Fabry disease is a genetic storage disease and can be treated with infusions for 20 years. Now there’s something new on the drug market: an oral enzyme replacement therapy with migalastat.
Fabry disease is a genetic disease and belongs to the lysosomal family storage diseases. The estimated frequency is regarding 1:40,000. Intravenous enzyme replacement therapy has existed for 20 years and, more recently, oral treatment with migalastat.
Die Fabry disease is the most common of the lysosomal storage diseases and results from a deficient activity of the enzyme α-galactosidase A (α-Gal A). This leads to progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. This can result in damage to many body tissues and organs. The classic form, which occurs in men with less than 1% α-Gal A enzyme activity, usually begins in childhood or adolescence with periodic crises of severe pain in the extremities, the appearance of vascular skin lesions, sweating abnormalities, characteristic corneal and lens opacities, and Proteinuria.
Fabry is getting sick
studies show that a gradual deterioration in renal function to terminal renal insufficiency usually occurs in males in their third to fifth decades of life. Most men develop cardiac and/or cerebrovascular disease – a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. In rare cases, females can be relatively asymptomatic over a normal lifespan or have symptoms as severe as those seen in males with the classic phenotype.
In contrast, late-onset forms occur in males with greater than 1% α-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade of life with left ventricular Hypertrophy, cardiomyopathy, Arrhythmia and show proteinuria. Kidney failure or cerebrovascular disease manifesting as stroke or transient ischemic attack may occur.
man thing
Fabry disease is an X-linked disease; the GLAgene is located on the long arm of the X chromosome. Consequently, female patients with the disease are heterozygous and affected to varying degrees. clinical symptoms in female Fabry patients can occur as a result of defective X chromosome inactivation. This may be the case, for example, if a higher percentage of X chromosomes are associated with the mutated GLAgene is expressed in a specific tissue.
Any father affected by the condition passes the condition on to all of his daughters, while all sons remain healthy. If the mother carries the mutated gene, her children – regardless of gender – have a 50% risk of inheriting the disease.
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Fabry is an affair of the heart
The whole body suffers, but the heart is particularly affected. Cardiac involvement remains the leading cause of death in Fabry patients. GB3 deposits are found in virtually all cardiac cells. Little is known regarding the mechanisms leading to organ damage.
Fabry hearts show myocardial hypertrophy, inflammation, apoptosis, Necrosis and fibrosisvalve thickening and narrowing of the intramural Coronary arteries. Cardiac manifestations therefore include LVH, heart failure, Angina pectoris, heart valve diseases, arrhythmias, cardiac conduction blocks and sudden cardiac death. The severity of cardiac involvement is the same in both classic and late-onset phenotypes.
Enzyme replacement therapy (ERT) has been shown to reduce or stabilize LV mass and wall thickness, reduce incidence, and delay the onset of clinical events.
Adjunctive therapy according to guidelines
As adjunctive therapy become loud guideline der European Society of Cardiology (ESC) ACE-Hemmer and Sartan used once morest heart disease and hypertension. Mineralocorticoid receptor antagonists may also be considered in patients with heart failure and LV systolic dysfunction. Beta blockers are recommended to reduce the frequency of atrial fibrillation/flutter controlled and should be considered in patients with angina pectoris or heart failure and LV systolic dysfunction. Ivabradine should be considered according to guidelines for the treatment of heart failure or angina pectoris.
Enzyme therapy is proven
Enzyme replacement therapy with recombinant α-galactosidase A has been available for clinical use since 2001 application approved. There are two commercially available preparations: agalsidase alfa and Agalsidase beta. Both are given intravenously every two weeks.
ERT should be started in men at the age of 16 regardless of symptom status. This can also be done at the age of 8 to 10 years. In men with late onset and in women with classic or late onset, left ventricular hypertrophy, cardiac fibrosis, or cardiac arrhythmia and conduction abnormalities are indications for starting ERT.
One Study comparing agalsidase alfa and agalsidase beta found that a greater proportion of patients had a decrease in LV mass index when treated with agalsidase beta for 1 year than with agalsidase alfa. However, no difference was found between agalsidase alfa and beta in terms of clinical events.
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swallowing instead of injecting
Oral therapy is now available in addition to intravenous ERT. The orphan drug Migalastat is a low molecular weight iminosugar analogue of the terminal galactose residue on GL-3. It binds selectively and reversibly to the active sites of accessible mutant forms of the α-galactosidase A enzyme. This binding allows migalastat to act as a pharmacological agent Chaperone to act. Migalastat-capable mutated forms of α-galactosidase A in the endoplasmic reticulum are altered and transport to lysosomes is facilitated.
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Factsheet Migalastat |
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disease name |
Morbus Fabry |
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Other names |
Fabry-Anderson disease |
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frequency |
1:40.000 |
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Impaired function/symptoms |
kidney diseases heart diseases Depression Skin and joint pain (angiokeratomas) Gastrointestinal complaints Anhidrosis |
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Genlokalisation |
Lysomal storage disease, α-galactosidase A deficiency |
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Orphan drugs |
Migalastat (Galafold®) |
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Effect |
Chaperone that binds selectively, reversibly, and with high affinity to certain mutant forms of α-galactosidase A and promotes transport to lysosomes |
Study situation is favorable
In preclinical studies migalastat increased the activity of α-galactosidase A in cultured lymphoblasts and fibroblasts derived from patients with Fabry disease.
In a Phase-I-Studie in healthy volunteers, migalastat hydrochloride (150 mg) administered twice daily resulted in a two-fold increase in wild-type α-galactosidase A activity in white blood cell lysates.
In Phase II Studies in patients with Fabry disease, oral migalastat (123 mg) once every other day resulted in increased activity of α-galactosidase A in blood, skin and kidneys and decreased levels of GL-3 in urine, skin and in certain kidney cell types. The beneficial responses were greater and more consistent in patients with migalastat-accessible GLA mutations than in patients with inaccessible mutations.
In the Phase-III-Study 57 adults (56% female) received one enzyme replacement therapy or migalastat. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment. There was no significant change with ERT. Predefined renal, cardiac, or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following switching from ERT to migalastat. Migalastat was generally safe and well tolerated.
Attraktiv in ATTRACT
The main objective of the 18-month, randomized, active-controlled ATTRACT-Studie by Huges et al. were to evaluate the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Cardiac effects, disease substrate, patient-reported outcomes (PROs), and safety were also assessed. Migalastat was generally safe and well tolerated in this study. No clinically relevant effects were identified in laboratory tests, EKGs, vital signs or physical examinations.
In this study, 18 months of migalastat treatment was associated with a statistically significant decrease in left ventricular mass index (LVMi); a non-significant change was observed in ERT-treated patients. Migalastat and ERT had similar treatment effects on renal function and compared favorably with a composite clinical endpoint. Migalastat was safe and well tolerated.
A new therapy option for everyone
Migalastat is therefore a promising oral alternative to ERT for male and female patients with Fabry disease and treatable mutations. The quality of life is significantly increased by the oral application and the secondary damage is reduced.
But there is more news: Another drug is already in the pipeline. Moss-aGal is a recombinant form of human α-galactosidase. It was produced in genetically modified Little Bladder Cap Moss (Physcomitrella patent). It is the world’s first drug candidate from moss.
Image source: Danilo.alvesd, unsplash
