Yoko Fujimoto

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimers disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aβ species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer's disease: A phase IIa, multicenter, randomized, adjuvant and placebo clinical trial

P1-338 SAFETY, TOLERABILITYAND IMMUNOGENICITY OFAN IMMUNOTHERAPEUTIC VACCINE (VANUTIDE CRIDIFICAR [ACC-001]) AND THE QS-21 ADJUVANT IN JAPANESE INDIVIDUALS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE: A PHASE IIA, MULTICENTER, RANDOMIZED, ADJUVANTAND PLACEBO CLINICALTRIAL Heii Arai, Hideo Suzuki, Tamotsu Yoshiyama, Kasia Lobello, Yahong Peng, Enchi Liu, Nzeera Ketter, Richard Margolin, Nicholas Jackson, Yoko Fujimoto, Juntendo University School of Medicine, Tokyo, Japan; Pfizer Japan Inc., Tokyo, Japan; Pfizer Japan Inc., Tokyo, Japan; Pfizer Inc., Collegeville, Pennsylvania, United States; Pfizer Inc., Collegeville, Pennsylvania, United States; Janssen Alzheimer Immunotherapy Research & Development, LLC, South San Francisco, California, United States; Janssen Alzheimer Immunotherapy Research & Development, LLC, South San Francisco, California, United States; Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; Pfizer Inc., Pearl River, New York, United States. Contact e-mail: heii@juntendo.ac.jp

Safety of the anti-amyloid monoclonal antibody ponezumab (PF-04360365) following a single-dose intravenous infusion in Japanese patients with mild-to-moderate Alzheimer's disease: Preliminary results

P1-454 SAFETY OF THE ANTI-AMYLOID MONOCLONAL ANTIBODY PONEZUMAB (PF-04360365) FOLLOWING A SINGLE-DOSE INTRAVENOUS INFUSION IN JAPANESE PATIENTS WITH MILDTO-MODERATE ALZHEIMER’S DISEASE: PRELIMINARY RESULTS Yoko Fujimoto, Izuru Miyoshi, Taro Ishibashi, Kanae Togo, Sadahiro Abe, James W. Kupiec, Martin M. Bednar, Pfizer Japan Inc., Tokyo, Japan; Pfizer Inc., New York, NY, USA. Contact e-mail: Yoko. Fujimoto@pfizer.com

Pharmacokinetics of ponezumab (PF-04360365) following a single-dose intravenous infusion in Japanese patients with mild-to-moderate Alzheimer's disease: Preliminary results

Background: The Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-Cog) is the most commonly used primary efficacy measure in Alzheimer’s disease clinical trials. In general, the (11 item) ADASCog has demonstrated sensitivity to change across a range of dementia severities. However, some clinical research studies now include some additional items (e.g. delayed word recall, maze test and digit cancellation) hoping to better assess the early stages of dementia as well as executive functioning. Earlier research has demonstrated considerable variability in how raters have been trained to administer and score the (11 item) ADAS-Cog in clinical trials. Additionally, with increased globalization of studies, the potential for considerable differences in rater experience exists. Initial qualification rates for raters attempting to participate in studies utilizing the 11 item ADAS-Cog were compared to studies utilizing some or all of the additional items. Methods: A proprietary database identified all raters who were trained on and who attempted to qualify to administer and score the ADAS-Cog in 32 clinical trials. Raters were stratified into 2 groups those tested on the original 11 item ADAS-Cog and those tested on scale versions that incorporated additional item(s). Testing consisted of watching and scoring a video of the scale being administered to a patient. Initial qualification rates (scoring to a predefined criteria) were compared. Results: In 26 studies employing the 11 item ADAS-Cog, 4223 of 4587 raters (92.1%) qualified to rate on their initial attempt. Additionally, 1313 raters out of 1595 (82.3%) potential raters in the 6 studies utilizing additional item(s) were successful on their initial attempts to qualify to rate. A chi-square analysis determined that this difference in initial qualification rates is significant (<0.0001). Conclusions: The incorporation of additional item(s) into the original 11 item ADAS-Cog appears to provide an added challenge to raters who attempt to qualify to rate in those studies. Possible explanations include training variability; lack of familiarity with these items, their administration and scoring, and what they aim to assess. Given the difference in initial qualification rates when additional item(s) are used, surveillance and analysis of raters’ performance on these items throughout a trial is warranted.

Possibility of Database Research as a Means of Pharmacovigilance in Japan Based on a Comparison with Sertraline Postmarketing Surveillance

BACKGROUND Many pharmacoepidemiologic studies using large-scale databases have recently been utilized to evaluate the safety and effectiveness of drugs in Western countries. In Japan, however, conventional methodology has been applied to postmarketing surveillance (PMS) to collect safety and effectiveness information on new drugs to meet regulatory requirements. Conventional PMS entails enormous costs and resources despite being an uncontrolled observational study method. This study is aimed at examining the possibility of database research as a more efficient pharmacovigilance approach by comparing a health care claims database and PMS with regard to the characteristics and safety profiles of sertraline-prescribed patients. METHODS The characteristics of sertraline-prescribed patients recorded in a large-scale Japanese health insurance claims database developed by MinaCare Co. Ltd. were scanned and compared with the PMS results. We also explored the possibility of detecting signals indicative of adverse reactions based on the claims database by using sequence symmetry analysis. Diabetes mellitus, hyperlipidemia, and hyperthyroidism served as exploratory events, and their detection criteria for the claims database were reported by the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS Most of the characteristics of sertraline-prescribed patients in the claims database did not differ markedly from those in the PMS. There was no tendency for higher risks of the exploratory events after exposure to sertraline, and this was consistent with sertralines known safety profile. CONCLUSIONS Our results support the concept of using database research as a cost-effective pharmacovigilance tool that is free of selection bias . Further investigation using database research is required to confirm our preliminary observations.

Recent Trends in the Practice of Procedural Sedation Under Local Anesthesia for Catheter Ablation, Gastrointestinal Endoscopy, and Endoscopic Surgery in Japan: A Retrospective Database Study in Clinical Practice from 2012 to 2015

ObjectivesTo investigate changes in sedation practice during 2012–2015, using a large health claims database, for catheter ablation (CA), gastrointestinal endoscopic examination (EE), and surgery (ES) after dexmedetomidine (DEX) was approved for procedural sedation in 2013. We assessed the trends of sedative utilization, sedative-analgesic combinations, and, additionally, incidence of complications from 2012 to 2015.MethodsUsing the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan), annual utilization proportions of the sedatives and sedative-analgesic combinations and occurrence of complications were calculated in patients with a record of local anesthesia and CA, EE, and/or ES but without general anesthesia used on the same day. The sedatives studied were DEX, propofol (PF), midazolam (MDZ), diazepam, flunitrazepam, thiamylal (TIA), thiopental (TIO), and ketamine.ResultsDEX was used most often for CA, followed by PF. From 2012 to 2015, the proportion of DEX increased from 30 to 36%, and that of PF slightly decreased from 29 to 27%. The order of utilization proportions did not change for EE or ES. The use of benzodiazepines, particularly MDZ, predominated. The top five sedative-analgesic combination patterns changed during the study period for CA, but not for EE or ES. The most common complications with CA, EE, and ES were bradycardia, nausea and vomiting, and respiratory depression, respectively. There were no changes in the complications’ trends for the procedures.ConclusionThe approved use of DEX for procedural sedation resulted in changes for CA, but not for EE or ES. The complication trends did not change.

Contact Dermatitis after Prescription of an Ophthalmic Ointment Containing Fradiomycin Sulfate: A Retrospective Database Study Using Japanese Health Insurance Claims Data

BackgroundTopical ointments containing fradiomycin sulfate, such as fradiomycin sulfate/methylprednisolone (F/M) and fradiomycin sulfate/betamethasone sodium phosphate (F/B), are known to cause allergic contact dermatitis (CD) in some patients, especially when used for the periocular region. F/M is commonly prescribed to patients for various conditions; however, there are no reports with respect to the incidence of CD caused by F/M in actual practice.ObjectiveThe aim was to investigate the incidence of CD using a data-based retrospective cohort study.MethodsUsing a Japanese health insurance claims database [MinaCare Co. Ltd. healthcare database (MinaCare HDB)], a comparative assessment was conducted of F/M and another combination drug (F/B) and two single-drug treatments (ophthalmic ointments with either an antibiotic or a steroid). The total data set consisted of 1,176,082 individuals in the MinaCare HDB, with 54,016 having received prescriptions for one of the four investigational drug regimens.ResultsOverall, the incidences of CD were similar in three of the four groups in this study (F/M 0.091; F/B 0.092; steroids 0.102), while being lower in the fourth group (antibiotics 0.060). Even after confirmation of a diagnosis of CD, prescriptions for the investigational drugs were repeatedly filled for some patients.ConclusionThis study demonstrated that there was no clear difference in the incidence of CD after filling prescriptions for F/M, F/B, and ophthalmic ointment containing a steroid, while the incidence with antibiotics was lower by 0.03–0.04 compared with the other groups. Considering the observation that the investigational drugs were repeatedly prescribed even after the diagnosis of CD, it is critical that the risk of CD with these prescribed topical ointments is better understood by primary care physicians in order to take appropriate countermeasures.

Strengthening/Building Alzheimer’s Disease Global Clinical Trial Site Capabilities and Capacity in and for Emerging Markets. Lessons Learned from Japan

Considering the difficulty of clinical development for Alzheimer’s Disease (AD), understanding each country’s specific situation is an important first step in reducing the operational burden on clinical trials while maintaining the quality of the study. In this chapter, the long history of clinical development for AD in Japan is introduced. There has been a lot of experience in Japan of AD clinical development from the time of developing donepezil to the current global development of AD disease-modifying drugs. However, this experience has not always been a success story and has often been the cause of much frustration, such as the failure of Phase III studies, high regulatory requirements, development and implementation of neuropsychological tests, influence of ethnic factors, etc. However, all of these points provide us with a good source from which we can learn about the challenges of the clinical trials and discuss how to strengthen the quality and efficiency. It’s important to take advantage of this experience for future success in the clinical development of AD, especially in emerging markets.