Dataset Information

Functional and Nonclinical Similarity of ABP 980, a Biosimilar of Trastuzumab.

ABSTRACT: PURPOSE:The in vitro and in vivo pharmacologic assessment of ABP 980 similarity to its reference product is intended to compare the activity of ABP 980 and trastuzumab and support the overall conclusion of similarity based on a comprehensive analytical and functional evaluation. METHODS:This work complements the primary assessment of functional similarity with additional in vitro assays, binding studies, and non-clinical studies including human epidermal growth factor receptor-2 (HER2) kinetic binding, HER2 signaling, HER2 internalization, synergy with docetaxel chemotherapy, Fc?R kinetic binding, primary natural killer and monocyte cell binding, antibody-dependent cellular phagocytosis activity, in vivo xenograft studies, and toxicokinetic parameters. RESULTS:The results contribute to the totality of evidence with respect to functional similarity and support that ABP 980 is similar to trastuzumab in all primary and secondary mechanisms of action. CONCLUSIONS:These results also support the scientific justification of extrapolation to all approved indications of trastuzumab given the established functional similarity of the two products and the same mechanisms of action across all conditions of use.

SUBMITTER: Jassem S

PROVIDER: S-EPMC6834741 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Functional and Nonclinical Similarity of ABP 980, a Biosimilar of Trastuzumab.

Jassem Shea S Wang Wei W Sweet Heather H Manoukian Raffi R Chow Vincent V Kanakaraj Palanisamy P Hutterer Katariina M KM Kuhns Scott S Foltz Ian N IN Chen Qing Q Ferbas John J McBride Helen J HJ

Pharmaceutical research 20191106 12

<h4>Purpose</h4>The in vitro and in vivo pharmacologic assessment of ABP 980 similarity to its reference product is intended to compare the activity of ABP 980 and trastuzumab and support the overall conclusion of similarity based on a comprehensive analytical and functional evaluation.<h4>Methods</h4>This work complements the primary assessment of functional similarity with additional in vitro assays, binding studies, and non-clinical studies including human epidermal growth factor receptor-2 ( ...[more]

PMID: 31696314

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Project description:ABP 980 (KANJINTI™, Amgen, Thousand Oaks, CA, USA; Amgen Europe B.V., The Netherlands) is a biosimilar to trastuzumab (Herceptin®), a monoclonal antibody that selectively binds human epidermal growth factor receptor-2 (HER2). Here we provide a brief overview of the totality of evidence (including analytical [structural and functional] characterization, nonclinical evaluation, and human pharmacokinetic [PK], pharmacodynamic, and clinical assessment comparing ABP 980 with trastuzumab reference product [RP]) that supported the approval of ABP 980, along with practical considerations on the reconstitution and use of the lyophilized product to ensure safe and effective administration. ABP 980 has been shown to be highly similar to the RP, with similar mechanism of action, binding, and potency. Key PK parameters, geometric means ratio (GMR [90% CI]) of Cmax and AUCinf, are comparable and within the equivalence margin of 0.80 to 1.25 (ABP 980: 1.04 [0.99-1.08] versus trastuzumab US: 1.06 [1.00-1.12]; ABP 980: 0.99 [0.95-1.03] versus trastuzumab EU: 1.00 [0.95-1.06]). No clinically meaningful differences were found between ABP 980 and RP in a comparative clinical trial in patients with HER2-positive early breast cancer. Pathological complete response-ABP 980: 48% versus RP: 41% (risk difference [RD], 90% CI: 7.3%, 1.2-13.4; relative risk [RR], 90% CI: 1.188, 1.033-1.366). Sensitivity analyses per central pathology review-ABP 980: 48%; RP: 42% (RD: 5.8%, -0.5 to 12.0; RR: 1.142, 0.993-1.312), with RD and RR falling within predefined equivalence margins. Similar to trastuzumab RP, KANJINTI™ is supplied as a sterile, lyophilized cake to be reconstituted with bacteriostatic water for injection (BWFI) for multiple-dose injection or sterile WFI for single use. Stability data support storage of reconstituted solution at 2-8°C (36-46°F), up to 28 days. Reconstituted solution can be diluted in infusion bags containing 0.9% saline and stored for up to 24 h prior to intravenous administration.

Project description:INTRODUCTION:Although the human epidermal growth factor receptor 2 (HER2) blocker trastuzumab is generally well tolerated, cardiotoxicity can be an important therapeutic limitation. OBJECTIVE:In this prespecified analysis, we compared the cardiac safety of the trastuzumab biosimilar ABP 980 (KANJINTI™) and the trastuzumab reference product (RP; Herceptin®) in the phase III LILAC study (ClinicalTrials.gov identifier NCT01901146). METHODS:In the neoadjuvant phase of LILAC, after run-in chemotherapy, 725 patients were randomized 1:1 to ABP 980 (n?=?364) or trastuzumab RP (n?=?361) plus paclitaxel (every 3 weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1 year; ABP 980-treated patients continued ABP 980 (ABP 980/ABP 980; n?=?364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP; n?=?190) or switched to ABP 980 (trastuzumab RP/ABP 980; n?=?171). Cardiac safety was monitored by computerized 12-lead electrocardiogram, and left ventricular ejection fraction (LVEF) was assessed by two-dimensional (2D) echocardiogram. LVEF decline was defined as LVEF value decrease from study baseline by???10 percentage points and to?<?50%. RESULTS:Over the entire study, 22 (3.1%) patients had protocol-defined LVEF decline; no meaningful between-group differences were observed (ABP 980/ABP 980: 2.8%; trastuzumab RP/trastuzumab RP: 3.3%; trastuzumab RP/ABP 980: 3.5%). The incidence of cardiac adverse events was low and comparable in the treatment groups. One grade 3 cardiac failure event reported in the trastuzumab RP/ABP 980 arm, and another in the trastuzumab RP/trastuzumab RP arm, were coincident with LVEF decline. One patient discontinued the investigational product during the adjuvant phase because of cardiac failure. CONCLUSION:These prespecified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and trastuzumab RP with respect to cardiac safety. No new cardiac safety signals were observed whether patients were receiving ABP 980 or switched from the RP to ABP 980.

Project description:Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China's Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efﬁcacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.

Dataset Information

Functional and Nonclinical Similarity of ABP 980, a Biosimilar of Trastuzumab.

Publications

Functional and Nonclinical Similarity of ABP 980, a Biosimilar of Trastuzumab.

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