Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Piramal Critical Care Limited, Suite 4, Ground Floor, Heathrow Boulevard East Wing, 280 Bath Road, West Drayton, UB7 0DQ, United Kingdom
Pharmacotherapeutic group: Other alimentary tract and metabolism products
ATC Code: A16AX06
Gaucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramide resulting in lysosomal storage of this material and widespread pathology. Miglustat is an inhibitor of glucosylceramide synthase, the enzyme responsible for the first step in the synthesis of most glycolipids. In vitro, glucosylceramide synthase is inhibited by miglustat with an IC50 of 20-37 µM. In addition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstrated experimentally in vitro. The inhibitory action on glucosylceramide synthase forms the rationale for substrate reduction therapy in Gaucher disease.
The pivotal trial of miglustat was conducted in patients unable or unwilling to receive ERT. Reasons for not receiving ERT included the burden of intravenous infusions and difficulties in venous access. Twenty-eight patients with mild to moderate type 1 Gaucher disease were enrolled in this 12-month non-comparative study, and 22 patients completed the study. At 12 months, there was a mean reduction in liver organ volume of 12.1% and a mean reduction in spleen volume of 19.0%. A mean increase in haemoglobin concentration of 0.26 g/dl and a mean platelet count increase of 8.29 L 109/l were observed. Eighteen patients then continued to receive miglustat under an optional extended treatment protocol. Clinical benefit has been assessed at 24 and 36 months in 13 patients. After 3 years of continuous miglustat treatment, mean reductions in liver and spleen organ volume were 17.5% and 29.6%, respectively. There was a mean increase of 22.2 L 109/l in platelet count, and a mean increase of 0.95 g/dl in haemoglobin concentration.
A second open, controlled study of miglustat randomised 36 patients who had received a minimum of 2 years of treatment with ERT, into three treatment groups: continuation with imiglucerase, imiglucerase in combination with miglustat, or switch to miglustat. This study was conducted over a 6-month randomised comparison period followed by 18 months extension where all patients received miglustat monotherapy. In the first 6 months in patients who were switched to miglustat, liver and spleen organ volumes and haemoglobin levels were unchanged. In some patients there were reductions in platelet count and increases in chitotriosidase activity indicating that miglustat monotherapy may not maintain the same control of disease activity in all patients. 29 patients continued in the extension period. When compared to the measurements at 6 months, disease control was unchanged after 18 and 24 months of miglustat monotherapy (20 and 6 patients, respectively). No patient showed rapid deterioration of type 1 Gaucher disease following the switch to miglustat monotherapy.
A total daily dose of 300 mg miglustat administered in three divided doses was used in the above two studies. An additional monotherapy study was performed in 18 patients at a total daily dose of 150 mg, and results indicate reduced efficacy compared to a total daily dose of 300 mg.
An open-label, non-comparative, 2-year study enrolled 42 patients with type 1 Gaucher disease, who had received a minimum of 3 years of ERT and who fulfilled criteria of stable disease for at least 2 years. The patients were switched to monotherapy with miglustat 100 mg t.i.d. Liver volume (primary efficacy variable) was unchanged from baseline to the end of treatment. Six patients had miglustat treatment prematurely discontinued for potential disease worsening, as defined in the study. Thirteen patients discontinued treatment due to an adverse event. Small mean reductions in haemoglobin [-0.95 g/dL (95% CI: -1.38, -0.53)] and platelet count [-44.1 × 109/L (95% CI: -57.6, -30.7)] were observed between baseline and end of study. Twenty-one patients completed 24 months of miglustat treatment. Of these, 18 patients at baseline were within established therapeutic goals for liver and spleen volume, haemoglobin levels, and platelet counts, and 16 patients remained within all these therapeutic goals at Month 24.
Bone manifestations of type 1 Gaucher disease were evaluated in 3 open-label clinical studies in patients treated with miglustat 100 mg t.i.d. for up to 2 years (n = 72). In a pooled analysis of uncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased by more than 0.1 units from baseline in 27 (57%) and 28 (65%) of the patients with longitudinal bone density measurements. There were no events of bone crisis, avascular necrosis or fracture during the treatment period.
Niemann-Pick type C disease is a very rare, invariably progressive and eventually fatal neurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurological manifestations are considered secondary to the abnormal accumulation of glycosphingolipids in neuronal and glial cells.
Data to support safety and efficacy of Yargesa in Niemann-Pick type C disease come from a prospective open-label clinical trial and a retrospective survey. The clinical trial included 29 adult and juvenile patients in a 12-month controlled period, followed by extension therapy for an average total duration of 3.9 years and up to 5.6 years. In addition 12 paediatric patients were enrolled in an uncontrolled substudy for an overall average duration of 3.1 years and up to 4.4 years. Among the 41 patients enrolled in the trial 14 patients were treated with Yargesa for more than 3 years. The survey included a case series of 66 patients treated with Yargesa outside of the clinical trial for a mean duration of 1.5 years. Both data sets included paediatric, adolescent and adult patients with an age range of 1 year to 43 years. The usual dose of Yargesa in adult patients was 200 mg t.i.d., and was adjusted according to body surface area in paediatric patients.
Overall the data show that treatment with Yargesa can reduce the progression of clinically relevant neurological symptoms in patients with Niemann-Pick type C disease.
The benefit of treatment with Yargesa for neurological manifestations in patients with Niemann-Pick type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re- appraised after at least 1 year of treatment with Yargesa, (see section 4.4).
Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number of patients with type 1 Gaucher disease, Fabry disease, HIV-infected patients, and in adults, adolescents and children with Niemann-Pick type C disease or type 3 Gaucher disease.
The kinetics of miglustat appear to be dose linear and time independent. In healthy subjects miglustat is rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolute bioavailability has not been determined. Concomitant administration of food decreases the rate of absorption (Cmax was decreased by 36% and tmax delayed 2 hours), but has no statistically significant effect on the extent of absorption of miglustat (AUC decreased by 14%).
The apparent volume of distribution of miglustat is 83 l. Miglustat does not bind to plasma proteins. Miglustat is mainly eliminated by renal excretion, with urinary recovery of unchanged drug accounting for 70-80% of the dose. Apparent oral clearance (CL/F) is 230 ± 39 ml/min. The average half-life is 6-7 hours.
Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in faeces. Several metabolites were identified in urine and faeces. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 h suggesting the presence of one or more metabolites with very long half-life. The metabolite accounting for this has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state.
The pharmacokinetics of miglustat is similar in adult type 1 Gaucher disease patients and Niemann-Pick type C disease patients when compared to healthy subjects.
Pharmacokinetic data were obtained in paediatric patients with type 3 Gaucher disease aged 3 to 15 years, and patients with Niemann-Pick type C disease aged 5-16 years. Dosing in children at 200 mg t.i.d. adjusted for body surface area resulted in Cmax and AUC values which were approximately twofold those attained after 100 mg t.i.d. in type 1 Gaucher disease patients, consistent with the doselinear pharmacokinetics of miglustat. At steady state, the concentration of miglustat in cerebrospinal fluid of six type 3 Gaucher disease patients was 31.4-67.2% of that in plasma.
Limited data in patients with Fabry disease and impaired renal function showed that CL/F decreases with decreasing renal function. While the numbers of subjects with mild and moderate renal impairment were very small, the data suggest an approximate decrease in CL/F of 40% and 60% respectively, in mild and moderate renal impairment (see section 4.2). Data in severe renal impairment are limited to two patients with creatinine clearance in the range 18-29 ml/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment.
Over the range of data available, no significant relationships or trends were noted between miglustat pharmacokinetic parameters and demographic variables (age, BMI, gender or race).
There are no pharmacokinetic data available in patients with liver impairment, in children or adolescents with type 1 Gaucher disease or in the elderly (>70 years).
The main effects common to all species were weight loss and diarrhoea, and, at higher doses, damage to the gastrointestinal mucosa (erosions and ulceration). Further effects seen in animals at doses that result in exposure levels similar to or moderately higher than the clinical exposure level were: changes in lymphoid organs in all species tested, transaminase changes, vacuolation of thyroid and pancreas, cataracts, nephropathy and myocardial changes in rats. These findings were considered to be secondary to debilitation.
Administration of miglustat to male and female Sprague-Dawley rats by oral gavage for 2 years at dose levels of 30, 60 and 180 mg/kg/day resulted in an increased incidence of testicular interstitial cell (Leydig cell) hyperplasia and adenomas in male rats at all dose levels. The systemic exposure at the lowest dose was below or comparable to that observed in humans (based on AUC0-lJ) at the recommended human dose. A No Observed Effect Level (NOEL) was not established and the effect was not dose dependent. There was no drug-related increase in tumour incidence in male or female rats in any other organ. Mechanistic studies revealed a rat specific mechanism which is considered to be of low relevance for humans.
Administration of miglustat to male and female CD1 mice by oral gavage at dose levels of 210, 420 and 840/500 mg/kg/day (dose reduction after half a year) for 2 years resulted in an increased incidence of inflammatory and hyperplastic lesions in the large intestine in both sexes. Based on mg/kg/day and corrected for differences in faecal excretion, the doses corresponded to 8, 16 and 33/19 times the highest recommended human dose (200 mg t.i.d.). Carcinomas in the large intestine occurred occasionally at all doses with a statistically significant increase in the high dose group. A relevance of these findings to humans cannot be excluded. There was no drug-related increase in tumour incidence in any other organ.
Miglustat did not show any potential for mutagenic or clastogenic effects in the standard battery of genotoxicity tests.
Repeated-dose toxicity studies in rats showed effects on the seminiferous epithelium of the testes. Other studies revealed changes in sperm parameters (motility and morphology) consistent with an observed reduction in fertility. These effects occurred at exposure levels similar to those in patients, but showed reversibility. Miglustat affected embryo/foetal survival in rats and rabbits, dystocia was reported, post- implantation losses were increased, and an increased incidence of vascular anomalies occurred in rabbits. These effects may be partly related to maternal toxicity.
Changes in lactation were observed in female rats in a 1-year study. The mechanism for this effect is unknown.
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