Enzyme Enhancement on Migalastat in Fabry Disease
Research type
Research Study
Full title
Changes in enzymatic activity of alphagalactosidase A in patients with Fabry Disease treated with an oral chaperone therapy.
IRAS ID
266436
Contact name
Uma Ramaswami
Contact email
Sponsor organisation
Royal Free Hospital NHS Foundation Trust
Duration of Study in the UK
1 years, 10 months, 13 days
Research summary
Anderson Fabry disease is a rare disease affecting both males and females. Therapy options include replacing the missing enzyme by two weekly intravenous infusions; and more recently oral chaperone therapy (a drug called migalastat), which helps in correcting the faulty proteins by enabling the function of the residual enzyme activity to be restored.
We have replaced the missing enzyme in fabry disease with enzyme replacement therapy for nearly two decades.
Oral chaperone therapy with a drug called Migalastat was licensed for use in Fabry Disease two years ago, which is made by the company Amicus. However, migalastat can be used only in about 60% of fabry patients. Amicus who makes this new oral chaperone therapy, tested each mutation (spelling mistake in the gene) to see if migalastat would work for that mutation and defined eligibility by a method they defined as ‘amenability to migalastat’. They did this by testing each mutation and analysed if the enzyme level was restored partially by migalastat in an in-vitro system (outside the body), then that particular mutation was defined as an amenable mutation.
Description of how amenability was measured: This was done in the laboratory by testing many different mutations (faults in the genes) using a laboratory method called HEK assay.
HEK assay is a cellular based assay (i.e. experiment in a petri dish using human embryonic kidney cells).
A plasmid is a DNA molecule that is separate from the chromosomal DNA in the cell and it can replicate (copy itself) independently. This system can be used to replicate the DNA in question (in this instance the fabry mutation). This is called a mutant plasmid.
This mutant plasmid can then be introduced into the HEK cells in a petri dish. This system will now produce enzyme that can be measured.
Depending on the severity of the spelling mistake, the enzyme level will vary depending on the fabry mutation.
Using the above system, each Fabry mutation (spelling mistake) was tested separately by transfecting the HEK cells (i.e. deliberately introducing the mutant DNA) with a specific fabry mutant plasmid.
Migalastat, the oral chaperone therapy is then added to the petri dish and the increase in enzyme level when this therapy is added to the HEK cells is measured.
The company defined amenability of a mutation to Migalastat, if there was a 3% absolute or 20% relative increase in enzyme activity from when it was measured before adding migalastat to the HEK assay.There are many mutations in the fabry gene and Amicus have tested about 700 mutations using this in vitro system to check the percentage increase in enzyme level with migalastat. This information is available in a freely available clinician website that Amicus have called migalastat amenability table. About 60% of all the mutations that we know of in Fabry Disease can potentially be treated with migalastat based on the information available for each mutation amenability done in the HEK assays.
Migalastat was approved for use in patients with Fabry Disease who have an amenable mutation as defined by Amicus as described above. The clinical trials assessed clinical findings such as reduction in thickness of the heart muscle, improvement in kidney function and onset of strokes. Measuring how much the enzyme level increased in the blood (plasma) or other tissues in patients on migalastat was not evaluated.
In this study we will measure the enzyme level when patients are taking migalastat. This will be done when they have their routine monitoring of clinical symptoms, and measuring biomarkers (surrogate tests to measure the efficacy of a treatment). The increases in enzyme activity on migalastat may or may not be different with different GLA mutations, which has also not been studied previously.
REC name
North West - Haydock Research Ethics Committee
REC reference
19/NW/0698
Date of REC Opinion
18 Nov 2019
REC opinion
Favourable Opinion