Ari Zimran

Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis

BACKGROUND Current treatment for Gauchers disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gauchers disease. METHODS We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gauchers referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gauchers disease activity). Patients were started on 100 mg oral OGT 918 three times daily. FINDINGS Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment. INTERPRETATION Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gauchers disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.

Effectiveness of Enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: A report from the Gaucher registry

PURPOSE Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. SUBJECTS AND METHODS Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. RESULTS Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. CONCLUSION Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Gaucher Disease: Clinical, Laboratory, Radiologic, and Genetic Features of 53 Patients

We have reviewed our experiences with the clinical, laboratory, radiologic, and genetic features of 53 patients with Gaucher disease. Most were evaluated during early adult life, with a mean age of 33 years. Our patients were evaluated in a referral center, and therefore the data need to be interpreted with caution when applied to the general patient population, which includes a greater proportion of very mild cases. Thirty-nine patients were Ashkenazi Jews, 13 were non-Jewish and 1 was half-Jewish. The most common presenting symptom was bleeding related to splenomegaly and thrombocytopenia. The chronic symptoms, evaluated an average of 20 years after the diagnosis had been established, were mainly skeletal. Splenectomy had been performed in 43% of our patients and there was no evidence that this procedure accelerated the progression of liver and bone involvement. DNA from the patients was examined for 20 different mutations. The association between the 1226G/1226G genotype and a milder clinical course, and between the 1226G/84GG and 1226/1448C genotypes with more severe clinical manifestations, was confirmed. Repeated follow-up examinations in 29 patients revealed that in the majority of the patients, progression of the disease occurs during childhood, adolescence, or early adulthood with a marked tendency for stabilization thereafter. This observation suggests that Gaucher disease in most of the patients is not a relentless progressive disorder but a rather stable disorder during adulthood. The indications for the newly introduced intravenous enzyme replacement therapy as well as of future experimental treatments should be examined in the light of the natural history of the disease.

A Plant-Derived Recombinant Human Glucocerebrosidase Enzyme—A Preclinical and Phase I Investigation

UNLABELLED Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing. TRIAL REGISTRATION ClinicalTrials.gov NCT00258778.

Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype

Gauchers disease is the most prevalent sphingolipid storage disease, characterised by substantial genetic and phenotypic variability. Cardiac manifestations are rare. We report 12 Arab Gauchers disease patients, 2-20 years of age, who presented with oculomotor apraxia but only slight classic signs of the disease. All but the youngest had calcifications of the aortic or mitral valves or both. All these patients were homozygous for the rare point mutation D409H (1342C). Valvular calcifications increased with age and showed progression during 2 years of follow-up. Two of the oldest patients underwent aortic valve replacement, and one sibling had died suddenly at age 16, before this study, Corneal opacities were another common feature. The potentially fatal course of this Gauchers disease variant, and the availability of a reliable PCR-based method for heterozygote detection, mean that population screening and genetic counselling in the geographic area at risk are important. Affected individuals should be closely monitored by echocardiography to gauge the need for valve replacement. The potential of enzyme replacement to prevent these cardiac complications cannot be ascertained at present, because of the high cost of therapy.

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 β-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.

Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease.

The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients and 342 ERT‐treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD.

Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience

Enzyme replacement therapy is the standard of care for symptomatic Gaucher disease. Velaglucerase alfa is a human beta-glucocerebrosidase produced in a well-characterized human cell line. A 9-month phase 1/2 open-label, single-center trial and ongoing extension study were conducted to evaluate safety and efficacy of velaglucerase alfa. Twelve symptomatic adult type 1 Gaucher patients (intact spleens) received velaglucerase alfa (60 U/kg per infusion) during phase 1/2. An extension study was offered to patients completing the trial; step-wise dose reduction (to 30 U/kg per infusion) was instituted. Eleven patients completed phase 1/2; 10 entered the extension; 9 patients reached 39 months of extension. No drug-related serious adverse events or withdrawals, and no antibodies were observed. Home therapy was successfully implemented during the extension. Statistically significant improvements (P < .004) were noted in mean percentage change from baseline to 9 months and baseline to 48 months for hemoglobin (+19.2%, +21.7%, respectively), platelet counts (+67.6%, +157.8%, respectively), normalized liver volume (-18.2%, -42.8%, respectively), and normalized spleen volume (-49.5%, -79.3%, respectively). These significant clinical changes and safety profile led to phase 3 trials and highlight the potential of velaglucerase alfa as alternative therapy for type 1 Gaucher disease. The extension trial is registered at http://www.clinicaltrials.gov as NCT00391625.

Replacement therapy with imiglucerase for type 1 Gaucher's disease

Gauchers disease, the most common sphingolipidosis, is caused by deficiency of the lysosomal enzyme glucocerebrosidase. Therapy with alglucerase (the placental enzyme) is safe and effective at various dosing regimens. We report the use of low-dose imiglucerase (the recombinant enzyme) at two dosing schedules: 15 u/kg once fortnightly or 2.5 u/kg thrice weekly. Mean reductions in spleen and liver volumes achieved (in all ten patients) by imiglucerase at 12 months were 36.4% and 14.5%, respectively; mean increase in haemoglobin and platelet counts were 13.4% and 25.7%. There were no serious side-effects. No significant differences were observed between the two schedules. Low-dose low-frequency imiglucerase may be an alternative cost-effective approach with satisfactory clinical response and uncompromised quality of life.

Low-dose enzyme replacement therapy for Gaucher's disease: Effects of age, sex, genotype, and clinical features on response to treatment☆

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gauchers disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gauchers disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gauchers disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.