% for
`60-min infusion; 11% for 30-min infusion) and did not result
`in discontinuations of LCM [31]. In another open-label study
`
`(n = 60), in which LCM was infused faster over 10, 15 or
`30 min for 2 -- 5 days (200 -- 800 mg/day), the incidence
`of adverse events was similar, with headache (5, 7, 8%) and
`dizziness (5, 6, 8%) being most commonly reported [32].
`
`7. Regulatory affairs
`
`LCM is approved as an adjunctive treatment for partial-
`onset seizures in patients aged ‡ 16 years by the European
`Commission (August 2008) and in patients aged ‡ 17 years
`by the FDA (October 2008). LCM injection for intravenous
`use is indicated as adjunctive therapy in the treatment of
`partial-onset seizures in patients with epilepsy (‡ 16 years of
`age in Europe and ‡ 17 years of age in the USA) when oral
`administration is temporarily not feasible.
`In a human abuse potential study, single-dose administra-
`tion of LCM 800 mg produced subjective euphoria-
`type responses in 15% of subjects (5/34), compared with
`0% in placebo. These euphoria-type responses were similar
`to those produced by alprazolam, but the duration of the
`euphoria was shorter. Two other pharmacokinetic studies
`also reported euphoria-type
`responses
`following single
`and multiple doses of LCM 300 mg and 800 mg (range
`6 -- 25%) compared with placebo (0%) [17,18]. Subsequently,
`LCM is designated a schedule IV drug even though the rate
`of euphoria at