STABILIZATION OF KIDNEY FUNCTION DECLINE AND CARDIOMYOPATHY IN MALE PATIENTS WITH CLASSIC FABRY DISEASE: A PRE- VS. POST-AGALSIDASE BETA TREATMENT FABRY REGISTRY ANALYSIS

Abstract Background and Aims Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic GLA gene variants. Males with the classic (more severe) phenotype have markedly deficient or no α-galactosidase A activity and early, progressive accumulation of glycosphingolipids (e.g. globotriaosylceramide [GL-3] and deacylated GL-3 [lyso-GL-3]) in cells and body fluids. Particularly compromised are vascular endothelial and smooth muscle cells, most kidney cell types (particularly podocytes), cardiomyocytes and neural cells. Cellular injury triggers inflammatory responses leading to fibrosis with multisystem involvement. Symptoms associated with small fiber neuropathy (e.g. neuropathic pain) appear in childhood, typically followed in adulthood by chronic nephropathy (proteinuria, reduced glomerular filtration rate [GFR]) that may evolve to end-stage renal disease, and progressive cardiomyopathy with left ventricular hypertrophy and early demise. We compared kidney function and cardiomyopathy outcomes after enzyme replacement therapy with agalsidase beta with treatment-naive outcomes in male patients with the classic form of FD. Method The self-controlled comparison (piecewise mixed linear modelling) used Fabry Registry (NCT00196742) data from males with GLA variants associated with the classic FD phenotype (dbfgp.org/dbFgp/fabry/). The patients had received agalsidase beta (average dose of 0.9 − 1.1 mg/kg every 2 weeks) and had ≥2 pre- and ≥2 post-baseline assessments. Baseline was defined as up to 6 months after start of treatment. Follow-up spanned from 5 years pre-treatment (preTx) to 5 years post-treatment (postTx). Patients on dialysis or with a kidney transplant were excluded. Assessed were slopes of estimated GFR (eGFR, CKDEPI equation), ultrasound derived interventricular septum thickness (IVSTd) and left ventricular posterior wall thickness (LVPWTd) during the preTx and postTx periods. Data were stratified by low renal involvement (LRI, ratios [g/g] urine protein-to-creatinine ≤0.5 or albumin-to-creatinine ≤0.3) and high renal involvement (HRI, ratios [g/g] >0.5 or >0.3, respectively). Ages at start of treatment (ageTx) and follow-up durations are expressed as medians. Results Compared with 1.1-year preTx data, eGFR decline was similar during 4.1-year postTx follow-up in 254 males, ageTx 30.8 years. eGFR slopes (preTx vs. postTx) were -2.22 vs. -2.66 ml/min/1.73 m2/year (Ppre-post difference=0.24). The changing patterns among the 165 LRI males, ageTx 25.4 years (slopes preTx vs. postTx: -1.73 vs. -1.92 ml/min/1.73 m2/year; Ppre-post difference=0.66), and the 68 HRI males, ageTx 38.2 years (slopes: -2.93 vs. -4.31 ml/min/1.73 m2/year; Ppre-post difference=0.04), were statistically different (Pinteraction<0.01). IVSTd remained stable among 73 males, ageTx 34.2 years, during 1.0-year preTx (slope=+0.02 mm/year, P0>0.05) and 4.1-year postTx follow-up (slopes=-0.02 mm/year, P0>0.05) (Ppre-post difference=0.83), where a P0 <0.05 indicates that the slope is significantly different from zero. LVPWTd increased preTx (slope=+0.33 mm/year, P0=0.01) but stabilized during postTx follow-up (slope=-0.09 mm/year, P0>0.05) in 87 males, ageTx 35.1 years (Ppre-post difference<0.01). Overall, patients with LRI had more stable cardiac ultrasound indices throughout follow-up. Conclusion In males with classic FD, treatment with agalsidase beta appeared to stabilize eGFR decline in LRI males. Overall, IVSTd remained stable throughout follow-up and LVPWTd, increasing during pre-treatment follow-up, stabilized post-treatment. Funding: Fabry Registry, abstract: Sanofi Genzyme.