292P Queen Elizabeth II Conference Centre London
Pharmacology 2015

A Bioequivalence Study for Hercules, a Biosimilar Trastuzumab Candidate in Development

Introduction: Trastuzumab, marketed as Herceptin, is a humanized monoclonal antibody which binds HER2-oncoprotein and is effective against breast cancer over expressing HER2. We here report the results of a Phase 1 study designed to investigate bioequivalence between Hercules and Herceptin. The assessment of bio similarity included not only pharmacokinetic (PK) but also pharmacodynamic (PD) equivalence.

Subjects and Methods: A single centre, single dose, randomized, double-blind, crossover study was conducted in 22 healthy males; 19 completed both 3-month periods separated by 2-8 week wash-out. On each period the volunteers received an 8mg/kg trastuzumab intravenous infusion over 90 minutes (Hercules or Herceptin). The main objective was PK bioequivalence (serum ELISA assay using anti-idiotypic antibody). For PD comparaison, ex-vivo serum antiproliferative activity on a breast cancer cell line (SKBR3) over expressing HER2 was assessed, as well as numerous ex-vivo and in-vitro immunomodulation markers. ANOVA was applied to PK and PD results. Safety included local and systemic tolerance, laboratory tests, echocardiography and immunogenicity.

Results: Time concentration curves and PK parameters were very close:

Parameter Units Hercules GeoMean (GeoCV%) Herceptin GeoMean (GeoCV%) Point Estimate (90% CI)
Cmax normalizeda g/mL 165 (15.7) 178 (15.6) 0.922 (0.876; 0.970)
AUC0-∞ normalizeda g.h/mL 45486 (22.7) 48350 (28.5) 0.937 (0.887; 0.989)
Tmax (median [range]) h 1.5 (1.4-9.0) 1.5 (1.3-9.0) -
T1/2 (day) Day 6.94 (22.6) 7.02 (26.3) 0.988 (0.943; 1.035)
CLb L/day 0.296 (22.7) 0.278 (28.5) 1.068 (1.011; 1.127)

a Normalized to 8.0 mg/kg dose; b Clearance normalized to 70 kg body weight; GeoCV% = Geometric Coefficient of Variation

Antiproliferative activity time curves were super imposable between both drugs, and concentration-effect relationships were similar (with 95%CI of 4%). Immunomodulation markers were essentially comparable. Satisfactory and similar safety profiles were observed without elicitation of immunogenicity or changes in cardiac left ventricular ejection fraction.

Conclusion: These results confirm pharmacokinetic bioequivalence for Hercules vs. Herceptin, but also demonstrate comparable antiproliferative activity, immunomodulation and safety profiles in healthy volunteers, providing strong support for bio similarity.