FP805
PROGRESSION OF NEPHROPATHY IN FABRY PATIENTS RECEIVING ENZYME REPLACEMENT THERAPY (ERT); RELATION TO ANTI-DRUG ANTIBODY (ADA) STATUS AND PROTEINURIA

INTRODUCTION AND AIMS: Fabry disease (FD) is an X-linked multisystem lysosomal storage disorder, affecting both males and females caused by the deficient of α-galactosidase-A (α-Gal-A) activity. Long-term disease manifestations include progressive renal failure, hypertrophic cardiomyopathy, cardiac rhythm disturbances, stroke and death. Two enzyme replacement therapies (ERT) are commercially available, agalsidase-alfa (Shire) and agalsidase-beta (Genzyme). The clinical benefit of ERT may not be as robust as anticipated, especially in the subset of males with ‘classic’ Fabry disease. A combination of factors, including dose, dosing interval, the presence of anti-drug antibodies (ADA), estimated glomerular filtration rate (eGFR), age and the timing of ERT initiation, and proteinuria could explain less than optimal responses to currently available ERT.

METHODS: In an effort to identify Fabry patients who continue to progressively lose kidney function, despite receiving standard ERT therapy (agalsidase-beta), 37 patients were analyzed for annualized eGFR, anti α-Gal-A antibody, serum-mediated inhibitory activity towards agalsidase-beta and proteinuria. All of these patients were screened for the BALANCE study (a head-to-head blinded comparison of pegunigalsidase-alfa to agalsidase-beta at 1 mg/kg every two weeks, NCT02795676) with change in eGFR as the the primary end-point.

RESULTS: These FD patients, both males and females, experienced progressive loss of kidney function while being treated with agalsidase-beta (treated for 1 to 12 years). At the time of screening for the study, the average annualized eGFR slope was -8.1 (SD=6.6) mL/min/1·73m²/year, the eGFR was 70.0 (SD=17.9) and 75.1 (SD=11.0) ml/min/1.73m² for males and females, respectively; the urine protein/creatinine ratio (UPCR) was 669 (SD=579) mg/gr for male and 45 (SD=25) mg/gr for females. Males initiated ERT treatment at 39 (SD=10) and females at 42 (SD=7) years of age. The male patients were at age of 43 (SD=11) and females at 47 (SD=9) years at screening. Of the 27 male patients, 15 (56%) were found to be ADA positive to agalsidase-beta, with titers ranging between 469 to 127933. These patients also had serum-mediated in-vitro enzyme inhibition with a mean of 84% (SD=11%) inhibition. None (0%) of the 10 females were ADA positive to the agalsidase-beta. More ADA-positive male patients (10/14=67%) had significant proteinuria (UPCR) ≥500 mg/gr than ADA-negative males (5/12=45%), with similar results seen when they were stratified at 60 mL/min/1·73m².

CONCLUSIONS: A) The screening stategy identified Fabry patients with severe, progressive Fabry nephropathy despite long-term ERT; B) 3 times as many males as females had severe Fabry nephropathy, consistent with estimates of skewed X-inactivation in classic female patients; C) Progressive Fabry nephropathy in females with classic mutations was not associated with severe proteinuria or ADA status, and D) Severe proteinuria was more frequently observed among ADA-positivite males. ADA may contribute to progressive loss of kidney function and heavier proteinuria in "classic" male Fabry patients receiving long term ERT at 1 mg/kg every two weeks.