Otsuka Beijing Research Institute

Objectives: To analyze the value of the WT1 mRNA expression level in the diagnosis and prognostic evaluation of myelodysplastic syndrome (MDS) . Methods: A total of 403 patients with MDS, suspected MDS, and acute myeloid leukemia secondary to MDS (AML-MDS) from eight clinical trial centers in China were included in this multicenter, prospective study. Nucleic acid was extracted from the peripheral blood (PB) and bone marrow (BM) samples and WT1 mRNA expression was measured using the WT1 mRNA assay kit. Results: A good correlation (r=0.778) was observed between the expression levels of WT1 mRNA in PB and BM. The expression levels of WT1 mRNA in both PB and BM increased with increasing FAB (French-American-British) or WHO (2008) (world health organization) classification scores, and increasing IPSS-R or WPSS-R prognostic scores. A statistically significant difference was observed in the expression levels of WT1 mRNA in PB and BM between MDS and AML-MDS patients (PB: 3.11±0.98 vs 4.57±0.53, P<0.05; BM: 3.73±0.93 vs 4.92±0.81, P<0.05). A statistically significant difference also existed in the expression levels of WT1 mRNA in PB and BM between the IPSS-R relatively low-risk group (extremely low-risk + low-risk) and the relatively high-risk group (medium risk + high risk + extremely high risk) MDS patients (PB: 2.60±0.76 vs 3.48±0.91, P<0.05; BM: 3.50±0.82 vs 3.89±0.97, P<0.05). Statistically significant differences were observed in the WT1 mRNA expression levels between the IPSS-R low-risk group (extremely low-risk + low-risk + moderate risk) and the high-risk group (high-risk + extremely high-risk) MDS patients in PB and BM (PB: 2.82±0.89 vs 3.61±0.85, P<0.05; BM: 3.61±0.84 vs 3.92±1.05, P<0.05). Statistically significant differences were also observed in the expression levels of WT1 mRNA in PB and BM of MDS patients between the WPSS-R relatively low-risk group (extremely low-risk + low-risk + moderate risk) and the relatively high-risk group (high-risk + extremely high-risk) (PB: 2.56±0.79 vs 3.61±0.82, P<0.05; BM: 3.45±0.83 vs 3.93±1.00, P<0.05) . Conclusion: A good correlation was observed between the expression levels of WT1 mRNA in PB and BM specimens of MDS patients, and the expression level of WT1 mRNA is related to the disease risk of MDS.

The present study aimed to evaluate the efficacy and safety of aripiprazole once-monthly (AOM) compared to oral aripiprazole in treating acute schizophrenia.

This randomized, double-blind, non-inferiority study recruited patients from 15 trial sites across China from May 2017 to April 2019. Patients with an acute psychotic episode received AOM at 400 mg or oral aripiprazole at 10-20 mg for 12 weeks. The primary and secondary efficacy endpoints were the difference in scores from baseline to week 10, as assessed on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively.

A total of 436 patients were randomized. Among them, 159/218 (72.9%) and 165/218 (75.7%) in the AOM and oral aripiprazole groups completed 10 weeks of treatment, respectively. The least-squares (LS) mean changes from baseline to endpoint (week 10) in PANSS were - 33.6 for the AOM group and - 34.8 in the oral aripiprazole group, respectively, with a difference of - 1.2 (95% CI: - 4.1, 1.7). The non-inferiority margin of AOM to oral aripiprazole was - 4.1, which was above the lower limit of the pre-defined margin. The altered CGI-S score was - 2.2 and - 2.3 in the AOM and oral aripiprazole groups, respectively. The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups. The rate of discontinuation due to TEAEs was 2.3% and 3.2% in the AOM and oral aripiprazole groups, respectively.

This study confirmed the efficacy and safety of AOM for the treatment of Chinese patients with acute schizophrenia. The non-inferiority of AOM to oral aripiprazole was established, with comparable efficacy and tolerability. These findings suggested that AOM could be used as a treatment option for patients experiencing an acute episode of schizophrenia.

ClinicalTrials.gov identifier: NCT03172871.

The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors.

Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing.

Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure.

OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored.

NCT01184807.