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

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‐naïve 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% one‐sided confidence interval in both populations lay within the pre‐defined non‐inferiority margin of ?1.0 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. J. Hematol. 88:179–184, 2013. © 2012 Wiley Periodicals, Inc.     

Thrombocytosis associated with enzyme replacement therapy in Gaucher disease

We describe a patient with an intact spleen and moderately severe symptoms of Gaucher disease in whom, after initiation of (low-dose) enzyme replacement therapy (ERT), thrombocytosis (720 x 10(9)/l) was documented. Checking the International Gaucher Registry database revealed that this patient is the only nonsplenectomized patient of more than 1,000 treated patients to experience ERT-induced thrombocytosis. Platelet counts dropped immediately after the discontinuation of ERT.     

Long‐term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment‐naïve patients with Gaucher disease

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell–expressed recombinant therapeutic protein. Herein, we report long‐term safety and efficacy results of taliglucerase alfa in treatment‐naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment‐related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36‐month results of taliglucerase alfa in treatment‐naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656–660, 2016. © 2016 Wiley Periodicals, Inc.     

Enzyme replacement therapy with taliglucerase alfa: 36‐month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase

Taliglucerase alfa is the first available plant cell‐expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB‐06‐002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB‐06‐002 who continued receiving taliglucerase alfa in extension Study PB‐06‐003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB‐06‐003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30–33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, ?1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), ?19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, ?51.5% (±8.1%; n = 10); and CCL18 concentration, ?36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment‐related adverse events were mild or moderate and transient. The 36‐month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661–665, 2016. © 2016 Wiley Periodicals, Inc.     

Outcome of type III Gaucher disease on enzyme replacement therapy: Review of 55 cases

Summary The European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines. Competing interests: None declared References to electronic databases: Neuronopathic Gaucher disease: OMIM #231000. Gaucher disease type II: OMIM #230900.     

Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.     

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized,double‐blind,multinational, Phase 3 study

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment‐naïve, anemic patients with GD1 (4–62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 10⁹/L (P=0.002); 45 U/kg: +66.4%; +40.9 × 10⁹/L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: ?50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: ?39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug‐related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease‐specific parameters measured demonstrated clinically meaningful improvements after 12 months. Am. J. Hematol. 88:166–171, 2013. © 2012 Wiley Periodicals, Inc.     

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

Summary  We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects. Competing interests: F.A. Wijburg provides consultancy services for Genzyme Corporation. References to electronic databases: Glucocerebrosidase, EC 3.2.1.45. Gaucher disease type I, OMIM #230800. Gaucher disease type II, OMIM #230900. Gaucher disease type III, OMIM #231000.     

Quality of life of 22 patients with type 1 Gaucher disease after enzyme replacement therapy

正Objective To investigate the living status and quality of life (QOL) in typel Gaucher disease (GD1) patients who underwent long-term enzyme replacement therapy (ERT) and identify possible relevant factors affecting QOL.Methods Clinical data and SF-36 questionnaires were recorded in 22 adult GD1 patients under regular ERT at Peking Union Medical Colleague Hospital     

Outcome of enzyme replacement therapy in patients with Gaucher disease type I. The Romanian experience

Summary Aim: This study reports the first evaluation of therapeutic response in Romanian patients with Gaucher disease type I, after therapy with Cerezyme recently became available in our country. Patients and methods: 24 patients (11–50 years) received Cerezyme 20–60 U/kg every two weeks for at least 18 months. Haemoglobin, platelet count, volume of the liver and spleen, plasma chitotriosidase and the severity score were assessed every 6 months; skeletal radiography and osteodensitometry were also monitored. Results: Eleven patients were splenectomized before start of therapy. Eight patients had anaemia (mean haemoglobin 9.4 g/dl) and 14 patients, of whom 13 were without splenectomy, had thrombocytopenia (mean 65 692/mm³). Haemoglobin values normalized after 6 months and the platelet count increased to 147 818/mm³ after 18 months of treatment. Splenomegaly improved (mean 13.8× to 5.6× normal), hepatomegaly improved (mean 1.4× to 1.06× normal), the severity score decreased (mean 15.9 to 8.4), plasma chitotriosidase levels showed a reduction from 40 956 to 11 266 nmol/h per ml plasma. Bone disease improved clinically in all patients; bone radiography and osteodensitometry showed no further disease progress. We observed a mean weight gain of 4.3 kg, an improvement in quality of life, and the absence of therapeutic adverse events. Conclusions: Enzyme replacement therapy administered for 18 months in Romanian patients with Gaucher disease type I led to a marked improvement in haematological parameters and hepato- and splenomegaly. In the majority of patients we observed no further progress of bone disease; for an improvement in skeletal disease, a longer treatment period is required. Competing interests: None declared References to electronic databases: Gaucher disease type I, OMIM #230800.     

Impaired microbicidal capacity of mononuclear phagocytes from patients with type I Gaucher disease: partial correction by enzyme replacement therapy

The higher susceptibility to serious bacterial infections in patients with Gaucher disease (GD) may be due in part to defective function of phagocytic cells. We studied five patients with GD (type I) and examined the ability of granulocytes and mononuclear phagocytes from these patients to phagocytose and kill Staphylococcus aureus and to generate superoxide anion (O2-) on stimulation with fully opsonized bacteria. Serum-opsonized staphylococci were ingested equally by phagocytic cells from patients and controls. In the presence of normal serum, the extent of killing of S aureus and the release of O2- by granulocytes over incubation periods of 60 minutes and 30 minutes, respectively, were also equivalent for patients and controls. However, we found that killing of viable bacteria and release of O2- by the patients' monocytes was significantly lower than that in cells from controls (P < .05 for both). The magnitude of differences in killing and O2- release between patients' cells and those from controls was even more profound with monocyte-derived macrophages. Enzyme augmentation with macrophage-targeted glucocerebrosidase preparation for 6 months at doses from 7.5 to 10 U/kg/wk resulted in significant increases of functional activities and O2- generation of monocytes and macrophages along with hematologic and hepatosplenic improvements. These data suggest that mononuclear phagocytes from GD patients are defective in their ability to kill bacteria and to generate reactive oxygen intermediates. Our data also suggest that enzyme substitution may improve functions of monocytes and macrophages in patients with GD that should make them more resistant to severe bacterial infection.     

Long-term effectiveness of enzyme replacement therapy in adults with Gaucher disease: results from the NCS-LSD cohort study

Objectives

To determine the effectiveness of enzyme replacement therapies (ERT) for adults with Gaucher disease (GD).

Design

A longitudinal, multi-centre cohort study, including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data.

Participants

Consenting adults (N?=?150, aged 16 to 83 years) with a diagnosis of GD who attended a specialist treatment centre in England. At recruitment, 131 patients were receiving ERT (mean treatment duration, 10.8 years; range 0–18 years).

Outcome measures

Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin; absence/presence of bone pain; spleen and liver volumes and AST levels.

Results

One hundred and fifty adults were recruited. Duration of ERT was associated with statistically significant improvements in platelet count (p?p?p?p?=?0.02).

Conclusions

These data provide further evidence of the long-term effectiveness of ERT in adults with GD.     

A pharmacokinetic analysis of a novel enzyme replacement therapy with Gene-Activated human glucocerebrosidase (GA-GCB) in patients with type 1 Gaucher disease

OBJECTIVES: To evaluate pharmacokinetics of Gene-Activated human glucocerebrosidase (GA-GCB), a novel enzyme replacement therapy, in patients with type 1 Gaucher disease. STUDY DESIGN: Open-label study of GA-GCB, administered as a 1-h intravenous (IV) infusion every other week was evaluated. The first three patients sequentially received one infusion each at 15 U/kg, 30 U/kg, and 60 U/kg at 2-week intervals and then continued with 60 U/kg/infusion every other week; subsequently nine more patients received GA-GCB at 60 U/kg/infusion every other week. Each patient received 20 infusions (40 weeks). Pharmacokinetic (PK) parameters reported are from blood samples collected at Weeks 1, 3, and 5 for dose-escalated patients and at Week 1 from the other nine patients. RESULTS: GA-GCB was rapidly cleared from the circulation and followed first-order elimination kinetics in the 12 patients who received IV infusions. Maximum serum concentration (C(max)) coincided with the end of the 1-h infusion. Both C(max) and area under the curve (AUC) were linearly proportional to dose from 15 U/kg to 60 U/kg. Elimination half-life was independent of dose; mean elimination half-life at 60 U/kg was approximately 10 min (range: 4-15 min). Mean serum clearance was 13 ml/min/kg (range: 9-20 ml/min/kg) and V(ss) (apparent volume of distribution) was approximately 18% body weight (range: 11-27% body weight). CONCLUSIONS: GA-GCB demonstrated linear PK parameters over clinically relevant doses (15 U/kg-60 U/kg) indicating that the dose of IV-administered GA-GCB to target tissues should also be linearly proportional to dose.     

Long-term effectiveness of enzyme replacement therapy in children with Gaucher disease: results from the NCS-LSD cohort study

Objectives

To determine the effectiveness of enzyme replacement therapies (ERT) for children with Gaucher disease (GD).

Design

A longitudinal cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Children on treatment contributed data before and during treatment. Children not on treatment contributed natural history data.

Participants

Consenting children (N?=?25, aged 1.1 to 15.6 years) with a diagnosis of GD (14 with GD1 and 11 with GD3) who attended a specialist treatment centre in England. At recruitment, 24 patients were receiving ERT (mean treatment duration, 5.57 years; range 0-13.7 years).

Outcome measures

Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin and absence/presence of bone pain.

Results

Duration of ERT was associated with statistically significant improvements in platelet count (p?p?p?=?0.02). The magnitude of effect on haematological parameters was greater in children with GD3 than in those with GD1.

Conclusions

These data provide further evidence of the long-term effectiveness of ERT in children with GD.