Totality of Scientific Evidence in the Development of ABP 980, a Biosimilar to Trastuzumab

Abstract

ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP 980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, a randomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.

Trastuzumab Biosimilars in the Therapy of Breast Cancer – “Real World” Experiences from four Bavarian University Breast Centres

“…Ist nachgewiesen, dass bei einer weiteren Indikation der Wirkmechanismus des Biosimilars gleich ist wie in der untersuchten Indikation (und liegen oben genannte Daten zu Pharmakokinetik, Immunogenität, Wirksamkeit und Sicherheit vor) kann die Zulassung für diese weitere Indikation erfolgen. Dies wird als Konzept der Extrapolation bezeichnet [3,4,6,7].…”

“…If it is demonstrated that the mechanism of action of the biosimilar in an additional indication is the same as in the indication studied (and if the above-mentioned data on pharmacokinetics, immunogenicity, efficacy and safety are available) marketing authorisation for this additional indication may be granted. This is termed the concept of extrapolation 3 , 4 , 6 , 7 .…”

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3

“…As described in European Public Assessment Reports for SB3 and ABP 980 [ 42 , 43 ], it has been acknowledged that the downward drifts in ADCC activity in some of the trastuzumab reference product batches used in these studies could have at least partially confounded the results by contributing to the observed differences in pCR rates between treatment arms and their relatively high upper CI limits [ 13 , 15 ]. Taking totality of evidence into account, SB3 and ABP 980 were therefore considered comparable, rather than superior, to the reference product, and approved as biosimilars of trastuzumab [ 15 , 42 , 43 , 45 ].…”

Totality of Evidence Supporting the Use of ABP 980, a Trastuzumab Biosimilar: Practical Considerations

“…Based on the sum of these results, the TOE for ABP 980 confirms that it is highly similar to trastuzumab RP, thereby supporting extrapolation to all approved indications of the RP [13]. Table 3 Preparation and use of ABP 980 [1,2] 1.…”

“…A comparison of the glycan profiles of ABP 980 and trastuzumab RP indicated that while the Fig. 1 Illustration depicting a stepwise totality of evidence (TOE) approach for demonstration of biosimilarity of ABP 980 to trastuzumab reference product [13] levels of specific species of glycans (e.g., A1G0F) in each may differ, the overall levels of key glycan groups (e.g., afucosylated, galactosylated, sialylated, and high mannose species) that have the ability to influence binding to the FccRIIIa receptor and affect antibody-dependent cellular toxicity (ADCC) were similar in both. Moreover, the predicted NK92 ADCC activity for any given glycan combination was found to be similar for ABP 980 and trastuzumab RP.…”