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

Abstract

BackgroundTwo recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes.MethodsIn this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex.Results387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar.ConclusionsTreatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

“…Both agalsidase-a and agalsidase-b have been demonstrated to benefit patients in the short term and, in observational studies, patients treated for up to 10 years showed stabilization of eGFR or a slowing of the progression of eGFR decline. 19,20,[28][29][30][31][32][33][34][35][36] The natural course of disease is associated with a rapid decline of renal function (eGFR decline up 12 ml/min per 1.83 m 2 per year) and left ventricular hypertrophy. 37 Tables 1 to 5 provide a general overview of the effects of both ERTs on symptoms and manifestations in patients with FD.…”

“…[38][39][40][41] Furthermore, ERT has been reported to stabilize renal function in terms of eGFR, whereas ERT's effect on proteinuria and albuminuria is inconsistent. 26,[29][30][31][32][33][34][35][36][37][42][43][44][45][46][47][48][49][50][51][52] If ERT is started before myocardial fibrosis has developed, a long-term improvement of myocardial morphology, function, and exercise capacity can be achieved. [53][54][55][56][57][58][59][60][61][62] It also leads to a reduction of cerebrovascular and thromboembolic events [63][64][65] and significant improvement in pain-related quality of life.…”

“…102 Recent studies have found that, once neutralizing ADAs occur, their formation seems to be irreversible, and that the majority of affected patients stay neutralizing ADA-positive over 10 years. 24,25,36 About 73% of patients treated with agalsidase-b and 24% of patients treated with agalsidase-a reportedly develop ADAs. 103,105 This difference might be explained by the different dosages of both drugs and the different cell lines producing them, as well as the CRIM status of the treated patients, which has not been taken into account thus far.…”

Longitudinal Study on Ocular Manifestations in a Cohort of Patients with Fabry Disease

“…However, a greater biochemical response and an improved ventricular mass was observed with agalsidase β(51). An improved estimated glomerular filtration rate (eGFR) is also associated with the use of agalsidase β after switching drug from agalsidase α formulation (52) A recent Cochrane report confirmed that agalsidase β may be associated to a lower incidence of cerebrovascular events than agalsidase α(53).…”

Neutralising anti‐drug antibodies in Fabry disease can inhibit endothelial enzyme uptake and activity

“…4), it was also demonstrated that the formation of neutralising anti-drug antibodies (ADA) reduce therapy efficiency, mainly in male patients (up to 70% of treated males). [5][6][7][8][9][10][11][12][13] Interestingly, ADAs demonstrate a high cross-reactivity for both recombinant enzymes (Linhorst et al 2004). 7 There is evidence that the risk for the formation of ADAs is mainly determined by the presence of endogenous enzyme 6,7 and the dose of infused recombinant enzyme.…”