(12) International Application Published Based on Patent Cooperation Treaty
`
`(19) World Intellectual Property Organization
`
` International Office
`
`
`(43) International Publication Date
`April 3, 2004
`
`
`
`(51) International Patent Classification7: A61K 31/496,
` A61P 25/18 // C07D 417/12
`(21) International Application No.: PCT/JP2003/010490
`(22) International Application Date: August 20, 2003
`(25) Language of International Application: Japanese
`(26) Language of Intl. Application Publication: Japanese
`(30) Priority Data:
`60/404,927 August 22, 2002 US
`(71) Applicant (for all designated states except US):
`Sumitomo Pharmaceuticals Co., Ltd., 2-8 Dosho-
`machi 2-chome, Chuo-ku, Osaka City, Osaka
`Prefecture 541-8510 (JP)
`(72) Inventor: and
`(75) Inventor/Applicant (for US only): NAKAMURA,
`Mitsutaka [JP/JP], c/o Sumitomo Pharmaceuticals Co.,
`Ltd., 2-8 Dosho-machi 2-chome, Chuo-ku, Osaka City,
`Osaka Prefecture 541-8510 (JP); OGASA, Masaaki
`[JP/JP], c/o Sumitomo Pharmaceuticals Co., Ltd., 2-8
`Dosho-machi 2-chome, Chuo-ku, Osaka City, Osaka
`Prefecture 541-8510 (JP); SAMI, Shunsuke [JP/JP],
`c/o Sumitomo Pharmaceuticals Co., Ltd., 2-8 Dosho-
`machi 2-chome, Chuo-ku, Osaka City, Osaka
`Prefecture 541-8510 (JP).
`
`(10) International Publication Number
`
`(74) Agent: KAWAMIYA, Osamu et al.; Aoyama &
`Partners, IMP Bldg., 3-7 Shiromi 1-chome, Chuo-ku,
`Osaka City, Osaka Prefecture 540-0001 (JP)
`
`Designated States
` (domestic):
`
`Designated States
` (broad): ARIPO Patent
`
`Eurasia Patent
`Europe Patent
`
`OAPI Patent
`
`
`
`Appended Published Documents:
`– International Search Report
`
`For two-character codes and other abbreviations, refer to
`“Guidance Notes on Codes and Abbreviations” in each
`periodically published PCT Gazette.
`
`
`
`
`
`
`
`
`
`
`
`
`(54) Title: THERAPEUTIC AGENT FOR SCHIZOPHRENIA
`
`
`
`(57) Abstract: Provided are a novel method for treatment of schizophrenia and a therapeutic agent used therein.
`
`The compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof (for
`
`example, hydrochloride) as an active compound is orally administered to a schizophrenic patient in a daily dose
`
`of 5 mg to 120 mg once per day. According to this method, wide-ranging symptoms of schizophrenia,
`
`especially positive symptoms and negative symptoms, can be relieved without extrapyramidal adverse drug
`
`reactions.
`
`
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 001
`
`

`

`Specification
`
`
`THERAPEUTIC AGENT FOR SCHIZOPHRENIA
`
`
`
`Technical Field
`
`The present invention relates to a novel method for treatment of schizophrenia and a novel therapeutic agent
`
`used therein. More particularly, the present invention relates to a method for improving schizophrenia without
`
`extrapyramidal adverse drug reactions by orally administering a prescribed dose of a specific
`
`bicycloheptanedicarboximide derivative once per day, and a therapeutic agent used in said method.
`
`
`Background Art
`
`Schizophrenia (split personality disorder) is a type of endogenous psychosis, developed mainly during
`
`adolescence. Over time, the personality of a patient progressively breaks down, culminating in mental decay in
`
`some patients. The symptoms of this disease are, for example, positive symptoms often observed during the
`
`early stage of the disease such as hallucination, delusion, etc., or negative symptoms such as apathy and
`
`withdrawal, or cognitive dysfunction such as impairments of concentration and learning abilities, etc. Moreover,
`
`there are other symptoms such as depression, anxiety, etc. as associated symptoms thereof.
`
`Medication is mainly employed in the treatment of schizophrenia, but the treatment of schizophrenia must
`
`be continued for a long time, and even after temporary recovery, there is a large risk of recurrence of
`
`schizophrenia after drug withdrawal, making it necessary to continue the medication forever. Therefore, adverse
`
`drug reactions are serious problems, and from this perspective, it has been desired to develop a medicine
`
`suitable for prolonged administration.
`
`Numerous therapeutic agents for schizophrenia have been used, such as various medicaments classified in
`
`the category of antipsychotics, for example, phenothiazine derivatives (e.g., chlorpromazine,
`
`methoxypromazine, etc.), thioxanthin derivatives having a similar structure to phenothiazine (e.g.,
`
`chlorprothixene, flupentixol, etc.), benzamide derivatives (e.g., sulpiride, sultopride, etc.), thienodiazepine
`
`derivatives (e.g., clotiazepam, etizolam, etc.), and further, butyrophenone derivatives (e.g., haloperidol,
`
`triperidol, etc.), diphenylbutylamine derivatives (e.g., pimozide, etc.), etc.
`
`However, phenothiazine derivatives, phenothiazine analogues, butyrophenone derivatives and the like cause
`
`serious adverse drug reactions including extrapyramidal syndrome exhibiting parkinsonism such as stiffness of
`
`skeletal muscles, muscle tremor, lack of facial expression, salivation, etc. Further, diphenylbutylamine
`
`derivatives may cause extrapyramidal syndrome in addition to insomnia. In addition, these conventional
`
`antipsychotics may be effective on only some of the symptoms of schizophrenia among positive symptoms,
`
`negative symptoms, and cognitive dysfunctions, and there is no drug effective on all of these symptoms.
`
`Therefore, it has been desired to develop a safe medicament that exhibits various excellent effects on
`
`schizophrenia as an antipsychotic without adverse drug reactions such as extrapyramidal syndrome.
`
`On the other hand, it has been known that imide derivatives of the following formula, which was found by
`
`colleagues of the present inventors, may be useful as antipsychotics (neuroleptic agents, antianxiety agents),
`
`especially as agents for treatment of schizophrenia, senile psychosis, bipolar disorder, and neurosis (US Patent
`
`No. 5,532,372).
`
`
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 002
`
`

`

`
`
`
`
`Here, Z is a group having the formula:
`
`
`
` D
`
`;
`
` is a group having the formula:
`
`;
`
`or
`
`, etc.;
`
` G
`
` is:
`
`
`
`
`
`and Ar is an aromatic group, aromatic heterocycle group, etc.
`
`
`
`Summary of the Invention
`
`The present inventors have intensively studied a series of imide derivatives with respect to many aspects
`
`including uses and doses thereof in order to find a novel agent for treatment of schizophrenia which is capable
`
`of exhibiting an excellent effect in the treatment of schizophrenia without adverse drug reactions such as
`
`extrapyramidal syndrome often observed in many conventional antipsychotics, and which can safely be
`
`administered for a long time. As a result, the present inventors found that (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`represented by the following formula:
`
`
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof such as a hydrochloride thereof is effective for relieving the wide-
`
`ranging symptoms of schizophrenia, and may treat schizophrenia very safely without extrapyramidal adverse
`
`drug reactions by orally administering a prescribed dose thereof once per day.
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 003
`
`

`

`Namely, the present invention provides a method for treatment of schizophrenia without extrapyramidal
`
`adverse drug reactions by oral administration of a prescribed amount of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide of the
`
`above formula (1) or a pharmaceutically acceptable salt thereof once per day, and further provides a therapeutic
`
`agent used in said method.
`
`
`
`Brief Description of the Drawings
`
`FIG. 1 is a graph showing the change with time in scores of the Brief Psychiatric Rating Scale (BPRS),
`
`which is an index of effect on schizophrenia, of the active compound of the present invention, (1R,2S,3R,4S)-
`
`N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2.1]heptanedicarboximide hydrochloride, and placebo in a double blind clinical trial.
`
`
`
`Detailed Description of the Invention
`
`As shown in experiments described hereinafter, when a prescribed dose of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-
`
`(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`hydrochloride was orally administered once per day for 6 weeks to patients with schizophrenia in the acute
`
`exacerbation phase, the present inventors found that excellent effects on wide-ranging symptoms were obtained,
`
`and surprisingly, almost none of the extrapyramidal adverse drug reactions observed in conventional
`
`antipsychotics were observed. In particular, abnormal electrocardiogram related to sudden death was not seen.
`
`Hence, the present inventors found this compound may be very safely used in the treatment of schizophrenia.
`
`Namely, the present invention provides a novel method for treatment of schizophrenia that improves wide-
`
`ranging symptoms of schizophrenia including positive symptoms, negative symptoms, and cognitive
`
`dysfunction, especially positive symptoms and negative symptoms, without extrapyramidal adverse drug
`
`reactions, the method comprising orally administering a prescribed dose of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-
`
`(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`of the above formula (1) or a pharmaceutically acceptable salt thereof, especially a hydrochloride thereof, to a
`
`schizophrenic patient once per day.
`
`The present invention also provides a novel agent for such treatment of schizophrenia.
`
`According to the present invention, excellent improvement effects on the wide-ranging symptoms of
`
`schizophrenia may be obtained by orally administering (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-
`
`yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]-heptanedicarboximide or a pharmaceutically
`
`acceptable salt thereof, for example, a hydrochloride, at a daily dose of 5 mg to 120 mg, preferably at a daily
`
`dose of 10 mg to 100 mg, more preferably at a daily dose of 20 mg to 80 mg, once per day. Further, in the
`
`therapeutic method of the present invention, adverse drug reactions such as extrapyramidal adverse drug
`
`reactions such as parkinsonism, dyskinesia, akathisia, etc., abnormal electrocardiogram, and hepatic dysfunction
`
`are hardly observed, and hence, the present method may be very safely used and is suitable for a prolonged
`
`treatment.
`
`Furthermore, when the present method is applied to a patient with schizophrenia in the chronic phase, the
`
`above active compound must be administered to said patient for a long time at a dose as low as possible, and in
`
`such a case, the daily dose of the active compound is in the range of 5 mg to 80 mg, preferably in the range of 5
`
`mg to 60 mg, more preferably in the range of 10 mg to 40 mg, and it is orally administered once per day.
`
`The therapeutic agent used in the method for treatment of schizophrenia of the present invention is in the
`
`form of an oral preparation that contains the compound of the above formula (1) or a pharmaceutically
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 004
`
`

`

`acceptable salt thereof, especially (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride, in an amount
`
`of 5 mg to 120 mg, preferably in an amount of 10 mg to 100 mg, more preferably in an amount of 20 mg to 80
`
`mg, per dosage unit. Examples of the oral preparation include tablets, granules, fine granules, powders, capsules,
`
`syrups, etc. These preparations should be in the form of a preparation for administration once per day.
`
`The above preparations may be prepared by a conventional method by using a conventional
`
`pharmaceutically acceptable carrier usually used in the preparation of a conventional pharmaceutical
`
`formulation, for example, excipients such as lactose, white sugar, glucose, starch, calcium carbonate, kaolin,
`
`talc, crystalline cellulose, silicic acid, etc., binders such as water, ethanol, gelatin, carboxymethylcellulose,
`
`shellac, methylcellulose, gum arabic, tragacanth powder, polyvinylpyrrolidone, etc., disintegrating agents such
`
`as sodium alginate, agar powder, laminaria powder, sodium hydrogen carbonate, polyoxyethylenesorbitan fatty
`
`acid esters, sodium laurylsulfate, stearic acid monoglyceride, etc., and lubricants such as purified talc, stearate,
`
`boric acid powder, polyethyleneglycol, etc.
`
`
`
`Experiments
`
`The method for treatment of the present invention and the effects thereof are illustrated in more detail by
`
`experiments described hereinafter.
`
`The active compound SM-13496 used in the experiments is (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`hydrochloride, and the meanings of the abbreviations used in the experiments are as follows.
`
`DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
`
`CGI-S: Clinical Global Impressions scale-Severity of Illness
`
`CGI-I: Clinical Global Impressions scale-Improvement
`
`AIMS: Abnormal Involuntary Movement Scale
`
`EPS: Extrapyramidal symptoms
`
`LOCF: Last Observation Carried Forward (LOCF Analysis: a method of using last not-missing data in cases of
`
`dropouts)
`
`BAS: Barnes Akathisia Scale
`
`SAS: Simpson-Angust Rating Scale (rating scale for extrapyramidal adverse drug reactions)
`
`PANSS: Positive and Negative Syndrome Scale (rating scale for positive/negative symptoms)
`
`
`
`Experiment 1
`
`Early Phase II Clinical Trial
`
`(1) Test method
`
`According to the outline shown in Table 1 below, a placebo-controlled double blind study was conducted on
`
`149 patients with schizophrenia in the acute exacerbation phase at 15 study centers in the U.S. Efficacy and
`
`safety were studied when SM-13496 at a dose of 40 mg or 120 mg or a placebo was orally administered once
`
`per day for 6 weeks after placebo washout.
`
`
`
`Table 1
`
`Name of
`
`Double-blind, randomized, fixed-dose, placebo-controlled, parallel-group, 6-week
`
`Clinical Trial
`
`efficacy, safety, and tolerability study of two dose levels of SM-13496 in patients with
`
`schizophrenia based on DSM-IV criteria in the acute exacerbation phase.
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 005
`
`

`

`Purpose
`
`To study efficacy and safety in patients with schizophrenia (DSM-IV criteria) in the acute
`
`exacerbation phase in a placebo-controlled, parallel-group, double-blind study.
`
`Subjects
`
`Inclusion criteria:
`
`1) Patients with schizophrenia determined according to DSM-IV criteria who are in the
`
`acute exacerbation phase
`
`2) Patients having an Extracted-BPRS Score of 42 or more, as well as a CGI-S Score of 4
`
`or more
`
`3) Patients having a Simpson-Angus Score of less than 2, as well an AIMS Score of less
`
`than 3
`
`4) Patients suffering from schizophrenia for more than 1 year
`
`5) Males and females aged 18-64 years
`
`Exclusion criteria:
`
`1) Patients with treatment-resistant schizophrenia
`
`2) Patients taking depot injections before finishing one therapy cycle
`
`3) Patients having strong suicidal ideation
`
`4) Patients with Parkinson’s disease, Alzheimer’s disease, drug addiction, convulsive
`
`disorders, epilepsy
`
`5) Women who are pregnant or may be pregnant, and lactating women
`
`6) Patients having drug hypersensitivity
`
`7) Any patients who are judged not to be suitable as subjects by principal investigator
`
`Study Design
`
`Placebo-controlled, randomized, parallel-group comparison, double-blind.
`
`Dosage and
`
`Oral administration of the test compound at a dose of 40 mg/day or 120 mg/day, or placebo
`
`Administration
`
`once per day for 6 weeks.
`
`Route
`
`Washout with placebo for one week (at least three days).
`
`Hospitalization during washout period and for two weeks after start of medication.
`
`Concomitant
`
`1) No concomitant use of other antipsychotics. If another antipsychotic has been taken, it is
`
`Drugs and
`
`necessary to set up a washout period before the trial, at least 3 days for oral drugs and for
`
`Combination
`
`one therapy cycle for depot injections.
`
`Therapy
`
`2) In case of onset of extrapyramidal symptoms, administration of an antiparkinson agent
`
`is allowed.
`
`3) In case of onset of insomnia, lorazepam is used.
`
`Number of
`
`At time of study design: 132 subjects (44 subjects each for the placebo group, the 40 mg-
`
`subjects
`
`treated group and the 120 mg-treated group).
`
`After completion of the trial: 149 subjects (50 subjects for the placebo group, 50 subjects
`
`for the 40 mg-treated group, and 49 subjects for the 120 mg-treated group).
`
`Endpoints
`
`Efficacy: PANSS, Extracted-BPRS, CGI-S/I
`
`Safety: EPS Rating scale (Simpson-Angus, Barnes, AIMS), vital signs (body temperature,
`
`blood pressure, pulse), 12-lead electrocardiogram, laboratory tests (hematologic tests,
`
`biochemical tests of blood, prolactin, urine test], psychosomatic conditions, fundus/slit-
`
`lamp microscopy, adverse events.
`
`
`
` (2) Test results:
`
`1) Evaluation of efficacy:
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 006
`
`

`

` (i) The data according to BPRS and PANSS (LOCF), and CGI-S and CGI-I at the end of the trial are shown
`
`in Table 2 and Table 3, respectively. As is shown in Table 2 and Table 3, the decreases in scores at the end of
`
`the trial (6 weeks after administration) from those prior to administration in the groups treated by SM-13496 40
`
`mg or 120 mg are statistically significant as compared to that in the placebo group with respect to BPRS, CGI-I
`
`and CGI-S evaluations. With respect to PANSS evaluation, a statistically significant difference in the decrease
`
`in score at the end of the study was seen between the SM-13496 120 mg-treated group and the placebo group,
`
`and an improvement in psychotic symptoms by SM-13496 was seen.
`
`
`
`Table 2
`
`Dose
`
`Placebo
`
`SM-13496 40 mg
`
`SM-13496 120 mg
`
`(number of subjects)
`
`(45)
`
`(47)
`
`Evaluation scale
`
`Mean (SD) Mean (SD)
`
`BPRS total score
`
`PANSS total score
`
`-4.0
`
`(8.45)
`
`-5.8
`
`(14.06)
`
`-10.0
`
`(12.79)
`
`-14.1
`
`(23.10)
`
`p value#
`0.014
`
`0.063
`
`(44)
`
`Mean (SD)
`
`-11.3
`
`(8.89)
`
`-17.4
`
`(15.70)
`
`p value#
`0.003
`
`0.010
`
`#: Two-tailed Dunnett’s t-test (comparison between test compound-treated groups and placebo group)
`
`Analysis of covariance using study center and test compound-treated groups as factors, and the values before
`
`administration as covariate
`
`
`
`Table 3
`
`Dose
`
`Placebo
`
`SM-13496 40 mg
`p value#
`0.004
`
`(n=41)
`
`Mean (SD)
`
`SM-13496 120 mg
`p value#
`0.002
`
`(n=40)
`
`Evaluation scale
`
`Mean (SD) Mean (SD)
`
`CGI-S
`
`(n=41)
`
`0.0 (0.77)
`
`-0.7 (1.12)
`
`-0.8 (1.03)
`
`CGI-I
`
`(n=45)
`
`(n=47)
`
`0.013
`
`(n=42)
`
`0.005
`
`4.0 (1.41)
`
`3.2 (1.56)
`
`3.0 (1.29)
`
`#: Two-tailed Dunnett’s t-test (comparison between test compound-treated groups and placebo group)
`
`Analysis of covariance using study center and test compound-treated groups as factors, and the values before
`
`administration as covariate
`
`
`
`(ii) Further, the appended FIG. 1 shows the changes in BPRS total score (LOCF). As is shown in FIG. 1, the
`
`decrease in BPRS scores from before administration in the SM-13496-treated groups are statistically
`
`significantly different from that in the placebo group at week 2 or later (p<0.05).
`
`(iii) The ratio of patients of which BPRS decreased 20% or more or patients exhibiting CGI-I of 1 or 2 at the
`
`end of the test, who are considered responders, is shown in Table 4. As is apparent from Table 4, there was a
`
`statistically significant difference between the SM-13496 40 mg-treated group or 120 mg-treated group and the
`
`placebo group.
`
`
`
`
`
`
`
`
`
`
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 007
`
`

`

`Table 4
`
`Dose
`
`Placebo
`
`SM-13496 40 mg
`
`SM-13496 120 mg
`
`(number of subjects)
`
`(45)
`
`(47)
`
`(44)
`
`
`
`Number of
`
`Number of
`
`p value#
`
`Number of
`
`p value#
`
`Responders
`
`cases
`
`10
`
`cases
`
`26
`
`0.002
`
`cases
`
`22
`
`0.007
`
`#: Cochran-Mantel-Haenszel test adjusting study centers (comparison between test compound-treated groups
`
`and placebo group)
`
`
`
`2) Evaluation of Safety:
`
`(i) Adverse events observed in 10% or more of the patients are shown in Table 5.
`
`
`
`Table 5
`
`
`
`Number of subjects
`
`50
`
`50
`
`49
`
`Placebo
`
`40 mg
`
`120 mg
`
`Number of subjects exhibiting adverse events (%) 36 (72)
`
`40 (80)
`
`38 (78)
`
`Number of subjects exhibiting serious adverse events (%)
`
`Number of subjects who dropped out due to adverse events (%)
`
`3 (6)
`
`2 (4)
`
`3 (6)
`
`3 (6)
`
`6 (12)
`
`6 (12)
`
`Occurrence of adverse events (%)
`
`Digestive disorders
`
`Nausea
`
`Headache
`
`Akathisia
`
`Dizziness (excluding rotatory vertigo)
`
`Sedation
`
`Drowsiness
`
`Exacerbation of schizophrenia
`
`6 (12)
`
`4 (8)
`
`2 (4)
`
`2 (4)
`
`5 (10)
`
`11 (22)
`
`5 (10)
`
`8 (16)
`
`3 (6)
`
`0 (0)
`
`3 (6)
`
`5 (10)
`
`2 (4)
`
`5 (10)
`
`4 (8)
`
`6 (12)
`
`9 (18)
`
`4 (8)
`
`2 (4)
`
`7 (14)
`
`5 (10)
`
`7 (14)
`
`5 (10)
`
`1 (2)
`
`A subject having multiple adverse events was counted as one.
`
`
`
`As is shown in Table 5, 114 subjects among 149 subjects (77%) showed adverse events, but most of them
`
`were mild or moderate. The number of subjects who dropped out from the trial due to the adverse events was
`
`higher in both of the groups treated with SM-13496 than in the placebo group.
`
`The main adverse events were sedation, nausea, headache, akathisia, and dizziness (excluding rotatory
`
`vertigo). The ratio of the subjects showing sedation was 10%, 18%, 14% in the placebo group, the SM-13496
`
`40 mg-treated group, and the SM-13496 120 mg-treated group, respectively. In the SM-13496 120 mg-treated
`
`group, nausea was observed more than in the other groups, but digestive disorders were observed less often than
`
`in the placebo group. Exacerbation of schizophrenia was observed less often in the SM-13496 40 mg- and 120
`
`mg-treated groups (4% and 2%, respectively) than in the placebo group (10%). Akathisia was observed only in
`
`the SM-13496-treated groups, i.e., 8% in the 40 mg-treated group and 14% in the 120 mg-treated group. The
`
`occurrence of adverse events in the groups treated with SM-13496 were the same as that in the placebo group.
`
`Body weight gain, bulimia, impotence, erectile dysfunction and convulsion were not observed.
`
`(ii) The serious adverse events observed in the above phase II clinical trial are shown in Table 6 below.
`
`
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 008
`
`

`

`Table 6
`
`
`
`Occurrence of serious adverse events (%)
`
`Exacerbation of paranoia
`
`Exacerbation of psychosis
`
`Exacerbation of schizophrenia
`
`Paranoid schizophrenia
`
`
`
`Placebo
`
`40 mg
`
`120 mg
`
`Number of subjects
`
`50
`
`50
`
`49
`
`Total (%)
`
`4 (8)
`
`3 (6)
`
`2 (4)
`
`0 (0)
`
`0 (0)
`
`4 (8)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`As is shown in Table 6, serious adverse events were observed in 4 cases of the placebo group, 3 cases of the
`
`SM-13496 40 mg-treated group and 2 cases of the SM-13496 120 mg-treated group, but a causal relationship
`
`with the test drug was ruled out.
`
`(iii) Further, the adverse drug reactions observed in this clinical trial are listed in the following Table 7.
`
`
`
`Table 7
`
`
`
`Number of subjects exhibiting adverse drug reactions (%) 22 (44)
`
`33 (66)
`
`35 (71)
`
`Number of subjects
`
`50
`
`50
`
`49
`
`Placebo
`
`40 mg
`
`120 mg
`
`Psychiatric disorders
`
`Restlessness
`
`Exacerbation of psychosis
`
`Agitation
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`2 (4)
`
`1 (2)
`
`Exacerbation of agitation
`
`Exacerbation of anxiety
`
`Insomnia
`
`Exacerbation of insomnia
`
`Nightmares
`
`Metabolic and nutritional disorders
`
`Anorexia
`
`Decrease in appetite
`
`Skin and hypodermis disorders
`
`Pruritus
`
`Infections and parasitic diseases
`
`Tinea pedis
`
`External otitis
`
`Parotiditis
`
`Urinary tract infection
`
`Vascular diseases
`
`Flushing
`
`Hot flashes
`
`Respiratory tract, thorax, and mediastinum disorders
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`2 (4)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 009
`
`

`

`Laryngopharynx pain
`
`Breathing difficulty
`
`Cardiac disorders
`
`Sinus tachycardia
`
`Palpitation
`
`Gastrointestinal disorders
`
`Nausea
`
`Vomiting
`
`Constipation
`
`Diarrhea
`
`Loose stools
`
`Tongue disorder
`
`Dyspepsia
`
`Flatulence
`
`Dry mouth
`
`Salivary hypersecretion
`
`Abdominal pain
`
`Systemic disorders and administration-localized conditions
`
`Fatigue
`
`Exacerbation of fatigue
`
`Hot sensation
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`0 (0)
`
`1 (2)
`
`3 (6)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`2 (4)
`
`3 (6)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`4 (8)
`
`2 (4)
`
`2 (4)
`
`3 (6)
`
`0 (0)
`
`1 (2)
`
`3 (6)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`3 (6)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`9 (18)
`
`3 (6)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`2 (4)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`Somnolence
`
`Nervous system disorders
`
`Sedation
`
`Akathisia
`
`Dizziness (excluding rotatory vertigo)
`
`Drowsiness
`
`Headache
`
`Extrapyramidal disease
`
`Tremor
`
`Exacerbation of akathisia
`
`Dystonia
`
`Anarthria
`
`Glossoplegia
`
`Cogwheel rigidity
`
`Trismus
`
`Musculoskeletal system and connective tissue disorders
`
`Muscle stiffness
`
`Myalgic pain
`
`Cervical rigidity
`
`Articular rigidity
`
`Melalgia
`
`1 (2)
`
`3 (6)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`3 (6)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`9 (18)
`
`4 (8)
`
`5 (10)
`
`4 (8)
`
`6 (12)
`
`1 (2)
`
`3 (6)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`7 (14)
`
`7 (14)
`
`5 (10)
`
`5 (10)
`
`1 (2)
`
`3 (6)
`
`3 (6)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 010
`
`

`

`Heavy feeling
`
`Laboratory tests
`
`Increase in blood prolactin level
`
`Increase in blood creatine phosphokinase level
`
`Abnormal electrocardiogram
`
`Weight loss
`
`Increase in total protein
`
`Abnormal liver function tests
`
`Renal and urinary tract disorders
`
`Polyuria
`
`Frequent urination
`
`Ocular disorders
`
`Blurred vision
`
`Dry eye
`
`
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`2 (4)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`0 (0)
`
`As is shown in Table 7, among the adverse events, the main adverse drug reactions of which the causal
`
`relationship to SM-13496 cannot be ruled out were sedation, nausea, akathisia, dizziness (excluding rotatory
`
`vertigo), somnolence, and headache. The occurrence of dystonia was low (less than 4%) in the SM-13496-
`
`treated groups. There was no clinically significant change in 12-lead electrocardiogram. There was no
`
`significant difference in the ratio of the patients having an abnormal change in laboratory test values among the
`
`groups. In the SM-13496-treated groups, a moderate increase in blood prolactin level was observed, but there
`
`was no clinically significant change in body temperature, respiration rate, funduscopic examination and slit-
`
`lamp microscopy.
`
`(iv) Further, the results of evaluation of the extrapyramidal symptoms of dyskinesia (by AIMS), akathisia
`
`(by BAS), and parkinsonism (by SAS) are shown in Table 8.
`
`
`
`Table 8
`
`
`
`Evaluation scale
`
`AIMS
`
`BAS**
`
`SAS
`
`Mean (SD) Mean (SD)
`
`Placebo*
`
`0.7 (2.63)
`
`SM-13496 40 mg*
`p value#
`0.978
`
`0.7 (2.88)
`
`Mean (SD)
`
`SM-13496 120 mg*
`p value#
`0.467
`
`0.2 (2.21)
`
`0.0 (0.97
`
`0.1 (1.04)
`
`-0.1 (0.96)
`
`0.1 (1.08)
`
`0.687
`
`0.588
`
`0.4 (0.94)
`
`0.1 (1.11)
`
`0.352
`
`0.808
`
`#: Two-tailed Dunnett’s t-test (comparison between treated groups and placebo group)
`
`Analysis of covariance using study center and treated groups as factors, and the values before administration as
`
`covariate
`
`*: n = 44-47 for each rating score
`
`**: BAS global score
`
`
`
`As is apparent from the results in Table 8, there was no significant difference in changes in score from
`
`before treatment or in total score between the treated groups. The ratio of patients requiring benztropine was
`
`24% in the SM-13496-treated groups and 18% in the placebo group.
`
`
`
`Industrial Applicability
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 011
`
`

`

`The method for treatment of schizophrenia and the agent used therein of the present invention exhibit an
`
`excellent effect on the improvement of wide-ranging schizophrenia including positive symptoms, negative
`
`symptoms, cognitive dysfunctions, especially positive symptoms and negative symptoms, without
`
`extrapyramidal adverse drug reactions, by orally administering a prescribed amount of (1R,2S,3R,4S)-N-
`
`[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo-
`
`[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof, especially a hydrochloride thereof,
`
`once per day to a patient with schizophrenia. Furthermore, since the present method and the agent used therein
`
`do not cause electrocardiogram abnormalities related to sudden death and do not exhibit excessive sedative
`
`effects, they may be very safely employed and may be suitable even for prolonged administration, and further,
`
`they may be applied safely even to elderly patients, and hence, the present method and the agent used therein
`
`are extremely excellent.
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 012
`
`

`

`CLAIMS
`
`1. A method for treatment of schizophrenia without extrapyramidal adverse drug reactions, the method
`
`comprising orally administering (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide represented by formula
`
`(1):
`
`or a pharmaceutically acceptable salt thereof as an active compound in a daily dose of 5 mg to 120 mg once
`
`per day.
`
`2. The method for treatment according to claim 1, wherein the active compound is (1R,2S,3R,4S)-N-[(1R,2R)-
`
`2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2.1]heptanedicarboximide hydrochloride.
`
`3. The method for treatment according to claim 1 or 2, wherein the method improves negative symptoms of
`
`schizophrenia.
`
`4. The method for treatment according to claim 1 or 2, wherein the method improves positive and negative
`
`symptoms of schizophrenia.
`
`5. The method for treatment according to claim 1 or 2, wherein the method comprises orally administering the
`
`active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in a daily dose of 20 mg to 80 mg
`
`once per day.
`
`6. The method according to claim 5, wherein the method improves negative symptoms of schizophrenia.
`
`7. The method according to claim 5, wherein the method improves positive and negative symptoms of
`
`schizophrenia.
`
`8. The method according to claim 1 or 2 for treatment of schizophrenia in the chronic phase, wherein the
`
`method improves schizophrenia without extrapyramidal adverse drug reactions by orally administering the
`
`active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in a daily dose of 5 mg to 80 mg
`
`once per day.
`
`9. The method for treatment according to claim 8, wherein the method improves negative symptoms of
`
`schizophrenia.
`
`10. The method for treatment according to claim 8, wherein the method improves positive and negative
`
`symptoms of schizophrenia
`
`11. The method for treatment according to claim 8, wherein the method comprises orally administering the
`
`active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in a daily dose of 10 mg to 40 mg
`
`once per day.
`
`Par Pharm., Inc.
`Exhibit 1012
`Page 013
`
`

`

`12. The method for treatment according to claim 11, wherein the method improves negative symptoms of
`
`schizophrenia.
`
`13. The method for treatment according to claim 11, wherein the method improves positive and negative
`
`symptoms of schizophrenia.
`
`14. A therapeutic agent for schizophrenia, the agent comprising (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`
`benzois