Until recently, the treatment of Fabry Disease has been non-specific with palliative management of disease complications. Conventional management particularly in childhood and adolescent years consists of pain relief with standard analgesic drugs. Some protection to the kidneys can be provided though the use of ACE inhibitors (angiotensin-converting enzyme) and angiotensin receptor blockers, drugs whose primary function is to reduce blood pressure. Dialysis or renal transplantation is available for patients experiencing end-stage renal failure, and antiarrhythmic agents and devices can be used to control irregular heart rhythms. Oral anticoagulants are recommended for stroke-prone patients. However, none of these measures are preventative.
After extensive pre-clinical studies in the 1990’s, the effectiveness of recombinant human a-galactosidase A replacement therapy was demonstrated in two pivotal studies involving two different, but closely related products, agalsidase alfa (common name: Replagal ®, provided by Shire Pharmaceuticals) and agalsidase beta (common name: Fabrazyme®, provided by Genzyme). Both studies demonstrated the benefits of enzyme replacement therapy to patients with Fabry Disease. One study showed significant clearance of GL3 from blood plasma and urine, the other showed symptomatic improvement in patient’s pain although marked differences in trial design make direct comparison difficult. Both products appeared to be safe as well as effective. Following approval in Europe in 2001, Fabry disease is now treated with enzyme replacement therapy (ERT).
In the UK, approximately 44% of Fabry patients are treated with Fabrazyme, with 49% of patients treated with Replagal; the remaining 5% are treated using chaperone therapy, described below (figures obtained from UK MPS Conference, 2009). Administration of Fabrazyme or Replagal is by infusion. Infusions are typically fortnightly, lasting between 90 minutes and 5 hours and are administered either in hospital or at home. In some cases adverse reactions (e.g. nausea, rash, low blood pressure) can occur during the initial infusions, but these can be well managed and subside within a relatively short period of time.
Monitoring of various parameters such as concentrations of GL3 in blood and urine, kidney function, cardiac rhythm, pain management, eye and skin involvement is carried out on an ongoing basis (e.g. annually) by a team of specialist consultants. ERT has been shown to improve secondary symptoms, but is more inconsistent regarding the alleviation of all of the primary symptoms. It has been shown that the earlier treatment starts the better, as some of the GL3 deposition cannot be simply reversed by ERT.
A relatively new product named Amigal (Amicus Therapeutics) is currently undergoing Phase II clinical trials. The product, which can be administered orally, is classified as a chaperone drug. The drug is believed to be effective at binding and transporting enzyme from its production point within a cell, to the lysosome. For it to be effective, the drug requires that some degree of a-galactosidase enzyme is being produced naturally by the body. It is therefore of limited or no use to classic Fabry male patients but is effective in treating females and variant Fabry patients.
It is possible that gene therapy will play a role in the treatment of Fabry Disease and other rare inherited metabolic diseases in the future.Long term international monitoring of patient survey data is carried out using confidential patient registries. There are two active registries:
- Fabry Registry by Genzyme, and
- Fabry Outcome Survey by Shire.