The long-term international safety experience of imiglucerase therapy for Gaucher disease

Starzyk, Kathryn; Richards, Susan; Yee, John; Smith, Sue; Kingma, Wytske

doi:10.1016/j.ymgme.2006.09.003

Cited by 111 publications

(73 citation statements)

References 13 publications

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“…In this study, differences in immunogenicity were observed between patients treated with velaglucerase alfa (0%) and imiglucerase (23.5%); antibody formation with imiglucerase was observed at a rate similar to that previously reported in the literature [20]. Although long-term data have not been published for imiglucerase, experience with alglucerase (placenta-purified glucocerebrosidase) indicates that most patients who seroconvert develop lowtiter IgG antibodies and become tolerant after 24 months of continuous therapy [21].…”

Section: Discussionsupporting

confidence: 79%

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Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

et al. 2013

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Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment-na€ ıve patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% onesided confidence interval in both populations lay within the pre-defined non-inferiority margin of 21.0 g/dL, confirming that velaglucerase alfa is non-inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am.

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Section: Discussionsupporting

confidence: 79%

“…There was no family history of epilepsy. Convulsions have not previously been reported in the 9-month Phase 1/2 study of velaglucerase alfa, its long-term extension [6], or a longterm pharmacovigilance safety program of imiglucerase [20], suggesting this event is unlikely to be treatment related.…”

Section: Discussionmentioning

confidence: 89%

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

et al. 2013

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“…In most patients with hypersensitivity-type IARs, the detection of antibodies to the enzyme indicates the induction of an adaptive humoral immune response that may account for the adverse effects (although some patients with IARs do not have detectable antibodies and vice versa). 2,3 Because each patient received only a single infusion in this phase I trial, no specific antibody formation was expected and none was detected. Instead, the pattern of positive and negative acute phase proteins and cytokines that peaked in the circulation 2-3 days after infusion is consistent with changes in hepatic protein synthesis related to an acute inflammatory response by the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

“…In many patients the onset of IARs coincides with the detection of IgG (and, rarely, IgE) antibodies against the infused enzyme. 2,3 ERT with olipudase alfa (recombinant human acid sphingomyelinase) is in clinical development for acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease (NPD; OMIM 607616) type A (NPD A) and type B (NPD B). Sphingomyelin, a major plasma membrane phospholipid, is hydrolyzed by acid sphingomyelinase (ASM) (EC 3.1.4.12) in lysosomes to yield ceramide and phosphorylcholine.…”

Section: Introductionmentioning

confidence: 99%

Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann–Pick disease type B (acid sphingomyelinase deficiency)

McGovern

Wasserstein

Kirmse

et al. 2016

Genetics in Medicine

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Purpose: Enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase) is being developed for Niemann-Pick disease type B (NPD B). Methods:A single-center, open-label, nonrandomized, singleascending-dose trial evaluated the safety of intravenous olipudase alfa (0.03-1.0 mg/kg) in 11 adults with NPD B. Patients were monitored in the hospital for 72 h after infusion and had follow-up visits on days 14 and 28.Results: Plasma ceramide, a product of sphingomyelin catabolism by olipudase alfa, showed dose-dependent elevations by 6 h postdose, or postinfusion. No serious adverse drug reactions (ADRs) occurred during the study. Acute phase reaction-type ADRs, as evidenced by elevated inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-8, and calcitonin) and constitutional symptoms (fever, pain, nausea, and/or vomiting) emerged 12-24 h following doses ≥0.3 mg/kg olipudase alfa. Three patients experienced hyperbilirubinemia. The study was terminated after a patient dosed at 1 mg/kg exhibited severe hyperbilirubinemia; he was subsequently diagnosed with Gilbert syndrome. Conclusion:The maximum tolerated dose of olipudase alfa in adults with NPD B was 0.6 mg/kg. First-dose ADRs were likely induced by elevated concentrations of ceramide (or its downstream derivatives) generated by the catabolism of accumulated sphingomyelin. Within-patient dose escalation to slowly catabolize sphingomyelin stores may be a strategy to mitigate first-dose ADRs in patients with NPD B.

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“…A coordinated approach considering a variety of therapeutic goals, rather than an exclusive focus on treating individual symptoms, may result in better long-term outcomes for GD1 patients [9]. The information in this benchmark analysis may assist physicians in choosing the appropriate treatment approach for each patient while considering the potential benefits and the overall safety profile of imiglucerase [22].…”

Section: Discussionmentioning

confidence: 99%

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

Weinreb¹,

Taylor²,

Cox

et al. 2008

American J Hematol

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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; ‡5 goals from 12.8% to 76.9%; ‡4 goals from 37.4% to 92.8%; ‡3 goals from 70.8% to 99.0%; and ‡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. Am. J. Hematol. 83:890-895, 2008. V

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The long-term international safety experience of imiglucerase therapy for Gaucher disease

Cited by 111 publications

References 13 publications

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann–Pick disease type B (acid sphingomyelinase deficiency)

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

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