Immunogenicity Assessment & Clinical Relevance

The generation of meaningful immunogenicity data with clinical relevance is beset with many challenges. Top of the list for 2017 is the challenge of cut point determination and assay validation. This conference addresses this with several case studies and a discussion with the FDA. A close second in the list of challenges is management of drug and target interference in the assay in both clinical and non-clinical studies. The third is Nab assays which continue to improve and evolve. There is uncertainty about when these should be implemented, their usefulness, how much time to devote to them and how to deal with all the variation. The fourth is the presence of pre-existing positive ADA activity in study patients as investigators have difficulty distinguishing between these and potential immune responses to the drug. The final is determining the relationship between assay data and the clinical outcome, particularly the impact on PK and efficacy.

This event will present industry case studies on how these challenges are addressed for a range of products, so that immunogenicity data can be assessed and presented to the regulatory authorities in a meaningful way.

Final Agenda

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Recommended Pre-Conference Short Courses*

• SC1: Mechanism of Action and Risk Based Approach for Developing Neutralizing Ab Assays
• SC2: Overcoming Drug Target Interference in ADA Assays

*Separate registration required

TUESDAY, October 24

7:30 am Registration & Morning Coffee

CRITICAL ISSUES WITH CUT POINTS AND NABs

8:40 Chairperson's Opening Remarks

Wendy White, Ph.D., Scientific Director & Fellow, Clinical Pharmacology, MedImmune, Inc.

8:45 Is There a Minimum Cut Point Value for an Immunogenicity Assay?

Robert J. Kubiak, Ph.D., Senior Manager, R&D, Translational Science, MedImmune LLC

Inherent variability of analytical methods sets a lower limit on cut point values used for immunogenicity testing. Such minimum cut points differentiate random fluctuations around the assay baseline from biological variability that may be caused by the presence of anti-drug antibodies (ADA). Using theoretical calculations and case studies, we show that attempts to increase assay sensitivity by using lower cut points may fail to identify additional meaningful ADA-positive samples.

9:15 Generating Clinically Relevant Immunogenicity Data: Setting Appropriate Assay Cut Points and Categorizing ADA Positivity

Michael Partridge, Ph.D., Staff Scientist, Bioanalytical Sciences, Regeneron, Inc.

Reporting overall ADA incidence, using highly sensitive assays with low cut points, can result in data that is not clinically relevant. Case studies will be presented showing how more clinically relevant ADA data can often be generated by either modifying the outlier removal process used to generate assay cut points or reporting only persistent ADA, which appears to be a better predictor of clinical impact.

9:45 KEYNOTE: Immunogenicity Cut Point Evaluation Process

Viswanath Devanarayan, Ph.D., Executive Director and Head, Global Statistics, Charles River Labs

The process of identifying and confirming the presence of anti-drug-antibodies (ADA) in patient samples has evolved considerably over the past decade. More recently, alternative formulae have been proposed for more definitively achieving the targeted false positive rate, albeit at the expense of lower cut points and potentially more false positives. Data from several assays will be used to illustrate the practical difference of the results derived from different formulae, and a fit-for-purpose recommendation is provided. We then present an updated flow-scheme for the cut point evaluation process that should be applicable for most immunogenicity assays in practice.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 Panel Discussion: Current Recommendations on the Setting of the Cutpoint

Susan Kirshner, Ph.D., Associate Chief, Immunology Lab, Therapeutic Proteins, Biotechnology, FDA/CDER

Wendy White, Ph.D., Scientific Director & Fellow, Clinical Pharmacology, Medimmune, Inc.

Viswanath Devanarayan, Ph.D., Executive Director and Head, Global Statistics, Charles River Labs

Jim McNally, Ph.D., Principal, McNally Bioanalytical Consulting LLC

• Rationale behind the current setting of the cutpoint
• Effect of removing “outliers” on setting of the cutpoint
• Proposals for overcoming this difficulty
• How to get the same sensitivity from a bioassay when those types of assays are not matrix or drug tolerant

11:40 Immunogenicity Challenges in Clinical Development of Biotherapeutics

Rong Zeng, Ph.D., Director, Bioanalytical Sciences, OncoMed Pharmaceuticals

Immune responses, particularly the induction of anti-drug antibodies (ADAs), may have severe impact on drug safety, bioavailability, and/or efficacy during clinical development of biotherapeutics. We would like to present clinical case studies regarding: 1) ADA interference on PK, 2) assay-related extreme high ADA titer, and 3) in-study cut point determination. Sharing our observation and the follow-up investigation of the immunogenicity challenges will contribute to better generation and interpretation of ADA data and its clinical relevance.

12:10 Strategies to Determine Assay Format for the Assessment of Neutralizing Antibody Responses to Biotherapeutics

Yuanxin Xu, Ph.D., Senior Scientific Director, Clinical Assay Development, Clinical Lab Sciences, Alnylam Pharmaceuticals

This presentation will highlight the strategic thinking process on NAb assay design from a recently published white paper based on the collective experience of industry and regulatory authors (NAbers) and reviewers. Assay platform selection is based on (i) the therapeutic MoA, (ii) the evidence of desirable assay performance characteristics, and (iii) risk of immunogenicity. Additional examples will be provided.

12:40 pm Session Break

12:45 Luncheon Presentation: Immunogenicity Risk Assessment: Using Human Preclinical Tools during Lead Selection and Optimization

Noel Smith, Ph.D., Senior Group Leader, Applied Protein Services, Lonza Biologics, plc

Immunogenicity is a common problem with therapeutic proteins and can impact both efficacy and safety. An immune response can lead to neutralization of the protein activity, altered PK/PD and even dangerous cytokine responses. Lonza has developed comprehensive preclinical safety and immunogenicity risk assessment tools to aid lead selection and optimization. These include tools to assess the risk of generating an unwanted T cell response and the assessment of cytokine release.

1:40 Session Break

NEUTRALIZING ANTIBODY ASSAYS

2:25 Chairperson's Remarks

Michael Partridge, Ph.D., Staff Scientist, Bioanalytical Sciences, Regeneron, Inc.

2:30 Development of an ADCC-Based NAb Assay for Immunogenicity Assessment of Ocrelizumab in Patients with Multiple Sclerosis

Shan Chung, Ph.D., Principal Scientist and Group Leader, Bioanalytical Sciences, Genentech, Inc.

Ocrelizumab selectively targets and depletes CD20-expressing B cells via Fc effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). This presentation will describe development, validation, and implementation of a novel neutralizing antibody assay based on ADCC activity of ocrelizumab. Employment of thaw-and-use cells to improve performance of the assay, and immunogenicity of repeated dosing of ocrelizumab in patients with multiple sclerosis will also be discussed.

3:00 Development and Validation of a Quantitative Cellular Imaging-Based NAb Assay to Address Challenges Associated with Flow Cytometry Assays

Keith Merdek, Ph.D., Principal Scientist, Bioanalytical Sciences & Biomarkers, Sanofi

A case study will be presented for development of cell-based NAb assays for a rare disease program consisting of a first and second generation enzyme replacement therapy. Development of a novel, quantitative cellular imaging-based approach as an alternative to flow cytometry to address challenges associated with assay sensitivity, reproducibility, matrix effects, throughput, operator friendliness, and instrument performance will be discussed. Challenges associated with bridging data across multiple platforms over several years will also be described.

3:30 An Innovative Approach for Detecting Neutralizing Antibodies Directed to Antibody-Derived Therapeutics Based on the Conventional Bridging ADA Assay Format

Veerle Snoeck, Ph.D., Research Fellow, Pharmacology, Immunogenicity, Ablynx BV

Neutralizing antibody (NAb) assays often require extensive pre-treatment steps. These not only reduce the NAb assay sensitivity, but often introduce a sensitivity difference between the ADA assay and the NAb assay. We developed an alternative NAb assay format based on the conventional bridging ADA assay that is highly drug- and target-tolerant and ensures the detection of NAb at the same sensitivity as the ADA assay, allowing unambiguous immunogenicity data interpretation.

4:00 Refreshment Break in the Exhibit Hall with Poster Viewing

4:40 Problem Solving Roundtable Discussions

Meeting Regulatory Expectations Regarding Immunogenicity Assessment

Moderators:
Susan Kirshner, Ph.D., Associate Chief, Immunology Lab, Therapeutic Proteins, Biotechnology, FDA/CDER
Lauren Stevenson, Ph.D., Director, Development Biomarkers and Bioanalytical Sciences, Biogen, Inc

• How and when to approach the regulators: Benefits of discussion with the regulators
• How much assessment is necessary? How much is too much when no additional value is gained?
• Neutralizing antibody assays: When should they be carried out and why?
• Challenges often encountered in translating the current guidances on immunogenicity testing for individual drug candidates

Critical Issues in Cut Points and ADA Assay Validation

Moderator: Michael Partridge, Ph.D., Staff Scientist, Bioanalytical Sciences, Regeneron, Inc.

• Experiences with cut point determination outlined in the April 2016 FDA draft guidance on assay
• Complications experienced and means of overcoming the difficulties
• Difficulties with analytical and biological variability
• Cut point determination between positive and negative samples for assay validation
• Interpretation of the validation data and relation to the clinical data

Strategies and Procedures to Reduce Interference in Immunogenicity Assays

Moderator: Jad Zoghbi, Ph.D., Senior Scientist, Biomarkers and Clinical Bioanalysis, Sanofi

• Clinical relevance of ADAs and the issue of drug interference in patient management
• Explore various methodologies for assessment of ADAs and the impact of drug interference on each
• How selecting the appropriate approach depends on the nature of the target

Late Stage Clinical and Post-Marketing Strategies: Evolving ADA Assays Over Time

Moderator: Tressa Allington, Ph.D., Development Scientist, Bioanalytical Development, Alexion

• Achieving highly sensitive assays while maintaining the link to clinical relevance
• Changing the positive controls over time
• Means of modifying cut points in new indications in a post-marketing setting
• Maintaining continuity and comparability of immunogenicity data over many years of clinical development and multiple indications

Challenges in Developing Neutralizing Antibody (Nab) Assays

Moderator: Shan Chung, Ph.D., Senior Scientist and Group Leader, BioAnalytical Sciences, Genentech, Inc.,

• Factors for selection of cell-based Nab vs. non-cell-based Nab assays
• Ligand binding assays and comparison with cell-based Nabs
• How you deal with poor drug tolerance, lack of sensitivity and matrix interference
• Interpretation of the results and implications for risk assessment

Dealing with Pre-Existing Positive ADA Activity in Study Patients

Moderator: Jim McNally, Ph.D., Principal, McNally Bioanalytical Consulting LLC

• Potential complications with pre-existing antibodies
• How to distinguish between pre-existing antibodies and potential immune responses to the drug and to determine a meaningful drug-induced response
• Examples seen in the clinic and their relevance
• Implications for humanized antibodies and novel humanized antibody products
• Implications regarding PK/PD safety and efficacy

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:15 Short Course Registration

Recommended Dinner Short Course*

• SC3: Validation of ADA Assays and Cut Point Calculations

*Separate registration required

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WEDNESDAY, October 25

7:30 am Morning Coffee

PRE-EXISTING POSITIVE ADAs, DRUG TARGET INTERFERENCE AND LOW ADA LEVELS

 8:20 Chairperson's Opening Remarks

Shan Chung, Ph.D., Senior Scientist and Group Leader, BioAnalytical Sciences, Genentech, Inc.

8:25 Case Studies on Handling Drug Target Interference

Mauricio Maia, Ph.D., Senior Scientist, BioAnalytical Sciences, Genentech, Inc.

Multimeric drug-target molecules present at high concentrations in ADA samples almost always lead to false-positive results in ADA ligand-binding bridging assays. This presentation will discuss why and how this can happen. We will describe the use of a simple decision tree to assess and mitigate the risk for target-induced false-positive ADA results. We will also discuss our own experience in handling these situations.

8:50 Development of Multiplex Sensitive Anti-Drug-Antibody (ADA) Assays for CRISPR/Cas9 Genomic Medicines

Junxia Wang, Ph.D., Associate Director, Immunosafety and Bioanalytical Development, Editas Medicine

The design and development of robust ADA assays for CRISPR/Cas9-based therapies present a unique challenge for the advancement of genomic medicines. To enable the screening of ADAs in response to a viral vector and a transgene protein product Cas9 in preclinical samples and human populations, we developed a sensitive immunogenicity assay which has great potential to detect low levels of ADAs, and allows for multiplexing of ADA measurements in a small sample.

9:15 Perspectives on Assays Used for Characterization of Immunogenic Responses and on Applying LBA Best Practice "Learnings" to Analytical Validation of Immunogenicity Risk Assessment Assays

Bonita (Bonnie) Rup, Ph.D., Biopharmaceutical Consultant, Bonnie Rup Consulting

Today, we consider best practices for developing drug-specific qualitative total ADA and NAb assays to be solidly established. However best practices for characterization assays, including titer and epitope/domain specificity assays, which are increasingly used to refine interpretation of immunogenicity data and stratify patient risk groups, may require further refinement. In addition, as we look to develop better, less immunogenic products, new assays are increasingly being applied to better assess immunogenicity risk, e.g. HLA binding and cell based antigen presenting cells and T cell activation assays. For these assays, too, there is a need to develop good practices for analytically validating, so that we can better understand how to interpret and apply the data they generate. This presentation will overview some remaining gaps for ADA characterization assays and then discuss how we may develop good practices for analytical validation of HLA binding assays.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

SPECIFIC PRODUCTS AND THERAPEUTIC AREAS

10:25 FEATURED PRESENTATION: FDA Perspectives on Gaining Regulatory Approval for a Biosimilar

Susan Kirshner, Ph.D., Associate Chief, Immunology Lab, Therapeutic Proteins, Biotechnology, FDA/CDER

I will discuss approaches for demonstrating absence of clinically meaningful differences, and how the study depends on the product. I will point out challenges to anticipate and stress the importance of carrying out a parallel immunogenicity study in a population that allows demonstration of no clinically meaningful differences in ADA induction. I will also discuss extrapolation of product use to multiple indications.

10:50 Challenges and Case Studies in Immunogenicity Assessment for Ultra-Rare Diseases

Tressa Allington, Ph.D., Development Scientist, Bioanalytical Development, Alexion Pharmaceuticals

The treatment of ultra-rare diseases poses unique challenges, including lack of patient matrices for validation, high levels of trough drug creating challenging tolerance conditions, and small numbers of patients enrolled in pivotal trials. The immunogenicity strategy for a monoclonal antibody under Phase III development for the treatment of devastating complement-mediated diseases will be reviewed, including unique factors contributing to assay interference and immune responses in healthy volunteers and patients.

11:15 Immunogenicity of Avelumab, an Immune Checkpoint Inhibitor Demonstrating Antitumor Activity

Joleen White, Ph.D., Director and Head, Project Support for New Biological Entities, Quantitative Pharmacology and Drug Disposition, EMD Serono

Avelumab is a human anti-PD-L1 IgG1 antibody, which blocks the interaction with PD-1 to potentiate T-cell cytotoxicity against tumor cells. Avelumab is approved by the FDA for the treatment of patients with two different types of cancer. The incidence of binding and neutralizing antibodies against avelumab was found to be low with no apparent impact on clinical pharmacokinetics, safety, or efficacy.

11:40 Neutralizing the Cost of Immunogenicity: Strategy and Case Studies

Lauren Stevenson, Ph.D., Director, Development Biomarkers and Bioanalytical Sciences, Biogen, Inc.

This presentation will highlight lessons learned over the course of development of multiple monoclonal antibody therapeutics regarding the incidence and impact of immunogenicity. Case studies will also be presented that highlight (1) the cost versus value of the development, validation and deployment of neutralizing antibody assays for low risk molecules, and (2) the concept of “biomarkers of NAbs” as an alternative approach.

12:10 pm Close of Immunogenicity Assessment and Clinical Relevance

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