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The atypical profile of ‘Seroquel’ (ICI 204,636) is supported by its lack of inductionof extrapyramidal symptoms
P.3 Psychotic disorders and antipsychotics in haloperidol-sensitized and drug-naive monkeys, which may translate to lack of EPS in man. ICI 204,636, like clozapine, does not cause sustained elevations of PRL after short-term administration to rats. These preclinical data were supported by data from Phase II clinical trials in which no differences between ICI 204,636 and placebo treatment groups were identified with regard to EPS, as assessed by Simpson Scale total scores, use of concomitant anticholinergic medications,and the incidence of motor system adverse events. Acute dystonic reactions were not reported. Further, there were no significantdifferencesbetweenICI 204,636 and placebo in decrease from baseline in PRL after 6 weeks of treatment. In a chlorpromazine-controlled trial, the decrease from baseline with ICI 204,636 was significantly greater than that with chlorpromazine (LSM change from baseline, ANCOVA) at the finalobservation(p = 0.003).Decreases in PRL were most likely the result of discontinuing prior treatment with standard antipsychotic medications,with a return to physiologic levels of dopamine-receptorblockadein the tuberoinfundibular systemduring treatment with either ICI 204,636 or placebo. PRL was again measured in a 6-week, multicenter, placebo-controlled, double-blind, Phase ill clinical trial conducted in North America. This trial evaluated the efficacy, tolerability, and optimal dose range of ICI 204,636 in the treatment of patients with acute exacerbation of schizophrenia (n = 360) with five fixed doses ofICI 204,636 (75, 150,300,600, 750 mg daily), one dose of haloperidol (12 mg daily), and placebo. PRL, from blood samples drawn before the morning dose of study medication, was assessed at baseline and after 6 weeks of treatment. The PRL data from this trial will be presented. Seroquel is a trademark, the property of Zeneca Limited.
I P.3.067I Reduction of the positive symptoms of schizophrenia by '8eroquel' (ICI204,636): Results from phase II andIII clinical trials WW Hong, L.A. Arvanitis. Central Nervous System Clinical Research, Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19850USA
Introduction: 'Seroquel' (ICI 204,636) is a promising new antipsychotic in Phase ill clinical development by Zeneca Pharmaceuticals. In vitro and in vivo preclinical experiments suggested ICI 204,636 would be an effective antipsychotic with a low propensity to cause extrapyramidal symptoms or sustained elevation of plasma prolactin. Phase II and ill clinical trials have confirmed that ICI 204,636 is effective in the treatment of the acute exacerbation of schizophrenia and that, across the dose range, it does not differ from placebo in the incidence of extrapyramidal symptoms or elevation of plasma prolactin. We present here data on the antipsychotic effect of ICI 204,636 with a focus on the positive symptoms of schizophrenia. Methods: Four trials (n = 716) were short-term ts 6 weeks), placebocontrolled, double-blind,randomized, parallel-group, safety,and efficacy trials in acute exacerbation of schizophrenia. Three of these wereflexibledose trials, and one employed five fixed doses of ICI 204,636 (75, 150, 300, 600, and 750 mg/day). The multiple fixed-dose trial also included a haloperidol group (haloperidol n = 52). A fifth trial (n = 201) was a 6-week, chlorpromazine-controlled, double-blind, randomized, parallelgroup, flexible-dose. safety, and efficacy trial in acute exacerbation of schizophrenia. In all trials, the Brief Psychiatric Rating Scale (BPRS) total and the Clinical Global Impression (COl) Severity of TIlness item scores were used to assess overall efficacy, and the BPRS positive symptom cluster score was used to assess selective effects on the positive symptoms of schizophrenia. Results: ICI 204,636 was consistently superior to placebo and comparable to haloperidoland chlorpromazinein the reduction from baseline of the BPRS total and COl Severity of Illness item scores as well as of the BPRS positive symptom cluster scores in subjects in acute exacerbation of schizophrenia.In the multiple fixed dose trial that compared five fixed doses of ICI 204,636 from 75 to 750 mg/day to placebo and one fixed dose of haloperidol, ICI 204,636 was superior to placebo and comparable to haloperidol in the reduction from baseline of the BPRS total and COl Severity of TIlness item scores as well as of the BPRS positive symptom cluster score at doses of 150 to 750 mg/day. The maximumclinical effect of ICI 204,636 occurred at the dose of 300 mg/day.
S4-125
Conclusions: ICI 204,636 is superior to placebo and comparable to standard agents in the treatment of the acute exacerbation of schizophrenia, as measured by the BPRS total, COl Severity of Illness item, and BPRS positive symptom cluster scores. Therefore, ICI 204,636 is intended as first-line therapy for the acute exacerbation of schizophrenia. Along with antipsychotic efficacy, the atypical tolerability profile of ICI 204,636 (ie across the dose range, extrapyramidal symptoms and prolactin not different from placebo) is expected to improve compliance and outcomecompared to standard agents. We are now in the process of establishing the efficacyand tolerabilityof ICI 204,636 in subpopulations of schizophrenia, such as the treatment resistant population. Seroquelis a trademark, the property of Zeneca Limited.
IP.3.06S!
Theatypical profile of '8eroquel' (ICI204,636) is supported by its lackof induction of extrapyramidal symptoms
WW Hong, L.A. Arvanitis. Central Nervous SystemClinical Research. Zeneca Pharmaceuticals, 1800Concord Pike, Wilmington, Delaware 19850USA
Introduction: The atypical antipsychotic, clozapine, has minimal extrapyramidal symptom (EPS) liability and does not cause sustained hyperprolactinemia. These features of atypical antipsychotics are expeeted to improve compliance, reduce hospitalizations, and enhance the quality of lives of patients with schizophrenia. 'Seroquel' (ICI 204,636) is a promising new antipsychotic with an atypical profile. Like clozapine, ICI 204,636 is limbic selective, and has minimal dystonic liability in haloperidol-sensitized and drug-naive monkeys, which may translate to minimal EPS in man. ICI 204,636, like clozapine, does not cause sustained elevations of plasma prolactin (PRL) after short-term administration to rats. These preclinical data were supported by data from Phase II and ill clinical trials in which no differences between ICI 204,636 and placebo were identified with regard to change from baseline in plasma PRL at endpoint.We present here EPS data from five placebo- or haloperidol-controlled ICI 204,636 Phase II and ill clinical trials. Methods: Four trials (n = 716) were short-term « 6 weeks), placebocontrolled, double-blind, randomized, parallel-group, safety, and efficacy trials in acute exacerbation of schizophrenia. Three of these were flexible-dose trials, and one was a multiple fixed-dosetrial. The multiple fixed-dose trial also had a haloperidol group (haloperidol n = 52). A fifth trial (n = 448) was a 6-week, haloperidol-controlled, double-blind, randomized, parallel-group, flexible-dose, safety, and efficacy trial in acute exacerbation of schizophrenia. All five trials had a minimum of a 48-hour drug-free period before randomization. In all trials, benztropine mesylateor an alternate EPS medication was given on an as-needed basis for EPS. EPS was assessed across all trials using the Simpson Scale and by comparing the use of EPS medications and the incidence of motor system adverse events between treatment groups. The Barnes Akathisia Scale was also used in one of the placebo-controlled trials. Results: ICI 204,636 was not different from placebo and superior to haloperidol when frequency distributions of grouped change from baseline scores for Simpson Scale total score were analyzed.leI 204,636 was not different from placebo when frequency distributions of grouped change from baseline scores for Barnes Akathisia Scale scores (all four items) were analyzed (n = 286). Use of EPS medication did not differ between ICI 204,636 and placebo groups, whereas more patients in the haloperidol groups received EPS medication than in the ICI 204,636 groups. A similar incidenceof motor system adverse events (eg cogwheel rigidity, tremor, and akathisia) was seen in the ICI 204,636 and placebo groups, whereas more patients in the haloperidol groups had motor system adverse events than in the ICI 204,636 groups. Conclusions: ICI 204,636, across the entire dose range, does not differ from placebo in the induction of EPS, and has much less EPS liability than haloperidol. These clinical results provide further support for the designationof ICI 204,636 as an atypical antipsychotic. We are currently testing the hypothesisthat the superior tolerability profile of ICI 204,636 will enhance compliance and outcome in schizophrenia. Seroquel is a trademark, the property of Zeneca Limited.
I P.3.067I Reduction of the positive symptoms of schizophrenia by '8eroquel' (ICI204,636): Results from phase II andIII clinical trials WW Hong, L.A. Arvanitis. Central Nervous System Clinical Research, Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19850USA
Introduction: 'Seroquel' (ICI 204,636) is a promising new antipsychotic in Phase ill clinical development by Zeneca Pharmaceuticals. In vitro and in vivo preclinical experiments suggested ICI 204,636 would be an effective antipsychotic with a low propensity to cause extrapyramidal symptoms or sustained elevation of plasma prolactin. Phase II and ill clinical trials have confirmed that ICI 204,636 is effective in the treatment of the acute exacerbation of schizophrenia and that, across the dose range, it does not differ from placebo in the incidence of extrapyramidal symptoms or elevation of plasma prolactin. We present here data on the antipsychotic effect of ICI 204,636 with a focus on the positive symptoms of schizophrenia. Methods: Four trials (n = 716) were short-term ts 6 weeks), placebocontrolled, double-blind,randomized, parallel-group, safety,and efficacy trials in acute exacerbation of schizophrenia. Three of these wereflexibledose trials, and one employed five fixed doses of ICI 204,636 (75, 150, 300, 600, and 750 mg/day). The multiple fixed-dose trial also included a haloperidol group (haloperidol n = 52). A fifth trial (n = 201) was a 6-week, chlorpromazine-controlled, double-blind, randomized, parallelgroup, flexible-dose. safety, and efficacy trial in acute exacerbation of schizophrenia. In all trials, the Brief Psychiatric Rating Scale (BPRS) total and the Clinical Global Impression (COl) Severity of TIlness item scores were used to assess overall efficacy, and the BPRS positive symptom cluster score was used to assess selective effects on the positive symptoms of schizophrenia. Results: ICI 204,636 was consistently superior to placebo and comparable to haloperidoland chlorpromazinein the reduction from baseline of the BPRS total and COl Severity of Illness item scores as well as of the BPRS positive symptom cluster scores in subjects in acute exacerbation of schizophrenia.In the multiple fixed dose trial that compared five fixed doses of ICI 204,636 from 75 to 750 mg/day to placebo and one fixed dose of haloperidol, ICI 204,636 was superior to placebo and comparable to haloperidol in the reduction from baseline of the BPRS total and COl Severity of TIlness item scores as well as of the BPRS positive symptom cluster score at doses of 150 to 750 mg/day. The maximumclinical effect of ICI 204,636 occurred at the dose of 300 mg/day.
S4-125
Conclusions: ICI 204,636 is superior to placebo and comparable to standard agents in the treatment of the acute exacerbation of schizophrenia, as measured by the BPRS total, COl Severity of Illness item, and BPRS positive symptom cluster scores. Therefore, ICI 204,636 is intended as first-line therapy for the acute exacerbation of schizophrenia. Along with antipsychotic efficacy, the atypical tolerability profile of ICI 204,636 (ie across the dose range, extrapyramidal symptoms and prolactin not different from placebo) is expected to improve compliance and outcomecompared to standard agents. We are now in the process of establishing the efficacyand tolerabilityof ICI 204,636 in subpopulations of schizophrenia, such as the treatment resistant population. Seroquelis a trademark, the property of Zeneca Limited.
IP.3.06S!
Theatypical profile of '8eroquel' (ICI204,636) is supported by its lackof induction of extrapyramidal symptoms
WW Hong, L.A. Arvanitis. Central Nervous SystemClinical Research. Zeneca Pharmaceuticals, 1800Concord Pike, Wilmington, Delaware 19850USA
Introduction: The atypical antipsychotic, clozapine, has minimal extrapyramidal symptom (EPS) liability and does not cause sustained hyperprolactinemia. These features of atypical antipsychotics are expeeted to improve compliance, reduce hospitalizations, and enhance the quality of lives of patients with schizophrenia. 'Seroquel' (ICI 204,636) is a promising new antipsychotic with an atypical profile. Like clozapine, ICI 204,636 is limbic selective, and has minimal dystonic liability in haloperidol-sensitized and drug-naive monkeys, which may translate to minimal EPS in man. ICI 204,636, like clozapine, does not cause sustained elevations of plasma prolactin (PRL) after short-term administration to rats. These preclinical data were supported by data from Phase II and ill clinical trials in which no differences between ICI 204,636 and placebo were identified with regard to change from baseline in plasma PRL at endpoint.We present here EPS data from five placebo- or haloperidol-controlled ICI 204,636 Phase II and ill clinical trials. Methods: Four trials (n = 716) were short-term « 6 weeks), placebocontrolled, double-blind, randomized, parallel-group, safety, and efficacy trials in acute exacerbation of schizophrenia. Three of these were flexible-dose trials, and one was a multiple fixed-dosetrial. The multiple fixed-dose trial also had a haloperidol group (haloperidol n = 52). A fifth trial (n = 448) was a 6-week, haloperidol-controlled, double-blind, randomized, parallel-group, flexible-dose, safety, and efficacy trial in acute exacerbation of schizophrenia. All five trials had a minimum of a 48-hour drug-free period before randomization. In all trials, benztropine mesylateor an alternate EPS medication was given on an as-needed basis for EPS. EPS was assessed across all trials using the Simpson Scale and by comparing the use of EPS medications and the incidence of motor system adverse events between treatment groups. The Barnes Akathisia Scale was also used in one of the placebo-controlled trials. Results: ICI 204,636 was not different from placebo and superior to haloperidol when frequency distributions of grouped change from baseline scores for Simpson Scale total score were analyzed.leI 204,636 was not different from placebo when frequency distributions of grouped change from baseline scores for Barnes Akathisia Scale scores (all four items) were analyzed (n = 286). Use of EPS medication did not differ between ICI 204,636 and placebo groups, whereas more patients in the haloperidol groups received EPS medication than in the ICI 204,636 groups. A similar incidenceof motor system adverse events (eg cogwheel rigidity, tremor, and akathisia) was seen in the ICI 204,636 and placebo groups, whereas more patients in the haloperidol groups had motor system adverse events than in the ICI 204,636 groups. Conclusions: ICI 204,636, across the entire dose range, does not differ from placebo in the induction of EPS, and has much less EPS liability than haloperidol. These clinical results provide further support for the designationof ICI 204,636 as an atypical antipsychotic. We are currently testing the hypothesisthat the superior tolerability profile of ICI 204,636 will enhance compliance and outcome in schizophrenia. Seroquel is a trademark, the property of Zeneca Limited.