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bioRxiv · 10.1101/2025.11.03.686224

M4 drug discovery: human drug predictions from integrated pre-clinical insights exemplified with a GLP1-R agonist

Silfvergren, O.·Rigal, S.·Schimek, K.·Simonsson, C.·Kanebratt, K. P.·Forschler, F.·Yesildag, B.·Marx, U.·Vilen, L.·Gennemark, P.·Cedersund, G.
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Abstract

A major recent breakthrough in the treatment of type 2 diabetes has been the development of glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, current translational frameworks struggle to predict the clinical outcomes of these drugs from preclinical data. There are several reasons for this struggle, which are generic for many drugs: GLP-1RAs act through multi-timescale mechanisms in which short-term effects propagate into long-term changes; no single preclinical system can capture all their effects in humans; and mechanistic extrapolation requires modelling numerous whole-body biological processes. To address this gap, we present a new extrapolation approach, M4 drug discovery, and retrospectively apply it to the GLP-1RA exenatide in a manner that is generalisable to other drugs. The method integrates: Multi-level data (cellular to whole-body), Multi-timescale data (minutes to months), Multi-species data (e.g., rodents to humans), and Mechanistic knowledge. In this study, we integrate human cell and animal data with drug-free human studies to successfully predict human pharmacokinetics (cost < {chi}2, p=0.05; 64 < 97) and the outcomes of a 30-week clinical trial (36 < 45). We found that integrating information across the four M4 axes improved predictive performance and physiological relevance: multi-species data inform pharmacokinetics, human cell data provide human population- and donor-specific potency estimates, animal data reveal additional drug effects not observable in cell cultures, and the multi-timescale mathematical modelling enables short-term effects of exenatide and meals to inform long-term changes in insulin sensitivity. This work provides new tools for drug extrapolations, supporting the community towards safer and more informed preclinical-to-clinical drug extrapolations.

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Silfvergren, O., Rigal, S., Schimek, K., Simonsson, C., Kanebratt, K. P., Forschler, F., Yesildag, B., Marx, U., Vilen, L., Gennemark, P., Cedersund, G.. 2025-11-05. M4 drug discovery: human drug predictions from integrated pre-clinical insights exemplified with a GLP1-R agonist. https://doi.org/10.1101/2025.11.03.686224

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