Reagila

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15 Mechanism of action The mechanism of action of cariprazine is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D 3, D 2 (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5‑HT 1A receptors (Ki values of 1.4-2.6 nM), and antagonist activity at serotonin 5‑HT 2B , 5‑HT 2A and histamine H 1 receptors (Ki values of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5‑HT 2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC 50 > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar in vitro receptor binding and functional activity profile as the parent active substance. Pharmacodynamic effects In vivo non-clinical studies demonstrated that cariprazine occupies D 3 receptors to a similar extent as D 2 receptors at pharmacologically effective doses. There was a dose-dependent occupancy of brain dopamine D 3 and D 2 receptors (with preferential occupancy in regions with higher D 3 expression) in patients with schizophrenia within the therapeutic dose range of cariprazine for 15 days. The effects of cariprazine on the QT interval were evaluated in patients with schizophrenia or schizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in 129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation was detected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated with cariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTc of > 500 msec in the study. Clinical efficacy and safety Efficacy with short-term use The efficacy of cariprazine for the treatment of acute schizophrenia was studied in three multi-center, multinational, randomized, double-blind, placebo-controlled 6-week studies including 1,754 patients with the age of 18 to 60 years. The primary endpoint was change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score and the secondary endpoint was change from baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acute schizophrenia studies. In a multinational placebo-controlled study using fixed doses of 1.5 mg, 3.0 mg and 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In another multinational placebo-controlled study using fixed doses of 3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In a third multinational placebo-controlled study using fixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. Results for the primary outcome parameter are summarized in Table 2 below. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint. Table 2. Change from baseline to week 6 in the PANSS total score in studies of acute exacerbations of schizophrenia—ITT population Baseline Mean ± SD Change LS mean (SE) Treatment difference versus placebo (95% CI) P-value PANSS total (MMRM) RGH-MD-16 (n=711) Placebo 97.3 ± 9.22 –13.29 (1.82) — — Cariprazine 1.5 mg/day 97.1 ± 9.13 –21.27 (1.77) –7.97 (–12.94, –3.01) 0.0017 Cariprazine 3 mg/day 97.2 ± 8.66 –21.45 (1.74) –8.16 (–13.09, –3.22) 0.0013 Cariprazine 4.5 mg/day 96.7 ± 9.01 –23.77 (1.74) –10.48 (–15.41, –5.55) < 0.0001 Risperidone 4 mg/day 98.1 ± 9.50 –29.27 (1.74) –15.98 (–20.91, –11.04) < 0.0001* RGH-MD-04 (n=604) Placebo 96.5 ± 9.1 –14.3 (1.5) — — Cariprazine 3 mg/day 96.1 ± 8.7 –20.2 (1.5) –6.0 (–10.1, –1.9) 0.0044 Cariprazine 6 mg/day 95.7 ± 9.4 –23.0 (1.5) –8.8 (–12.9, –4.7) < 0.0001 Aripiprazole 10 mg/day 95.6 ± 9.0 –21.2 (1.4) –7.0 (–11.0, –2.9) 0.0008* RGH-MD-05 (n=439) Placebo 96.6 ± 9.3 –16.0 (1.6) — — Cariprazine 3 to 6 mg/day 96.3 ± 9.3 –22.8 (1.6) –6.8 (–11.3, –2.4) 0.0029 Cariprazine 6 to 9 mg/day 96.3 ± 9.0 –25.9 (1.7) –9.9 (–14.5, –5.3) < 0.0001 CI = confidence interval; ITT = intent to treat; LS mean = least squares mean; PANSS = Positive and Negative Syndrome Scale. *compared to placebo Efficacy with long-term use The efficacy of cariprazine for maintaining antipsychotic effect was investigated in a randomized-withdrawal, long-term clinical study. Totally, 751 patients with acute symptoms of schizophrenia received cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of 3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mg cariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary outcome of the study was time to relapse. By the end of the study 49.0% of placebo-treated patients versus 21.6% of cariprazine-treated patients had a relapse of schizophrenic symptoms. Time to relapse (92 vs. 326 days-based on the 25 th percentile) was therefore significantly longer in the cariprazine group than in the placebo group (p=0.009). Efficacy in predominantly negative symptoms of schizophrenia The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophrenia was investigated in a 26-week, multi-centre, double-blind, and active-controlled clinical study. Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was investigated compared to risperidone (dose range 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms of schizophrenia (n=461). 86% of patients were less than 55 years old, 54% of them were male. Persistent predominant negative symptoms were defined as symptoms lasting for a period of at least 6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factor score for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flat affect, N4: avolition, and N6: poverty of speech) and PANSS factor score for positive symptoms ≤ 19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptoms and clinically relevant parkinsonism (EPS) were excluded. Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the primary efficacy parameter, PANSS factor score for negative symptoms (PANSS-FSNS) (p< 0.001). However, a statistically significant difference (p=0.002) in favour of cariprazine over risperidone was observed from Week 14 onward (Table 3). Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the secondary efficacy parameter, Personal and Social Performance (PSP) total score (p< 0.001). However, a statistically significant difference (p< 0.001) in favour of cariprazine over risperidone was observed from Week 10 onward (Table 3). Differences on the Clinical Global Impression Severity (p=0.005) and Improvement (p< 0.001) scales, as well as PANSS-FSNS response rates (PANSS FSNS ≥ 30% improvement at Week 26; p= 0.003) were supportive of findings on the primary and secondary efficacy parameters. Table 3 Summary of results in study RGH-188-005 Efficacy parameter Cariprazine LS mean Risperidone LS mean Estimated treatment difference 95%CI p-value PANSS-FSNS at Baseline 27.8 27.5 - - - PANSS-FSNS at Week 26 18.5 19.6 - - - PANSS-FSNS CfB to Week 26 -8.9 -7.4 -1.5 -2,4; -0.5 0.002 Total PSP at Baseline 48.8 48.2 - - - Total PSP at Week 26 64.0 59.7 - - - Total PSP CfB to Week 26 14.3 9.7 4.6 2.7; 6.6 <0.001 CfB= change from baseline Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with cariprazine in one or more subsets of the paediatric population in the treatment of schizophrenia. See section 4.2 for information on paediatric use.