Neal J. Weinreb

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.

Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease

Background Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. Methods The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. Results 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. Conclusions This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease

The effect of enzyme replacement therapy (ERT) on bone crisis and bone pain was investigated in patients with Gaucher disease (GD) type 1 followed over 4 years. Data from the International Collaborative Gaucher Group Gaucher Registry were used. Only patients with bone crisis and/or bone pain data for 1 year prior to ERT, and for each of 3 years after the start of ERT, were included. Bone crises were reported in 17% of patients during the year before starting ERT. The frequencies of bone crises decreased to 5%, <1% and 3% for 1, 2, and 3 years after initiation of treatment, respectively (p < 0.0001). Bone pain followed a similar pattern of response. Bone pain was reported in 49% of patients the year before treatment and decreased to 30% in the first year, 29% in the second year, and 30% in the third year of ERT (p < 0.0001). ERT is associated with a reduction in bone crisis and bone pain in patients with GD type 1 . This study shows that significant improvements in symptoms of skeletal disease are achievable clinical outcomes and treatment goals in GD type 1.

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.

Acceleration of retarded growth in children with Gaucher disease after treatment with alglucerase.

OBJECTIVES The incidence and severity of growth retardation in children with type 1 Gaucher disease and the response to enzyme replacement therapy with alglucerase were studied. STUDY DESIGN A retrospective analysis of growth in 99 children and adolescents with type 1 Gaucher disease before treatment, and in 54 of those subjects during treatment, was done. Growth was compared with gender, age, and dosage of replacement enzyme. RESULTS Linear growth was normal in the first 1 to 2 years of life and then decelerated. Height was at or below the 5th percentile in 50% of all subjects immediately before treatment. The mean z score was -1.49 (95% confidence interval, -1.83 to -1.16), corresponding to the 6.8th percentile for height. Seventy-two percent were below the 50th percentile and 50% were at or below the 5th percentile for mid-parental height (p <0.001). One and one-half years after treatment was started, the estimated mean z score for all subjects was -1.01, which corresponds to the 16th percentile for height. Normal growth was achieved within 4 to 30 months in eight of nine subjects who were at or below the 5th percentile. It occurred only in those receiving higher doses (60 to 120 U/kg per 4-week period) of alglucerase. There was a significant association between z scores for height before treatment and liver enlargement (r= 0.57; p < 0.01). CONCLUSIONS Half of the subjects who manifest type 1 Gaucher disease in childhood have growth retardation. Treatment with adequate amounts of modified enzyme replacement was effective in normalizing linear growth.

Imiglucerase (Cerezyme) improves quality of life in patients with skeletal manifestations of Gaucher disease.

Health‐related quality of life (HRQOL) can be diminished in patients with type 1 Gaucher disease (GD) owing to the debilitating clinical manifestations of this chronic disease. This study investigates the impact of imiglucerase treatment on HRQOL of patients with type 1 GD and bone involvement. Thirty‐two previously untreated type 1 GD patients with skeletal manifestations including bone pain, medullary infarctions, avascular necrosis, and lytic lesions received biweekly imiglucerase (at 60 U/kg). The Short Form‐36 Health Survey (SF‐36) was administered at regular intervals to assess HRQOL. Mean baseline SF‐36 physical component summary (PCS) scores were diminished relative to US general population norms. Low PCS scores were more common in patients with medullary infarction, lytic lesions, and higher bone pain severity scores. Statistically significant improvements were observed for all eight SF‐36 subscales after 2 years of treatment. Mean PCS and mental component summary (MCS) scores increased to within the normal range after 2 years of treatment and were maintained through year 4. Large HRQOL gains were observed even in patients with the most advanced disease and lowest baseline PCS scores. Imiglucerase treatment has a significant positive impact on HRQOL of type 1 GD patients with skeletal disease, including those with bone infarctions, lytic lesions, and avascular necrosis.

Osteopenia in Gaucher disease develops early in life: Response to imiglucerase enzyme therapy in children, adolescents and adults

BACKGROUND In Gaucher disease (GD), acid-β-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to imiglucerase enzyme therapy, differs by the age of the patient. OBJECTIVE We hypothesized that osteopenia develops early in life, during the natural course of type 1 Gaucher disease (GD1), and that its response to treatment is maximal during this period. METHODS We examined data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry of patients treated with imiglucerase between the ages of 5 and 50 years. Lumbar spine bone mineral density (BMD) (determined by dual-energy X-ray absorptiometry (DXA) and expressed as Z-scores) at baseline and for up to 10 years on imiglucerase were analyzed in children (ages ≥ 5 to <12 years), adolescents (≥ 12 to <20 years), young adults (≥ 20 to < 30 years), and older adults (≥ 30 to < 50 years). BMD was correlated with other disease characteristics. Pre-treatment, descriptive statistics were applied to 5-year age categories. Non-linear mixed effects regression models were used to analyze DXA Z-scores over time after treatment with imiglucerase. RESULTS Pre-treatment, low BMD was prevalent in all age groups, most strikingly in adolescents. DXA Z-scores were at or below -1 in 44% of children (n=43), 76% of adolescents (n=41), 54% of young adults (n=56) and 52% of older adults (n=171). The most common GBA1 genotype was N370S heteroallelic. Baseline hematological and visceral manifestations in the 4 age groups were similar. In children with DXA Z-scores ≤-1 at baseline, imiglucerase therapy for 6 years resulted in improvement of mean DXA Z-scores from -1.38 (95% CI -1.73 to -1.03) to -0.73 (95% CI -1.25 to -0.21); in young adults DXA Z-scores improved from -1.95 (95% CI -2.26 to -1.64) to -0.67 (95% CI -1.09 to -0.26). BMD also improved in older adults, but the magnitude of the improvement was lower compared to younger patients. CONCLUSIONS Low bone density is common in GD1 with the highest prevalence rate in adolescence, a developmental period critical to attainment of peak bone mass. Imiglucerase results in amelioration of osteopenia in all age groups, with the greatest improvements in younger patients.

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment

We studied the effect of long‐term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1).

The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry.

PURPOSE Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients. METHODS STUDY TYPE Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier). DATA SOURCE The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism. RESULTS The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years. CONCLUSIONS The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.