Challenges of non-clinical safety testing for biologics: A Report of the 9th BioSafe European Annual General Membership Meeting

Abstract

New challenges and other topics in non-clinical safety testing of biotherapeutics were presented and discussed at the nineth European BioSafe Annual General Membership meeting in November 2019. The session topics were selected by European BioSafe organization committee members based on recent company achievements, agency interactions and new data obtained in the non-clinical safety testing of biotherapeutics, for which data sharing would be of interest and considered as valuable information. The presented session topics ranged from strategies of in vitro testing, immunogenicity prediction, bioimaging, and developmental and reproductive toxicology (DART) assessments to first-in-human (FIH) dose prediction and bioanalytical challenges, reflecting the entire space of different areas of expertise and different molecular modalities. During the 9 th meeting of the European BioSafe members, the following topics were presented and discussed in 6 main sessions (with 3 or 4 presentations per session) and in three small group breakout sessions: 1) DART assessment with biotherapeutics: what did we learn and where to go?; 2) Non-animal testing strategies; 3) Seeing is believing: new frontiers in imaging; 4) Predicting immunogenicity during early drug development: hope or despair?; 5) Challenges in FIH dose projections; and 6) Non-canonical biologics formats: challenges in bioanalytics, PKPD and biotransformation for complex biologics formats. Small group breakout sessions were organized for team discussion about 3 specific topics: 1) Testing of cellular immune function in vitro and in vivo; 2) MABEL approach (toxicology and pharmacokinetic perspective); and 3) mRNA treatments. This workshop report presents the sessions and discussions at the meeting.

Toxicologic Pathology Forum: Considerations Regarding Determination of Adversity for Immunopathology Findings in Nonclinical Toxicology Studies with Immune-Modulating Therapeutics

“…Reliably forecasting immunogenicity, in particular ADAs, in humans from animal studies is still not possible because immune processes and the translatability between species that lead to ADAs are not yet fully understood. 10 For example, in nonclinical studies of atezolizumab, a monoclonal antibody immuno-oncology agent that acts as a checkpoint inhibitor to block programmed death-ligand 1 (PD-L1), cynomolgus monkeys developed minimal to mild, multi-organ arteritis/periarteritis with increased circulating leukocyte numbers and C-reactive protein levels, as well as, infusion reactions following repeat administration of a low dose. 46,47 ADAs were also detected in the majority of treated animals.…”

“…9,11 While several guidelines on assigning adversity in toxicology studies are published, their practical application in determining what is a harmful or adverse change in the immune system still presents a challenge. [9][10][11]13 A test article may have both on-target and off-target immune-related effects, and these may be direct or indirect. Ascribing and assigning adversity to direct and indirect test article-related effects remains a central component and expectation in the context of these guidelines, but the decision of what changes connote "harm" within the test system is more indistinct.…”

“…Adversity assessment of immune system changes builds on publications highlighting best practices and factors to consider when evaluating a nonclinical safety study. [8][9][10][11][12][13][14] These position articles suggest that adversity should be based on the nonclinical studies with translatability considered after the primary adversity assessment in the nonclinical study. 11 This stepwise approach adds clarity to the interpretation of a pathology finding that is considered adverse in the animal model and whether it can be considered relevant in humans.…”