THE OHIO STATE UNIVERSITY LIBRARIES
`Received onz 02-25-03
`BPL-B1o Sci/Pharm Lib.
`RM1D84
`C.l
`1
`'\ ( . 2-
`JJ D. 10
`
`Jn t"l'\
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 001
`
`

`
`Drugs
`of the
`Future
`
`Editor: J.R. Prous
`Chemical Editorial Staff: J. Castaiier, R.M. Castaiier, M. del Fresno, L. Martin, J. Prous
`Editorial Staff: M. Bayes, M. Culleii-Young, P. Leeson, N.E. Mealy, X. Rabasseda, L. Revel, J. Silvestre, L.A. Sorbera
`
`Contributing Editors:
`M. Abou-Gharbia (USA), S.K. Ahn (S. Korea), L. de Angelis (Italy), E. de Clercq (Belgium), G. Eastland (USA), J. Engel
`(Germany), R.A. Fromtling (USA), J. Garcfa-Rafanell (Spain), R.G. Glushkov (Russia), L. Hansson (Sweden), S.J. Hopkins (UK), A.
`Hoshi (Japan), J. Kim (S. Korea), H. Koch (Austria), P. Kocis (USA), S.K. Kulkarni (India), G. Leclerc (France), M. Levin (USA),
`W. Uischer (Germany), R. Mannhold (Germany), M. Neuman (France), M. Nikolova (Bulgaria), M. N6gn'ldi (Hungary), R. Panchagnula
`(India), J.T. Penta (USA), S. Radl (Czech Rep.), J. Ruyun {China), F. Uckun (USA), J.T. Xie (China), R.K.-Y. Zee-Cheng (USA)
`
`Drugs of the Future is a monthly publication designed to provide in monograph form information on new drugs from their
`first phases of development up to their marketing.
`
`An information Update section appears monthly providing the most recent information available on drugs whose mono(cid:173)
`graphs were published in the same-numbered issue of previous volumes. Drug information in this section can be con(cid:173)
`sulted by developmental phase or alphabetical order.
`
`Articles on topical fields, presented by leading specialists, explore the innovative areas of drug research and highlight the
`mechanisms by which drugs act, relating chemical structures to specific biological activities.
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 002
`
`

`
`Drugs
`of the
`Future
`
`Contents
`
`Volume 27, Number 10, 2002
`
`Monographs
`923 Erlotinib Hydrochloride. Oncolytic, EGF receptor inhibitor. L.A. Sorbera, J. Castaner, J.S. Silvestre, M. Bayes
`935 Minodronic Acid. Treatment of osteoporosis, Treatment of bone metastasis, Treatment of multiple myeloma.
`L.A. Sorbera, J. Castaner, P.A. Leeson
`942 Pipendoxifene. Treatment of breast cancer, Estrogen receptor modulator. L.A. Sorbera, J. Castaner, J.S. Silvestre
`
`961
`
`Review Articles
`949 Biological activities of resveratrol and its analogs
`F. Wolter, J. Stein
`Carrier systems for the treatment of inflammatory bowel disease
`A. Lamprecht, A. Stallmach, Y. Kawashima, C.-M. Lehr
`973 Present and future pharmacotherapy for benign prostatic hyperplasia
`S.A. Doggre/1
`987 Small-molecule glucagon receptor antagonists
`A. Ling
`
`Annual Review: Psychopharmacologic Drugs
`998 Aripiprazole
`1001 Blonanserin
`1002 Deramciclane Fumarate
`1002 Duloxetine Hydrochloride
`1005 E-5842
`1005 Escitalopram Oxalate
`1007 Gepirone Hydrochloride
`1008
`lloperidone
`
`1010 Lamotrigine
`1013 Lesopitron Dihydrochloride
`1014 MDL-100907
`1014 Nemifitide Ditriflutate
`1015 Org-5222
`1016 Pagoclone
`1016 Perospirone Hydrochloride
`1017 Pregabalin
`1018 Vilazodone Hydrochloride
`1019 Spotlights
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 003
`
`

`
`Drugs of the Future 2002, 27(10): 995-1027
`Copyright© 2002 PROUS SCIENCE
`CCC: 0377-8282/2002
`
`Annual Review 2002
`
`Psychopharmacologic Drugs·
`
`N.E. Mealy, R. Castafier, L. Martin, M. del Fresno, L. Revel, M. Bayes, M. Stringer,
`L.A. Sorbera, P. Cole, M. Guile//- Young, P.A. Leeson, J. Prous
`
`Abstract
`
`This month's Annual Review is dedicated to updated information on psychopharmacologic drugs. The fol(cid:173)
`lowing table lists 86 drugs under development in this area, some of which have been published in previous
`issues of the journal and others that have been marketed for an indication other than that discussed in the
`review. Information on the following 17 products is updated here: aripiprazole, blonanserin, deramciclane
`fumarate, duloxetine hydrochloride, E-5842, escitalopram oxalate, gepirone hydrochloride, iloperi(cid:173)
`done, lamotrigine, lesopitron dihydrochloride, MDL-100907, nemifitide ditriflutate, Org-5222, pago(cid:173)
`clone, perospirone hydrochloride, pregabalin and vilazodone hydrochloride. A new addition to the
`Annual Review series, entitled Spotlights, begins this month and provides profiles of drugs which have not
`been previously published in the journal but are under active development in the area under review. Drugs
`featured in the Spotlights section this month are: abaperidone hydrochloride, ACR-16, agomelatine,
`ANPH-101, ANPH-102, aprepitant, AR-A2, AVE-5997, bifeprunox, cannabidiol, CEE-310, CP-122721,
`CX-516, DOV-216303, DU-125530, E-6039, elzasonan hydrochloride, EMR-62218, eplivanserin, eszopi(cid:173)
`clone, gaboxadol, GW-353162, GW-597599, indiplon, itriglumide, levetiracetam, LU-36,138, LY-156735,
`LY-354740, melatonin, NBI-34041, NE-100, NGD-96-3, ocinaplon, olanzapine/fluoxetine, OPC-14523,
`Org-24448, Org-34167, Org-34517, osanetant, R-673, R-1204, saredutant, SB-271046, SB-723620,
`secretin (synthetic human), SEP-174559, sertindole, (R)-sibutramine metabolite, SL-65.1498, SLV-308,
`SLV-310, SLV-313, SLV-314, SLV-319, SM-13496, SNEC-2, sodium oxybate, SR-58611, SR-144190, TAK-
`375, talnetant and valproic acid sodium salt.
`
`We remind our readers that the Prous Science Integrity database provides continously updated informa(cid:173)
`tion on the products covered in this Annual Review.
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 004
`
`

`
`996
`
`Drug
`
`Annual Review 2002: Psychopharmacologic Drugs
`Indication/ Action
`Source
`
`Abaperidone Hydrochloride
`ACR-16
`Agomelatine
`ANPH-101
`ANPH-102
`Aprepitant1
`AR-A2
`Aripiprazole 1
`
`AVE-5997
`Bifeprunox
`Blonanserin1
`Cannabidiol
`CEE-310
`CP-122721
`CX-516
`
`Deramciclane Fumarate1
`DOV-216303
`DU-125530
`Duloxetine Hydrochloride1
`E-58421
`E-6039
`Elzasonan Hydrochloride
`EMR-62218
`Eplivanserin
`Escitalopram Oxalate 1
`
`Eszopiclone
`Gaboxadol
`Gepirone Hydrochloride1
`GW-353162
`
`GW-597599
`
`lloperidone 1
`lndiplon
`ltriglumide 1
`Lamotrigine 1•2
`Lesopitron Dihydrochloride 1
`Levetiracetam 1•2
`LU-35-138
`LY-156735
`LY-354740
`MDL-1009071
`Melatonin
`NBI-34041
`
`NE-100
`Nemifitide Ditriflutate1
`NGD-96-3
`Ocinaplon
`Olanzapine/Fiuoxetine
`OPC-14523
`Org-24448
`Org-34167
`Org-34517
`Org-52221
`Osanetant
`
`Aventis Pharma
`Solvay/Lundbeck
`Dainippon Pharmaceutical
`GW Pharmaceuticals
`GeNeS
`Pfizer
`Cortex/Organon
`Rush Presbyterian-St. Luke's Med. Center
`Orion Corp./Pharmacia
`DOV Pharmaceutical
`Solvay
`Lilly/Shionogi
`Esteve
`Esteve
`Pfizer
`Merck KGaA
`Sanofi-Synthelabo
`Lundbeck/Forest
`Lundbeck!Forest
`Lundbeck
`Sepracor
`Lund beck
`Organon
`GlaxoSmithKiine
`
`GlaxoSmithKiine
`
`Ferrer
`Carlsson Research
`Servier
`Ancile
`Ancile
`Merck & Co.
`AstraZeneca
`Otsuka/Bristoi-Myers Squibb
`
`Antipsychotic
`Antipsychotic
`Antidepressant
`Sleep disorders
`Anxiolytic
`Antidepressant
`Antidepressant
`Antipsychotic
`Bipolar disorder
`Antipsychotic
`Antipsychotic
`Antipsychotic
`Antipsychotic
`Sleep disorders
`Antidepressant
`Antipsychotic
`Autism
`Generalized anxiety disorder
`Antidepressant
`Antidepressant
`Antidepressant
`Antipsychotic
`Antidepressant
`Antidepressant
`Antipsychotic
`Antipsychotic
`Antidepessant
`Panic disorder
`Social anxiety disorder
`Sedative/Hypnotic
`Sleep disorders
`Antidepressant
`Antidepressant
`Bipolar disorder
`Antidepressant
`Anxiolytic
`Antipsychotic
`Novartismtan
`DOV PharmaceuticaVNeurocrine Biosciences Sleep disorders
`Rotta
`Anxiolytic
`GlaxoSmithKiine
`Bipolar disorder
`Esteve
`Generalized anxiety disorder
`UCB
`Bipolar disorder
`Lund beck
`Antipsychotic
`Lilly/Phase 2 Discovery
`Sedative/Hypnotic
`Lilly
`Anxiolytic
`Aventis Pharma
`Sleep disorders
`Paladin/Neurim
`Sleep disorders
`Neurocrine Biosciences
`Antidepressant
`Neurocrine Biosciences/GiaxoSmithKiine
`Anxiolytic
`Taisho
`Antipsychotic
`lnnapharma
`Antidepressant
`Neurogen/Pfizer
`Sleep disorders
`DOV Pharmaceutical/Elan
`Generalized anxiety disorder
`Lilly
`Antidepressant
`Otsuka
`Antidepressant
`Cortex/Organon
`Antipsychotic
`Organon
`Antidepressant
`Organon
`Antidepressant
`Organon
`Antipsychotic
`Sanofi-Synthelabo
`Antidepressant
`Antipsychotic
`
`Phase
`
`I
`I
`Ill
`II/III
`II
`Ill
`I
`R-2002
`Ill
`I
`II
`Ill
`I
`II
`II
`II
`II
`Ill
`I
`II
`Pre reg
`II
`I
`II
`I
`II
`L-2002
`L-2002
`Ill
`Ill
`11/111
`Pre reg
`I
`I
`II
`II
`Ill
`Ill
`I
`Ill
`II
`Clinical
`I
`I
`I
`I
`Pre reg
`I
`I
`II
`IIIII I
`I
`II
`Ill
`II
`II
`II
`II
`Ill
`II
`II
`
`Continued
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 005
`
`

`
`Drug
`
`Pagoclone1
`
`Perospirone Hydrochloride 1
`L-2001
`Pregabalin 1
`R-673
`R-1204
`
`Saredutant1
`SB-271046
`SB-723620
`
`Secretin, Synthetic Human
`SEP-174559
`Sertindole
`(R)-Sibutramine Metabolite
`SL-65.1498
`SLV-3081
`
`SLV-310
`SLV-313
`SLV-314
`SLV-319
`SM-13496
`SNEC-2
`Sodium Oxybate
`SR-58611
`SR-144190
`
`TAK-375
`Talnetant
`Valproic Acid Sodium Salt1•2
`Vilazodone Hydrochloride1
`
`Annual Review 2002: Psychopharmacologic Drugs
`Source
`Indication/ Action
`
`lndevus
`
`Anxiolytic
`Generalized anxiety disorder
`Sumitomo Pharmaceuticals/Mitsubishi Pharma
`
`Pfizer
`Roche
`Roche
`Roche
`Sanofi-Synthelabo
`GlaxoSmithKiine
`GlaxoSmithKiine
`
`ChiRhoCiin/Repligen
`Sepracor
`Lund beck
`Sepracor
`Sanofi-Synthelabo
`Solvay
`
`Solvay
`Solvay
`Solvay
`Solvay
`Sumitomo Pharmaceuticals
`Synaptic
`Orphan Medical
`Sanofi-Synthelabo
`Sanofi-Synthelabo
`Sanofi-Synthelabo
`Takeda
`GlaxoSmithKiine
`Dainippon Pharmaceutical
`Merck KGaA!GiaxoSmithKiine
`
`Generalized anxiety disorder
`Antidepressant
`Anxiolytic
`Antidepressant
`Antidepressant
`Antipsychotic
`Antidepressant
`Anxiolytic
`Autism
`Anxiolytic
`Antipsychotic
`Antidepresant
`Anxiolytic
`Antidepressant
`Anxiolytic
`Antipsychotic
`Antipsychotic
`Antipsychotic
`Antipsychotic
`Antipsychotic
`Antidepressant
`Anti narcoleptic
`Antidepressant
`Antidepressant
`Anxiolytic
`Sedative/Hypnotic
`Antipsychotic
`Bipolar disorder
`Antidepressant
`
`1Previously published in Drugs of the Future. 2Launched for another indication.
`
`997
`
`Phase
`
`Ill
`II
`Antipsychotic
`
`II
`II
`I
`I
`II
`I
`I
`I
`Ill
`I
`R-2001
`
`L-2002
`II
`I
`I
`II
`II
`R-2002
`II
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 006
`
`

`
`998
`
`Annual Review 2002: Psychopharmacologic Drugs
`
`Aripiprazole
`
`'
`The first of a new generatipn pf, ?typical ~ntipsy­
`chotics, aripiprazale (OPC-14597, Abilif~)' acts as a
`dop<}mine D2 and 5-HT1A rec!'lptor eartial agoplst and
`a 5-HT2 receptor antagonist. The compound has been
`sugge~ted t9 act as a doRamine/5-HT ~ystem stabiliz(cid:173)
`er (1-4). The FDA just approved the" NDk f,(led by
`Otsuka and licensee Bristoi-Myli!rS S~uibb for .its use in
`the treatment ,.of schizophrerija. It is also. undergoing
`phase Ill clinical testing by both companies for the
`treatment of bipolar disorder. An MAA is under review
`in Europe (5-7).
`
`The cardiovascular effects of aripiprazole were com(cid:173)
`pared to those of haloperidol in a halothane-anesthetized
`canine model. The drugs were infused over 10 min at
`escalating doses of 0.03, 0.3 and 3.0 mg/kg with 20-min
`intervals between doses. Aripiprazole at doses of
`0.03-0.3 mg/kg had positive chronotropic, inotropic and
`dromotropic effects and resulted in shortening of the ven(cid:173)
`tricular effective refractory period and repolarization
`phase. Dose-dependent decreases in total peripheral
`resistance were also observed. At 0.1 mg/kg/min, esmolol
`antagonized these changes. The 3.0 mg/kg dose of arip(cid:173)
`iprazole attenuated the cardiac effects produced by the
`lower doses and induced negative chronotropic, dro(cid:173)
`motropic and hypotensive actions and prolongation of the
`ventricular effective refractory period and repolarization
`phase. The only significant change seen with the lowest
`dose of haloperidol was a decrease in peripheral resis(cid:173)
`tance. Haloperidol 0.3-3.0 mg/kg produced dose-depen(cid:173)
`dent negative chronotropic, inotropic and hypotensive
`effects, intraventricular conduction delay and prolonga(cid:173)
`tion of the ventricular effective refractory period and repo(cid:173)
`larization phase. These effects were accompanied by a
`further decrease in peripheral resistance. Aripiprazole
`had less potent inhibitory effects on cardiovascular para(cid:173)
`meters than haloperidol at clinically relevant exposure,
`and appeared to be safer than haloperidol as it. did not
`induce afterdepolarization or prolong the ventricular elec(cid:173)
`trical vulnerable period (8).
`Patients with stable chronic schizophrenia treated
`with 15 mg/day of aripiprazole presented greater impro(cid:173)
`vement in efficacy parameters (PANSS [Positive And
`Negative Syndrome Scale] total score and PANSS posi(cid:173)
`tive subtotal score) and a lower relapse rate than place(cid:173)
`bo-treated patients. Aripiprazole showed a favorable
`safety and tolerability profile comparable to placebo (9).
`
`The safety, tolerability and pharmacokinetics of arip(cid:173)
`iprazole were assessed in 12 children and 11 adolescents
`with conduct disorder. Dosing was revised according to
`weight due to nausea and sedation in younger subjects
`to 1 mg if< 25 kg, 2 mg if 25-50 kg, 5 mg if 50-70 kg and
`10 mg if> 70 kg. The drug was safe and well tolerated,
`with no serious adverse events or clinically relevant
`changes in vital signs, EGG or laboratory parameters,
`and accumulation was comparable among children, ado(cid:173)
`lescents and adults (1 0).
`A multicenter, double-blind, placebo-controlled trial in
`404 patients with acute exacerbations of schizophrenia or
`schizoaffective disorder randomized patients to receive
`once-daily aripiprazole 20 or 30 mg, twice-daily risperi(cid:173)
`done 6 mg or placebo for 4 weeks following a washout
`periood. Aripiprazole and risperidone proved to be signif(cid:173)
`icantly more effective than placebo in terms of changes
`from baseline in the total PANSS and the positive and
`negative subscales of the PANSS, as well as the Clinical
`Global Impression severity of illness and improvement
`scores. The active treatment groups also showed a sig(cid:173)
`nificantly higher responder rate compared to placebo.
`Aripiprazole was not associated with worsening of
`extrapyramidal symptoms, increase in serum prolactin or
`changes in Q-Tc interval compared to placebo, whereas
`risperidone produced a significant increase in prolactin
`levels (11, 12). The results of this study and some that fol(cid:173)
`low are summarized in Table I.
`The effects of short- and long-term administration of
`aripiprazole on weight were evaluated in a meta-analysis
`of several 4-6-week studies (n=1648), as well as a 1-year
`study (n=1294) and a 26-week trial (n=255). Patients
`either experienced slight gain in weight or weight loss
`when treated with aripiprazole. Studies with an active
`control showed that aripiprazole-related weight gain was
`similar to that with haloperidol and less than that with
`olanzapine. Neither short- nor long-term administration of
`aripiprazole was associated with prolongation of the Q-T
`interval, and its low potential for extrapyramidal symp(cid:173)
`toms, prolactin elevation and somnolence was also
`confirmed (13-16).
`In the 1-year study in patients (n=1294) with acute
`relapse of chronic schizophrenia, aripiprazole 30 mg/day
`resulted in higher response rates than haloperidol 10
`mg/day (62.4% vs. 54.9%) and induced significant
`improvements in negative symptom scores and depres(cid:173)
`sive symptom. Doses could be reduced to 20 and
`7 mg/day, respectively (17, 18).
`Aripiprazole was safe, effective, well tolerated and
`demonstrated linear pharmacokinetics at doses of 30-90
`mg/day in a randomized, double-blind study in 40 patients
`with stable schizophrenia or schizoaffective disorder. In
`this study, doses of 30, 45, 60, 75 and 90 mg/day were
`evaluated over 15 days. The only adverse event associ(cid:173)
`ated with a gradual increase in the aripiprazole dose from
`30 mg/day to 90 mg/day was a higher incidence of
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 007
`
`

`
`Drugs Fut 2002, 27(1 0)
`
`999
`
`Table 1: Clinical studies of aripiprazole (from Prous Science lntegrityi!Y).
`
`Indication
`
`Design
`
`Treatments
`
`Schizophrenia Randomized,
`double-blind,
`multicenter
`
`Aripiprazole, 20 mg od x 4 wk (n=1 01)
`Aripiprazole, 30 mg od x 4 wk (n=191)
`Risperidone, 3 mg bid x 4 wk (n=99)
`Placebo (n=1 03)
`
`Schizophrenia Pooled/
`meta-analysis
`
`Aripiprazole x 4-52 wk
`Haloperidol, 10 mg od x 4-52 wk
`Risperidone, 6 mg/d x 4-6 wk
`Olanzapine, 6 mg od x 4-26 wk
`Placebo
`
`Schizophrenia Randomized,
`double-blind,
`multicenter
`
`Aripiprazole, 30 mg od x 52 wk (n=861)
`Haloperidol, 10 mg od x 52 wk (n=433)
`
`Schizophrenia Randomized,
`double-blind
`
`Aripiprazole, 30 mg/d x 15 d (n=12)
`Aripiprazole, 45 mg/d x 15 d (n=7)
`Aripiprazole, 60 mg/d x 15 d (n=7)
`Aripiprazole, 75 mg/d x 15 d (n=7)
`Aripiprazole, 90 mg/d x 15 d (n=7)
`
`Schizophrenia Randomized,
`double-blind,
`multicenter
`
`Aripiprazole, 15 mg/d x 26 wk
`Placebo
`
`Bipolar
`disorder,
`mania
`
`Randomized,
`double-blind,
`multicenter
`
`Aripiprazole, 30 mg (decreased to 15 mg if not
`tolerated) x 3 wk
`Placebo
`
`n
`
`Conclusions
`
`Ref.
`
`404 Aripiprazole was safe and as effective 12
`as risperidone in the treatment of
`positive and negative symptoms of
`patients with relapsed schizophrenia
`or schizoaffective disorder
`
`13-16, 30
`
`1648 Aripiprazole induced a minimal
`weight gain when compared with
`haloperidol, with a greater difference
`versus olanzapine, in patients with
`schizophrenia or schizoaffective
`disorder. Both short- and long-term
`treatment with aripiprazole were
`associated with a low potential for EPS,
`weight gain, increase in prolactin levels,
`QTc prolongation and somnolence
`
`15, 18
`
`1294 Greater response rates, lower
`discontinuation rates and higher
`improvements in negative subscale
`scores and depressive symptoms were
`found for aripiprazole compared with
`haloperidol in patients with schizophrenia.
`The incidence of extrapyramidal adverse
`events was lower with aripiprazole
`
`19, 20
`
`40 Treatment with aripiprazole 30-90
`mgld was safe, well tolerated and
`effective in controlling symptoms in
`patients with schizophrenia or schizo(cid:173)
`affective disorder, although there was
`an increased incidence of akathisia and
`tachycardia in the 90-mg dose group
`
`310 Aripiprazole was well tolerated , with
`an adverse event profile similar to that
`of placebo and effective in decreasing
`the number of patients with relapse,
`increasing the time to relapse by 2-fold
`and improving the PANSS score in
`patients with stable chronic schizophrenia
`
`21
`
`262 Aripiprazole was well tolerated and
`effective in inducing significant impro(cid:173)
`vements in the Young Mania Rating
`Scale Total score in patients with acute
`and bipolar mania
`
`22, 23
`
`Schizophrenia Randomized
`
`Aripiprazole, 30 mg/d (abrupt discontinuation
`311 Switching to aripiprazole was safe,
`well tolerated and effective in
`of other antipsychotics) x 8 wk (n=104)
`Aripiprazole, 30 mg/d + current antipsychotics
`improving PANSS and CGI scores in
`patients with schizophrenia or schizo-
`(tapering off over 2 wk) x 8 wk (n=104)
`Aripiprazole, 10-30 mg/d (titrated over 2 wk) +
`affective disorder, showing less
`extrapyramidal events, reduced weight
`current antipsychotics (tapering off over 2 wk)
`and decreased serum prolactin levels
`x 8 wk (n=103)
`------------------------------------------------------------------------------------------------
`169 Compared with olanzapine,
`26
`Aripiprazole, 30 mg od x 26 wk (n=76)
`Schizophrenia Open,
`aripiprazole significantly improved
`multicenter
`Olanzapine, 15 mg o.d. x 26 wk (n=93)
`secondary verbal memory and induced
`less weight gain in patients with stable
`schizophrenia
`
`24, 25
`
`Schizophrenia Open,
`pooled/
`meta-analysis
`
`Aripiprazole, 30 mg/d x 14 d ~ Aripiprazole,
`30 mg/d x 22 d + Lithium (titrated from 900 mg
`until serum concentrations 1.0-1.4 mEq/1
`for >1=5 d) x 22 d (n=7)
`Aripiprazole, 30 mg/d x 14 d ~ Aripiprazole,
`30 mgld x 22 d + Valproate semisodium,
`50-125 mg/1 x 22 d (n=6)
`
`13
`
`Concomitant administration of
`aripiprazole and either lithium or
`valproate semisodium was safe and
`well tolerated by patients with
`schizophrenia or schizoaffective disorder
`
`27
`
`Continued
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 008
`
`

`
`1000
`
`Annual Review 2002: Psychopharmacologic Drugs
`
`Table I (Cont.): Clinical studies of aripiprazole (from Prous Science Integrity®).
`
`Indication
`
`Design
`
`Treatments
`
`n Conclusions
`
`Aripiprazole, 2 mg od x 4-6 wk (n=59)
`Schizophrenia Pooled/
`meta-analysis Aripiprazole, 10 mg od x 4-6 wk (n=165)
`Aripiprazole, 15 mg od x 4-6 wk (n=207)
`Aripiprazole, 20 mg od x 4-6 wk (n=199)
`Aripiprazole, 30 mg od x 4-6 wk (n=263)
`Haloperidol, 10 mg od x 4-6 wk (n=167)
`Risperidone, 6 mg od x 4-6 wk (n=1 00)
`Placebo (n=380)
`
`1540 All aripiprazole doses higher than
`2 mg od significantly improved the
`positive and negative symptoms of
`schizophrenia and schizoaffective
`disorder just 1 week after
`beginning therapy
`
`Ref.
`
`28, 29
`
`akathisia and tachycardia that resulted in no discontinua(cid:173)
`tions (19, 20).
`A multicenter, randomized, double-blind, placebo-con(cid:173)
`trolled trial in 310 chronic, stable schizophrenic patients
`was conducted to assess relapse after treatment with
`aripiprazole 15 mg/day for 3 months. Compared with
`placebo, significantly fewer patients taking aripiprazole
`relapsed (57% and 34%, respectively), and the drug
`doubled the time to relapse. Aripiprazole was well
`tolerated (21 ).
`Aripiprazole 30 mg/day or placebo was administered
`to 262 patients with acute bipolar mania for 3 weeks in a
`randomized, double-blind phase Ill trial. Aripiprazole was
`well tolerated and significantly superior to placebo in the
`primary efficacy measure, the Y-MRS total score, as well
`as in the response rate (40% vs. 19%). The drug was
`effective within the first week of treatment (22, 23).
`A multicenter, randomized, open-label phase Ill study
`compared the effects of switching from typical or atypical
`antipsychotic monotherapy to aripiprazole monotherapy
`in a population of 311 patients suffering from chronic, sta(cid:173)
`ble schizophrenia or schizoaffective disorder. Switching
`was equally safe and effective when it was done abruptly
`or over a 2-week period (tapering off the previous antipsy(cid:173)
`chotic with or without gradually increasing the aripipra(cid:173)
`zole dose administered to the patients) (24, 25).
`Aripiprazole 30 mg once daily was better than olanza(cid:173)
`pine 15 mg once daily in improving the secondary verbal
`memory of patients with schizophrenia, although both
`treatments were equally effective in improving general
`cognitive function and the clinical situation of the
`patients (26).
`The pharmacokinetics and safety of coadministration
`of aripiprazole and lithium or divalproex sodium were
`investigated in 2 open-label studies in patients with schiz(cid:173)
`ophrenia or schizoaffective disorder. Aripiprazole 30
`mg/day was given on days 1-14 and either lithium or
`divalproex sodium on days 15-36. While the mood-stabi(cid:173)
`lizing agents affected pharmacokinetic variables of arip(cid:173)
`iprazole, the pharmacokinetics of the active metabolite
`were only slightly altered. Coadministration of these
`agents was deemed safe by the investigators (27).
`Meta-analyses of multicenter, double-blind, placebo(cid:173)
`controlled studies of aripiprazole treatment in patients
`
`with acute relapse of schizophrenia or schizoaffective dis(cid:173)
`order found that the drug was significantly better than
`placebo in antipsychotic efficacy at doses over 2 mg/day.
`Significant efficacy was seen 1 week after initiating
`treatment. It also showed a good safety and tolerability
`profile, with no significant changes in akathisia scale
`scores, plasma prolactin or Q-Tc prolongation compared
`to placebo or reference drugs (haloperidol, risperidone).
`Moreover, aripiprazole was associated with a lower
`increase in body weight (28-30).
`
`1. Jordan, S., Koprivica, V., Chen, R., Dunn. R .. Tottori, K., Kikuchi. T ..
`Altar, C.A. The antipsychotic aripiprazole is a potent, partial agonist at the
`human 5-HT1A receptor. Eur Neuropsychopharmacol 2001, 11 (Suppl. 3):
`Abst P.2.059.
`
`2. Jordan, S., Chen, R., Johnson, J., Regardie, K., Tadori, Y., Kikuchi, T.
`Aripiprazole is a potent, partial agonist at cloned human D2L and native rat
`A receptors. Eur Neuropsychopharmacol 2002, 12(Suppl. 3): Abst
`5-HT1
`P.2.094.
`
`3. Byars, A., Burris, K., Jordan, S., Tottori, K., Likuchi, T., McQuade. R.
`Aripiprazole: A dopamine-serotonin system stabilizer. Eur Neuropsycho(cid:173)
`pharmacol 2002, 12(Suppl. 3): Abst P.2.085.
`
`4. Jordan, S., McQuade, R.D., Koprivica, V., Chen, R., Tottori, K., Kikuchi,
`T., Altar, C.A. Aripiprazole is a potent partial agonist at 5-HT1A receptors.
`J Psychopharmacol 2002, 16(3. Suppl.): Abst A29.
`
`5. FDA issues approvable letter for aripiprazole. DailyDrugNews.com
`(Daily Essentials) Sept 4, 2002.
`
`6. Aripiprazole submitted for FDA review as a treatment for schizophrenia.
`DailyDrugNews.com (Daily Essentials) Nov 12, 2001.
`
`7. European MAA submitted for aripiprazole for treatment of schizophre(cid:173)
`nia. DailyDrugNews.com (Daily Essentials) Dec 18, 2001.
`
`8. Sugiyama, A., Satoh, Y .. Hashimoto, K. In vivo canine model compari(cid:173)
`son of cardiohemodynamic and electrophysiological effects of a new
`antipsychotic drug aripiprazole (OPC-14597) to haloperidol. Toxicol Appl
`Pharmacal 2001, 173(2): 120.
`
`9. Carson, W., McQuade, R., Saha, A., Torbeyns, A., Stock, E.
`Aripiprazole versus placebo for relapse prevention in patients with chron(cid:173)
`ic schizophrenia. Eur Neuropsychopharmacol 2002, 12(Suppl. 3): Abst
`P.2.077.
`
`10. Blumer, J.L., Finding, R., Kauffman, R., Batterson, R., Gilbert, D.,
`Bramer, S .. Brown, K., Salazar, D. Pharmacokinetics (PK), tolerability and
`safety of aripiprazole (AR) in children (C) and adolescents (AD) with con(cid:173)
`duct disorder. Clin Pharmacal Ther 2002, 71 (2): Abst MPI-3.
`
`11. Yeung, P.P., Carson, W.H., Saha, A., McQuade, R.D., Ali, M.,
`Stringfellow, J.C. Efficacy of aripiprazole, a novel antipsychotic, in schizo(cid:173)
`phrenia and schizoaffective disorder: Results of a placebo-controlled trial
`with risperidone. Eur Neuropsychopharmacol 2001, 11 (Suppl. 3): Abst
`P.2.040.
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 009
`
`

`
`Drugs Fut 2002, 27(1 0)
`
`1001
`
`12. Yeung, P., Kujawa, M., Carson, W.H., Saha, A., Ali, M., Ingenito, G.
`Aripiprazole and risperidone versus placebo in schizophrenia and
`schizoaffective disorder. J Psychopharmacol 2002, 16(3, Suppl.): Abst
`A30.
`
`13. Jody, D. et al. Meta-analysis of weight effects with aripiprazole. Annu
`Meet Am Psychiatr Assoc (May 18-23, Philadelphia) 2002, Abst NR367.
`
`22. Keck, P.E. et al. Aripiprazole versus placebo in acute mania. Annu
`Meet Am Psychiatr Assoc (May 18-23, Philadelphia) 2002, Abst NR314.
`
`23. Marcus, R., Saha, A., Jody, D., Tourkodimitris, S., Archibald, D.,
`Iwamoto, T. Aripiprazole versus placebo
`in acute mania. Eur
`Neuropsychopharmacol2002, 12(Suppl. 3): Abst P.2.081.
`
`14. Jody, D., Saha, A., Iwamoto, T., Biswas, D., Lin, C-Y., Marcus, R.,
`McQuade, R. Meta-analysis of weight effects with aripiprazole. Eur
`Neuropsychopharmacol2002, 12(Suppl. 3): Abst P.2.084.
`
`24. Medori, R., Gharbia, N., Saha, A., Ali, M., Stock, E., Ingenito, G.
`Switching to aripiprazole monotherapy. Eur Neuropsychopharmacol 2002,
`12(Suppl. 3): Abst P.2.091.
`
`15. McQuade, R., Saha, A., Kaplita, S., Archibald, D., Iwamoto, T., Stock,
`E. Meta-analysis of the safety and tolerability profile of aripiprazole in
`schizophrenia. Eur Neuropsychopharmacol 2002, 12(Suppl. 3): Abst
`P.2.083.
`
`16. Stock, E.G. et al. Meta-analysis of cardiac safety with aripiprazole.
`Annu Meet Am Psychiatr Assoc (May 18-23, Philadelphia) 2002, Abst
`NR364.
`
`17. McQuade, R., Carson, W., Saha, A., Ingenito, G., Ali, M., Archibald, D.
`Aripiprazole for long-term maintenance treatment of schizophrenia. Eur
`Neuropsychopharmacol 2002, 12(Suppl. 3): Abst P.2.078.
`
`18. Kujawa, M.J. et al. Aripiprazole for long-term maintenance treatment
`in schizophrenia. Annu Meet Am Psychiatr Assoc (May 18-23,
`Philadelphia) 2002, Abst NR376.
`
`25. Casey, D.E. et al. Switching to aripiprazole monotherapy. Annu Meet
`Am Psychiatr Assoc (May 18-23, Philadelphia) 2002, Abst NR310.
`
`26. Carson, W., Cornblatt, B., Saha, A., Ali, M., Kern, R., Green, M.
`Neurocognitive benefits of aripiprazole versus olanzapine in stable psy(cid:173)
`chosis. Eur Neuropsychopharmacol 2002, 12(Suppl. 3): Abst P.2.086.
`
`27. Citrome, L.L. et al. Pharmacokinetics and safety of aripiprazole and
`concomitant mood stabilizers. Annu Meet Am Psychiatr Assoc (May
`18-23, Philadelphia) 2002, Abst NR317.
`
`28. Lieberman, J.A. et al. Meta-analysis of the efficacy of aripiprazole in
`schizophrenia. Annu Meet Am Psychiatr Assoc (May 18-23, Philadelphia)
`2002, Abst NR353.
`
`19. Saha, A.A. et al. Safety and tolerability of aripiprazole at doses high(cid:173)
`er than 30 mg. Annu Meet Am Psychiatr Assoc (May 18-23, Philadelphia)
`2002, Abst NR354.
`
`29. Carson, W.H., Stock, E., Saha, A.A., Ali, M., McQuade, A.D., Kujawa,
`M.J., Ingenito, G. Meta-analysis of efficacy of aripiprazole in the treatment
`of schizophrenia. J Psychopharmacol 2002, 16(3, Suppl.): Abst A32.
`
`20. Auby, P., Saha, A., Ali, M., Ingenito, G., Wilber, R., Bramer, S. Safety
`and tolerability of aripiprazole at doses higher than 30 mg. Eur
`Neuropsychopharmacol 2002, 12(Suppl. 3): Abst P.2.079.
`
`21. Pigott, T.A. et al. Aripiprazole versus placebo in the treatment of chron(cid:173)
`ic schizophrenia. Annu Meet Am Psychiatr Assoc (May 18-23,
`Philadelphia) 2002, Abst NR351.
`
`30. Marder, S.R., Saha, A.A., Kaplita, S.B., Archibald, D.G., McQuade,
`A.D., Iwamoto, T., Stock, E. Safety and tolerability meta-analysis of arip(cid:173)
`iprazole in schizophrenia. J Psychopharmacol 2002, 16(3, Suppl.): Abst
`A31.
`
`Original monograph- Drugs Fut 1995, 20(9): 884.
`
`Blonanserin
`
`Pharmacokinetic/pharmacodynamic data from 11
`schizophrenic patients treated with blonanserin at a mean
`daily dose of 12 ± 6.0 mg/day were analyzed. The results
`demonstrated significant correlations between daily dose
`and plasma levels, between plasma level and anti-02
`activity, between plasma levels and anti-5-HT2A activity,
`and between anti-02 and anti-5-HT2A activity, indicating
`that the pharmacological activity of the drug is due to the
`parent compound. It also showed relatively balanced
`activity against 5-HT and dopamine. Little intra- and inter(cid:173)
`individual variation was observed (2, 3).
`Blonanserin was compared with haloperidol in an
`8-week, double-blind study that included 263 patients
`with schizophrenia. Treatment with blonanserin at doses
`of 8-24 mg/day was at least as effective as haloperidol
`(4-12 mg/day) in improving the Final Global Improvement
`Rating (FGIR) score {61.2% vs. 51.3% of patients having
`at least moderate improvement) and was associated with
`a lower incidence of extrapyramidal adverse reactions
`(52.7% vs. 75.4%) (4).
`
`1 . Almira// Prodesfarma granted exclusive rights to Japanese antipsychot(cid:173)
`ic. DailyDrugNews.com (Daily Essentials) May 25, 2001.
`
`F
`
`An antipsychotic agent with potent dopamine 0 2
`and 5-HT2A receptor-antagonist properties, blonan(cid:173)
`serin (A0-5423) was developed by Oainippon Phar(cid:173)
`maceutical, which has licensed the drug to Almirall
`Prodesfarma for exclusive development a11d market(cid:173)
`ing worldwide except for Japan, China, Taiwan an<;t
`South Korea. Blonanserin is expected to be effective
`against both positive and negative symptoms of schiz(cid:173)
`ophrenia, as well as to have few adverse effects, VI.,
`extrapyramidal symptoms and hyp9tension.)t is ~ur­
`rently in phase Ill trials in Japan and phase I evalua(cid:173)
`tion in Europe for the treatment of schizophrenia (1 ).
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 010
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`

`
`1002
`
`Annual Review 2002: Psychopharmacologic Drugs
`
`2. Suzuki, H., Morokawa, Y., Gen. K., Takagi, H., Yamaguchi, N., Tanaka,
`C., Aoba, A. Concentration of AD-5423 (blonaserin), and its plasma
`anti-dopamine (D~ and anti-serotonin (5-HT2) activity, and the plasma
`serotonin/dopamine (SID) ratio.
`In! J Neuropsychopharmacol 2002,
`5(Suppl. 1): Abst P.3.W.081.
`
`3. Akimoto, T., Morokawa, Y., Gen, K., Yamagida, H., Kishiro, M.,
`Kamimura, M., Yamaguchi, N., Aorba, A. The change over time in the
`
`plasma concentration of AD-5423 (blonaserin) and its plasma anti-sero(cid:173)
`tonin (5-HT2)/anti-dopamine (D~ activity (SID) ratio. In! J Neuropsy(cid:173)
`chopharmacol 2002, 5(Suppl. 1 ): Abst P.1.E.044.
`
`4