Therapeutics and Clinical Risk Management
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`Clinical potential of lurasidone in the management
`of schizophrenia
`
`This article was published in the following Dove Press journal:
`Therapeutics and Clinical Risk Management
`24 June 2011
`Numt
`{i
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`lowed
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`is
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`article
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`has
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`Ludovic Samalin
`Marion Garnier
`Pierre-Michel Liorca
`
`Abstract: Lurasidoneis anew second-generation antipsychotic approved in October 2010 by the
`food and Drug Administration for the treatment ofschizophrenia. Like other second-generation
`antipsychotics, lurasidone is a powerful antagonist of D, dopamine and SHT,, serotonin recep~
`tors, but differs from the other second-generation antipsychoticsin its action profile for certain
`Centre Hospitalier Universitaire,
`Clermont-Ferrand, France
`receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for SHT,
`receptors andhasahigh affinity for SHT,, serotonin receptors, compatible with favorable effects
`on cognitive function and an antidepressant action. By contrast, lurasidone has a lowaffinity
`for o, and o,.-adrenergic and SHT,.. serotonin receptors, and noaffinity for histaminergic H, or
`muscarinic M_ receptors, suggesting a better tolerability profile than the other second-generation
`antipsychotics. Lurasidone has demonstrated its efficacy in several short-term trials in acute
`schizophrenia, promptly and significantly reducing total Positive and Negative Syndrome Scale
`and Brief Psychiatric Rating Scale scores compared with placebo, Several long-term studies
`are in progressto assess its efficacy in the maintenance treatment ofschizophrenic patients. The
`efficacyof lurasidone with regard to cognitive functions and depressive symptoms scems good,
`but requires further work. Lurasidone differs from the other second-generation antipsychotics
`by having a good tolerability profile, in particular for cardiometabolic tolerability. However,it
`seemsto havea significant although moderate link with the occurrence of akathisia, extrapyra-
`midal symptoms, and hyperprolactinemia atthe start oftreatment. This tolerance profile greatly
`broadensthe scope of second-generation antipsychotics and so supports the viewofsome authors
`thatthe term “second-generation antipsychotic”is now outdated. Other therapeutic perspectives
`of jurasidone are assessed here, in particular bipolar depression.
`Keywords: lurasidone, sccond-generation antipsychotic, schizophrenia, cfficacy, safety
`
`Correspondence: L Samalin
`Centre Médico-Psychologique
`B, Centre Hospitalier Universitaire,
`BP 69, 63003 Ciermont-Ferrand
`Cedex |, France
`Tel +33 04 7375 2125
`Fax +33 04 7375 2126
`Email Isamalin@chu-clermontferrand.fr
`
`subsait pour masaumrige «ow anos
`Haseyr nic
`NERS:
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`REN
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`CONFIDENTIAL
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`Managementissues in schizophrenia
`Schizophrenia is a serious chronic mentalillness that appears in late adolescence or
`carly adulthood, and affects about 1%of the world’s population.' It is a heterogencous
`condition characterized by positive and negative symptoms, and is often associated
`with cognitive disorders and symptoms of depression.
`Pharmacological treatmentis based essentially on antipsychotics. These drugs are
`central to care because they offer the only efficacious treatment for most of the symp-
`toms. They allowboth treatment of acute phases and the prevention ofrelapses.
`Clozapine, introduced into the US in 1988,differed from classical neuroleptics not
`only in its greater efficacy but also, more importantly, by having markedly reduced neu-
`rologicaleffects.” With this compound as leader, the atypical antipsychotics appeared at
`the end ofthe 1990s. However, atypicalnessis a catch-all classification that is extremely
`
`Therapeutics and Clinical Risk Management 201 1:7 239-250
`© 2011 Samalin et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
`
`239
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`Slayback v. Sumitomo
`IPR2020-01053
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`

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`Samalin et al
`
`difficult to exploit operationally. The atypical antipsychotics
`form a heterogeneous group that have a pharmacodynamic
`action on neurotransmissionthatis different from thatof the
`
`neuroleptics, with involvement of other neurotransmission
`systems, few or no induced extrapyramidal effects, and stron-
`ger activity on negative schizophrenic symptoms.’ This very
`loose definition prompted a new terminology, ie, the terms
`“first-generation” and “second-generation” antipsychotics,
`which have been in use since 2004.
`
`The second-generation antipsychotics are recommended
`in various guidelinesasfirst-line treatment in view oftheir
`better neurological tolerability, and their greater efficacy
`on negative, cognitive, and depressive symptoms.*’ They
`include the chemical entities amisulpride, aripiprazole,
`asenapine, clozapine, iloperidone, olanzapine, paliperi-
`done, quetiapine, risperidone, sertindole, ziprasidone, and
`zotepine.
`The superiority of second-generation antipsychotics
`over first-generation antipsychotics has been the subject of
`much debate, based on several meta-analyses published since
`2000. Some authors are not convinced of the superiority
`of second-generation antipsychotics and point to the poor
`methodological quality of the comparative trials in terms
`of evaluation criteria, dropouts, and choice and dose of
`comparator.*” A more recent meta-analysis singled out four
`second-generationantipsychotics that displayed greater over-
`all efficacy compared with first-generation antipsychotics,
`namelyclozapine, amisulpride, risperidone, and olanzapine.
`The other second-generation antipsychotics were no more
`efficacious than the older first-generation antipsychotics,
`even for negative symptoms."”
`This difference in efficacy among the second-generation
`antipsychotics was confirmed in a meta-analysis of head-
`to-head comparisons of second-generation antipsychotics.
`Olanzapine was found to be more efficacious than
`aripiprazole, quetiapine, risperidone, and ziprasidone, and of
`similar efficacy to amisulpride and clozapine." This difference
`among second-generation antipsychotics showed up mainly in
`the Positive and Negative Syndromescale (PANSS) positive
`symptomsubscores, and was small in the PANSSnegative
`symptom subscores, CATIE(Clinical Antipsychotic Trials in
`Intervention Effectiveness) and CUtLASS (Cost Utility of
`the Latest Antipsychotic Drugs in Schizophrenia Study) gave
`similar results, except that clozapine stood apart from both
`first-generation antipsychotics and other second-generation
`antipsychoti¢s.'*"*
`Concerning tolerability, whereas second-generation antip-
`sychotics induced much weaker neurological side effects,
`
`240
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`Dovesey-an
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`they induced metabolic (weight gain, hyperglycemia, and
`dyslipidemia) and cardiac side effects (QT prolongation)
`requiring regular monitoring. Differences were also found
`among the second-generation antipsychotics. Although
`inducing fewer extrapyramidal effects compared withfirst-
`generation antipsychotics, risperidone was associated with
`greater use of antiparkinsonian medication than clozapine,
`olanzapine, quetiapine, and ziprasidone.'* Also, concerning
`metabolic side effects, olanzapine and clozapine produced
`more weight gain than all the other second-generation
`antipsychotics, and olanzapine produced a higherrise in cho-
`lesterol than aripiprazole, risperidone, and ziprasidone,'*
`Overall, these recent data confirm that second-generation
`antipsychotics are not a homogeneous group, that each
`second-generation antipsychotic possesses distinct phar-
`macodynamic properties, and that consequently any new
`member may be of therapeutic interest. Lurasidone is a
`second-generation antipsychotic that was approved by the
`Food and Drug Administration (FDA) in October 2010 for
`the treatment of schizophrenia. Here we present the data
`available for this new agent concerning its pharmacological
`properties, efficacy, and tolerability in schizophrenic patients,
`and showthe position of lurisadone with respect to the other
`second-generation antipsychotics,
`
`Data sources
`A literature search using the keywords “lurasidone” and
`“schizophrenia” was undertaken using the databases PubMed
`and EMBASEto find all the relevant studies published in
`English. Additional references were identified from http://
`wwvw.fda.gov and http://clinicaltrials.gov.'® Data were also
`collected from product user information." Searches were last
`updated on March 12, 2011,
`
`Pharmacology and drug
`interactions
`Pharmacological profile
`Lurasidone is a benzoisothiazol derivative (SM-13496:
`(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-( 1,2-benzisothiazol-3-yl)
`piperazin-1-ylmethyl] cyclohexylmethyl] hexahydro-4,
`7-methano-2//-isoindole-1,3-dione hydrochloride).
`Like the other second-generation antipsychotics, lurasi-
`done is a powerful antagonist of the dopamine D, and sero-
`tonin SHT,, receptors, with a strong affinity for the SHT,,
`receptor (K, = 0.470-0.357 nM) and very highselectivity
`for the D, receptor (K, = 0.329-0.994 nM) 264, 16, and 30
`times greater, respectively, compared with D,, D,, and D,
`receptors.'* In a preliminary trial using positron emission
`
`Therapeutics and Clinical Risk Management 201 1:7
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`

`

`Bovesryas
`
`Lurasidone for schizophrenia
`
`tomodensitometry in 21 healthy subjects, it was shown that
`the degree ofoccupation ofD,receptorsat lurasidone dosages
`of 10, 20, 40, 60, and 80 mg ranged from 41.3% to 43.3%,
`31% to 54.8%, 63.1% to 67.5%, 77.4%to 84.3%, and 72.9%
`to 78.9%,respectively, An antipsychotic response, for which
`an occupation of60%-~80%ofthe receptorsis required, could
`thus be expected from 40 mg/day.'*
`Lurasidone differs from other second-generation
`antipsychoticsin its actionprofile for certain receptors. In vitro
`studies haye shownthat lurasidone is the second-generation
`antipsychotic that shows the greatest affinity for SHT_
`receptors (K, = 0,495—2.10 nM) and a high affinity for SHT,,
`receptors.'*"” SHT, receptors are abundant in the thalamic
`and hypothalamic regions involved in the regulation of sleep,
`and in the cortical areas and the regions of the hippocampus
`and raphe nuclei involved inmemory and mood regulation.?°*!
`Therefore, via these two receptors, lurasidone should have
`favorable effects onmemory and cognitive functions,together
`withan antidepressive and anxiolytic action.”
`In contrast with its high affinity for the SHT, and SHT,,
`receptors, lurasidone has a moderate affinity for o.,.-
`adrenergic receptors, a very weak affinity for «,-adrenergic
`and serotonin SHT,,. receptors, and no affinity for histamin-
`ergic H, or muscarinic M, receptors.'*'” Throughits action
`on these different receptors, lurasidone should have a better
`tolerability profile than the other antipsychotics, in particular
`less risk oforthostatic hypertension (c,. and , receptors),
`less weight gain (H, and SHT,, receptors), less sedative effect
`(H, and M,receptors) and feweranticholinergic effects (M,
`receptors).'*
`In vivo studies in animal models have shown that, com-
`pared with other antipsychotic drugs, lurasidone carries a low
`risk for extrapyramidal symptomsor central nervous system
`depressive effects (motor coordination, muscle relaxation,
`anesthesia potentiation, bradykinesia, and catalepsy).'”
`
`Pharmacokinetics
`Lurasidone is rapidly absorbed after oral administra-
`tion, reaching peak concentrations (T_.) in 1-3 hours.”
`Absorption is dose-dependent. For dosages in the range of
`20-160 mg/day, the area under the curve (AUC) and peak
`concentration (C,) increase linearly with the absorbed
`dose.'’ Absorption is apparently favored by eating, as could
`be observed for ziprazidone. About 9%-19% of the dose
`administered is absorbed with no associated food intake,
`whereas AUC and C_are increased three-fold whenatleast
`350 calories of food is ingested concomitantly, Eating has
`no effect onT
`
`Steady-state is reached within seven days. Fora lurasidone
`dose of 40 mg, a distribution volume estimated at 6173 L
`and a clearance of 3902 mL/nin have beenreported.'’ The
`meanelimination half-life in trials including healthy subjects
`given a single dose of 100 mg/day was 12.2~18.3 hours,
`reaching 36 hours after nine days. The meanhalf-life in
`schizophrenic patients with single doses of 120-160 mg/day
`was 28.8-37.4 hours.'®
`
`The lurasidone molecule binds very strongly to
`plasma proteins (99.8%), in particular to albumin and
`cl-glycoprotein.* Lurasidone is metabolized in the liver,
`principally by the cytochrome P450 (CYP) isoenzyme,
`CYP3A4, into three active and two inactive metabolites.
`
`The main active metabolite, ID-14283, an exohydroxy
`metabolite, is rapidly detected in the serum, witha C,. value
`equal to 26% of the starting material. It has a comparable
`pharmacological profile, but a shorterlife (748-10 hours)
`than lurasidone. The other two metabolites, ID-14326 and
`ID-11614, are present at extremely low levels of 3% and
`1%, respectively.'*
`Lurasidone crossesthe placentalbarrier.'* Approximately
`89%is excreted in urine and stools. After administration of
`
`['°C]-lurasidone, 80% ofthe radioactivity was found in stools
`and 9%in urine.”
`
`C,, and AUC values increased in patients with mild,
`moderate, or severe renal and hepatic insufficiency, suggest-
`ing that dosages should be adapted in these subjects.'’ There
`seems to be no impact of race or age on the pharmacokinetics.
`Blood assays carried out in psychotic patients aged 65-85
`years taking lurasidone 20 mg/day showed concentrations
`identical to those in young subjects.'”
`
`Drug interactions
`Because of hepatic metabolismof lurasidone by CY P3A4,
`there is a risk of drug interaction if lurasidone is taken
`concomitantly with inhibitors or inducers of this enzyme
`(diltiazem, ketoconazole, or erythromycin).'"'*? Because
`lurasidone is not metabolized by CYP2D6, coprescription
`with inhibitors of CYP2D6, such as fluoxetine, paroxetine,
`and quinidine, needs no dosage adaptation. Lurasidone is
`not a substrate for P glycoprotein. No drug interactions have
`been observed when lurasidone is coprescribed with P gly-
`coprotein substrates such as digoxin, or CY P3A4 substrates
`such as midazolam,oral contraceptives, or lithium.'”!* The
`high plasma protein-binding poweroflurasidone, especially
`towards albumin and «1-glycoprotein, should be taken into
`account to avert certain drug interactions, in particular in
`undernourished subjects or the elderly.
`
`nebasis your mnawswscript|wom
`241
`Therapeutics and Clinical Risk Management 201 1:7
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`

`

`Samalin et al
`
`Efficacy in schizophrenia
`The efficacy of lurasidone in acute schizophrenia was
`assessed ineight trials (Table 1). Six short-term (six-week)
`randomized, double-blind, placebo-controlled trials (of
`which three used an active comparator, ie, haloperidol,
`olanzapine, or quetiapine) in acute schizophrenia, a short-
`term (three-week) randomized, double-blind controlled trial
`(versus ziprasidone) in stable outpatients with schizophrenia
`or schizoaffective disorder, and a short-term (cight-weck)
`randomized, double-blind dose-response study in inpatients
`and outpatients with schizophrenia.
`The primary efficacy endpoint in all the trials was the
`mean change in PANSS or Brief Psychiatric Rating Scale
`(BPRS)total score from baseline to endpoint. Secondary
`endpoints included changes in Clinical Global Impression
`of Severity (CGI-S) and PANSSsubscale scores. One study
`evaluated cognitive efficacy with a subset of the MATRICS
`Consensus Cognitive Battery (MCCB) and Schizophrenia
`Cognition Rating Scale.
`Placebo-controlled trials (except for one failed trial)
`demonstrated antipsychotic efficacy in all primary and
`secondary efficacy measures in favor of lurasidone 80 mg/
`day. With the exception of two trials (one failed trial and
`D1050229), efficacy was found at lurasidone doses of 40,
`120, and 160 mg/day.
`A pooled analysis based on five PANSSfactor scores
`(positive, negative, disorganized thought, hostility, and
`depression/anxiety) was performed from four short-
`term, double-blind, placebo-controlled trials (D1050006,
`D1050196, D1050229, and D1050231).> Despite the inclu-
`sion ofa trial that did not find lurasidone to be efficacious
`
`at 40 or 120 mg/day, pooled data found lurasidone to be
`significantly better than placebo in improving all five PANSS
`factor scores. At week 6, changed scores andeffect sizes were
`significant compared with placebo among patients treated
`with lurasidone at 40 mg, 80 mg, and 120 mg (Table 2).
`Significant improvement in the different scores (BPRS,
`PANSS, and CGI-S) was observed by days 3-7 for the
`80-160 mg/day doses.'*"*?’ In a study of stable patients,
`lurasidone 120 mg/day had an efficacy comparable with
`that of ziprasidone 160 mg/day, but with an earlier onset of
`improvement in PANSStotal score (by day 7).** These trials
`suggest an carly onset of treatment effect for lurasidone.
`Trial results did not suggest any additional benefit of
`lurasidone 120 mg/day over 40 mg/day or 80 mg/day (based
`on observed mean differences from placebo).'° Pooled analy-
`sis found the treatment effect of lurasidone to be consistent
`
`across the dosage range, with no clear superiority of the
`
`Dovesey-an
`
`highest lurasidone dose.** No dose-response relationship for
`lurasidone was found,
`
`A dose-response study of furasidone 20, 40, and 80 mg/
`day found that the 40 mg/day and 80 mg/day doses were
`associated with significant improvements from baseline on
`the PANSS and BPRS, and were significantly better than
`20 me/day.”” The starting dose of lurasidone recommended
`by the FDA is 40 mg once daily, and the maximumdose is
`80 mg once daily.
`The receptor binding profile of lurasidone, with high
`affinity for SHT,, SHT,,, and c,. receptors, and negligible
`affinity for muscarinic M, and histaminic H, receptors, was
`associated with a potential effect on cognitive function in
`schizophrenia.'* Data from placebo-controlled studies dem-
`onstrated a significant improvement in the PANSScognitive
`symptoms subscale (including conceptual disorganization,
`poorattention, and difficulty in abstract thinking).”” However,
`this subscale has not demonstrated a close correlation with
`
`performance-based cognitive tests.*°
`The cognitive effect of lurasidone was evaluated in
`comparison with ziprasidone in a short-term, randomized,
`double-blind trial. The outcome measures used were a
`
`performance-based cognitive assessment battery with most
`ofthe tests coming from the MCCBandan interviewer-rated
`measure ofcognitive functioning, ie, the Schizophrenia Cog-
`nition Rating Scale. There were no between-group treatment
`differences in these ratings, but lurasidone demonstrated
`significant within-group improvement from baseline on the
`MCCBcomposite score (? = 0.026) and onthe Schizophrenia
`Cognition Rating Scale (P < 0.001), unlike ziprasidone. The
`very short duration of this trial, using a high dose of lurasi-
`done (120 mg/day) and the use of an incomplete battery of
`tests set somelimits to this study, which now requires further
`workto evaluate the cognitive effects of lurasidone.
`Secondary analysis of one trial evaluated the efficacy of
`lurasidonein patients with schizophrenia who were experiencing
`clinically significant depressive symptoms (Montgomery-Asberg
`Depression Rating Scale [MADRS] > 12).*' Lurasidone-treated
`patients had significantly improved mean MADRS scores in the
`total sample (P= 0.026) and in the subgroup with MADRS> 12
`(P=0,04) compared with placebo (last observation carried for-
`ward). This trial is the only one to provide information onthe
`efficacy oflurasidone in the treatment ofdepressive symptoms
`associated with schizophrenia, Double-blind Phase TI trials
`are ongoing to confirm this potential benefit in schizophrenic
`patients with depressive symptoms,
`The long-term efficacy of lurasidone in schizophrenia is
`being assessed from the extension phases of the short-term
`
`Siasemit yes ataRUBUTIpS|Sr eur ece
`
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`242
`Therapeutics and Clinical Risk Management 201 1:7
`Bavepceri
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`CONFIDENTIAL
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`Therapeutics and Clinical Risk Management 201 1:7
`Ehsves- seas
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`CONFIDENTIAL
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`

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`244
`
`Siasemit yes ataRUBUTIpS |
`Bavegcert
`
`Sr
`
`eur
`
`ece
`
`CONFIDENTIAL
`
`Therapeutics and Clinical Risk Management 201 1:7
`
`

`

`Bovesryas
`
`Lurasidone for schizophrenia
`
`Table 2 Results of a pooled analysis based on a five-factor model of schizophrenia”
`Lurasidone 120 mg/day
`Five PANSS
`Lurasidone 40 mg/day
`Lurasidone 80 mg/day
`Effect
`Changefrom P
`Effect
`Effect
`factor scores
`Change from
`=P
`Changefrom P
`size
`baseline
`size
`size
`baseline
`baseline
`0.42
`<0,00
`8.25
`0.47
`<0.00!
`0.35
`<0.001
`-7.92
`8.48
`Positive factor
`0.31
`0.002
`-5.21
`0.25
`0.02
`OAI
`<0.001
`—5.59
`4.96
`Negative factor
`0.50
`<0.00|
`~5.22
`0.47
`<0.00i
`0.40
`<0.001
`—4.86
`5.10
`Disorganized thought
`0.44
`<0,00/
`287
`0.33
`0,002
`0.25
`<0.013
`~2.33
`—2.58
`Hostility
`0.26
`0.012
`-3.01
`0.35
`0.002
`031
`0.002
`3.14
`-3.23
`Depression/anxiety
`Notes: Five PAINSS factor scores were analysed using MMRM analysis. Adjusted effect sizes were calculated from an ANCOVAanalysis (LOCF endpoint) as the between-
`treatment groupdifference in least squares mean change scores divided by the pooled standard deviation of the change scores. Reprinted from Schizophrenia Research, 117,
`Loebel A Cucchiaro } Silva R, Ogasa M, Severs J, Marder SR, Efficacy of lurasidone in schizophrenia: Results of a pooled analysis based on a S-factor mode! of schizophrenia,
`267. 2010. with permission from Elsevier.
`Abbreviations: ANCOVA, analysis of covariance: LOCElast observation carried forward; MMRM, mixed-effect model repeated measure; PANSS, Positive and Negative
`SyndromeScale.
`
`trials and a six-month open-label extension trial evaluating the
`efficacy oflurasidone for the treatment ofschizophrenia in sub-
`jects switched from other antipsychotic agents. Only data from
`Sunovion Pharmaceuticals have reported the maintenance of
`clinical effect in lurasidone-treated patients for up to eight months
`(6.5 months extension) inthe PEARL (Program to Evaluate the
`Antipsychotic Response to Lurasidone) 2 extensiontrial’?
`
`Commonadverse events
`Safety data based on pooled analyses fromfive short-term,
`placebo-controlled studies included 1004 lurasidone-treated
`patients and 455 placebo-treated patients.'*!’“The most com-
`mon adverse reactions (incidence = 5%and at least twicethe
`rate of placebo)in patients receiving lurasidone were akathisia
`(15%), nausea (12%), sedation (12%), somnolence (11%),
`parkinsonism (11%), insomnia (8%), agitation (6%), anxiety
`(6%), and dystonia (5%). Apparent dose-related adverse reac-
`tions were akathisia and somnolence, Other common adverse
`
`Safety and tolerability
`The safety assessmentis based on data from over 2600 human
`subjects exposed to lurasidone (in Phase I, fl, and HT studies)
`with almost 500 patients exposed for more than six months and
`225 for more than one year.'® These data were assessed in the
`short-term trials already described and their long-term extension
`phases (Table 1). The first results ofthe PEARL safety tral over
`12 months were also included.“ Additional information is
`
`events did not appear to be dose-related.
`The long-term, risperidone-controlled trial substantiated
`the favorable profile of lurasidone, with a significantly lower
`incidence of somnolence, constipation, and weight increase
`(Table 3)='** This tral also suggested that akathisia, nausea, and
`vomiting may occur more frequently with lurasidone than with
`provided in the product monograph.'’ The dose range examined
`risperidone. Similar results were observed ina short-term, quetia-
`pine-controlled trial The short-term,ziprasidone-controlled trial
`in the Phase II and III trials was 20-120 mg/day (doses up to
`600 mg/day were evaluated in PhaseItrials).
`found a statistically significant difference only in sedation.**
`
`Table 3 Commonadverse eventsfor lurasidone versus active comparator*®??3*
`Long-term trials
`Adverse
`Short-term trials
`D1050237 (12 months)
`D1050233 PEARL 3 (6 weeks)
`event(%)
`D1050254 (3 weeks)
`Lurasidone
`Ziprasidone
`Lurasidone
` Lurasidone
`Quetiapine
`Placebo
` Lurasidone
`Risperidone
`
`120 mg/day
`[60mgiday
`80 mg/day
`160 mg/day
`600 mg/day
`40-120 mg/day
`2-6 mg/day
`Akathisia
`3.3
`66
`8
`9
`2
`|
`14.3
`79
`Nausea
`7.3
`46
`8
`66
`3.4
`3.3
`16.7
`10.9
`
`3.3
`16
`-
`~
`-
`-
`4
`8
`Vomiting
`
`Parkinsonism=— - 5.6 66 3.4 0 43 54
`
`
`
`
`
`
`Somnolence
`6,7
`99
`4
`66
`13.4
`08
`13.6
`17.8
`Sedation
`47
`11.3
`-
`-
`-
`-
`-
`-
`Insomnia
`10.7
`93
`-
`-
`-
`-
`-
`-
`Headache
`67
`46
`-
`-
`~
`-
`-
`-
`Dizziness
`2.7
`66
`48
`58
`i34
`17
`-
`-
`Dry mouth
`-
`~
`1.6
`1.7
`76
`08
`=
`~
`
`Constipation=— - 24 O8 67 25 19 6.3
`
`
`
`
`
`
`Weight gain
`-
`-
`08
`1.7
`6.7
`0.8
`93
`19.8
`
`
`
`
`
`Therapeutics and Clinical Risk Management 201 1:7 admis your manuscript}wren 245
`
`CONFIDENTIAL
`
`

`

`Samalin et al
`
`Extrapyramidal symptoms,akathisia,
`and dyskinesias
`Data provided by clinical trials were assessed on the
`Simpson Angus Rating Scale for extrapyramidal symp-
`toms, the Barnes Akathisia Scale for akathisia, and the
`Abnormal Involuntary Movement Scale for dyskinesias.
`In the short-term, fixed-dose, placebo-controlled trials for
`schizophrenia, treatment-emergent extrapyramidal side
`effects (excluding akathisia and restlessness) were observed
`in 14.7% oflurasidone-treated patients compared with 5.1%
`of placebo-treated patients.'®’? Akathisia was observed in
`15%of lurasidone-treated patients compared with 3.3%
`of placebo-treated patients. The incidence of dystonia
`for lurasidone-treated patients was 4.7% versus 0.7% for
`placebo-treated patients.
`The mean change from baseline for lurasidone-treated
`patients was comparable with placebo-treated patients for
`extrapyramidal symptoms and dyskinesias, and was very
`close to placebo-treated patients for akathisia (lurasidone 0.2,
`placebo 0.0). The percentage of patients who shifted from
`normal to abnormal was greater in lurasidone-treated patients
`versus placebo for the Barnes Akathisia Scale (lurasidone
`16%, placebo 7.6%) and the Simpson Angus Rating Scale
`(lurasidone 5.3%, placebo 2.5%). Only akathisia appeared to
`be dose-related, but the greatest incidence of extrapyramidal
`side effect (including dystonia) occurred with the highest
`dose oflurasidone (120 mg/day). Akathisia is a common
`neurological adverse event with lurasidone, and is the most
`often reported side effect. Reported extrapyramidal side
`effects amounted to 22% and reported dystonia to 7% for
`patients treated with lurasidone doses of 120 mg daily. Long-
`term treatment with antipsychotic drugs, especially at high
`dosages,is associated with the risk oftardive dyskinesia. Data
`onthe potential risk for tardive dyskinesia are still lacking,
`
`Dovesey-an
`
`because ofthe limited information available from long-term
`clinicaltrials.
`
`Metabolic side effects
`Glucose metabolism
`
`Pooled data from short-term, placebo-controlled studies
`showed a mean increase in fasting glucose of 1.4 mg/dL in
`the lurasidone group compared with a 0.6 mg/dL increase in
`the placebo group.'*”»> There was no dose-responserelation-
`ship in the lurasidone group (Table 4). Changes in fasting
`glucose (mean from baseline and proportion ofpatients with
`shifts to = 126 mg/dL)in lurasidone-treated patients were not
`statistically different from placebo-treated patients.
`The uncontrolled longer-term trials (primarily open-label
`extension studies) reported a mean change in glucose of
`+1.6 mg/dL at weck 24 (n = 186), +0.3 mg/dL at week 36
`(n= 236), and +1.2 mg/dL at week 52 (n= 244),'”
`In trials with an active comparator, a similar change in
`glucose was reported between lurasidone and ziprasidone
`(+4.7 versus +4.8 mg/dL).* In pooled short-term trial analy-
`sis. the median changesin glucose associated with lurasidone
`was unchanged (0.0), increased for olanzapine and haloperi-
`dol (+4.0 and +2.0, respectively), and for placebo remained
`essentially unchanged (+1.0).'* In a longer-termsafety trial,
`the median change from baseline in glucose observed was
`significantly different (P= 0.001) in favor of lurasidone, with
`a mean decrease of —-0.5 mg/dL versus a meanincrease of
`3.0 mg/dL for risperidone.
`
`Dyslipidemia
`In short-term trials, mean increases were not observed for
`total cholesterol, low-density lipoprotein cholesterol, or
`triglyceride indices in the lurasidone group (Table 4).'°'’°
`Changes in fasting cholesterol and triglycerides (mean
`
`Table 4 Metabolic effects of lurasidone from short-term triais'*'”
`Placebo
`Lurasidone
`
`120 mg/day
`80 mg/day
`40 mg/day
`20 mg/day
`>uumamenmaar nmarmeameameenaasaemeaaaeaaenaanaadaaaemamaaseameaaneiseemeemmnaemeenmmemnemennnmneecS
`Mean change from baseline (mg/dL)
`0.7
`~0.6
`2.5
`0.9
`2.5
`= 126 maldL (%)
`8.6
`11.7
`143
`10.0
`10.0
`Total cholesterol
`
`Mean change from baseline (mg/dL)
`240 mefdl (%)
`Triglycerides
`Mean change from baseline (mg/dL)
`=200 m g/dL (%)
`Weight
`
`Mean change from baseline (kg)
`
`-8.5
`66
`
`-15.7
`12.5
`
`0.26
`
`-123
`13.8
`
`-29.1
`14.3
`
`0.15
`
`-94
`7.3
`
`-6.2
`14.0
`
`0.67
`
`9.8
`6.9
`
`-14.2
`8.7
`
`L.l4
`
`-38
`38
`
`=3.|
`10.5
`
`0.68
`
`Siasemit yes ataRUBUTIpS|Sr eur ece
`
`
`246
`Therapeutics and Clinical Risk Management 201 1:7
`Bevezcert
`
`
`
`CONFIDENTIAL
`
`

`

`Bovesryas
`
`Lurasidone for schizophrenia
`
`from baseline and proportion of patients with shifts) in
`jurasidone-treated patients were not