Genetic variants in C5 and poor response to eculizumab.

BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear. METHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients. RESULTS: Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. CONCLUSIONS: The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).

Efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with multiple sclerosis: Interim analysis of the randomized placebo-controlled study.

BACKGROUND: The use of dimethyl fumarate has not been reported in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis. OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis. METHODS: APEX was a phase 3, multinational trial, which consisted of a 24-week, randomized (1:1), double-blind study where patients received dimethyl fumarate 240 mg or placebo twice daily, followed by an open-label extension where all patients received dimethyl fumarate 240 mg. The primary endpoints were the total number of new gadolinium-enhancing (Gd+) lesions in Weeks 12-24 (Part I) and long-term safety (Part II). This post-hoc subgroup analysis evaluated the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis (n=52) up to Week 72 (24 weeks Part I and 48 weeks Part II). RESULTS: Dimethyl fumarate reduced the mean total number of new gadolinium-enhancing lesions at Weeks 12-24 by 94% versus placebo; the number of patients who had a relapse over 24 weeks was reduced by 72%. Adverse events leading to discontinuation of the study drug were reported in 9% of patients receiving placebo/dimethyl fumarate and 4% of patients in dimethyl fumarate/dimethyl fumarate. CONCLUSIONS: Dimethyl fumarate demonstrated sustained efficacy and acceptable tolerability in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis for 72 weeks.

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised, Double Blind, Placebo-Controlled, Phase III APEX Study and its Open-Label Extension.

INTRODUCTION: The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS. METHODS: Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded. RESULTS: Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups. CONCLUSION: The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01838668. FUNDING: Biogen Japan Ltd.

The burden of multiple sclerosis in Japan.

AIMS: Multiple sclerosis (MS) is a disabling autoimmune disease affecting the central nervous system. Few studies have examined the effect of MS on patient outcomes in Japan. The study aim was to quantify MS burden in Japan by comparing MS respondents to matched controls on patient outcomes. MATERIALS AND METHODS: Data from seven administrations of the nationally representative Japan National Health and Wellness Survey (2009-2014 and 2016) were used (n = 181,423). Respondents self-reporting MS diagnosis were compared with respondents not reporting MS. Matched controls were selected using propensity scores. Respondents with MS and matched controls were compared on health-related quality-of-life (HRQoL), work productivity and activity impairment, healthcare resource utilization, and costs. Comparisons were made using Chi-square tests or one-way ANOVAs. RESULTS: A total of 96 respondents with MS and 480 matched controls were included in the analyses. MS respondents reported worse mental (44.35 vs 47.51, p < .05), physical (33.11 vs 49.04, p < .001), and role (37.78 vs 47.11, p < .001) component summary scores (minimally important difference is 3.0). Additionally, MS respondents reported decrements on every health profile sub-scale (p < .001) and 5-Level EuroQoL-5 Dimensions outcome (p < .01). MS respondents also reported more healthcare provider visits (13.78 vs 6.13) and hospitalizations (3.02 vs 0.70; both, p < .001), leading to higher direct costs. For work productivity and activity impairment, MS respondents reported more absenteeism (17.50% vs 5.57%), presenteeism (38.11% vs 21.62%), overall work impairment (46.68% vs 25.27%), and activity impairment (46.88% vs 24.90%, all, p < .001), leading to higher indirect costs. LIMITATIONS: Japan NHWS data are cross-sectional, and causal relationships cannot be established. Due to the self-reported nature of the data, responses could not be independently verified. CONCLUSIONS: Results suggest MS in Japan is associated with poorer HRQoL and greater work and activity impairment, healthcare resource use, and costs. Improved MS management could benefit both patients and society.

Safety and Effectiveness of Natalizumab: First Report of Interim Results of Post-Marketing Surveillance in Japan.

INTRODUCTION: Natalizumab, a humanized anti-α4 integrin monoclonal antibody, received marketing approval in Japan in 2014 for the treatment of multiple sclerosis (MS). Because the previous large-scale clinical trials of natalizumab were mainly conducted in Europe and North American countries, and data in patients with MS from Japan were limited, we conducted an all-case post-marketing surveillance of natalizumab-treated MS patients from Japan to investigate the safety and effectiveness of natalizumab in a real-world clinical setting in Japan. Here, we report the results of an interim analysis. METHODS: During the observation period of 2 years, all patients who were treated with natalizumab subsequent to its approval in Japan were followed. The effectiveness of natalizumab was assessed by examining the changes in expanded disability status scale (EDSS) score and annualized relapse rate (ARR) from baseline. Safety was assessed by analyzing the incidence of adverse drug reactions (ADRs). RESULTS: The safety analysis included 106 patients (mean age 39.3 years; women 62.3%) whose data were collected until the data lock point (February 7, 2016). The effectiveness analysis included 75 patients. The majority of patients had relapsing-remitting MS (93/106 patients; 87.7%). The mean length of treatment exposure in the present study was 6.6 months. During the 2-year observation period, no significant change in the EDSS was observed, while the ARR decreased significantly from baseline (72.9% reduction, p = 0.001). ADRs and serious ADRs were observed in 11.3% and 3.8% of patients, respectively; however, no new safety concerns were detected. No patient had progressive multifocal leukoencephalopathy (PML) during the present study period. CONCLUSION: The safety and effectiveness of natalizumab were confirmed in Japanese patients with MS in clinical practice. Nevertheless, potential risks including PML require continuous, careful observation. FUNDING: Biogen Japan Ltd (Tokyo, Japan).