Safety and tolerability of agalsidase beta infusions shorter than 90 min in patients with Fabry disease: post-hoc analysis of a Japanese post-marketing study.

BACKGROUND: Agalsidase beta, an enzyme replacement therapy for Fabry disease, is dosed biweekly at 1 mg/kg body weight, with increasing infusion rates based on tolerability. The US label specifies ≥ 90-min infusions for all patients; the US and EU labels require ≤ 15 mg/hr infusions in patients < 30 kg. The Japanese label allows infusions up to 30 mg/hr, allowing < 90-min dosing for some patients weighing < 45 kg. Japanese post-marketing data were analyzed for rate of infusion-associated reactions (IARs), adverse events (AEs), and serious AEs (SAEs) based on infusion rate and patient attributes (weight, antibody status). RESULTS: Data were available for 436 reduced-duration infusions (< 90 min) and 2242 standard infusions (≥ 90 min). SAEs were rare (0.6%), and the frequency of all safety events decreased over the treatment course. Little impact of infusion duration on safety outcomes was observed: IARs and AEs were numerically more common when infusion duration was ≥ 90 min compared to < 90 min (IARs: 2.0% vs 0.9%; AEs: 2.9% vs 1.4%), while the rate of SAEs was similar (0.4% vs 0.5%). IAR, AE, and SAE frequencies decreased significantly with increasing infusion rates, and this trend was consistent in patients < 30 kg. Safety events tended to be less frequent in patients < 30 kg vs those ≥ 30 kg (IARs: 1.8% vs 2.1%; AEs: 2.3% vs 3.6%; SAEs: 0.0% vs 0.6%), although the differences were not statistically significant. IARs occurred in < 1% of all infusions in the < 30 kg group, 84% of which were < 90 min. More anti-agalsidase beta antibody-positive patients experienced IARs (41.9% vs 30.7%; P = 0.0445) and AEs (61.1% vs 49.3%; P = 0.0497) vs antibody-negative patients; however, there was no significant difference in the frequency of SAEs. In patients with available data, no changes in antibody status were observed after infusion durations were reduced to < 90 min. CONCLUSIONS: The results of this post-hoc analysis demonstrated no significant impact of infusion duration on safety outcomes, and no significant difference in outcomes between patients of different weights. These findings suggest that infusion times in patients who are tolerating treatment can, with careful monitoring, be gradually decreased.

A survey on the patient journey in Fabry disease in Japan.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency in α-galactosidase that is frequently diagnosed late after disease onset. While previous studies have focused on the multisystem manifestations that can lead to delayed or incorrect diagnosis and management, none have investigated the entire patient journey, and few have examined the patient's disease experience. Objective: To investigate the path to diagnosis from disease onset, and the impact of the disease on daily life, among individuals with FD in Japan. Methods: A nationwide survey of patients with FD receiving enzyme replacement therapy (ERT) was conducted between March 27 and June 11, 2018. Participants were recruited via patient support groups or physicians. Respondents completed a questionnaire eliciting information on sociodemographic status, self-perceived health status, initial and current clinical manifestations, the process of diagnosis, and impact on their life. Responses were analyzed descriptively. Results: Data from 40 respondents were analyzed (17 males and 23 females; 77.5% aged ≥30 years). Mean ERT duration was 7.7 years. Mean time from disease onset to diagnosis was 18.7 years (16.7 years [males] vs 20.3 years [females]). The final diagnosis was made most commonly by pediatricians (38%). Forty percent of respondents felt relieved and 30% felt anxious when diagnosed, and when initiating ERT, 48% felt more positive about their daily life. Nevertheless, 85% reported that treatment affected their lives/work, and most (73%) experienced difficulties in their relationships with others. Conclusion: Efforts are needed to achieve early diagnosis of patients with FD in Japan, to improve clinician awareness, and improve the psychosocial issues associated with FD.

Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies.

BACKGROUND: Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice. RESEARCH DESIGN AND METHODS: The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time. RESULTS: Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype. CONCLUSIONS: Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice. CLINICAL TRIAL REGISTRATION: NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta).