Development of a new G-CSF product based on biosimilarity assessment.

BACKGROUND: Zarzio, a new recombinant human granulocyte colony-stimulating factor (filgrastim), was evaluated in healthy volunteers and neutropenic patients in phase I and III studies. PATIENTS AND METHODS: Healthy volunteers in randomized, two-period crossover studies received single- and multiple-dose s.c. injections of 1 microg/kg (n = 24), 2.5 microg/kg (n = 28), 5 microg/kg (n = 28), or 10 microg/kg (n = 40), as well as single-dose i.v. infusions of 5 microg/kg (n = 26), of Zarzio or the reference product (Neupogen). Filgrastim serum levels were monitored; pharmacodynamic parameters were absolute neutrophil count (all studies) and CD34(+) cells (multiple-dose studies). Supportive efficacy and safety data were obtained from an open phase III study in 170 breast cancer patients undergoing four cycles of doxorubicin and docetaxel (Taxotere) chemotherapy, receiving Zarzio (300 or 480 microg) as primary prophylaxis of severe neutropenia. RESULTS: The results of the studies in healthy volunteers confirm the comparability of the test and reference products with respect to their pharmacodynamics and pharmacokinetics. Confidence intervals were within the predefined equivalence boundaries. In the phase III study in breast cancer patients, the administration of Zarzio was efficacious and safe, triggering no immunogenicity. CONCLUSION: The results of these studies demonstrate the biosimilarity of Zarzio with its reference product Neupogen.

Totality of the evidence at work: The first U.S. biosimilar.

On March 6(th) 2015, the Food and Drug Administration (FDA) approved filgrastim-sndz (Zarxio) as the first biosimilar in the United States (US) for all indications of the reference product. Filgrastim-sndz is a biosimilar of Amgen's Neupogen and is mainly used to treat neutropenia in cancer patients receiving chemotherapy. This article presents a summary of the analytical and clinical studies submitted by Sandoz and describes how the information was integrated to provide the 'totality of the evidence' leading to the approval of the biosimilar.

Pharmacokinetic similarity of biologics: analysis using nonlinear mixed-effects modeling.

Our objective was to show, using two examples, that a pharmacokinetic (PK) similarity analysis can be performed using nonlinear mixed-effects models (NLMEM). We used two studies that compared different biosimilars: a three-way crossover trial with somatropin and a parallel-group trial with epoetin-α. For both data sets, the results of NLMEM-based analysis were compared with those of noncompartmental analysis (NCA). For the latter analysis, we performed an NLMEM-based equivalence Wald test on secondary parameters of the model: the area under the curve and the maximal concentration. Somatropin PK was described by a one-compartment model and epoetin-α PK by a two-compartment model with linear and Michaelis-Menten elimination. For both studies, similarity of PK was demonstrated by means of both NCA and NLMEM, and both methods led to similar results. Therefore, for establishing similarity, PK data can be analyzed by either of the methods. NCA is an easier approach because it does not require data modeling; however, NLMEM leads to a better understanding of the underlying biological system.

Long-term safety and efficacy of the recombinant human growth hormone Omnitrope® in the treatment of Spanish growth hormone deficient children: results of a phase III study.

INTRODUCTION: This phase III study in growth hormone (GH) deficient (GHD) children with growth retardation was designed to demonstrate the safety and efficacy of longterm treatment with the recombinant human GH Omnitrope® (Sandoz BioPharmaceuticals, Holzkirchen, Germany). METHODS: Treatment-naïve, prepubertal Spanish children (n=70) with isolated GHD were treated with Omnitrope 0.03 mg/kg/day subcutaneously. Changes in height, height standard deviation score (HSDS), height velocity (HV), HV standard deviation score (HVSDS), serum insulin-like growth factor (IGF)-1, and insulin-like growth factor binding protein (IGFBP)-3 levels were recorded. RESULTS: Omnitrope treatment provided a good growth response after 4 years, shown by a significant increase in mean body height (31.1 cm [95% CI: 29.6-32.6]), HSDS (Tanner) (1.42 [1.13-1.70]), HV (2.4 cm [1.7-3.1]), and HVSDS values (3.5 [2.7-4.3]). Mean IGF-1 and IGFBP-3 serum levels also increased significantly. CONCLUSION: At a dose of 0.03 mg/kg/day, Omnitrope was safe, effective, and well tolerated during long-term treatment of children with GHD.