WO2008025781A1 - Bifeprunox doses for treating schizophrenia - Google Patents
Bifeprunox doses for treating schizophrenia Download PDFInfo
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- WO2008025781A1 WO2008025781A1 PCT/EP2007/058958 EP2007058958W WO2008025781A1 WO 2008025781 A1 WO2008025781 A1 WO 2008025781A1 EP 2007058958 W EP2007058958 W EP 2007058958W WO 2008025781 A1 WO2008025781 A1 WO 2008025781A1
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Definitions
- the present invention relates to a daily dose of bifeprunox for the treatment of a patient with schizophrenia, the treatment with bifeprunox of patients with stable schizophrenia and of patients with actute exacerbations of schizophrenia and to a pharmaceutical composition comprising a dose of at least one bifeprunox compound.
- Schizophrenia is a lifelong disabling psychiatric disorder characterized by severe and variable symptoms, including positive and negative symptoms, cognitive deficits and depression.
- the course of the illness can be divided into 4 major phases: premorbid, acute, stable/maintenance and late course.
- the premorbid phase refers to symptoms, which occur before the onset of positive symptoms.
- the acute phase patients experience overt positive symptoms such as delusions and hallucinations.
- the stable/maintenance phase may be divided into two subphases. The first 5 to 10 years of illness are often characterized by multiple exacerbations of positive symptoms, with more stable periods interspersed between acute episodes.
- This subphase is followed by a plateau phase which is characterized by a stabilization of symptoms and a reduced number of exacerbations.
- Key treatment goals during the maintenance phase are to facilitate the patient's return to the community and establish a long-term maintenance plan.
- positive symptoms tend to diminish with age and many patients with long-term impairments regain some degree of social and occupational competence, however, the effects of years of dysfunction are rarely overcome.
- Compounds currently used to treat schizophrenia have been associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, the metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension, and obesity), prolonged QTc intervals, glucose abnormalities, and the exhibition of extrapyramidal symptoms. For example, prolonged QTc intervals, i.e., the corrected QT interval in an electrocardiogram, can lead to problematic heart rhythms, or heart arrhythmias. Similarly, the weight gain observed with conventional atypical antipsychotics, such as risperidone and olanzapine, has been associated with an increased risk of cardiovascular disease and diabetes mellitus.
- conventional atypical antipsychotics such as risperidone and olanzapine
- schizophrenia treatment using medication may be over extended periods of time.
- these undesirable side effects affect patients on a daily basis as well as contributing to their long-term health.
- These side effects may also lead to noncompliance with a patient's treatment regimen.
- the present inventors have discovered that treating schizophrenia patients with (a pharmaceutical composition) comprising a dose of at least one bifeprunox compound, particularly a daily dose of 20-30 mg, makes it possible to reduce and/or avoid one or more of these side effects and one or more symptoms of schizophrenia.
- the dose is administered once-daily.
- Embodiments of specific doses are a 20 mg dose and 30 mg dose. Particularly preferred is a daily dose of 20 mg.
- Favourable effects of this treatment include, but are not limited to, reduction of the Positive and Negative Syndrome Scale (PANSS) total score in a patient, maintenance of body weight, maintenance and/or improvement of triglycerides levels and/or total cholesterol levels, maintenance of clinical stability of schizophrenia in particular in patients with chronic, stable schizophrenia (treatment effects are e.g. an increase of the time to deterioration), improvement of one or more psychotic symptoms or maintenance and or/reduction of extrapyramidal signs and symptoms (EPS) profile similar to baseline measurements before administration.
- PANSS Positive and Negative Syndrome Scale
- EPS extrapyramidal signs and symptoms
- Other favourable effects are a reduction of the incidence of hyperglycemia and/or one or more diabetes-related adverse events.
- bifeprunoxis used for the long-term treatment of a patient with schizophrenia, in particular in a daily dose of 20-30 mg.
- long term treatment refers for example to at least 3 months or at least 6 months treatment.
- hydrochloric acid salt of this compound (7-[4-([1 ,1'-biphenyl]-3-ylmethyl)-1- piperazinyl]-2(3H)-benzoxazolone (bifeprunox) is described and claimed in WO97/36893 and the monomethanesulfonate salt is described and claimed in WO02/066449.
- the direct formation of the monomethanesulfonate salt by the reaction between the reactive mesylate ester of N,N,N-bis(2-ethanol)-m- phenylbenzyl amine and 7-amino-2(3H)-benzoxazolone is disclosed.
- a stable polymorph of bifeprunox monomethanesulfonate salt is disclosed and claimed in WO 2005/016898.
- bifeprunox compounds are bifeprunox N-oxides.
- a bifeprunox N-oxide is disclosed and claimed in WO 2007/023141.
- Bifeprunox compounds are indicated for the treatment of CNS (central nervous system) disorders, including schizophrenia, other psychotic disorders (in particular psychosis) and Parkinson's disease.
- dosage strength or dose is expressed in an amount equivalent to a bifeprunox base.
- bifeprunox base refers to the compound 7-
- bifeprunox compound(s) refers to the active compound 7-[4-([1 ,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxa-zolone, its N-oxide and pharmaceutically acceptable salts, solvates and hydrates thereof.
- N-oxide When the N-oxide is used as the bifeprunox compound, the amount in milligrams is the same amount as the amount the person skilled in the art would select for the bifeprunox compound without the oxide.
- pharmaceutically acceptable salts of bifeprunox or its N-oxide may be obtained using standard procedures well known in the art, for example, by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid.
- the present disclosure is directed to the use of bifeprunox in the treatment of schizophrenia for maintaining, reducing and/or improving conditions associated with the treatment of schizophrenia by administering to a patient in need thereof a pharmaceutical composition comprising a dose of at least one bifeprunox compound.
- the pharmaceutical composition comprises at least one bifeprunox compound in an amount ranging from 5 mg to 40 mg, such as, from 10 mg to 40 mg or further for example, from 20 mg to 30 mg of a bifeprunox compound.
- bifeprunox is used in the treatment of a patient with schizophrenia having weight problems or susceptible to weight problems.
- An embodiment of the invention relates to a daily dose of bifeprunox for the treatment of a patient with schizophrenia, wherein the dose is 20-30 mg of at least one bifeprunox compound. Particularly, said dose is useful for maintaining clinical stability in a patient with stable schizophrenia, and more particularly chronic, stable schizophrenia. Embodiments thereof are a dose of 20 mg and a dose of 30 mg, respectively.
- the present invention relates to a daily dose of bifeprunox for the treatment of a patient with acutely exacerbated schizophrenia wherein the dose is 20-30 mg of at least one bifeprunox compound.
- the dose is 20-30 mg of at least one bifeprunox compound.
- Embodiments thereof are a dose of 20 mg and a dose of 30 mg, respectively, used in said treatment with favourable side effects.
- An embodiment of the present invention relates to bifeprunox for use in the treatment of patients (in particular with schizophrenia) with psychoses and mood disorders wherein bifeprunox (i.e. at least one bifeprunox compound) is administered in combination with the mood-stabilizing drug lithium, and a kit for said use.
- bifeprunox i.e. at least one bifeprunox compound
- a further embodiment of the present invention relates to bifeprunox for use in the treatment of patients with a CNS disorder (in particular with schizophrenia) wherein at least one bifeprunox compound is administered in combination with an antidepressant (in particular an SSRI, specifically paroxetine), and a kit for said use.
- an antidepressant in particular an SSRI, specifically paroxetine
- FIG. 1 For example fluconazole
- FIG. 1 For example fluconazole
- FIG. 1 For example fluconazole
- FIG. 1 For example fluconazole
- FIG. 1 For example ketoconazole and carbamazepine
- FIG. 1 For example paroxetine
- FIG. 1 For example famotidine
- the at least one bifeprunox compound comprises bifeprunox mesylate.
- the at least one bifeprunox compound is bifeprunox mesylate.
- the bifeprunox mesylate may be chosen from the ⁇ , Y, or ⁇ crystalline polymorphic forms, and mixtures thereof.
- the at least one bifeprunox compound comprises at least one polymorphic form chosen from the ⁇ and Y polymorphic forms.
- ⁇ bifeprunox mesylate The crystalline polymorphic form of ⁇ bifeprunox mesylate according to the present disclosure is defined by at least the physicochemical parameters as disclosed in WO 2005/016898
- the present disclosure provides bifeprunox mesylate in which at least about 50 percent by weight (wt. %), at least about 60 wt. %, at least about 70 wt. %, at least about 80 wt. %, at least about 90 wt. %, or at least about 95 wt. % of the bifeprunox mesylate is in the polymorphic ⁇ form.
- the pharmaceutical composition is substantially devoid of any ⁇ or ⁇ polymorphic forms of bifeprunox mesylate.
- the bifeprunox mesylate provided by the present disclosure comprises less than 10 wt. %, less than 5 wt.
- bifeprunox mesylate is in the polymorphic ⁇ form.
- the preparation of polymorphic form ⁇ can be carried out according to the procedures decribed in WO 2005/016898.
- the at least one bifeprunox compound according to the present disclosure can be formulated into dosage forms in which the active substance is present in the solid form by methods known in the art. Examples of said dosage forms are (optionally coated) tablets, capsules, granular aerosols, suppositories and suspensions. Such dosage forms can be prepared by mixing the at least one bifeprunox compound with inert pharmaceutically acceptable excipients and carriers.
- compositions of the present disclosure can comprise at least one pharmaceutical excipient.
- suitable excipients include suspending agents (for example, gums, xanthans, cellulosics and sugars), humectants (for example, sorbitol), solubilizers (for example, ethanol, water, PEG and propylene glycol), surfactants (for example, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives, antioxidants (for example, parabens, and vitamins E and C), anti-caking agents, coating agents, chelating agents (for example, EDTA), stabilizers, antimicrobial agents, antifungal or antibacterial agents (for example, parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (for example, sugar, sodium chloride), thickening agents (for example, methyl cellulose), flavoring agents (for example, chocolate, thalmant
- One illustrative dosage form comprises, apart from the milled and sieved dose of the active substance (bifeprunox as described herein), lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (for example, type A), sodium stearyl fumarate and optionally colloidal anhydrous silica.
- lactose is present in an amount of about 20% to about 90% by weight, about 70% to about 90% by weight, or about 75% to about 85% by weight, based on the total weight of the tablet core.
- Microcrystalline cellulose is present in an amount of about 5% to about 90% by weight, about 10% to about 15% by weight, or about 11 % to about 12% by weight, based on the total weight of the tablet core.
- Sodium starch glycolate e.g. type A
- Sodium stearyl fumarate is present in an amount of about 0.1 % to about 1.5% by weight, about 0.6% to about 1.3% by weight, or about 1.0% by weight, based on the total weight of the tablet core.
- Colloidal anhydrous silica is optionally added to the formulation in order to improve the flow properties of the powder. If desired, colloidal anhydrous silica is typically present in an amount of about 0.05% to about 0.5% by weight or about 0.4% by weight, based on the total weight of the tablet core.
- the amount of optional coating is about 2.0% to about 5.0% by weight, about 3.0% to about 4.0% by weight, or about 3.5% by weight, based on the total weight of the tablet core.
- the pharmaceutical compositions comprising the at least one bifeprunox compound according to the present disclosure can be administered to a subject, for example a human subject, in need thereof.
- the present disclosure is also directed to, but not limited to, reducing a PANSS total score in a patient, maintaining body weight, maintaining and/or improving triglycerides levels and/or total cholesterol levels, maintaining clinical stability of schizophrenia, improving one or more psychotic symptoms or maintaining an EPS profile similar to baseline measurements before administration.
- the present disclosure is also directed to methods for reducing the incidence of hyperglycemia and/or diabetes-related adverse events. These methods are exemplified in the following clinical examples provided below.
- U.S. Patent Application Nos. 10/920,361 , 10/920,386, and 11/354,652 are hereby incorporated herein by reference in their entireties.
- Fig.1 shows Panel 34 PANSS Positive Score (FAS, LOCF).
- Fig.2 shows Panel 35 PANSS Negative Score (FAS, LOCF).
- Fig.3 shows Panel 36 PANSS General Psychopathology Score (FAS, LOCF).
- Fig.4 shows Panel 42 Proportion of Patients with at Least a 25%
- Fig. 5 shows Panel 43 Proportion of Patients with a CGI-I Score of 2 or
- EXAMPLE 1 EFFICACY OF BIFEPRUNOX IN THE TREATMENT OF SCHIZOPHRENIA [037] A six-week, randomized, double-blind, placebo-controlled and risperidone referenced study was used to assess the efficacy and safety of fixed doses of bifeprunox in the treatment of schizophrenia. A total of 599 subjects were randomized.
- Treatment started with a single-blind placebo lead-in period of at least three days, followed by titration from 0.25 mg up to 30 mg/day or 40 mg/day of bifeprunox for bifeprunox-treated subjects.
- Risperidone-treated subjects were titrated from 2 mg to 6 mg daily over a three-day period and maintained at 6 mg/day for the remainder of the treatment period.
- Rating scale assessments were performed weekly, except for week 5, to measure the change from baseline to endpoint of the PANSS total score. Other assessments included: PANSS positive symptom subscale score, PANSS negative symptom subscale score, PANSS general pschopathology subscale score, BPRS total score, BPRS psychosis score, the CGI-S score, the CGI-I score, responder rates based on the PANSS total score, and the Calgary Depression Scale for Schizophrenia (CDSS).
- CDSS Calgary Depression Scale for Schizophrenia
- Safety and tolerability measures included physical examinations, weight, waist circumference, vital signs, 12-lead electrocardiogram (ECG), clinical laboratory assessments (hematology, biochemistry, urinalysis, special laboratory assessments for prolactin, IGF-1 , IGFBP-3, thyroid function), need for anticholinergic treatment during double-blind treatment period, concomitant medication use, adverse event monitoring and assessments of normal movement.
- ECG electrocardiogram
- clinical laboratory assessments hematology, biochemistry, urinalysis, special laboratory assessments for prolactin, IGF-1 , IGFBP-3, thyroid function
- need for anticholinergic treatment during double-blind treatment period concomitant medication use
- adverse event monitoring and assessments of normal movement included physical examinations, weight, waist circumference, vital signs, 12-lead electrocardiogram (ECG), clinical laboratory assessments (hematology, biochemistry, urinalysis, special laboratory assessments for prolactin, IGF-1 , IGFBP-3, thyroid function
- the 20 mg bifeprunox treatment group showed a statistically significant difference from placebo for the primary endpoint of change from baseline to endpoint in PANSS total score.
- the mean change (standard deviation) from baseline to endpoint in PANSS total score was -13.5 (20.1 ) for the 30 mg bifeprunox group, -10.3 (20.5) for the 40 mg bifeprunox group, -7.7 (19.2) for the placebo group, and -19.7 (19.3) for the risperidone group.
- the 30 mg bifeprunox group showed notable differences from placebo for CGI-S score, PANSS negative symptom subscale score, and PANSS positive symptom subscale score. Notable differences were also observed between the 30 mg bifeprunox group and placebo for the change from baseline to endpoint in PANSS general psychopathology subscale score, BPRS total score, BPRS psychosis cluster score, PANSS responder rate, and CGI-I responder rate.
- a PANSS responder refers to a subject whose PANSS total score decreased by 20% or more from baseline to endpoint.
- a CGI-I responder refers to a subject who was categorized as "very much improved" or "much improved" in the CGI Global Improvement scale at endpoint.
- the bifeprunox groups had a lower incidence of N to H shifts in triglycerides, VLDL, and LDL, and a higher incidence of N to L shifts in total cholesterol and VLDL compared with the placebo and risperidone groups.
- the secondary objectives were to assess the efficacy of bifeprunox in treating schizophrenia using the positive symptom sub-scale score of the PANSS, the negative symptom sub-scale score of the PANSS, the general psychopathology sub-scale of the PANSS, the Brief Psychiatric Rating Scale (BPRS) total score derived from the PANSS, the BPRS psychosis derived from the PANSS, the Clinical Global Impressions Severity of Illness score (CGI-S), the Clinical Global Impressions Improvement score (CGI-I), and responder rate based on the PANSS total score and CGI-I responder rate.
- BPRS Brief Psychiatric Rating Scale
- Bifeprunox treated subjects were titrated up to 5 mg, 10 mg or 20 mg according to a standardized titration schedule (Day 1 : 0.125 mg, Day 2: 0.25 mg, Day 3: 0.5 mg, Day 4: 1.0 mg, Day 5: 2.0 mg, Day 6: 5.0 mg, Day 7: 10.0 mg, Day 8: 20 mg).
- a standardized titration schedule Day 1 : 0.125 mg, Day 2: 0.25 mg, Day 3: 0.5 mg, Day 4: 1.0 mg, Day 5: 2.0 mg, Day 6: 5.0 mg, Day 7: 10.0 mg, Day 8: 20 mg.
- subjects were maintained at that dose for the remainder of the six-week treatment period.
- Risperidone treated subjects were titrated to 6 mg over three days (Day 1 : 2 mg, Day 2: 4 mg, Day 3: 6 mg) using a once-daily regimen.
- the percentage of subjects with at least one severe TEAE was lowest in the 20 mg bifeprunox group (11 subjects, 10%) followed by the placebo group (15 subjects, 13%). For the remaining groups, the percentage of subjects with at least one severe TEAE ranged from 16% to 18%.
- the incidence of TEAEs considered to be severe was similar ( ⁇ 5% difference) between the 20 mg bifeprunox group and the placebo group for all TEAEs. There were no dose-related trends in the bifeprunox groups in overall incidence, incidence of related, or incidence of severe TEAEs observed for any event.
- the total number of subjects with at least one AE that led to discontinuation was similar among treatment groups (5 mg bifeprunox: 13 subjects, 11 %; 10 mg bifeprunox: 17 subjects, 14%; 20 mg bifeprunox: 11 subjects, 10%; placebo: 15 subjects, 13%; risperidone: 17 subjects, 14%).
- the most common (reported by >2% of subjects in any treatment group) AEs that led to discontinuation were agitation, aggravated psychosis, and aggravated schizophrenia NOS. There were no treatment group differences in incidence of AEs leading to discontinuation of study medication between the 20 mg bifeprunox group and the placebo group.
- PANSS Positive and Negative Symptom Scale
- PK data of bifeprunox in schizophrenic subjects were also assessed and are presented in a separate report (combined with data from study S 1543003).
- BP systolic/diastolic blood pressure
- ECG Clinical laboratory assessments (hematology, biochemistry, urinalysis, special laboratory assessments for prolactin, IGF-1 , IGFBP-3, and thyroid function), need for anticholinergic treatment during double-blind treatment period, concomitant medication use, adverse event (AE) monitoring, and assessments of abnormal movement including the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), and Abnormal Involuntary Movement Scale (AIMS).
- SAS Simpson-Angus Scale
- BAS Barnes Akathisia Scale
- AIMS Abnormal Involuntary Movement Scale
- bifeprunox-treated subjects were titrated from 0.25 mg up to 30 mg/day or 40 mg/day according to a standardized titration scheme over an eight-day period. When the assigned dose was reached, subjects were maintained at that dose for the remainder of the six week treatment period. Risperidone-treated subjects were titrated from 2 mg to 6 mg daily over a three-day period and were subsequently maintained at 6 mg/day for the remainder of the treatment period. Rating scale assessments for efficacy and abnormal movement disorders were done weekly except for Week 5. Safety assessments were performed at Screening, during treatment and at the end of the study. Subject satisfaction with study medication was assessed at Week 6. Samples of blood were obtained at Weeks 2, 4, and 6 for determination of bifeprunox in plasma. Blood samples were also obtained at Screening/Baseline, Week 3, and Week 6 for clinical laboratory assessments.
- Diagnosis and Main Criteria for Inclusion Male or female subjects 18-75 years of age with schizophrenia (per DSM-IV-TR criteria). Subjects had to have a total score on the PANSS between 70 and 120; at least two of four PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) had to have a score ⁇ 4; and the score on the CGI-S had to be at least 4.
- the mean change (SD) from Baseline to Endpoint in PANSS total score was -13.5 (20.1 ) for the 30 mg bifeprunox group, -10.3 (20.5) for the 40 mg bifeprunox group, -7.7 (19.2) for the placebo group, and -19.7 (19.3) for the risperidone group.
- the treatment effect values (for mean change from Baseline at Endpoint [LOCF]) corresponding to the difference between bifeprunox and placebo were: -5.9 for the 30 mg bifeprunox group and -3.2 for the 40 mg bifeprunox group.
- TEAEs occurring in at least 5% of subjects in any treatment group, those having a higher ( ⁇ 2% difference) incidence in the 40 mg bifeprunox group compared with the 30 mg bifeprunox group included nausea, vomiting, toothache, anorexia, akathisia, dizziness, headache, and insomnia.
- the incidence of severe TEAEs was generally low ( ⁇ 1 % incidence) with the exception of TEAEs of psychotic disorder ( ⁇ 6%) and schizophrenia (3% each in the bifeprunox and placebo groups and 2% in the risperidone group).
- the incidence of severe TEAEs was generally comparable across treatment groups and there was no difference between bifeprunox treatment groups in the incidence of severe TEAEs for any event.
- Special interest TEAEs were defined prior to database lock and included events related to suicide, suicide attempt, sexual dysfunction, syncope, vasovagal attack, and postural hypotension. A total of 76 subjects (13%) overall reported at least one TEAE of special interest during the study.
- the percentage of subjects with at least one special interest TEAE was higher in the bifeprunox and risperidone treatment groups (12%-16%) compared with the placebo group (6%).
- the majority of TEAEs of special interest occurred in ⁇ 1% of subjects in any treatment group. Dizziness was the most commonly reported and occurred at a slightly higher incidence in the bifeprunox treatment groups compared with the other two groups.
- the bifeprunox groups had a lower incidence of N to H shifts in triglycerides, VLDL, and LDL and a higher incidence of N to L shifts in total cholesterol and VLDL compared with the placebo and risperidone groups.
- the incidence of markedly abnormal total cholesterol values was similar across treatment groups (1 % to 2%). Markedly abnormal triglyceride values were reported by slightly fewer subjects in the 40 mg bifeprunox group compared with other groups.
- the 30 mg bifeprunox treatment group showed a notable difference from placebo (based on nominal p-values) for the three key secondary efficacy endpoints, change from Baseline to Endpoint in CGI-S, PANSS Negative, and Positive Symptom subscale scores; statistical significance was not achieved based on the step- down procedure for these three key secondary efficacy endpoints. Notable differences were observed between the 30 mg bifeprunox group and placebo at Endpoint for most of the other secondary efficacy parameters (change from Baseline to Endpoint in PANSS general psychopathology subscale score, BPRS total score, and BPRS psychosis cluster score).
- Methodology This was a Phase III, six week randomized, double-blind, placebo- controlled, olanzapine-referenced, parallel group, multi-center study of the efficacy, tolerability, and safety of bifeprunox in adult subjects with schizophrenia. There were four treatment arms in this study, approximately 144 subjects per arm. The treatment groups were: bifeprunox 20 mg/day, bifeprunox 30 mg/day, olanzapine 15 mg/day, and placebo.
- bifeprunox-treated subjects were titrated from 0.25 mg up to 20 mg/day or 30 mg/day according to a standardized titration scheme over a seven- or eight-day period, respectively.
- subjects were maintained at that dose for the remainder of the six week treatment period.
- Olanzapine-treated subjects began dosing at 10 mg/day for the initial seven day period and, were subsequently maintained at 15 mg/day for the remainder of the treatment period.
- Subjects were hospitalized (if not already inpatients) after eligibility for study entry was verified, starting from the Screening Visit until at least 10 days after Baseline.
- Subjects could be hospitalized longer than 10 days if considered medically necessary by the Investigator. Rating scale assessments for efficacy and abnormal movement disorders were done weekly except for Week 5. Safety assessments were performed at Screening, during treatment and at the end of the study. Subject satisfaction with study medication was assessed at Week 6. Samples of whole blood were obtained at Weeks 2, 4, and 6 for determination of bifeprunox in plasma. Number of Subjects (Planned, Consented, Randomized and Analyzed): A total of 576 subjects with schizophrenia were planned for inclusion in the study.
- Diagnosis and Main Criteria for Inclusion Male or female subjects 18-75 years of age with schizophrenia (per DSM-IV-TR criteria). Subjects must have had a total score on the PANSS between 70 and 120; at least two of four PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) must have had a score > 4; the score on the CGI-S must have been at least 4.
- Test Product, Dose and Mode of Administration Bifeprunox tablets, total daily dose 20 mg or 30 mg (one 20 mg tablet and one 10 mg tablet) administered orally using a once daily dosing regimen.
- TEAEs with a higher incidence (>5% difference) in the bifeprunox groups compared with the placebo group included nausea, vomiting, and constipation. In general, no clear dose-related increase in the incidence of individual TEAEs was observed in the bifeprunox groups.
- TEAEs with a slightly higher (>2% difference) incidence in the 30 mg bifeprunox group compared with the 20 mg bifeprunox group included fatigue, dizziness, and sedation.
- the percentage of subjects with at least one severe TEAE was comparable in the bifeprunox treatment groups and the placebo group (9% to 12%) and slightly less in the olanzapine treatment group (6%).
- TEAEs of special interest occurred in ⁇ 1% of subjects in any treatment group.
- the most commonly reported TEAE of special interest was dizziness which had a slightly higher incidence in the bifeprunox treatment groups compared with the other two groups (30 mg bifeprunox: 15 subjects, 10%; 20 mg bifeprunox: 13 subjects, 8%; placebo: nine subjects, 6%; olanzapine: eight subjects, 5%).
- Other special interest TEAEs occurring in at least two subjects within a treatment group included syncope vasovagal (30 mg bifeprunox: two subjects) and orthostatic hypotension (30 mg bifeprunox: three subjects).
- the percentage of subjects with at least one SAE was least in the olanzapine treatment group (six subjects, 4%) followed by the bifeprunox groups (20 mg: 15 subjects, 10%; 30 mg: 12 subjects, 8%), with the highest incidence of SAEs noted in the placebo group (20 subjects, 13%).
- the most commonly reported SAEs were psychotic disorder (4% of subjects overall) and schizophrenia (2% overall).
- the incidence of these SAEs was similar or lower in the bifeprunox groups compared with the placebo group.
- Two subjects in the 30 mg bifeprunox group had a SAE of syncope vasovagal compared with no subjects in the other treatment groups.
- Olanzapine at a dose of 15 mg was used as an active reference in this study.
- the magnitude of the improvements seen in the bifeprunox dose groups was higher than those seen in the placebo group, but lower than those seen in the olanzapine group for most efficacy endpoints.
- Bifeprunox was well tolerated at both dose levels. The rate of withdrawal due to adverse events was lower in the bifeprunox groups compared with the placebo group. Adverse events appearing more frequently in bifeprunox treated subjects than in placebo subjects were mainly gastrointestinal in nature and mild to moderate in severity. Only two subjects (in the 20 mg bifeprunox group) discontinued study medication due to gastrointestinal AEs (one subject discontinued due to nausea, one subject discontinued due to nausea and vomiting). The percentage of subjects with at least one SAE was lower in the bifeprunox groups (7% to 8%) compared with the placebo group (13%). The most commonly reported SAEs were psychotic disorder (4% overall) and schizophrenia (1 % overall).
- BX20 Patients allocated to the BX groups were up- titrated from 0.25mg/day over 7 days (BX20) or 8 days (BX30), and then continued on these doses for the remainder of the study. Efficacy assessments were made at baseline (except CGI-I) and at Weeks 1 , 2, 4, 6, and 9, and at Months 3, 4, 5, and 6. Safety assessments were performed at screening, during treatment, and at the end of the study. At predetermined time points, blood samples were obtained for drug concentration analysis of BX and its major metabolites (3'- and 4'-sulfate conjugates of BX), and pharmaco-economic assessments were performed.
- Diagnosis and Main Inclusion Criteria Patients with a primary diagnosis of schizophrenia, according to DSM-IV-TR criteria, for more than 2 years, who: had a PANSS total score ⁇ 60 and a CGI-S score ⁇ 4 (moderately ill) at screening and baseline; had PANSS items P7 (hostility) and G8 (uncooperativeness) scores ⁇ 4 (moderate) at screening and baseline; were between 18 and 65 years of age (extremes included); were inpatients, partially hospitalized, or outpatients followed up in a day care program within 90 days; and prior to screening had no modification of antipsychotic medication within 1 month prior to screening.
- the Cox proportional hazards model gave an estimated hazard ratio of 0.66 (BX20) and 0.65 (BX30) relative to PBO; that is, the risk of deterioration was approximately 1.5 times higher for patients in the PBO group than for patients in the BX20 or BX30 groups.
- Bifeprunox was also statistically significantly superior to PBO in the analysis of time to deterioration based on the PPS. Since most of the patients in the PPS participated for most of the study, the results were very close to the results of the primary analysis, both for the estimated hazard ratios and the p-values obtained. This illustrates the robustness of the conclusion of the primary efficacy analysis.
- the secondary efficacy variable was the PANSS total score at Week 6.
- the mean CGI-S scores (FAS, LOCF) decreased in both BX groups until Week 6, after which the scores stabilised. In the PBO group, the mean CGI-S scores decreased until Week 4, after which the scores tended to increase. In the per- visit LOCF analysis (FAS, ANCOVA) of the mean CGI-S scores, the BX groups were statistically significantly superior to the PBO group at Months 3, 4, 5, and 6 for BX20 and Months 5 and 6 for BX30.
- BX20 was not statistically significantly different from PBO at any time points.
- BX30 was statistically significantly superior to PBO in PANSS total scores from Week 6 onwards and in PANSS positive subscale scores from Week 2, onwards whereas BX30 was not statistically significantly different from PBO from Week 2 onwards in PANSS negative subscale scores.
- the mean total cholesterol and mean LDL calculated decreased from baseline to Month 6 in all groups (except non-fasting PBO patients) irrespective of treatment and fasting/non-fasting condition.
- the mean VLDL calculated and triglycerides decreased from baseline to Month 6 in all groups (except non-fasting BX30 patients) irrespective of treatment and fasting/non-fasting condition.
- the mean HDL increased from baseline to Month 6 in all groups irrespective of treatment and fasting/non-fasting condition.
- the adjusted mean HDL cholesterol values increased from baseline to Month 6 in all three treatment groups irrespective of fasting/nonfasting condition (PBO: 0.04/0.06 (fasting/non-fasting); BX20: 0.07/0.08; BX30: 0.07/0.08mmol/L). There were no statistically significant differences between either of the BX groups and the PBO group. [089] The adjusted mean triglycerides values decreased from baseline to
- the adjusted mean weight change from baseline to Month 6 was -0.8kg in the PBO group, -0.3kg in the BX20 group, and -0.5kg in the BX30 group.
- the adjusted mean weight decreases in the BX20 and the BX30 group were not statistically significantly different from that in the PBO group.
- Endpoint in PANSS total score was -9.7 (17.5) for the bifeprunox 5 mg group, -5.0 (18.3) for the bifeprunox 10 mg group, -11.3 (17.0) for the bifeprunox 20 mg group , -5.3 (16.3) for the placebo group, and -15.7 (14.9) for the risperidone group.
- the treatment effect values corresponding to the difference between bifeprunox and placebo mean change from Baseline at Endpoint (LOCF) were -4.1 , 0.6, and -5.8 for the bifeprunox 5 mg, 10 mg, and 20 mg groups respectively.
- CLINICAL STUDY TWO The mean change (SD) from Baseline to Endpoint in PANSS total score was -13.5 (20.1 ) for the 30 mg bifeprunox group, -10.3 (20.5) for the 40 mg bifeprunox group, -7.7 (19.2) for the placebo group, and -19.7 (19.3) for the risperidone group (as indicated in the below Table).
- the treatment effect values (for mean change from Baseline at Endpoint [LOCF]) corresponding to the difference between bifeprunox and placebo were: -5.9 for the 30 mg bifeprunox group and -3.2 for the 40 mg bifeprunox group.
- CLINICAL STUDY ONE The Table below presents mean PANSS positive subscale scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were -1.1 , 0.7, -1.5 for the bifeprunox 5 mg, 10 mg, and 20 mg groups respectively.
- a statistically significantly greater decrease (unadjusted p 0.037) at
- Endpoint was seen in PANSS positive subscale score for the comparison of the treatment effect estimates for the bifeprunox 20 mg group and placebo.
- Symptom subscale scores at Baseline and the change from Baseline by visit using LOCF for the ITT population were -4.5 (6.6) for the 30 mg bifeprunox group, -4.2 (6.9) for the 40 mg bifeprunox group, -2.5 (6.0) for the placebo group, and - 7.2 (6.6) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -1.9 for the 30 mg bifeprunox group, and -1.7 for the 40 mg bifeprunox group.
- SEP1 did not yield a significant result, and therefore SEP2 and SEP3 were not evaluated (see Section 7.4.1.1 ).
- Notable differences between 30 mg bifeprunox and placebo treatment groups were also observed at Week 2 through Week 4 (p ⁇ 0.006).
- CLINICAL STUDY FOUR The mean PANSS positive subscale scores (FAS, LOCF) decreased over time in both BX groups until Week 9, after which the scores increased minimally. In the PBO group, the mean PANSS total scores decreased until Week 2, after which the scores increased steadily (Fig. 1 ; Panel 34). In the per-visit LOCF analysis (FAS, ANCOVA) of the PANSS positive subscale scores, treatment with BX20 or with BX30 was statistically significantly superior to that with PBO from Week 6 onwards.
- PANSS Negative CLINICAL STUDY ONE The Table below presents mean PANSS negative subscale scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the bifeprunox 5 mg, 20 mg, and risperidone 6 mg groups showed the greatest improvement over time.
- Estimates of the treatment effect (bifeprunox - placebo) at Endpoint LOCF were -1.0, -0.3, -1.4 for the Bifeprunox 5 mg, 10 mg, and 20 mg groups respectively.
- CLINICAL STUDY TWO The Table below presents PANSS Negative Symptom subscale scores at Baseline and the change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in PANSS Negative Symptom subscale scores was -3.1 (5.6) for the 30 mg bifeprunox group, -2.2 (5.4) for the 40 mg bifeprunox group, -1.8 (5.6) for the placebo group, and -3.8 (5.5) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -1.4 for the 30 mg bifeprunox group and -0.9 for the 40 mg bifeprunox group.
- SEP1 did not yield a significant result, and therefore SEP2 and SEP3 were not evaluated.
- CLINICAL STUDY THREE The Table below presents PANSS Negative Symptom subscale scores at Baseline and the change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in PANSS Negative Symptom subscale score was -3.3 (5.0) for the 20 mg bifeprunox group, -3.1 (5.2) for the 30 mg bifeprunox group, -2.4 (5.1 ) for the placebo group, and - 4.6 (5.2) for the olanzapine group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -0.9 for the 20 mg bifeprunox group and -0.6 for the 30 mg bifeprunox group. No differences with nominal p-values ( ⁇ 0.05) were observed between the placebo group and either of the bifeprunox dose groups at Week 6/Endpoint or at any other time point during the study (Week 1 through Week 4).
- CLINICAL STUDY FOUR The mean PANSS negative subscale scores (FAS, LOCF) decreased in both BX groups until Week 6, after which the scores stabilized (Fig.2; Panel 35). In the PBO group, the scores decreased until Week 4, after which the scores tended to increase (Panel 35).
- the LOCF analysis of the PANSS total scores shows that when the last observation was carried forward, the PANSS total scores in the BX groups remained stable.
- the changes in both BX groups were statistically significantly superior to that in the PBO group from Week 6 onwards.
- BX20 was statistically significantly superior to PBO Week 4 onwards.
- the OC analysis of the PANSS total scores shows that patients who continued in the study improved over time (Panel 29).
- the changes in both BX groups were statistically significantly superior to that in the PBO group at a number of time points including Week 6, but excluding Month 6.
- CLINICAL STUDY ONE General psychopathology scores decreased from Baseline to Week 6 for each of the bifeprunox treatment groups as shown in theTable below.
- the estimate of the treatment effect of bifeprunox using LOCF was -2.2, 0.4, and -2.8 for the bifeprunox 5 mg, 10 mg, and 20 mg groups respectively.
- the mean change (SD) from Baseline to Endpoint in PANSS general psychopathology subscale score was -6.0 (10.2) for the 30 mg bifeprunox group, -3.8 (10.1 ) for the 40 mg bifeprunox group, -3.5 (9.7) for the placebo group, and -8.6 (9.8) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -2.5 for the 30 mg bifeprunox group and -0.7 for the 40 mg bifeprunox group. Notable differences were observed between the 30 mg bifeprunox group and placebo from Week 2 through Endpoint (p ⁇ 0.025). There were no notable differences between the 40 mg bifeprunox group and placebo at any timepoint during the study (Week 1 through Endpoint).
- CLINICAL STUDY FOUR The mean PANSS general psychopathology subscale scores generally followed the same pattern as the PANSS total scores.
- the mean PANSS general psychopathology subscale scores (FAS, LOCF) decreased in both BX groups until Week 6, after which the scores stabilized (Fig.3; Panel 36).
- the mean PANSS general psychopathology subscale scores decreased until Week 2, after which the scores increased steadily (Panel 36).
- both BX20 and BX30 were statistically significantly superior to PBO from Week 9 onwards.
- BX20 was statistically significantly superior to PBO at Week 6.
- CLINICAL STUDY TWO The table below presents mean BPRS total scores (derived from the PANSS) at Baseline and change from Baseline in BPRS total scores at each post-Baseline visit for the ITT population (LOCF).
- the mean change (SD) from Baseline to Endpoint in BPRS total score was -8.1 (12.3) for the 30 mg bifeprunox group, -6.5 (11.7) for the 40 mg bifeprunox group, -4.9 (11.5) for the placebo group, and -12.2 (11.7) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -3.2 for the 30 mg bifeprunox group and -1.9 for the 40 mg bifeprunox group. Notable differences were observed between the 30 mg bifeprunox group and placebo from Week 2 through Endpoint (p ⁇ 0.019). No notable differences were seen between the 40 mg bifeprunox group and placebo at any time point during the study (Week 1 through Endpoint).
- CLINICAL STUDY TWO The Table below presents mean BPRS psychosis cluster score at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in BPRS psychosis cluster score was -3.2 (4.2) for the 30 mg bifeprunox group, -2.6 (4.4) for the 40 mg bifeprunox group, -1.8 (3.5) for the placebo group, and -4.9 (4.0) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -1.4 for the 30 mg bifeprunox group and -1.0 for the 40 mg bifeprunox group.
- CLINICAL STUDY THREE The Table below presents mean BPRS psychosis cluster score at Baseline and the mean change from Baseline by visit using LOCF for the ITT population. The mean change (SD) from Baseline to
- Endpoint in BPRS psychosis cluster score was -3.1 (3.9) for the 20 mg bifeprunox group, -3.2 (4.4) for the 30 mg bifeprunox group, -2.6 (4.0) for the placebo group, and -4.9 (4.0) for the olanzapine group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -0.6 for the 20 mg bifeprunox group and -0.5 for the 30 mg bifeprunox group. No notable differences were observed between the placebo group and either of the two bifeprunox dose groups at Endpoint or at any other time point during the study (Week 1 through Week 4).
- CLINICAL STUDY TWO The Table below presents mean CGI-S scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population (LOCF).
- the mean change (SD) from Baseline to Endpoint in CGI severity of illness score was -0.69 (1.19) for the 30 mg bifeprunox group, -0.54 (1.12) for the 40 mg bifeprunox group, -0.37 (1.07) for the placebo group, and -1.06 (1.20) for the risperidone group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: - 0.28 for the 30 mg bifeprunox group and -0.18 for the 40 mg bifeprunox group.
- CLINICAL STUDY THREE The Table below presents mean CGI Severity of Illness scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in CGI severity of illness score was -0.63 (0.98) for the 20 mg bifeprunox group, -0.62 (1.03) for the 30 mg bifeprunox group, -0.49 (1.06) for the placebo group, and -1.03 (1.00) for the olanzapine group.
- the treatment effect values (bifeprunox - placebo) at Endpoint LOCF were: -0.13 for the 20 mg bifeprunox group and -0.09 for the 30 mg bifeprunox group. No differences were notable with nominal p-values ( ⁇ 0.05) between the placebo group and either of the bifeprunox dose groups at Week 6/Endpoint or at any other time point during the study (Week 1 through Week 4).
- CLINICAL STUDY TWO The percentages of subjects who reported much or very much improvement from Baseline to Endpoint (LOCF) were: 36% in the 30 mg bifeprunox group, 28% in the 40 mg bifeprunox group, 25% in the placebo group, and 52% in the risperidone group (Table below). At Endpoint, no notable differences were observed between placebo and either of the two bifeprunox dose groups; however, notable differences between the 30 mg bifeprunox group and placebo were seen at Week 2 through Week 4 (p ⁇ 0.024). No notable differences were seen between the 40 mg bifeprunox group and placebo at any time point during the study (Week 1 through Endpoint). Data for Week 2 through Endpoint are summarized in the Table below.
- CLINICAL STUDY THREE The Table below presents frequencies for the se categories of CGI Improvement ratings by visit using LOCF for the ITT population. Statistical differences among treatment groups regarding the mean CGI Improvement score were evaluated using a CMH test stratified by pooled center applied to the frequencies of the seven CGI Improvement categories with modified ridit scores. The percentages of subjects who reported much or very much improvement combined, (derived by summing the corresponding individual percentages in Table 23) from Baseline to Endpoint were: 38% in the 20 mg bifeprunox group, 34% in the 30 mg bifeprunox group, 32% in the placebo group, and 46% in the olanzapine group.
- CLINICAL STUDY ONE The PANSS responder rates were higher for each of the bifeprunox treatment groups compared to the placebo group. The PANSS responder rates were 28%, 24%, and 34% for the three dose groups respectively using the 20% definition from the study protocol. Responder rates for PANSS using all four definitions are presented in the Table below.
- CLINICAL STUDY TWO A PANSS responder was defined as a subject whose PANSS total score decreased by 20% or more from Baseline to Endpoint based on LOCF data. As exploratory analyses, responder rates were also analyzed using a 30%, 35%, 40%, and 50% definition of responder. Summaries of the PANSS responder rates at Endpoint (LOCF) are presented in the Table 25 below.
- the PANSS responder rates were slightly higher for the two bifeprunox treatment groups compared to the placebo group.
- the PANSS 20% responder rates were: 36% in the 30 mg bifeprunox group, 30% in the 40 mg bifeprunox group, 26% in the placebo group, and 54% in the risperidone group.
- the PANSS 30% responder rates were: 24% in the 30 mg bifeprunox group, 22% in the 40 mg bifeprunox group, 14% in the placebo group, and 31 % in the risperidone group.
- a PANSS responder was defined as a subject whose PANSS total score decreased by 20% or more from Baseline to Endpoint As exploratory analyses, responder rates were also analyzed using a 30%, 35%, 40%, and 50% definition of responder Summaries of the PANSS responder rates at Endpoint (LOCF) are presented in the Table below
- the 20% PANSS responder rates were slightly higher for the two bifeprunox treatment groups compared to the placebo group 42% of the subjects in the 20 mg bifeprunox group, 39% of the subjects in the 30 mg bifeprunox group, 32% of the subjects in the placebo group, and 54% of the subjects in the olanzapine group improved by 20% or more from Baseline to Endpoint in PANSS total score
- more stringent criteria (30% - 50%) for definition of responder were used, differences between the 20 mg or 30 mg bif
- CLINICAL STUDY FOUR The proportion of patients with a >25%, >35%, >45%, or >55% reduction in PANSS total score relative to baseline at each visit (PANSS responders) is shown by LOCF (Fig. 4; Panel 42).
- CLINICAL STUDY ONE A CGI responder is defined as a subject who is categorized as "very much improved” or “much improved” on the CGI Improvement scale. The CGI responder rates for the bifeprunox 5 mg and 20 mg groups were higher than the responder rates for the placebo group. No statistically significant differences were seen for any of the three bifeprunox dose groups when compared to placebo.
- CGI responder is defined as a subject who is categorized as "very much improved” or "much improved” on the CGI Improvement scale. Summaries of CGI-I responder rates at Endpoint (LOCF) are presented in Table 3.10.0 (LOCF) and Table 26. The CGI-I responder rates were: 38% in the 20 mg bifeprunox group, 34% in the 30 mg bifeprunox group, 32% in the placebo group, and 46% in the olanzapine group. No notable differences were observed between the placebo group and either of the two bifeprunox dose groups.
- CDSS CLINICAL STUDY TWO Calgary Depression Scale for Schizophrenia scores are presented in the Table below.
- This Table presents mean CDSS scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in CDSS score (LOCF) was -0.66 (3.64) for the 30 mg bifeprunox group, 0.01 (3.66) for the 40 mg bifeprunox group, -0.39 (3.45) for the placebo group, and -0.89 (3.42) for the risperidone group.
- the treatment effect values (bifeprunox, placebo) at Endpoint LOCF were: -0.38 for the 30 mg bifeprunox group and 0.29 for the 40 mg bifeprunox group. No notable differences were observed between placebo and either of the two bifeprunox dose groups at Endpoint or at any other timepoint during the study (Week 1 through Week 4).
- CLINICAL STUDY THREE The Table below presents mean CDSS scores at Baseline and the mean change from Baseline by visit using LOCF for the ITT population.
- the mean change (SD) from Baseline to Endpoint in CDSS score was -1.30 (3.85) for the 20 mg bifeprunox group, -0.79 (3.02) for the 30 mg bifeprunox group, -0.59 (4.20) for the placebo group, and -1.47 (3.95) for the olanzapine group.
- the treatment effect values (bifeprunox, placebo) at Endpoint LOCF were: -0.54 for the 20 mg bifeprunox group and -0.34 for the 20 mg bifeprunox group. No notable differences were observed between the placebo group and either of the two bifeprunox dose groups at Endpoint or at any other time point during the study (Week 1 through Week 4).
- CLINICAL STUDY FOUR The proportion of patients with a CGI-I score ⁇ 2 at each visit (CGI-I responders; FAS, LOCF) is show below in the Table (Fig. 5; Panel 43).
- EPS were assessed using treatment -emergent adverse events such as akathisia, dyskinesia, parkinsoniam, etc. and/or formal rating scales such as SAS, BAS, and/or AIMS.
- the SAS is used to measure Parkinsonian-type symptoms in patients exposed to antipsychotics.
- the scale consists of 10 items, each rated on a 5-point scale ranging from 0(complete absence of the condition) to 4 (presence of the condition in extreme form).
- the SAStotal score is defined as the sum of all item scores, and the range is 0 to 40.
- a SAS total score of up to 3 is considered normal.
- the BAS is used to rate observable, restless movements of drug-induced akathisia as well as the subjective awareness of restlessness and any distress associated with the akathisia.
- the scale consists of 3 items that is rated from 0 (no evidence of akathisia) to 3 (severe akathisia).
- the BAS total score is defined as the sum of the these three BAS item scores and ranges from is 0 to 9.
- a global clinical assessment of akathisia is rated from 0 (no evidence of akathisia) to 5 (severe akathisia).
- AIMS Abnormal Involuntary Movement Scale 18
- the AIMS designed to record the occurrence of dyskinetic movements, consists of 12 items. Items 1 to 7 measure specific involuntary movements on a scale from 0 (none) to 4 (severe). Items 8 to 10 measure global assessment of abnormal movement on a scale from 0 (no awareness) to 4 (aware, severe distress). Items 11 and 12 are questions regarding the dental condition of the patient, with yes/no answers.
- the total score is calculated by summing AIMS items 1 through 10 and ranges from 0 to 40; the non-global total score is calculated by summing items 1 through 7.
- TEAEs related to EPS The proportion of patients with TEAEs related to EPS was lower in the PBO group (4%) than in either of the BX groups (BX20: 10%; BX30: 15%).
- TEAEs related to EPS for which there were >3 patients in either BX group relative to the PBO group comprised: BX20 - akathisia; BX30 - dyskinesia, akathisia, extrapyramidal disorder.
- the BAS score consists of an objective score, a score awareness of restlessness, a score of distress related to restlessness, a 3-item total score, and a global clinical assessment score. There were no statistically significant differences among the treatment groups at Baseline or Endpoint for the objective score, awareness of restlessness score, distress related to restlessness score, the 3-item total score, or the global clinical assessment score.
- CLINICAL STUDY TWO Simpson-Angus Scale global scores were evaluated as normal or abnormal at Baseline and Endpoint.
- the percentages of subjects with abnormal SAS scores were: 14% in the 30 mg bifeprunox group, 11 % in the 40 mg bifeprunox group, 7% in the placebo group, and 6% in the risperidone group.
- the percentage of subjects with abnormal SAS scores between Baseline and Endpoint decreased in the bifeprunox groups, were unchanged in the placebo group, and increased in the risperidone group.
- the percentages of subjects with abnormal SAS scores ranged from 7% in the 40 mg bifeprunox and placebo groups to 14% in the risperidone group.
- the BAS score consists of an objective score, a subjective awareness of restlessness score, a score of distress related to restlessness, a 3-item total score, and a global clinical assessment score.
- CLINICAL STUDY THREE Simpson-Angus Scale global scores were evaluated as normal or abnormal at Baseline and Endpoint. At Baseline, the percentages of subjects with abnormal SAS scores ranged from 6% to 10%. At Endpoint, the percentages of subjects with abnormal SAS scores ranged from 3% to 8%. The percentage of subjects with abnormal SAS scores decreased between
- the BAS score consists of an objective score, a subjective awareness of restlessness score, a score of distress related to restlessness, a 3-item total score, and a global clinical assessment score.
- the objective score 0.421
- distress related to restlessness score 0.254
- the 3-item total score 0.865
- There was a statistically significant difference among treatment groups at Baseline for the subjective distress related to restlessness score (p 0.029), but not for any other scores.
- the mean BAS total scores in all three treatment groups ranged and from 0.44 to 0.46. There were minor fluctuations in the mean BAS total score in all three treatment groups during the study, and at Month 6, the mean BAS total scores ranged from 0.05 to 0.17 (APTS, OC).
- the adjusted mean maximal changes from baseline to Month 6 in BAS total scores were ⁇ 0.6 in each treatment group (APTS, OC, ANCOVA). There were no clinically relevant differences between any of the treatment groups in BAS total scores.
- the mean AIMS total scores in all three treatment groups were low and ranged from 1.04 to 1.35 at baseline. There was for all treatment groups an initial increase in the adjusted mean scores (largest in the BX30 group), after which the mean scores decreased over time; at Month 6, the scores had returned to baseline level in all three treatment groups (PBO: 0.11 ; BX20: 1.08; BX30: 0.86 (APTS, OC)).
- the adjusted mean changes in AIMS total scores in the BX20 (all time points) and BX30 (Months 5 and 6) groups were not statistically significantly different from those in the PBO group, whereas the adjusted mean change for BX30 (from Week 1 to Month 4) group was.
- the adjusted mean maximal changes from baseline to Month 6 in AIMS total score were small (PBO: 0.39; BX20: 1.21 ; BX30: 2.45, APTS, OC, ANCOVA). None of the differences were considered clinically significant.
- the mean weight loss for subjects in the bifeprunox treatment groups was approximately 1 Ib (5 mg bifeprunox, -1 0 Ib, 10 mg bifeprunox, -1 3 Ib, 20 mg bifeprunox, -0 6 lbs)
- the placebo treatment group had a mean weight gain of 1 9 lbs
- the mean weight change of subjects in the risperidone treatment group was a 4 8 Ib increase Increases in weight
- the percentages of subjects whose weight increased by more than 7% in the bifeprunox treatment groups (2 to 4%) were less than or similar to the percentage observed in the placebo treatment group (5%)
- the percentage of subjects whose weight decreased by more than 7% was higher in the bifeprunox treatment groups (5 mg, 6%, 10 mg, 7%, 20 mg, 8%) than in the placebo treatment group (3%)
- No subjects in the risperidone treatment group decreased their weight by ⁇ 7%
- CLINICAL STUDY THREE Small decreases in mean body weight were observed in the bifeprunox treatment groups and the placebo group, while an increase was noted for the olanzapine treatment group. At Endpoint, the mean weight changes were: -2.3 lbs in 20 mg bifeprunox group; -1.1 lbs in 30 mg bifeprunox group; -1.3 lbs in placebo group; and 5.2 lbs in olanzapine group. Mean changes at Week 6 were comparable to those at Endpoint ( Table below).
- Weight and BMI and changes therein relative to baseline are summarized in the Tables below.
- the adjusted mean weight and BMI decreased from baseline to Month 6.
- the adjusted mean weight change from baseline to Month 6 (APTS, OC, ANCOVA) was -0.8kg in the PBO group, -0.3kg in the BX20 group, and - 0.5kg in the BX30 group.
- the adjusted mean weight decreases in the BX20 and the BX30 group were not statistically significantly different from that in the PBO group.
- Weight decreased was reported as a TEAE for patients in all treatment groups (PBO: 5%; BX20: 8%; BX30: 8%) (Panel 45). Weight increased was reported as a TEAE for patients in the PBO group (1.8%) and in the BX30 group (1.2%).
- the primary efficacy variable was the time to deterioration and the analysis was based on the FAS.
- the proportion of patients who deteriorated was 59% in the PBO group, 41 % in the BX20 group, and 38% in the BX30 group.
- the Cox proportional hazards model gave an estimated hazard ratio of 0.66 (BX20) and 0.65 (BX30) relative to PBO; that is, the risk of deterioration was approximately 1.5 times higher for patients in the PBO group than for patients in the BX20 or BX30 groups.
- CLINICAL STUDY FOUR The adjusted mean HDL cholesterol values increased from baseline to Month 6 in all three treatment groups irrespective of fasting/non-fasting condition (PBO: 0.04/0.06 (fasting/nonfasting); BX20: 0.07/0.08; BX30: 0.07/0.08mmol/L). There were no statistically significant differences between either of the BX groups and the PBO group.
- the adjusted mean triglycerides values decreased from baseline to Month 6 in all three treatment groups irrespective of fasting/non-fasting condition (PBO: -0.06/-0.22 (fasting/non-fasting); BX20: -0.16/-0.21 ; BX30: -0.37/-0.03mmol/L). There were no statistically significant differences between either of the BX groups (except BX30 (fasting)) and the PBO group.
- the adjusted mean fasting glucose values increased from baseline to Month 6 in all three treatment groups (PBO: 0.10; BX20: 0.13; BX30: 0.09mmol/L) and there were no statistically significant differences between either of the BX groups and the PBO group.
- Panel 50 below summarizes the lipid profile at baseline (mean values) and at Month 6 (mean change from baseline) in fasting and non-fasting patients.
- the meantotal cholesterol and mean LDL calculated decreased from baseline to Month 6 in all groups (except non-fasting PBO patients) irrespective of treatment and fasting/non- fasting condition.
- the mean VLDL calculated and mean triglycerides decreased from baseline to Month 6 in all groups (except non-fasting BX30 patients) irrespective of treatment and fasting/non-fasting condition.
- the mean HDL increased from baseline to Month 6 in all groups irrespective of treatment and fasting/nonfasting condition.
- Hyperglycemia in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics.
- the incidence of hyperglycemia and diabetes-related adverse events (such as hyperglycemia, elevated blood glucose, impaired glucose tolerance, diabetes mellitus, inadequately controlled diabetes) in patients treated with bifeprunox was 0.5% (5/1050) and in placebo-treated patients was 0.6% (3/469) in six-week placebo- controlled trials. In a 26-week placebo-controlled trial, no patients reported hyperglycemia or diabetes-related adverse events.
- CLINICAL STUDY ONE Changes in PR, QT, QTc, QRS intervals and heart rate over time were evaluated by assessing changes in mean values between Baseline and Endpoint. There was very little change in mean values for PR, QTc, or QRS intervals between Baseline and Endpoint in any treatment group. Mean changes for these intervals ranged from approximately -2 msec to 4 msec. There were no trends in mean changes by treatment group. Changes in mean heart rate between Baseline and Endpoint ranged from -1.5 bpm to 0.9 bpm. There were no trends in mean changes by treatment group.
- the objective of this study is to assess the pharmacokinetics (PK) of bifeprunox.
- the PK of bifeprunox in healthy subjects were investigated based on a pooled analysis of PK parameters from 21 clinical pharmacology studies.
- the pooled analysis included PK profiles after single and multiple doses to 132 and 399 subjects, respectively, and explored the potential effects of age, gender, body weight, and race.
- PK in patients with schizophrenia were investigated using a population PK approach based on samples from 376 patients in phase Il studies and 434 patients in phase III studies.
- Bifeprunox was rapidly absorbed after oral administration (t max from 1.5 to 2 hours at all dose levels).
- Bifeprunox multiple-dose PK were dose-proportional in the 20-40 mg/day range.
- Bifeprunox was eliminated with a mean plasma steady-state half-life of 14.4 hours.
- Administration of a 40 mg dose with a standard high- fat meal was associated with a slight delay in t max (1.5 hours) and a small increase in C m a x (10%) and AUC (29%).
- Bifeprunox is approximately 99% bound to serum proteins.
- Bifeprunox is metabolized by CYP2C9, CYP3A4 and to a lesser extent, CYP2D6.
- Bifeprunox exposure was increased by co-administration with fluconazole (CYP2C9 inhibitor) and to a minor extent ketoconazole (CYP3A4 inhibitor), but not by coadministration with paroxetine (CYP2D6 inhibitor) and famotidine (a H2-antagonist). Bifeprunox exposure was reduced by co-administration of carbamazepine (CYP3A4 inducer). Co-administration of the narrow therapeutic index compounds warfarin and lithium (see EXAMPLE 3b) with bifeprunox did not affect the PK of these compounds to any relevant extent. In CYP2C9 slow/intermediate metabolizers, higher plasma levels of bifeprunox were observed than in subjects with normal enzyme activity.
- PURPOSE Bifeprunox, a partial agonist for dopamine D2 and 5-HT1 A receptors, is being developed for the treatment of schizophrenia. Because bifeprunox may be used in combination with the mood-stabilizing drug lithium for the treatment of patients with psychoses and mood disorders, the effect of multiple doses of bifeprunox on the pharmacokinetic (PK) profile of lithium was evaluated. Lithium has a narrow therapeutic index that can complicate therapy, and serum levels greater than 1.5 mmol/L carry a greater risk of lithium toxicity than do lower levels. METHODS: This was a single center, double-blind, randomized, placebo-controlled, parallel-design study in 48 healthy male subjects.
- Lithium, steady-state Cmax, AUC over the dosing interval (0-t), and renal clearance (CL-R) values were compared between the bifeprunox and placebo groups using ANCOVA with baseline values of lithium measured on day 8 as covariate.
- AUC(O-t) of lithium in the bifeprunox group but the ratios of the geometric least square means and the 90% confidence intervals (Cl) of the two treatments for AUC, Cmax, and CL-R were within the predefined range of 0.80 to 1.25.
- Combined administration of bifeprunox up to 40 mg per day and lithium 450 mg twice daily was well tolerated.
- Treatment with all bifeprunox doses were titrated up to target dose, beginning with a dose of 0.125 mg on day 1 , 0.25 mg on day 2, 0.5 mg on day 3, 1 mg on day 4, 2 mg on day 5, and 5 mg on day 6, 10 mg on day 7 or 20 mg on day 8, while treatment with risperidone was titrated over 3 days.
- PANSS Positive and Negative Symptom Scale
Abstract
Description
Claims
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JP2009526089A JP2010501626A (en) | 2006-08-31 | 2007-08-29 | Bifeprunox dose to treat schizophrenia |
EP07802975A EP2059245A1 (en) | 2006-08-31 | 2007-08-29 | Bifeprunox doses for treating schizophrenia |
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WO2010060742A1 (en) * | 2008-11-03 | 2010-06-03 | Solvay Pharmaceuticals B.V. | Combination of bifeprunox and an antipsychotic drug with d2/5-ht2a receptor antagonistic activity for treating cns disorders |
JP2017048247A (en) * | 2009-06-25 | 2017-03-09 | アルカーメス ファーマ アイルランド リミテッド | Heterocyclic compounds for treatment of neurological and psychological disorders |
US10238651B2 (en) | 2014-03-20 | 2019-03-26 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
US10639376B2 (en) | 2012-09-19 | 2020-05-05 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
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WO2010070061A1 (en) * | 2008-12-19 | 2010-06-24 | Abbott Healthcare Products B.V. | Compositions, kits and methods of a titration schedule for bifeprunox compounds |
WO2011023796A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Healthcare Products B.V. | Bifeprunox for treating addiction |
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WO2010060742A1 (en) * | 2008-11-03 | 2010-06-03 | Solvay Pharmaceuticals B.V. | Combination of bifeprunox and an antipsychotic drug with d2/5-ht2a receptor antagonistic activity for treating cns disorders |
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JP2017048247A (en) * | 2009-06-25 | 2017-03-09 | アルカーメス ファーマ アイルランド リミテッド | Heterocyclic compounds for treatment of neurological and psychological disorders |
EP2445502B1 (en) | 2009-06-25 | 2017-06-21 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
EP3309151A1 (en) | 2009-06-25 | 2018-04-18 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
US10023537B2 (en) | 2009-06-25 | 2018-07-17 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
US10112903B2 (en) | 2009-06-25 | 2018-10-30 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
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US10639376B2 (en) | 2012-09-19 | 2020-05-05 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
US11406632B2 (en) | 2014-03-20 | 2022-08-09 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
US10813928B2 (en) | 2014-03-20 | 2020-10-27 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
US10238651B2 (en) | 2014-03-20 | 2019-03-26 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
US11931355B2 (en) | 2014-03-20 | 2024-03-19 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
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KR20090063228A (en) | 2009-06-17 |
NO20091243L (en) | 2009-03-25 |
JP2010501625A (en) | 2010-01-21 |
WO2008025780A1 (en) | 2008-03-06 |
AU2007291234A1 (en) | 2008-03-06 |
CA2661800A1 (en) | 2008-03-06 |
JP2010501626A (en) | 2010-01-21 |
BRPI0715445A2 (en) | 2014-05-13 |
IL196867A0 (en) | 2009-11-18 |
CA2661120A1 (en) | 2008-03-06 |
EP2059244A1 (en) | 2009-05-20 |
AU2007291235A1 (en) | 2008-03-06 |
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EP2059245A1 (en) | 2009-05-20 |
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