Zavesca (miglustat) Results

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Zavesca was discussed by five speakers at the European Working Group on Gaucher Disease meeting in Barcelona on 14-16 October 2004. Zavesca was licensed in November 2002 for the use of patients with mild to moderate Type 1 Gaucher disease for whom enzyme replacement therapy is unsuitable.

A Report on Three Patients

Dr Derralynn Hughes of the Gaucher Clinic at the Royal Free Hospital in London gave her experience of treating three patients suffering from Type 1 Gaucher disease with Zavesca who have poor venous access.

'The Advisory Council to the European Working Group on Gaucher Disease considers that patients with Type 1 Gaucher disease with mild to moderate disease manifestations who are unsuitable for enzyme replacement therapy are eligible for treatment with miglustat (Zavesca). We have three patients who have started taking miglustat after being assessed as unsuitable for enzyme replacement therapy.

'The first patient, a 54 year old male, carrying the N370S mutation with the other mutation unknown, had received enzyme replacement therapy for nine years despite difficulty accessing his veins for infusion. Regular travel outside the UK to visit his family also made enzyme replacement therapy less convenient.

'Flatulence and diarrhoea after starting miglustat treatment ameliorated with reduction of the dose from 100mg three times a day to 100mg twice a day, loperamide (anti-diarrhoea) treatment and introduction of a lactose-free diet. Resumption of miglustat 100mg three times a day after two months was associated with flatulence but not diarrhoea.

'The patient's neurological status and cognitive ability, assessed by the Mini-Mental State Examination, have remained normal since starting treatment. He has recently stopped Zavesca treatment due to having to undergo an operation to remove his appendix.

'The second patient, an 81 year old male, with the genetic mutations N370S/N370S, had persistent problems with infusing enzyme replacement therapy due to a tremor associated with Parkinson's syndrome. After six weeks of miglustat, 100 mg three times a day, his chitotriosidase levels remained stable and his neurological status was unchanged.

'The third patient, a 23 year old female, with the genetic mutations D409H/N370S, had her spleen removed eight years ago. She had frequent problems with self-infusions of enzyme replacement therapy due to poor vein access. At the start of taking oral miglustat, her full blood count was normal. Her chitotriosidase levels, which reduced from over 25,000 to 2,756 nmol/hr/ml after seven years of enzyme replacement therapy were 2,854 nmol/hr/ml after four months of treatment with miglustat, 100 mg three times a day. Occasional diarrhoea during the first month of miglustat treatment resolved spontaneously while dyspepsia (indigestion) reported at the two month follow-up responded satisfactorily to lansoprozole treatment. She has subsequently stopped taking Zavesca as she wants to become pregnant.

'In addition two more patients have recently started Zavesca treatment.'


Dr Rene Heitner, who runs the Gaucher Clinic at the Johannesburg Hospital in South Africa, reported on a young woman who was taking miglustat when she became pregnant. She subsequently had a healthy child. 'Embryo-foetal toxicity studies on animals have not demonstrated any impact on development of new-borns but an increase in pre- and post-implantation loss and reduction in rabbit litter weight. However, the potential risks in human pregnancy are unknown, leading the contra-indication of miglustat during pregnancy.

'I would like to report a case of pregnancy started while the patient was on miglustat and its outcome. The woman with Type 1 Gaucher disease was aged 32 and treated with miglustat, 100mg three times a day, in a clinical trial. After 2½ years without drug interruption, she presented with a migraine and investigation led to the diagnosis of a nine week pregnancy. Miglustat was immediately discontinued. She was counselled with respect to termination of the pregnancy but declined this option.

'She subsequently had a normal pregnancy and was delivered at term by caesarean section. The baby was a healthy female weighing 2.27 kg with no abnormalities noted. The baby has since been closely monitored and at 14 months was completely well with normal physical and neurological examinations. Her mother has since resumed treatment with miglustat.

'Despite this single case with a favourable outcome, and in view of the preclinical data available today, pregnancy remains contraindicated with miglustat.'

Bone Marrow Improvement

Dr Carla Hollak reported the beneficial effects of Zavesca in two female patients with Type 1 Gaucher disease at the Academic Medical Center in Amsterdam, where they have been followed for more than five years and are the longest treated patients with Zavesca so far.

'Bone marrow involvement was assessed every 12 months using an MRI technique for measuring the displacement of fatty marrow by Gaucher cells. Low bone marrow fat has been found in patients with Gaucher disease and reflects the degree of infiltration with Gaucher cells.

'The two patients have received Zavesca continuously for more than five years. The first patient had mild enlargement of the spleen and liver, had a low platelet count and bruised easily at the start of treatment. The second patient had a splenectomy and complete bilateral hip prostheses (two total hip replacements) 25 years ago. She also suffered from mild anaemia and fatigue.

'Both patients showed gradual reduction in the size of their livers and in the first patient who still had her spleen, this also reduced in size. Their platelet counts increased and chitotriosidase levels decreased over time.

'With respect to bone marrow involvement, the first patient showed a progressive improvement in fat content in her bone marrow over six years with a trend towards the normal range indicating the clearance of storage cells from the bone marrow. The second patient, with very severe bone disease, showed an improvement until her third year of treatment and has remained stable until now.

General improvement

Dr Greg Pastores, who runs a Gaucher Clinic at the NYU School of Medicine in New York, reported on his experience with miglustat (Zavesca) in symptomatic Type 1 Gaucher disease after 24 months.

He said: 'We enrolled 14 adult patients with Type 1 Gaucher disease who had an enlarged liver and spleen. They had either discontinued enzyme replacement therapy or never started it. At the start and follow-up at 24 months, in addition to traditional blood and imaging tests, we performed a detailed neurological examination, with assessment of tremor and nerve conduction tests.

'Three patients did not complete the baseline studies or comply with the treatment regimen. Of nine patients, one withdrew at 3 months because of gastrointestinal complaints and another at six months because of a tingling sensation in both hands (neurological examination showed there was no change since before he started the drug).

'Despite the small number of patients (seven), results were consistent with earlier studies; demonstrating stabilisation and improvement in all key clinical Gaucher disease features. By 24 months, decreases were noted in liver and spleen volume and chitotriosidase and platelet levels. There were no clinically significant abnormalities in neurological, neuropsychological or nutritional assessments.

Cognitive Testing

Dr Deborah Elstein of the Gaucher Clinic at the Shaare Zedek Hospital in Jerusalem explained that during the course of clinical trials using Zavesca for adults with Type 1 Gaucher disease, the question of decreased cognitive function was raised. A battery of tests were employed to assess the extent of this observation. Performance in untreated patients was compared with that of patients receiving enzyme replacement therapy and with that of those receiving Zavesca; some repeat measures were taken 12-24 months after the initial testing session.

'All patients performed less well than non-Gaucher patients in sub-tests involving visual-spatial and executive functioning. Zavesca patients appeared to have significantly higher scores than the other groups, particularly in the visual-spatial sub-test. These pre-liminary findings should allay the fears of cognitive dysfunction due to Zavesca and may have ramifications for future indication for the drug. In all the other neurological tests, the results were the same between the different groups.

Dutch patient takes Zavesca for 6½ years

A Dutch woman aged 49 described her symptoms of Gaucher disease at the EWGGD meeting in Barcelona and how she has taken Zavesca for 6½ years.

She was diagnosed when she was five years old when she had to have her spleen removed. She had suffered from bone inflammation as a child and was always tired. She attended a special school in her early teens but after puberty, her condition improved and she was able to attend a secondary school.

However she then had to undergo two hip replacements in her twenties. She stopped work and became disabled but during this time she married and had a daughter. She also suffered from pain in her back and her liver was enlarged. When she was 35 years old, she had to have two revised hip replacements.

She then went to see Dr Carla Hollak, a specialist in Gaucher disease in 1995. She had not wanted to have regular infusions so decided to go on the Zavesca trial. She took and still takes the pill three times a day.

She lost about 3 kilos in weight in the beginning and had some diarrhoea (thin motions) which did not bother her. She says she has never felt so good in her life and is able to work and walk fairly long distances. Her liver has become smaller and she is less tired. She is happy taking Zavesca.

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Source: Gauchers News May 2005.
Copyright © Gauchers Association 2005.