Gregory M. Pastores

Effectiveness of Enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: A report from the Gaucher registry

PURPOSE Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. SUBJECTS AND METHODS Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. RESULTS Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. CONCLUSION Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Enzyme Therapy in Type 1 Gaucher Disease: Comparative Efficacy of Mannose-Terminated Glucocerebrosidase from Natural and Recombinant Sources

Gaucher disease, an inborn error of glycosphingolipid metabolism, is the most frequent lysosomal storage disease [1]. Non-neuronopathic or type 1 disease is the most common variant and the most prevalent genetic disease among Ashkenazi Jews [2, 3]. Various point mutations, deletions, and insertions within the glucocerebrosidase (acid -glucosidase, EC 3.2.1.45) locus at chromosome 1q21 result in a deficiency of this lysosomal enzyme [4, 5]. The subsequent accumulation of glucocerebroside (glucosylceramide) in cells of monocyte-macrophage lineage leads to the visceral manifestations of anemia, thrombocytopenia, hepatosplenomegaly, skeletal disease, and, less frequently, primary lung involvement [1]. Gaucher disease has become a prototype genetic disease for the development of prenatal diagnosis [6], genotype-phenotype correlations [2, 7, 8], and effective therapy [9-13]. On the basis of the clear efficacy of targeted enzyme therapy [10], recent studies [9, 12, 14, 15] in more than 90 patients have established that regular infusions of enzyme purified from placenta (alglucerase [Ceredase; Genzyme Corp., Cambridge, Massachusetts]) lead to regression of the clinical manifestations of Gaucher disease. In addition, antibody-mediated and non-antibody-mediated adverse events have occurred in only 5% to 7% of treated patients [15, 16]. Ceredase is a commercial form of placenta glucocerebrosidase that has been modified for targeting mannose receptor sites on macrophages and other cells [17, 18]. A theoretical limitation to the use of Ceredase is the remote possibility of infective contaminants in the preparation from human placenta. A practical limitation is the finite availability of acceptable placentae. For each patient, approximately 10 to 12 tons of placentae or about 50 000 per year are needed as source material for Ceredase. Enzyme produced by heterologous expression of human complementary DNA (cDNA) for glucocerebrosidase in eukaryotic cells could eliminate both of these limitations. To determine the efficacy of recombinant glucocerebrosidase, we did a randomized, double-blind, parallel trial with mannose-terminated glucocerebrosidase (alglucerase, Ceredase) from human placenta and the human enzyme that is produced in Chinese hamster ovary cells and deglycosylated to expose mannose residues in the oligosaccharide chains (imiglucerase, Cerezyme [Genzyme Corp.]). Methods Thirty patients with non-neuronopathic type 1 Gaucher disease were entered into the trial after consent was obtained. Deficiency of glucocerebrosidase (5% to 15% of mean normal activities) was shown by natural or artificial substrates in peripheral blood mononuclear cells, cultured skill fibroblasts, or lymphoblastoid cell lines obtained from each patient [19, 20]. Inclusion criteria for the study were as follows: 1) enzymatically confirmed glucocerebrosidase deficiency; 2) patient age between 2 and 75 years; 3) an intact, enlarged spleen; 4) a hemoglobin level at least 10 g/L less than the lower limit of normal; and 5) in women, a willingness to avoid pregnancy during the trial. Exclusion criteria were as follows: 1) inability to comply with study requirements; 2) previous receipt of any form of glucocerebrosidase; 3) total splenectomy; 4) a concurrent major medical disorder, such as active infectious disease or substance abuse; and 5) positive serologic response to hepatitis B surface antigen or human immunodeficiency virus (HIV) type 1, or both. The patients had moderate to severe Gaucher disease. The study was a double-blind, parallel trial with random assignment to Ceredase or Cerezyme. We categorized randomization into three groups according to patient age: 1) younger than 12 years; 2) 12 to 17 years; and 3) older than 17 years. In each study center, patients were independently randomly assigned in blocks by age and were assigned study numbers. All study personnel except the pharmacist at each institution were blinded to the allocated treatment. No children younger than 12 years were enrolled in the study. Of the 30 patients enrolled, 17 were male and 13 were female (age range, 12 to 69 years). Of the 7 patients between 12 and 17 years of age, 4 received Ceredase and 3 received Cerezyme. Twenty-three patients older than 17 years were enrolled; 11 of them received Ceredase and 12 received Cerezyme. The groups of patients treated with Ceredase or Cerezyme did not differ in sex distribution, age, weight, or height. All patients received Cerezyme or Ceredase at a dose of 60 U/kg body weight once every 2 weeks for 9 months. Complete hematologic and clinical chemistry data were available for this period. At this dose, complete data for hepatic and splenic volumes were available for all patients for the first 6 months. Hepatic and splenic volumes were evaluated in the 16 patients from the Mt. Sinai School of Medicine at 9 months, just before a dose-reduction study began. The hepatic and splenic volumes of the patients from the National Institutes of Health (NIH) were evaluated at 12 months. We did not include these data in our report. We did analyses of variance and other statistical analyses using Systat software (Systat Inc., Evanston, Illinois). In addition to physical examinations, clinical laboratory studies were done to monitor both therapeutic efficacy and potential toxic effects, including total serum acid phosphatase levels, angiotensin-converting enzyme levels, serum bilirubin levels, hemoglobin levels, platelet counts, peripheral blood leukocyte counts, and serum iron and clotting studies. At baseline and at study completion, hepatitis B surface antigen assay; HIV-1 serologic testing; serum protein electrophoresis; and complement C3, C4, and CH-50 studies were done. Hepatic and splenic volumes were estimated by computed tomography (at Mt. Sinai School of Medicine) [12, 15] or magnetic resonance imaging (at NIH) [21]. We calculated the increases over normal volumes by assuming that the hepatic and splenic masses (1 g/mL density) were 2.5% and 0.2% of body weight, respectively [22]. To avoid biasing the results because of the nearly universal weight gain in treated patients, we averaged the body weight of adults over the study period. In children (patients younger than 18 years), we calculated the hepatic and splenic volumes on the basis of body weight at each time point to allow for growth. We monitored the formation of antibodies to natural or recombinant glucocerebrosidases every 3 months by radioimmunoprecipitation assay [16]. Adverse events were monitored at each infusion. Before each infusion, we also obtained a history of intra-infusion adverse events. Ceredase was supplied as a clear liquid solution stored at 4 C, solubilized in the presence of albumin. Cerezyme was purified from culture media of Chinese hamster ovary cell clones that contained numerous copies of the human glucocerebrosidase cDNA. Carbohydrate removal to expose core mannose moieties was done by the sequential exoglycosidase treatment used to produce Ceredase. The amino acid sequences of glucocerebrosidase in Ceredase and Cerezyme were identical except for a single amino acid substitution of a histidine for a natural arginine at position 495 in the latter. The lack of effect of this amino acid change on the catalytic function of glucocerebrosidase has been documented [23]. Cerezyme was supplied as a lyophilized powder containing mannitol, sodium citrate, and polysorbate 80. Cerezyme as lyophilized powder was stored at 4 C until use. Immediately before administration, Cerezyme was reconstituted with sterile water to a concentration of 40 U/mL. Ceredase or Cerezyme stocks were diluted in 0.9% NaCl just before infusion. During the study, the patients were weighed at each infusion, and the total dose to be administered was adjusted to 60 U/kg on the basis of the current weight. A unit of enzyme activity (U) is defined as the amount of enzyme required to cleave 1 mol of p-nitrophenol--d-glucopyranoside per minute. Results Hematologic Findings The effects of Ceredase and Cerezyme infusions on hemoglobin levels by 6 and 9 months are shown in Tables 1 and 2. Neither the mean initial hemoglobin level (approximately 107 g/L) nor changes in hemoglobin levels differed between the two treatment groups. During the first 6 months of therapy, hemoglobin levels increased by a mean of 17.1 g/L. In patients with hemoglobin levels less than 120 g/L, 54% and 30% of the patients receiving Ceredase and Cerezyme, respectively, achieved this or a greater level by 6 months. Sixty-nine percent and 40%, respectively, of patients receiving Ceredase and Cerezyme achieved these levels by 9 months. The rates at which hemoglobin levels increased by 10 and 15 g/L were also similar. An average of 92 days was required for the hemoglobin level to increase 10 g/L in the Ceredase group, whereas an average of 77 days was needed in the Cerezyme group. For the Ceredase and Cerezyme groups, hemoglobin levels increased 15 g/L in 113 and 125 days, respectively. None of the above differences was significant (P > 0.2). In both treatment groups, we observed lesser degrees of response in patients with higher initial hemoglobin levels. However, this conclusion was strongly influenced by two patients who had initial hemoglobin levels less than 90 g/L and large responses to treatment, that is, an increase of more than 30 g/L during the first 6 months of therapy. Table 1. Clinical Findings from Patients with Type I Gaucher Disease Treated with Ceredase and Cerezyme* Table 2. Effects of Ceredase and Cerezyme on Hematologic Measurements All patients in the study had thrombocytopenia (mean platelet count, approximately 71.5 109/L). About half (7 of 15) of the patients in each group had increases in platelet counts of 20% and 40% or more during the 6- and 9-month treatment periods, respectively (Table 2). These responses to therapy did not differ between the Ceredase and Cerezyme groups. In each group and in the entire st

Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal α-galactosidase A, and the subsequent accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Males with classical Fabry disease develop early symptoms including pain and hypohidrosis by the second decade of life reflecting disease progression in the peripheral and autonomic nervous systems. An insidious cascade of disease processes ultimately results in severe renal, cardiac, and central nervous system complications in adulthood. The late complications are the main cause of late morbidity, as well as premature mortality. Disease presentation in female heterozygotes may be as severe as in males although women may also remain asymptomatic. The recent introduction of enzyme replacement therapy to address the underlying pathophysiology of Fabry disease has focused attention on the need for comprehensive, multidisciplinary evaluation and management of the multi-organ system involvement. In anticipation of evidence-based recommendations, an international panel of physicians with expertise in Fabry disease has proposed guidelines for the recognition, evaluation, and surveillance of disease-associated morbidities, as well as therapeutic strategies, including enzyme replacement and other adjunctive therapies, to optimize patient outcomes.

Long-term Efficacy and Safety of Laronidase in the Treatment of Mucopolysaccharidosis I

OBJECTIVE. Our goal was to evaluate the long-term safety and efficacy of recombinant human α-l-iduronidase (laronidase) in patients with mucopolysaccharidosis I. PATIENTS AND METHODS. All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6–43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean ± SEM. RESULTS. All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of −0.78 percentage points per year. The 6-minute walk distance increased 31.7 ± 10.2 m in the first 2 years, with a final gain of 17.1 ± 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 ± 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4° ± 3.6°) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 ± 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment. CONCLUSIONS. This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes.

Enzyme-Replacement Therapy With Agalsidase Alfa in Children With Fabry Disease

CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5–18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS. Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS. Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease.

The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients and 342 ERT‐treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD.

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

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

The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross‐sectional study. In addition, the relative risk (RR) of cancer in patients compared with age‐, sex‐, and ethnic‐group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17–54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49–6.79), and overall cancer risk (RR 1.80, 95% CI 1.32–2.40) was increased. Homozygous N370S GD leads to adult‐onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol., 2009.

Individualization of long-term enzyme replacement therapy for Gaucher disease

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous condition affecting multiple organ systems. Patients with nonneuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, MA) reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, due to the variable pattern and severity of disease, and the uncertain manner of progression, implementation of treatment, choice of initial and maintenance imiglucerase dose, and evaluation of the therapeutic response must be tailored to the individual patient. For the past 14 years, the US Regional Coordinators of the International Collaborative Gaucher Group have individually and collectively developed extensive clinical experience in managing patients with Gaucher disease. In this review, we present recommendations for initial imiglucerase treatment and subsequent dose adjustments based on a schedule of regular assessment and monitoring, and achievement and maintenance of defined therapeutic goals.

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study.

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48‐month, prospective, non‐randomized, open‐label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase‐naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre‐treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual‐energy X‐ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near‐normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.