The proof-of-concept clinical study has been designed as a single center, double-blind, randomized, placebo-controlled, crossover study in 25 patients affected by a specific CF mutation (delF508). As a primary endpoint the study 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 study to become available at the end of 2008. These results, if positive, will determine the need, size and duration of future studies.

Jean-Paul Clozel, MD and Chief Executive Officer, commented: ”Actelion’s decision to engage in Cystic Fibrosis with miglustat reinforces the company’s commitment to rare genetic diseases with significant unmet medical needs. It also reflects our interest to fully explore the potential of the unique pharmacological properties of miglustat for new indications.”

Details about the clinical proof-of-concept study can be found on: http://trials.actelion.com or http://www.clinicaltrials.gov/

About Cystic Fibrosis

Cystic Fibrosis is an autosomal recessive genetic disorder that leads to a multi-system organ dysfunction; it is the most common fatal genetic disorder in the Caucasian population [1]. CF involves all epithelial cells, and classically impacts the lungs, sinuses, pancreas, liver/bile ducts, intestines, reproductive tract, bones, and sweat glands. The most serious consequence of CF is respiratory disease. Due to mucus hyperviscosity, individuals with CF develop chronic lung infections, leading to chronic inflammation and lung scarring. Progressive lung dysfunction is the most significant cause of morbidity and mortality with a median survival age of approximately 30 years. Current therapy for CF involves mucolytics, antibiotics to prevent bacterial colonization and lung infection, and nutritional management [2]. 

CF is caused by functional defects of the CFTR protein, a chloride channel that controls ion and water content in epithelial cells. A large number of mutations can affect the CFTR protein, delF508 being the most frequent one. The delF508 mutation gives rise to a CFTR protein that retains some function, but which is not transported properly to the plasma membrane. As a result, ion and water movements through the epithelial cell membrane are abnormal, causing mucus hyperviscosity.

About miglustat and Cystic Fibrosis

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 CFTR protein to the plasma membrane and thus to restore its function [3]. In addition, correction of the delF508 trafficking by miglustat was associated with the normalization of Ca²⁺ homeostasis and mobilization in CF cells [4]. 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.

About Zavesca^® (100 mg miglustat) and type 1 Gaucher disease

Zavesca^® (100 mg miglustat) is indicated for the oral treatment of mild to moderate type 1 Gaucher Disease. Zavesca^® may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable. It is approved in the European Union, United States, Canada, Switzerland, Brazil, Australia and Israel.

Zavesca^® safety information

Gastrointestinal events, mainly diarrhea, have been observed in more than 80% of patients treated with Zavesca^®, ei ther at the onset of treatment or intermittently during treatment. The majority of cases is mild and is expected to resolve spontaneously on therapy. In clinical practice, diarrhea has been observed to respond to diet modification (reduction of lactose and other carbohydrate intake), to taking Zavesca^® away from meals, and/or to anti-diarrheal medication such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Zavesca^® has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease and CF.

Peripheral neuropathy has been reported in type 1 Gaucher patients treated with Zavesca^®. Patients should undergo a neurological exam at the start of treatment and regularly thereafter. Zavesca^® should be reassessed in patients who develop symptoms of peripheral neuropathy. Zavesca^® may cause fetal harm if administered to a pregnant woman and is contraindicated in women who are or who may become pregnant; patients should be apprised of the potential hazard to the fetus. There is a risk of impaired fertility in men. Men should maintain reliable contraceptive methods and not plan to conceive while taking Zavesca^® and for three months thereafter.

There are no safety data on miglustat in CF patients.

References

1.    Ratjen F and Döring G (2003) Cystic fibrosis. Lancet 361: 681–689.

2.    Norez C, Noel S, Wilke M, Bijvelds M, Jorna H, Melina P, de Jonge H and Becq F (2006) Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the α-glucosidase inhibitor miglustat. FEBS Letters 580(8): 2081-2086.

3.    Antigny F, Norez C, Becq F and Vandebrouck C (2007) Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR. Cell Calcium (Epub ahead of print).

4.    Zeitlin PL (2007) Emerging drug treatments for cystic fibrosis. Expert Opin Emerg Drugs 12(2): 329-336.

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer^®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer^® through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Tracleer^® is commercially available in 35 countries worldwide. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium – the single layer of cells separating every blood vessel from the blood stream. Actelion’s over 1,500 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SWX Swiss Exchange (ticker symbol: ATLN).

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