Lecture DETAILS of M1 – ADA/NAb Guidance Day

• Lecture 1
  On-going Challenges on Harmonization of Immunogenicity Assessment, Reporting and Monitoring Post-Approval
  - Dr. Robert Kubiak, Senior Manager R&D, AstraZeneca
  • Building on recent Industry/Regulators' recommendation on Post-Approval Immunogenicity Monitoring
    • 2020 Part 3 (Page 453 - Strategy for post-approval monitoring of immunogenicity)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0007
    • 2019 Part 3 (Page 2229 - Clinical relevance of ADA)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2019-0271
    • 2016 Part 3 (Page 2482 -Assay Changes during the Post-market Phase)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2016-4989
  • Current industry efforts to harmonize the 2020 Industry/Regulators' recommendations for Immunogenicity based on US FDA Guidance, EU EMA Guideline and Industry Best Practice
    • Assessment, Reporting and Monitoring
  • Cut Points
    • Why do Cut Points tend to be low and very similar across different methods and modalities?
    • Does this indicate that Cut Points do not reflect the biology of the samples but mostly the assay?
    • Is the determination of Cut Points for different indications really useful since current methods of cut point determination tend to give very similar cut points?
  • Sensitivity
    • Is the Industry putting too much emphasis on determination of sensitivity and drug tolerance using surrogate controls?
  • Different ways of reporting Titer:
    • Challenges for Calculating MRD for ACE or SPEAD methods
  • ADA impact on PK and PD
    • Why is the correlation between the titer value and its effect on PK and PD often low?
    • Is titer in ADA assay not reflective of how ADA binds its target?
  • Reporting
    • Limitations of ADA category definitions
    • Evaluable vs. non-evaluable subjects
    • Positive vs negative subjects
    • Persistent vs transient ADA
  • Post-approval Monitoring
    • Is there a good measure of impact of ADA incidence / titer on efficacy?
    • With the exception of anti-TNF biotherapeutics, does detection of ADA provide any new actionable information?
  • Case Studies: Immunogenicity monitoring post approval till reaching ADA negative post treatment in the clinical studies, requirement, value and challenges

 

• Lecture 2
  Immunogenicity Testing Strategies and their Harmonization - Overcoming soluble target presence in drug tolerant ADA Assay
  - Dr. Gregor Jordan, Lab Head, Roche
  • Building on recent Industry/Regulators' recommendations on Harmonizing Expectations for Drug Tolerant ADA Assay in presenceof Soluble Target
    • 2017 Part 3 (Page 1982 -Release soluble target from therapeutic-target complex)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2017-4974
    • 2019 Part 3 (Page 2228 - Expectations for Approaches Regarding Drug Tolerance & Assay Specificity)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2019-0271
  • Theoretical consideration for improving the Drug Tolerance
    • Impact on false positive results of Monomeric target when there is a switch of therapeutic drug
    • What if more therapeutic drugs for the same indication are available and a switch of patients is necessary?
  • Soluble targets generation of false-positive signal ADA assays
    • Is a depletion of soluble target without additional reagent (e.g anti target binder) possible?
    • Overcoming high background signal due to soluble target interference
    • Current strategies to mitigate false-positive signal
    • Recommendations on using competitive blockers to inhibited soluble target interference and increased target tolerance levels
    • Pros/cons of using target immunodepletion using magnetic beads conjugated with an anti-target antibody
    • Advantages of developing the ADA assay under mild acidic conditions
    • Alternative strategies for mitigating target interference when standard anti-target antibodies are ineffective
  • Harmonizing immunogenicity testing for high throughput and easy execution approaches for mitigating soluble target interference
    • High tolerance ADA Assays
    • Reduced false positives
  • Case studies: Novel approaches how to tackle the presence of soluble target and how to translate the challenge of rapid turnaround analysis in a robust and drug tolerant ADA assay

 

• Lecture 3
  Biosimilar ADA Assay Validation & Harmonization - How to demonstrate appropriateness of one assay approach
  - Dr. Johann Poetzl, Head Program Management Bioanalytics, Sandoz
  • Building on recent Industry/Regulators' recommendations on Biosimilar ADA Assay Harmonization
    • 2015 Part 3 (Page 3117 - One-assay and two-assay approaches)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio.15.226
    • 2016 Part 3 (Page 2484 - One assay preferred)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2016-4989
    • 2020 Part 3 (Page 449 - Assay performing similarly with both products)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0007
  • Immunodepletion curves
    • Use of biosimilar candidate vs reference product applied to demonstrate appropriateness of one assay approach
    • What acceptance criteria should be applied?
    • Discussion on proposals for acceptance criteria
  • Looking for a sensitive range to demonstrate suitability of one assay
    • Starting concentration for ADA Positive Control high or low?
    • Effects close to detection limit may increase complexity of immunodepletion curve result interpretation
  • Positive Control
    • Polyclonal, monoclonal, anti-Fab or anti-"full-protein"
  • Capture Reagent
    • Critical role in demonstrating appropriateness of one assay approach
  • Current best practice to demonstrate that ADA assay can adequately detect antibodies against both biosimilar and originator
    • Practical recommendations to harmonize ADA Assays for optimal comparative immunogenicity assessment of biosimilars
    • Two-assay (based on the biosimilar and originator respectively)
    • One-assay approach (based on the biosimilar)
    • On-going challenges in immunogenicity assessment to evaluate differences between biosimilarproduct and the originator product
    • Evaluation of incidence and severity of human immune responses
  • The use of one assay approach
    • Elimination of "between-assay" variability
    • Cut points: one screening and one confirmatory CP
    • Sample analysis: both the biosimilar and the reference product analyzed using the same assay
    • Additional parameters to evaluateto gain confidence that one assay can detect antibodies against both the biosimilar and the originator
    • Understanding how to perform a harmonized antigenic equivalence comparison
    • Positive Control (PC): how to assess the ability of the biosimilar and the originator to bind in a similar manner to the PC
    • Evaluation of drug tolerance in confirmatory assays
  • Case Studies: Lessons learned from recent Biosimilar ADA assay applications, bioanalytical comparability testing, challenges and regulatory feedbacks

• Lecture 4
  New Developments in Bispecific monoclonal Antibody (BsmAb) Immunogenicity: Challenges and strategies for harmonizing next-generation of bispecific antibody immunogenicity testing & reporting
  - Dr. Kate Peng, Director Department BioAnalytical Sciences, Genentech
  • Building on recent Industry/Regulators’ recommendation on Bispecific monoclonal Antibody (BsAb) Immunogenicity
    • 2015 Part 3 (Page 3118 - ADA testing for Bispecific)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio.15.226
    • 2020 Part 2A (Page 315 - Development of BsAbs)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0005
  • Value of applying integrated approaches for bsAb immunogenicity assessment
    • Observation of unexpected immunogenicity outcomes during bsAb development
    • BsAb greater risk for immunogenicity
      • More engineering modifications
      • Complexed manufacturing processes
    • Well-established immunogenicity assessment strategy for the conventional monospecific Ab may not be adequate for BsAbs
    • Limitations of available tools for bsAb immunogenicity assessment
  • Considerations on using a combination of tools for BsAb immunogenicity assessment
    • In silico, in vitro and in vivo studies
    • Innovative assay development strategies when comparing BsmAbs to the conventional monospecific antibody therapeutics
  • Current experience in development, submission, review, and approval ofBsAbs
    • Lesson learnt from Regulatory expectations for bispecific
    • Importance of MoA to design the right immunogenicity strategy
  • Case Studies: New immunogenicity findings of a BsAb and how to harmonize the approaches to achieve specific and sensitive ADA assays

 

• Lecture 5
  Development of an Appropriately Designed PK assay to NAb impact on Exposure of Bispecific Drugs - An integrated PK/NAb approach
  - Dr. Gregor Lotz, Group Leader Bioanalytics, Roche
  • Building on recent Industry/Regulators' recommendation on T-Cell Engaging Bispecific Antibodies
    • 2020 Part 2A (Page 315 - Bispecific redirected T cell molecules)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0005
  • Use of selected specific ADA PCfor accurate evaluation of ADA
    • Impact on exposure
    • Interference on target-antigen binding
    • Lesson learnt on mosunetuzumab, glofitamab and cevostamab
  • Bioanalytical strategy for bispecific drugs customized depending on
    • MOA
    • Target biology
    • Availability of the critical reagents
    • Positive Control (PC)
  • Novel development of PK assay of a T-Cell Bispecific Drug based on its MoA
    • Advanced structural binding analysis of ADAs to specificbispecific drug sites
    • Assessment of impact on targeting
    • Identification of relevant patient ADA binding features
    • Strategies to select an appropriate anti-idiotypic ADA-positive controls (PC) with similar binding features
    • Innovative approaches for developing assay bispecific drugs binding to two different targets on two different cells simultaneously
  • Case Studies: new data on investigational T-cell engaging bispecific antibodies, development of a novelPK assay to evaluate neutralizing anti-drug-antibody impact on exposure of T-cell bispecific drugs

 

• Lecture 6
  ADA Characterization for Biotherapeutics in Oncology and Ophthalmology: New methods for ADA-specificity and ADA Isotype analysis
  - Dr. Kay-Gunnar Stubenrauch, Head Large Molecule Bioanalytical Sciences 1, Roche
  • Building on recent Industry/Regulators' recommendations on Expectations for ADACharacterization, Specificity and Isotyping
    • 2018 Part 3 (Page 1990 - Isotyping assays to Characterize Dynamics of ADA responses)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2018-0287
  • Adaption of the Fit-for-Purpose (FFP) and Context of Use (COU) philosophy from Biomarkers to Immunogenicity Testing and new methods for
    • ADA specificity
    • ADA Isotype analysis
  • Complex ADA response induced by Multi Domain Biotherapeutics (MDB)
    • "Unsuitability of classical ADA assays" and new challenges for some MDB to
      • Specify ADAs
      • Identify the immunogenic domains of aMDB
  • Novel methods for ADA characterization to specify immunogenic responses against a MDB
    • Including specific consideration of assay reagents
    • Development of Domain Detection assays (DDA)
    • Domain Competition Assays (DCA)
    • Strategies for assessment of multi-specific ADA responses
  • Characterization ofADA isotypes to elucidate the mechanism of immune responses
    • Isotyping performed using a FFP approach when necessary to answer specific questions
    • When are isotyping or domain-specific assays needed?
  • Case studies: Purpose-driven approaches of extended ADA characterization for Biotherapeutics in Oncology and Ophthalmology with evaluation of domain-specific ADA responses

• Lecture 7
  Challenges and Approaches in developing a "living" Integrated Summary of Immunogenicity (ISI) for US FDA & EU EMA submissions: Sanofi's global experience and perspectives
  - Dr. Sue Richards, Presidential Scientific Fellow Translational Medicine and Early Development Sanofi
  • Building on recent Industry/Regulators’ recommendation to develop an Integrated Summary of Immunogenicity (ISI)
    • 2019 Part 2 (Page 2124 - Integrated Immunogenicity Summary)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2019-0270
    • 2020 Part 2B (Page 348 - Best practices for immunogenicity submissions)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0005
  • Best practices for immunogenicity submissions for Integrated Summaries of Immunogenicity
    • ISI as "living" integrated summary document
    • Populating ISI early in product development
    • ISI update as the clinical program progresses through IND stages into BLA and post-approval stages
    • Practical aspects in generating a “living” integrated immunogenicity summary document or folder
    • Using a "folder" approach where relevant information, reports are stored
    • Developed a report template used for all programs
    • ISI Statistical Analysis Plan (SAP) to address what data/analysis populations
  • Industry experience and lessons learnt in submitting ISI to EMA and FDA and reporting
    • ADA Incidence, titer, onset, persistence/transience
    • Neutralizing capacity of detected ADA
    • Impact on drug PK and PD and association with clinical outcome
  • Is an ISI harmonization really needed?
    • Currently no ISI harmonized methodology
    • Use of flexible ISI approach
    • Alignment to product development stage
    • Alignment to product risk profile
    • Considerations around risks to safety, PK, PD and efficacy
  • Case Studies: Lessons learned in developing a "living" Integrated Summary of Immunogenicity (ISI) for US FDA & EU EMA submissions

 

• Lecture 8
  Recent Developments in a PK, PD, ADA Integrated Approach vs. NAb Assay
  - Dr. Anders Holm Millner, Principal Scientist Immunogenicity Assessment, Novo Nordisk
  • Building on recent Industry/Regulators' recommendations on PK, PD, ADA Integrated Approach
    • 2018 Part 3 (Page 1988 - PK, PD, ADA data correlation & the merit of NAb assays)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2018-0287
    • 2019 Part 2 (Page 2124 - Integrated Immunogenicity Summary)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2019-0270
    • 2020 Part 2B (Page 348 - Best practices for immunogenicity submissions)
      Link: https://www.future-science.com/doi/pdf/10.4155/bio-2021-0005
  • Importance of using an integrated data approach instead of using in vitro NAb assays for low risk immunogenicity molecules
    • What an appropriate PK assay should be
    • What is required for PD marker or biomarker
    • How these data can be correlated to binding ADA for revealing neutralization
    • When the integrated data approach would be more valuable than in vitro NAb assay
    • Which PK assay format are appropriate to use for both PK and NAb
    • When it is possible to make the same conclusions from this correlation without NAb data
  • Current strategies to identify the neutralizing effect without NAb assays
    • Clinical value of NAb assays for low risk molecules
    • Understanding when in vivo neutralizing activity of ADAs is required
  • Case Studies: Evaluation of PK, PD, ADA data correlation where NAb assays are not needed; PK assay used to monitor the presence of in vivo neutralizing activity and relationship with clinical outcomes

 

• Lecture 9
  Differences between China NMPA Immunogenicity Guideline and US FDA & EU EMA Guidance/Guideline
  - Dr. Tong-Yuan Yang, Senior Scientific Director Biotherapeutics, Janssen
  • The 2021 China NMPA "Technical Guideline for Drug Immunogenicity Study"
    • Structure and Content
    • ADA Assay Method Development and Validation
  • Assessment of validation parameters for non-clinical assays
  • Expectations for in vitro cytokine release tests for non-clinical data package
  • Definition of titer
  • Characterization of ADA responses
    • Isotyping
    • Domain specificity
    • Neutralization activity
  • Neutralization Assay and when Cell-Based Assay are sufficient
  • PK, PD, ADA Integrated Approach vs. NAb Assay
    • PK and PD assays as indicative for the presence of NAbs
  • ADA Assay Precision, Selectivity and Drug Tolerance
  • What about the Integrated Summary of Immunogenicity (ISI)?
  • Case Studies: Possible harmonization of Immunogenicity Guedelines

• Lecture 10
  Immunogenicity Assay Comparability for Biologics: Current perspectives from CDER Office of Biotechnology Products
  - Dr. JoaoPedras-Vasconcelos, Sr. Staff Fellow Office of Biotechnology Products, US FDA
  • Currently, ADA Assay Comparability is not possible due to differences among the bioanalytical methods used
  • At the 2019 WRIB an approach to attempt the comparability of bioanalytical methods for immunogenicity assessment was proposed for the first time within the global bioanalytical community including
    • How to implement this approach in ADA assay development within same clinical program
    • How to use Bioanalytical method comparability as the first potential step toward the evaluation of clinical immunogenicity comparability within the same program
  • The discussion on ADA Comparability across drug programs continued in 2020-2021 within the Industry. However:
    • No official position or recommendations from Regulators
      • Currently, this is the realm of meta-analysis and needs to interpreted with care
      • Regulators do not recommend it
    • No assay comparability data using platform agnostic methods or covering more than one drug have been submitted to Regulatory Agencies yet

 

• Lecture 11
  ADA Assays Comparability: Importance of & Lot-lot bridging, Sanofi's Experience
  - Dr. Rachel Palmer, Head Biomarkers and Clinical Bioanalysis, Sanofi
  • Considerations on a lack of formal guidance on criteria to demonstrate ADA Assay Comparability
  • Method Transfer
    • What to do when anADA Assay transfers are required during the lifecycle of a program
    • Method transfers to support analysis in difference countries
    • Transition from internal to external labs when all data is needed for the filing
  • Parameters to consider in ADA Assay Comparability
    • Antibody status vs titer match
    • Patient samples with and without antibodies
    • Matrix spiked with PC antibodies
  • Criteria for ADA Assay Comparability
    • Percentage match positive/ negative
    • Percentage of titers must match between +/- 1 titer dilution
  • Current Regulatory Expectations
    • Currently, ADA Assays Comparability can only be done in the same clinical program using bridging studies with blinded positive and negative samples tested in prior assay, and retested in second assay
    • Comparability between different assays within the same program requires bridging studies with retesting positive and negative samples from original study
    • At least 90-95% concurrence in sample testing should be achieved to be able to pool total immunogenicity data across various studies in the clinical program
    • Regulators only accept ADA Assays Comparability within the same clinical program, not across clinical programs with different drugs
  • Case Studies: Illustrate potential approaches for ADA Assay Comparability and Discussion of options if results do not meet Assay Comparability Criteria

 

• Lecture 12
  ADA Assay Comparability: Sharing the Latest Data on the Evolution of the CP-ARC Concept, Roche's Experience
  - Dr. Roland Staack, Head Large Molecule Bioanalytical Sciences 2, Roche
  • Unpublished & Unpresented brand-new data in support of the CP-ARC concept
    • Anti-drug Antibody–Reagent Complexes at Cut-Point
    • Next Step in the controversial discussion on ADA Assay Comparability
    • Moving the CP-ARC concept forward from the initiation phase
    • Working on further aspects to support CP-ARC concept
  • Improving the current situation to enable a better comparability of ADA assays
    • Status of Industry/Regulators scientific discussions sound comparability of the bioanalyticalmethods
    • What if the Assay comparability fails?
  • Regulatory Expectations for Immunogenicity Assay Comparability
    • What is the next stepto achieve the ultimate goal of comparability of the clinical immunogenicity of differentcompounds
  • How to reach a global bioanalytical community consensus at WRIB
    • How the assay performance parameters should be reported for ADA Assay Comparability
      • Sensitivity
      • Drug tolerance
    • Evaluation of avidity binding
  • Case Studies: Novel data and concepts which may change the current way of doing ADA analysis