Risk-based testing for anti-drug neutralizing antibodies during development of biological therapeutics

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1 Risk-based testing for anti-drug neutralizing antibodies during development of biological therapeutics April 18 th, 2016 AAPS National Biotechnology Conference, Boston, MA Shalini Gupta, PhD Amgen Inc. 1

2 Basis of Risk Assessment for Immunogenicity Theoretical Immunogenic Potential of the therapeutic Based on past experience with a similar molecule or modality Presence/absence of critical quality attributes that could impact immunogenicity MoA of drug, e.g. immunomodulatory therapy (or not) Status of the patient s immune system : compromised or activated? Safety risk to patient Can anti-drug antibodies (ADAs) cross-react and neutralize an endogenous protein? Can ADAs cross link the drug and cause super agonism? Loss of efficacy to administered drug? Is the drug life-saving? Do alternative therapies exist? Cross-reactive ADAs to another drug that a patient could benefit from? Based on these considerations, biological therapeutics may be classified as high, moderate or low risk in the context of immunogenicity 2

3 Risk Categories for General Classes of Product Types Product type Risk category Reason Recombinant human cytokine, growth factor, hormone or enzyme High ADAs can cross-react and neutralize endogenous protein causing clinical sequelae Monoclonal antibodies Low ADAs impact efficacy that can be managed by alternate treatment Novel modalities Moderate Lack of previous clinical experience regarding immunogenicity rates and/or impact 3

4 Immunogenicity Testing Strategy (conventional) Binding ADA assay Samples > Assay Cut Point Confirmatory ADA assay Positive NAb assay Impact Assessment PK/PD/Safety ADA Characterization (as needed) High Risk Molecules All Phases of Clinical Development NAb assay included in testing strategy ADA characterization performed as needed 4

5 Strategy For High Risk Molecules (no change from conventional) Binding ADA assay Samples > Assay Cut Point Confirmatory ADA assay Positive NAb assay Impact Assessment PK/PD/Safety ADA Characterization (as needed) High Risk Molecules All Phases of Clinical Development NAb assay included in testing strategy ADA characterization performed as needed 5

6 Risk-based Revised Strategy For Low Risk Molecules for Consideration Binding ADA assay Samples Binding ADA assay Samples > ACP Confirmatory ADA assay > ACP Confirmatory ADA assay Positive Impact Assessment PK/PD/Safety Positive NAb assay Trigger Observed NAb Assay Or PD marker? Impact Assessment PK/PD/Safety Low Risk Molecules Early Development Studies Trigger-Based NAb Testing Low Risk Molecules Late Development Studies NAb included in testing strategy Assumption : Risk category reviewed by regulatory authorities 6

7 Bioanalytical Perspective On Trigger-based NAb testing Regulatory input is important for this approach The trigger needs to be well-defined Bioanalytical efforts are still needed to prepare in case a clinical trigger is observed including: NAb assay format selection Availability of a NAb positive control Giving thought to the level of assay development, qualification and/or validation needed NAb+/- results originating from a NAb test enable easier study interpretation 7

8 Application of Risk-based NAb Strategy to Different Product types Product Type Endogenous protein Risk Category Assay Type Phase 1 Phase2 Phase 3 Bioanalytical preparedness High NAb Yes Yes Yes NAb assay developed and validated prior to Phase I MAb (standard) Low NAb No Trigger based Yes NAb assay format considered; feasibility experiments performed at early stage of drug development MAb (unique) e.g. ADCs, engineering in Fc region, etc. Low or Moderate NAb No Trigger based Yes NAb assay format considered; feasibility experiments performed at early stage of drug development Bi-specific Low or Moderate NAb Trigger based Trigger based Yes NAb assay formats for the 2 active sites considered; feasibility experiments performed at early stage of drug development Assumption: Regulatory Input sought prior to Phase 1 for NAb assay inclusion/exclusion 8

9 Conclusions A conventional approach towards immunogenicity testing has involved the use of both binding and neutralizing antibody assays throughout the drug development cycle It is well accepted by industry that high risk products should continue to use the conventional approach for immunogenicity testing For low risk molecules there is an opportunity to apply a risk based approach by using a trigger-based approach for NAb testing Seeking regulatory input is highly recommended Bioanalytical preparedness efforts should be pursued if a trigger-based NAb testing approach is adopted Late stage development and pivotal clinical trials benefit from inclusion of a NAb assay in the testing strategy since these facilitate data integration, study interpretation and marketing approval 9