Immunogenicity: Regulatory and Clinical Case Studies


Managing and predicting immune response from biological therapies can be challenging to the drug development scientist, especially as new constructs and immunotherapy approaches continue to be discovered. The regulatory approaches to ensuring safety of new products needs to take into account what has been learned in the clinic to date. This meeting will review case studies of clinical candidates in order to learn the most clinically relevant information for immunogenicity, and also share insights from regulators on winning approaches for ensuring safety of biologic drugs.

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MONDAY, APRIL 25

7:00 am Registration and Morning Coffee


REGULATORY PERSPECTIVE

8:30 Chairperson’s Remarks

Narendra Chirmule, Ph.D., Senior Vice President, Biocon Research Labs


8:40 KEYNOTE PRESENTATION

Talk Title to be Announced

Amy Rosenberg, Ph.D., Director, Therapeutic Proteins, FDA/CDER


9:10 Update on EU Regulatory Environment for Immunogenicity Assessment of Therapeutic Proteins

Paul Chamberlain, NDA Advisory Board

The EU regulatory environment for assessment of immunogenicity-related risks for therapeutic proteins continues to evolve, broadly in parallel to that in USA, but with some differences in detail. This presentation will summarize: 1) Main changes introduced by September 2015 draft revision of main EU immunogenicity guideline, including feedback from stakeholder discussion. 2) Learnings for recent product reviews.

9:40 Immunogenicity of Biologics and Biosimilars: Clinical Impact of Aggregates, Glycosylation and Other Post-Translational Modificiations

Narenda Chirmule, Ph.D., Senior Vice President, Biocon Research Labs

Assessment of clinical immunogenicity is a critical step in establishing biosimilarity. We will present our experience in development, validation and implementation of the immunogenicity assessment strategy for Biologics and Biosimilars. The presentation will discuss the unique challenges involved immunogenicity assessment, which in the final step towards demonstrating the similarity to the reference licensed product, with “totality of evidence”.

10:10 Coffee Break


PRECLINICAL STUDIES

10:45 Chairperson’s Remarks

Theo Rispens, Ph.D., Senior Scientist, Immunopathology, Sanquin

10:50 Humanized Mice as a Tool to Measure Immunogenicity

Michael Brehm, Ph.D., Professor, Program in Molecular Medicine, University of Massachusetts Medical School

The development of severely immunodeficient IL2rgnull mice that support engraftment of functional human immune systems has enabled the in vivo study of human immunity. This presentation will include a general overview of these humanized mouse models, describing currently available strains, the protocols to generate humanized mice, the strengths of each system and a discussion of the application of these models to study immunogenicity.

11:20 Talk Title To Be Announced

Mark Milton, Ph.D., Executive Director, DMPK-Biologics PKPD, Novartis Institutes for Biomedical Research Inc.

11:50 Clinical Implications of Immunogenicity of TNF Inhibitors

Theo Rispens, Ph.D., Senior Scientist, Immunopathology, Sanquin

Many patients treated with adalimumab or infliximab develop anti-drug antibodies (ADA) to these TNF inhibitors. However, there remains controversy about the clinical consequences of ADA formation, which is in part due to different assay methodologies and testing strategies. This presentation will address the characteristics of ADA responses to TNF inhibitors and the relationship between drug concentration, ADA, and clinical outcome.

12:20 pm How to Develop a “Fit-for-Purpose” Development Pathway that is Associated with “Faster to Market” Options for Clinical Development

Niamh Kinsella, Principal Consultant, Vice President, Early Stage Product Development, NDA Regulatory Science Ltd.

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:50 Session Break


2:20 Problem-Solving Breakout Discussions

Immunogenicity Assessment of Bioassays

Paul Chamberlain, NDA Advisory Board

  • What are the regulatory priorities?
  • What is the relative importance of intrinsic versus extrinsic factors as potential sources of difference?
  • How does this influence the clinical evaluation of immunogenicity?
  • Does the measurement of relative ADA response require additional control(s) to minimize impact of bioanalytical bias?
 

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing


PLENARY KEYNOTE SESSION

4:00 Chairperson’s Remarks

4:10 The Promise of Cancer Immunotherapy: An Overview of Recent Advances and Jounce’s Approach to Delivering the Right Therapy to the Right Patient

Deborah_LawDeborah Law, D. Phil. CSO Jounce Therapeutics, Inc.

As immunotherapies become an increasingly important component of cancer treatment the challenge will be to identify ways to provide the best therapy(s) to the individual. This presentation will provide an overview of current cancer immunotherapies as well as highlight some of the challenges ahead including selection of optimal combinations, moving outside of T cell-directed approaches, and will highlight how Jounce Therapeutics is using its Translational Science Platform as an approach to develop and deliver the right therapy to the right patient.

4:50 Antibody as Drugs: Then, Now and Tomorrow

Paul_CarterPaul J. Carter, Ph.D., Senior Director and Staff Scientist, Antibody Engineering, Genentech

Antibodies have grown into a clinically and commercially important drug class with more than >45 antibodies marketed for imaging or therapy in the USA and/or Europe and with ~$63 billion in worldwide sales in 2013.  This presentation will highlight progress in developing antibody drugs and consider opportunities for future innovation.  


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

6:45 End of Day

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TUESDAY, APRIL 26

8:00 am Morning Coffee


DETERMINING CLINICAL RELEVANCE

8:25 Chairperson’s Remarks

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

8:30 Statistical Considerations in Design of Multi-Tiered Methods to Detect and Confirm the Presence of ADAs in Clinical Studies

Harry Yang, Ph.D., Senior Director R&D, Medimmune, LLC

Biopharmaceuticals have an inherent propensity to elicit immunogenic responses. Key to successful evaluation of immunogenicity is to have well developed and validated assays. This talk will focus on statistical strategies related to ADA assay validation, sample size determination, cut point estimation in the presence of outliers and skewed distributions. In addition, we will explore ways to combine information from screening and confirmatory assays, so as to derive optimal cut point.

9:00 Linear epitope mapping, binding strength, and neutralization of interferon-beta using patient-derived monoclonal antibodies: Results from ABIRISK

Florian Deisenhammer, Ph.D., Clinical Department of Neurology, Innsbruck Medical University

One of the goals of the ABIRISK project (www.abirisk.eu) is to isolate monoclonal anti-drug antibodies (mADA) for use as positive controls in binding and neutralization assays. We isolated 5 different mADA which showed very high affinity binding to IFNb with kinetics constants in the picomolar range. The nature of the binding sites will be explored by linear epitope mapping in order to identify critical sites for neutralization. This work will help understanding the complexity of drug neutralization and guide how to properly use mADA as positive controls in neutralization assays.

9:30 Measures of a Clinically Relevant Immune Response: Weighing between the Sensitivity and Impactful Response

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

The immunoassays currently employed for the immunogenicity assessment are highly sensitive and can detect low signals of anti- therapeutic immune responses. However, the impact of such responses on exposure and efficacy requires further evaluation. The relevance of ADA impact on PK depends on the study design and impact on PD. The onset and magnitude of the ADA response on PK and PD will also be discussed in the context of clinical relevance.

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


DETERMINING CLINICAL RELEVANCE (CONT.)

10:50 De-Immunizing Immunotoxins

Ira Pastan, M.D., Co-Chief, Molecular Biology, National Cancer Institute, National Institutes of Health

Many non-human proteins have beneficial therapeutic properties, but cannot be administered repeatedly to humans, because of their immunogenicity. We have developed an immunotoxin targeting mesothelin-expressing malignancies (SS1P) that contains a portion of Pseudomonas exotoxin A. The protein has shown activity against mesothelioma in human and we have been improving its usefulness by identifying and removing T cell and B cell epitopes.

11:20 Impact of Target Interference in PK and ADA Assays and Potential Mitigation Strategies

Manoj Rajadhyaska, Ph.D., Director, Bioanalytical Sciences, Regeneron Pharmaceuticals Inc.

Ligand binding assays are susceptible to interfering target molecules that can distort assay results by generating false positive or negative signals or blocking desired assay interactions. If not properly characterized and mitigated, these artefactual results can impact the result interpretation. With the help of some case studies, the mechanistic aspects of the variety of ways by which target interference can occur will be discussed with potential mitigation strategies for each case.

11:50 PANEL DISCUSSION: Determining a Clinical Relevant Response

Moderator: Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

This panel will discuss:

-What determines a clinically relevant response?

-Are assays too sensitive?

-The relevance of ADA impact on PK

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing


Clinical Case Studies

2:00 Chairperson’s Remarks

Sally Fischer, Ph.D., Principal Scientist, Development Sciences, Genentech

2:05 Robust Immune Response to a Product Related Impurity and Impact on Immunogenicity Rate of an Antibody Therapeutic

Sally Fischer, Ph.D., Principal Scientist, Development Sciences, Genentech

A product related impurity was identified in the material used in clinical study. To assess the potential ability of patients to develop an immune response to the impurity and impact on immunogenicity of the therapeutic two bridging ELISA were developed and validated. Samples from treated subjects were evaluated in both assays. This presentation will discuss the results of the immunogenicity assessment to the impurity and observed immunogenicity rate of the antibody therapeutic.

2:35 Immunogenicity: Why and How

Michel Awwad, Ph.D., former Director, Pharmacokinetics & Dynamics & Metabolism, Merrimack Pharmaceuticals

Biologics are increasingly being used as therapeutic products for treatment of many different diseases ranging from neurological to cancer and other immunological diseases. Understanding, predicting, measuring and attempting to avoid the immune response to these biologics is critical to develop efficacious drugs.

3:05 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


CLINICAL CASE STUDIES (CONT.)

4:25 Positive Effects in Reducing Immunogenicity Target Interference

Erik Meyer, Ph.D., Senior Scientist, GlaxoSmithKline

During Phase II clinical studies, a high incidence of immunogenicity did not correlate with decreased PK profiles or loss of drug efficacy. Drug target analysis revealed its accumulation during treatment, with target interference possibly impacting immunogenicity analysis. Subsequent immunogenicity assay modifications reduced the ADA positive rate and supported clinical observations for additional clinical studies.

4:55 ERT Immunogenicity and Experimental Immune Tolerance Induction: Results of a BioMarin Sponsored Advisory

Brian Long, Ph.D., Senior Scientist, Immunology Assessment, BioMarin

Enzyme replacement therapies (ERT) for the treatment of lysosomal storage diseases (LSD) have demonstrated great success in attenuating the disease phenotype for many rare and debilitating disorders. We convened an advisory board of treating physicians and key opinion leaders where we reviewed the current data regarding immunogenicity with ERTs and contemporary immune tolerance inducing regimens; the results of which are presented.

5:25 End of Immunogenicity: Regulatory and Clinical Case Studies

5:30 Registration for Dinner Short Courses


Recommended Dinner Short Course*

SC9: Overcoming the Challenges of Immunogenicity Assessment

*Separate registration required



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