Update on role of agalsidase alfa in management of Fabry disease

Fabry disease (FD) is an X-linked lysosomal storage disorder that affects both men and women. The manifestations of this heterogeneous disease are multisystemic and progressive. Prior to the development of enzyme replacement therapy, the management and treatment for Fabry disease was largely nonspecific and supportive. Because enzyme replacement therapy became commercially available in 2001, a variety of clinical benefits in Fabry patients have been consistently reported, including improved renal pathology and cardiac function, and reduced severity of neuropathic pain and improved pain-related quality of life. This update focuses on published data on the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa, and gives a brief overview on some of the outstanding management issues in the treatment of this complex disease

Hypochondroplasia: Clinical and molecular spectrum and response to growth hormone therapy.

Hypochondroplasia (HCH) is a genetic disorder of short stature with a wide spectrum of clinical severity, from short-limbed dwarfism to proportionately short children with diminution of the pubertal growth spurt. The invariable radiological feature is a lack of increase in interpedicular distance between lumbar vertebrae LI to L5 and with short pedicles. 73 children with clinical and radiologically proven HCH were screened for the C1620A and C1620G mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Both these mutations resulted in an asparagine to lysine substitution in codon 540 (Asn540Lys) of the proximal tyrosine kinase domain of FGFR3. In mutation negative patients (n=45), single strand conformation polymorphism analysis was performed to screen for sequence variants in the tyrosine kinase and transmembrane domains of FGFR3 gene. 28/73 (38%) patients were heterozygous for the C1620A mutation and these patients had severe HCH with disproportionate short stature. No patient in this study had the C1620G mutations or mutations in the transmembrane domain described in Achondroplasia (ACH). The mutation negative patients although short, were not obviously disproportionate and presented later with short stature relative to their family height. A sequence variant, a nucleotide insertion in intron 12 was found in a small proportion of mutation negative patients and in normal individuals, presumably reflecting a sequence polymorphism with no functional significance. The patients were divided into C1620A mutation positive (group 1) and C1620A mutation negative groups (Group 2) and the responses to recombinant human growth hormone (r-hGH) therapy was analysed in both groups. The majority were prepubertal at the start of treatment (88%). 16 patients in Group 1 and 22 patients in Group 2 received r-hGH at a median dose of 30U/m2/week (16-44 U/m2/week). Responses to r-hGH therapy between 1-5 years were significant in both groups, with children under 10 years of age having a significantly better response. This response was predominantly due to an increase in the length of the back in the mutation positive group, thus accentuating the existing disproportion. In the mutation negative group, there was a more proportionate growth response. The response to growth hormone therapy in ACH was also analysed and compared with responses to r-hGH therapy in HCH. The C1620A positive HCH group had a similar response to r-hGH therapy when compared to ACH. The phenotype within these two groups was also similar. However, the severity of short stature and disproportion in children with C1620A positive HCH was less severe than those with ACH. Genotyping of patients with HCH permits the definition of patients into C1620A positive and negative groups. This allows critical examination of the efficacy of growth hormone treatment of what is otherwise a rather heterogeneous group of patients, defined by radiological parameters alone. Further analysis of the 2.5kb mRNA performed in other centres has not identified any further mutations in FGFR3 in the C1620A mutation negative group. Future collaborative work with other centres will be needed to clarify the situation in these patients and whether they have mutations in FGFR3 or in other genes

Editorial : Genetics of familial hypercholesterolemia: New insight-Volume II

Non peer reviewe

Editorial: Genetics of Familial Hypercholesterolemia: New Insight

Non peer reviewe

Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A 10- Year Fabry Outcome Survey (FOS) Analysis

Agalsidasa alfa; Teràpia de reemplaçament enzimàtic; Malaltia de FabryAgalsidasa alfa; Terapia de reemplazo de enzimas; Enfermedad de FabryAgalsidase alfa; Enzyme replacement therapy; Fabry diseasePurpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9–67.3) for females (n=62), 34.4 (18.0–66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; −0.55 [−1.12, +0.01]) and slightly declined in males (n=79; −1.99 [−2.45, −1.54]). With impaired kidney function (eGFR 48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [−0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.The Fabry Outcome Survey is sponsored by Shire Human Genetic Therapies, Inc., a member of the Takeda group of companies. Shire International GmbH, a member of the Takeda group of companies, provided funding to Excel Medical Affairs for support in writing and editing this manuscript and participated in data collection and analysis

Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry

Agalsidase alfa; Cardiovascular outcomes; Renal outcomesAgalsidasa alfa; Resultados cardiovasculares; Resultados renalesAgalsidasa alfa; Resultats cardiovasculars; Resultats renalsBackground Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD. Results FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies. Conclusion FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease.FOS is funded by Takeda Pharmaceuticals International AG, which also assisted in analyzing the data and preparing the manuscript. Takeda Development Center Americas, Inc. provided funding to Excel Medical Affairs for support in writing and editing this manuscript

A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide

Background: Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifesta‑ tions and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs. Methods: The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of beneft, in selected countries, through donation of ERT to nonproft organiza‑ tions, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company. Results: As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year. Conclusions: The response rate for follow-up data at 1 year was high, with data collected for>90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These fndings suggest that the program can beneft selected patients previously unable to access disease-specifc treatments. Further inno‑ vative solutions and eforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world

Long-term outcomes with agalsidase alfa enzyme replacement therapy : analysis using deconstructed composite events

Altres ajuts: This work was supported by Shire International GmbH.This is a retrospective analysis of Fabry Outcome Survey data from children/adults (n = 677) receiving agalsidase alfa enzyme replacement therapy for a median of 3 years, examining cerebrovascular, cardiac, and renal morbidity endpoints separately. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and males were more likely to experience cardiac and renal events at a younger age than females

Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events

This is a retrospective analysis of Fabry Outcome Survey data from children/adults (n = 677) receiving agalsidase alfa enzyme replacement therapy for a median of 3 years, examining cerebrovascular, cardiac, and renal morbidity endpoints separately. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and males were more likely to experience cardiac and renal events at a younger age than females