Mici Phillips

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.

A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.

Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: early Access Program results from Jerusalem.

BACKGROUND Decreased spleen and liver volumes and increased hemoglobin levels and platelet counts usually occur with enzyme replacement therapy (ERT) in symptomatic patients with Gaucher disease. Because of decreased supply of imiglucerase, an FDA-approved Early Access Program (EAP) allowed use of a new, pre-licensed ERT, velaglucerase alfa. This report provides safety and efficacy findings in patients on EAP velaglucerase alfa who completed 6, 9, or 12 months as intravenous every-other-week ERT. METHOD EAP was approved by the Israeli Ministry of Health. All patients enrolled in the EAP were included for safety measures; only those with >6 month evaluations of hemoglobin, platelet counts, and liver and spleen volumes were included for efficacy. Descriptive statistics were employed. RESULTS Among 71 EAP patients, there were no drug-related serious adverse events or withdrawals; one patient (1.4%) with previous hypersensitivity to a different ERT had a drug-related allergic reaction. Of 44 patients with appropriate time-period evaluations, 8 patients were treatment-naïve and responded well to velaglucerase alfa. The 36 switch-over patients remained at imiglucerase low-doses; a majority of patients showed improvements in each efficacy parameter. CONCLUSION Switch-over from imiglucerase (10-224 months) was safe and in several patients velaglucerase alfa induced a booster-effect.

Phenotype in patients with Gaucher disease and Parkinson disease.

BACKGROUND Previous reports have shown an increased risk for Parkinson disease (PD) among type 1 Gaucher disease (GD) patients. However, the number of the reported cases of GD/PD is small and it is unknown whether certain GD phenotypes are associated with an increased PD risk. OBJECTIVE To present GD and PD characteristics of adults affected by both diseases from a large Israeli GD clinic, and assess whether certain GD characteristics are associated with a higher risk for PD. METHODS Medical files of patients >18years between 1990 and 2010 were reviewed for PD signs or symptoms. Available patients with PD underwent an additional neurological examination. Demographic and GD characteristics were compared between GD patients with and without PD using t-test and Fisher exact. Kaplan-Meier survival curves were used to estimate age-specific risk for PD among males and females. Age-specific risk for PD was compared between males and females using Cox Hazard ratio model. RESULTS 510 type 1 GD adults (233 males; 45.7%), were evaluated. 11 PD patients were identified (2.2%). Among those with GD/PD cognitive impairment was common (7/11). Two patients underwent successful deep brain stimulation (DBS). PD diagnosis was associated with male gender (81.8% versus 44.9% male, p=0.027) and older age (mean age, PD=62.8, non-PD=47.1, p=0.004). GD phenotype and severity did not differ between the two groups, including mean Zimran Severity Score index (7.7 versus 8.3), percent splenectomized (15.8% versus 27.3%), history of avascular necrosis (13.0% versus 27.3%) and percent ever treated with enzyme replacement (49.4% versus 45.5%). CONCLUSION Male gender and older age are risk factors for PD among GD patients, but GD severity is not associated with increased risk for PD. Further research is required to assess which GD patients are at a higher risk for PD, and why.

Sixteen years of prenatal consultations for the N370S/N370S Gaucher disease genotype: What have we learned?

Although prenatal diagnosis and genotyping are available for Gaucher disease, genetic counseling for an affected childs parents reflects the inability to predict disease course with certainty. The purpose of this survey is to ascertain disease status of children identified by prenatal screening.

Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease

Background and purpose Gaucher disease is heterogeneous. One of the most devastating complications is bone involvement, ranging from mild osteopenia to osteonecrosis, but no markers have been discovered to predict onset and/or progression. We describe our experience in a large referral center using drilling for juxta-articular osteonecrosis in young patients with Gaucher disease. Patients and methods We retrospectively reviewed medical data from all patients who were recommended to undergo drilling for osteonecrosis of juxta-articular bone of the femoral head, the humeral head, or upper tibia for acute osteonecrosis at a pre-collapse stage. Results 11 patients (mean age 34 years) underwent drilling of 12 joints with juxta-articular osteonecrosis; 3 (mean age 51 years) refused intervention. 9 joints that were drilled showed advancing joint degeneration within 0.5 to 4 years. 3 joints have undergone replacement. Of the 3 joints that did not undergo drilling, 2 have undergone replacement and 1 has collapsed with osteoarthritis. Interpretation We found equally poor outcome with and without drilling. Effective intervention can only be achieved by improving our understanding of bone physiology and pathophysiology in Gaucher disease.