Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene. These mutations result in deficient amounts of an enzyme called alpha-galactosidase A being produced that, in turn, causes a type of fat called globotriaosylceramide (Gb3 or GL-3) to accumulate inside cells.
An enzyme replacement therapy (ERT) called Fabrazyme is approved as first-line treatment for people with Fabry disease. But alternative treatment options, such as substrate reduction therapy (SRT), are showing encouraging results in clinical trials.
Here are a few pointers about ERT and SRT, and the advantages and drawbacks of each approach.
What is ERT?
ERT is a way of replacing the defective or deficient enzyme in a disease, which, in the case of Fabry, is alpha-galactosidase A. The newly introduced enzyme can substitute for the workings of the natural enzyme, helping to ease disease symptoms.
An ERT called PRX-102, by Protalix BioTherapeutics, is now in the Phase 3 BRIDGE study (NCT03018730), and the company is expected to file an application requesting its approval with the FDA by mid-2020.
ERT cannot cure Fabry disease, although it does treat its root cause. It must be administered at regular intervals throughout a patient’s life.
What are the limitations of ERT?
The body can mount an immune response against ERT, as the enzyme that is injected into the blood may be recognized as foreign. In some cases, this can include life-threatening allergic shock reaction called anaphylaxis.
Not all tissues and organs equally benefit from ERT. For example, the enzyme cannot cross the blood-brain barrier, which means it is not effective in preventing the cerebrovascular disease and stroke typically seen in patients with type 1 Fabry disease.
Although ERT has been shown to be beneficial over a 10-year period, concerns such as continued progression of heart disease and advancing kidney problems remain, especially when administered at later disease stages.
What is SRT?
SRT is aimed at decreasing the amount of the substrate, or molecule, on which the enzyme acts — ceramide in the case of the Fabry disease. This inhibits (blocks) the activity of the enzyme glucosylceramide synthase (GCS), which ultimately prevents the production of Gb3 so as to make the lack of a fully functioning alpha-galactosidase A enzyme much less of a problem.
SRTs such as Lucerastat by Idorsia, and Venglustat by Sanofi Genzyme, are in different phases of clinical testing. Lucerastat in an ongoing Phase 3 study (NCT03425539) that may still be enrolling eligible adult patients at sites across the U.S., Europe, Canada and Australia.
Can SRT offer a better alternative to ERT?
Unlike ERT, SRT does not cause an immune reaction as there is no enzyme being delivered. SRT can be administered orally, which minimizes the inconvenience of having to undergo an intravenous injection with each treatment. SRT can also easily cross into the blood-brain barrier, and so work to alleviate the neurological complications of Fabry disease.
That being said, SRTs must be properly evaluated before they might be approved and come into use. The long-term effects of reducing levels of enzyme substrates, such as ceramides, are still unclear.
Which one would be best?
Currently, ERT is the only approved treatment option for people with Fabry disease. A safety and efficacy comparison with SRT may be possible in the future. It may also be possible to combine ERT and SRT for maximum clearance of Gb3 from all tissues, as was demonstrated in a mouse model of Fabry disease.
For the moment, the effectiveness of ERT can be enhanced by such lifestyle interventions as proper stress management, following required dietary guidelines, ensuring good heart health, and caring for your kidneys. Immunosuppressants may also minimize the possibility of allergic reactions to ERT.
Last updated: Feb. 6, 2020
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