Amenable Mutations Research Articles

PRO65 VARIABILITY IN AGE AT LOSS OF AMBULATION BY GENOTYPE AMONG BOYS WITH DUCHENNE MUSCULAR DYSTROPHY

Duchenne muscular dystrophy (DMD), caused by loss of dystrophin, is associated with early loss of ambulation (LOA) and death. While severities of clinical phenotypes are correlated with underlying genotypes, a full synthesis of these relationships is lacking. This review’s objective was to summarize published data for age at LOA with DMD genotype. A systematic review using MEDLINE and EMBASE identified articles describing the natural history among patients with known DMD genotype. To focus on a more homogeneous group, 1) this analysis was restricted to patients treated with corticosteroids (CS) and 2) DMD genotypes were categorized according to amenability of mutations to potential exon skipping therapies. Outcomes included mean (95% confidence interval [CI]) and median age at LOA, as defined by original investigators. From 7,291 publications, 8 studies met inclusion criteria. Five studies presented individual patient data on age at LOA. Mean (95%CI) age at LOA ranged from 10.1 (9.9-10.2; n=2, exon 52 skip amenable) and 10.2 (9.4-11.1; n=16, exon 53 skip amenable) years; to 12.6 (10.8-14.3) years (n=13, exon 44 skip amenable). Median age at LOA ranged from 10.0 (n=3, exon 53 skip amenable) to 12.0 (n=2, exon 55 skip amenable) years. Three studies reported median age at LOA from samples where not everyone had experienced LOA; estimates ranged from 12.0 (n=27, exon 45 skip amenable) to 20 (n=74, exon 44 skip amenable) years. Variability in LOA age by DMD genotype was observed. Those amenable to exon 52 and 53 skipping showed more severe phenotypes in terms of age at LOA compared to those with exon 55 or 44 skip amenable mutations. These findings are consistent with published estimates from large registries. Caution is needed when comparing LOA from studies where designs and inclusion criteria differed. Furthermore, the natural history of certain genotypes is better characterized.

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy

BackgroundPatients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically...

Mutation spectrum of α-Galactosidase gene in Japanese patients with Fabry disease.

The efficacy of pharmacological chaperone therapy for Fabry disease depends on the type of α-galactosidase A (GLA) mutations. Here, we examined the mutation spectrum of the GLA gene among patients from 115 Japanese families with Fabry disease. Of these, no pathogenic mutations were identified in six families (5.2%). In total, 73 different disease-causing mutations were identified: 41 missense (56.2%), 11 nonsense (15.1%), four in frame deletion (5.5%), 10 frameshift (13.7%), six splice site (8.2%), and one intronic (1.4%) mutations. The GLA mutations detected in later-onset phenotype patients with end-stage renal disease overlapped with those seen in classical patients, indicating that it is difficult to differentiate between these two phenotypes from gene mutations. Additionally, 33 families (28.7%) had amenable mutations to the pharmacological chaperone migalastat. In conclusion, our study is informative when considering genetic counseling and pharmacological chaperon therapy for Fabry disease.

Migalastat for the treatment of Fabry disease

ABSTRACTIntroduction: Fabry disease, a rare X-linked disorder of α-galactosidase A deficiency, leads to progressive multiorgan damage.Areas covered: Enzyme replacement therapy (ERT) is the current standard of care for Fabry disease; however, many patients progress despite treatment and the intravenous infusions present several challenges. Migalastat, an orally administered, small molecule pharmacological chaperone, binds to and stabilizes specific mutant forms of α-galactosidase A. Migalastat is approved in several countries for Fabry disease in patients with amenable GLA mutations; amenable mutations are identified using a good laboratory practice-validated assay. Data from clinical trials demonstrated that migalastat effectively reduces disease substrate, stabilizes renal function, decreases cardiac mass and improves gastrointestinal signs and symptoms in patients with Fabry disease and amenable mutations. Across trials, migalastat was generally well tolerated; headache was the most frequently reported treatment-emergent adverse event. Long-term treatment with migalastat was associated with sustained reduction in left ventricular mass index and evidence of left ventricular hypertrophy regression; migalastat was generally well tolerated over 48 months of treatment. An ongoing Phase III extension study will provide further evidence of the long-term safety and efficacy of migalastat.Expert opinion: Given the convenience of the orally administered small molecule and the efficacy and safety demonstrated in pivotal Phase III trials, migalastat offers a viable alternative to ERT for patients with Fabry disease and migalastat-amenable mutations.

Treatment in Fabry disease

Fabry disease is an X-linked inborn disease caused by deficit of alpha-galactosidase A. This results in accumulation of glycosphingolipids in all cells and tissues. All males should receive enzyme replacement treatment in case of very low or undetectable levels of alpha-galactosidase A. Female carriers and males with marginally levels of alpha-galactosidase A should be treated in case of renal, neurologic o cardiac manifestations. There are two intravenous formulations of human recombinant enzyme, agalsidase alpha and agalsidase beta, showing similar efficacy and safety. Patients with amenable mutations of alpha-galactosidase can be treated with oral migalastat hydrochloride. Migalastat hydrochloride is a pharmacological chaperone that facilitates trafficking of alpha-galactosidase A to lysosomes increasing enzyme activity. Patients treated with migalastat hydrochloride had significant improvements in left ventricular mass and gastrointestinal symptoms.

Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial

BackgroundFabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations.MethodsWe evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301).ResultsAfter 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031).ConclusionsMigalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease.Trial registrationNCT00925301; June 19, 2009.

Anderson-Fabry disease.

Anderson-Fabry disease.

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease.

The use of personalized medicine to treat rare monogenic diseases like lysosomal storage disorders (LSDs) is challenged by complex clinical trial designs, high costs, and low patient numbers. Hundreds of mutant alleles are implicated in most of the LSDs. The diseases are typically classified into 2 to 3 different clinical types according to severity. Moreover, molecular characterization of the genotype can help predict clinical outcomes and inform patient care. Therefore, we developed a simple cell culture assay based on HEK293H cells heterologously over-expressing the mutations identified in Fabry and Pompe disease. A similar assay has recently been introduced as a preclinical test to identify amenable mutations for Pharmacological Chaperone Therapy (PCT) in Fabry disease. This manuscript describes an amended cell culture assay which enables rapid phenotypic assessment of allelic variants in Fabry and Pompe disease to identify eligible patients for PCT and may aid in the development of novel pharmacochaperones.

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment

ObjectiveDeficiency of α-galactosidase A (αGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3...

The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Purpose:Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.Methods:A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease–causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies.Results:Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay.Conclusion:The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med19 4, 430–438.

Social preference weights for treatments in Fabry disease in the UK: a discrete choice experiment

Objective: Fabry disease is a rare inherited lysosomal storage disorder caused by deficiency of α-galactosidase A. Effective enzyme replacement therapies are available that are administered intravenously. However, a new oral treatment is being developed as an alternative option for patients with amenable mutations. This study was designed to understand the value that people place on the different features of treatments for Fabry disease.Research design and methods: A discrete choice experiment (DCE) was designed to assess the importance of different aspects of treatments for Fabry disease. The attributes included overall survival, mode of administration, treatment related reactions, treatment related headaches and risk of antibody formation. Attributes were combined using a published orthogonal array into choice sets. A research panel was used to survey the UK general public. The mixed logit model was used to estimate strength of preference for the attributes and marginal rates of substitution (MRSs). Disutilities were estimated from the DCE data for changes in each attribute.Results: The sample (n = 506) was broadly representative of UK demographics. The logit model revealed that all attributes were significant predictors of choice. Participants were significantly more likely to choose a treatment which meant an increase in their life expectancy by 1 year (odds ratio = 1.574; 95% CI = 1.504–1.647) and significantly less likely to choose self-administered intravenous (IV) treatment compared to an every other day tablet (OR = 0.426 95% CI = 0.384–0.474). Estimated disutilities were −0.0543 (self-administered infusion), treatment related headaches 12 times a year (−0.0361) and infusion reactions six times a year (−0.0202).Conclusions: The survey revealed a significant preference for oral treatment compared with IV even in the context of a treatment that can extend overall survival. MRSs were used as a basis for estimating disutilities associated with changes in attribute levels which could be used to weight QALYs. It is possible that other important treatment attributes are missing from this research which may have provided further insights. It would also be useful to extend this research to include Fabry disease patients so their preferences can be assessed against the societal perspective.

Migalastat: First Global Approval.

Migalastat (Galafold™)-a small molecule drug developed by Amicus Therapeutics that restores the activity of specific mutant forms of α-galactosidase-has been approved for the treatment of Fabry disease in the EU in patients with amenable mutations. Fabry disease is a rare disorder that results in a deficiency or absence of α-galactosidase, leading to accumulation of globotriaosylceramide in the lysosomes of various cells. This article summarizes the milestones in the development of migalastat leading to this first approval in the EU for the long-term treatment of adults and adolescents aged ≥16 years with a confirmed diagnosis of Fabry disease.

Phase 3 FACETS study of migalastat HCl for Fabry disease: post hoc GLA mutation-based identification of subjects likely to show a drug effect

Fabry disease is caused by more than 800 different mutations in the GLA gene that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), resulting in accumulation of globotriaosylceramide (GL-3) and end-organ damage. Migalastat HCl (1-deoxygalactonojirimycin HCl, AT1001, GR181413A) is an investigational pharmacological chaperone that selectively binds and stabilizes α-Gal A, leading to increased cellular levels and greater lysosomal activity. Previously, a “research” human embryonic kidney (HEK) cell-based in vitro assay was developed to identify migalastat-responsive mutant forms of αGal A. The FACETS study (NCT00925301) compared migalastat to placebo in subjects with GLA mutations categorized as “amenable” to migalastat based on the research in vitro assay available at study initiation. The primary endpoint of this study was the percent change from baseline in kidney interstitial capillary (IC) GL-3 inclusions (responder analysis, 50% reduction threshold), which was not met. Meanwhile, a GLP-validated assay was created (“GLP HEK assay”) and testing of all mutant forms was completed before unblinding of the 6-month data. Approximately 90% of mutations remained in the same category of “amenable” or “non-amenable” using the same predefined in vitro criteria. However, 15 of 67 subjects enrolled in the study express mutant forms of α-Gal A considered to be nonamenable based on the GLP HEK assay, including 8 subjects with mutation R342Q. These 15 subjects may not be sufficiently responsive to migalastat, and may have impacted the previously reported study results. To explore the effect of migalastat in subjects with GLP HEK amenable mutations only, a post hoc analysis of the change from baseline (difference) in kidney IC GL-3 inclusions was conducted using an ANCOVA model with covariate adjustment for the baseline value and treatment-by-baseline interaction. Analysis of the quantitative difference and inclusion of baseline values in the analysis is the most appropriate measure of an effect on kidney IC GL-3 as many values were low at baseline. This analysis was first applied to all subjects in themITT population (n = 30 per group). Themean change from baseline in the migalastat group was a decrease of 0.22 ± 0.11 inclusions per capillary (IPC) (-66 inclusions per 300), and the placebo group showed an increase of 0.06 ± 0.09 IPC (+18 per 300); p = 0.052. The data were also analyzed for subjects with GLP HEK amenable mutations only (n = 25 migalastat, n = 21 placebo). The change from baseline in the migalastat group was a decrease of 0.31 ± 0.12 IPC (-93 per 300), while the placebo group showed an increase of 0.10 ± 0.13 IPC (+30 per 300); p = 0.0024. These findings were observed in the presence of a significant treatmentby-baseline interaction. This analysis demonstrates a measurable drug effect on change from baseline in kidney IC GL-3 inclusions during the first 6 months of treatment with migalastat, which is more pronounced in subjects with GLP HEK amenable mutations and higher baseline values. Additional data will be presented to support use of the GLP HEK assay to identify Fabry disease subjects with mutations that are most likely to demonstrate a drug effect with migalastat HCl.

A Phase 2 study of migalastat hydrochloride in females with Fabry disease: Selection of population, safety and pharmacodynamic effects

BackgroundFabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every other day (QOD) to females with FD. MethodsThis was an open-label, uncontrolled, Phase 2 study of 12weeks with extension to 48weeks in nine females with FD. Doses of 50mg, 150mg and 250mg were given QOD. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells. ResultsMigalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries. ConclusionsMigalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing. Trial registrationClinicaltrial.gov: NCT00304512.