Miglustat (Zavesca®) is a low-molecular-weight inhibitor of glucosylceramide synthase and α-glucosidase. Zavesca® (100 mg miglustat) is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease, and may only be used in those patients for whom enzyme replacement therapy is unsuitable. It is approved for this indication in 37 countries including the US and EU since 2003. Zavesca® is also approved in the EU for the treatment of progressive neurological manifestations in adult and pediatric patients with Niemann-Pick type C disease.

Current status
In 2008, Actelion initiated a Phase IIa proof-of-concept clinical trial with miglustat in cystic fibrosis (CF). It is the first time that miglustat has been 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 15 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.

The proof-of-concept study with miglustat in cystic fibrosis has concluded and Actelion is currently analyzing study results.

Available data
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 chloride channel function. In addition, miglustat was able to normalize Ca2+ homeostasis and the ENaC Na+ channel activity in delF508 CFTR 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.

Milestones
2007 - Phase IIa proof-of-concept study initiated
2006 - First publication demonstrating the effects of miglustat in delF508 CF cells
2024 - Use-patent expiry

Key scientific literature
Antigny F., Norez C., Becq F. and Vandebrouck C. Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR. Cell Calcium. 43, 175-83; 2008.

Dechecchi M.C., Nicolis E., Norez C., Bezzerri V., Borgatti M., Mancini I., Rizzotti P., Ribeiro C.M., Gambari R., Becq F. and Cabrini G. Anti-inflammatory effect of miglustat in bronchial epithelial cells. J. Cyst. Fibros. 7, 555-65; 2008. 

Noel S., Wilke M., Bot A., De Jonge H. and Becq F. (2008). Parallel improvement of sodium and chloride transport defects by miglustat in cystic fibrosis epithelial cells. J. Pharmacol. Exp. Ther. 325:1016-23; 2008.

Norez C., Noel S., Wilke M., Bijvelds M., Jorna H., Melin P., DeJonge H. and Becq F. Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. FEBS Lett. 508, 2081-86; 2006.

Ratjen F. and Döring G. Cystic fibrosis. Lancet. 361, 681-89; 2003