Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human ß-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.

Glucocerebrosidase gene mutations in black South Africans with Gaucher disease.

Gaucher disease (GD) is caused by mutations in the glucocerebrocidase gene (GBA) and presents with variable severity. Type 1 is characterized by the lack of neurological symptoms in childhood, whereas types 2 and 3 are early onset neuronopathic forms and result in premature death. Only type 1 GD has been reported in black South Africans and the cases are clinically severe. In this study both GBA mutations were identified in 18/19 black GD patients. Two mutations accounted for 2/3 of all observed disease causing alleles: p.T36del (c.222-224delTAC) (17/38 alleles) and RecNcil (8/38 alleles). Three novel variants were identified and assessed as being likely pathogenic mutations: c.413delC, W357C and D405V. Haplotype analysis supported a single origin for the p.T36del mutation in black South Africans on a haplotype background that is rare in the present population. We hypothesise that the p.T36del results in intracellular mislocalisation of the protein, but confirmation of the altered function of this allele awaits functional studies. A diagnostic test for GD has been implemented for black South Africans.

The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause).

BACKGROUND: The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or imiglucerase-treated females. METHODS: A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. KEY RESULTS: Menarche: May be delayed in girls with GD. Menorrhagia: Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann-Whitney U test: p=0.001). Fertility: There is no evidence of decreased fertility in GD. Pregnancy: Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) chi(2)p=0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) chi(2)p<0.0005): and a reduced risk of Gaucher-related complications during the post partum period (untreated 15/71 (21.1%); treated 3/43 (7%) chi(2)p=0.014). There is no evidence to date of any untoward effect of alglucerase and/or imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or imiglucerase. Menopause: The impact of GD on menopause requires further study especially in relation to bone pathology. CONCLUSIONS: On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period.

South African guidelines for the management of Gaucher disease, 2011.

BACKGROUND: Gaucher disease is an autosomal recessive lysosomal glycosphingolipid storage disorder resulting from a deficiency of lysosomal enzyme acid ß-glucosidase (glucocerebrosidase). This partial enzyme deficiency results in accumulation of glycosphingolipid-laden macrophages (Gaucher cells) throughout the liver, spleen, bone marrow, skeleton, lungs and brain (only in types 2 and 3). OBJECTIVE: These guidelines aim to provide a standard of care for patients with Gaucher disease in keeping with international standards, but also realistic for South Africa, and to provide a shared-care model for treating physicians and funders regarding care for these patients. RECOMMENDATIONS: All healthcare professionals involved in the diagnosis and management of Gaucher disease should take note of and implement these guidelines in clinical practice as far as possible. VALIDATION: These guidelines were developed through consensus by the Lysosomal Storage Disorder Medical Advisory Board. They are largely based on the UK 2005 National Guidelines for Gaucher Disease, but include new treatment recommendations for enzyme replacement therapy based on subsequent publications. The Southern African Society for Human Genetics (SASHG) (who have endorsed the guidelines) and the National Osteoporosis Foundation of South Africa (NOFSA) provided valuable input. GUIDELINES SPONSOR: Genzyme initiated the project and sponsored the meetings of the Advisory Board and all costs generated by these meetings. CONCLUSION: It is intended that these guidelines will enable all patients suffering from Gaucher disease to be diagnosed and offered the best possible care available.

Low-dose N-butyldeoxynojirimycin (OGT 918) for type I Gaucher disease.

The objective of this study was to evaluate the efficacy and safety of low-dose substrate balance therapy with OGT 918 for the treatment of adults with Gaucher disease. Eighteen patients with Gaucher disease from two centers were enrolled in an open-label 6-month study of OGT 918, 50 mg taken three times daily (TID), followed by an optional extended-use phase. Changes in liver and spleen volume at 6 and 12 months, as well as routine hematological and biochemical parameters on a monthly basis, were evaluated. During the extension, dosage was increased to 100 mg TID in patients in one center to improve the response. Seventeen patients completed 6 months; of 16 patients in the extension phase, 13 were evaluable at 12 months. Percentage changes in liver (-5.9%, P = 0.007) and spleen (-4.5%, P = 0.025) volumes and in chitotriosidase levels (-4.6%, P = 0.039) at 6 months were commensurately lower than those reported previously in an open-label trial using 100 mg TID; hemoglobin and platelet counts were not boosted. At 12 months there were further mean decreases from baseline in liver volume (-6.2%, P = 0.037), spleen volume (-10.1%, P < 0.05), and chitotriosidase levels (-15.3%, P < 0.05) as well as mean changes of +1.2 and +14.7% in hemoglobin and platelet concentrations, respectively [correction]. There were no serious adverse effects throughout the 6-month study period; common side effects were diarrhea (94%) and weight loss (67%), comparable to the incidence in the original trial. We conclude that OGT 918 was safe and effective at 50 mg TID, but shows dose dependency in ameliorating parameters of Gaucher disease relative to the results noted in the seminal trial; there was no improvement in the rate of hematological response and no reduction in side effects. Results from the extension wherein some patients were dose increased suggest that 100 mg TID should be the preferred starting regimen for patients with symptomatic type I Gaucher disease.