Cariprazine short-term efficacy

Cariprazine was tested in three pivotal, multinational, randomised, double-blind, placebo-controlled trials in non-elderly adults (18-60) hospitalised for an acute exacerbation of schizophrenia (mean duration of disease 11.4 years). Six weeks of treatment with cariprazine demonstrated statistically superior improvements in the primary (PANSS total score) and secondary (CGI-S) efficacy outcomes vs. placebo over its entire dose range studied. The onset of significant superiority vs. the placebo response in PANSS total scores was generally observed as early as week 2 for the lower cariprazine doses (1.5-3.0 mg/day and already at week 1 for the higher doses (4.5 mg/day and above).

CARIPRAZINE SHORT-TERM EFFICACY

After a proof-of-concept dose-ranging study, three pivotal phase IIb/III, double-blind, randomised trials^2,3,4 were conducted to assess the efficacy of cariprazine vs. placebo in patients with acute exacerbation of schizophrenia (Table). In two of the trials, active comparators (risperidone³ or aripiprazole⁴) were also included for assay sensitivity, but the studies were statistically powered with a sample size for placebo-comparisons only.

Primary efficacy outcome – PANSS total score

The decrease of PANSS total score from baseline after 6 weeks of treatment is shown on Figure 1. As expected, there was a substantial placebo response, resulting in a continuous decrease of PANSS total score during the 6-week double-blind treatment phase of the trials. Compared to placebo, patients on cariprazine demonstrated a significantly superior and clinically relevant additional decrease in PANSS score over the entire dose range studied, i.e., from 1.5 mg to 9 mg once daily with clear dose-response. Nevertheless, a statistically significant separation of effects from placebo is observed earlier (1 week after randomisation) with the higher doses (4.5 mg/day and above).^2-4 But even the lowest dose of cariprazine (1.5 mg/day, i.e., the recommended starting dose) demonstrated continuous, significant improvement in PANSS total score from the second week of treatment, and this superior efficacy was maintained throughout the remainder of the study.²

 

Despite the substantial placebo response, the effect of cariprazine on the primary efficacy measure was 50-67% greater (when cariprazine dose groups are pooled within each study – Figure 2).¹¹ Taking the dose groups separately, these improvements in total PANSS scores with cariprazine were 41-79% greater vs. the placebo response.^2-4

Despite the significant placebo response, cariprazine (pooled doses) consistently improved PANSS total scores by an additional 50% or more.¹¹

Secondary efficacy outcome – CGI-S score

The CGI-S score categorizes the severity of the global impression of mental diseases as rated by the expert clinician. Severity categories are as follows: normal subjects are rated 1, borderline 2, mildly ill 3, moderately ill 4, markedly ill 5, severely ill 6, and the extremely ill patients are rated 7.⁷ Average baseline value in the three pivotal trials was nearly 5.^2-4

Similarly to the PANSS outcomes, cariprazine was consistently superior to placebo on this key efficacy outcome.^2-4 When patients were pooled according to baseline disease severity in a post hoc analysis,¹² an increased efficacy was observed in patients with more severe baseline status. In the most severe group of patients with a CGI-S ≥6 at baseline (severely or extremely ill, N=161), response rates were especially high (74% any improvement in CGI-S), even when compared to the high placebo response rate (42% any improvement). A clinically remarkable shift from CGI-S ≥6 (severely or extremely ill) to CGI-S ≤3 (mildly ill, borderline or normal) occurred in a significantly greater proportion with cariprazine vs. placebo (42% vs. 18%, P<0.01) (Figure 3).

In the subgroup of severely/extremely ill patients (CGI-S ≥6, N=161) at baseline…
Cariprazine reduced disease severity in 74% (vs. 42% on placebo), and
42% of them shifted from the severely/extremely ill category to the mildly
ill, borderline or normal state (CGI-S ≤3) (vs. 18% on placebo, p<0.01).¹²

 

 

Safety outcomes in the short-term efficacy trials

A post-hoc safety/tolerability analysis⁵ in patients with acute exacerbations of schizophrenia was performed using the data of the four phase II/III trials.^1-4 Safety population was defined as all patients who received ≥1 dose of study drug. Subgroups according to categories of modal daily dose (which is defined as the most frequently administered dose per patient) were separately analysed: 1.5–3 mg/day, 4.5–6 mg/day, and 9–12 mg/day. Cariprazine was generally well tolerated.

The incidence of treatment-emergent adverse events (TEAE) versus placebo was similar for cariprazine 1.5–3 mg/day and higher for cariprazine 4.5–6 and 9–12 mg/day. There was a dose–response relationship for akathisia, extrapyramidal symptoms, and diastolic blood pressure as well as some laboratory parameters (creatine phosphokinase [CPK] and transaminase elevations). Cariprazine was associated with small (∼1 to 2 kg) increases in body weight vs. placebo, but no difference was observed in metabolic parameters, prolactin level, or QTc prolongation (>500 ms). Within the 1.5-6.0 mg/day dose range approved by the EU (EMA) and US (FDA) regulatory agencies, cariprazine was generally safe and well tolerated in patients with schizophrenia.⁵