Therapeutic drug monitoring (TDM) for large molecules is not widely practiced despite reported benefits in patient outcomes for some immune-mediated inflammatory diseases. A joint US-FDA (OCP)/AAPS workshop was convened in February 2024, to discuss the potential benefits, limitations, and future considerations for implementation of large molecule TDM. TDM presents opportunities for precision medicine that incorporate facets of clinical pharmacology, immunogenicity, regulated bioanalysis, healthcare economics, and clinical practice. A roundtable discussion will further the challenges and benefits of incorporating TDM into the drug development process. 

Evaluating the clinical effects of immunogenicity has become more challenging with the advent of highly sensitive ADA assays that result in a higher proportion of ADA-positive participants. This talk will discuss the challenges associated with constructing a cross-functional group to investigate potential clinical effects on PK, PD, efficacy, and safety. Displays helpful for exploration of the data and in distilling meaningful clinical effects will be presented.

This presentation will discuss incorporating immunogenicity information into the prescribing information for human drugs and biological products.

This talk discusses the use of immune humanized mice to assess immunogenicity in drug development. It explores the methodology for creating and utilizing these mice to mimic human immune responses, providing a valuable preclinical tool for predicting immunogenic reactions to therapeutics. The focus is on enhancing the accuracy of immunogenicity assessments, which is crucial for the safety and efficacy of new drugs, particularly biologics and biosimilars.

Despite great promise, the immunogenicity of gene therapies remains one of the biggest challenges. Immunogenicity can impact the safety, efficacy, and long-term durability of gene therapies. Addressing immunogenicity-associated challenges is critical to realizing the full potential of these life-saving therapies. In my talk, I will discuss FDA’s perspective on the immunogenicity associated with gene therapies.

Despite the high safety profile demonstrated in clinical trials, adeno-associated virus (AAV)-mediated gene therapy still faces considerable obstacles due to its immunogenicity. Here, by leveraging ex vivo T cell assay, the prediction of epitope binding to major histocompatibility complex Class-II alleles, sequence-conservation analysis in AAV phylogeny, and site-directed mutagenesis, we show that the replacement of amino acid residues in a promiscuous and most immunodominant T cell epitope in the AAV9 capsid with AAV5 sequences, abrogates the immune responses of peripheral blood mononuclear cells to the chimeric vector while preserving its functions, potency, cellular specificity, transduction efficacy, and biodistribution.

Many drug modalities in clinical development are significantly more complex than traditional monoclonal antibodies. While the ADA assessment strategy for mAbs is well-established in White Papers and regulatory guidance, the immunogenicity evaluation requirements for newer modalities are still largely undefined. In this presentation we will discuss several newer modalities and the immunogenicity challenges for ADA/NAb testing, focusing on how the overall immunogenicity assessment will be used to inform clinical decisions.

Cellular immune responses have the potential to impact clinical safety and efficacy of various modalities including gene, cellular, and protein-based therapies. In this presentation, we will discuss how variables such as patient blood draw, transit conditions, peripheral blood mononuclear cell isolation, and storage can impact downstream assays that assess cellular immune responses to therapeutics.

• Variables related to blood storage and isolation methods can significantly impact the ability to detect cellular immune responses
• Assays used for measuring of cellular immune responses can require different sample collection and processing considerations
• Proper controls for assessing cellular responsiveness need to be considered

With the recent approval for Winrevair, we believe it is valuable to share Merck's experience in immunogenicity data analysis and reporting, as well as our approaches for analyzing the clinical impact of immunogenicity. These efforts have culminated in the development of the Integrated Summary of Immunogenicity (ISI) contributing to FDA approval for Winrevair.

Immunogenicity is monitored at patient level and reported at study level, however, aggregate program-level data may provide a broader understanding of treatment-induced immunogenicity to protein therapeutics. We report data from an mAb therapeutic across multiple studies that include an examination of the impact of dose, route of administration, sample time points, and patient populations. We highlight the relationships among these aforementioned variables, as well as important implications for development of therapeutic proteins in the future.

Subcutaneous delivery of therapeutic proteins can increase patient compliance and reduce burden on healthcare systems compared to intravenous infusion. However, subcutaneous administration has been proposed to increase immunogenicity. We reviewed anti-drug antibody (ADA) data for various protein therapeutics that were administered both intravenously and subcutaneously, and overall, no difference in immunogenicity incidence was observed. Although administration route may in some instances influence ADA, other risk factors are likely more impactful.

This presentation will focus on a case study from one of Boehringer Ingelheim’s multi-domain biotherapeutic programs to demonstrate our strategies for detection and characterization of Pre-Existing Antidrug Antibodies (PE-ADA) towards multi-domain biotherapeutics. This case will provide in detail the specialized reagents and tool molecules along with the methods used to characterize the domain specificity and identify the location of PE-ADA in clinical ADA samples. In addition, this presentation will share our strategy for the development of a clinical ADA method to distinguish between PE-ADA and TE-ADA in clinical ADA samples from pivotal trials.

Drug tolerance is a critical attribute of anti-drug antibody (ADA) assays for assessing clinical immunogenicity. Dr. James Zanghi, PhD, at Genentech, will present a case study where a therapeutic product required reassessment of the assay drug tolerance to meet both increased drug exposure demands and more rigorous validation requirements since the product’s launch. The strategy to overcome these issues while working within challenging timelines may be broadly applied to other therapeutics. Dr. Zanghi will address ADA assay development strategies for consideration of the entire duration of a product’s lifecycle.