Taliglucerase alfa plasma concentration in adult patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in adult patients for 120-minute infusions showing dose-dependent increase (linear plot): a) on day 1; b) at week 38. Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p

Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease

<div><p>Taliglucerase alfa is a beta-glucocerebrosidase enzyme replacement therapy approved in the United States, Israel, and other countries for treatment of Type 1 Gaucher disease in adults, and is the first approved plant cell—expressed recombinant protein. In this report, taliglucerase alfa pharmacokinetics were assessed in adult and pediatric patients with Gaucher disease from separate multicenter trials of 30 Units/kg and 60 Units/kg doses infused every 2 weeks. Serial blood samples were obtained from adult patients following single-dose administration on day 1 (n = 26) and multiple doses at week 38 (n = 29), and from pediatric patients following administration of multiple doses of taliglucerase alfa for 10–27 months (n = 10). In both adult and pediatric patients, maximum plasma concentration (C_max), area under the plasma concentration-time curve from time zero to last measureable concentration (AUC_0-t), and from time zero to infinity (AUC_0-∞) were higher after 60 Units/kg dose than 30 Units/kg dose. No tendency for accumulation or change in taliglucerase alfa pharmacokinetic parameters over time from day 1 to week 38 was observed with repeated doses of 30 or 60 Units/kg in adults. After multiple doses, mean (range) dose-normalized pharmacokinetic parameters were similar for adult versus pediatric patients receiving 60 Units/kg: C_max expressed in ng/mL/mg was 42.4 (14.5–95.4) in adults and 46.6 (34.4–68.4) in pediatric patients, AUC_{0 t} expressed in ng•h/mL/mg was 63.4 (26.3–156) in adults and 63.9 (39.8–85.1) in pediatric patients, t_1/2 expressed in minutes was 34.8 (11.3–104) in adults and 31.5 (18.0–42.9) in pediatric patients and total body clearance expressed in L/h was 19.9 (6.25–37.9) in adults and 17.0 (11.7–24.9) in pediatric patients. These pharmacokinetic data extend the findings of taliglucerase alfa in adult and pediatric patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov. <a href="http://clinicaltrials.gov/show/NCT00376168" target="_blank">NCT00376168</a> (in adults); <a href="http://clinicaltrials.gov/show/NCT01411228" target="_blank">NCT01411228</a> (in children)</p></div

Taliglucerase alfa plasma concentration in pediatric patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in pediatric patients for approximately 100-minute infusions showing dose-dependent increase (linear plot). Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p

Summary of PK parameters of taliglucerase alfa in pediatric patients.

<p>AUC_0–t, area under the plasma concentration-time curve from time zero to the last sampling time; AUC_0–∞, area under the plasma concentration-time curve extrapolated from time zero to infinity; CL, total body clearance; C_max, maximum plasma concentration; PK, pharmacokinetics; SD, standard deviation; T_max, time of maximum plasma concentration; t_1/2, elimination half-life; U/kg, Units/kg; V_ss, volume of distribution during steady-state.</p><p>Summary of PK parameters of taliglucerase alfa in pediatric patients.</p

Assay cut-point determination.

<p>Percent (%) Immunodepletion by HRP of healthy individual serum samples. The data show three independent runs and their mean± standard deviation. Individuals 5 and 40 (highlighted) were identified as outliers, and were excluded from the calculation.</p

Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems—The taliglucerase alfa story

<div><p>Plants are a promising alternative for the production of biotherapeutics. Manufacturing <i>in-planta</i> adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies.</p></div

Glycan composition of TGA and HRP.

<p>Glycan composition of TGA and HRP.</p

Schematic representation of the assay.

<p>A stepwise format (1–5) was developed for the binding of serum antibodies to TGA (A) with HRP and (B) without prior HRP incubation, showing a response reduction in the presence of HRP.</p

Total ADA and anti-plant glycan antibodies prevalence found in GD patient population treated with TGA.

<p>(A) Data evaluated from ERT-naïve patient samples and (B) ERT-experienced patient samples. *One patient of the ERT-experienced group, was counted for both baseline ADA and treatment induced ADA, since he was ADA positive at baseline and had a treatment-boosted following treatment with TGA (had ≥6-fold higher titer after TGA treatment).</p

A Consort flowchart of the clinical studies included in the study.

<p>Consort flowchart shows all three studies with original enrolment, number of excluded subjects and the final amount of subjects included in the immunogenicity tests.</p