Actelion Ltd (SWX: ATLN) announced the online publication in "The Lancet Neurology" of the one-year results from a randomized controlled study evaluating safety and efficacy of miglustat (Zavesca®) in patients suffering from Niemann-Pick type C (NP-C) [1]. NP-C is an autosomal recessive genetic disease affecting children, juveniles and adults, characterized by progressive, severe and heterogeneous neurological manifestations, and reduced life expectancy [2].

Horizontal saccadic eye movement (HSEM)-α velocity has improved in miglustat treated juvenile/adult patients versus those receiving standard care; results reached statistical significance when patients taking benzodiazepines, a known confounder, were excluded (p=0.028). Children showed an improvement of HSEM-α velocity of similar magnitude. Improvement in swallowing capacity, stable auditory acuity and a slower deterioration in ambulatory index were observed in juvenile/adult treated patients.

The safety profile in this study evaluating miglustat 200 mg three times daily was consistent with safety information generated with the use of miglustat 100 mg three times daily in patients with type 1 Gaucher disease, particularly with regards to weight loss and gastrointestinal disturbances.

Marc Patterson, M.D., FRACP, Mayo Clinic, Rochester, Minnesota, USA, and Ed Wraith, M.D., FRCPCH, Royal Manchester Children's Hospital, Biochemical Genetic Unit, Manchester, UK commented: "We are encouraged by the 12-month data analysis which provides the first evidence that treatment with miglustat is able to affect the course of the disease in NP-C patients, as shown by stabilization or slowing down of markers of neurological progression. We consider that disease stabilization or slowing of disease progression are worthwhile clinical goals, with or without improvement of function".

These published results, together with the recently analyzed data from the 2-year extension of the study with miglustat in NP-C patients, have served as the basis for a regulatory filing currently under discussion with European Health Authorities; orphan drug designation has already been granted in the EU. The data have not yet been filed with the FDA.

Additional information on the clinical study

The study was carried out in two sites: Columbia University, New York (USA) and The Royal Manchester Children's Hospital (UK). Twenty-nine NP-C patients (>12 years) were randomized to receive either miglustat 200 mg three times daily (n=20) or standard care (n=9) for 12 months. Twelve children under 12 years of age were included in a separate cohort; all received miglustat at the same dosage adjusted for body surface area.

The primary efficacy endpoint of this study was change from baseline in horizontal saccadic eye movement (α), a measure of saccade velocity. This parameter was selected because it is impaired in most NP-C patients. HSEM-α was assessed at screening and month 12, and two assessments were performed at each time point separated by a break of at least one hour. Patients had a general ophthalmologic evaluation before assessment of HSEM to exclude other causes of visual impairment. The local assessors were blinded to the patients' treatment status, whereas data for both study sites were sent to a blinded central assessor for final evaluation.

Twenty-five (86%) of the 29 juvenile/adult patients have completed the 12-month study period, and entered the 12-month extension period, whereas four have discontinued treatment (three in the miglustat group, one in the standard care group). Ten (83%) of the 12 pediatric patients have completed the first 12-month study period, and entered the 12-month extension period, whereas two have discontinued treatment.

Niemann-Pick type C

NP-C is a fatal, recessively inherited neurodegenerative disease primarily affecting children and teenagers, but which can strike at any age. It is caused by a mutation in one of two different genes NPC-1 (the most common) or NPC-2. Over 230 different gene mutations have been identified, many unique to individual patients. These two genes are involved in the trafficking of lipids and other large molecules within the cells - a key process in cellular maintenance.

The intricacies of this complex process are the subject of active research. The symptoms are proportional to the excess storage of cholesterol and glycosphingolipids (GSL) within certain cells in the body, including the brain. NP-C is relentlessly progressive and most patients die within five to ten years of diagnosis. Neurological deterioration is a key feature of the disease and can manifest itself as clumsy movements, impaired balance, slow and slurred speech, difficulty in swallowing, impaired rapid eye movements, hearing loss and seizures. Intellectual decline is universal but may be subtle in the early stages of illness. In the final stages of the disease, affected children and young adults are frequently bedridden, with limited muscle control and intellectual impairment. NP-C is difficult to diagnose owing to the variable age of onset and heterogeneity of the symptoms. There is currently no treatment option approved for this condition.

Substrate Reduction Therapy

Substrate reduction therapy is a novel therapeutic strategy for lysosomal storage diseases that uses reversible inhibitors of glucosylceramide synthase - the first committed step of GSL synthesis - such as miglustat, to diminish GSL accumulation. It is the accumulation of GSL that contributes to neuronal dysfunction and ultimately neuronal death in several areas of the central nervous system.

Miglustat is a small molecule with a large tissue distribution and is orally available; its ability to cross the blood-brain barrier renders miglustat a suitable agent for treating neurological diseases such as NP-C. Administration of miglustat was shown to reduce GSL accumulation in neurons and prolonged survival in murine models of lysosomal storage disorders, including NP-C. In mice and cats with NP-C, miglustat administration resulted in reduced GSL accumulation, delayed onset of neurological dysfunction and increased survival (in mice) [3].

About Zavesca® in type 1 Gaucher Disease

Zavesca® (miglustat 100 mg capsule) is the first oral treatment option for adults with type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. It is the first in a new class of drugs known as substrate reduction therapy. Zavesca® reduces the rate of formation of glucosylceramide, a glycosphingolipid that accumulates in Gaucher disease, to a level that can be cleared by the remaining enzyme, thus preventing the build up of excess glucosylceramide in cells. Zavesca® is approved in the European Union, United States, Canada, Switzerland, Brazil, Australia and Israel.

Zavesca® safety information

Gastrointestinal events, mainly diarrhoea, have been observed in more than 80 per cent of patients treated with Zavesca®, either at the outset of treatment or intermittently during treatment. The majority of cases are mild and are expected to resolve spontaneously on therapy. In clinical practice, diarrhoea 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-diarrhoeal medication such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhoea 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.

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 foetus. 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.


[1] Patterson MC, Vecchio D, Prady H, Abel L and Wraith JE (2007) Miglustat in Niemann-Pick C disease: results of the first 12 months' treatment. Lancet Neurol (online publication).

[2] Review: Vanier MT and Millat (2003) Niemann-Pick disease type C. Clin Genet 64:269-281.

[3] Zervas M, Somers KL, Thrall MA, Walkley SU (2001) Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol 11:1283-1287.

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 and Japan, as well as Canada, Australia and Switzerland. 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 focuses 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).