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 and assess whether certain GD characteristics are associated with a higher risk for PD.Methods: Medical files of patients >18 years 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 (22%). 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 83), 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. (C) 2012 Elsevier Inc. All rights reserved.

On page 5767 in the 24 November 2011 issue, there are errors in the affiliations. The affiliation of the eleventh author (Heitner) is misspelled. The correct affiliation is University of Witwatersrand. The affiliation of the last author (Aviezer) is incomplete. His academic affiliation, Faculty of

Gheona Altarescu, Mali Szleifer, Sharon Hashmueli and David Aviezer Heitner, Hanna Rosenbaum, Pilar Giraldo, Atul Mehta, Glen Park, Mici Phillips, Deborah Elstein, Terreros Muñoz, Sergio E. Solorio-Meza, Dominick Amato, Gloria Duran, Fiorina Giona, Rene Ari Zimran, Einat Brill-Almon, Raul Chertkoff, Milan Petakov, Francisco Blanco-Favela, Eduardo disease taliglucerase alfa, a novel enzyme replacement therapy for Gaucher expressed recombinant glucocerebrosidase, − Pivotal trial with plant cell

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague–Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (−18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.

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.

Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naïve patients have now completed 4 years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3 ± 1.5 g/dL (baseline: 11.3 ± 1.5 g/dL) and 95% (baseline: 68,700 ± 21,200/mm3), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3 ± 9.5 MN) and 28% (baseline: 1.7 ± 0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: − 1.6 ± 1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of eliglustat reported at 1 and 2 years to 4 years.

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.

Abstract Abstract 1104 Introduction: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme acid β-glucosidase. This enzymatic deficiency leads to accumulation of undegraded glucosylceramide primarily in tissue macrophages (Gaucher cells) and results in multisystemic manifestations, including thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. The variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores, Semin Hematol. 2004;41(suppl 5):4–14). Eliglustat, a novel, small molecule, specific inhibitor of glucosylceramide synthase, is currently under clinical development as an oral substrate reduction therapy for GD1. Objective: To report long-term efficacy and safety results of eliglustat. Methods: This ongoing, open-label, uncontrolled, multicenter, Phase 2 clinical trial enrolled 26 adults with GD1 not on treatment for the previous 12 months, who had splenomegaly with thrombocytopenia and/or anemia. Efficacy outcomes included changes from baseline in hemoglobin, platelets, spleen and liver volumes, and bone mineral density (mean±SD); biomarker levels (median); and achievement of therapeutic goals for anemia, thrombocytopenia, splenomegaly, and hepatomegaly. Results: Nineteen patients completed 3 years of treatment; 7 patients discontinued the trial. After 3 years, hemoglobin increased by 2.6±1.39 g/dL (from 11.3±1.63 to 13.8±1.37); platelets increased by 91±65.9% (from 70,000±21,700 to 126,800±40,500/mm3); and spleen and liver volumes (multiples of normal, MN) decreased by 61±12.2% (from 16.8±9.5 to 6.2±3.6 MN) and 29±15.8% (from 1.7±0.5 to 1.2±0.3 MN), respectively. Most patients met long-term therapeutic goals for hemoglobin (100%), spleen volume (100%), liver volume (89%), and platelets (63%). All patients met ≥3 therapeutic goals at 3 years. GD1 biomarkers were elevated in most patients pre-treatment. Statistically significant decreases (P<0.0001) following eliglustat treatment were seen in median plasma GL-1 (80%, from 12.15 to 2.70 μg/mL) and GM3 (64%, from 19.25 to 6.60 μg/mL), which normalized; and median chitotriosidase (80%, from 7304 to 1426 nmol/hr/mL) and CCL-18 (73%, from 3560 to 789.3 ng/mL), which both remained above normal. Mean lumbar spine BMD increased by 0.6 Z-score (from −1.3±1.0 to −0.7±1.1). Eliglustat was well tolerated. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs were viral infections (6 pts); urinary and upper respiratory tract infections (4 pts each); and headache, increased blood pressure, abdominal pain and diarrhea (3 pts each). Eight drug-related AEs, all mild, occurred in 6 patients. Conclusions: Eliglustat has shown promising efficacy and safety, with clinically meaningful hematologic, visceral, and bone improvements. Most patients met long-term therapeutic goals. Eliglustat was well-tolerated through 3 years and continues to have a safety profile that supports clinical investigations in Phase 3 studies. Disclosures: Peterschmitt: Genzyme: Employment. Lukina:Genzyme: Honoraria. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Protalix: Research Funding; Shire HGT: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Actelion: Research Funding; Amicus: Research Funding. Arreguin:Genzyme: Research Funding. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment.

Abstract 3216 This icon denotes a clinically relevant abstract

Abstract 3791 Background: Gaucher disease type 1 (GD1), an inherited lysosomal storage disorder, is characterized by a deficiency of acid β-glucosidase and accumulation of glucosylceramide in lysosomes causing organomegaly, thrombocytopenia, anemia, and bone disease. Eliglustat tartrate (formerly Genz-112638) is a novel, specific inhibitor of glucosylceramide synthase under development as an oral substrate reduction therapy for the treatment of GD1. Purpose: To report updated efficacy and safety observations in GD1 patients after 2 years of treatment with eliglustat tartrate in an ongoing Phase 2 clinical trial. Methods: This is an open-label, uncontrolled, multicenter, Phase 2 clinical trial of eliglustat tartrate (50 or 100 mg bid, depending on trough plasma level of drug) in 26 previously untreated adults with GD1. Entry criteria required that patients have splenomegaly with thrombocytopenia (platelet count: 45,000 to 100,000 mm3) and/or anemia (hemoglobin: 8.0–10 g/dL, females; 8.0–11 g/dL, males). Efficacy results included changes from baseline in hemoglobin and platelet levels, spleen and liver volumes, biomarkers, bone mineral density (BMD), and other skeletal findings. Hematologic and visceral parameters were assessed centrally every 3 to 6 months; MRI, DXA, and X-rays were performed yearly and reviewed centrally. Achievement of Gaucher disease therapeutic goals for hemoglobin, platelet counts, and organ volume also was assessed at 2 years. Results: Thirty-month hematologic, organ volume, and biomarker data will be available for presentation. Six of the 26 enrolled patients discontinued the Phase 2 study. Results (mean changes from baseline ± SD) are currently available in up to 20 patients who completed 2 years of treatment with eliglustat tartrate. For these patients, hemoglobin level increased by 2.1±1.5 g/dL (11.2±1.6 to 13.3±1.5 g/dL), and platelet count increased by 81.5±56.0% (67,900±20,900/mm3 to 119,200±42,400/mm3). Spleen volume (as multiples of normal, MN) decreased by 52.4±10.7% (17.95 MN to 8.14 MN), and liver volume decreased by 23.9±12.8% (1.69 MN to 1.24 MN). Mean chitotriosidase and CCL18 decreased by 75.4% and 75.2%, respectively. Through 2 years, no bone crises or reductions in mobility were reported. Femur MRI showed improvement of the dark marrow signal in 8/18 patients, indicating reduction of the infiltration of the bone marrow by Gaucher cells; the rest of the patients remained stable (10/18 patients). In addition, there were no new lytic lesions or bone infarcts; existing lytic lesions remained stable, and of 7 existing infarcts, 1 improved and 6 remained stable. Mean lumbar spine BMD increased by 7.8±10.6% (P=0.010), DXA T-Score by 0.6±0.8 (P=0.012), and DXA Z-Score by 0.6±0.7 (P=0.003), with major gains among osteoporotic/osteopenic patients. After 2 years, most patients met short-term therapeutic goals published by Pastores et al (Semin Hematol 2004;41[suppl 5]:4–14); more patients met goals for hemoglobin (95%), liver volume (95%), and spleen volume (90%) than for platelet count (60%). Overall, 85% (17/20) of patients met established therapeutic goals for ≥3 of 4 parameters after 2 years. Eliglustat tartrate was well tolerated in this trial up to 2 years. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs reported during 2 years were viral infections (6 patients), and urinary tract infections, increased blood pressure, and abdominal pain (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients. Summary/Conclusions: In this Phase 2 study, eliglustat tartrate has shown promising efficacy as a potential oral substrate reduction therapy for GD1. After 2 years, patients with GD1 treated with eliglustat tartrate continued to show improvements in hematologic, organ volume, and bone parameters with a safety profile that supports ongoing treatment. Three controlled Phase 3 studies are underway: one in untreated patients (ENGAGE), one in patients switching from enzyme replacement therapy (ENCORE), and another that compares different dose regimens of eliglustat (EDGE). Disclosures: Lukina: Genzyme Corporation: Honoraria. Peterschmitt:Genzyme Corporation: Employment. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme Corporation: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Kaper:Genzyme Corporation: Employment. Haque:Genzyme Corporation: Employment. Puga:Genzyme Corporation: Employment.

Gaucher disease induces some metabolic abnormalities so increased serum ferritin appears in more than 60% at diagnosis. The storage of glucosylceramide in macrophages produces an inflammatory response with iron recycling deregulation and release of cytokines. Iron homeostasis is controlled by the circulating peptide hepcidin and its production is influenced by inflammatory cytokines.Iron damages cells by excess of catalyzing reactive oxygen species, removal of the excess iron has a positive influence on the response to treatment and survival in patients with iron overload.We have analyzed some inflammatory biomarkers of macrophage activation and related to the iron profile, including hepcidin and liver iron deposits determined by MRI, in 8 type 1 GD patients with hyperferritinemia. We have explored the changes in this profile after 4 months under therapy with two different iron chelators, deferoxamine or deferasirox, by evaluating response, adverse events and quality of life. We observed a significant reduction in serum ferritin and hepcidin levels and in liver iron deposits. No differences were observed in chitotriosidase activity, CCL18/PARC concentration and IL-4, IL-6, IL-7, IL-10, IL-13, MIP-1α, MIP-1β,TNF-α cytokine levels. After two years on follow-up, clinical and analytical data were improved and stable ferritin levels maintained less than 700 ng/dL.

Objective Although prenatal diagnosis and genotyping are available for Gaudier disease, genetic counseling for an affected child's 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 screeningMethods All carrier couples for glucocerebrosidase mutations who were counseled at our large Gaucher Clinic were included, none had genotyped the fetus Medical status of children was assessed by questionnaires and data were collected front clinic charts and/or telephone contact with the parentsResults Of 34 children born. 1 died in utero, 5 fetuses (N370S/N370S) aborted Of 21 genotyped N370S/N370S. 7 children had Gaudier-like symptoms/signs but for only one child (two symptoms.) were these ascribable to Gaucher disease, tour children had non-Gaucher symptoms/signsConclusion Of 21 children whose parents pursued prenatal counseling for Gaudier disease and were found to have the N370S/N370S genotype. none has presented with severe disease with follow-up of 15 years The Israeli experience shows that Gaucher disease N370S screening does not identify children requiring treatment, but rather leads to termination of asymptomatic fetuses, this may lead to reconsideration of guidelines regarding Gaucher screening Copyright (C) 2010 John Wiley & Sons. Ltd

Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean ± SD, 81% ± 56%), hemoglobin level (20% ± 15%), spleen volume (-52% ± 11%), and liver volume (-24% ± 13%). Mean platelet count increased ∼ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥ 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% ± 10.6% (P = .01) and T-score 0.6 ± 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150.

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.

The only prognostic markers in Gaucher disease, the most common lysosomal storage disorder, are young age at first symptom/sign and the presence of null/severe mutations, both being predictive of more severe phenotypes. Therefore, it would be helpful to know whether siblings with the same genotype can be expected to experience comparable phenotypic expression. All non-neuronopathic sibling pairs in our referral clinic (1993-2008) with the same genotype were included. For each pair, gender, date of birth, severity score index at presentation, age at diagnosis and first symptom/sign, presence of bone involvement, spleen status, and use of enzyme replacement therapy were tabulated. There were 90 pairs of siblings: two sets of identical twins; 24 pairs of brothers, 24 pairs of sisters, and 42 pairs of mixed gender. For all measures of disease severity used, only in sibling pairs with an older sister and a younger brother were phenotypes significantly different between siblings. Thus, this large cohort of sibling pairs with type 1 Gaucher disease confirmed that, in general, the phenotypic expression in the younger sibling will be similar enough to that of an older affected sibling that genetic counseling may use those findings in a prognostic way.

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.

Abstract 1349 This icon denotes an abstract that is clinically relevant.

Bone-related complications in Gaucher disease are considered to be poorly responsive to specific enzyme replacement therapy. Polymorphisms of candidate genes associated with low bone density were investigated to see whether they are correlated with bone mineral density (BMD) and bone involvement in Gaucher disease. Genotyping for polymorphisms in candidate genes (interleukins 1 alpha and 1 beta, interleukin-1 receptor antagonist; cytochrome P450; collagen 1A1; low-density Lipoprotein Receptor; bone morphogenic protein 4; vitamin D receptor; and estrogen receptor 2 beta) were performed using standard methodologies. BMD was measured by dual energy X-ray absorptiometry (DXA). One hundred and ninety-four patients and 100 controls were genotyped for the above polymorphisms. Thirteen haplotypes were obtained, with several correlations with BMD in patients; also, a haplotype (T889-T3954-C511-240VNTR of IL1) was significantly correlated with T-scores and Z-score for femur neck and lumbar spine (p = 0.01) in patients. Haplotypes of bone-specific candidate genes associated with BMD may predict severity of these features in Gaucher disease.