Pharmacokinetic Similarity of the Proposed Biosimilar ABP 980 and Trastuzumab in Healthy Subjects 

Vladimir Hanes, Vincent Chow, Nan Zhang, Richard Markus

Amgen Inc., Thousand Oaks, CA, USA.

 

Abstract

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab reference product (RP) in a single-blind study where 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, US FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration–time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (Cmax). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for Cmax and AUCinf had to be within the predefined equivalence criteria of 0.80–1.25. The GMRs and 90% CIs for Cmax and AUCinf, respectively, were: 1.04 (0.99–1.08) and 1.06 (1.00–1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95–1.03) and 1.00 (0.95–1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92–1.00) and 0.95 (0.90–1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80–1.25. Adverse events (AEs) were reported in 42 (84.0%), 39 (75.0%), and 43 (78.2%) subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. Treatment-related AEs (i.e., AEs assessed as possibly or probably related to study drug) were reported in 33 (66.0%), 33 (63.5%), and 39 (70.9%) subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or AEs leading to study discontinuation and no binding or neutralizing antidrug anti-bodies were detected. In conclusion, this study demonstrated the PK similarity of ABP 980 to trastuzumab RP, as well as that between trastuzumab (US) to trastuzumab (EU) thereby completing the scientific bridge between reference products acquired from different sources. No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies.

FULLTEXT

 

Introduction

ABP 980, an immunoglobulin G (IgG) monoclonal antibody (mAb), is being developed as a biosimilar to Herceptin® (trastuzumab). In the European Union (EU), United States (US), and much of the rest of the world, Herceptin® is approved for treatment of metastatic breast cancer, early breast cancer, and metastatic gastric cancer1,2 and it is the standard of care for patients with HER2-overexpressing breast cancer.3-5 ABP 980 has been demonstrated to have the same primary (i.e., amino acid sequence) and higher order structure as trastuzumab reference product (RP) and, like trastuzumab RP, binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2).6 By binding HER2 receptors, ABP 980 and trastuzumab block receptor activation and subsequent proliferation of HER2-overexpressing cells.

 

The regulatory requirement for biosimilar development focuses on the totality of evidence to demonstrate biosimilarity and recommends a step-wise approach that starts with the demonstration of analytical (i.e., structural and functional) similarity which forms the foundation for the development of biosimilars. This step is followed by preclinical assessments and phase 1 clinical pharmacology studies including human pharmacokinetic [PK]/pharmacodynamic [PD] evaluations. Finally, at least one phase 3 clinical confirmation study is conducted in a representative indication to assess similar, efficacy, safety and immunogenicity to complete the totality of evidence. 7,8

 

For assessments discussed here, the trastuzumab RP was acquired from both the US and EU. The US and EU laws define the RP as that approved in the local jurisdiction. Thus, for approval in the US, the proposed biosimilar must be shown to be similar to the RP approved in the US and for approval in the EU, it must be shown to be similar to the RP approved in the European Economic Area. From a regulatory perspective, acceptability of reliance on the clinical data generated utilizing a foreign-sourced comparator is contingent upon successful establishment of the scientific bridge. The “scientific bridge” should demonstrate that in addition to the foreign-sourced RP being structurally and functionally similar to the locally-sourced RP using the comprehensive analytical similarity assessment, it should also demonstrate PK equivalence in a phase 1 study such as the one discussed here.

 

In this study, we compared the PK profiles of ABP 980 and trastuzumab RP in healthy males.

 

Methods and Results

The primary objective of this phase 1 study was to determine PK equivalence between ABP 980 and trastuzumab RP. The RP was acquired from the United States (FDA-licensed trastuzumab), as well as from the EU (EU-authorized trastuzumab) to complete the scientific bridge as required by the regulatory guidance for biosimilars development. The safety and tolerability of ABP 980 were also assessed and compared to that of trastuzumab RP.

 

The study was a randomized, single-blind, single-dose, three-arm, parallel-group study, in which healthy adult male patients 18–45 years of age were randomized 1:1:1 to ABP 980, FDA-licensed trastuzumab, or EU-authorized trastuzumab. Patients received a single 6 mg/kg IV infusion of ABP 980, FDA-licensed trastuzumab, or EU-authorized trastuzumab over 90 minutes on Day 1. Body weight from Day -1 was used to calculate dose.

 

PK equivalence was assessed mainly by area under the serum concentration−time curve (AUC)] from time 0 extrapolated to infinity (AUCinf) and the maximum serum concentration (Cmax) following a 6 mg/kg IV infusion of either ABP 980, FDA-licensed trastuzumab, or EU-authorized trastuzumab.

 

PK similarity was considered to have been demonstrated if the 90% confidence intervals (CIs) for the ratio of least square geometric means (GMs) of primary PK parameters of ABP 980 vs. trastuzumab RP fell within the standard bioequivalence criteria of 0.80 and 1.25. The 90% CI for ratio of the least square GMs for PK parameters was estimated using an analysis of covariance model adjusted for treatment and ethnicity using the PK parameter population.

 

Patients were screened within 28 days prior to receiving study drug. Eligibility was confirmed and pre-dose procedures were conducted on Day -1. Patients remained in the clinical pharmacology unit (CPU) for at least 24 hours after dosing for assessments and returned to the CPU on Days 3, 5, 9, 15, 22, 29, 36, 43, 50, and Day 64 (end-of-study [EOS] visit) for safety evaluations and PK assessments.

 

Serum concentrations of ABP 980 and the RP were determined using a validated electrochemiluminescent assay. Adverse event (AE) monitoring occurred throughout the study; all AEs and serious AEs (SAEs) were reported.

 

One hundred forty-eight of 157 patients (94.3%) completed the study; 9 subjects (5.7%) discontinued from the study prematurely (3 subjects in the trastuzumab [US] group and 6 subjects in the trastuzumab [EU] group). The baseline characteristics and disposition were similar between ABP 980 and trastuzumab RP.

 

The GMs of PK parameters were similar following a single IV infusion of ABP 980 or trastuzumab for the overall PK parameter population. Both peak and overall exposures were similar across treatments, as was the tmax. The mean terminal elimination half-life (t½) was estimated to be 6 to 7 days; for all patients in each treatment arm, AUClast accounted for ≥ 90% of the total AUC, confirming the adequacy of the duration of PK sampling across treatments. The 90% CIs of the ratios of the GMs for the comparison of ABP 980 with trastuzumab, were fully contained within the bioequivalence criteria of 0.80 to 1.25 for both the primary PK parameters (AUCinf and Cmax) and the secondary PK parameter (AUClast), confirming the PK similarity between ABP 980 and trastuzumab RP.

 

The geometric mean ratios and 90% CIs for Cmax and AUCinf, respectively, were: 1.04 (0.99-1.08) and 1.06 (1.00-1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95-1.03) and 1.00 (0.95-1.06) for ABP 980 versus trastuzumab (EU); 0.96 (0.92-1.00) and 0.95 (0.90-1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80 to 1.25. Adverse events (AEs) were reported in 42 (84.0%), 39 (75.0%), and 43 (78.2%)subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. Treatment-related AEs (i.e., AEs assessed as possibly or probably related to study drug) were reported in 33 (66.0%), 33 (63.5%), and 39 (70.9%) subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or AEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected.

 

Discussion

This study was conducted to meet regulatory guidelines for the development and approval of biosimilar agents. Regulatory agencies recommend a stepwise developmental approach designed to determine the similarity of the proposed biosimilar to the reference product with respect to analytical (structural and functional) characteristics, PK profile, and clinical efficacy, safety, and immunogenicity. Based on comprehensive analytical similarity assessments, ABP 980 was shown to be similar to trastuzumab RP with respect to primary and higher-order structure, HER2 binding affinity, inhibition of proliferation, and in vitro anti-body-dependent cell-mediated cytotoxicity.6 The results of this phase 1 PK study further support that ABP 980 is similar to trastuzumab RP by demonstrating equivalence between the two with respect to PK profile. A single 6 mg/kg IV infusion of ABP 980 in healthy male subjects resulted in a similar PK profile to the RP with respect to the primary PK parameters of AUCinf and Cmax. For both PK parameters, the 90% CIs were contained within the prespecified standard equivalence margin of 0.8–1.25. The safety and tolerability of ABP 980 and the RP also were comparable and consistent with what is known for trastuzumab. No new or unexpected safety signals were noted.

 

The study design used here also allowed a direct comparison between the RP sourced from different regions, trastuzumab (US) and trastuzumab (EU). This direct comparison between the RP sourced from different regions has important regulatory and clinical implications as it allows for completing the scientific bridge between RPs sourced from different regions.

 

As with all biologic agents, the risk for developing binding or neutralizing anti-drug antibodies (ADAs) must be carefully assessed. In this study, immunogenicity was evaluated by assaying blood samples for the presence of binding or neutralizing ADAs on Day 1 before infusion and at the end-of-study visit. No subject in any treatment arm developed ADAs. This finding is consistent with previous studies demonstrating a low incidence of ADAs with trastuzumab.

 

In conclusion, in this Phase I study, there were no differences between ABP 980 and trastuzumab RP with respect to PK profile, safety, and tolerability after a single IV infusion. No subject tested positive for binding ADAs. In addition to the results of structural and functional characterization, these results provide further support that the proposed biosimilar ABP 980 is similar to trastuzumab RP.

 

The Table below lists the pharmacokinetic parameters of ABP 980 and the RP as obtained in this phase 1 PK study. The Figure shows the PK profile of ABP 980 and the RP. These data provide confirmation that the PK profile of ABP 980 is similar to the RP.

 

Table. Statistical assessment of pharmacokinetic parameters

GM geometric means; LS least squares; n number of non-missing observations

Note: Statistical model includes treatment and ethnicity as fixed effects

Figure. Mean serum concentration-time profiles for ABP 980 ands trastuzumab; linear scale (top) and expanded scale (top inset); semi-logorhithmic scale (bottom). Error bars = SD.

 

 

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