Gaucher disease – eliglustat tartrate
Patients with Gaucher disease have a deficiency of the enzyme β-glucocerebrosidase, which means that glucosylceramide will accumulate in the lysosomes of their cells
Patients with Gaucher disease have a deficiency of the enzyme β-glucocerebrosidase, which means that glucosylceramide will accumulate in the lysosomes of their cells.
There are three forms of the disease – types 1, 2 and 3. Type 1 is the most common, and it does not involve the CNS in the way the other two forms do. The visceral organs are affected in all three forms, particularly the liver, spleen and bones – the spleen and liver typically become very enlarged. Those with the Type 1 form usually have a low level of enzyme activity.
Treatment relies on enzyme replacement therapy with a mannose-terminated recombinant enzyme, which binds to macrophages through mannose receptors and is then trafficked to the lysosomes. It takes some time before the effects are evident – six months for most of the symptoms, but it can be up to two or three years before the skeletal symptoms improve.
A new treatment, miglustat, is an a-glucosidase inhibitor that was first developed for use in HIV patients, but is now licensed for use in patients with Gaucher disease not suited to enzyme replacement as it also exhibits a degree of inhibition against glucosylceramide synthase. However, it frequently causes side- effects, including diarrhoea, abdominal swelling, tremor and weight loss, and the clinical improvements are typically less good and slower than is seen with enzyme replacement. Genzyme’s eliglustat is being developed as a more effective inhibitor.1
In an open label, single arm Phase II trial, 26 patients with type 1 Gaucher disease and splenomegaly plus thrombocytopenia and/or anaemia were given 50 or 100mg oral doses of eliglustat tartrate twice a day, with the dose determined by plasma drug concentrations.2
After 52 weeks, 77% of the patients had an improvement in at least two of these three symptoms, and 91% of the 22 patients who completed the entire 52 weeks of the study. It was well tolerated, with just seven mild and transient adverse events being seen in six patients related to treatment.
Results of this trial after two years have also been reported.3 Continued improvements were seen in the 20 patients who remained in the trial, with statistically significant improvements from baseline being seen in platelet count, haemoglobin level, spleen volume and liver volume. Lumbar spine bone mineral density also increased, and no safety related trends appeared.
references:
1. L. Lee J. Biol. Chem. 1999, 274, 14662
2. E. Lukina et al. Blood 2010, 116, 893
3. E. Lukina et al. Blood 2010, 116, 4095
