Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors

Abstract

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

α-d-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

“…ERT with intravenous administration of recombinant human a-D-galactosidase (agalsidase beta, Fabrazyme® or agalsidase alpha, Replagal®) reduces the levels of Gb3 and lyso-Gb3 in some tissues of Fabry patients, but its clinical efficacy is still limited. [5][6][7]43 The limited enzyme stability in plasma is a major drawback, and it is for this reason that enzyme active site binders that stabilize recombinant enzyme in circulation are pursuedwith Gal-DNJ 8 (Migalastat®) currently in use in the clinic as the benchmark. Here we report the design and synthesis of the rst-in-class conformational glycosidase inhibitor and agal A stabilizing agent, a-cyclosulfamidate 4.…”

“…The 4 C 1 minimum of the substrate extends towards the TS-like 4 H 3 conformation, indicating that cyclosulfate 2 in a 4 H 3 conformation could be transiently populated on-enzyme, favoring the nucleophilic attack and formation of a glycosyl-enzyme adduct. The FELs of 3-5 show that substitution of the cyclic sulfate trap by cyclic sulfamidates (3 and 4) or sulfamide (5) does not signicantly affect the conformational preferences. The local B 2,5 minimum in 4 is more pronounced, probably due to a hydrogen bond between the 2-OH and one cyclosulfamidate oxygen (Fig.…”

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: An international cohort study

“…Recently, we have described the absolute slopes for eGFR, LVMI of patients on treatment stratified for phenotype and sex which might be used as benchmark for future studies. 30 This study also emphasises the fact that in some patients there is irreversible damage to organs such as the kidneys, which will not be reversed. It was shown that in patients with advanced kidney disease, the risk…”

Treating lysosomal storage disorders: What have we learnt?

“…Some work on developing such starting and stopping criteria has been done . It is easy to portray such efforts as being about restricting treatment and saving costs, but that narrative, which does not come solely from the pharmaceutical industry, should be resisted.…”