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

Abstract

FOS, Fabry outcome survey; 95% CI, 95% confidence interval; LRI, low renal impairment; HRI, high renal impairment; mGFR, measured glomerular filtration rate; OR, odds ratio. 62 95% CI, 95% confidence interval; FOS, Fabry outcome survey; LRI, low renal impairment; HRI, high renal impairment; LVMI, left ventricular mass index; LVM, left ventricular mass; MWT, mean wall thickness; LVH, left ventricular hypertrophy; IVST, interventricular septum thickness; RWT, relative wall thickness; LVWT, left ventricular wall thickness.

Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1‐year Phase 1/2 clinical trial

“…Immunogenicity is an important concept in the use of ERT in FD. In clinical trials, 68% and 73% of adults (both sexes and males, respectively) treated with agalsidase beta and 24% to 56% of male adults treated with agalsidase alfa developed ADAs, with a high incidence of neutralizing antibodies . The presence of neutralizing ADAs has been associated with reduced pharmacodynamic and clinical responses, such as severely impaired cardiac structural disease burden and renal outcome, increasing lyso‐Gb3 levels, and worse severity score values …”

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

“…In affected patients with FD under ERT, enzyme elimination by macrophages is of clinical therapeutic relevance, since the amount of infused AGAL for (endothelial) uptake is further limited. 4 Our initial experiments demonstrated that the fluorescence intensity of the labelled AGAL is associated with increasing AGAL activities after uptake in endothelial cells. By contrast, the intracellular fluorescence intensities and enzymatic activities differed after incubation with individual patients' sera, pointing towards an uptake of AGAL/ ADA-complexes in these cells, which fail to dissociate after internalisation even under lysosomal pH conditions.…”

“…Although a beneficial effect of both compounds on disease progression and manifestations has been shown in general (reviewed in Ref. ), 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) …”

“…2,3 Although a beneficial effect of both compounds on disease progression and manifestations has been shown in general (reviewed in Ref. 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).…”

In Vitro and In Vivo Amenability to Migalastat in Fabry Disease

“…Since 2001, enzyme replacement therapy (ERT) with agalsidase-alfa (Replagal, Shire/Takeda) and agalsidase-beta (Fabrazyme, Sanofi Genzyme) is available for treatment, resulting in intracellular Gb 3 reduction, leading to a clinical stabilization or at least a slowed disease progression in males and females. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 A second treatment option based on a pharmaceutical chaperone (migalastat, 1-deoxygalactonojirimycin [DGJ]; Galafold, Amicus Therapeutics) has been approved in Europe since May 2016, in Canada since September 2017, in Japan since March 2018, and in the United States since August 2018 for long-term treatment of FD in adults (≥18 years of age in United States and Canada, ≥16 years in other countries) for patients with an amenable mutation and an estimated glomerular filtration rate (eGFR) ≥30 mL/min per 1.73 m 2 . Amenability, which means the response in terms of increasing enzymatic activities of an AGAL mutation to migalastat, is currently being tested in a cell culture-based good laboratory practice (GLP) assay.…”