The substrate is down: is the IV out?

The effectiveness of a new substrate reduction agent (eliglustat tartrate) in the initial treatment of patients with type 1 Gaucher disease (GD) is described in this issue of Blood by Lukina and colleagues.¹  The hope is that this finding will lead to the first efficacious oral therapy for GD.

The discovery of the nature of the enzyme deficiency in GD²  led to the production of an extracted placental-derived enzyme and then recombinant enzyme. The therapeutic application of these products, first reported in 1991, has become the standard of care for GD patients and has resulted in major benefits for large numbers of patients around the world.³  The benefits include improvements in hemoglobin and platelet counts, reduction in size of organs enlarged by infiltration by glucosylceramide-laden macrophages (liver and spleen), and improvement in bone marrow infiltration and secondary skeletal effects. Very few patients are intolerant of enzyme replacement therapy but the need for intravenous infusions every 2 weeks for life is both daunting and logistically difficult. An alternate approach to reducing the accumulation of ceramide is to interrupt the pathway of synthesis. The first approved molecule using this approach was miglustat (Zavesca), which was shown to have activity in a majority of patients in small studies and has resulted in its marketing for adult patients for whom enzyme replacement is “not an option.” This agent has had only limited application internationally because of concerns about toxicity and efficacy. Results of a maintenance study have been published⁴  and a further maintenance study has recently been completed, follow-up with results forthcoming.

This report of a multinational phase 2 study in 26 previously untreated patients with type 1 (nonneuronopathic) GD treated with eliglustat, a newer substrate reduction agent, showed that a majority of subjects achieved the composite primary endpoint for efficacy. This was most evident in reduction of liver and spleen size (22 patients of 26 at risk) and an increase in hemoglobin (9 of 10 at risk) and platelet count (16 of 25 at risk). Meaningful and sustained improvements in the recognized biomarkers of disease activity, chitotriosidase and CCL18, were also observed and improvement in bone density Z and T scores in the lumbar spine (but not the femur) occurred. Bone marrow infiltration and areas of infarction were apparently stable except in 1 patient with progressive infarction. This most important complication of GD requires further evaluation as improvement with enzyme replacement has been reported to take years in some patients.⁵  Unlike miglustat, neither intolerance nor neurologic effects such as tremor or peripheral neuropathy was observed and only mild gastrointestinal events were seen in 3 patients. Two patients treated with eliglustat developed asymptomatic cardiac tachyarrhythmias.

Like all studies of extremely rare conditions, the size of the patient population and the lack of a control arm are significant shortcomings of a trial of therapeutics in extremely rare hematologic conditions, although at least one recent example suggests that randomized trials in some rare disorders may be possible, provided suitable short-term endpoints are identified.⁶ 

An oral medication with apparent significant activity in this group of patients with a serious very rare disease would be a welcome addition. Longer-term follow-up in this and other patient populations is required to determine whether the observed effects are sustained and/or bone consequences are improved, and to evaluate the nature and incidence of any long-term toxicities.