Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease

Abstract

BackgroundFabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy.MethodsThe outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed.Results81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months.ConclusionsThis 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

Anti-proteinuric therapy and Fabry nephropathy; factors associated with preserved kidney function during agalsidase-beta therapy

“…25 In addition, neutralising antibodies directed against agalsidase-beta may be another factor that may limit the success in controlling proteinuria and/ or stabilising renal function. 26 The importance of the age at which ERT is initiated was recently emphasised 12 and is confirmed by the present findings, suggesting that severe underlying changes in renal structure 21 may limit the beneficial effects of controlling urine protein excretion. Regression analysis (table 4) showed that the age at which ERT was started was the only significant factor associated with risk of renal progression in patients for whom ACE inhibitor or ARB therapy controlled the average UPCR to ≤0.5 g/g, thus confirming and extending the recent report from Germain et al…”

“…13 The overall results were similar for the two randomised studies; patients with higher baseline eGFR and lower UPCR had significant preservation of renal function when treated with agalsidase-beta. [11][12][13] We previously demonstrated in a small, open-label single-centre study that treatment with ACE inhibitors or angiotensin receptor blocker (ARB) to maintain UPCR <0.5 g/24 h was associated with stabilisation of renal function even in Fabry patients at high risk for progression of nephropathy.…”

Fabry Liga: Klinikinis Atvejis Ir Literatūros Apžvalga

“…Lyginant Agalzidazę alfa ir Agalzidazę beta, akivaizdžių skirtumų tarp fermentų nenustatyta. 2015 m. atlikta Germaino ir kitų patyrusių specialistų iš viso pasaulio apžvalga, kurios metu įvertinti dešimties metų gydymo PFT rezultatai [31]. Tyrimas parodė, kad, skiriant PFT jaunesniame amžiuje ir esant mažesniam organų taikinių pažeidimui, rezultatai geresni nei skiriant vyresniame amžiuje esant didesniam organų pažeidimui.…”

The Impact of Fabry Disease on Reproductive Fitness

“…The scientific literature offers several theoretical factors that could contribute to decreased fitness in males with FD including: mechanical blockage of the vas deferens due to glycolipid storage, autonomic dysfunction, reduced life expectancy, depression and decreased social adaptive functioning, or personal choice Wagner et al 2014;Arends et al 2015;Germain et al 2015;Waldek et al 2009). In order to provide accurate genetic counseling about their reproductive fitness to individuals affected by FD, we conducted a multi-center, large scale study to determine if reproductive fitness is decreased in males with FD and, if so, delineate specific risk factors or issues related to decreased fitness.…”