Long-Term Safety and Efficacy of Blonanserin Transdermal Patches in Japanese Patients with Schizophrenia: A 52-Week Open-Label, Multicenter Study

Abstract

Background Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation. Objective The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia. Methods An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8-16 mg/day blonanserin tablets for 6 weeks and then 40-80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40-80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1-2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form. Results A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application s...

Striatal Dopamine D2 Receptor Occupancy Induced by Daily Application of Blonanserin Transdermal Patches: Phase II Study in Japanese Patients With Schizophrenia

“…The peak occupancy of blonanserin tablets in this study was slightly higher than that of blonanserin patches, although satisfactory clinical effects were obtained in a placebo-controlled phase III study and 52-week long-term study of blonanserin patches at doses of 40 mg/d and 80 mg/d ( Iwata et al, 2020a , 2020b ). Lower peak occupancy in blonanserin patches compared with tablets may be attributed to maintenance of a certain level of both plasma blonanserin concentration and associated dopamine D 2 receptor occupancy.…”

“…Importantly, there were no serious adverse events and no patients discontinued either treatment as a result of adverse events. Based on the present results and previous findings with oral blonanserin, target doses of 40 mg/d and 80 mg/d were established for a phase III study of blonanserin transdermal patches ( Iwata et al, 2020b ) and a study conducted to properly assess the long-term safety and efficacy of this formulation ( Iwata et al, 2020a ). Results of the phase III study found statistically significant decreases in the PANSS total score over 6 weeks, especially in the blonanserin 80-mg patch group, which was associated with a moderate effect size (0.555) vs placebo ( Iwata et al, 2020b ).…”

“…Studies of adherence are conducted over periods of at least 12 weeks or considerably longer in the case of observational studies. In this regard, in a 52-week study, DAI-10 scores and questionnaire results indicated that the positive attitude toward blonanserin transdermal patch treatment held by a certain proportion of patients did not change during long-term treatment ( Iwata et al, 2020a ). There is also a methodological limitation of using base dopamine D 2 occupancy in healthy volunteers to calculate the dopamine D 2 receptor occupancy, similar to that noted in a previous study ( Tateno et al, 2013 ).…”

“…Blonanserin (Lonasen, Sumitomo Dainippon Pharma Co., Ltd.) is an atypical antipsychotic approved for use in Japan, Korea, and China ( Harvey et al, 2019 ; Iwata et al, 2020a ). Blonanserin has a high affinity for dopamine D 2 , D 3 , and serotonin 5-HT 2A receptors and is a full antagonist at dopamine D 2 /D 3 receptors but has low affinity for dopamine D 1 , 5-HT 1A , 5-HT 3 , α/β-adrenergic, histaminic, and muscarinic receptors ( Deeks and Keating, 2010 ).…”

Pharmacokinetic Evaluation of Blonanserin Transdermal Patch: Population Analysis and Simulation of Plasma Concentration and Dopamine D2 Receptor Occupancy in Clinical Settings

“…The 4 studies conducted in male and female patients with schizophrenia were (1) a positron emission tomography (PET) study for 2 weeks 9 (D4904019 [JapicCTI‐121914]); (2) a confirmatory study for 6 weeks 10 (D4904020 [NCT02287584, JapicCTI‐142688]); (3) a long‐term study for 52 weeks 11 (D4904040 [NCT02335658, JapicCTI‐152765]); and (4) a multiple application study for 2 weeks (D4904063 [JapicCTI‐142423]). The names and locations of study sites are listed in Table 1 and Table S1.…”