Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach
Hsiao-Tzu Chien, Helen Prior, Laura Andrews, Leon van Aerts, Annick Cauvin, David O. Clarke, Kaushik Datta, Maggie Dempster, Noël Dybdal, Wendy Freebern, Lolke de Haan, Danuta Herzyk, Adam Hey, Thomas Kissner, Sven Kronenberg, Michael W. Leach, Donna Lee, Katrin Schütte, Fiona Sewell, Kevin Trouba, Peter Ulrich, Lucinda Weir, Peter van Meer
Abstract
To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs.