Gaucher disease, a rare disorder, is caused by inherited deficiency of the
enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started
therapy during a prolonged period when there were essentially no alternatives to
imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence.
OBJECTIVES: Two authors independently assessed the risk of bias in the included studies, and extracted relevant data.
MAIN RESULTS: Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum
biomarkers (
chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to
enzyme replacement therapy of previously untreated individuals with
type 1 Gaucher disease. Two studies investigated maintenance
enzyme replacement therapy in people with stable
type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction
therapy, enzyme replacement therapy and a combination thereof as maintenance
therapy in people with
type 1 Gaucher disease previously treated with
enzyme replacement therapy. One study examined substrate reduction
therapy in people with chronic neuronopathic (
type 3) Gaucher disease who continued to receive
enzyme replacement therapy.Treatment-naïve participants had similar increases in haemoglobin when comparing those receiving
imiglucerase or
alglucerase at 60 units/kg,
imiglucerase or velaglucerase alfa at 60 U/kg,
taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for
imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of
taliglucerase alfa, and when comparing
imiglucerase to
alglucerase. Spleen and liver volume reductions were not significantly different in any
enzyme replacement therapy product or dose comparison study. Although a dose effect on serum
biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two
enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose.A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment.There are, as yet, no randomized trials of substrate reduction
therapy in treatment-naïve patients that can be evaluated.
Miglustat monotherapy appeared as effective as continued
enzyme replacement therapy for maintenance of hematological, organ and
biomarker responses in people with
type 1 Gaucher disease previously treated with
imiglucerase for at least two years. In those with neuronopathic
Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when
enzyme replacement therapy was augmented with
miglustat.One randomized controlled study assessing substrate reduction
therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review.
AUTHORS' CONCLUSIONS: The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic
rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate
biological response parameters.
Enzyme replacement therapy given at 30 to 45 units/kg
body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for
rare diseases such as
type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in
Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety - with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this
chronic condition.