Enzyme Replacement Therapy (ERT)

Since the molecular basis of Fabry disease is a deficiency of α-GAL A, replacement of this enzyme is critical to successful therapy. Accumulation of GL-3 is both a direct consequence of low or absent α-GAL A levels and the pathogenic basis for the disease cascades leading to clinical manifestations of Fabry disease. Therefore, GL-3 levels in clinically relevant tissues are important markers of the efficacy of any disease-specific treatment for Fabry disease.

Furthermore, given the degree of GL-3 substrate accumulation in certain cell types with low turnover rates (podocytes, cardiomyocytes, vascular smooth muscle), prolonged treatment at adequate dose levels may be necessary to achieve clearance from these compartments.

The rationale for enzyme replacement therapy is to restore a level of enzyme activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation, resulting in clinical benefit.

Cardiac Variants –No Vascular GL-3 Accumulation

The existence of cardiac variants in itself provides a rationale for enzyme replacement therapy ^{[1, 2]} Despite only low residual α-GAL A levels, these patients have few or none of the major clinical manifestations of classical Fabry disease and instead present with cardiomegaly and proteinuria at an age when classical Fabry patients would be more severely affected or would have died [3, 4] Tissue biopsies or autopsy studies of cardiac variants reveal GL-3 accumulation only in the myocardium and not in the vasculature of the heart or other tissues ^[1]. This suggests that even residual levels of α-GAL A can prevent GL-3 from accumulating in the vasculature, and that this clearance may be associated with an important clinical benefit, even if clearance from other cell types is less marked.

The 10-year success story of Cerezyme^®, enzyme replacement therapy for type I Gaucher disease, also strongly supports the rationale for ERT in Fabry disease.

The heart as a major marker of therapeutic effect

If females carrying a Fabry mutation (heterozygotes) develop clinical disease, the heart is almost always involved. Thus, the female phenotype and the cardiac variant indicate that the heart has a higher α-GAL A need than most other tissues, and this has implications for therapeutic goal setting and evaluation of drug effects. As shown by the different phenotypes seen during natural course, different organs may have different enzyme needs and respond differently to ERT (that is, along different dose-response curves), also dependent on pharmacokinetic aspects (e.g. higher doses are typically delivered to the liver than to the heart). Therefore, therapeutic effects need to be evaluated per organ, and one cannot assume that a good effect on one parameter guarantees a good effect in all organs.

Hierarchy of therapeutic parameters

Given the two distinct goals of therapy – alleviating symptoms as well as prevent late, life-threatening complications – and the fact that a variety of different subclinical parameters can be assessed, it is useful to analyze the efficacy of ERT (and different regimens thereof) by means of six different categories of subclinical or clinical outcomes (see Table I).

Table I. Hierarchy of therapeutic effects

Since August 2001, there are 2 enzyme replacement therapies available in Europe for the treatment of Fabry disease: agalsidase β (Fabrazyme®, Genzyme) and agalsidase α (Replagal^®, Shire).

In the United States, the FDA only accepted Fabrazyme^® for the treatment of Fabry patients.

For more information on Fabrazyme^®, please visit About Fabrazyme

References

1. Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, Gass A, Winston J, Dikman S, Fallon JF, Brodie S, Stacy CB, Mehta D, Parsons R, Norton K, O’Callaghan M, Desnick RJ. A Phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001a; 68:711-22.

2. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ. Safety and efficacy of recombinant human α-galactosidase A-replacement therapy in Fabry’s disease. N Engl J Med 2001b; 345(1):9-16.

3. Nakao S, Takenaka T, Maeda M, Kodama C, Takana A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, Tanaka H. An atypical variant of Fabry’s disease in men with left

ventricular hypertrophy. N Engl J Med 1995; 333(5):288-93

4. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop D, Desnick RJ. An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 1991; 324:395-9.