Replagal (agalsidase alfa) / Samaritan Pharma, Takeda - LARVOL DELTA

Progress and Challenges in the Treatment of Fabry Disease. (PubMed, BioDrugs) - "Current approved treatment includes enzyme replacement therapy (agalsidase alfa [0.2 mg/kg body weight], agalsidase beta or pegunigalsidase alfa [both 1.0 mg/kg body weight]) every other week intravenously or, if a responding ('amenable') α-galactosidase A mutation is present, oral pharmacological chaperone therapy (migalastat 123 mg, every other day). Future therapeutic options may include substrate reduction therapy, gene therapy, messenger RNA therapy, and/or vesicle-packaged enzyme replacement therapy. This review presents current and future treatment options with advantages and disadvantages of the different treatment options."

Journal • Cardiomyopathy • Cardiovascular • CNS Disorders • Fabry Disease • Gene Therapies • Genetic Disorders • Hypertrophic Cardiomyopathy • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Renal Disease

New drugs available for Fabry disease. (PubMed, Kidney Blood Press Res) - "This review focuses exclusively on newly available drugs and future therapeutic approaches for treating FD, including migalastat, pegunigalsidase alfa, substrate reduction therapy (SRT), and gene therapy. Migalastat provides benefits such as oral administration and non-immunogenicity; however, it is only appropriate for patients with "amenable" GLA variants. The recently approved pegunigalsidase alfa is a pegylated form of α-Gal A manufactured in plant cell cultures, with apparent reduced immune response and prolonged circulating half-life. SRT (venglustat, lucerastat) reduces Gb3 synthesis, helping to normalize metabolic processes while offering certain advantages such as oral administration, non-immunogenic properties, and the possible crossing of the blood-brain barrier. Clinical trials in human and animal model studies are currently investigating ex-vivo and in-vivo gene therapy techniques, showing positive early outcomes. Messages: The ongoing development..."

Journal • Review • Cardiovascular • Fabry Disease • Gene Therapies • Genetic Disorders

Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy. (PubMed, Mol Genet Metab Rep) - "The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years). Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD."

Journal • Fabry Disease • Genetic Disorders

Safety analysis of self-administered enzyme replacement therapy using data from the Fabry Outcome and Gaucher Outcome Surveys. (PubMed, Orphanet J Rare Dis) - P, P=N/A | "These findings suggest that self-administration of agalsidase alfa or velaglucerase alfa infusions are not associated with additional safety risks compared with HCP-supported infusions and are a suitable option for qualifying patients. Further research is warranted to support these findings and to explore further the long-term safety and efficacy of ERT self-administration. FOS trial registration: ClinicalTrials.gov, NCT03289065. Registered 01 April 2001, https://clinicaltrials.gov/study/NCT03289065 . GOS trial registration: ClinicalTrials.gov, NCT03291223. Registered 27 July 2010, https://classic."

Journal • Cardiovascular • Fabry Disease • Gastroenterology • Gastrointestinal Disorder • Gaucher Disease • Genetic Disorders • Infectious Disease • Metabolic Disorders

Impact of enzyme replacement therapy and migalastat on disease progression in females with fabry disease. (PubMed, Orphanet J Rare Dis) - "We conclude that treatment of females with agalsidase-beta, agalsidase-alfa, and migalastat was safe. Independent of the chosen treatment regimen, nearly all patients presented with a stable disease course over time. In our cohort, a comparison of therapy efficacies showed no relevant clinical differences between the groups."

Clinical • Journal • Fabry Disease • Genetic Disorders

CARAT: A Study to Evaluate the Effect of Venglustat Tablets on Left Ventricular Mass Index in Male and Female Adult Participants With Fabry Disease (clinicaltrials.gov) - P3 | N=104 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Jul 2027 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ May 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Fabry Disease • Genetic Disorders

Effects of Current Therapies on Disease Progression in Fabry Disease: A Narrative Review for Better Patient Management in Clinical Practice. (PubMed, Adv Ther) - "Four treatments are currently available for patients with FD; three enzyme replacement therapies (ERTs; agalsidase alfa, agalsidase beta, and pegunigalsidase alfa) and one pharmacological chaperone (migalastat). Real-world data raise concerns about effective in vivo amenability of some genetic variants. Future studies with direct treatment comparisons in patients with FD are needed."

Journal • Review • Cardiovascular • CNS Disorders • Fabry Disease • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Nephrology • Pain • Rare Diseases • Renal Disease

A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies. (PubMed, J Inherit Metab Dis) - P3 | "BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks...Thirty patients were enrolled (24 males); 23 previously received agalsidase beta...Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease."

Journal • P3 data • Fabry Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

2024 Update of the TSOC Expert Consensus of Fabry Disease. (PubMed, Acta Cardiol Sin) - "Recent advances in pharmacological approach including enzyme replacement therapy (agalsidase alfa or beta), oral chaperone therapy (migalastat), and substrate reduction therapy (venglustat) aim to prevent from irreversible organ damage. Genotype- and gender-based monitoring of treatment effects through biomarker (Lyso-Gb3), renal assessment, and cardiac responses using advanced imaging modalities are key steps to optimizing patient care in FD."

Journal • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Cognitive Disorders • Congestive Heart Failure • Fabry Disease • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Comparative study on incorporation of three recombinant human α-galactosidase A drugs (agalsidases) into cultured fibroblasts and organs/tissues of Fabry mice. (PubMed, Mol Genet Metab Rep) - "But their affinity for domain 9 of cation-independent mannose 6-phosphate receptor (CI-M6PR), which exists in various cells, was higher in the order: agalsidase beta biosimilar 1 (agalsidase beta BS) > agalsidase beta > agalsidase alfa, which almost coincided with the experimental results regarding the efficiency of their incorporation into cultured fibroblasts derived from a Fabry mouse. On the other hand, no differences in the efficiency of their uptake or reduction of the accumulated substances were observed in the liver, probably due to asialoglycoprotein receptors expressed on the surface of hepatocytes. This information will be useful for making a suitable ERT plan for individual Fabry patients with various backgrounds and for developing new ERT drugs in the future."

Journal • Preclinical • Fabry Disease • Genetic Disorders • ASGR

Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement. (PubMed, Int J Mol Sci) - "This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration."

Journal • Review • Fabry Disease • Genetic Disorders

Clinical outcomes in elderly patients receiving agalsidase alfa treatment in the Fabry Outcome Survey. (PubMed, Mol Genet Metab) - "Continuation and initiation of agalsidase alfa treatment in patients aged 65 years or older with Fabry disease were associated with stabilization of proteinuria and minimal increases in cardiac (LVMI) and renal (eGFR) outcomes."

Clinical data • Journal • Fabry Disease • Genetic Disorders • Nephrology • Renal Disease • Transplantation

What is confirmed in the treatment of Fabry's disease? (PubMed, Inn Med (Heidelb)) - "The treatment comprises enzyme replacement therapy (ERT), agalsidase alfa, 0.2 mg/kg body weight (BW), agalsidase beta 1.0 mg/kg BW or pegunigalsidase alfa 1.0 mg/kg BW every 2 weeks i.v. or oral chaperone therapy (one capsule of migalastat 123 mg every other day) in the presence of amenable mutations. This article summarizes the data on the treatment of Fabry's disease and on complications in practice. The current guideline recommendations are addressed and new study results that could expand the therapeutic repertoire in the future are discussed."

Journal • Review • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • CNS Disorders • Gene Therapies • Hypertrophic Cardiomyopathy • Lysosomal Storage Diseases • Metabolic Disorders • Nephrology • Rare Diseases • Renal Disease

Long-term safety of enzyme replacement therapy with agalsidase alfa in patients with Fabry disease: post-marketing extension surveillance in Japan. (PubMed, Mol Genet Metab Rep) - "Additionally, long-term agalsidase alfa treatment sustained the initial reduction in Gb3 concentrations without increasing the rate of anti-agalsidase antibody positivity. These findings suggest that agalsidase alfa treatment demonstrates continued safety and sustains patients' clinical course over the long term."

Journal • P4 data • Fabry Disease • Genetic Disorders • Metabolic Disorders

Judicialization of high priced medications in Argentina: quali-quantitative study (PubMed, Medicina (B Aires)) - "Judicialization focused on very highpriced medications for rare or oncological diseases. The rulings were mostly in favor of the plaintiff, and access times to the medication took a long time. The mass media anticipated the judicial processes."

Journal • Retrospective data

Agalsidase alfa long-term effect on left ventricular hypertrophy in Fabry disease. (PubMed, Medicina (B Aires)) - "Our results are in line with previous literature of comparable FD populations and probably represent the first study of its kind in Argentina. We here highlight the importance of cardiac morphometric stability as a positive outcome of ERT."

Journal • Observational data • Retrospective data • Atrial Fibrillation • Cardiovascular • Fabry Disease • Fibrosis • Genetic Disorders • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Nephrology • Rare Diseases • Renal Disease

A Study of REPLAGAL® in Treatment-naive Chinese Participants With Fabry Disease (clinicaltrialsregister.eu) - P3 | N=20 | Sponsor: Takeda Development Center Americas, Inc

New P3 trial • Fabry Disease • Genetic Disorders

Rapidly progressive cognitive impairment resulting in heavy psychosocial burden in a patient with Fabry disease undergoing hemodialysis: a case report. (PubMed, BMC Nephrol) - "Despite treating with long-term ERT, it is necessary to determine the psychosocial burden derived from the progression of cognitive impairment in patients with FD undergoing hemodialysis."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Fabry Disease • Genetic Disorders • Psychiatry

Therapeutic Apheresis in Fabry Disease (ERA-EDTA 2024) - "In the treatment of FD, we have enzyme replacement therapy (ERT) with Agalsidase-alfa (Replagal®), Agalsidase-beta (Fabrazyme®), and chaperones (Migalastat®). With these results, we confirm that PE is more efficient in removing IgG-aGAL but also eliminates LysoGb3, whereas LDL-apheresis is a very effective technique for removing Lyso-Gb3 but also contributes to antibody removal. Based on these findings, we consider TA to be an effective adjunctive tool for FD treatment, even as a standalone treatment. However, these are very preliminary results and should be reproduced with a larger number of patients."

Dyslipidemia • Fabry Disease • Genetic Disorders

A Study of Replagal in Children and Adults With Fabry Disease in India (clinicaltrials.gov) - P4 | N=5 | Active, not recruiting | Sponsor: Shire | Trial completion date: Nov 2024 ➔ Nov 2026 | Trial primary completion date: Oct 2024 ➔ Oct 2026

Trial completion date • Trial primary completion date • Fabry Disease • Genetic Disorders

A systematic literature review on the health-related quality of life and economic burden of Fabry disease. (PubMed, Orphanet J Rare Dis) - "FD remains associated with a high cost and healthcare resource use burden, and reduced QoL compared with healthy populations. Integrating information from QoL and economic assessments may help to identify interventions that are likely to be of most value to patients with FD."

HEOR • Journal • Review • CNS Disorders • Fabry Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Pain • Rare Diseases

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease. (PubMed, Front Genet) - "Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. The confidence interval had a lower limit above the prespecified value of -3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective."

Journal • Review • Fabry Disease • Genetic Disorders • Glomerulonephritis • Immunology • Lupus Nephritis • Nephrology

Humanistic Burden of Fabry Disease and Associated Utility Values (ISPOR 2024) - " We conducted an SLR in May 2022 (updated April 2023) to identify studies reporting humanistic burden and utility data in patients with FD who are either untreated or treated with enzyme replacement therapy (ERT) (pegunigalsidase alfa, agalsidase alfa, agalsidase beta), migalastat, venglustat, and lucerastat. The studies identified in this SLR add to our understanding of the humanistic burden of FD since almost 10 years ago. The results suggest utility values increase with ERT treatment, but patient burden has remained stable over time. Long-term data with existing therapies may provide additional insights on outcomes including pain, disease severity, and quality of life."

Fabry Disease • Fatigue • Gastrointestinal Disorder • Genetic Disorders • Pain

Use of Single Arm Studies/Disconnected Observational Studies in Comparative Effectiveness of Treatments for Fabry Disease: A Network Meta-Analysis Using a 3-Level Hierarchical Model (ISPOR 2024) - "For eGFR, numerically better results were observed with agalsidase alfa 0.2 mg/kg EOW versus placebo (mean difference [MD]: 0.75 [95% CrI: -1.46, 2.78]), undefined ERT (MD: 0.56 [95% CrI: -2.36, 3.52]), agalsidase beta 0.2 mg/kg EOW (MD: 0.09 [95% CrI: -1.51, 1.73]) and migalastat 150 mg (MD: 0.66 [95% CrI: -1.99, 3.35]). NMA results showed no differences in efficacy using both RCTs and observational studies in FD. Several limitations of the NMA should be acknowledged including the differences in inclusion criteria, endpoint definition, disease phenotype, and study designs."

HEOR • Observational data • Retrospective data • Fabry Disease • Genetic Disorders

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data. (PubMed, Drug Des Devel Ther) - "In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD."

Journal • Real-world • Real-world evidence • Review • Cardiomyopathy • Cardiovascular • CNS Disorders • Fabry Disease • Genetic Disorders • Hypertrophic Cardiomyopathy • Neuralgia • Pain • Vascular Neurology