Are 6-month chronic toxicity studies always necessary for nonclinical safety assessment of therapeutic monoclonal antibodies?

6-month toxicity studies have historically been conducted to support marketing authorization of monoclonal antibodies (mAbs) for chronic indications. A working group consisting Netherlands Medicines Evaluation Board (MEB), NC3Rs, European Partnership for Alternative Approaches to Animal Testing (EPAA) and industry representatives recently evaluated if a 6-month toxicity study is necessary to assess the long-term safety of mAbs (Chin et. al. 2023 Regulatory Toxicology and Pharmacology). Data on First-in-Human (FIH)-enabling and chronic toxicity studies were analyzed for 142 mAb programs covering various therapeutic areas including inflammatory diseases, oncology, CNS, respiratory diseases and others. Standard, modified, or other mAb sub-types that have complementarity-determining region (CDR) binding domains were chosen for the analysis while Fc-fusion proteins, homologous proteins without CDR binding domains and antibody drug conjugates (ADCs) were out of scope. 

Either no toxicities or no new toxicities were identified in 6-month chronic studies for 71% mAb programs analyzed. For the other 29% mAb programs, novel adverse findings were observed in 6-month studies and 85% of those novel findings were deemed of concern for human safety. Therefore, a 6-month chronic toxicity study may be required in some cases to fully uncover potential safety effects in humans.   

Industry experience indicated that the toxicological profile determined in the 3-month studies did not differ from those in 6-month studies for 30 out of 32 mAb programs (2016 workshop). Likewise, the current analysis identified that by conducting 3-month studies, the rate of new toxicities of human concern found in 6-month studies was reduced to 9%. This suggests that 3-month studies may be sufficient to identify most if not all clinically-relevant toxicity effects.

The working group further developed an integrated weight-of-evidence model to determine the need for 6-month study based on primary pharmacology (e.g. target novelty, target expression, mode of action, Fc effector function), in vitro/in vivo data (e.g., nonclinical and clinical experience with similar molecules, reversibility and severity of toxicity) and clinical indication. 

The working group proposed that the necessity to perform 6-month toxicity studies will need to be considered on a case-by-case basis.

The working group further discussed critical aspects on species selection, number of species to be used, number of necessary studies, number of groups and group sizes, inclusion of recovery animals among others.

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