As the immunogenicity field is moving forward, the focus has shifted from detection to outcome management in clinical settings and what it means to patients when realizing the clinical manifestation of immunogenicity. This year’s conference
will focus on new case studies and how to use immunogenicity data in clinical study and patient therapy choices.
Final Agenda
Sunday, April 30
SC1: Preclinical and Clinical Assessment of Immunogenicity: Multidomain Therapeutics and New Modalities, Including Gene Therapy and CAR T
SC5: In silico Immunogenicity Predictions (Hands-On) Workshop
*Separate registration required.
MONDAY, APRIL 30
7:00 am Registration (Commonwealth Hall) and Morning Coffee (Harbor Level)
8:30 Chairperson’s Remarks
Vibha Jawa, PhD, Director, Immunogenicity Strategy for Biologics and Vaccines, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.
8:40 FDA Perspective on Clinical Management
Amy S. Rosenberg, MD, Division Director, Office of Biotechnology Products, FDA/CDER
Immune responses to therapeutic proteins can be highly problematic if they neutralize life-saving therapeutics, cross react to endogenous proteins with non-redundant functions, or abrogate the efficacy of highly effective therapeutic proteins.
Two strategies are increasingly being explored for mitigation: deimmunization of protein therapeutics and Immune tolerance induction (ITI). ITI is being increasingly explored in the context of autoimmune diseases, transplantation, and immune
responses to life saving therapeutic proteins. Approaches that focus on antigen specificity, rather than global immune suppression are of greatest interest, but their utility may be limited by the clinical time frame for tolerance induction
and clinical urgency. The development of “deimmunized” protein therapeutics has proven a daunting task but ultimately may have great utility. There is a clear need to better understand epitope spread and generation of subdominant
T cell clones in this context.
9:10 Ten Years of Clinical Experience with Immunogenicity in Pompe Disease: Lessons Learned
Stephanie Austin, MS, MA, CGC, Genetic Counselor, Senior Research Program Leader, Duke University Medical Center
Cross reactive immunological material (CRIM)-negative infantile Pompe disease (IPD) usually develop high anti-drug antibodies (ADA) and a prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and/or IVIG is a standard of
care. However, predicting the development of ADA is challenging in CRIM-positive infantile Pompe disease. We evaluated a scoring method for predicting individualized risk of ADA based on the sequence of their residual GAA and their HLA DR1
alleles. This and other clinical updates will be presented.
9:40 Clinical Relevance of Detecting Anti-Infliximab Antibodies with a Drug-Tolerant Assay: Post Hoc Analysis of the TAXIT Trial
Ann Gils, PhD, Professor, Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
To evaluate the clinical relevance of anti-drug antibodies (ADA), ADA of 76 patients of the TAXIT trial who presented with an infliximab trough concentration (TC)<3µg/mL at screening were measured using both a drug-sensitive (DS)
and drug-tolerant (DT) assay. The immunogenicity detection rate increased from 21% (DS) to 63% (DT). Q4 patients required a higher cumulative infliximab dose. All but one patient of Q4 were also ADA positive using DS.
10:10 Networking Coffee Break (Harbor & Mezzanine Level)
10:45 Chairperson’s Remarks
Vibha Jawa, PhD, Director, Immunogenicity Strategy for Biologics and Vaccines, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.
10:50 Clinical Immunogenicity Assessment: Decision-Enabling Immunogenicity Data and Analyses
M. Benjamin Hock, PhD, Director of Immunogenicity, BioMarin Pharmaceutical Inc.
The commentary, “A Proposal to Redefine Clinical Immunogenicity Assessment” [Mytych et al., 2017, AAPS J; PMID: 28247192] described criteria whereby ADA bioanalysis might not take place by default for a low-risk protein therapeutic.
One principle behind that argument is that ADA data should facilitate patient/physician- or product/program- decision-making.
11:20 Demystifying Immunogenicity Testing for Biotherapeutics
George R. Gunn, III, PhD, Head, Immunogenicity and Clinical Immunology, Bioanalysis, Immunogenicity and Biomarkers,
In Vitro/In Vivo Translation Platform, GlaxoSmithKline
Immunogenicity assessment of biologic therapeutics is a scientific and regulatory expectation. Bioanalytical complexities, sampling strategies and interpretation approaches can contribute to differences observed for anti-drug antibody (ADA)
incidences reported for biotherapeutics, even those with similar mode of action and patient population. Here we will put immunogenicity assessments into context regarding method limitations, capabilities and the interpretation of the clinical
consequences of immunogenicity.
11:50 Rigorous Reagent Characterization and Life Cycle Management Is Critical for the Consistent Performance of Bioanalytical Assays: A Clinical Case Study
Kun Lu, PhD, Staff Scientist, Protein Biochemistry Group, Regeneron Pharmaceuticals, Inc.
Robust and reproducible bioanalytical assay performance depends on the quality of critical protein reagents (CPR). Data will be presented to demonstrate the quality of CPRs using a set of biochemical and biophysical characterization assays.
Additionally, a clinical case study will be presented to demonstrate the importance of formulation conditions for CPRs when working with modified reagents, specifically ruthenium labeled reagents.
12:20 pm Early Development Strategy for Bacterial- or Viral-Vectored Gene Therapies: 2 Case Studies
Jennifer Sims, Non-Clinical Expert, NDA Advisory Board, NDA Group
Aligning product attributes & process variables with a preclinical program that enables translation into a risk management strategy for gene therapies is a challenge. We will present examples illustrating how an effective risk assessment
may integrate a consideration of factors associated with transgene & vector components. This can be used to guide manufacture, product quality & preclinical study design decisions, while anticipating regulatory priorities for early
clinical development, including mitigating the risks of undesirable immunogenicity.
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own
1:50 Session Break
2:20 (Commonwealth Hall)
Clinical Utility of Therapeutic Drug Concentration Monitoring (TDM) in Patients with Inflammatory Bowel Disease.
Moderator: Adam Cheifetz, MD, Director, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center; Associate Professor of Medicine, Harvard Medical School
- Identify the roles of TDM in clinical practice and review the data
- Discuss proactive vs. reactive TDM and potential benefits of proactive TDM
- Discuss challenges in implementing TDM in clinical practice
Immunogenicity and Hypersensitivity Responses
Moderators:
Soumi Gupta, PhD, Director of Immunogenicity, Translational Sciences, BioMarin Pharmaceutical Inc.
M. Benjamin Hock, PhD, Director of Immunogenicity, BioMarin Pharmaceutical Inc.
- Clinical diagnosis of hypersensitivity
- Molecular mechanisms of hypersensitivity
- Can varieties of ADA characterization facilitate post-hypersensitivity decision making (for a clinical program, and for patients/physicians)?
Defining a Tailored Risk-Based Immunogenicity Strategy Throughout Drug Development Program: One Size Does Not Fit All.
Moderators:
Sandra Garces, MD PhD, Senior Medical Advisor, Global Patient Safety, Eli Lilly
Vibha Jawa, PhD, Director, Biologics and Vaccine Bioanalytics, Merck
- Low vs. high risk situations
- Identify sequence and attribute-related risks using preclinical tools like algorithms and in vitro assays to define initial strategy
- Understand the risk due to drug MoA: can immune modulation impact the risk profile of a biologic?
- Consider clinical indication and patient population to understand expected clinical risks
- Early vs. late phase studies
- different questions at different phases
- IgM responses and ADA monitoring during washout period until return to baseline: why and when?
- how to use previous historical/legacy data to improve the cost-efficiency of next phases
- Defining the important clinical questions related to safety and efficacy (general vs. molecule-specific) to assess the clinical relevance of drug related immunogenicity
3:20 Networking Refreshment Break (Harbor & Mezzanine Level)
4:00 Chairperson’s Remarks
Peter Fung, PhD, Senior Manager Product Marketing, NanoTemper Technologies
4:10 Challenges and Opportunities in Engineering Protein Biopharmaceuticals
K. Dane Wittrup, PhD, C.P. Dubbs Professor, Chemical Engineering and Biological Engineering; Associate Director, Koch Institute
for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Arthur C. Clarke’s First Law posits that “When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong.”
Bearing this in mind, in this talk I will highlight areas of protein drug development that appear poised for breakthroughs in the coming decade or so.
4:55 The Next Generation of Cancer Immunotherapy: Targeting Myeloid Immune Checkpoints
Kipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women’s Hospital
Immune cells of the myeloid lineage hold tremendous potential as effectors of cancer immunotherapy. The CD47/SIRPα axis is a key molecular pathway that governs the interaction between myeloid cells and tumors. Therapies that target the
interaction are effective across multiple preclinical models of cancer and are now under investigation in clinical trials. Further studies have revealed additional regulators of myeloid cell activation that can be exploited as myeloid
immune checkpoints.
5:40 Welcome Reception in the Exhibit Hall with Poster Viewing (Commonwealth Hall)
7:15 End of Day
TUESDAY, MAY 1
8:00 am Registration (Commonwealth Hall) and Morning Coffee (Harbor Level)
8:25 Chairperson’s Remarks
Sandra Garces, MD PhD, Senior Medical Advisor, Global Patient Safety, Eli Lilly
8:30 Proactive Therapeutic Drug Monitoring and Improved Outcomes over Standard of Care or Reactive Therapeutic Drug Monitoring
Adam Cheifetz, MD, Director, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center;
Associate Professor of Medicine, Harvard Medical School
Currently, empiric dose escalation or reactive TDM is standard of care in the treatment of inflammatory bowel disease (IBD). Reactive testing is cost-effective and better directs care in IBD. However, there is some evidence that proactive
testing of anti-TNF concentrations and antibodies to anti-TNF and optimization to a therapeutic window improves outcomes when compared to empiric dose escalation or reactive testing.
9:00 Immunogenicity of Therapeutic Antibodies: Monitoring Antidrug Antibodies in a Clinical Context
Theo Rispens, PhD, PI Antibody Structure and Function, Sanquin
Immunogenicity is one of the factors that may impact efficacy and safety of therapeutic antibodies in patients. Many immunogenicity assays are available for testing anti-drug antibodies (ADA), but the relationship between ADA and clinical
outcome is often not clear. This presentation will address different types of immunogenicity assays and their clinical relevance in terms of drug tolerance, relation with PK, neutralizing antibodies, potential adverse events associated
with ADA and prediction of future loss of response.
9:30 PANEL DISCUSSION:
Moderator: Sandra Garces, MD PhD, Senior Medical Advisor, Global Patient Safety, Eli Lilly
Panelists:
Amy S. Rosenberg, MD, Division Director, Office of Biotechnology Products, FDA/CDER
George R. Gunn, III, PhD, Head, Immunogenicity and Clinical Immunology, Bioanalysis, Immunogenicity and Biomarkers, In Vitro/In Vivo Translation Platform, GlaxoSmithKline
Theo Rispens, PhD, Immunopathology, Sanquin Research, Amsterdam, The Netherlands
Boris Gorovits PhD, Senior Director, Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc
- What have we learned from using drug tolerant ADA assays in a clinical setting?
- Perspectives of FDA, sponsors, clinicians on the need of continuing to refine ADA assays (towards higher sensitivity and drug tolerance) and developing ADA tolerant PK assays
- What is the clinical usefulness of using ADA tolerant PK assays?
- How should clinicians use and interpret different types of PK and ADA assays?
10:00 Coffee Break in the Exhibit Hall with Poster Viewing (Commonwealth Hall)
10:50 Chairperson’s Remarks
Darshana Jani, Senior Manager, Global Assay Lead, Drug Development, Pfizer
10:50 Use of Risk Assessment Information from Preclinical Stage to Drive Clinically Relevant Immuno-genicity Strategy for Human Trials
Diana Montgomery, PhD, Principal Scientist, Predictive and Clinical Immunogenicity, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.
Unwanted immunogenicity to therapeutic proteins can impact the exposure (PK), response (PD) and drug safety, however the clinical manifestations can show a wide range of variation between different drugs. This presentation will cover both
the in silico algorithm and in vitro based risk assessment strategy put in place for several drugs in discovery and how the strategy was refined for molecules with immunomodulatory targets. Examples will be used to illustrate possible
relationships between predictive tools and clinical outcomes.
11:20 How Can Clinicians Use Immunogenicity Information to Better Understand Clinical Heterogeneity
Sandra Garces, MD, PhD, Senior Medical Advisor for Immunogenicity, GPS Medical and Benefit-Risk Management,
Eli Lilly and Company
Biologic therapies have significantly improved the prognosis of many patients with chronic inflammatory diseases. However, clinical responses to those therapies are very heterogeneous, varying from non-response to loss of response or to
complete clinical remission. In cases of therapeutic failure, an empirical switch to any other approved biologic represents a common practice. In cases of clinical remission, no clear guidance exists to maintain, reduce or discontinue
therapy. Therapeutic drug monitoring (drug levels and ADA) can work as a tool to help us understand clinical heterogeneity and adopt tailored therapeutic decisions that can improve the cost-effectiveness of biologic therapies.
11:50 Hemophilia A: A Case Study of Optimizing Patient Populations to Assess Immunogenicity
Steven Arkin, MD, Executive Director, Clinical Programs, Rare Disease Research Unit, Pfizer Worldwide R&D
Replacement biologics generated through recombinant DNA technology are used to treat many rare diseases but carry the risk of novel antigenic epitopes. Antibody immune responses observed in clinical studies may occur as a class effect
or in response to the novel epitopes. By use of sub-populations at minimum risk for background antibody immune response, it is possible to characterize immunogenicity risk for the respective drug in the context of the small studies
that are feasible in rare disease conditions.
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 (Commonwealth Hall)
2:00 Chairperson’s Remarks
Darshana Jani, Senior Manager, Global Assay Lead, Drug Development, Pfizer
Karen Thudium, PharmD, MSc, Head, Clinical Pharmacology Program, Cell and Gene Business Unit, Novartis
2:35 Immunogenicity Profile of an Enzyme-Substitution Therapy and Impact on Safety and Efficacy
Soumi Gupta, PhD, Director of Immunogenicity, Translational Sciences, BioMarin Pharmaceutical, Inc.
We have developed an extensive suite of assays to characterize the immunogenicity profile of an enzyme-substitution therapy in late-stage development. Here we will discuss the interpretation of that ADA data, and the impact of
immunogenicity on safety and efficacy of a novel therapeutic.
3:05 Regulatory Expectations for Immunogenicity Assessment of Viral Vector-Based Gene Therapy Modality
Boris Gorovits, PhD, Senior Director, Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing (Commonwealth Hall)
4:25 Immunogenicity Screening for Designing Antibody Therapeutics, A Case of Emicizumab (Preclinical)
Chiyomi Kubo, PhD, DVM, Scientist, Research Division, Chugai Pharmaceutical Co., Ltd.
Immunogenicity of antibody therapeutics may reduce efficacy, safety and success rate of development. This talk will present a case study to screen anti-factors IXa/X bispecific humanized IgGs for a low immunogenic candidate
on the basis of the activity observed in preclinical in vitro assay. In the Phase III-HAVEN1 trial where approximately 100 patients received the finally selected one, emicizumab, none tested
positive for ADA (Oldenburg J et al. NEJM. 2017).
4:55 Cellular and Humoral Immune Responses in AAV-Mediated Gene Therapy
Katherine A. High, MD, Co-Founder, President and Head of R&D, Spark Therapeutics
Recombinant adeno-associated viral vectors (AAVs) are quickly becoming the preferred vector for gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting
hemophilia B patients 10 years ago, immune responses to the AAV capsid have emerged as an issue that must be optimally managed to achieve therapeutic success. This talk will utilize data from clinical trials to illustrate
optimal monitoring and management of human immune responses to the AAV vector, with a goal of achieving best outcomes in AAV-based gene transfer. A better understanding of both pre-treatment neutralizing antibodies, and
cytotoxic T cell responses to recombinant AAV will lead to more efficacious gene transfer protocols in patients.
5:25 End of Immunogenicity Case Studies and Clinical Management
5:30 Registration for Dinner Short Courses (Commonwealth Hall)
SC13: Sub Visible Protein Particles in Immunogenicity: Measurement, Characterization and Impact
Björn Boll, PhD, Head, Particle Lab and Higher Order Structure Protein Analytics, Physical Chemical Analytics, Novartis Pharma AG
Anacelia Ríos Quiroz, PhD, Scientist, Group Leader Particle Lab, Pharma Technical Development Europe (Biologics) Analytics (PTDE-A), F. Hoffmann-La Roche Ltd.
*Separate registration required.