PURPOSE:Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. METHODS:In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. RESULTS:Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. CONCLUSION:In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD.

Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α‐galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half‐life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open‐label, 3‐month dose‐ranging study, followed by a 9‐month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment‐emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half‐life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m2 at baseline, remaining stable throughout treatment. Three patients developed treatment‐induced IgG ADAs; following 1 year's treatment, all became ADA‐negative. Nearly all treatment‐emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.

This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab (R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: [-8.77% to 10.17%]) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL.

Gaucher disease is an inherited metabolic disease characterized by β-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.

Infection by cytomegalovirus (CMV) is a major cause of morbidity among immunosuppressed patients, especially after solid organ transplantation. The risk of CMV after organ transplantation is strongly related to the serology of the donor and the recipient. The objective of this study was to analyze the outcomes and costs of pre-emptive therapy in patients after liver transplantation with donor-positive/recipient-negative (D+/R−) serostatus.This retrospective study analyzed all patients who underwent liver transplantation with CMV serostatus D+/R− between January 2012 and December 2015. The service protocol adopts pre-emptive therapy. The outcomes and costs of this therapy are described.Of the 119 patients undergoing liver transplantation, 19 were D+/R− and entered the main analysis. Of these, 7 had positive polymerase chain reaction (PCR) results, and 1 developed CMV disease. Of the 6 patients who received no treatment, none developed CMV disease. Analyzing costs, pre-emptive therapy for these patients generated service savings of R$32,346.00.Although outcomes of universal prophylaxis and pre-emptive therapy are similar, pre-emptive therapy save on costs and have to be considered in patients with high-risk CMV disease after liver transplantation.

Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage ≥ 2.In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria < 30 mg/g; 2) albuminuria 30–299 mg/g; 3) albuminuria > 300 mg/g; 4) glomerular filtration rate (GFR) < 60 mL/min/1.73 m2. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-β-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria).Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ = − 0.289; p = 0.003) or N-acetyl-β-glucosaminidase (ρ = − 0.448; p < 0.001), which were stronger than with albumin (ρ = − 0.274; p = 0.019). There was also better diagnostic accuracy of N-acetyl-β-glucosaminidase to predict CKD stage ≥ 2.These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.

Molecular imaging of the earliest events related to the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) could facilitate therapeutic development and patient management. We previously reported that 18F-fluoro-2-deoxyglucose (18F-FDG) PET identifies ALI/ARDS prior to radiographic abnormalities. The purpose of this study was to establish the time courses of 18F-FDG uptake, edema and neutrophil recruitment in an endotoxin-induced acute lung injury model and to examine molecular events required for 14C-2DG uptake in activated neutrophils.Lung uptake of 18F-FDG was measured by PET in control male Sprague Dawley rats and at 2, 6 and 24 h following the intraperitoneal injection of 10 mg/kg LPS. Lung edema (attenuation) was measured by microCT. Neutrophil influx into the lungs was measured by myeloperoxidase assay. Control and activated human donor neutrophils were compared for uptake of 14C-2DG, transcription and content of hexokinase and GLUT isoforms and for hexokinase (HK) activity.Significant uptake of 18F-FDG occurred by 2 h following LPS, and progressively increased to 24 h. Lung uptake of 18F-FDG preceded increased CT attenuation (lung edema). Myeloperoxidase activity in the lungs, supporting neutrophil influx, paralleled 18F-FDG uptake. Activation of isolated human neutrophils resulted in increased uptake of 14C-2DG, expression of GLUT 3 and GLUT 4 and expression and increased HK1 activity.Systemic endotoxin-induced ALI results in very early and progressive uptake of 18F-FDG, parallels neutrophil accumulation and occurs earlier than lung injury edema. Activated neutrophils show increased uptake of 14C-2DG, expression of specific GLUT3, GLUT4 and HK1 protein and HK activity.18F-FDG pulmonary uptake is an early biomarker of neutrophil recruitment in ALI and is associated with specific molecular events that mediate 14C-2DG uptake in activated neutrophils. 18F-FDG PET may provide a potential mechanism for early diagnosis and therapeutic assessment of ALI/ARDS.

Anti-drug antibodies may develop with biological therapies, possibly leading to a reduction of treatment efficacy and to allergic and other adverse reactions. Patients with Gaucher disease were tested for anti-drug antibodies every 6 or 12 weeks in clinical studies of velaglucerase alfa enzyme replacement therapy, as part of a range of safety endpoints. In 10 studies between April 2004 and March 2015, 289 patients aged 2–84 years (median 43 years) were assessed for the development of anti-velaglucerase alfa antibodies. Sixty-four patients were treatment-naïve at baseline and 225 patients were switched to velaglucerase alfa from imiglucerase treatment. They received velaglucerase alfa treatment for a median of 36.4 weeks (interquartile range 26.4–155.4 weeks). Four patients (1.4%) became positive for anti-velaglucerase alfa IgG antibodies, two of whom had antibodies that were neutralizing in vitro, but there were no apparent changes in patients' platelet counts, hemoglobin levels or levels of CCL18 and chitotriosidase, suggestive of clinical deterioration after anti-velaglucerase alfa antibodies were detected, and no infusion-related adverse events were reported. Less than 2% of patients exposed to velaglucerase alfa tested positive for antibodies and there was no apparent correlation between anti-velaglucerase alfa antibodies and adverse events or pharmacodynamic or clinical responses.

Asthma and/or allergic rhinitis have been associated with sleep disorders. The aim of this study was to evaluate sleep disorders in Latin-American children (4–10 years) from nine countries, with persistent asthma (A) and/or allergic rhinitis (AR) and in normal controls (C).Parents from 454 C children and 700 A and/or AR children followed up in allergy reference clinics completed the Children's Sleep Habits Questionnaire (CSHQ) which is a retrospective one-week questionnaire composed of 33 questions composed of seven subscales (bedtime resistance, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing and daytime sleepiness). The total scale of CSHQ and the subscales were compared between groups C and A+AR, A (n = 285) vs. AR (n = 390), and between controlled A (CA, n = 103) vs. partially controlled/uncontrolled A (UA, n = 182).The comparison between C and A+AR showed no significant differences in age (6.7 years vs. 7.0 years, respectively), mean Body Mass Index and total scale of CSHQ (53.3 vs. 63.2, respectively) and the subscales were significantly higher in the A+AR group. Comparison between groups A and AR, except for sleep anxiety, showed significantly higher values for CSHQ total scale (66.9 vs. 61.0, respectively) and subscales for group A. The UA group showed significantly higher values for total CSHQ scale and subscales in comparison to CA (71.1 vs. 59.4, respectively).Latin-American children with asthma and/or allergic rhinitis showed sleep disorders identified by the CSHQ when compared to normal controls. Despite being treated, asthma causes sleep impairment, especially when uncontrolled.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT.Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24–120).In 69 patients (42 males, 27 females, mean age 44.6 ± 13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242–128 mg/g (p = 0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤ 60 ml/min/1.73 m2 (log Rank 12.423, p = 0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p = 0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models.GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.El objetivo de este estudio es realizar un mapa del tratamiento actual de la enfermedad de Fabry en España, analizando el efecto de diferentes factores en el desarrollo de eventos clínicos a largo plazo.Análisis observacional retrospectivo multicéntrico. Criterios de inclusión: pacientes diagnosticados y tratados de enfermedad de Fabry. Se recogieron datos generales en relación con el diagnóstico, síntomas y tipo mutación, tipo de tratamiento recibido, evolución renal y cardiológica. Durante un tiempo de seguimiento de 60 meses (24-120), se recogió el primer evento clínico tras el inicio de tratamiento sustitutivo enzimático definido como mortalidad, evento renal, cardiológico o neurológico.Se incluyeron 69 pacientes (42 H, 27 M) con una edad media de 44,6 ± 13,7 años. A los cinco años de tratamiento, el FGe y la hipertrofia ventricular izquierda se mantuvieron estables, y la albuminuria tiende a disminuir, siendo este descenso más significativo en el grupo de pacientes tratados con beta-galactosidasa (de 242 a 128 mg/g (p = 0,05). Veintiún pacientes sufrieron un evento clínico (30%): seis renales, dos neurológicos y 13 cardiológicos (incluidas tres muertes). Los pacientes con ERC (FGe < 60) antes del inicio de tratamiento tuvieron más eventos (log-rank 12.423, p = 0,001), manteniéndose la predicción si excluíamos los eventos renales (log-rank 4.086 (p = 0,043) en hombres y mujeres. La peor función renal al inicio del tratamiento aumentó entre tres y siete veces el riesgo de eventos clínicos en diferentes modelos de Cox ajustados.La función renal al inicio de tratamiento sustitutivo enzimático es la principal predictora de desarrollo de eventos clínicos a largo plazo, tanto en hombres como mujeres. El inicio de tratamiento sustitutivo enzimático precoz antes del desarrollo de ERC mejoraría el pronóstico.

CO RR EC TE D P RO OF with type 1 Gaucher disease (GD) in the United States, Israel, Australia, Canada, and other countries, and is approved for treatment of pediatric patients in the United States, Australia, and Canada, and for hematologic manifestations in pediatric patients with type III GD in Canada. Study PB-06-005 was a Phase 3B, multicenter, doubleblind, multiple-dose, randomized trial that examined the safety and efficacy of taliglucerase alfa through 12 months. Treatment-naive patients aged 2 to b18 years with GD requiring enzyme replacement therapy based on clinical condition were randomized to receive either 30 or 60 U/kg of taliglucerase alfa every other week. A total of 11 patients were allocated to taliglucerase alfa (n = 6, taliglucerase alfa 30 U/kg; n = 5, taliglucerase alfa 60 U/kg), were treated, and completed Study PB-06-005. Due to small patient numbers, there were numerical imbalances in disease parameters between the 30-U/kg and 60-U/kg groups at baseline. However, clinically, they were comparable at baseline: Patients in the 2 dose groups had similarly mild anemia, similar risks of bleeding based onplatelet count, andmuch larger than normal organ volumes. Mean percentage changes from baseline were used to compare the response between the dose groups and as a measure of control for numerical imbalances in baseline disease parameters. Results through 12months demonstrated that taliglucerase alfa 30 and 60 U/kg, respectively, increased mean hemoglobin concentration (+13.8% and +15.8%) and mean platelet count (+30.9% and +73.7%), while also reducing mean multiples of normal in spleen volume (−34.1% and−48.5%), multiples of normal in liver volume (−14.5% and −25.0%), chitotriosidase activity (−58.5% and −66.1%), and CCL18 concentration (−50.6% and −52.6%). Although statistical analysis was not possible due to the small numbers of patients, both treatment groups demonstrated clinically meaningful improvement from baseline in these disease parameters with numerically greater improvement observed in the 60-U/kg dose group. The authors wish to acknowledge fellow investigator Dr. Rene Heitner who passed away in January, 2012. This study was sponsored by Protalix BioTherapeutics. Pfizer and Protalix entered into an agreement in November 2009 to develop and commercialize taliglucerase alfa.

Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty‐seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every‐other‐week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug‐related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti‐velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z‐score. Improvements were maintained over longer‐term treatment. Velaglucerase alfa had a good long‐term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008‐001965‐27; www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. © 2015 Wiley Periodicals, Inc.

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9‐month, global, randomized, double‐blind, non‐inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment‐naïve patients aged 3–73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent‐to‐treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per‐protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent‐to‐treat and per‐protocol populations, respectively. The lower bound of the 97.5% one‐sided confidence interval in both populations lay within the pre‐defined non‐inferiority margin of −1.0 g/dL, confirming that velaglucerase alfa is non‐inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross‐reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am. J. Hematol. 88:179–184, 2013. © 2012 Wiley Periodicals, Inc.

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment‐naïve, anemic patients with GD1 (4–62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 109/L (P=0.002); 45 U/kg: +66.4%; +40.9 × 109/L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: −50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: −39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug‐related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease‐specific parameters measured demonstrated clinically meaningful improvements after 12 months. Am. J. Hematol. 88:166–171, 2013. © 2012 Wiley Periodicals, Inc.

Abstract Abstract 3214 BACKGROUND Type 1 Gaucher disease (GD1) is a chronic, multisystem disease that varies considerably among individuals with regard to organ involvement, presentation, severity, and progression rate. Because hematologic signs and symptoms are common (e.g., anemia, thrombocytopenia, splenomegaly, and hepatomegaly), treatment is often guided by a hematologist. OBJECTIVE To describe the safety and tolerability of velaglucerase alfa after 15 months of treatment in an ongoing, open-label extension study (HGT-GCB-044 [ClinicalTrials.gov identifier, NCT00635427]) in GD1 patients who received either velaglucerase alfa or imiglucerase in a preceding 9-month, double-blind, randomized, Phase III trial (HGT-GCB-039 [NCT00553631]). METHODS In HGT-GCB-039, treatment-naïve GD1 patients aged ≥2 years were randomized to velaglucerase alfa or imiglucerase as a continuous 60-minute intravenous infusion (60 U/kg body weight every other week [EOW]; 9 months). HGT-GCB-039 completers could enroll in extension study HGT-GCB-044, receiving velaglucerase alfa (60 U/kg EOW; ongoing). Safety and tolerability were assessed after 15 months of participation in HGT-GCB-044 (i.e., after a total of 2 years of enzyme replacement therapy). RESULTS Of 35 patients enrolled in HGT-GCB-039, 34 received study drug and 32 completed the trial (1 velaglucerase alfa patient was lost to follow-up after a serious adverse event [AE] of life-threatening convulsion, which was considered unrelated to treatment; 1 imiglucerase patient withdrew consent because of AEs). This analysis included only the 32 patients completing HGT-GCB-039 who enrolled in the HGT-GCB-044 extension phase: 16 had received velaglucerase alfa (median age, 38 years [range, 8–60 years]; 50% [n=8] male; 56% [n=9] splenectomized) and 16 had received imiglucerase (median age, 27 years [range, 4–59 years]; 44% [n=7] male; 63% [n=10] splenectomized). These patients had received velaglucerase alfa for 24 months (continuous velaglucerase alfa group) or imiglucerase for 9 months + velaglucerase alfa for 15 months (imiglucerase-switch group) at the time of the current analysis. No differences were observed between the safety profiles of the continuous velaglucerase alfa and imiglucerase-switch treatment arms (Table). AEs most commonly reported (≥20% of patients) during the extension phase were nasopharyngitis and arthralgia in the continuous velaglucerase alfa group and headache and upper respiratory tract infection in the imiglucerase-switch group. Most AEs were mild or moderate in severity and, apart from the patient who was lost to follow-up in HGT-GCB-039 after a convulsion, there were no other life-threatening AEs. None of the serious AEs were considered drug related. The proportion of patients with infusion-related AEs remained low in HGT-GCB-044. Anti-imiglucerase antibodies developed in 4 patients receiving imiglucerase in trial HGT-GCB-039, 1 of whom discontinued following multiple infusion-related AEs and did not enter HGT-GCB-044. This patient also had anti-velaglucerase alfa antibodies, which was attributed to assay cross-reactivity, as he had never been exposed to velaglucerase alfa. No patients developed anti-velaglucerase alfa antibodies during the first 9 or subsequent 15 months of drug exposure. CONCLUSIONS Velaglucerase alfa was generally well tolerated in both the continuous velaglucerase alfa and imiglucerase-switch arms of these controlled clinical trials. Although 4 patients had anti-imiglucerase antibodies in trial HGT-GCB-039, no patient has developed anti-velaglucerase alfa antibodies over the course of the trials to date. Disclosures: Mehta: Shire HGT: Consultancy. Giraldo:Shire HGT: Consultancy. Kisinovsky:Shire Argentina: Consultancy. Kishnani:Shire HGT: Honoraria; Genzyme: Honoraria; Pfizer: Honoraria. Barton:Shire HGT: Employment. Wang:Shire HGT: Employment. Crombez:Shire HGT: Employment. Bhirangi:Shire HGT: Employment. Zimran:Shire HGT: Consultancy; Protalix: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Actelion: Honoraria; Pfizer: Honoraria.