Years Of Enzyme Replacement Therapy Research Articles

Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long-term enzyme replacement therapy

BackgroundLate-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD. ObjectiveWe analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters. MethodsThree symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations. ResultsWe detected a decrease in thigh muscle volume of 6.7% (p<0.001) and an increase in lower leg muscle volume of 8.2% (p=0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R2=0.68, p<0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles. ConclusionsThe results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome.

Diagnosis, quality of life, and treatment of patients with Hunter syndrome in the French healthcare system: a retrospective observational study.

BackgroundMucopolysaccharidosis II (MPS II) is associated with a broad spectrum of chronic and progressive, life-limiting symptoms. Idursulfase is approved for MPS II enzyme replacement therapy (ERT) in over 50 countries. This retrospective study evaluated the MPS II burden, organization of clinical care, and effects of idursulfase treatment on the disease in France.MethodsMPS II patients who had received idursulfase ERT in the French healthcare system were enrolled. In addition to clinician and patient questionnaires, the Clinical Global Impression-Improvement (CGI-I); Patient Global Impression-Improvement (PGI-I); KIDSCREEN-27, and EuroQoL-5D for adult patients scales were used to assess quality of life (QoL) and efficacy.ResultsFifty-two patients were enrolled from 5 sites in France. The majority of patients (69.2%) presented a severe MPS II phenotype with progressive neurocognitive impairment. Major impacts on QoL were apparent, with at least 1 member of the family having to reorganize working hours (45.5%) or to stop working (22.7%). KIDSCREEN-27 and EuroQoL-5D scale scores were well below those for referent (control) populations. Most families (70.0%) experienced a diagnostic delay of at least 3 years after the initial observation of symptoms. The MPS II diagnosis was often delivered without adequate sensitivity, psychological support, or comprehensive information about the disease. The study population had received a mean of 3.8 ± 1.3 years ERT. Forty-four percent of patients with the attenuated phenotype (without progressive neurocognitive impairment) showed symptom improvement during both the first year (Period 1) and from the end of the first year of treatment to “the present” (Period 2), as measured by CGI-I/PGI-I. 30.3% and 9.1% of severe patients experienced symptom improvement during Periods 1 and 2, respectively, while 63.6% and 51.5% displayed no change. The most common adverse reactions reported were skin rash and other infusion-associated reactions.ConclusionsMPS II adversely affects multiple domains of QoL for patients and families, requiring multiple healthcare services and social aid programs. The majority of patients with either phenotype experienced either improvement or stability in their symptoms during the first year of ERT, but this was clearly less so for patients with the severe phenotype after the first year of treatment.

Mucopolysaccharidosis VI

Introduction:Mucopolysaccharidosis VI (MPS VI) is the result of the absence of arylsulfatase B leading to the abnormal lysosomal accumulation of glycosaminoglycans. Two different phenotypes have been described to date, namely, rapidly progressive and slowly progressive. Aim:To present the evolution of a slowly progressive phenotype of MPS VI in a patient after 2 years of enzyme replacement therapy. Case report:A 26-year-old man diagnosed with MPS VI at 9 years of age started enzyme replacement therapy with galsulfase due to cardiac, pulmonary, neurologic, and joint involvement. After 10 months of treatment, improvement in quality-of-life scales and walk test was evident. Because of persistent symptomatology associated with narrow cervical spinal canal, decompressive surgery was performed. After 2 years of treatment, there was a clear improvement in the respiratory, motor, and cardiac functions as well as in the spinal symptoms. Discussion:The evolution of our patient leads to the conclusion that the combined treatment of galasulfase and decompressive surgery should be indicated at an early stage in order to achieve best outcome for the patient.

Adult Fabry patients in Sweden - Baseline data and Outcome of Four-Year Enzyme Replacement Treatment in a Male Cohort without Proteinuria

Background: Fabry disease is a rare X-linked lysosomal storage disease caused by defective activity of the lysosomal enzyme α-galactosidase A. The objective was to study the baseline characteristics of Fabry patients in Sweden, Furthermore, to study the effect of 4 years of ERT (enzyme replacement therapy) in an open study of a subcohort of Fabry men with no or mild proteinuria (<1 gram/day). Patients and methods: Thirty-four Swedish Fabry patients were enrolled in the baseline study during a 10 year period. We present baseline data for both men and women. The effect of 4 years of ERT was studied in an open study of a subcohort of 12 Fabry men with no or mild proteinuria. In the first 12-18 months this subcohort received the licensed dose of agalsidase alfa (Replagal ® ) 0.2 mg/kg body weight every other week and the men were then switched to a reduced dose of agalsidase beta (Fabrazyme ®), 0.5 mg/kg body weight every other week. Results: Swedish Fabry patients showed a similar prevalence of classical symptoms compared to Fabry patients from other countries, except for a lower prevalence of renal complications in the Swedish women. The 4 years of ERT of men with no or mild proteinuria resulted in maintained kidney function. In addition, there was no increase in left ventricular mass. Conclusion: The study indicates that ERT stabilizes kidney function in Fabry patients with no or mild proteinuria and has a cardioprotective effect.

Foot Process Effacement Is an Early Marker of Nephropathy in Young Classic Fabry Patients without Albuminuria

In Fabry disease, globotriaocylceramid (GL3) starts to accumulate in kidney cells in utero, and continues to accumulate throughout childhood and adulthood with progressive tissue damage, which may lead to renal failure. Material and Methods: Eight children with classical Fabry disease, median age 12 (range 4-16 years) had a renal biopsy performed before the initiation of enzyme replacement therapy (ERT). All patients were normalbuminuric and had normal GFR. Three patients were re-biopsied after three or five years. Results: In all patients, significant GL3-accumulation was found in several types of kidney cells with high amounts of GL3 in the podocytes. Segmental podocyte foot process effacement was shown in all but two patients; no effacement was seen neither in the youngest male patient at 4 years of age nor in a male aged 12. A 12-year-old female patient had normal podocyte foot processes before the start of ERT, but de novo foot process flattening and unchanged high score of podocyte GL3 accumulation were seen in the re-biopsy after three years of ERT (agalsidase alpha 0.2 mg/kg/every other week). Two boys showed worsening of podocyte effacement in kidney biopsy after five years of agalsidase alpha 0.2 mg/kg/eow. Conclusions: Podocyte foot process effacement was found in the majority of eight young classical Fabry patients of both genders after the age of 11 years, without clinical signs of Fabry nephropathy. Kidney biopsies are essential in the early diagnosis of nephropathy and in the evaluation of the response to enzyme replacement therapy of early Fabry nephropathy.

Encore - a Randomized, Controlled, Open-Label Non-Inferiority Study Comparing Eliglustat to Imiglucerase in Gaucher Disease Type 1 Patients Stabilized on Enzyme Replacement Therapy: 24-Month Results

Introduction: Eliglustat is a novel oral substrate-reduction therapy in development for adults with Gaucher disease type 1 (GD1). This open-label Phase-3 trial (ENCORE, NCT00943111, Genzyme, a Sanofi company, Cambridge, MA), the largest randomized, controlled trial in GD1 to date, evaluated eliglustat and imiglucerase treatment in patients who had previously reached pre-specified therapeutic goals after ≥3 years of enzyme replacement therapy. We report efficacy data from the 12-month primary analysis period (PAP) and the first 12 months of the extension period in which all patients received eliglustat.Methods: Patients were randomized 2 to 1 eliglustat to imiglucerase. The primary efficacy endpoint was percent of patients remaining stable on a pre-specified composite of spleen, liver, hemoglobin, and platelet parameters. As this was a non-inferiority trial, efficacy analyses were performed on the per-protocol population (99 eliglustat and 47 imiglucerase patients).Results: Eliglustat was non-inferior to imiglucerase: after 12 months of treatment, 85% of eliglustat and 94% of imiglucerase patients maintained all 4 goals (lower bound of 95% CI of difference [-17.6%] within the pre-specified [-25%] non-inferiority margin). Of the 159 patients treated in this study, 145 (91%) completed 24 months of treatment. During the 12-month extension period, continued stability was seen in most patients in both groups. Among 99 of 106 patients who continued on eliglustat, stability was seen in spleen volume (96% of patients), hemoglobin (97%), platelet count (94%), and liver volume (96%). In 47 of 53 patients who received imiglucerase in the PAP and then eliglustat in the trial extension, continued stability was seen also in spleen volume (97% of patients), hemoglobin (100%), platelet count (90%), and liver volume (95%). Most adverse events were mild or moderate in severity. No new safety concerns have arisen after 24 months.Conclusions: Eliglustat was non-inferior to imiglucerase in maintaining stability after 12 months of treatment in patients previously stabilized on enzyme replacement therapy. In the 12-month trial extension, clinical stability was maintained in most patients who remained on eliglustat for 24 months and in most patients who switched from imiglucerase to eliglustat. DisclosuresRosenbloom:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Off Label Use: Eliglustat is an investigational drug for the treatment of Gaucher disease type 1. Cox:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Drelichman:Genzyme, a Sanofi Company: Consultancy, Honoraria. Cravo:Genzyme, a Sanofi Company: Consultancy, Honoraria. Balwani:Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel reimbursement Other. Burrow:Biomarin: Consultancy, Honoraria, Travel reimbursement, Travel reimbursement Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Martins:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Lukina:Shire: Consultancy, Honoraria, Travel reimbursement, Travel reimbursement Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Ross:Genzyme, a Sanofi Company: Employment. Angell:Genzyme, a Sanofi Company: Employment. Peterschmitt:Genzyme, a Sanofi Company: Employment.

T.P.22: Two cases of late-onset Pompe disease treated with enzyme replacement therapy: Clinical outcome for 3 years follow-up

Pompe disease is a progressive neuromuscular disorder, caused by an inherited deficiency of acid alpha-glucosidase (GAA). Treatment of pompe disease with enzyme replacement therapy (ERT) may reverse, stabilize or slow disease progression. We present 2 cases of Late-onset pompe disease (LOPD) treated with ERT for about 3years. Case 1: A 33-year-old man was admitted in our hospital for dyspnea. At 16years old, He felt progressive weakness of his lower limbs. At 18years old, He felt tiredness when he climbed the stairs. At 29years old, he had mild respiratory difficulty. At 33years old, he admitted in our hospital and showed proximal weakness, low forced vital capacity (FVC) and elevated creatine kinase (CK) level. On dried blood spot (DBS) test and molecular analysis, low GAA activity and two mutations (c.1309C>T, c.1316T>A) were detected. He applied non-invasive positive pressure ventilation (NIPPV) and treated with ERT for 3years. For two years with ERT, he can walk without assistance for some minutes and his other symptoms were improved. But, for 3rd year with ERT, symptoms were slightly deteriorated and he could not walk without assistance beyond 5min. Case 2: A 53-year-old woman was admitted with slowly progressive proximal weakness of the lower limbs. At 12years old, she had difficulty climbing stairs. At 47years old, she experienced breathing difficulty in the supine position. At 48years old, she admitted to hospital to evaluate her weakness and use the NIPPV. She showed proximal weakness, low FVC and normal CK level. On DBS test and molecular analysis, low GAA activity and two mutations (c.1316T>A, c.2238G>C) were detected. After 3years of ERT treatment, she presented slightly improved clinical course. After three years, she can walk without assistance beyond 500 meters and use NIPPV during only sleep. Our findings show that ERT had a stabilized or improving therapeutic effect of neuromuscular deficits in LOPD patients during 3years of ERT.

Study of enzyme replacement therapy for Gaucher Disease: comparative analysis of clinical and laboratory parameters at diagnosis and after two, five and ten years of treatment.

ObjectiveTo evaluate the impact of enzyme replacement therapy for Gaucher Disease on clinical and laboratory parameters after two, five and ten years of treatment.MethodsData were collected from patient records and analyzed using BioEstat software (version 5.0). Student's t-test, Analysis of Variance (ANOVA), Wilcoxon test and Kruskal–Wallis test were used for statistical analysis. Hepatomegaly and splenomegaly were analyzed using the Kappa test.ResultsThere was a significant increase in hemoglobin levels (p-value <0.01) and platelet counts (p-value = 0.01) within two years of therapy. At the same time, the frequencies of splenomegaly (p-value <0.01) and hepatomegaly (p-value <0.05) reduced. These results were similar at five and ten years of enzyme replacement therapy.ConclusionsThere are substantial and quick (within two years) laboratory and clinical responses to enzyme replacement therapy. These improvements continue as long as enzyme replacement therapy is administered every two weeks, as recommended by the literature.

Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy.

Gaucher disease (GD) is caused by deficiency of the enzyme glucocerebrosidase catalysing the regular lysosomal degradation of glucosylceramide. In the common non-neuropathic variant of GD, glucosylceramide-laden macrophages (Gaucher cells) accumulate in various tissues. Gaucher cells secrete chitotriosidase, an active chitinase, resulting in increased plasma chitotriosidase levels, which can be sensitively monitored by an enzyme activity assay. Plasma chitotriosidase is a rough estimate of body burden of Gaucher cells. Non-neuronopathic GD is presently treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). We addressed the question whether plasma chitotriosidase acts as (predictive) marker of clinical manifestations in non-neuronopathic GD patients receiving treatment. Reductions in plasma chitotriosidase during therapy correlated with corrections in liver and spleen volumes and showed positive trends with improvements in haemoglobin and platelet count and bone marrow composition. The occurrence of long-term complications and associated conditions such as multiple myeloma, bone complications, Parkinson's disease, hepatocellular carcinoma and pulmonary hypertension positively correlated with the plasma chitotriosidase level pre-therapy, the average plasma chitotriosidase during 3years of ERT and the residual plasma chitotriosidase after 2years of ERT. In summary, plasma chitotriosidase is a valuable marker in the assessment and follow-up of GD patients.

Fabry disease: multidisciplinary evaluation after 10 years of treatment with agalsidase Beta.

Fabry disease is an X linked disorder of metabolism due to deficient α-galactosidase A activity. Enzyme replacement therapy (ERT) with agalsidase Beta was approved by EMA in 2001 and FDA in 2003. Six patients were enrolled. Baseline data was measured for renal, cardiac, and cerebrovascular functioning. We compared baseline quality of life scales with the current results. These parameters were assessed during the 10years of follow-up period. Before ERT four patients showed normal eGFR, one stage 2 of CKD, and one hyperfiltration stage. All presented microalbuminuria and just two cases showed proteinuria. After 10years of ERT, no patient showed decrease in renal functioning. One patient decreased from proteinuria to microalbuminuria range. Before treatment one case showed left ventricular (LV) hypertrophy and LV Mass Index was abnormal in two female patients. After 10years echocardiographic values did not present progression to LVH and one female showed regression to normal values of LV posterior wall and interventricular septum. Brain MRI showed ischemic lesions in one female and vertebrobasilar dolichoectasia in one male. From baseline and during the follow-up period MRI did not progress to new ischemic lesions and there were no clinical signs of cerebrovascular damage. After 10years quality of life showed improvement in all domains measured. Early treatment of agalsidase Beta is related to a better outcome regarding stability and regression of signs and symptoms in Fabry disease. Our results in patients with mild organ involvement showed good outcomes and support an early and continuous ERT.

Late‐onset Pompe disease after 4 years of enzyme replacement therapy: An autopsy case

AbstractWe report an autopsy case of advanced late‐onset Pompe disease (juvenile type). At 15 years‐of‐age, the patient experienced proximal weakness and subsequently required non‐invasive positive pressure ventilation. Enzyme replacement therapy was initiated at 37 years‐of‐age, which improved pinch power and alleviated respiratory distress. At age 41 years, repetitive pneumothorax led to respiratory failure and death. Autopsy excluding the brain showed few vacuoles and periodic acid–Schiff‐positive fibers in the left rectus femoris, compared with the contralateral muscle biopsy carried out at 21 years‐of‐age. Vacuolar changes were also less evident than previous autopsy cases without enzyme replacement therapy. The findings suggest that enzyme replacement therapy might have suppressed myovacuolopathy in our patient with advanced late‐onset Pompe disease. Apart from vacuolopathy, the autopsied muscle showed marked myofiber atrophy and fibrosis, suggesting that disuse atrophy could have contributed to the muscle weakness.

Chitotriosidase variants in patients with Gaucher disease. Implications for diagnosis and therapeutic monitoring

ObjectivesHuman plasma chitotriosidase (ChT) activity, a biomarker for evaluating and monitoring Gaucher disease (GD), varies in the general population owing to variants in the CHIT1 gene. Our aim is to determine the frequency of the c.1049_1072dup24 (dup24) and p.G102S polymorphisms, their influence on plasma ChT activity, and its change with enzyme replacement therapy (ERT). Design and methodsThe study included 269 type1 GD patients. Genomic DNA was genotyped using PCR, restriction isotyping and agarose gel electrophoresis. ChT activity was measured with the 4-methylumbelliferyl-β-D-N,N′,N″triacetylchitotrioside substrate at non-saturating concentrations at diagnosis, before beginning therapy and after one year on ERT. ResultsAllele frequencies for dup24 and p.G102S were 0.22 and 0.27, respectively. Four percent of patients were homozygous and 37% heterozygous for dup24, and 9% homozygous and 37% heterozygous for p.G102S. The presence of dup24 and p.G102S polymorphisms in the CHIT1 gene significantly reduced plasma ChT activity in naïve patients. By contrast, the percentage of ChT activity decrease after one year of ERT was independent of the presence of these genetic variants. ConclusionsThis study indicates that genotyping for c.1049_1072dup24 and p.G102S polymorphisms will improve the interpretation of plasma chitotriosidase activity at diagnosis but, this is not mandatory for monitoring of enzyme replacement therapy.

Oxidative Stress, Trace Elements, and Circulating Microparticles in Patients With Gaucher Disease Before and After Enzyme Replacement Therapy

We studied the level of lipid peroxide, nitric oxide (NO), trace elements (TEs), and microparticles (MPs) in Gaucher disease (GD) before and after 1 year of enzyme replacement therapy (ERT). A total of 15 children with GD and 15 healthy controls were enrolled in this study. Serum level of lipid peroxide, NO, and TEs was determined. The MPs were detected by flow cytometry. The level of lipid peroxide was significantly higher in the patients than in the controls even after ERT. Although NO level was normalized in the patients after ERT, zinc and copper were still lower in the patients after ERT. The percentages of various MPs were significantly higher in the patients than in the controls both before and after ERT. There were positive correlations between chitotriosidase and both lipid peroxide and total MPs. The GD is associated with alteration in oxidant and antioxidant status and high level of circulating MPs.

Agalsidase Benefits Renal Histology in Young Patients with Fabry Disease

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Enzyme Replacement Therapy in an Attenuated Case of Mucopolysaccharidosis Type I (Scheie Syndrome): A 6.5-Year Detailed Follow-Up

We present the 6.5-year follow-up of a boy with Scheie syndrome whose therapy was initiated at age 2.5 years. Detailed anthropometric features, echocardiography, ophthalmologic and audiologic examinations, psychologic tests, joint range of motion, skeletal radiographs, ultrasound studies of liver and spleen volumes, urinary glycosaminoglycans, and antibodies were documented. After 6.5 years of enzyme replacement therapy, the patient experienced a decline in overall status, and the disease progressed significantly despite treatment. The patient's height at age 9 was equal to that at age 6. The patient developed heart insufficiency and a deterioration of airway flow. The patient's intelligence quotient remained unchanged, i.e., at the average level of 86 on the Terman-Merill Scale. Magnetic resonance imaging revealed cervical spinal canal stenosis and marked spinal cord compression with myelopathy. A worsening of carpal tunnel syndrome was also evident. Ophthalmologic evaluation revealed increased central corneal thickness and intraocular pressure. In audiologic assessment, the patient's results were similar to those after 3 years of treatment. The only benefit involved temporarily improved passive and active shoulder flexion. Overall, the benefit of enzyme replacement therapy with laronidase on Scheie syndrome appeared minimal.

A renal variant of Fabry disease: A case with a novel Gal A hemizygote mutation

Fabry disease is caused by an X-linked recessive inborn error of glycosphingolipid metabolism with deficient activity of a lysosomal enzyme, alpha-galactosidase A (α-GalA). A 46 year-old man with progressive kidney disease showed on kidney biopsy electron microscopic evidence of Fabry disease. The patient had no systemic manifestations of Fabry disease, despite residual α-GalA activity, therefore genetic testing was done by direct DNA sequencing, demonstrating a new GAL A gene mutation (C174G-exon 3). After three years of enzyme replacement therapy (agalsidase beta) treatment, a second biopsy was done. Although there was demonstrable clearance of intracellular inclusions, remarkable podocyte activation was evident. This report represents an unusual renal variant of Fabry disease and provides histologic data on long-term follow up after enzyme replacement therapy.

Dynamic changes of lipid profile in Romanian patients with Gaucher disease type 1 under enzyme replacement therapy: a prospective study

Dyslipidemia in Gaucher disease includes reduced total, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol (C). No prospective analysis of lipid profile changes in treatment-naïve patients under enzyme replacement therapy (ERT) is available. We analyzed lipid profile changes during ERT in a prospective controlled manner. Twelve treatment-naïve patients, Gaucher disease type 1 (GD1), 29.5 ± 12.9 years, 4M/8F. Diagnosis was made by enzymatic measurement and mutational analysis. Total-, LDL-, and HDL-C, triglycerides (TG), and LDL subfractions were assessed before the start of ERT with imiglucerase and biannually for 3 years. Patients were matched with healthy controls before and after 3 years of ERT. At baseline, we found severely reduced HDL-C concentrations (23.6 ± 5.4 mg/dl) and enhanced LDL/HDL ratios (3.1 ± 0.7). HDL-C increased after 6 months (29.2 ± 5.7, p = 0.023), LDL/HDL ratio decreased after 30 months (2.5 ± 0.5, p = 0.039). TG, even not consistently enhanced at baseline (128 ± 31.3 mg/dl), yet higher than in controls (p < 0.001), decreased after 18 months, being comparable with controls after 3 years of ERT. Small, dense LDL (mg/dl) increased continuously without significant difference to controls. After 3 years of ERT, only reduced HDL-C concentrations persisted as a potentially atherogenic alteration; however, mean concentrations markedly improved (42.9 ± 8.3 mg/dl, p < 0.001). Lipid parameters correlated with six markers of disease severity. This is the first prospective controlled study regarding lipid profile dynamics during ERT (glucocerebrosidase) in initially treatment-naïve GD1 patients. The most important changes were reduced HDL-C and enhanced LDL/HDL ratio. Their dynamics during ERT and correlations with markers of disease activity suggest that they can be considered markers of disease severity and follow-up in Gaucher patients under treatment.

Consensus treatment recommendations for late‐onset Pompe disease

Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease. A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued.

Two-Year Safety and Tolerability of Velaglucerase Alfa in Patients with Type 1 Gaucher Disease, Including Patients Switched From Imiglucerase: Phase III Trial HGT-GCB-039 and Extension,

Abstract 3214 BACKGROUNDType 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. OBJECTIVETo 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]). METHODSIn 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.Patients, n (%)*0–9 months (HGT-GCB-039)9–24 months (HGT-GCB-044)DescriptionVelaglucerase alfa(n=16)Imiglucerase → velaglucerase alfa(n=16)Velaglucerase alfa(n=16)Imiglucerase → velaglucerase alfa(n=16)Experienced ≥1 AE15 (94)15 (94)15 (94)13 (81)Experienced ≥1 drug-related AE8 (50)5 (31)2 (13)4 (25)Experienced ≥1 infusion-related AE5 (31)3 (19)2 (13)1 (6)Experienced ≥1 severe AE2 (13)1 (6)3 (19)2 (13)Drug-related2 (13)000Experienced ≥1 serious AE2 (13)03 (19)3 (19)Experienced ≥1 life-threatening AE0000*Patients who completed HCT-GCB-039 and entered HCT-GCB-044; the 2 patients who discontinued HCT-GCB-039 are not included. CONCLUSIONSVelaglucerase 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.

Early cognitive development in children with infantile Pompe disease

This report describes the cognitive development of 17 children with infantile Pompe disease who participated in a 52-week clinical trial of enzyme replacement therapy (ERT) via biweekly infusion of Myozyme® (alglucosidase alfa). Subjects were six months of age or younger (adjusted for gestational age) upon initiation of ERT. The Mental Scale of the Bayley Scales of Infant Development-Second Edition (BSID-II) was administered to obtain a Mental Development Index (MDI) at baseline and weeks 12, 26, 38, and 52 of ERT to assess cognitive development in this treated cohort. Data regarding motor development were also obtained at the same visits and these were used to determine correlations between cognitive and motor development. Over the course of the study, two subgroups of subjects emerged: high responders who were sitting independently and/or ambulating by week 52 (n=13) and limited responders who showed minimal motor gains throughout the first year of ERT (n=4). In the high responder group, MDI scores on the BSID-II remained stable throughout the study and were within normal limits. Positive correlations between cognitive and motor development were also present. These data suggest that the cognitive function of infants up to 18months of age with Pompe disease is unaffected by the possible presence of glycogen in the central nervous system. Continued investigation of the cognitive development of older survivors is warranted.