Although Fabry disease is inherited X-linked, affected women can be just as severely affected as male patients. Unfortunately, there are no standardized criteria for when an affected female patient should be treated with a Fabry-specific therapy. One focus of our clinical research is to close this knowledge gap so that female patients with Fabry disease in particular can be treated timely before irreversible end organ damage occurs.

Multicenter Female Fabry Study (MFFS) – impact of early ERT start on clinical manifestations in females with Fabry disease

Description

A prospective multicenter study of Germany, Austria and Switzerland

Investigational sites

Fabry disease center Münster, University Hospital Münster (principal investigator)

Fabry disease center Berlin - Charité - Universitätsmedizin Berlin, Campus Mitte (CCM)

Fabry disease center Cologne, University Hospital Cologne

Fabry disease center Hamburg, University Hospital Hamburg

Fabry disease center Hannover, University Hospital Hannover

Fabry disease center Mainz, University Medical Center Mainz

Internal medicine practice, Müllheim

Clinic and Polyclinic for Internal Medicine, University Hospital Zurich, Switzerland

Morbus Fabry Center, AKH WIEN, Austria

Background and rationale

Fabry disease (FD; OMIM #301500) is an X-linked (Xq22.1) inborn error of glycosphingolipid catabolism resulting from deficient alpha-galactosidase A activity (GLA; 300644) leading to a progressive lysosomal accumulation of glycosphingolipids (mainly globotriaosylceramide [Gb3]) within the vascular endothelium, as well as renal, cardiac, and neuronal cells (Zarate & Hopkin, 2008; Najafian et al. 2001). These accumulations result in a multisystemic disease with early myocardial failure and stroke, end-stage renal disease and severely decreased life expectancy. The enzymatic deficiency is based on GLA gene mutations (n >600) (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GLA). Enzyme replacement therapy (ERT) is based on infusions of biotechnologically produced GLA enzyme (Agalsidase alfa, Replagal, 0.2 mg/kg BW every other week, Shire Pharmaceuticals, UK, and Agalsidase beta, Fabrazyme, 1 mg/kg BW every other week, Sanofi Genzyme, USA), to compensate for the  loss of endogenous enzyme.

Although X-linked inheritance and X-lionization in females (mosaic pattern) may explain why FD-specific symptoms and manifestations are delayed and often milder in heterozygous affected females, lionization is not a sufficient model to explain the observed bright variability in disease progression in females. Furthermore, less is known about the vascular damage. Furthermore, it is unclear which affected women benefit from ERT and when ERT should be initiated.

Our previous study (Lenders et al. 2016) comprising 261 females with FD (6 German Fabry centers) revealed that the treatment concept for females with FD in Germany is in line with the current European Fabry guidelines (Biegstraaten et al. 2015). However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females. Furthermore, elevated lyso-Gb3 levels in females seem to be a marker of disease burden, even if the prognostic value of lyso-Gb3 levels for ERT initiation in females needs evaluation in future observational studies.

Study objectives

Evaluation of a large female Fabry cohort (Germany, Austria, Switzerland, 9 centers, ~277 females) with well characterized clinical phenotypes at 3 time points to assess the impact of early ERT start in affected females compared to males (n~60).

Reevaluation of consensus criteria for ERT initiation in females with FD. Analysis of the impact of early ERT start in affected females (compared to males) with special focus on vasoprotection.

Course of the study

To address the studies objectives, 3 groups of females (group 1: “long-term ERT”; group 2: “long-term ERT naïve” (without ERT); group 3: “new on ERT”) will be analyzed at 3 time-points (t_-1, t₀, t₁): In the “new on ERT” group: t₀ = last visit of female patients naïve to ERT; t₁ = visit of female patients after a 12 month follow-up on ERT. All female patients on ERT or naïve to ERT will be analyzed at t₀ and t₁ with a 12 month interval. In females on “long-term ERT” an additional time point (t_-1) will cover the last naïve status, while t₀ covers an actual visit. In “long-term ERT naïve” females t_-1 will cover the first visit of females. A group of male patients (n=60) will be included as a control group.

Funding

A comprehensive funding of this study is provided by Takeda (previously Shire), Germany.