Brumshtein B.,Weizmann Institute of Science |
Aguilar-Moncayo M.,University of Seville |
Benito J.M.,University of Seville |
Garcia Fernandez J.M.,University of Seville |
And 6 more authors.
Organic and Biomolecular Chemistry | Year: 2011
Cyclodextrin-based host-guest chemistry has been exploited to facilitate co-crystallization of recombinant human acid β-glucosidase (β-glucocerebrosidase, GlcCerase) with amphiphilic bicyclic nojirimycin analogues of the sp2-iminosugar type. Attempts to co-crystallize GlcCerase with 5-N,6-O-[N′-(n-octyl)iminomethylidene]nojirimycin (NOI-NJ) or with 5-N,6-S-[N′-(n-octyl)iminomethylidene]-6-thionojirimycin (6S-NOI-NJ), two potent inhibitors of the enzyme with promising pharmacological chaperone activity for several Gaucher disease-associated mutations, were unsuccessful probably due to the formation of aggregates that increase the heterogeneity of the sample and affect nucleation and growth of crystals. Cyclomaltoheptaose (β-cyclodextrin, βCD) efficiently captures NOI-NJ and 6S-NOI-NJ in aqueous media to form inclusion complexes in which the lipophilic tail is accommodated in the hydrophobic cavity of the cyclooligosaccharide. The dissociation constant of the complex of the amphiphilic sp2-iminosugars with βCD is two orders of magnitude higher than that of the corresponding complex with GlcCerase, allowing the efficient transfer of the inhibitor from the βCD cavity to the GlcCerase active site. Enzyme-inhibitor complexes suitable for X-ray analysis were thus grown in the presence of βCD. In contrast to what was previously observed for the complex of GlcCerase with the more basic derivative, 6-amino-6-deoxy-5-N,6-N-[N′-(n-octyl)iminomethylidene]nojirimycin (6N-NOI-NJ), the β-anomers of both NOI-NJ and 6S-NOI-NJ were seen in the active site, even though the α-anomer was exclusively detected both in aqueous solution and in the corresponding βCD:sp2-iminosugar complexes. Our results further suggest that cyclodextrin derivatives might serve as suitable delivery systems of amphiphilic glycosidase inhibitors in a biomedical context. © 2011 The Royal Society of Chemistry.
News Article | December 21, 2016
(Reuters) - Dutch scientists have developed an artificial leaf that can act as a mini-factory for producing drugs, an advance that could allow medicines to be produced anywhere there is sunlight. The work taps into the ability of plants to use sunlight to feed themselves through photosynthesis, something industrial chemists have struggled to replicate because sunshine usually generates too little energy to fuel chemical reactions. The leaf-inspired micro factory mimics nature's efficiency at harvesting solar radiation by using new materials called luminescent solar concentrators with very thin channels through which liquid is pumped, exposing molecules to sunlight. "Theoretically, you could use this device to make drug compounds with solar energy anywhere you want," said lead researcher Timothy Noel at Eindhoven University of Technology. By doing away with the need for a power grid, it may be possible one day to make malaria drugs in the jungle or even medicines on Mars in some future space colony, he believes. The device, made from silicone rubber, can operate even when there is diffuse light, which means it will work under cloudy skies. However, there is still a way to go to scale up the process to make it commercially viable. Noel and his colleagues, who published their research in the science journal Angewandte Chemie on Wednesday, are now trying to improve energy efficiency further and increase output. Because the artificial leaf relies on micro-channels to bring chemicals into direct contact with sunlight, each unit needs to be small - but they could be easily linked together to increase production. "You can make a whole tree with many, many different leaves placed in parallel," Noel told Reuters. "These are very cheap things to make, so there is a lot of potential." He thinks the process could start to become broadly available to chemical engineers within five to 10 years. It is not the first time that scientists have drawn inspiration from plants when considering novel ways to manufacture pharmaceuticals. In 2012, the U.S. Food and Drug Administration approved a drug called Elelyso from Pfizer and Protalix Biotherapeutics for Gaucher disease, a rare genetic condition, made with genetically modified carrot cells. Other researchers are also cultivating crops that have been specially bred to produce useful medicines and vaccines in their leaves.
News Article | November 28, 2016
In terms of revenue, the global lysosomal storage diseases therapeutics market is projected to register a healthy CAGR of 10.0% over the forecast period and is estimated to be valued at US$ 14.36 Bn by 2026. In the report, Persistence Market Research analyzes the key factors and trends impacting the growth and performance of the global lysosomal storage diseases therapeutics market over the forecast period. An increasing diagnosis rate due to increasing awareness and financial incentives for orphan drug development to recover R&D costs is the primary factor fueling the growth of the global lysosomal storage diseases therapeutics market. Also, an increasing focus of major biopharmaceutical companies on the research and development of drugs for the treatment of rare diseases is expected to boost the global lysosomal storage diseases therapeutics market during the forecast period. Moreover, the number of treatment options currently in the pipeline is further expected to bolster revenue growth of the global lysosomal storage diseases therapeutics market during the forecast period. However, heterogeneity of the disease leading to underdiagnoses of lysosomal storage diseases, lack of treatment options, and high cost of treatment are factors likely to hamper the growth of the global lysosomal storage diseases therapeutics market over the forecast period. Advent of therapies targeting neuropathic manifestations by crossing blood brain barrier (BBB) and therapies that overcome immune response and have better tissue selectivity will define the future landscape of the global lysosomal storage diseases therapeutics market. Global lysosomal storage diseases therapeutics market has been segmented on the basis of Indication (Gaucher's Diseases, Fabry Diseases, Pompe’s Syndrome, Mucopolysaccharidosis, Others); Type of Therapy (Enzyme Replacement Therapy, Stem Cell Therapy, Substrate Reduction Therapy, Others); End User (Hospitals, Clinics); and Region (North America, Latin America, Europe, Asia Pacific (APAC), and Middle East & Africa (MEA)). The Gaucher's Diseases indication segment is estimated to account for 29.7% revenue share of the global lysosomal storage diseases therapeutics market by 2016 end. The Enzyme Replacement Therapy segment was valued at US$ 4,833.8 Mn in 2015 and is expected to exhibit the highest CAGR of 10.0% over the forecast period to reach US$ 13.58 Bn by 2026 end. The Hospitals end user segment is expected to witness 2.8X increase in revenue over the forecast period and is expected to create absolute $ opportunity of US$ 346.2 Mn in 2017 over 2016. Among regions, Europe is expected to be the dominant regional market in the global lysosomal storage diseases therapeutics market during the forecast period. The Europe market accounted for the highest revenue share of 34.8% and was valued at US$ 1,773.2 Mn in 2015; and is expected to witness a CAGR of 10.2% during the forecast period. North America is expected to be the second most lucrative market in the global lysosomal storage diseases therapeutics market and is estimated to represent absolute $ opportunity of US$ 159.6 Mn in 2017 over 2016. Shire PLC, Pfizer, Inc., Sanofi, BioMarin Pharmaceutical Inc., Actelion Ltd., Raptor Pharmaceutical Corp., Protalix Biotherapeutics Inc., and Amicus Therapeutics, Inc. are some of the companies operating in the global lysosomal storage diseases therapeutics market. Top market players are investing in focused R&D initiatives to develop innovative products for the treatment of rare diseases and are looking to drive growth in established markets through strategic partnerships, collaborations, and acquisitions. The report discusses individual strategies of these companies in terms of increasing focus on rare diseases, initiatives to increase awareness, and enhancing distribution base. The report concludes with strategic recommendations for players already present in the market and new players planning to enter the global lysosomal storage diseases therapeutics market.
Zimran A.,Hebrew University of Jerusalem |
Brill-Almon E.,Protalix Biotherapeutics |
Chertkoff R.,Protalix Biotherapeutics |
Petakov M.,University of Belgrade |
And 17 more authors.
Blood | Year: 2011
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, parallelgroup, 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 treatmentnaive 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 reductionwas 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. © 2011 by The American Society of Hematology.
A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase
Pastores G.M.,New York University |
Petakov M.,University of Belgrade |
Petakov M.,Institute of Endocrinology |
Giraldo P.,Hospital Universitario Miguel Servet |
And 9 more authors.
Blood Cells, Molecules, and Diseases | Year: 2014
Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2. years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60. U/kg body weight) and regimen of administration (every 2. weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9. months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348. © 2014 Elsevier Inc.
PubMed | University of Witwatersrand, Hebrew University of Jerusalem, KK Womens and Childrens Hospital, Hospital Universitario Miguel Servet and 3 more.
Type: | Journal: Blood cells, molecules & diseases | Year: 2016
Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-nave (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-nave) or the same dose as previously treated with imiglucerase every other week. In treatment-nave patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm
PubMed | Royal Melbourne Hospital, Emory University, Hospital Universitario Miguel Servet, National University of Ireland and 5 more.
Type: Journal Article | Journal: American journal of hematology | Year: 2016
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.
PubMed | Protalix Biotherapeutics, BIO Manguinhos Oswaldo Cruz Institute and Hemorio Hospital
Type: | Journal: Blood cells, molecules & diseases | Year: 2017
We evaluated retrospectively, efficacy and safety of taliglucerase alfa for Gaucher disease in a Brazilian population. Thirteen patients were included for efficacy analysis only one of them nave to enzyme replacement therapy. All the parameters evaluated remained stable throughout treatment (mean duration 3,5years). Only three patients (out of 35) had to discontinue treatment due to a serious adverse event. In conclusion, treatment with taliglucerase alfa was found to be safe and efficient.
Bracoud L.,BioClinica |
Ahmad H.,BioClinica |
Brill-Almon E.,Protalix Biotherapeutics |
Chertkoff R.,Protalix Biotherapeutics
Blood Cells, Molecules, and Diseases | Year: 2011
Purpose: To achieve minimal inter-observer variability in assessment of spleen and liver volume changes using a novel MRI reading method in the context of a phase III clinical trial of a new therapy for Gaucher disease. Materials and methods: Abdominal MRI examinations at screening and after 6 and 9. months' exposure to a novel plant-cell-derived recombinant enzyme, taliglucerase alfa, were taken in 31 patients with Gaucher disease and at least 8-fold greater than expected splenomegaly. Transverse T2, T1, and in/out-of-phase, and coronal T1 sequences were performed using standardized settings across 11 sites globally. Spleen and liver volumes were semi-automatically delineated using an automatic segmentation algorithm followed by manual correction by experienced technologists using advanced editing tools. Data of all randomized patients were then submitted for efficacy evaluation to two independent experts blinded to time-point and treatment. Results: Mean (± SD) percent variability over all time-points was 0.30%. ± 0.46% for spleen and 0.53%. ± 0.69% for liver using 178 spleen and liver volumes measured twice. Adjudication due to ≥ 5% variability between observers was not required. Conclusion: The measurement method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional manual methods, supporting the accuracy of the results. Given the observed minimal variability rates among multiple readers, a single read of each volume would be sufficient. © 2010 Elsevier Inc.
Tekoah Y.,Protalix Biotherapeutics |
Tzaban S.,Protalix Biotherapeutics |
Kizhner T.,Protalix Biotherapeutics |
Hainrichson M.,Protalix Biotherapeutics |
And 3 more authors.
Bioscience reports | Year: 2013
The glycosylation of recombinant β-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize β-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post-translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory-approved β-glucocerebrosidase enzymes have no effect on their function or distribution.