Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch

Abstract

Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3-0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m(2) (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0-606) mg/g to 216 (0-2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate.

Figure 1.

Overview of data completeness for general FD data and cardiac, renal, and neurologic assessment. The upper row shows the mandatory data and the lower row the optional data (green, data available; red, data not available).

Figure 2.

Decrease in renal function under agalsidase-beta dose reduction and switch to agalsidase-alfa. Change in renal function quantified by (A) eGFR (calculated with the CKD–Epidemiology Collaboration formula) and (B) albuminuria (albumin-to-creatinine ratio) from spot urine for the three visits. Appropriate values are given as medians (95% confidence intervals). Asterisks mark significant changes between baseline and prospective visits. P values are given in the figures.

Figure 3.

Overview of the study design. After the baseline visit, the treatment strategy for the following year was chosen by an FD specialist physician team and the patient: (1) continue the regular dose of agalsidase-beta of 1.0 mg/kg every other week; (2) reduce the agalsidase-beta dose to 0.3 or 0.5 mg/kg every other week; or (3) switch to a regular dose of agalsidase-alfa at 0.2 mg/kg every other week.