Effect of miglustat on bone disease in adult Type 1 Gaucher Disease (GD1): results of a pooled analysis

Reduction of bone pain in more than 80% of the GD1 patients after 2 years miglustat therapy – Improvement in Bone Mineral Density – No new bone crisis or fractures

LONDON – 17 September 2007 – Actelion UK Ltd announces the publication of  "Effect of miglustat on bone disease in adult type 1 Gaucher disease: a pooled analysis of three multinational open label studies" (Pastores et Al) in Clinical Therapeutics, vol 29, number 8, 2007.

This pooled analysis investigates the efficacy of miglustat (Zavesca®) in controlling bone manifestations, such as bone pain, osteopenia and osteoporosis, bone crisis and fractures, in Gaucher Disease type 1 (GD1) patients. The data in this analysis are drawn from the miglustat pivotal studies OGT 918 – 001, 004, 005.

Bone manifestations are considered among the most painful and debilitating components of Gaucher Disease type 1 highly impacting on patients’ quality of life(1)(2). It has been estimated that bone pain occurs in more than half of GD1 patients and that 26% will develop bone crisis (1)(2); in addition GD1 has been shown to affect bone metabolism leading to an increase in bone resorption, which causes a decrease in bone mineral density (BMD), osteopenia and osteoporosis in the majority of the GD1 patients(2).

The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients’ mean (SD) age was 41.2 (13.1) years. The most frequent bone related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41/65 [63%] patients).

This paper, led by Dr. Gregory Pastores, associate professor of neurology and pediatrics at the New York University School of Medicine, has shown that at two years 83% (54/65) of the patients reported no bone pain.  The reductions in bone pain were comparable among all subgroups, including high-risk patients (i.e. splenectomized).  Moreover, there were no new cases of “bone crisis”, osteonecrosis or fracture; BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) (P < 0.001). As early as 6 months after the initiation of miglustat monotherapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [P = 0.012] and 0.21 [P = 0.017], respectively) and 24 months (0.21 [P = 0.015] and 0.18 [P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients (P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006).

Lead investigator Dr Gregory Pastores commented: “Bone disease in patients with Gaucher Disease type1 can be a source of severe debilitation and remains a major management issue.  The beneficial effect of miglustat on bone manifestations and especially on bone pain in these patients might be explained by its wide tissue distribution even in deep organs such as bone and by a direct effect on bone cells.”  

Zavesca® is currently not approved for the treatment of bone manifestations in Gaucher disease type 1.

Notes to Editor

About Gaucher's disease

Gaucher's disease is a rare genetic disorder, which results from reduced activity of glucocerebrosidase, a key enzyme responsible for the metabolism of glycosphingolipids (GSL - a subclass of fats).  Symptoms include enlargement of spleen and liver, bone disease, anaemia, intense fatigue, and in some cases lung involvement.

About Zavesca® in type 1 Gaucher Disease

Zavesca® (Miglustat) is the only oral treatment option approved for adults with type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. It is the first in a 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 the macrophage cells.  Zavesca® is approved and available in the European Union, United States, Canada, Switzerland, Brazil, Australia and Israel.

Zavesca® safety information

Mild-to-moderate tremor was reported in approximately 30% of patients in all Zavesca® trials combined.  Many cases were resolved spontaneously within 1 to 3 months; dose reduction may ameliorate tremor within days;3 patients claimed tremor as one of the reasons for withdrawal from the clinical trials although 1 of these was considered unrelated to Zavesca®.

The most common adverse reactions in Zavesca® trials combined were diarrhoea and weight loss. Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% 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. Weight loss was mild (6%–7% of total body weight); most prevalent in the first year of treatment and stabilized thereafter; no patients claimed weight loss as a reason for withdrawal from the clinical trials
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 foetal 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)   Mankin HJ, Trahan CA, Barnett NA, Laughead J, Bove CM and Pastores GM. A questionnaire study for 128 patients with Gaucher disease. Clin Genet 2006: 69: 209-217

2)   Pastores et al (2004) Effect of miglustat on bone disease in adult type 1 Gaucher disease: A pooled analysis of three multinational open-label studies. Semin Hematol

3)   Charrow J, Dulisse B, Grabowski GA and Weinreb NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet 2007: 71: 205-211
About Actelion UK Pharmaceuticals Ltd

“Actelion” is an independent biopharmaceutical company that focuses on the discovery, development and marketing of innovative drugs for significant unmet medical needs.  Actelion Pharmaceuticals UK & Ireland is a subsidiary of Actelion Ltd, which has its corporate headquarter in Allschwil/Basel, Switzerland.  Actelion markets bosentan (Tracleer®), an orally available dual endothelin receptor antagonist, for pulmonary arterial hypertension and miglusgat (Zavesca®), a small molecule oral therapy for the treatment of type 1 Gaucher disease, both in the UK and Ireland.

Healthcare Republic does not have an editorial influence or input in to these press releases. The views expressed within these documents are not endorsed by Healthcare Republic or Haymarket Medical Publications Limited.

Enquiries should be directed to any contacts listed within the press releases.


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