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`The Official Scientific Journal of the
`Coilegium Internationale
`Neuro—psychnpharmacologicum
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`snfibliéd By theiBr-itigh Library - "The world's knéWlfiglgéwng {BIT 2005
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`ALKERMES V. OTSUKA
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`IPR2017-00287
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`Page 1 of 3
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`OTSUKA EXHIBIT 2005
`ALKERMES v. OTSUKA
`IPR2017-00287
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`

`
`The International journal of
`Neuropsychopharmacology
`
`Official Scientific Journal of the
`
`Collegium Internationale Neuro—psychopharmacologicum (CINP)
`
`
`Volume5 ° Supplement1
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`°
`
`June 2002
`
`Abstracts from the XXIII'CINP Congress,
`Montréal June 23—27, 2002
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`Page 2 of 3
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`, dose reduction was allowed to aripiprazole 20 mg and haloperidol 7 mg. Efficacy
`evaluations inchrded PANSS and MADRS scores.
`Results: A significantly greater proportion of patients treated with aripiprazole
`demonstrated response and remained on treatment at weeks 8, 26, and 52 corn—
`pared to haloperidol (Week 52: 40% vs 27%, p<0.00l). Aripiprazole produced
`statistically significant
`improvements in the PANSS Negative Subscale Score
`at weeks 26 and 52 (both p<0.03). Aripiprazolc also demonstrated significant
`improvement from baseline in depressive symptoms as shown in the MADRS at
`weeks 8, 26. and 52, compared to haloperidol (all p<0.03). The discontinuation
`rate due to an adverse event was significantly lower in the aripiprazole group
`than in the haloperidol group (p<0.00l). The overall incidence of EPS-related
`adverse events was significantly lower with aripiprazole than with haloperidol
`(p< 0.00l). Both treatments resulted in comparable weight gain. There was no
`significant difference in QT, interval between both groups.
`Conclusion: Aripiprazole may represent
`the next-generation antipsychotic
`leading to increased compliance in schizophrenia due to significantly greater
`improvements in negative and depressive symptom, and a superior safety and
`tolerability profile compared to haloperidol.
`
`P.4.E.033 ARIPIPRAZOLE vs. PLACEBO IN THE TREATMENT
`or cnaomc SCHIZOPHRENIA
`
`
`W.H. Carson' T.A. Pigottz, A.R. sm’, Mw Ali’, R.D. McQuadc‘. A.F.
`Torbeyns’, ac. Stock'. [Bristol-Myers Squibb, Wallinglbrd, cr; ’unruem-ry of
`Flort'da, Gainesuille. FL: ’OLrulta Maryland Research .Irulirule, LLC. Rackuille,
`MD; lBristol Myers Squibb, Lawrenceuille. NJ, USA: JBrisrol»Myers Squibb,
`Waterloo. Belgium
`
`Objective: To assess relapse prevention with aripiprazole compared to placebo
`over 26 weeks in patients with chronic but stable schizophrenia.
`Methods: A multicenter, randomized, double-blind. placebo—controlled study
`was conducted in 310 patients with chronic schizophrenia considered stable (no
`significant improvement or worsening in last 3 months and baseline PANSS=82)
`randomized to aripiprazole 15 mg/day or placebo. Efficacy measures included
`timedol—relapse, number of relapses and PANSS total score.
`-
`Results: Compared to placebo, treatment with aripiprazole was shown to be
`effective in increasing time-to—relapse. and resulted in significantly fewer patients
`relapsing at endpoint versus placebo (34% vs. 57%, respectively). Aripiprazole
`produced significantly greater improvement in PANSS total score and PANSS
`positive subscale score, compared to placebo. Patients on aripiprazole showed
`continuing stability on the PANSS negative subscale score. Aripiprazole was
`generally well tolerated with an adverse event profile comparable to placebo. No
`clinically significant changes occurred in SAS, AIMS, and Barnes Akathisia
`scores in either group. There were no elevations in plasma prolactin levels
`with aripiprazole compared to placebo. No clinically important cardiac risks
`were associated with aripiprazole. Weight gain associated with aripiprazole was
`comparable to placebo.
`Conclusion: Aripiprazole was demonstrated to delay the rate of and time to
`relapse in patients with chronic schizophrenia, doing so with a favorable safety
`and tolerability profile. Aripiprazole, therefore. represents an important addition
`to the current antipsychotic armamentarium.
`
`P.4.E.034 SWITCHING To ARIPIPRAZOLE MONOTHERAPY
`
`0. Casey], A.R. Saha1_ M.w. Aliz. D.N. Jody), MJ. Kujawa‘, 5.0. Stocks. G.G.
`lngenitol.
`’ Mental Illness Research. Education and Clinical Center; Portland,
`VA: zOLt-uka Maryland Research Institute. LLC. Roclwille. MD; ’Brt'rlol-Myers
`Squibb, Lawrenceuille, NJ; 4Bristol-Myers Squibb, Plainsbaro, NJ; JBristol-
`Myers Squibb. Walling/0rd. CT. USA
`
`Objectives: To assess the safety and tolerability of switching patients fi'om
`current antipsychotic therapy to aripiprazole, a newly developed antipsychotic,
`with a unique mechanism of action (dopamine-serotonin system stabilizer). The
`impact on efficacy was also evaluated.
`Methods: This multicenter, randomized. 8-week, open-label Phase lll study
`involved 311 patients with chronic, stable schizophrenia or schizoaffective dis-
`order who had received monotherapy with a typical (haloperidol or thioridazine)
`or atypical (risperidone or olanzapine) antipsychotic for 21 month. Patients
`were randomized into 3 groups: Group 1 — lmrncdiate initiation of 30 mg/day
`aripiprazole with simultaneous abrupt discontinuation of current antipsychotic
`(n=lO4), Group 2 — Immediate initiation of 30 mg/day aripiprazole while
`tapering ofi‘ current antipsychotic over 2 weeks (n=lO4), Group 3 — Titration
`of aripiprazole over 2 weeks (from 10 mg/day to 30 mg/day) while tapering off
`current antipsychotic (n=103).
`
`R4.E. Antipwchotics and schizophrenia — 4
`
`8187
`
`Results: Safety and tolerability results were similar across treatment groups.
`There were no difi'erenct: in discontinuations due to adverse events across the
`three groups. Antipsychotic efficacy was maintained in all groups throughout the
`study and improvement was seen from baseline in PANSS—total, -negative_ and
`—positive subsmlm, and CGl-lmprovement Score.
`Conclusions: Switching to aripiprazole is safe and well-tolerated and can be
`initiated at an efficacious dose without having to gradually increase the dose of
`aripiprazole.
`
`P.4.E.035 PHARMACOKJNETICS AND SAFETY OF
`ARIPIPRAZOLE AND CONCOMITANT MOOD
`STABILIZERS
`
`
`1.. Citrome' K losiassenz, N. Bark], K_S. Brown‘, s. Mallikaarjun’, 0.5.
`Salazar‘.
`'Nalhan-S. Kline Irutirule; ’Arlhur P. Noyes Research Foundation,
`Norn'slown. PA: " Bronx Psychiatric Center: Bronx. NY: lBristol—Myers Squibb,
`Milliny'ord, CT: JOLruka Maryland Research lrutimle. LLC. Rachrille, MD, USA
`
`Objective: To assess the pharmacokjnetic and safety profile of aripiprazole,
`an antipsychotic with a unique phannacologic profile of dopamine D; partial
`agonism, serotonin SHTM partial agonism, and SHTM antagonism, when coad-
`ministered with lithium or divalproex sodium.
`Methods: TWO open—label. sequential treatment design studies were conducted
`in chronically institutionalized patients with schizophrenia or schizoafiective
`disorder requiring treatment with lithium (n=7) or divalproex sodium (n=6).
`Patients received aripiprazole 30 mg/day on Days l—l4 and aripiprazole with
`concomitant therapy on Days 15—36. Lithium was titrated from 900 mg until
`serum concentrations reached 1.0—1.4 mEq/L for >5 days. Divalproex sodium
`was titrated to 50—l25 mg/L.
`Results: Coadministration with lithium increased mean Cm. and AUC values
`of aripiprazole by about [9% and 15%, respectively. while the apparent oral
`clearance decreased by 15%. There was no effect on the steady state phar-
`macokinetics of the active metabolite of aripiprazole. Coadministration with
`divalprocx sodium decreased the AUC, Cm, and Cm“ of aripiprazole by 24%,
`26%, and 22%, respectively, with minimal effects on the active metabolite.
`Spontaneous adverse events reported with coadministration of aripiprazole and
`therapeutic doses of lithium or divalproex sodium were consistent with those
`observed with monotherapy of aripiprazole. There were no clinically. relevant
`electroencephalographic changes.
`Conclusion: Aripiprazole can be administered safely with therapeutic doses
`of lithium or divalproex sodium in patients with schizophrenia or schizoalfective
`disorder.
`
`P.4.E.036 [LOPERIDONE ADMINISTERED TWICE-DAILY OR
`ONCE-DAILY IS WELL TOLERATED: A PROSPECTIVE
`DOUBLE-BLIND, RANDOMIZED, PARALLEL-GROUP,
`STUDY
`'
`
`M. Schmidt, T. Mak‘tovits-Gupta, Z. Lin. A. Guven. Nouanis Pharmaceuticals
`Corp, East Hanover. USA
`
`Objective: To compare the safety, tolerability and efficacy of bid and qd dosing
`regimens of iloperidone with haloperidol in patients with chronic schizophrenia.
`Method: Patients (n=120) were randomized in a 222:] ratio to receive bid
`iloperidone (lng/d), employing either alternate day or daily titration schedules,
`or bid haloperidol (lSmg/d). Patients were maintained on these doses until Day
`28, after which the iloperidone patients were re—randomized to receive either
`iloperidone 4 mg bid or 8 mg qd from Days 29 to 42. The dosage could be
`increased to 12 mg/d afier Day 35 if required. The PANSS was used to assess
`efficacy.
`Results: Both bid and qd dosing regimens were generally well tolerated and
`the dropout rate due to AE's was similar in all groups (6—9%). iloperidone was
`not associated with an increase in EPS, and concomitant use of benzt'ropine was
`low in both bid and qd groups (4% each, compared with 64% in the haloperidol
`group).' Efficacy achieved during the first four weeks of treatment was maintained
`at Day 42 in both dosing groups. There were no significant dificrences between
`groups on the PANSS at any timepoint.
`Conclusions: Both qd and bid dosing of iloperidone were safe and well toler-
`ated. The incidence of EPS was low with iloperidone compared to haloperidol.
`There was no loss of efficacy in switching from bid to qd dosing of iloperidone.
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