Ferreira AC 1 , Sequeira S 1 1 Metab Unit, Dona Estefânia Hosp, CHLC, Lisboa, Portugal Background: Children with Gaucher disease type I (GD1) are usually treated with enzyme replacement therapy (ERT) at a dose of 30-60U/Kg/ 2 W. Recently, due to an acute shortage supply of imiglucerase, a reduced dose or a reduced infusion frequency was recommended. Objective: To evaluate the effects of a reduced infusion frequency of imiglucerase over 15 months of follow-up. Patients and Methods: Three patients were treated with ERT since a median age of 7 years (range 5-12). Only one had bone crisis and Erlenmeyer deformations. Median duration of treatment before dose reduction was 3 years (range 1-8). ERT resulted in total regression of symptoms, normalization of hematological parameters and progressive improvement of chitotriosidase in all patients. In August 2009 infusion schedule was changed from a media 45U/Kg every two weeks to every four weeks. Results: All patients remained asymptomatic and with no major change on hematological parameters except for one patient who presented subnormal platelet count. All patients showed an upward trend in chitotriosidase values. Comments: Although a longer follow-up is needed, is probable that even children completely stabilized can probably not be kept on lower doses even though the reduction of frequency of the infusions represent a lower social burden. Background: Bone pathology is a major concern in type 1 Gaucher disease. Methods: We evaluated BMD in all 10 patients enrolled in the ongoing, interventional study TKT025EXT (4 men, 6 women; median age 35 years ). Through 69 months, the mean velaglucerase alfa dose was 40 U/kg; 4 patients received concomitant bisphosphonates. Results: At baseline, at the lumbar spine (LS) and femoral neck (FN) respectively, 1 and 4 patients had osteoporosis; 8 and 5 had osteopenia; and 1 and 1 were normal (per WHO T-score-based categorization). Status change occurred only in patients not receiving bisphosphonates: osteopenic-to-normal (2 LS and 1 FN) and osteoporotic-to-osteopenic (1 FN) by Month 69. BMD improved significantly at the LS by Month 24 and at the FN by Month 33. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved with treatment (LS and FN both P<0.01); subgroup analysis of patients not receiving bisphosphonates showed similar results. Conclusions: Velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction (60 to 30 U/kg during Year 2 of therapy) and significant baseline skeletal pathology. Conflict of Interest declared. ). Most AEs were mild or moderate: most common were nasopharyngitis in 15 patients, headache in 15, nausea in 12. 11 patients (5%) experienced a severe AE, considered possibly drug-related in 3 (1%); 7 (3%) a serious AE, considered possibly drug-related (migraine) in 1 (0.5%). Mean hemoglobin and platelets improved in naïve patients and remained stable in switch patients. Conclusion: A clinically heterogeneous group of 211 GD1 patients successfully transitioned to velaglucerase alfa, which was generally well tolerated, supporting this ERT as a GD1 treatment option. Conflict of Interest declared. Giraldo P 6 , Kisinovsky I 7 , Bavdekar A 8 , Gupta N 4 , Kishnani PS 9 , Sureshkumar EK 10 , Wang N 11 , Crombez E 11 , Bhirangi K 11 Background: Therapeutic goals for GD1, a heterogeneous, multisystem disease, facilitate an individualized approach to long-term management. Methods: In HGT-GCB-039, treatment-naïve GD1 patients aged>=2 years were randomized to imiglucerase or velaglucerase alfa (60U/kg every other week [EOW]; 9 months). HGT-GCB-039 completers could enroll in extension HGT-GCB-044, receiving velaglucerase alfa (60U/kg EOW; ongoing). Results: 34 patients received study drug (17 imiglucerase, 17 velaglucerase alfa). 16 patients from each group entered HGT-GCB-044 and are included in this analysis. Hemoglobin concentration, platelet count, liver and spleen volumes were evaluated against therapeutic goals (based on Pastores et al, 2004) . At HGT-GCB-039 baseline, 0/32 patients met all goals (3 goals for splenectomized, 4 goals for non-splenectomized patients). After 9 months, 13/16 patients achieved all goals in both the continuous velaglucerase alfa and imiglucerase-to-velaglucerase alfa groups. After additional 15 months' exposure (in HGT-GCB-044; 24 months total), 16/16 and 15/16 achieved all goals, respectively; 1 splenectomized patient failed to achieve the hemoglobin goal. Conclusions: Most velaglucerase alfa-treated GD1 patients achieved all hematologic, liver and spleen therapeutic goals by Month 9, with comparable achievement in imiglucerase-treated patients. After 2 years, all patients who had received continuous velaglucerase alfa, and the majority transitioned from imiglucerase, had achieved all goals. Conflict of Interest declared. Harmatz P 10 , Fernhoff P 11 , Rhead W 12 , Longo N 13 , Giraldo P 14 , Zahrieh D 15 , Crombez E Background: We report outcomes in type 1 Gaucher disease (GD1) patients transitioned from imiglucerase to velaglucerase alfa. Methods: In trial TKT034, GD1 patients aged>=2 years, on imiglucerase (>=22 consecutive months at 15-60U/kg every other week), with a stable dose and hematologic parameters for>=6 months, switched to velaglucerase alfa (same U/kg, 60-minute intravenous infusion). TKT034 completers could enroll in the extension HGT-GCB-044. Results: 38/40 patients treated in TKT034 continued into HGT-GCB-044 (prior imiglucerase exposure 22-192 months; ages 9-71 years; 24% <18 years; 47% male; 8% splenectomized). After 2 years, the mean changes (95% CI) in hemoglobin concentration, platelet count, and spleen and liver volumes normalized to body weight were 0 g/dL (−0.3, 0.3), 8.0% (1.1, 15.0) , -8.1% (−14.1, -2.2) , and −1.2% (−4.8, 2.4) , respectively-all within the pre-specified clinically significant limits of stability: ±1 g/dL, ±20%, and ±15%, respectively. The majority of patients maintained all therapeutic goals met at baseline for these 4 parameters. The mean change (95% CI) in CCL18 concentration was −50.9% (−55.5, -46.3) and in chitotriosidase activity, -34.5% (−42.2, -26.9 Harmatz P 10 , Fernhoff P 11 , Rhead W 12 , Longo N 13 , Giraldo P 14 , Zahrieh D 15 , Crombez E 15 Background: Adverse events (AEs) are important considerations for physicians treating type 1 Gaucher disease (GD1) with ERT. Methods: In TKT034, 40 GD1 patients receiving stable imiglucerase for > =22 months switched to velaglucerase alfa for 12 months (protocol-specified continuous 60-minute infusion; otherwise, same regimen and U/kg as prior imiglucerase treatment). 2 patients discontinued (1 for personal reasons, 1 due to a hypersensitivity reaction during the first infusion); all 38 patients completing the study elected to continue in the extension. AEs were elicited by non-leading questions or discovered through observation, laboratory reports, or patient complaint. IRAEs were defined as beginning<=12 hours after infusion start and possibly or probably related to study drug. Results: In the 38 patients receiving 24 months of velaglucerase alfa, median prior imiglucerase exposure was 65 months (range 22-192) . The most common AEs (>20% of patients) were headache, nasopharyngitis, pharyngolaryngeal pain, cough, arthralgia, myalgia, and fatigue. Most AEs were mild or moderate and none led to study discontinuation. 6 SAEs occurred in 5 patients (none study drug-related). 9/38 patients experienced>=1 IRAE. Conclusions: In GD1 patients transitioned from imiglucerase, velaglucerase alfa was generally well tolerated through 2 years; no drug-related SAEs occurred and most patients experienced no IRAEs. Conflict of Interest declared. Background: Standard of care for Gaucher disease(GD), the deficiency of lysosomal enzyme glucocerebrosidase, is enzyme replacement therapy (ERT). ERT is highly effective in reversing the visceral and hematologic manifestations, but skeletal and pulmonary complications, and inflammatory component respond variably. We report the first-year experience with velaglucerase-alpha(VPRIV®), a gene-human glucocerebrosidase by providing specific case examples. Methods: 15 (12 F: 3 M) GD1 patients were treated with VPRIV®, 30 to 60 IU/kg, for one year. At initiation of therapy, splenectomized patients (n=4), 2 naïve to ERT, had significant disease-load, presenting with transfusion dependency, increased pulmonary pressures, systemic inflammation and skeletal involvement. Chitotriosidase(CHITO) was followed as a GD marker, and antibodies were obtained in selected patients. Results: Among patients with mild-moderate GD, hematological parameters and CHITO remained stable. In severely afftecteds, the clinical response was observed usually within first 3 months of therapy. Changes in CHITO ranged between normal levels to a more than 50% decrease. There were three infusion-related events, but antibody development was not observed. Conclusions: The success in clinical response may concur with better in vitro internalization of velaglucerase-alpha, into macrophages. Nevertheless, having different enzymes will provide an opportunity to re-evaluate initiation of ERT, and management of non-responders in GD. Conflict of Interest declared. Background: Pompe disease is caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase (GAA), which results in progressive accumulation of glycogen in lysosomes of various tissues, mainly muscle. Recombinant human GAA (rhGAA) given as bi-weekly infusions, known as enzyme replacement therapy (ERT), is the primary treatment for Pompe patients. While generally effective, the rhGAA has a short circulating halflife, low tissue uptake, and can elicit immune responses that adversely affect tolerability and efficacy. AT2220 (1-deoxynojirimycin) is a small molecule pharmacological chaperone that binds endogenous GAA in cells and tissues, resulting in increased GAA lysosomal levels and activity. Objective: To determine if AT2220 also interact with exogenous rhGAA (i.e ERT) to improve its pharmacological properties. Results: In human plasma, AT2220 increased the stability and minimized denaturation of rhGAA at neutral pH/37°C. In rats, oral co-administration of AT2220 increased the circulating half-life of rhGAA by~2-fold. In GAA KO mice, oral co-administration of AT2220 resulted in up to 2.5-fold greater tissue uptake and glycogen reduction compared to rhGAA alone. Conclusions: Collectively, these data indicate that AT2220 stabilizes rhGAA, and leads to improved uptake and glycogen turnover. Based on these findings, a Phase 2a study of AT2220 with rhGAA has been initiated. Conflict of Interest declared. Background: Enzyme replacement therapy (ERT) in glycogen storage disease type 2 (GSD2) has been demonstrated to be safe and effective in short term studies. Objectives: To evaluate effects of ERT in juvenile GSD2 patients after 48 months of treatment. Patients and methods: 8 patients (mean age 10.9±1.9 years) treated with 20 mg/Kg of ERT biweekly up to 48 months were included. Walton Scale (WS), 6 minutes walking test (6 MWT), vital capacity, forced expiratory volume, arterial pCO2, and muscle enzymes were analyzed retrospectively. Results: After 48 months ERT was well tolerated in all subjects. Significant improvement of 6 MWT (p<0.03), and a stabilization or reduction of WS were observed in all patients. Parameters of respiratory function remained stable, and shortened time of required ventilatory support was observed in the 2 patients already ventilatory dependent at the beginning of the study. A significant reduction in muscle enzymes (p<0.03) was evidenced. Conclusions: Although the relative small number of patients included, this study demonstrate that ERT in juvenile GSD2 is able to improve motor function and stabilize ventilatory function after 4 years of therapy. The best results were achieved when ERT was started before the onset of the clinical manifestations of the disease. Maltase acid deficiency (Pompe disease), leads without treatment to hypertrophic cardiomyopathy muscle weakness, and premature death. Enzyme replacement therapy (ERT: rhGGA) is poorly efficient in crossreactive immunological material (CRIM) negative patients. In these patients, immunologic reaction can neutralize rhGGA . We described a CRIM negative (proven on fibroblasts) 30-months-old boy treated by ERT since two months of age. The disease is due to a homozygous mutation in the GAA gene (p.R870x). The cardiomyopathy rapidly improved, while the muscle weakness improved partially. Intially, he presented pulmonary infections, asthma, swallowing difficulties which led to a feeding by gastrostomy. The second year of life was marked by a real improvement in muscle weakness without anymore pulmonary infections. At 2 years old, he presented an anaphylactic reaction to the treatment while there was a slight increase of rhGGA antibodies (IgG: 1/100). Under steroid therapy he supported the next ERT infusions. Despite moderate psychomotor retardation, he clearly continue to progress on the gross motor development and on respiratory function. This is the first case of successful ERT in a CRIM negative child. Immunologic studies are pending to assess the immunological functions of this child who did not produce high levels of rhGGA antibodies.