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Cariprazine as monotherapy for the treatment of schizophrenia patients with predominant negative symptoms

Interview with Dr György Németh at ECNP 2015

Gyorgy Nemeth 2nd Rough Edit-HD 1080p

Abstract

P.3.d.053 Cariprazine as monotherapy for the treatment of schizophrenia patients with predominant negative symptoms: a double-blind, active controlled trial M. Debelle, G. Németh, E. Szalai, B. Szatmári, J. Harsányi, A. Barabássy, I. Laszlovszky; Gedeon Richter Plc., Medical Division, Budapest, Hungary

Introduction: Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy for the treatment of schizophrenia, including in three 6-week, randomized, double-blind, placebo-controlled, phase II/III clinical trials in patients with acute psychotic exacerbations and in one relapse prevention clinical trial in stabilized patients. Post hoc analysis of the 6-week efficacy trials on a subset of patients with high levels of negative symptoms demonstrated significantly greater improvement relative to placebo [1, 2]. The objective of this clinical trial was to evaluate the efficacy, safety, and tolerability of cariprazine relative to another antipsychotic in an adequate and well-conducted clinical trial in patients with predominant negative symptoms of schizophrenia.

Methods: This study was a multinational, randomized, double-blind, risperidone-controlled, parallel group clinical trial in adult patients with predominant, negative symptoms of schizophrenia. To be enrolled in the clinical trial and randomized to study treatment, patients had to have with predominant negative symptoms, defined as PANSS factor score for negative symptoms (PANSSFSNS) ≥ 24 and at least 2 of the 3 core negative symptoms scored at least 4; PANSS factor score for positive symptoms (PANSS-FSPS) ≥ 19; no clinically relevant depressive symptoms and no or limited extrapyramidal symptoms; assessed as stabilized with predominant negative symptoms for a retrospective 6-month period prior to screening, and for a prospective 4-week period prior to randomization. Following 2 weeks of cross-titration and discontinuation of previously taken antipsychotic(s), patients were treated with either cariprazine target dose 4.5 mg/d, or with risperidone target dose 4 mg/d for 24 weeks. The primary efficacy parameter was the improvement in negative symptoms, defined as change from baseline (CfB) to endpoint in PANSS-FSNS. The secondary efficacy parameter was functional improvement, defined as CfB to endpoint in Personal and Social Performance Scale (PSP) total score.

Results: 461 patients were randomized 1:1 to double-blind risperidone (n = 231) or cariprazine (n = 230) treatment. PANSSFSNS (27.5 in risperidone, 27.7 in cariprazine treatment groups, respectively), PSP total score (48.1, 48.8 respectively) and PANSS-FSPS (8.6, 8.8 respectively) were similar at baseline in the two treatment groups. 77.4% of the patients completed the 26- week study treatment duration, in both groups. CfB at week 26 in the primary parameter, PANSS-FSNS, was significantly larger in the cariprazine treatment group than in the risperidone treatment group (LSMD= −1.47; 95% CI: [-2.39, −0.53]; p = 0.002; MMRM, ITT). CfB at week 26 in the secondary parameter, PSP total score, showed similarly a significantly greater improvement with cariprazine when compared to risperidone (LSMD= 4.63; 95% CI: [2.71, 6.56]; p<0.001; MMRM, ITT). Patients tolerated the study treatment well, as reflected by low discontinuation rates due to AEs. The most common adverse events (≥10%) during study treatment were insomnia (10.0%), and headache (10.4%), both in the risperidone treatment group.

Conclusions: 26-week cariprazine treatment, given as antipsychotic monotherapy, was significantly more effective on negative symptoms and on functioning than risperidone in patients with predominant negative symptoms of schizophrenia. Cariprazine treatment was generally well tolerated in this study.

References [1] Debelle, M., Faradzs-zade, S., Szatmari, B. et al., 2014. Cariprazine in negative symptoms of schizophrenia: Post hoc analyses of a fixed-dose, placebo and active controlled trial. Eur Neuropsychopharm 24 (Suppl. 1), S534. [2] Debelle, M., Faradzs-zade, S., Szatmari, B. et al., 2015. Cariprazine in negative symptoms of schizophrenia: Post hoc analyses of a fixed-dose Phase III, randomized, double-blind, placebo- and active-controlled trial, EPA15-0567, Abstract 0242, Vienna.

Disclosure statement: The study was supported by Gedeon Richter Plc.

According to lead researcher Dr György Németh (Chief Medical Officer, Gedeon Richter):

“The positive symptoms of schizophrenia can be controlled by drugs, but this is the first study ever to show a significant effect of a compound on negative symptom compared to another antipsychotic. It seems that with cariprazine, we may be able to treat both the positive and negative symptoms with a single medication.”

Commenting, ECNP Executive Committee Member Professor Andreas Meyer-Lindenberg said:

“Treatments for the negative symptoms of schizophrenia are still urgently needed as these are critical predictors for patient’s recovery and reintegration. The current results suggest that D3-dopaminergic mechanisms may play a role in both causing and treating emotional flatness, which deserve further confirmation”.