Efficacy of Erenumab for Migraine Prevention in Japanese Patients with Episodic and Chronic Migraine: Results of a Post-Hoc Pooled Analysis.

INTRODUCTION: Erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide receptor, is approved in Japan for the prevention of adult migraine. This post-hoc analysis evaluated the efficacy of erenumab in Japanese patients with low-frequency episodic migraine (LFEM) versus those with high-frequency episodic migraine (HFEM) and chronic migraine (CM). METHODS: A pooled analysis of data from the 24-week double-blind treatment phases (DBTPs) of phase 2 and 3 studies evaluated the efficacy of once-monthly erenumab 70 mg in Japanese patients. Patients were categorized into subgroups by monthly migraine days (MMD): LFEM and HFEM/CM. The main efficacy outcomes were change from baseline in MMD, acute migraine-specific medication treatment days (MSMD), and six-item Headache Impact Test (HIT-6™) scores. RESULTS: Patients with migraine (n = 532) were included in the analysis (LFEM, n = 215; HFEM, n = 215; CM, n = 102). Overall, mean age was 44 years, 86.5% were female, and 63.3-88.2% had used or were taking migraine preventive treatment at baseline. Throughout the DBTP, the placebo-adjusted mean change from baseline in MMD, MSMD, and HIT-6 scores with erenumab was similar across LFEM and HFEM/CM subgroups. The proportion of patients achieving at least 50% or 75% reduction from baseline in MMD and MSMD was similar across migraine frequency groups. Reduction in MMD moderately correlated with improvement in HIT-6 scores in the LFEM and HFEM/CM groups. Furthermore, the proportion of patients converting from HFEM/CM to LFEM during the DBTP was higher in the erenumab group than in the placebo. CONCLUSION: In Japanese patients with different migraine frequencies, erenumab treatment resulted in significant improvements in MMD, MSMD, and headache impact. This pooled analysis of data from phase 2 and 3 studies increases confidence that erenumab is efficacious in patients with high MMD, which is associated with increased disability.

Long-term efficacy and safety of erenumab in Japanese patients with episodic and chronic migraine: results from a 28-week open-label treatment period of a randomised trial.

OBJECTIVES: To evaluate the 1-year efficacy and safety of once-monthly erenumab 70 mg following a 24-week double-blind treatment period (DBTP) of a phase III randomised study of Japanese patients with episodic migraine (EM) or chronic migraine (CM). DESIGN: Multicentre open-label study. SETTING: A total of 41 centres in Japan. PARTICIPANTS: Patients completing the DBTP continued into the 28-week open-label treatment period (OLTP). 254 of 261 (97.3%) randomised patients continued into the OLTP; 244 (93.5%) completed treatment. INTERVENTIONS: Once-monthly subcutaneous erenumab 70 mg. MAIN OUTCOME MEASURES: Changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication treatment days (MSMD) reported via patient eDiary; proportion of ≥50% and ≥75% responders in MMD reduction from baseline; incidence and exposure-adjusted incidence of treatment-emergent adverse events (TEAEs). RESULTS: At week 24 of the DBTP, the mean (SE) change from baseline in MMD for the erenumab group was -3.8 (0.4) days (EM, -3.0 (0.4); CM, -5.2 (0.8)); in MSMD, -2.6 (0.4) days (EM, -2.1 (0.4); CM, -3.4 (0.7)). At the end of the OLTP (52 weeks postbaseline), the mean (SE) change from baseline in MMD was -4.7 (0.3) days (EM, -3.4 (0.3); CM, -6.9 (0.6)); in MSMD, -3.3 (0.3) days (EM, -2.4 (0.3); CM, -4.6 (0.5)). The proportion of ≥50% responders for MMD reduction in the erenumab group was 34.1% at week 24; 44.4% at week 52. The exposure-adjusted incidence of TEAEs was 219.7 per 100 patient-years during the OLTP (DBTP, 251.0 for the erenumab group). The most common TEAEs during the OLTP were nasopharyngitis, constipation and influenza. No new safety concerns were identified. CONCLUSIONS: Erenumab treatment was associated with reduced migraine frequency in Japanese patients with EM or CM for up to 1 year. Overall safety results from the OLTP were consistent with DBTP results. TRIAL REGISTRATION NUMBER: NCT03812224.

Early onset of efficacy with erenumab for migraine prevention in Japanese patients: Analysis of two randomized, double-blind, placebo-controlled studies.

PURPOSE: In two 24-week migraine prevention studies in Japan, erenumab was associated with significantly greater reductions in migraine frequency versus placebo over Weeks 13-24 (primary endpoint). This post hoc analysis evaluated the onset of efficacy within the first 4 weeks after the initiation of erenumab from the 24-week double-blind periods of these studies. METHODS: Placebo-adjusted differences in least squares mean (LSM) change from baseline in weekly migraine days (WMD) were assessed weekly in each study and by migraine type (episodic (EM]/chronic [CM]) (Study 20170609). RESULTS: A total of 407 patients from Study 20120309 (70 mg: N = 135; 140 mg: N = 136; placebo: N = 136) and 261 patients from Study 20170609 ([EM] 70 mg: N = 78; placebo: N = 81; [CM] 70 mg: N = 52; placebo: N = 50) were included. For Study 20120309, onset of efficacy was observed as early as Week 1 in favor of erenumab versus placebo. Placebo-adjusted differences in LSM (95% confidence interval [CI]) change from baseline in WMD at Week 1 were -0.38 (-0.71 to -0.05; p = .022) and -0.49 (-0.82 to -0.16; p = .004) in favor of erenumab 70 and 140 mg, respectively. For Study 20170609, significant placebo-adjusted differences were observed with erenumab 70 mg at Week 1 in patients with EM (LSM [95% CI]: -0.55 [-0.97 to -0.12; p = .012]), and at Week 2 in patients with CM (LSM [95% CI]: -0.81 [-1.53 to -0.09; p = .028]) and for the overall population (LSM [95% CI]: -0.71 [-1.09 to -0.33; p < .001]). CONCLUSIONS: Erenumab treatment significantly reduced WMD compared with placebo. Onset of erenumab efficacy occurred as early as Week 1 in patients with migraine.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

OBJECTIVE: To assess long-term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients. BACKGROUND: Previously published results from the double-blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM. METHODS: Patients completing the 24-week placebo-controlled DBTP could continue into the 76-week open-label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine-specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6-item Headache Impact Test (HIT-6™) score, and safety (exposure-adjusted patient-incidence of adverse events [AEs], calculated as number of patients per 100 patient-years). RESULTS: Of 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of -2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of -1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT-6™ score was 58.4 (5.4) at baseline with a change of -6.4 (8.2) at week 100. The exposure-adjusted patient-incidence of AEs during the OLTP was 207.1/100 patient-years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient-years) or placebo (257.3/100 patient-years) during the DBTP, and no new safety signals were detected during the OLTP. CONCLUSION: Long-term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.

A Single-Dose, Open-Label, Randomized, Two-Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat.

Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food.

Evaluation of the Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Pyrimethamine in Healthy Male Subjects of Japanese and European Ancestry.

The pharmacokinetics of pyrimethamine have been evaluated in various populations but have not been reported in subjects of Japanese ancestry following administration as a single-agent tablet. Furthermore, although pyrimethamine pharmacokinetics after a single dose of the single-agent tablet studied in Western countries have been reported, these studies are old, and the ancestry of the subjects was not specified. Consequently, this study investigated the pharmacokinetics and safety of a single oral 50-mg dose of pyrimethamine in healthy male subjects of Japanese and European ancestry. Seven subjects of each ancestry group were administered pyrimethamine, along with calcium folinate. After absorption, pyrimethamine was eliminated, with a mean half-life of 122.8 hours in Japanese subjects and 99.5 hours in European subjects. The mean Cmax and AUC0-t were 433.8 ng/mL and 59.63 µg·h/mL in Japanese subjects and 372.7 ng/mL and 42.83 µg·h/mL in European subjects. No safety concerns were reported during the study. Although pyrimethamine exposure was slightly higher in subjects of Japanese than of European ancestry, a considerable overlap in the range of parameter values was observed. Considering the range of pyrimethamine exposure reported previously, difference in exposure observed in this study would not be considered of note.

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants.

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [Cmax ] and area under the concentration-time curve [AUC0-t ]) increased in an approximately dose-proportional manner. The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in Cmax and AUC0-t , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms.

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Evaluations Following Single Oral Doses of GSK2330672 in Healthy Japanese Volunteers.

GSK2330672 is an inhibitor of the ileal bile acid transporter, designed to have minimal systemic exposure, and is under development as a potential therapeutic for pruritus associated with primary biliary cholangitis and other cholestatic liver diseases. A phase 1, double-blind, placebo-controlled, 4-period crossover study was conducted to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of GSK2330672 in healthy Japanese participants. Sixteen healthy male participants received single oral doses of GSK2330672 (10-180 mg) or placebo in each period. No serious adverse events and no adverse events leading to study discontinuation or withdrawal were reported. Drug-related adverse events reported included gastrointestinal symptoms (mostly diarrhea) and positive fecal occult blood tests, and were all mild and resolved without any interventions. GSK2330672 was undetectable in the majority of participants' plasma. Pharmacodynamic observations included a tendency for total serum bile acids to reduce and for serum 7α-hydroxy-4-cholesten-3-one, a key intermediate of bile acid synthesis, to increase with increasing doses of GSK2330672. In the context of recently published indications of potential efficacy for cholestatic pruritus in non-Japanese populations, these data support further evaluations of GSK2330672 in Japanese patients.

Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects.

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single-center, double-blind, randomized, placebo-controlled, parallel, single- and repeat-ascending-dose study. Thirty-six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single-dose session (session 1), a repeat-dose session (session 2), a 10-day washout period between the sessions, and then a follow-up visit 10 ± 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [Cmax ] and area under the concentration-time curve [AUC]) increased with dose in an approximately proportional manner. Plasma Tmax was achieved rapidly at approximately 0.08 hours, and the terminal elimination half-life (T1/2 ) was approximately 40 hours. Tmax and T1/2 did not change between days or doses in the single- and repeat-dose sessions. Following 10 daily doses of 200, 500, and 700 µg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC0-24 ) and R(Cmax ) were 2.4-3.0 and 1.5-1.7, respectively. Steady state was achieved by 6-7 days, based on trough observed plasma drug concentration (Ctrough ) values.

Long-term efficacy and safety of lamotrigine monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures: An open-label extension study.

PURPOSE: To investigate the efficacy and safety of long-term lamotrigine (LTG) monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. METHODS: Six Japanese patients and one South Korean patient were enrolled in the extension phase of the study after completing the 12-week maintenance phase of an open-label clinical study of LTG monotherapy. During the extension phase, patients underwent efficacy and safety evaluation every 12 weeks. RESULTS: Of the seven patients, six patients completed the extension phase. The seizure-free rate confirmed by hyperventilation (HV)-electroencephalography ranged from 71.4% to 100.0% at each visit up to Week 168 of the extension phase. Similar effects were confirmed by HV-clinical signs and seizure diaries. Although no unexpected adverse events were observed, one Japanese patient was withdrawn from the extension phase due to mild drug-related rash developed 842 days after the start of LTG. CONCLUSION: Although the number of patients is limited, long-term LTG monotherapy appeared to be effective and generally well tolerated in Japanese and South Korean pediatric patients with typical absence seizures.

Clinical evaluation of ropinirole controlled-release formulation at 18-24 mg/day in Japanese patients with Parkinson's disease.

INTRODUCTION: There has been no clinical data on Japanese patients with Parkinson's disease with which to examine whether motor symptoms improve and to assess the safety profile after the dose of ropinirole was increased in those who had not achieved an optimal response to the ropinirole immediate-release formulation 15 mg/day or the controlled-release (CR) formulation 16 mg/day. METHODS: This was a multicenter, randomized, double-blind study, followed by an open-label, long-term study. Participants were randomized at a ratio of 3:1 to the high-dose ropinirole CR (18-24 mg/day) group or the maintenance ropinirole CR 16 mg/day group. RESULTS: In the high-dose ropinirole CR group (N = 61), the Japanese unified Parkinson's disease rating scale Part III total score at week 12 was significantly decreased compared with the baseline total score (-4.8 ± 5.95, [95% CI, -6.3 to -3.2], p < 0.001). However, a comparable decrease was also observed in the maintenance ropinirole CR 16 mg/day group (N = 20) (-5.7 ± 5.18, [95% CI, -8.1 to -3.3]), with no statistically significant difference in the adjusted mean change between the high-dose and maintenance groups (0.5 [95% CI, -2.4 to 3.4]). Plasma drug concentrations increased at doses higher than 16 mg/day, but did not increase significantly in a dose-dependent manner at doses of 18-24 mg/day. No adverse events were found that would affect the known safety profile of ropinirole. CONCLUSION: This study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance ropinirole CR group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01929317.

Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multi-center, uncontrolled, open-label study.

PURPOSE: To evaluate the efficacy and safety of lamotrigine (LTG) monotherapy for treating Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. METHODS: Twenty patients with newly diagnosed typical absence seizures aged 4-12 years were enrolled in the study and were administered LTG at an initial dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Thereafter, the dose was increased by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until patients were confirmed to be seizure free induced by hyperventilation (HV). After confirmation, the dose was increased by one level (0.6 mg/kg/day). If the patient was found to be seizure free by HV-electroencephalography (EEG) on the following two consecutive visits, the patient entered the 12-week maintenance phase. After the maintenance phase, patients could enter the extension phase if clinically indicated. RESULTS: The seizure-free rate confirmed by HV-EEG at the end of the maintenance phase was 35.0% (7/20 patients). Most of patients who were confirmed to be seizure free during the escalation phase had maintained seizure control during the 12-week maintenance phase and the 12-week extension phase. The most frequently noted adverse events were bronchitis, headache, and rash (20% each). No serious adverse events were reported. CONCLUSION: Lamotrigine monotherapy in Japanese and South Korean children with typical absence seizures was well tolerated and 35.0% of patients were seizure free at the end of maintenance phase.

Frontal and right temporal activations correlate negatively with depression severity during verbal fluency task: a multi-channel near-infrared spectroscopy study.

Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive, on-the-spot, functional neuroimaging technique allowing detection of the spatiotemporal characteristics of brain activity. Previous NIRS studies indicated the oxy-hemoglobin (oxy-Hb) increase during a verbal fluency task (VFT) is attenuated in patients with major depressive disorder (MDD) as compared with healthy controls. However, the possible relationship between depression symptom severity and oxy-Hb change on NIRS has not yet been elucidated. To examine this relationship, we recruited 30 patients with MDD and 30 age-, gender- and intelligence quotient-matched controls. All underwent NIRS during VFT. As expected, the oxy-Hb increase during the task was significantly smaller in patients than in controls. After false discovery rate correction using 31 channels, the mean increase in oxy-Hb during the task showed a significant negative correlation with the total score of the Hamilton Rating Scale for Depression 21-item version (ch25: rho = -.56; FDR-corrected p: .001). When each item of the HAM-D21 was examined individually, insomnia early in 9 channels (rho = -.63 to -.46; FDR corrected p: .000-.014), work and activity in 2 channels (rho = -.61 to -.57; FDR corrected p: .001 to .003) and psychomotor retardation in 12 channels (rho = -.70 to -.44; FDR corrected p: .000-.018) showed significant negative correlations with the mean oxy-Hb increase in the right frontal temporal region. Although it is possible that our results were affected by medication, these data suggest reduced right frontal temporal activation on NIRS during VFT is related to the symptom severity of MDD.

[Genetically modified animals as models for psychiatric diseases].

Animal models of mental disorders as well as physical disorders have been useful tools to elucidate pathophysiology of the complex disorders and develop new therapeutics. Transgenic mice including gene knockout animals have been produced by gene targeting technology. Monoamine system which is target of antipsychotics and antidepressants has very important roles in pathology of functional psychosis. In this review, we would like to introduce monoamine transporter knockout mice that we had generated as animal models of mental disorders including schizophrenia and drug abuse.