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.     

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.     

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.     

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.     

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.     

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.     

Enzyme replacement therapy and bony changes in Egyptian paediatric Gaucher disease patients

Summary Background. In Gaucher disease, the infiltration of the bone marrow by glucocerebroside-laden macrophages (Gaucher cells) triggers a diverse pattern of skeletal disease that results in crippling complications. Reliable ascertainment of the severity and pattern of skeletal disease is essential to determine disease status and the response to enzyme replacement therapy (ERT). Although there is ample documentation of reversal of haematological and visceral disease by ERT, there is a paucity of data on skeletal response to ERT in children. Aim. To delineate the pattern of bone disease in children with Gaucher disease in Egypt and to evaluate its response to ERT. Method. Twenty-two children with Gaucher disease were treated with ERT. Phenotyping by clinical, laboratory and radiological criteria was performed at baseline and following 11.2 ± 4 months of ERT. Genotyping for glucocerebrosidase (GBA) mutations was performed by gene sequencing, and genotype–phenotype correlations were performed. Results. Two-thirds of the patients were from consanguineous pedigrees and 14/22 patients were homozygous or compound heterozygous for L444P and D409H mutations. Bone involvement was detected by plain radiology in 11 children (50%) and in 16 (73%) by magnetic resonance imaging (MRI). There was no correlation of severity of bone involvement and GBA genotype. ERT ameliorated bone disease: 10 of the 11 children with abnormal radiographic findings at baseline showed improvement in skeletal lesions; while 9/16 showed improvement of marrow disease by MRI. Radiographic sensitivity and specificity were 62% and 82% compared to MRI for detection of bone involvement in this patient population. At baseline, bone pain was present in 5 patients and ERT resulted in complete symptomatic remission in all of them. ERT was associated with significant improvement in growth parameters and amelioration of haematological and visceral involvement. Conclusion. Symptomatic and radiological skeletal disease is common in children with Gaucher disease in Egypt. MRI is the most accurate technique for detecting early skeletal involvement. There was no correlation between severity of skeletal involvement and GBA genotype. ERT was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain. Communicating editor: Guy Besley Competing interests: None declared     

Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long‐term data from phase III clinical trials

Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty‐seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every‐other‐week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug‐related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti‐velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z‐score. Improvements were maintained over longer‐term treatment. Velaglucerase alfa had a good long‐term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008‐001965‐27; www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. © 2015 Wiley Periodicals, Inc.     

Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among the Ashkenazi Jews (q approximately 0.047). The disease results from inherited defects of acid beta-glucosidase and the accumulation of the substrate, glucosylceramide, in cells of monocyte/macrophage origin. The therapeutic response to macrophage-targeted (alpha-mannosyl-terminated) alglucerase (Ceredase, at 60 to 15 IU/kg every 2 weeks) was analyzed in 33 patients (age range, 2 to 63 years; 15 splenectomized) with extensive Gaucher disease over periods of 6 to 24 months. The efficacy of several different doses and dosage reductions was evaluated. In patients with anemia (n = 30) and/or thrombocytopenia (n = 19), hemoglobin levels and platelet counts increased by 0% to 178% and 15% to 155%, respectively, within 3 to 12 months. In patients with splenomegaly (n = 17) and/or hepatomegaly (n = 28), liver and spleen volumes decreased in 6 months from 7% to 64% and 8% to 84% by 12 months, respectively. Hematologic and visceral improvements were noted at any doses between 60 and 15 IU/kg every 2 weeks. Furthermore, these positive initial therapeutic responses were persistent throughout therapy, with doses reduced by 50%. Pulmonary Gaucher disease did not improve clinically in 3 patients. Unrelated cirrhotic (n = 2), cholestatic (n = 1), or renal disease (n = 1) did not influence the rate of patient improvement. Two of five patients who developed serum antibodies against alglucerase during the first 6 to 12 months of therapy had mild antibody reactions. This study shows similar regression of clinical Gaucher disease manifestations with enzyme therapy, using doses between 30 and 60 IU/kg every 2 weeks. Therapeutic efficacy was not diminished after 50% to 75% dose reductions or in the presence of anti-enzyme antibodies.