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

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5767-5773 ◽  
Author(s):  
Ari Zimran ◽  
Einat Brill-Almon ◽  
Raul Chertkoff ◽  
Milan Petakov ◽  
Francisco Blanco-Favela ◽  
...  
Keyword(s):  
Adverse Events ◽  
Plant Cell ◽  
Gaucher Disease ◽  
Dose Group ◽  
Hypersensitivity Reactions ◽  
End Points ◽  
Platelet Counts ◽  
Enzyme Replacement ◽  
End Point ◽  
Unit Dose

Abstract 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. This study was registered at www.clinicaltrials.gov as NCT00376168.

Immune Thrombocytopenia in Type I Gaucher Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3200-3200 ◽  
Author(s):  
Hanna Rosenbaum ◽  
Tina Napso ◽  
Lilach Bonstein
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Immune Modulation ◽  
Hematological Parameters ◽  
Autoimmune Disorder ◽  
Type I ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Platelet Counts ◽  
Enzyme Replacement

Abstract Backgound: Type I Gaucher disease (GD) the non-neuronopathic form is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and/or infiltration of bone marrow by the lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in treated GD patients within 12–24 months of treatment. In GD patients, including ERT treated, with persistent low platelet counts other ethiological factors should be considered. Goals: To determine the etiology of persistent thrombocytopenia in Type I GD patients and to evaluate their clinical course and hematological parameters. Methods: Flow cytometric technique was used to detect platelet-surface associated IgG/M (PSIgG/M) in a cohort of 24 Type I GD patients followed at the Gaucher clinic in Haifa, Israel. The evaluated hematological parameters of the thrombocytopenic GD patients include: bleeding phenomena, concurrence of autoimmune phenomena, hematological malignancies and bone marrow findings. Results: Twenty four Type I GD patients, 15 females and 9 males with an age range of 35 to 80 years (median 53 years) were included in the study. Seventeen of the evaluated 24 patients were thrombocytopenic with platelet counts less than <100×109/l and 7/24 were in the normal range. Bone marrow aspirate was performed in 16 of the 17 thrombocytopenic patients and showed normal or hyperplasic megakariopoiesis together with Gaucher cells infiltrates. Six of the 17 thrombocytopenic patients received ERT for at least 24 months with no effect on the low platelet counts. Elevated platelet surface IgG was detected in 16/17(94%) of GD patients with thrombocytopenia and in only 1/7 (14%) of non thrombocytopenic patients (p<0.0001). In 6/17 of the thrombocytopenic patients, surface IgM (PSIgM) was found, in addition to the PSIgG. Those six patients are known with monoclonal IgM (concomitant Waldenstrom macroglobulinemia), markedly elevated polyclonal IgM levels, or lupus like autoimmune disorder which may have been responsible for the positive PSIgM. Only three thrombocytopenic patients with platelet counts less than 40×109/l had bleeding tendency (mainly purpura) with no response to steroid treatment (two of them were also resistant to ERT concerning their thrombocytopenia). Conclusions: Thrombocytopenia in Type I GD is related to either infiltration of bone marrow compromising megakariopoiesis or hypersplenism, but immune factors should also be considered. Despite the lack of response to steroids, the observed megakaryocytic hyperplasia in Gaucher infiltrated marrows, the failure to respond to ERT, and the presence of platelet surface antibodies in the thrombocytopenic patients, strongly implicate autoimmune etiology. The present study demonstrates that surface platelet antibodies may play a role in refractory thrombocytopenic GD patients. Since the role of splenectomy is controversial in GD, immune modulation approach should be considered.

Analysis of Spanish Experience During Imiglucerase Shortage

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4725-4725
Author(s):  
Pilar Giraldo ◽  
Pilar Irún ◽  
Pilar Alfonso ◽  
Jaime Dalmau ◽  
MAngeles Fernández-Galán ◽  
...  
Keyword(s):  
Haemoglobin Level ◽  
Gaucher Disease ◽  
Bone Pain ◽  
Position Statement ◽  
Activity Increase ◽  
Platelet Counts ◽  
Enzyme Replacement ◽  
European Working ◽  
Before And After ◽  
Risk Patients

Abstract Abstract 4725 In the last twenty years enzyme replacement therapy (ERT) with imiglucerase has been a clinically effective for Gaucher disease (GD). The recombinant glucocerebrosidase administered intravenously - usually at biweekly intervals by lifelong has improved the quality of life of patients, avoided spleen removal and bone complications. In the last months an acute shortage of imiglucerase manufactured by the Genzyme Corporation (MA, USA) has occurred as a result of viral contamination firstly and other deficiencies in the production facility. In September 2009 a position statement based on the findings of the European Working Group for Gaucher Disease and European Gaucher Alliance, established a set of key recommendations about identification and monitoring of at-risk patients threatened. In Spain the follow-up of patients and the strict complementation of rules of therapy have permitted to obtain a profile of the situation in a group of patients with restricted ERT. Patients and Methods: A total of 50 GD1 patients have been analyzed before and after 6 and 12 months of imiglucerase shortage. Have been excluded for analysis children in order to dose reduction has been minimal as well as patients who have switched to another ERT or miglustat therapy. Results: Gender: 25 males/25 females. Mean age of group: 45.3±15.3 (range:18-84) SSI at diagnosis(Dx): 8.7±3.8 (range:3-19) Chitotriosidase (CT) activity at Dx:13,383±12,783 nM/mL.h; CCL18/PARC at Dx: 767±1,198 ng/mL. 20% of patients were splenectomized and 78% had bone disease at Dx. During shortage 23 patients (46%) discontinued therapy, in this period only one patient suffered a bone crisis and other anaemia as complications. Mean reduction of haemoglobin level: 2.7% (NS), platelet counts: 5.4% (NS). CT activity was increased 135% (p<0.03) and CCL18/PARC 8.2% (p<0.08). In 17 patients (34%) imiglucerase was reduced at 50%, in this period seven patients (41.0%) suffered a bone pain and four patients (23.5%) required support therapy. Mean reduction of haemoglobin level 2.9% (NS), no changes in platelet counts. CT activity increase 48.2% (p<0.03) and not changes in CCL18/PARC concentration was observed. In addition in 3 patients (6%) the reduction was 75% and 7 patients (14%) switched to another ERT (4 patients) or miglustat (3 patients). Conclusions: In our experience, the shortage of imiglucerase in the last months has produced a incidence in bone pain of 20% and one case with anaemia and significant increase of CT activity and no significant changes in blood counts and CCL concentration, 14 % patients has required switch another therapy. Disclosures: Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma.

scholarly journals Open-Label, Expanded Access Study of Taliglucerase Alfa in Patients with Gaucher Disease Requiring Enzyme Replacement Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3755-3755
Author(s):  
David J. Kuter ◽  
Michael Wajnrajch ◽  
Betina Hernandez ◽  
Rong Wang ◽  
Raul Chertkoff ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Research Funding ◽  
Hemoglobin Concentration ◽  
Open Label ◽  
Expanded Access ◽  
Platelet Counts ◽  
Enzyme Replacement ◽  
Treatment Naïve ◽  
Previously Treated

Abstract Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study. Disclosures Kuter: BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

Longer-Term Assessment of Trastuzumab-Related Cardiac Adverse Events in the Herceptin Adjuvant (HERA) Trial

2010 ◽  
Vol 28 (21) ◽  
pp. 3422-3428 ◽  
Author(s):  
Marion Procter ◽  
Thomas M. Suter ◽  
Evandro de Azambuja ◽  
Urania Dafni ◽  
Veerle van Dooren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Adverse Events ◽  
Early Breast Cancer ◽  
End Points ◽  
Trastuzumab Treatment ◽  
End Point ◽  
Neo Adjuvant Chemotherapy ◽  
Cardiac Adverse Events

Purpose We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy. Patients and Methods The HERA trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 (HER2) –positive early breast cancer. Eligible patients had normal left ventricular ejection fraction (LVEF; ≥ 55%) after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Cardiac function was monitored throughout the trial. This analysis considers patients randomly assigned to 1 year of trastuzumab treatment or observation. Results There were 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, though it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% v 0.0%; confirmed significant LVEF decreases, 3.6% v 0.6%) In the trastuzumab group, 59 of 73 patients with a cardiac end point reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point. Conclusion The incidence of cardiac end points remains low even after longer-term follow-up. The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year, but it remains relatively constant thereafter.

Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study

2013 ◽  
Vol 31 (28) ◽  
pp. 3517-3524 ◽  
Author(s):  
Philip J. Johnson ◽  
Shukui Qin ◽  
Joong-Won Park ◽  
Ronnie T.P. Poon ◽  
Jean-Luc Raoul ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Adverse Events ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Fibroblast Growth Factor Receptors ◽  
First Line ◽  
Dual Inhibitor ◽  
End Points ◽  
End Point

Purpose Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. Patients and Methods Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. Results The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. Conclusion Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

scholarly journals The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial

2018 ◽  
Vol 29 (12) ◽  
pp. 2890-2899 ◽  
Author(s):  
Valeria Saglimbene ◽  
Suetonia C. Palmer ◽  
Marinella Ruospo ◽  
Patrizia Natale ◽  
Ausilia Maione ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Adverse Events ◽  
Cardiovascular Risk Factors ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Angiotensin Receptor Blockers ◽  
Controlled Trial ◽  
End Points ◽  
End Point

BackgroundThe comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear.MethodsIn a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events.ResultsBecause of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%).ConclusionsPatients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

RESPONSE TO ENZYME REPLACEMENT THERAPY IN PATIENTS WITH GAUCHER DISEASE TYPE I

2019 ◽  
Vol 22 (06) ◽  
pp. 103-117
Author(s):  
Mays Al-Tai ◽  
Deia Al-Asady ◽  
Rula Hamid
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Gaucher Disease ◽  
Disease Type ◽  
Type I ◽  
Enzyme Replacement

scholarly journals Development of the “Hamburg Best Practice Guidelines for ICV−Enzyme Replacement therapy (ERT) in CLN2 Disease” Based on 6 Years Treatment Experience in 48 Patients

2021 ◽  
pp. 088307382198915
Author(s):  
Christoph Schwering ◽  
Gertrud Kammler ◽  
Eva Wibbeler ◽  
Martin Christner ◽  
Johannes K.-M. Knobloch ◽  
...  
Keyword(s):  
Patient Safety ◽  
Adverse Events ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Practice Guidelines ◽  
Best Practice ◽  
Vision Loss ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Enzyme Replacement ◽  
Best Practice Guidelines

Intracerebroventricular enzyme replacement therapy (ICV-ERT) for CLN2 disease represents the first approved treatment for neuronal ceroid lipofuscinosis (NCL) diseases. It is the first treatment where a recombinant lysosomal enzyme, cerliponase alfa, is administered into the lateral cerebral ventricles to reach the central nervous system, the organ affected in CLN2 disease. If untreated, CLN2 children show first symptoms such as epilepsy and language developmental delay at 2-4 years followed by rapid loss of motor and language function, vision loss, and early death. Treatment with cerliponase alfa has shown to slow the rapid neurologic decline. However, the mode of administration by 4 hour-long intracerebroventricular infusions every 14 days represents a potentially greater risk of infection compared to intravenous enzyme replacement therapies. The Hamburg NCL Specialty Clinic was the first site worldwide to perform intracerebroventricular enzyme replacement therapy in children with CLN2 disease. In order to ensure maximum patient safety, we analysed data from our center from more than 3000 intracerebroventricular enzyme replacement therapies in 48 patients over 6 years with regard to the occurrence of device-related adverse events and device infections. Since starting intracerebroventricular enzyme replacement therapy, we have also developed and continuously improved the “Hamburg Best Practice Guidelines for ICV–Enzyme Replacement Therapy (ERT) in CLN2 Disease.” Results from this study showed low rates for device-related adverse events and infections with 0.27% and 0.33%, respectively. Therefore, following our internal procedural guidelines has shown to improve standardization and patient safety of intracerebroventricular enzyme replacement therapy for CLN2 disease.

Sign in / Sign up

Export Citation Format

Share Document