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:
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.