Therapeutics and Clinical Risk Management
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`Clinical potential of lurasidone in the management
`of schizophrenia
`
`Tlis article was published in the {allowing Dove Press journal;
`Therapeutics and Chrial Risk Management
`24jime20|l
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`Ludovic Samalin
`Marion Garnier
`Pierre-Michel Llorca
`
`Centre Hospitalier Universitaire.
`Clermont-Ferrand, France
`
`CorrespondencezL Samalin
`Centre Médico-Psycholog‘que
`8. Centre Hospitalier Universrtare.
`BP 69. 63(XB Clermont-Ferrand
`Cedex l.Frnnce
`Tel +33 04 7375 2125
`Fax +33 04 7375 2l26
`Email lsamalm@chu-clermontierrandh
`
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`Abstract: Lurasidonc is a new second-generation antipsychotic approved in October 2010 bythc
`Food and [hug/\dmmistration for the treatment ofschizophrenia. Like other second-generation
`
`antipsychotics, lurasidone is a mnerf'ul mitagonist of D2 dopamine and SHT“ serotonin recep-
`tors. but differs from the other second-generation anttpsychotics in its action profile for certain
`receptors. Lumsidonc is the second—generation antipsychotic with the greatest affinity for SI lT7
`receptors and has a high affinity for SHTM serotonin receptors, compatible with favorable etTects
`on cognitive function and an antidepressant action. By contrast, lurasidone has a low affinity
`
`for «I and (EC-adrcncrgic and 511T“. serotonin receptors. and no affinity forhistamincrgic 11' or
`muscarinic M l receptors, suggesting a better tolerahility profile than the other second-generation
`antipsychotics. Lumsidone has demonstrated its ctficncy in mvcml 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 progress to times its efficacy in the maintenance treatment ot‘schizophrcnic patients. The
`cfi’icacy ofltuasidonc with regard to cognitive functions and depressive symptoms scents good.
`but requires further work, Lurasidonc dificts from the other second-generation antipsychotics
`by having a good tolerability profile, in particular for cardiomctalmlic tolcrability. llowever. it
`seems to have a significant although moderate link with the occurrence ofakathisizt, cxtmpyra-
`midal symptoms, and hyperprolactincmia at the start oftreatment. This tolerance profile greatly
`broadens the scope ofsccond-gcncration antipsychotics and so supports thc vicw ofsomc authors
`that thetcrm “second-generation antipsychntic“ is now outdated. Other therapeutic perspectives
`of lurasidone are assessed here. in particular bipolar depression.
`Keywords: lurasidone, second-generation anti psychotic, schizophrenia. efficacy. safety
`
`Management issues in schizophrenia
`Schizophrenia is a serious chronic mental illness that appears in late adolescence or
`early adulthood and affects about I% of the world’s population.‘ It is a hetcrogcncous
`condition characterized by positive and negative symptoms. and is often associated
`with cognitive disorders and symptoms of depression.
`Pharmacological treatment is based essentially on antipsychotics. These drugs are
`central to care because they offer the only efficacious treatment for most of the symp-
`toms. They allow both treatment of acute phases and the prevention of relapses.
`C lompinc. introduced into the US in 1988. differed from classical neurolcptics not
`only in its greater efficacy but also. more importantly. by having markedly reduced neu-
`rological effects.3 With this compound as leader, the atypical antipsychotics appeared at
`the end ofthe i9905. However. atypicalness is a catchall classification that is extremely
`
`Therapeutics and Clinical Risk Management 20l lt'l 239—250
`© 201 I Samalin et a|.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.
`
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`Samalin et al
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`difficult to exploit operationally. The atypical antipsychotics
`form a heterogeneous group that have a pharmacodymmic
`action on neurotransmission that is different from that of the
`
`neuroleptics. with involvement of other tteurotiansmission
`systems. few or no induced exttapyramidal ett‘ects. and stron-
`ger activity on negative schimphrenic symptoms} This very
`loose definition prompted a new terminology. ie. the terms
`"first—generation“ and “second-generation“ antipsychotics.
`which lave been in use since 2004.
`
`The second-generation antipsychotics are recommended
`in various guidelines as first—line treatment in view of their
`better neurological tolerability. and their greater efficacy
`on negative. cognitive. and depressive symptoms!“7 They
`include the chemical entities amisulpride. aripiprazole.
`asenapine. clozapine, iloperidone. olanzapine, paliperi-
`done, quetiapine. risperidone, sertindole. zipmsidone. and
`aotepine.
`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.W A more recent meta-analysis singled out four
`second-generation antipsychorics that displayed greater over—
`all efficacy compared with first-generation antipsychotics.
`namely clozapine. amisulpride. risperidone. and olanzapine.
`The other second—generation antipsychotics were no more
`etficacious 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.
`Olanzapinc was found to he more efficacious than
`aripipraaole. 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 Syndrome scale (PANSS) positive
`symptom subseores. and was small in the PANSS negative
`symptom subscores. CATI E (Clinical Antipsychotic Trials in
`Intervention Effectiveness) and CUtLASS (Cost Utility of
`the LatestAntipsychotic Drugs in Schimphrenia Study) gave
`similar results. except that clozapine stood apart from both
`first-generation ant ipsychotics and other second-generation
`antipsychotics.”-”
`Concerning tolerability. whereas second—generation antip-
`sychotics induced much weaker neurological side effects.
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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 exnapyramidal effects compared with first-
`generation antipsychotics, risperidone was associated with
`greater use of antiparkinsonian medication than clozapine.
`
`olanzapine, quetiapine. and ziprasidone.“ Also, concerning
`metabolic side effects, olanzapine and clozapinc produced
`more weight gain than all the other second-generation
`antipsychotics. and olanrapine produced a higher rise 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
`preperties. efficacy. and tolerability in schiZOphrenic patients.
`and show the position oflurisadone 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 EMBASE to find all the relevant studies published in
`English. Additional references were identified front htth/
`mwvfdagov and http://clinicaltrialstgov.‘° 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 beuzoisothiazol derivative (SM—13496:
`
`(3aR.4S.7R,7aS)—2-[t mam-2444 l.2-ben7.isothiazol-3-yli
`pipcrazin-l-ylmethyl] cyclohexylmethyl] hexahydro-4.
`7-methano-2l-I-isoindole—1.3-dione hydrochloride).
`Like the other second-generation antipsychotics. lurasi-
`
`done is a powerful antagonist of the dopamine D2 and sero-
`tonin Sl-lT2A receptors. with a strong affinity for the 5HTM
`receptor (KI = 0470-0357 an and very high selectivity
`for the D2 receptor ( Ki = 0.329~0.994 mm 264. 16. and 30
`times greater, respectively. compared with D.. D3. and D;
`receptors.“ In a preliminary trial using positron emission
`
`Therapeutics and Clinical Risk Management 20| l:7
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`Dewey-mm
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`Lurasidone lor schizophrenia
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`tomodensitometry in 2l healthy subjects. it was shown that
`
`the degree ofoccupation ofD2 receptors at lurasidone dosages
`of ll). 20, 40. 60. and 80 nrg ranged from 41.3% to 43.3%.
`51% 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%-SO% ofthe receptors is required could
`thus be expected from 40 mg/day."
`Lttrasidone differs from other second—generation
`antipwchotics in its action profile for certain receptors. In vitro
`studies have shown that lurasidone is the second-generation
`
`anti psychotic that shows the greatest affinity for SHT7
`receptors (Ki = 0.495—2. l0 nM) amt a high affinity for SHTM
`receptors!“ SHT7 receptors are abtutdant in the thalamic
`and hypothalamic regions involved in the regulation of sleep.
`and in the cortical areas and the regions of the hippocampus
`and raphc nuclei involved inmemory and mood regulation.ml
`Therefore. via these two receptors, lurasidonc should have
`favorable effects on memory and cognitive fttnctr'om. together
`with an antidepressive and anxiolytic action.”
`
`In contrast with its high affinity for the SHT7 and SHTIA
`receptors. lurasidone has a moderate affinity for ur-
`adrenergic receptors. a very weak affinity for a, -adrenergic
`and serotonin SHTx receptors, and no affinity for histamin-
`ergic l-l| or rnuscarinic Ml receptors."~” Through its action
`on these difl‘erent receptors. lurasidone should have a better
`tolerability profile than the other antipsychotics, in particular
`
`less risk of orthostatic hypertension (nth. and (XI receptors).
`less weight gain (H1 and SHTK. receptors). less sedative etTect
`(HI and M] receptors) and fewer anticholinergic effects (ME
`receptorsl.”
`In vivo studies in animal models have shown that. com-
`
`pared with other antipsychotic drugs, lrrrasidone carries a low
`risk for extrapyramidal symptoms or central nervous system
`depressive effects (motor coordination. muscle relaxation.
`anesthesia potentiation. bradykinesia, and catalepsyl.lu
`
`Pharmacokinetics
`
`Lurasidone is rapidly absorbed after oral administra-
`
`tion, reaching peak concentrations (Tm) in 1—3 hours.”
`Absorption is dose—dependent. For dosages in the range of
`20460 mg/day. the area under the curve (AUC) and peak
`
`concentration (Cm) increase linearly with the absorbed
`dose.‘7 Absorption is apparently favored by eating. as could
`be observed for ziprazidone. About 9%~--l9% of the dose
`administered is absorbed with no associated food intake.
`
`whereas AUC and Cm. are increased three-fold when at least
`350 calories of food is ingested concomitantly. Eating has
`
`no etTect on Tm.”
`
`Steady-state is reached within seven days. Fora lurasidone
`dose of 40 mg. a distribution volume estimated at 6173 I.
`and a clearance of 3902 mL/ruin have been reported.” The
`mean elimination haltllife intrials including healthy subjects
`given a single dose of 100 mg/day was 12.2—18.3 hours.
`reaching 36 hours after nine days. The mean half-life in
`schizophrenic patients with single doses of 120— l 60 mg’day
`was 28.8—37.4 hours.ls
`
`The lurasidonc molecule binds very strongly to
`plasma proteins (99.8%). in particular to albumin and
`al-glycoprolein.” Lurasidone is rnetaboliud in the liver.
`principally by the cytochrome P450 (CYP) isoenzyme.
`CYP3A4. into three active and two inactive metabolites.
`
`The main active metabolite, lD-l4283, an exohydroxy
`
`metabolite, is rapidly detected in the serum. witha Cm value
`equal to 26% of the starting material. It has a comparable
`pharmacological profile. but a shorter life (7.48—10 hours)
`than lurasidone. The other two metabolites. lD-14326 and
`
`lD-l16l4, are present at extremely low levels of 3% and
`1%. respectively.”
`Lurasidonc crosses the placental barrier.“ Approximately
`89% is excreted in urine and stools. After administration of
`
`[“(‘l-lurasidone. 80% ofthe radioactivity was found in stools
`and 9% in urine.”
`
`CW 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 metabolism of ltuasidone by CYP3A4.
`there is a risk of drug interaction if lurasidorte is taken
`concomitantly with inhibitors or inducers of this enzyme
`
`tdiltiazem. ketoconazole. or erythrornycinl."-""’3 Because
`lurasidone is not metabolized by CYP2D6. coprescription
`with inhibitors of CYPZDo. such as fiuoxetine, paroxetine,
`and quinidine. needs no dosage adaptation. Lurasidone is
`not a substrate f0r P glycoprotein. No drug interactions have
`been observed when lurasidone is coprescribed with P gly-
`coprotein substrates such as digoxin. or CYP3A4 substrates
`such as midazolam. oral contraceptives. or litltium."~“ The
`high plasma protein-binding power of Iurasidone, especially
`towards albumin and otl—glycoprotein. should be taken into
`account to avert certain drug imeractions. in particular in
`undemourished subjects or the elderly.
`
`Therapeutics and Clinlcal Risk Management 20l l:7
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`Samalm et al
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`Efficacy in schizophrenia
`The efficacy of lurasidone in acute schizophrenia was
`assessed in eight trials (Table 1). Six short-term (six-week)
`randomized. double-blind. placebo-controlled trials (of
`which three used an active comparator, ie. haloperidol,
`olanmpine. or quctiapine) in acute scliimphrenia, a short-
`term (thee—week) randomized. double-blind controlled trial
`
`(versus ziptasidone) in stable outpatients with schimphrcnia
`or schizoafi‘ectivc disorder. and a short-tenn (eight-week)
`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 PAN-SS 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 PANSS subscale 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
`Dl050229). efficacy was found at lurasidone doses of 40,
`120. and 160 mg/day.
`A pooled analysis based on five PANSS factor scores
`(positive. negative. disorganized thought. hostility, and
`depression/anxiety) was performed from four short—
`term, double-blind. placebo-controlled trials (Dl050006.
`D1050196. 01050229. and Dl05023l )f’ Despite the inclu-
`sion of a trial that did not find lurasidone to be efficacious
`
`at 40 or IZO mg/day, pooled data found lurasidone to be
`significantly better than placebo in improving all five PANSS
`factor scores. At week 6. changed scores and efi‘ect 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 (501-8) was observed by days 3—7 for the
`80—160 mg/day doses.“-2"'=7 in a study of stable patients,
`lurasidone |20 mg/day had an efficacy comparable with
`that of ziprasidone I60 org/day. but with an earlier onset of
`improvement in PANSS total score (by day 7)." These trials
`suggest an early onset of treatment effect for lurasidonc.
`Trial results did not suggest any additional benefit of
`lurasidone 120 mg/day over 40 mg/day or 80 mgjday (based
`on observed mean differences from placebo).“‘ Pooled analy—
`sis foruid the treatment efiect of lurasidone to be consiStent
`
`across the dosage range. with no clear superiority of the
`
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`Dove‘g. *"iii
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`highest lurasidone dose.” No dose-response relationship for
`lurasidone was found.
`
`A dose-response study of lumsidone 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 mg/day." ‘lhe starting dose of Iurasidone recommended
`by the FDA is 40 mg once daily, and the maximum dose is
`80 mg once daily.
`The receptor binding profile of lurasidone, with high
`
`affinity for SHTT. SHTM. and an. receptors. and negligible
`affinity for muscarinic M. and histaminic l-ll receptors. was
`associated with a potential effect on cognitive function in
`schizophrenia” Data from placebo-controlled studies dem-
`onstrated a significant improvement in the PANSS cognitive
`symptoms subscale (including conceptual disorganization.
`poor attention, and difficulty in abstract thinking).27 However,
`this subscale has not demonstrated a close correlation with
`
`perfomiance—bmcd cognitive tests.“
`The cognitive efiect of lurasidone was evaluated in
`comparison with ziprasidone in a short-term. randomized,
`double—blind trial. The outcome measures used were a
`
`perfonnance-based cognitive assessment battery with most
`ofthe tests coming from the MCCB and an 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
`MC CB composite score (P = 0.026) and on the Schizophrenia
`Cognition Rating Scale (I’ < 0.001). unlike ziprasidone. The
`very short duration of this trial. using a high dose of lurasi-
`donc ( I20 lug/(lay) and the use ofan incomplete battery of
`tests set some limits to this study. which now requires further
`work to evaluate the cognitive effects of lurasidone.
`Secondary amlysis of one trial evaluated the efficacy of
`lurasidone in patients with schizophrenia who were experiencing
`
`clinically significant deptc$ive symptoms (Momgunery-Asbcrg
`Depression Rating Scale [MADRS] > 12).“ Unasidone—treated
`patients had significantly improved mean MADRS scores in the
`total sample (P:0.026) arri 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 on the
`efficacy ol‘iurasidone in the treatment ofdepressive symptoms
`associated with schizophrenia. Double-blind Phase III trials
`are ongoing to confirm this potential benefit in schimphnenic
`patients with depressive symptoms.
`The long-term efi‘icacy of lurasidone in schizophrenia is
`being assessed from the extension phases of the short-term
`
`Therapeutics and Clinical Risk Management 20| l:7
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`

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`CONFIDENTIAL
`
`

`

`Davey-Mu
`
`Lurasidone lor schizophrenia
`
`Table 2 Results of a pooled analysis based on a fare-factor model of schizophrenia‘5
`Five PANSS
`Lurasldone 40 mglday
`Lurasidone 60 mglday
`
`Lurasidone I20 nag/day
`
`P
`
`P
`
`factor “M“
`
`P
`
`Elfect
`Change from
`Eflect
`Change from
`Effect
`Change from
`size
`bnellne
`size
`baseline
`size
`basellne
`0.42
`<0.00 l
`—8.25
`0.47
`((100 |
`—8.48
`0.35
`4.0.00]
`—7,92
`Posmve factor
`0.3 I
`0.002
`—5.2 I
`0.25
`0.02
`4.96
`0.4I
`<0.00l
`65.59
`Negative factor
`0.50
`<0.00l
`—-5.22
`0.47
`<000I
`~-5. IO
`0-40
`<0.00l
`4.86
`Disorganized thought
`0.44
`<0.00l
`—7_87
`0.33
`0.002
`—2.58
`0.25
`<0.0|3
`—2.33
`Hostility
`0.26
`0.0 | 2
`—3.0|
`0.35
`0.002
`—3.23
`0.3 I
`0002
`-3. | 4
`Depressron/anxioty
`Notes: Five PANSS lactor scores were analysed uslng MMKM andysls Adlrnted died slres were calculated 1mm an ANCOVA analysts (lOCF endpoint) as the between-
`ueatmens group dillerance in least: squares moan change scores divided by the pooled standard donation oi the change scores. Rapr'nted lrom Schizophrema Research I I7.
`Loebel A Cucdiiuol Silva R. 09331 M. Saver: J. Harder SR. Efficacy olluruidone in schimphrenin.‘ Results oh pooled Imiysia based on a S—iactor model ol sdizophrenin.
`267. 20I0. with permission lrom Elsm‘er.
`Abbreviation: ANCOVA. analysis of oovariancn: LOCF. In! observation camod lorward: MMRM. nimd-oflcct modal repeat-d must": FANSS. Positiw and N-gztiw
`Syndrome Scale.
`
`trials and a six-month open-label extension trial evaluating the
`cfi‘icacy oflumsidonc for the truatmcnt ofschimphrcnia in sub-
`jects switched from other antipsychotic agents. Only data from
`Stmovion Plunmaceutimls have reported the maintenance of
`clinical died in lumsidonc-trcatcd patients for up to eight months
`(6.5 months extension) in the PEARL (Program to Evaluate the
`Antipsychotic Response to Lurasidone) 2 extension trial.-12
`
`Safety and tolerability
`The safety amesment is based on data from over 2600 human
`subjects exposed to ltrrasidone (in Phase I. II. and III studies)
`withalrmst 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 extensim
`phasos (Table l). The first results ofthe PEARL safety trial over
`12 months were also inclrrded”--“ Additional information is
`
`provided in the product monograph.I ’Thc dose range cxaminsd
`in the Phase II and III trials was 20—120 mg/day (doses up to
`600 mglday were evaluated in Phase I trials).
`
`Common adverse events
`
`Safety data based on pooled analyses from five short—term.
`placebo-controlled studies included 1004 lurasidonc-treated
`paticntsand455 placebo-treated pationts.”-”""I'hc most com-
`mon adverse reactions (incidence 2 5% and at least twice the
`
`rate of placebo) in patients rccciving lurasidonc wen: akathisia
`(15%). nausea (12%). sedation (12%). somnolcncc (11%).
`
`parkinsonism (11%), insomnia (8%). agitation (6%), anxiety
`(6%). and dystonia (5%). Apparent dosc-rclatcd adverse mac-
`tions were akathisia and somnolence. Other common adverse
`
`events did not appear to be dose-related.
`The long—term. risperidone—controllod trial substantiated
`the favorable profile of lurasidone. with a significantly lower
`incidence of somnolencc, constipation, and weight increase
`(Table 3).~"-“ This trial also suggested that akathisia. musea. and
`vomiting may occur more frequently with lumsidone than with
`rispcridonc. Similar results were observed in a short-tom. quetia-
`pinecontrollod trial .-“ The slnrt—term. ziprasidonecomolled trial
`found a statistically significant difference only in sedation.2R
`
`Table 3 Common adverse events for lur‘asldone versus active comparator‘"m‘
`Long-term trials
`Admins
`Short-term trials
`orosom (I 2 months)
`01050233 PEARL 3 (6 weelo)
`event (’6)
`01050254 (3 weeks)
`Lurasldone
`lemldone
`Lurasldone
`Lumldone
`Quethplne
`Placdao
`Lumldone
`Rlsperldone
`
`I20 mg/day
`l60 mglday
`80 mglday
`l60 myday
`“0 mglday
`40—!20 rug/day
`2-6 mg/day
`Akathista
`3.3
`6.6
`8
`9
`2
`l
`I43
`7.9
`Nausea
`7.3
`4.6
`8
`6.6
`3.4
`3.3
`| 6.7
`l0.9
`
`8
`Vomiting
`Park] monlsm —
`Sormolence
`6.7
`Sedation
`4.7
`Insomnia
`I0.7
`Headache
`6.7
`Dizziness
`2.7
`Dry mouth
`—
`Constipation
`—
`Weight gain
`-
`
`4
`—
`9.9
`l l.3
`9.3
`4.6
`6.6
`—
`-
`—
`
`-—
`5.6
`4
`—
`-
`..
`4.8
`L6
`2.4
`0.8
`
`—-
`6.6
`6.6
`-
`~
`,.
`5.8
`L7
`0.8
`L7
`
`-
`3.4
`l 3.4
`-
`—
`»
`13.4
`7.6
`6.7
`6.7
`
`—
`0
`0.8
`-
`~
`~»
`I]
`0.8
`2.5
`0.8
`
`IO
`4.3
`| 3.6
`-
`—
`~
`-
`—
`| .9
`9.3
`
`33
`5.4
`I7.B
`-
`~
`~—
`-
`—
`6.9
`I93
`
`Therapeutics and Clinical Risk Management 20l l:7
`
`’r"-"'“’~tm'"~"‘“w'r'-
`
`"
`
`~
`
`i'kwe- »
`
`.-
`
`245
`
`CONFIDENTIAL
`
`

`

`Samalin et al
`
`Extrapyramidal symptoms, akathisia,
`and dyskineslas
`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.
`ln the short—term. fitted—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-trcated 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 akatliisia (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 Banies Akathisia Scale (lurasidonc
`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 cxtrapyramidal
`side effect (including dystonia) occurred with the highest
`dose of lurasidonc (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
`on the potential risk for tardive dyskinesia are still lacking,
`
`Down}. *1”
`
`because ofthe limited information available fiom long-term
`clinical trials.
`
`Metabolic side effects
`Glucose metabolism
`
`Pooled data front short-term. placebo-controlled studies
`showed a mean increase in fasting glucose of 1.4 rngi'dL in
`the Iurasidone group compared with a 0.6 mg/dL increase in
`the placebo group.”-"-” There was no dose-response relation-
`ship in the lurasidone group (Table 4'). Changes in fasting
`glucose (mean from baseline and proportion ofpatients with
`shifts to 2126 nrg:'dL) in lurasidone-mted patients were not
`statistically difi‘erent from placebo—treated patients.
`The uncontrolled longer-tenn trials (primari ly open-label
`
`extension studies) reported a mean change in glucose of
`+1.6 mgidL at week 24 (n = l86). +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 lumsidone and ziprasidone
`(+4.7 versus +4.8 mg/dL).29 ln pooled short-term trial analy-
`sis. the median changes in glucose associated with lurasidonc
`was unchanged (0.0). increased for olanzapinc and haloperi -
`do] (+4.0 and +2.0, respectively), and for placebo remained
`essentially unchanged (+l.0)." in a longer-temi safety trial.
`the median change from baseline in glucose observed was
`significantly different (P = 0.00l) in favor of lurasidone. with
`a mean decrease of —0.5 mg/dL versus a mean increase 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 effect: of lurasidonc from short-term tn‘als“"’
`Placebo
`Lumidone
`
`l20 rug/day
`80 rug/day
`40 mglday
`‘20 mglday
`Gaga}.................................................................................................................................................................................................................................-
`Mean mange from baseline (mg/dL)
`~OJ
`—0.6
`2.5
`-0.9
`2.5
`> I 26 mgldL (‘73)
`as
`l 1.7
`I43
`l0.0
`|0.0
`Total cholesterol
`
`Mean change from baseline (mg/dL)
`> 240 mgfdl. (Yo)
`Triglycerides
`Mean change from baseline (mg/til.)
`5:200 m gldL (76]
`We‘ght
`
`Mean change from baseline (kg)
`
`—8.S
`6.6
`
`-IS.7
`IZS
`
`0.26
`
`—- 11.3
`13.8
`
`—-29.l
`14.3
`
`-O.I S
`
`-9.4
`7.3
`
`-6.2
`MD
`
`0.67
`
`—9.8
`6.9
`
`- I4.2
`8.7
`
`I I4
`
`—3.8
`3.8
`
`-3.l
`10.5
`
`0.68
`
`246
`
`iohznitymvms-mmp;
`Ur-t’e‘,
`..
`
`..
`
`.
`
`CONFIDENTIAL
`
`Therapeutics and Clinical Risk Management 20| l:7
`
`

`

`m)\'e;'-"’\i\
`
`Lurasidone tor schizophrenia
`
`from baseline and proportion of patients with shifts) in
`lurasidone—treated patients were not significantly different
`from placebo-treated patients.
`The uncontrolled longer-term studies (primarily open-
`label extension studies) reported no increase in mean change
`oftotal cholesterol and triglycerides.*7 Lurasidone was asso
`ciated witha mean change in total cholesterol and triglycer-
`ides (mg/d1.) of—4,2 (n = 186) and —13.6 (n = 187) at week
`24. —l.‘) (n = 238) and —3.5 (n = 238) at week 36. and —3.6
`
`(n = 243) and —6.5 (n — 243) at week 52, respectively.
`In active comparator—controlled studies. treatment with
`lurasidone versus riprasidone was associated with a greater
`reduction in triglycerides (—2.6 versus +22.4 mg/dL) and
`similar endpoint reduction in total cholesterol (—6.4 versus
`4.