Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long‐term disease‐specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty‐eight of 40 patients (aged 9–71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12‐month, open‐label clinical study, and for 10–50 months in an extension study. The most common adverse events (AEs) judged to be drug‐related in the extension were fatigue and bone pain. No drug‐related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10⁹/L at baseline, were given at least one 15 U/kg‐dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti‐imiglucerase antibodies at baseline. This patient tested positive for anti‐velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes. Am. J. Hematol. 90:592–597, 2015. © 2015 Wiley Periodicals, Inc.     

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase

Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT‐1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open‐label, 12‐month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9–71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment‐related: a Grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE‐related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa Phase 3 clinical trial program. Am. J. Hematol. 88:172–178, 2013. © 2012 Wiley Periodicals, Inc.     

Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease

IntroductionTherapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy.AimTo benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology).MethodsIn an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long-term extension. After 1 year, patients who achieved ≥ 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline.ResultsAt baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved ≥ 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals.DiscussionIn this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after ≥ 2 years dose reduction.     

Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction

Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-na?ve symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1.     

Nonprecipitous changes upon withdrawal from imiglucerase for Gaucher disease because of a shortage in supply

Because of an unpredicted and unavoidable shortage in global supplies of imiglucerase for Gaucher disease, we collected clinical and laboratory data from patients who were evaluated ≤ 6 months before drug withdrawal and then retested before/during reinstatement of therapy. Hemoglobin, platelet counts, and liver and spleen index volumes by ultrasound as well as chitotriosidase were evaluated as percent change over time and relative to dose-years of exposure to enzyme therapy. Deterioration was seen in all four clinical parameters and in chitotriosidase activity in most patients and even among patients who stopped for only 3 months. No patient consistently showed nondeterioration in all five parameters. Platelet counts were most sensitive to therapy withdrawal. There was no overt correlation between percent change in these parameters and dose-years of therapy. Although we no longer think that drug vacations should be considered as a form of maintenance for patients requiring enzyme therapy for Gaucher disease, but if necessary—for compelling personal reasons—one may be reassured that a short-term drug interruption is not likely to lead to irreversible complications or return to baseline values of critical clinical parameters.     

A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase

To assess the extent to which patients with type 1 Gaucher disease (GD1) receiving individualized enzyme replacement therapy with imiglucerase attain six defined therapeutic goals. One hundred and ninety-five GD1 patients enrolled in the ICGG Gaucher Registry, all of whom had data available for hemoglobin, platelet count, liver volume, spleen volume, bone pain, and bone crises at first infusion and after 4 years of therapy with imiglucerase, were evaluated for achievement of published therapeutic goals. The proportion of patients who met all six therapeutic goals increased from 2.1% at first infusion to 41.5% at 4 years; > or =5 goals from 12.8% to 76.9%; > or =4 goals from 37.4% to 92.8%; > or =3 goals from 70.8% to 99.0%; and > or =2 goals from 95.4% to 99.5%. All patients met at least one goal at first infusion and after 4 years of treatment. The proportion of patients meeting specific therapeutic goals increased for all parameters between first infusion and 4 years of therapy: platelet count (24.6%-79.5%), spleen volume (25.6%-78.5%), liver volume (45.6%-90.8%), bone pain (62.6-70.3%), hemoglobin (68.2-91.8%), and bone crises (91.8-99.0%). On average, patients who received higher doses of imiglucerase achieved a greater number of therapeutic goals. This analysis provides a benchmark for evaluating the utility of a disease management approach for GD1 based on monitoring achievement of therapeutic goals after treatment with imiglucerase.     

Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient.

Imiglucerase, the recombinantly produced enzyme, is gradually replacing the human placental derived alglucerase in the treatment of gaucher patients. We describe the first case, to the best of our knowledge, of an anaphylactoid reaction to imiglucerase in a patient who tolerated alglucerase. The patient was diagnosed at the age of 2 4/12 years with anemia and hepatosplenomegaly. Over the years he had suffered from marked splenomegaly, thrombocytopenia and recurrent bleeding episodes. At the age of 24 he started treatment with imiglucerase. After 3 months of treatment, immediately after starting an infusion, he experienced flushing, cough, tachycardia, palpitation, chest pain and excessive sweating, which reoccurred on a consecutive administration. Substitution with alglucerase was tolerated well, with only mild rash when he was premedicated with benadryl. Immediate skin tests to alglucerase, imiglucerase and gelatin were negative. IgG against alglucerase was undetectable. The in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase). This sensitivity to imiglucerase but not to alglucerase, raises the question of future treatment for this patient, since the production of alglucerase may cease, once imiglucerase production will cover the need for replacement enzyme.     

Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry

This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase‐treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991‐1995, 1996‐2000, 2001‐2005, 2006‐2009), and splenectomy status pre‐ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non‐splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non‐splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.     

High incidence of cholesterol gallstone disease in type 1 Gaucher disease: characterizing the biliary phenotype of type 1 Gaucher disease

Background  

In Gaucher disease (GD), lysosomal glucocerebrosidase deficiency results in glucosylceramide accumulation in macrophage lysosomes. Hepatocytes do not accumulate glucosylceramide due in part to biliary secretion. Although gallstones (GS) occur in type 1 Gaucher disease (GD1), the chemical nature of stones, their association with metabolic parameters, and whether bile composition is altered are not understood. We assessed the prevalence of GS, their chemical composition, biliary lipids, and associated metabolic factors.     

Hepatopulmonary syndrome: a complication of type 1 Gaucher disease

Gaucher's disease is a not exceptional lysosomial disease in Tunisia. Type 1 is by far the most common one. Pulmonary involvement is considered to be rare in type 1 Gaucher's disease. Pulmonary hypertension, infiltration of the lungs with Gaucher cells, and severe hypoxemia due to intrapulmonary arterial-venous shunts, have been described in case reports and small case series. We reported the case of hepatopulmonary syndrome in a 14-year-old boy with type 1 Gaucher disease. The diagnosis of Gaucher disease was established, at 2 years age, by enzyme assay of leucocyte β-glucosidase. The patient presented dyspnoea, digital clubbing and cyanosis of the lips. The arterial blood gas found severe hypoxaemia with PaO(2) at 56.9 mmHg. The diagnosis of hepatopulmonary syndrome, in our patient, was confirmed by demonstration of the intrapulmonary shunting using contrast-enhanced echocardiography and the technetium-99m-labeled macroaggregated albumin. The patient was treated by symptomatic measure, long term oxygen therapy because the insufficiency of the enzyme replacement therapy. Screening for hypoxemia in children with liver disease should be considered.     

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

PurposeInvestigate 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.MethodsStudy 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.ResultsThe 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.ConclusionsThe 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.     

Hyperferritinemia and iron overload in type 1 Gaucher disease

Hyperferritinemia occurs in Gaucher disease but its clinical spectrum or its association with systemic iron overload and HFE mutations are not known. In 114 patients with Type 1 Gaucher disease, we determined serum ferritin, transferrin saturation and HFE genotype. The results were correlated with the extent of hepatosplenomegaly, overall Gaucher disease severity score index, and response to enzyme replacement therapy. In a subset of patients with radiological and/or laboratory evidence of systemic iron overload, liver biopsy was performed. There was a mean 3.7‐fold elevation of serum ferritin over the upper limit of normal (ULN). Prior splenectomy was associated with most severe hyperferritinemia compared to patients with intact spleen (6.53 × ULN vs. 2.69 × ULN, P = 0.003). HFE genotyping revealed two patients homozygous for H63D mutation and 30% of patients heterozygote carriers of H63D mutation; no patients harbored C282Y mutation; there was no correlation of ferritin with HFE genotype. Ferritin level correlated with liver volume (Pearson correlation coefficient = 0.254, P = 0.035) and it was negatively correlated with hemoglobin (r = ?0.315, P = 0.004); there was no relationship with other indicators of Gaucher disease activity. Enzyme replacement therapy (ERT) resulted in amelioration of hyperferritinemia: 707 ± 898 ng/ml vs. 301 ± 310 ng/ml (P = 0.001), transferrin saturation remained normal. Three patients were suspected of clinical iron overload, confirmed on liver biopsy. Iron accumulation was variably noted in hepatocytes and Kupffer cells. There is a high prevalence of hyperferritinemia in Type 1 Gaucher disease that is associated with indicators of disease severity, reversed by ERT and is not related to HFE mutations. Am. J. Hematol. 2010. © 2010 Wiley‐Liss, Inc.     

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

Velaglucerase alfa is a human β‐glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7‐year experience of the now‐completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9‐month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug‐related adverse event or required premedication. No patient developed anti‐drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and ?42% (?53%, ?31%) and ?78% (?94%, ?62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near‐normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters. Am. J. Hematol. 90:577–583, 2015. © 2015 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.     

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.