Agalsidase beta 35mg powder for solution for infusion vials

In 2016, a systematic review and a meta-analysis of existing data on the effects of switch from agalsidase beta to alfa in patients with Fabry disease showed that the switch was well tolerated and associated with stable disease progression. However, additional evidence that supports the need for an update of the review on the long-term effects of switching to agalsidase alfa, with a mention on the effects of reswitch to agalsidase beta, has emerged. Relevant papers were identified on PubMed, Cochrane, ISI Web, and Scopus databases from September 2015 to December 2021. Analyzed parameters were clinical events, changes in organ function or structure, disease related symptoms, lyso-globotriasolylceramide 3 (lyso-Gb3) plasma levels, presence of antidrug antibodies, and adverse effects. In total, 15 publications were evaluated, with a total of 353 subjects. The results of the review confirmed some points of the previous analysis with some new important information. After the switch from agalsidase beta to alfa, an increased number of clinical events, a significant loss of renal function, and an increase in lyso-Gb3 levels were reported; conversely, lyso-Gb3 levels decreased after the switch from agalsidase alfa to beta. The results confirm the importance of dose and recommend that patients be monitored through intensified surveillance, including lyso-Gb3 levels every 6 months.

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Background Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE ( NCT02795676 ) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than −2 mL/min/1.73 m 2 /year who had received agalsidase beta for ≥1 year. Methods Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. Results Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18–60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m 2 and median (range) eGFR slope was −7.3 (−30.5, 6.3) mL/min/1.73 m 2 /year. At 2 years, the difference between median eGFR slopes was −0.36 mL/min/1.73 m 2 /year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. Conclusions Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. Trial registration number NCT02795676 .

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Background Agalsidase beta is used to treat Fabry disease (FD); however, data on cardiac and cerebrovascular outcomes with agalsidase beta treatment come from studies with limited numbers of patients. Methods A systematic literature review of studies reporting on the efficacy and effectiveness of agalsidase beta in FD was conducted. Studies were identified in searches of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from January 2000–June 2022. Outcomes of interest included cardiac structure and mass, cardiac events, and cerebrovascular events. Results Fifty-two citations (41 studies) were included. Reductions in interventricular septal thickness (IVST) and/or left ventricular posterior wall thickness (LVPWT) were demonstrated in six studies (follow-up 1–6 years, n = 4 using echocardiography, n = 2 cardiac MRI). IVST ranged from 12.1–14.9 mm at baseline and 10.8–14.1 mm at follow-up (all p < 0.05). LVPWT ranged from 11.7–16.0 mm at baseline and 10.7–13.0 mm at follow-up (all p < 0.05). Significant reductions in cardiac mass were demonstrated after 1 year of treatment in a single-arm study using cardiac MRI [left ventricular mass (LVM) 193–178 g; LVM index 102–94 g/m 2 ; both p < 0.05]. Rates of composite cardiac events (3.8%–24.0%; four studies, follow-up 2–10 years) and cerebrovascular events (0.0%–18.9%; 12 studies, follow-up 1–10 years) were numerically lower than rates for placebo (follow-up 3 years). Conclusion Literature over the last 20 years indicates that agalsidase beta treatment may lead to stabilization or regression of cardiac structural thickness and mass, and reduction in cardiac and cerebrovascular events relative to placebo.

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BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. RESULTS: = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. CONCLUSIONS: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.

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Abstract Fabry Registry data were analyzed among 83 agalsidase beta‐treated patients with Fabry disease who switched to migalastat. Outcomes (estimated glomerular filtration rate [eGFR], urine protein‐creatinine ratio [UPCR], plasma globotriaosylceramide [GL‐3], plasma globotriaosylsphingosine [lyso‐GL‐3], interventricular septal wall thickness [IVST], left posterior wall thickness [LPWT], left ventricular mass index [LVMI]) were assessed using linear mixed models to estimate annual change over time in the pre‐ and postswitch periods. eGFR decreased throughout both periods (preswitch: −0.85 mL/min/1.73 m 2 /year; postswitch: −1.96 mL/min/1.73 m 2 /year; both p < 0.0001), with steeper decline postswitch ( p pre/post = 0.01) in both classic and late‐onset patients. UPCR increased significantly postswitch ( p pre/post = 0.003) among classic patients and was stable in both periods among late‐onset patients. GL‐3 trajectories worsened postswitch across phenotypes ( p pre/post = 0.0005 classic, 0.02 late‐onset). LPWT was stable preswitch (0.07 mm/year, p = 0.25) and decreased postswitch (−0.51 mm/year, p = 0.0005; p pre/post = 0.0009), primarily among late‐onset patients. IVST and LVMI slopes varied significantly by phenotype. Among classic patients, IVST and LVMI were stable and decreasing, respectively preswitch and increasing postswitch ( p pre/post = 0.02 IVST, 0.01 LVMI). Among late‐onset patients, IVST significantly decreased postswitch ( p pre/post = 0.0003); LVMI was stable over time ( p pre/post = 0.89). Ultimately, eGFR and GL‐3 trajectories worsened postswitch across phenotypes, while UPCR and cardiac measures worsened among classic and stabilized/improved among late‐onset patients. These findings indicate variability in long‐term outcomes after switching from ERT to migalastat, underscoring the importance of careful monitoring.

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ABSTRACT Background Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalizable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD. Methods Agalsidase beta–treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalization in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years. Results Overall, eGFR slopes for 1:1-matched untreated and treated adult patients [122 pairs (72.1% male)] were −3.19 and −1.47 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 53.9%, P = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were −3.29 and −1.56 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 52.6%, P < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 (P = .003) and 0.67 (P = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized in most within 6 months of treatment initiation. Conclusion Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalization of elevated pre-treatment levels in most patients.

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