Principal Scientist, Regulated Bioanalytics Merck & Co., Pennsylvania
Immunogenicity is a critical component for biotherapeutic drug development as it may impact drug exposure, efficacy, and safety. Immunogenicity reporting is a scientific and regulatory requirement for BLA filing. The Integrated Summary of Immunogenicity (ISI) is the recommended venue for immunogenicity reporting and a new requirement in the marketing authorization application for biotherapeutics in ICH regions (EU, USA, and Japan). ISI is a comprehensive document covering immunogenicity risk assessment, bioanalytical methodology, immunogenicity result and potential clinical impact. Development of ISI requires close collaboration of function areas across Bioanalytical, Quantitative Pharmacology, Statistical and Data Programming, CMC, Clinical, Safety, Regulatory and Medical Writing. Here, we report the process of developing ISI for a novel receptor and Fc fusion protein for both US and EMA market authorization applications.
Biologic-A, an investigational therapeutic fusion protein is currently being prepared for both US and Europe market authorization application. Immunogenicity assessment for Biologic A includes 2 Phase 2 studies and 1 Phase 3 study. A multi-tiered testing strategy was applied to assess Biologic-A immunogenicity. ADA testing for Phase 2 studies was performed with validation cut points established using serum matrix from healthy volunteers. The false positivity rate (FPR) for Phase 2 studies combined (0.8%) fell outside of the 2% to 11% range considered adequate by regulatory agencies to detect ADA response. Therefore, in line with regulatory guidance, Phase 3 study applied in-study ADA cut points derived statistically using pretreatment serum samples from participants in Phase 3. Applying the in-study cut points, the FPR from Phase 3 sample analysis was 7.1% and fell within the target 2% to 11%.
The incidence of anti-drug antibody (ADA) in response to the treatment in the 3 studies ranged from 9.6% to 25.9%. ADAs were most commonly detected shortly after initial treatment, with a median ADA onset of ~3 weeks after the initial dose of biologic-A. Longer biologic-A exposure was not associated with an increase in ADA incidence. The ADA titer was low with median ADA titer of 40 (range: < 20, 640) in all 3 studies. ADA responses were transient (duration < 16 weeks) in ~55% of ADA positive participants. One ADA positive participant in Phase 2 (0.8% of all treated participants in Phase 2) showed neutralizing antibody activity (NAb). NAb activity in Phase 3 study was evaluated with a more sensitive NAb assay, and 11 ADA positive participants in Phase 3 (6.8% of all anti-biologic-A treated participants in Phase 3) showed neutralizing activity. Immunogenicity impact analyses for PK, PD, efficacy, and safety were conducted for pooled Phase 2 studies and separately for Phase 3. No clinically meaningful effect of anti-Biologic-A antibody or NAb development was observed.
Learning Objectives:
Upon completion, audience will gain conceptual framework:
What is immunogenicity and why is immunogenicity testing important?
Upon completion, audience will gain conceptual framework:
How to conduct immunogenicity testing for clinical studies?
Upon completion, audience will gain conceptual framework:
How to evaluate immunogenicity clinical impact?
Upon completion, audience will gain conceptual framework:
How to prepare immunogenicity data for regulatory submission?