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

Recommended Pre-Conference Short Courses*

October 22, 10:00 AM - 1:00 PM

SC1: Mechanism of Action and Risk-Based Approach for Developing Neutralizing Ab Assays

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Weifeng Xu, PhD, Senior Research Investigator, Bioanalytical Science, Bristol-Myers Squibb

October 22, 2:30 - 5:30 PM

SC2: Overcoming Drug Target Interference in ADA Assays

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Lilia Macovei, PhD, Senior Scientist, BioMedicine Design, Pfizer, Inc.

October 22, 6:15 - 9:15 PM

SC3: Validation of ADA Assays and Cut Point Calculations

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Michael Partridge, PhD, Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.

Recommended Pre-Conference Symposium*

  • October 22: Immunology for Biotherapeutics

* Separate registration required.

Tuesday, October 23

7:30 am Registration and Morning Coffee

CRITICAL ISSUES IN CUT POINTS AND ADA ASSAY VALIDATION

8:25 Chairperson’s Opening Remarks

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

8:30 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.

9:00 In vitro Immunogenicity Assay Analytical Validation and Harmonization

Jochem Gokemeijer, PhD, Associate Director, Molecular Discovery Technology, Bristol-Myers Squibb

Immunogenicity assays are widely used preclinically in biologics drug development to assess immunogenicity liabilities and select development candidates. Variations in assay set ups, lack of common standard, or agreed upon analytical validation make it challenging to compare results and limit the utility of these assays. Here we will discuss analytical validation as well as cross-industry work to harmonize these assays.

9:30 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.

10:00 Sponsored Presentation (Opportunity Available)

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

MANAGING INTERFERENCE IN ADA AND NAB ASSAYS

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

CLINICALLY RELEVANT ADA ASSAYS / MANAGING PRE-EXISTING ANTIBODIES

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

Theresa J. Goletz, PhD, Global Head, New Biological Entities and Drug Disposition, EMD Serono Research & Development 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 Assay Design Strategies and Clinical Impact of Pre-Existing ADA

Kevin Larimore, PhD, Senior Scientist, Bioanalytical Sciences, BioMarin Pharmaceutical, Inc.

Situations where anti-drug antibodies (ADAs) are present in a large fraction of untreated individuals present particular challenges for ADA assay development. We will discuss several non-standard approaches to cut point assessment for anti-PEG antibody assay design that were implemented to overcome the challenge of pre-existing anti-PEG antibodies in clinical trial subjects before initiation of treatment. The clinical impact of pre-existing and treatment-induced anti-PEG antibodies will be discussed.

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

4:40 Problem Solving Roundtable Discussions

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: Theresa J. Goletz, PhD, Global Head, New Biological Entities and Drug Disposition, EMD Serono Research & Development Institute, Inc.

Table 3: Challenges in Developing Neutralizing Antibody Assays

Moderator to be Announced

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 to be Announced

Table 7: Immunogenicity Testing for Biosimilars

Moderator to be Announced

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

6:30 Close of Day

Wednesday, October 24

7:30 am Morning Coffee

THE QUEST FOR CLINICALLY MEANINGFUL NAB ASSAYS / REGULATORY PERSPECTIVES

7:55 Chairperson’s Remarks

Theresa J. Goletz, PhD, Global Head, New Biological Entities and Drug Disposition, EMD Serono Research & Development Institute, 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 Sponsored Presentation (Opportunity Available)

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

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 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.

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

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