Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers.
This is an update of a Cochrane review first published in 2010, and previously updated in 2013.
To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease.
We searched the Cystic Fibrosis and Genetic Disorders Group’s Inborn Errors of Metabolism Trials Register (date of the most recent search: 08 July 2016). We also searched ‘Clinical Trials’ on The Cochrane Library, MEDLINE, Embase and LILACS (date of the most recent search: 24 September 2015).
Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease.
Data collection and analysis
Two authors selected relevant trials, assessed methodological quality and extracted data.
Nine trials comparing either agalsidase alfa or beta in 351 participants fulfilled the selection criteria.
Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference -1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome in either of the trials.
One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% confidence interval -2.09 to -1.31); heart, mean difference -0.90 (95% confidence interval -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% confidence interval -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.
Only two trials compared agalsidase alfa to agalsidase beta. One of them showed no significant difference between the groups regarding adverse events, risk ratio 0.36 (95% confidence interval 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; (95% confidence interval 0.03 to 2.57).
Two trials compared different dosing schedules of agalsidase alfa. One of them involved three different doses (0.2 mg/kg every two weeks; 0.1 mg/kg weekly and; 0.2 mg/kg weekly), the other trial evaluated two further doses to the dosage schedules: 0.4 mg/kg every week and every other week. Both trials failed to show significant differences with various dosing schedules on globotriaosylceramide levels. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores.
One trial comparing agalsidase alfa to agalsidase beta showed no significant difference for any adverse events such as dyspnoea and hypertension.
The methodological quality of the included trials was generally unclear for the random sequence generation and allocation concealment.
Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease.
Plain language summary
Treatment for Anderson-Fabry disease
Anderson-Fabry disease, a rare disorder, is caused by a deficiency of the enzyme alpha-galactosidase A. This leads to the build-up of a fatty material called globotriaosylceramide in various cells in the body. Globotriaosylceramide is formed of three sugars and a fatty substance called ceramide, and is found in most cells of the body. Untreated individuals may suffer from pain, skin, eye and gastrointestinal problems. Fabry disease may cause potentially life-threatening complications such as kidney damage, heart attack and stroke. One type of treatment available is enzyme replacement therapy with either agalsidase alfa or beta, which replaces the missing or deficient enzyme.
The evidence is current to: 08 July 2016.
Nine studies enrolled 351 participants. The studies used different formulations of the enzyme, Agalsidase alfa or beta, and compared them to placebo (a ‘dummy’ treatment) or to each other. Comparison was also made in regard to different dosing schedules.
Two studies comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma. The combined effects were not significant between the treatment and placebo groups. The study that reported pain and pain-related quality of life showed an improvement for participants receiving treatment over the six-month observation period. Death was not an outcome in either study.
One of the three studies comparing agalsidase beta to placebo reported on globotriaosylceramide and showed improvement in kidney, heart and composite results. There was no significant difference for death and no studies reported on pain.
Only two studies compared agalsidase alfa to agalsidase beta. One of them showed no significant difference for any adverse events such as dyspnoea, hypertension and gastrointestinal symptoms – these are not adverse events as gastrointestinal problems are actually a symptom, as may be hypertension in the context of renal disease.
Two studies compared different dosing schedules of agalsidase alfa. No differences were found among the schedules for self-assessed health state or for pain scores.
In summary, studies comparing enzyme replacement therapy to placebo show significant results in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior, though included trials were small in sample size. With regards to safety, adverse events (i.e., rigors, fever) were more significant with agalsidase beta as compared to placebo.
Quality of the evidence
From the information available in most of the study reports, we were not able to clearly judge whether all volunteers had equal chances of being in either of the treatment groups and whether they would have known in advance or during the study which treatment they were receiving.