A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a nonhemophilic state.

BACKGROUND: Emicizumab, a factor (F) VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment option for people with hemophilia A (PwHA). However, a small proportion of PwHA still experience bleeds even under emicizumab prophylaxis, as observed in the long-term outcomes of clinical studies. A more potent BsAb may be desirable for such patients. OBJECTIVES: To identify a potent BsAb to FIXa and FX, NXT007, surpassing emicizumab by in vitro and in vivo evaluation. METHODS: New pairs of light chains for emicizumab's heavy chains were screened from phage libraries, and subsequent antibody optimization was performed. For in vitro evaluation, thrombin generation assays were performed with hemophilia A plasma. In vivo hemostatic activity was evaluated in a nonhuman primate model of acquired hemophilia A. RESULTS: NXT007 exhibited an in vitro thrombin generation activity comparable to the international standard activity of FVIII (100 IU/dL), much higher than emicizumab, when triggered by tissue factor. NXT007 also demonstrated a potent in vivo hemostatic activity at approximately 30-fold lower plasma concentrations than emicizumab's historical data. In terms of dose shift between NXT007 and emicizumab, the in vitro and in vivo results were concordant. Regarding pharmacokinetics, NXT007 showed lower in vivo clearance than those shown by typical monoclonal antibodies, suggesting that the Fc engineering to enhance FcRn binding worked well. CONCLUSION: NXT007, a potent BsAb, was successfully created. Nonclinical results suggest that NXT007 would have a potential to keep a nonhemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab.

Meta-analysis of Dropout Rates in Placebo-Controlled Randomized Clinical Trials of Atypical Antipsychotics Assessed by PANSS.

BACKGROUND AND OBJECTIVES: Subject dropout rates in placebo-controlled randomized clinical trials (RCTs) of antipsychotics are high. The missing values due to dropout represent a potential source of bias in clinical trials. We aimed to identify the potential factors affecting subject dropout in atypical antipsychotics RCTs by conducting a meta-analysis. METHODS: Placebo-controlled RCTs for atypical antipsychotics using positive and negative syndrome scale (PANSS) as a psychiatric assessment scale were selected by database search. The potential factors affecting subject dropout, such as publication year, study design, and operational factors, were analyzed by meta-regression. RESULTS: Forty-seven placebo controlled RCTs of atypical antipsychotics of which results were published between 1993 and 2018 were identified through the database search. In the multivariate meta-regression analysis, earlier publication year, older age of subjects, and longer study duration were significantly associated with high subject dropout rates in placebo-controlled clinical trials of atypical antipsychotics. CONCLUSION: Subject dropout rates in clinical trials of atypical antipsychotics published between 1993 and 2018 year decreased over time. Study duration should be taken into consideration when designing future studies, where short study periods yet appropriate for evaluating the efficacy of new atypical antipsychotics are preferable. Additionally, previous medications and the degree of subject satisfaction with antipsychotics might affect subject dropout rate.

Correction to: Meta-analysis of Placebo Response in Randomized Clinical Trials of Antipsychotic Drugs Using PANSS Focusing on Different Approaches to the Handling of Missing Data.

In the original publication, the Estimate column with values under Multivariate meta-regression (LOCF) in Table 1 was missed. The corrected table is shown below.

Meta-analysis of Placebo Response in Randomized Clinical Trials of Antipsychotic Drugs Using PANSS Focusing on Different Approaches to the Handling of Missing Data.

BACKGROUND AND OBJECTIVE: Schizophrenia treatment has been shifting to resocialization by efficacious antipsychotic drugs. However, even some of the pivotal studies of approved new antipsychotic drugs with proven efficacy had failed due to high placebo response. The aim of this study was to identify the potential factors affecting placebo response by meta-analysis for randomized clinical trials for antipsychotic drugs using Positive and Negative Syndrome Scale (PANSS) focusing on the current methodological change in the handling of missing data [from last observation carried forward (LOCF) to mixed-effect models for repeated measures (MMRM)] for successful future clinical trials. METHODS: Recent trends in the degree of placebo response were investigated between publication year (1993 to 2016) and the mean change of PANSS total score in the placebo arm. The potential factors affecting the degree of placebo response, such as study design and operational factors, were analyzed separately by meta-regression for LOCF- and MMRM-based data. RESULTS: There was no correlation between publication year and the mean change of PANSS score in the placebo arm in schizophrenia studies of 10 years applying MMRM. The number of countries and treatment setting in MMRM-based data and study duration in LOCF-based data were significantly associated with placebo response. CONCLUSION: Placebo response in schizophrenia clinical trials published between 2007 and 2016 has not increased over time. Differences in the healthcare environment among countries were suggested to affect the evaluation of antipsychotic drugs. Further analyses on the potential factors of placebo response for MMRM-based data are required.