Evaluating and Reporting the Immunogenicity Impacts for Biological Products—a Clinical Pharmacology Perspective

Abstract

Abstract. Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA's clinical pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (n = 108) reported the incidence of immunogenicity and 49% (n = 59) reported immunogenicity impact on efficacy. However, only 26% (n = 31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before vs. after ADA formation) is a useful alternative to betweensubject (ADA+ vs. ADA−) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time.KEY WORDS: clinical pharmacology assessment; immunogenicity data for approved biological products; impact on clinical pharmacokinetics and efficacy; incidence of anti-drug antibodies and neutralizing antibodies.

Assessment of the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab

“…The exposure–response and PK–pharmacodynamic models for tildrakizumab estimated EC 50 values at 0·36 μg mL −1 (90% confidence interval 0·22–0·61) and 0·25 μg mL −1 , respectively, implying that at these exposure levels at least half of the maximum effect in PASI 75 can be expected . The finding that the effects of ADAs on PK are more sensitive than the effects on clinical response has also been observed with other biologics …”

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

“…86,87 ADAs against therapeutic mAbs can appear transiently or throughout the entire treatment period; can cause immune reactions such as anaphylaxis, cytokine release, and hypersensitivity; and may lead to complete or partial loss of efficacy because of target neutralization. The presence of ADAs can alter the PK of the drug, which in turn can influence safety and efficacy.…”

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Biologics

“…However, not all ADAs affect the efficacy and/or safety of the biologic: the titer (ie, amount), binding affinity, and ability to neutralize the biologic's activity also determine whether ADA formation is detrimental to therapy with the affected biologic. Humanized biologics have a low incidence of antidrug antibodies, and most do not neutralize the activity of the drug . The incidence reporting for immunogenicity is highly variable and dependent on the assay measuring the antidrug–antibody.…”