A Plant-Derived Recombinant Human Glucocerebrosidase Enzyme—A Preclinical and Phase I Investigation

Abstract

Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing.Trial RegistrationClinicalTrials.gov NCT00258778

Pharmacokinetics of novel plant cell-expressed taliglucerase alfa in adult and pediatric patients with Gaucher disease

“…In pediatric patients, dose-normalized exposure indicated dose proportionality between 30 and 60 Units/kg. Previously, Aviezer et al [22] reported an earlier, Phase 1 study of the PK of taliglucerase alfa in healthy adult volunteers (n = 6) who received escalating doses administered intravenously at separate clinic visits (15 Units/kg on day 8, 30 Units/kg on day 15, and 60 Units/kg on day 22). Maximum plasma concentration of taliglucerase alfa was reached by approximately 80 min after the start of infusion.…”

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

“…12 Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a carrot cell-expressed human recombinant ␤-glucocerebrosidase enzyme for IV treatment of Gaucher disease. 13 Expression of taliglucerase alfa is targeted in the plant cell to the storage vacuoles using a plant-specific C-terminal sorting signal that dictates the formation of the desired mannose structure in vivo, and unlike imiglucerase, does not require subsequent exposure of mannose residues in vitro. 14 Furthermore, taliglucerase alfa evinces biologic activity comparable with imiglucerase and its pharmacokinetic profile implies a prolonged half-life compared with imiglucerase, 13 although this is currently of unclear clinical relevance.…”

Velaglucerase alfa

“…Initial reports 13,14 of the effects of treatment withdrawal in adult patients with stable disease suggest that, when appropriately monitored, some patients may safely interrupt treatment for a short period of time because irreversible complications are unlikely to occur in a couple of months. Alternatively, some patients have been switched to miglustat (the oral substrate reduction therapy) or to other ERTs -either velaglucerase alfa or taliglucerase alfa (developed by Protalix, which is produced in plant cells 15 ) -that have been made available through expanded access programmes. The collection of information on each patients' well being and their disease parameters following treatment switches is of utmost importance, which may be best achieved by creating an independent database of clinical assessments and standardized laboratory measurements, such as markers for Gaucher's storage cells 16,17 .…”