Specialized Workshop M1 - Monday May 06, 2024: 7am to 5:30pm - Discussion Topic List

"Advanced Strategies for Immunogenicity of Biotherapeutics "

Most Recent Developments on Immunogenicity Regulations Harmonization, Testing & Reporting, Risk-Based Approaches, MAPPs Prediction, Mitigation and Management; Immunogenicity of Complex/Novel Biotherapeutics and Biosimilars; Newest Case Studies in Immunogenicity Assessment, Pre-Existing Antibodies Interpretation and Clinical Relevance; Challenges Associated with Reporting NAb data; Latest Progress in Improving Cut Point, False Positivity Rate (FPR) and Drug/Target Tolerance/Interference; Final Proposal for Cross-Validation; Industry/Regulators Focused and Interactive Discussions on Immunogenicity Reporting, Submissions Outcome and recent Controversial Issues; Interactive Regulatory Updates on the US FDA Draft Immunogenicity Labeling Guidance & Lesson Learned on Integrated Summary of Immunogenicity (ISI)

Session 1: Evolution of Immunogenicity Assessment Beyond ADA and NAb: Focus on Clinical Relevance

  • Topic 1:

    Limitations of the Standard Approach for Assessing ADA Incidence in Clinical Trial and Novel Systematic Assessment of the impact of ADA sampling frequency/timing and assay drug tolerance on reported ADA incidences: Impact by drug high doses and high levels of patient attrition, missing temporal information for individual immune responses, use of sparse sampling may result in inaccurate accounting of patient ADA
    Dr. Yuan Song, Executive Director, BioAnalytical Sciences, Genentech

  • Topic 2:

    Progressive Applications of Model-Informed Assay Development (MIAD) for ADA Assays: MIAD potential to guide the improvement of drug tolerance and pave the way towards Absolut ADA Quantification rather than titers. MRD: Guidance compliance or not compliance? Is it possible to improve ADA assays by not following the Guidance? How important is the variability of the binding kinetics of formed ADAs on the assay read-out?
    Dr. Roland Staack, Head of Bioanalytics and Biomarkers, Roche

  • Topic 3:

    When is the Confirmatory Tier Required in the Immunogenicity 3-Titer Testing Strategy and when is it not? Recognizing that the 3 tiers are variations of the same method and data amongst the tiers are highly correlated, new discussions on the value of the confirmatory assay, considerations on the strong correlation between the S/N and confirmatory result based on clinical data on ADA patient characterization and PK/PD interpretation
    Mr. Daniel Baltrukonis, Clinical Bioanalytics Head, Biologics & Immunogenicity, Pfizer

Session 2: Complex Immunogenicity Characterization for Bispecific Therapeutic Proteins and mAb Therapy for Alzheimer Disease

  • Topic 4:

    Complex Immunogenicity Characterization for Bispecific Antibodies (BsAb): Higher BsAb immunogenicity than regular mAb due to highly engineered with none-native Ig sequences, BsAb ADA assays for pre-existing reactivity, proposed NAb assay strategy, determination of domain specificity of ADA in both pre-existing and treatment-emergent ADAs to develop an effective immunogenicity assessment for clinical development
    Dr. Weiping Shao, Senior Director and Head of Regulatory Bioanalysis, Astra Zeneca

  • Topic 5:

    Innovative Application of Multiplex NAb Assay Format for Bispecific Therapeutic Proteins to increase operational efficiency and reflect drug MOA, challenges associated with the Cell-Based NAb assays with tedious cell maintenance, assay variation, and limited drug tolerance vs use of AlphaLISA and Synthetic Multi-transmembrane Protein as the surrogate for membrane bound receptor protein that has multi-pass transmembrane domains
    Dr. Bonnie Wu, Associate Scientific Director, Bioanalytical Sciences, J&J Innovative Medicine

  • Topic 6:

    Multitiered Immunogenicity Testing Strategy to detect/characterize ADA/NAb for IgG1 antibody targeting existing amyloid plaques in adults with Alzheimer's disease, evaluation Treatment-Emergent (TE) ADA from mAb therapy for the treatment of Alzheimer's disease in treated participants from pivotal clinical trials, evaluation of Impact of ADA on PK, amyloid plaque clearance and clinical efficacy/safety
    Dr. Garrett Mullins, Executive Director, Clinical Immunogenicity, Eli Lilly and Co.

Session 3: Final Proposal on Cross-validation for ADA/NAb Assays and Re-evaluation of Minimum Noise Reduction & False Positive Range

  • Topic 7:

    New Developments to how to Successfully Perform Cross-Validation of Immunogenicity Assays between Labs or after Assay Modification: Improved design of cross-validation and sample preparation, in-study samples vs spiking surrogate PC in matrix, defining feasible acceptance criteria, mitigation and evaluation of difference between cross-validation results, data analysis and its impact on clinical relevance and safety
    Dr. Luying Pan, Senior Director, Clinical Biomarker Innovation and Development, Takeda

  • Topic 8:

    Final Proposal of how to Analytically Approach Cross-validation for both ADA and NAb assays: In contrast to PK assays, no Regulatory Guidance is currently available describing the cross-validation; how to define a test set and a sufficient number of samples within this test set to be analyzed for cross-validation, how to evaluate the results using objective statistical tests, scenarios for which cross-validation is deemed necessary
    Dr. Daniel Kramer, Global Scientific Advisor Immunogenicity, Sanofi

  • Topic 9:

    What are the Common Noise Sources in the Cut Point (CP) Determination during ADA assay development/validation? When not follow the universal principle to reduce noise to minimum in ADA assay? What is an advantage to use raw assay signal data over using the normalized data (S:N ratio) for the CP determination? How to deal with the Supersensitive ADA Assay with low noise and low CP to ensure the long-term robustness?
    Dr. Sam Song, Associate Director, Immunogenicity, Takeda

  • Topic 10:

    What is the Formula for Calculation of the False Positive Rate (FPR) for comparison against the 2-11% range? Considerations on the industry practice for Screening CP set with 5% false positive rate generating from 2 to 11% of false positives and CP determination using pre-dose samples if the assay generates false positives outside of the 2-11% range, discussion on a novel proposal for the evaluation of False Positive Range based on study size
    Dr. Robert Kubiak, Associate Director, Clinical Immunogenicity, Astra Zeneca

Session 4: Further Developments in Risk-Based Approaches for Immunogenicity Prediction & Mitigation

  • Topic 11:

    Latest Approaches in the Development of in vitro Assays used to Mitigate Immunogenicity Risk: Implication in the US FDA effort on BsUFA III Regulatory Research Pilot program for Biosimilars/Generic Peptide ANDA, advance use of PBMC Cytokine Release with MSD Output: Overcoming challenges in bringing an in vitro assays into a validated stage, advantages in using multiparametric in vitro assays to establish risk of Innate Immune Response Modulating Impurities (IIRMIs). 
    Dr. Michele Rasamoelisolo, Senior Director & Head of Specialty Bioanalytics, Teva

  • Topic 12:

    Further Developments in Major Histocompatibility Complex (MHC) Associated Peptide Proteomics (MAPPs) for Predicting Immunogenicity strategy to support the development of novel Biotherapeutics from in-silico to in-vitro assessment, MAPPs requirements for number of donors, cell numbers, and assay performance, use of T-cell activation assays to confirm peptides identified by MAPPs, different cell-based methods
    Dr. Federico Riccardi Sirtori, Director, Head of NBE-DMPK Innovative BioAnalytics, EMD Serono

  • Topic 13:

    Advantages, Opportunities and Challenges of MAPPs: Lead selection of candidates in the pre-clinical phase of development for potential deimmunization strategy, identifying sequence-specific root causes for clinical immunogenicity, understand PTMs and monitor their impact on presented MHC-II peptides, mechanistic understanding with respect to predicted T-cell epitopes and use in conjunction with T Cell activation assays
    Dr. Ola Saad, Distinguished Scientist, BioAnalytical Sciences, Genentech

Session 5: 2024 White Paper in Bioanalysis

  • 2024 White Paper on Advanced Strategies for Immunogenicity of Biotherapeutics

    Consensus & Conclusions on Advanced Strategies for Immunogenicity of Biotherapeutics for 2024 White Paper

Session Finale: ASK THE REGULATORS! Interactive Panel Discussion with All the Regulators

  • Regulatory Feedbacks on Submitted Studies and Inspection/Audit Outcomes on Immunogenicity

    Regulatory Panelists:

    • Dr. Daniela Verthelyi (US FDA CDER)
    • Dr. Zuben Sauna (US FDA CBER)
    • Dr. Mohanraj Manangeeswaran (US FDA CDER)
    • Dr. Seth Thacker (US FDA CDER)
    • Dr. Vijaya Simhadri (US FDA CBER)
    • Dr. Meenu Wadhwa (UK MHRA)
    • Dr. Sandra Diebold (UK MHRA)
    • Dr. Sandra Prior (UK MHRA)
    • Mr. Christian Mayer (Austria AGES / EU EMA)
    • Dr. Adrian Wong (Health Canada)
    • Dr. Akiko Ishii (Japan MHLW)

Agenda at a Glance Agenda at a Glance