20 years of real-world evidence data for fabry disease – Organised by SANOFI GENZYME

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Sima Canaan-Kühl, Germany

2021 marks the twentieth anniversary of the approval of agalsidase-beta as a treatment for Fabry disease, as pointed out in her introduction by Sima Canaan-Kühl, Charité Berlin, who chaired the symposium. Over the last twenty years, considerable insights into the disease’s variability have been gained, and recommendations and guidelines have been published. However, there are still some burning questions, such as how to further optimize treatments and outcomes, or how to improve the diagnosis of patients at an early age.

Optimization of fabry disease patients management after more than 20 years of clinical experience

Camilla Tøndel, Norway

As Camilla Tøndel, Bergen, Norway, pointed out in her talk, many achievements have been made, indeed. Before 2001, there was no effective Fabry treatment at all, which meant that many affected families had no hope. She reported on two brothers (13 and 14 years of age) who were her first Fabry patients back in 2001, whom she treated with enzyme replacement therapy with great success. Over a period of weeks, not only did their Gb3 levels drop significantly, but also their clinical conditions improved, especially their GI problems and pain. In 2008, Tøndel and colleagues published a kidney biopsy study that included the two brothers. Both biopsies showed significant pathology, but although the patients had normal albuminuria levels at the beginning of the study, both patients developed microalbuminuria after two years.

The doctors doubled the dose of agalsidase alfa, which resulted in substantial clearance of podocyte inclusions. After seven years of treatment (five years after the baseline biopsy), the younger brother had been switched to full-dose agalsidase beta due to sinus arrest and his need for a pacemaker, whereas the older one stayed on double-dose agalsidase alfa. After 14 years. a dose-dependant effect on kidney histology was seen between the brothers, although it still did not translate into functional parameters. The younger brother underwent another biopsy 17 years after treatment initiation, and it showed no fibrosis, but healthy kidney tissue.

In a study presented at the ERA-EDTA Congress, Camilla Tøndel showed for six classical male Fabry patients that the initiation of ERT at a relatively young age may clear long-lived kidney cells of Gb3 and protect the kidneys from significant functional loss over a very long period. Another important insight was that the reduction of Gb3 in podocytes is higher on a high dose compared to a low dose of agalsidase. In a study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, unbiased quantitative morphometric electron microscopic studies were performed on biopsied kidney samples from patients and seven living transplant donors (serving as controls). Here again, it was found that GL3 accumulation was associated with podocyte injury and loss. The study indicates that podocyte injury and loss play an important role in the progression of Fabry nephropathy. As Camilla Tøndel concluded, it is therefore very important to start therapy early enough in the process.

However, this requires early diagnosis, which is increasingly achieved nowadays, compared to 20 years ago, when patients were often not diagnosed with Fabry disease until severe symptoms developed – although there are still exceptions.

Asked about the main biomarkers for monitoring patients, Camilla Tøndel pointed out that renal biopsy is an invasive procedure, but provides important insights and should be performed in patients every few years. In the intervals between biopsies, she recommended that attention be paid to three non-invasive biomarkers, in particular. Firstly, the albumin-creatinin-ratio as a general biomarker. Secondly, she emphasised that GFR should be measured from time to time, because in contrast to eGFR it is a biomarker that is independent of muscle mass. She pointed out that eGFR may be misleading in children in puberty. The third biomarker she recommended was lyso-GL3: “We see podocytes in the urine and we see a reduction of podocytes in the urine after treatment. That is very interesting as a biomarker, but many centres do not have that yet.”

Lessons learned after two decades of fabry disease treatment

Alberto Ortiz, Spain

Before Alberto Ortiz, Madrid, Spain, gave an overview of treatment options, he reminded the audience that Fabry disease affects many more men than women, and that one has to differentiate between classic Fabry disease, in which the endothelium is full of glycolipids, and late-onset Fabry disease, in which there are no glycolipids in the endothelium. The conclusions Alberto Ortiz drew were that (1) the female population may not be best for assessing glycolipid deposits and (2) that patients with late-onset disease may not be best for assessing endothelial deposits.

Alberto Ortiz pointed out that there are phase 2 and phase 3 studies on agalsidase alfa and phase 3 studies on agalsidase beta, as well as a 5-year extension study and a 10 year follow-up, which assessed endothelial Gb3 deposits and/or pain as primary endpoints, and a phase 4 study which studied the event rate as the primary endpoint. In all these trials, most of the patients were males. Furthermore, it was shown that agalsidase beta was more effective in reducing endothelial Gb3 deposits in phase 2/3 studies, although Alberto Ortiz acknowledged that the endothelial findings may not apply to podocytes.

The Canadian Fabry Disease Initiative (CFDI) conducted a head-to-head comparison between agalsidase alfa (0.2 mg /kg EOW) and agalsidase beta (1 mg /kg EOW) with a follow-up of ten years and thus assessed the long-term impact of enzyme replacement therapy (ERT). The primary endpoints were renal, cardiac and neurological events. Unfortunately, the study was underpowered (132 patients were enrolled, 600 had been planned for enrolment) and therefore was unable to show any statistically valid significance. However, the most common events were renal events (renal replacement therapy, doubling of serum creatinine, and proteinuria > 3.5 g/day) in males – and in this subgroup a highly significant effect became obvious. Agalsidase beta was more effective in reducing renal events (p=0.006). As Ortiz pointed out, this result is quite plausible from the biological perspective as well, because agalsidase beta had a greater impact in terms of reducing endothelial deposits than agalsidase alfa in placebo-controlled trials. It also has an effect on lyso-Gb3, which is also known to be pathogenic.

For migalastat, in contrast, there have only been two phase 3 trials with renal endpoints so far, but no long-term data or head-to-head comparisons. Moreover, most of the patients in these studies were female, and interpreting data on female patients is known to be difficult when it comes to Fabry disease. Although some women may progress to the point where they need dialysis, they are simply not the majority of female patients, so it is more difficult to identify the effects of treatment.

Alberto Ortiz then presented real-world data showing that more than 50% of male patients with classic disease are treated with agalsidase beta.

An analysis of Fabry Registry data from 2016 provided further information on the incidence of severe clinical events over time for adult patients treated with agalsidase beta. It was shown that the incidence rate for severe clinical events decreases after the first 6 months of treatment, although the median age at which agalsidase beta therapy was started was 40 years, which was quite late. Alberto Ortiz pointed out that even older patients benefit from the treatment, although the treatment is more effective when started earlier.

Further reading


Najafian B et al. Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss.J ASN April 2020, 31 (4) 865-875

Schiffmann R et al. Enzyme Replacement Therapy in Fabry Disease. A Randomized Controlled Trial. JAMA. 2001;285(21):2743-2749

Ortiz A et al. Diagnosis and treatment of Fabry disease. Med Clin (Barc) 2017 Feb 9; 148(3):132-138.

Sirrs SM, Bichet DG, Casey R, Clarke JT, Lemoine K, Doucette S, West ML. CFDI investigators. Outcomes of patients treated through the Canadian Fabry disease initiative. Mol Genet Metab 2014;111:499–506.

Arends M et al. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet 2018; 55: 351-8

Ortiz A et al. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry. J Med Genet 2016; 53: 495-502