Cambridge Healthtech Institute’s 10th Annual
Immunogenicity Assessment & Clinical Relevance
Assay Strategy for Meaningful Evaluation
October 23-24, 2018
The industry continues to be challenged by the development, application and interpretation of immunogenicity assays. Recently the FDA have advocated a more stringent approach for cutpoint setting and assay validation creating further difficulties. Moreover,
the industry remains uncertain about when the more challenging neutralizing antibody assays should be applied, and which type of assay is reliable and acceptable. Additional ongoing challenges concern managing drug and target interference, understanding
and handling the impact of pre-existing antibodies, and interpreting the clinical significance of assay data.
Final Agenda
Tuesday, October 23
7:30 am Registration and Morning Coffee (Foyer)
8:25 Chairperson’s Opening Remarks
Lauren Stevenson, PhD, Director, Development Biomarkers and Bioanalytical Sciences, Biogen, Inc.
8:30 FEATURED PRESENTATION: Updating Immunogenicity Risk Assessment During Study Conduct
Joleen T White, PhD, Director, Head of Project Support, NBE Drug Disposition, EMD Serono
Immunogenicity risk assessment is a scientific process that evolves as data emerge. This presentation will discuss when and how you revisit a strategy including case studies about updating immunogenicity risk assessment and adding, removing, or amending
associated analyses. It includes: changing the cut point in response to in-study validation results; adding characterization assays for specific purposes; modifying an immunogenicity sampling schedule; and including additional statistical analyses
based on preliminary findings.
9:00 Reporting Clinically Relevant ADA Data: The Importance of Determining Appropriate Cut Points & Critical Reagents
Michael Partridge, PhD,
Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.
Selection of ADA assay cut points is critical as it determines the threshold for positivity. Furthermore, numerous assay-related factors impact method performance and the data generated. ADA cut points are greatly affected by the population (normal/diseased)
selected to determine these values, the number of samples, and the statistical approach for outlier removal. Storage conditions for critical reagents can also impact ADA results, increasing false positives and unnecessary confirmation analysis.
Cases studies will be presented discussing the impact of these factors on immunogenicity assessment for biotherapeutics.
9:30 Case Study on Delineation of Immunogenicity Confirmatory Assay Full Validation Strategy, and Implementation of Assay Cut Point Factor Assessment Guidelines
Mauricio Maia, PhD, Senior Scientist,
BioAnalytical Sciences, Genentech, Inc.
This presentation will delineate the approach we are following for full-validation of confirmatory immunogenicity assays. We will also outline the strategy currently in place at Genentech for scientifically sound implementation of clinical assay in-study
cut points (CPs). Our new practices provide improved clarity and efficient decision-making for when and how CPs should be reset. With multiple specific recommendations, our strategy also allows for careful consideration of each project’s
unique context, including its immunogenicity risk-assessment.
10:00 Sponsored Presentation (Opportunity Available)
10:15 Coffee Break in the Exhibit Hall with Poster Viewing (Edison D)
10:55 Understanding and Overcoming Drug Interference in NAb Bioassays
Zhihua Jiang, PhD, Senior Scientist, BioMedicine Design, Pfizer, Inc.
Neutralizing antibodies (NAb) bioassay relevant to drug mode of action is recommended by the regulatory authorities for immunogenicity assessment. However, drug interference is a significant obstacle in NAb bioassay development comparing to ADA assay.
This talk will present a few case studies, in which different strategies were developed for sample pre-treatment to improve drug tolerance of bioassay. The analytical challenges in overcoming drug interference of NAb bioassay will be discussed.
11:25 ADA Interference of PK Immunoassays in Preclinical Studies
Christian Ruzanski, PhD, Senior Scientist, Bioanalysis,
Novo Nordisk A/S
An important prerequisite in understanding the PK, PD, and their relationship to safety of a therapeutic is the accurate measurement of the therapeutic’s concentration in non-clinical and clinical samples. ADAs can interfere with the concentration
measurement of therapeutic levels and accordingly prevent accurate details about in vivo exposure. Here we present two case studies of homogenous PK immunoassays in the non-clinic where ADA assay inference prevented
accurate concentration determination of the therapeutic in the highest dose group.
11:55 Alternatives to the Current Acid-Dissociation-Based Anti-Drug Antibody Extraction to Increase ADA Recovery in Immunogenicity Testing
Weifeng Xu, PhD, Senior Research Investigator,
Bioanalytical Science, Bristol-Myers Squibb
Drug-interference is a big challenge for immunogenicity testing for monoclonal Ab therapeutics. Although Beads-Extraction with Acid Dissociation (BEAD) has been successfully developed to overcome drug interference, ADAs can be denatured and lost during
the process due to harsh acid treatment. An alternative way of overcoming drug interference other than acid-dissociation is much needed to preserve ADA activity. A couple of innovative approaches will be discussed in this presentation.
12:25 pm Sponsored Presentation (Opportunity Available)
12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:25 Session Break
2:25 Chairperson’s Remarks
Michael Partridge, PhD, Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.
2:30 Developing Robust ADA Assays Focused on Clinically Relevant Responses
Chris Stebbins, PhD, Principal Scientist, Translational Medicine, Biogen, Inc.
Unlike PK assays, ADA assays need appropriate background to be preserved for ideal performance. This presentation will describe the redevelopment of assays to appropriately capture biological variability and ensure detection of a clinically relevant
response. Case studies will be presented.
3:00 KEYNOTE PRESENTATION: Impact of Presence of Pre-Existing Antibodies on Immunogenicity Assessment Strategy
Seema Kumar, Assoc Director & Sr Project Manager, Quantitative Pharmacology & Drug Disposition, EMD Serono R&D Institute Inc.
While all biotherapeutics have the potential to induce an antidrug antibody response (ADA), for some, pre-existing ADAs are observed in drug-naïve matrix. The presence of pre-existing ADAs may influence the bioanalytical approach and data analysis,
both preclinically and clinically. Clinical case studies of biotherapeutic candidates in development for oncology or non-oncology indications for which pre-existing ADA were detected will be presented.
3:30 Case Study on Challenges of Immunogenicity Assessment for a Short Peptide Therapeutic
Mitra Azadeh, PhD, Principal Scientist, Bioanalytical & Biomarker Development, Shire
There are unique challenges associated with the development of immunogenicity assays for short peptide therapeutics. Their small size reduces their antigenicity and the likelihood of success for positive control generation. Their shorter sequence
also renders them less effective capture and detection agents for standard immunoassays. This presentation reviews the case study of a short peptide drug and the strategies used to develop a sensitive and drug tolerant immunogenicity assay.
4:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Edison D)
4:40 Problem Solving Roundtable Discussions
Edison EFG
Table 1: Cutpoints for Screening and Confirmatory Assays: Managing Change
Moderator: Mauricio Maia, PhD, Senior Scientist, BioAnalytical Sciences, Genentech, Inc.
Table 2: Dealing with Pre-Existing Positive ADA Activity in Study Patients
Moderator: Seema Kumar, Assoc Director & Sr Project Manager, Quantitative Pharmacology & Drug Disposition, EMD Serono R&D Institute Inc.
Table 3: Challenges in Developing Neutralizing Antibody Assays
Moderator: Terry P. Combs, PhD, Senior Scientist, BioMedicine Design, Pfizer, Inc.
Table 4: The Challenge of Drug- and Matrix-Interference in Immunogenicity Testing
Moderator: Weifeng Xu, PhD, Senior Research Investigator, Bioanalytical Science, Bristol-Myers Squibb
Table 5: Late Stage Clinical and Post-Marketing Strategies: Evolving ADA Assays Over Time
Moderator: Mitra Azadeh, PhD, Principal Scientist, Bioanalytical & Biomarker Development, Shire
Table 6: Meeting Regulatory Expectations Regarding Immunogenicity Assessment
Moderator: William Hallett, PhD, Biologist, OPQ/OBP, CDER, FDA
Table 7: Immunogenicity Testing for Biosimilars
Moderator: Haoheng Yan, PhD, MD, Chemist, OPQ/OBP, CDER, FDA
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing (Edison D)
6:30 Close of Day
Wednesday, October 24
7:30 am Morning Coffee (Foyer)
7:55 Chairperson’s Remarks
Lynn Kamen, PhD, Scientist, Bioanalytical Sciences, Genentech, Inc.
8:00 Case Study on Post-Marketing Requirement to Develop an Appropriately Sensitive NAB Assay: Is It Clinically Meaningful?
Devangi Mehta, PhD, Associate Director, Development Biomarkers and Bioanalytical Sciences, Biogen, Inc.
This presentation will highlight lessons learned during the development of low-risk monoclonal antibody therapeutics regarding the incidence and impact of immunogenicity. A case study will be presented that evaluates the cost versus value gained of
developing, validating, and deploying neutralizing antibody assays for a low risk molecule versus using the “biomarkers of NAbs” approach.
8:30 FEATURED PRESENTATION: Best Practices for Successful Immunogenicity Assay Review by the Agencies
William Hallett, PhD, Biologist, OPQ/OBP, CDER, FDA
An immunogenicity assessment often includes validated screening, confirmatory, and neutralizing assays at the time of BLA submission. The submission of validation reports that occasionally include poorly defined criteria and confusing nomenclature
leads to information requests that may result in miscommunication between reviewers and sponsors, resulting in delays. This talk will focus on best practices to improve the quality of immunogenicity submissions.
9:00 FDA Regulatory Perspective on Immunogenicity Testing for Biosimilars
Haoheng Yan, PhD, MD, Chemist, OPQ/OBP, CDER, FDA
A clinical study or studies assessing the immunogenicity of the proposed biosimilar product and that of the innovator product is essential in a 351(k) application (biosimilar pathway). We will discuss the FDA’s expectation on the immunogenicity
study design, the assay development and validation, and assessment of results specific to biosimilar applications.
9:30 Q&A with the Morning's Speakers
10:00 Coffee Break in the Exhibit Hall with Poster Viewing (Edison D)
10:40 Development of Neutralizing Antibody Assay for Supporting Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Lessons and Strategies
Lilia Macovei, PhD, Senior Scientist,
BioMedicine Design, Pfizer, Inc.
Chimeric Antigen Receptor T-cells (CART) is a personalized therapy that uses the patient’s own T cells or healthy donor’s T-cells, engineered to express artificial T-cell receptors designed to convey MHC-independent target recognition.
These therapies have recently shown great promise in treating hematological cancers. The Nab assay development, unique challenges and immunogenicity strategy to detect anti-CART receptor neutralizing antibodies will be presented.
11:10 Selection of a Ligand-Binding Neutralizing Antibody Assay for Benralizumab: Comparison with an Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Cell-Based Assay
Yuling Wu, PhD, Associate Director, Clinical Pharmacology & DMPK, MedImmune
To support the clinical development of benralizumab (anti–IL5Rα mAb), we developed and validated a CLBA (competitive ligand-binding assay) and a CBA (cell-based assay). Data from assay validation and clinical sample testing demonstrated
that the CLBA is more sensitive in detecting NAb activities and more drug-tolerant than the CBA. Moreover, the data from clinical samples demonstrated that the CLBA yielded more positive samples than the CBA. The CLBA detects neutralizing activity
in common with the CBA. These results, along with the more precise nature of the CLBA, support the choice of the CLBA over the CBA for future clinical trials for benralizumab.
11:40 Immunogenicity Challenges Surrounding Immunogenicity Assessment of Gene Therapy Vectors
Terry P. Combs, PhD, Senior Scientist, BioMedicine Design, Pfizer, Inc.
Environmental exposure to adeno-associated viruses (AAVs) could lead to the production of neutralizing antibodies for current gene therapy vectors. Hence, the transformative power of gene therapy on patients’ lives is linked to the standardization
of diagnostics for preexisting antibodies (Abs). This presentation will summarize lessons learned thus far from method development research at Pfizer on plate-based assays for preexisting Abs to AAV8 and SPARK-9001 currently in trials for Hemophilia
B.
12:10 pm Close of Immunogenicity Assessment & Clinical Relevance