GP2015 Etanercept (Hexal) Pre-Filled Syringe EU Enbrel 50mg Randomised, double-blind, single-dose, crossover study Healthy adult male volunteers (n=54; 54PPP) 90% CIs of the geometric mean ratios of AUClast, AUCinf and Cmax were within the prespecified acceptance criteria of 80-125%. All samples from the pre-dose (Day 1) in each study period were ADA negative. Three subjects had a confirmed ADA response at the follow up visit (Day 29, Period 2) with a low titre close to the detection limit (treatment sequence GP2015/Enbrel). [10] GP2015 Etanercept Autoinjector GP2015 Etanercept Pre-Filled Syringe Randomised, open-label, single-dose, crossover study Healthy male volunteers (n=51; 48PPP) 90% CIs of the geometric mean ratios of AUClast, AUCinf and Cmax were within the prespecified acceptance criteria of 80-125%. No ADAs were detected during the treatment periods nor at the follow-up visit. Filgrastim Pegfilgrastim (Apotex) Neulasta 6mg Randomised, single-dose, crossover study Healthy adult volunteers (n=66; 49M/17F; 56PPP) 90% CIs of the geometric mean ratios of AUClast, AUCinf and Cmax were within the prespecified acceptance criteria of 80-125%. 95% CIs of the geometric mean ratios of each of the PD parameters (ANC, AUECt, and Emax) were fully contained within the prespecified acceptance criteria of 80-125%. No samples at the 0 and 672 hr timepoints (n=190) were identified as ADA positive. [11] Biosimilar Candidate Reference Product Study Design Study Population PK Outcomes (and PD reported) Immunogenicity Outcomes Reference Human Growth Hormone neutralising point
r-hGH (Cristália Produtos Químicos Farmacêuticos) Genotropin Pfizer 12.8IU Randomised, open-label, single-dose, crossover study Healthy adult volunteers (n =38; 19M/19F; 34PPP) Pharmacokinetics 90% CIs of the geometric mean ratios of AUClast, AUCinf and Cmax were within the prespecified acceptance criteria of 80-125%. Pharmacodynamics 90% CIs of the geometric mean ratios of each of the PD parameters (AUECt and Emax for IGF-1 and IGFBP-3) were fully contained within range of Not assessed. [12] Biosimilar Candidate Reference Product Study Design Study Population PK Outcomes (and PD reported) Immunogenicity Outcomes Reference Rituxumab
PF-05280586 Rituximab (Pfizer) US (Rituxan) and EU (MabThera) Rituximab 1000mg Randomised, two-dose, study (1:1:1) Patients with active rheumatoid arthritis on a background of methotrexate and inadequate response to anti-TFN therapy (n=220; 50M/170F; 198PPP) 90% CI of ratios for Cmax, AUCT, AUC0–∞ and AUC2-90% CIs of the geometric mean ratios of AUClast, AUCinf and Cmax were within the prespecified acceptance criteria of 80-125%. No observed differences among groups in the CD19+ B cell count versus time profile and the parameters determined (B cell AUClast, Cmin, Tmin and τ). No observed differences among treatment groups in the incidence of ADAs, time of ADA emergence or ADA titres. No samples were positive for antibodies. Thirteen patients tested positive for ADAs at baseline (n=4, n=6 and n=3 receiving PF-05280586, rituximab-EU and rituximab-US, respectively). Of these, eight (n=4, n=3 and n=1, respectively) tested negative in all subsequent post-dose samples. The remaining 5 patients tested positive for ADAs at at least one post-dose time-point. A total of 26 patients tested positive for ADAs at at least one post-dose time (n=7, n=10 and n=9 receiving PF-05280586, rituximab-EU and rituximab-US, respectively). Of these, 22 patients did not have detectable levels of ADAs until Day 85 or later (n=6, n=7 and n=9, respectively). [13] Potential biosimilar medicines that demonstrate appropriate pharmacokinetic parameters in phase I studies are then subject to phase III clinical trials to evaluate efficacy and safety outcomes in comparison with the reference product. Within the update period there were three reports describing the clinical outcomes obtained in phase III clinical trials of potential biosimilar medicines.
17. Miranda-Hernandez, M.P., et al., New alternatives for autoimmune disease treatments: Physicochemical and clinical comparability of biosimilar etanercept. Journal of Immunology Research, 2016. 2016: p. no pagination. 18. Isakov, L., et al., Statistical Primer on Biosimilar Clinical Development.