About Miglustat

Miglustat is a low-molecular weight inhibitor of glucosylceramide synthase and glucosidase. With its unique physico-chemical properties miglustat exhibits a large volume of distribution and has the capacity to access deep organs such as brain, bone and lung.

Miglustat in Type 1 Gaucher Disease

Current Status

The MAINTENANCE trial is evaluating the long-term safety and efficacy of miglustat as maintenance therapy after a switch from enzyme replacement therapy (ERT) in mild-to-moderate adult Type 1 Gaucher (GD1) patients with stable disease. Patient recruitment for the MAINTENANCE trial is ongoing.

Supporting Studies

Zavesca® (miglustat 100 mg) is the only oral drug available for the treatment of GD1; the product was approved on the basis of three international open-label clinical trials. The rationale for the use of miglustat in GD1 is to help balance the overall level of glucosylceramide by reducing its production to a level compatible with breakdown by residual glucocerebrosidase activity, a unique mode of action known as "substrate reduction therapy". Recently, results from a pooled analysis of the three open-label clinical trials have shown that miglustat monotherapy may reduce the incidence of bone pain and improve bone mineral density in GD1 patients, including those with a high risk of bone loss - such as splenectomized and osteoporotic patients (Pastores et al, Clin. Ther. 2007 29, 1645-1654).

Miglustat in Cystic Fibrosis

Current Status

In October 2007, Actelion initiated a Phase IIa proof-of-concept clinical trial with miglustat in cystic fibrosis (CF). It is the first time that miglustat is being tested in a clinical setting involving CF patients. The proof-of-concept clinical trial has been designed as a single center, double-blind, randomized, placebo-controlled, crossover study in 25 CF patients affected by the specific delF508 mutation. As a primary endpoint, the trial will investigate the effect of miglustat on the nasal potential difference, a sensitive and non-invasive functional test for the cystic fibrosis transmembrane conductance regulator (CFTR). Defects of CFTR are responsible for the characteristic morbidities of the disease.

Actelion expects full results of this proof-of-concept clinical trial to become available at the end of 2008. These results, if positive, will determine the need, size and duration of future studies.

Supporting Studies

Preclinical studies, performed by Dr. F. Becq (CNRS, Université de Poitiers, France) have shown that miglustat is able to correct the transfer of the mutated delF508 CFTR protein to the plasma membrane and thus to restore its function. In addition, miglustat was able to normalize Ca2+ homeostasis and ENaC activity in CF cells, and to reduce the inflammatory response in bronchial epithelial cells. These observations suggest that using a pharmacological agent such as miglustat to restore the trafficking of delF508 could improve not only the chloride channel activity of CFTR but also other CFTR-dependent cellular functions.

Miglustat in Niemann-Pick disease type C

Current Status

In February 2008, Actelion has taken the decision to withdraw the application for the extension of indication on the use of miglustat (Zavesca®) for the treatment of progressive neurological manifestations in patients with Niemann-Pick type C disease (NP-C). This decision was taken following an oral explanation with the European Committee for Medicinal Products for Human Use (CHMP) and Actelion is currently evaluating its options to resubmit an application at a later stage.  At that point in time, new, relevant data from an ongoing survey of NP-C patients treated with miglustat could be provided in order to support an extension of indication.