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

Non peer reviewe

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

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

Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease : A Fabry Outcome Survey analysis

Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m 2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m 2 /y compared with − 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m 2.7 /y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data