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Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors
Pamela J Farrell1, Christopher J Zopf2, Huey-Jing Huang2
1Biological Sciences (P.J.F., H.-J.H., De.B., C.H., J.B., A.F., J.M., A.Pl., P.R., U.B., J.E., C.J.L.), Chemistry (Z.S.C., C.Mc.), and Drug Metabolism and Pharmacokinetics (Da.B.), Takeda California, San Diego, California; Modeling and Simulation, Takeda Boston, Cambridge, Massachusetts (C.J.Z.); and Translational Research Institute for Metabolism and Diabetes, Florida Hospital Campus, Orlando, Florida (C.Ma., A.Pa.) m.farrell@att.net.
Target engagement biomarkers, like NMet14-3-3γ, help select effective MetAP2 inhibitors for obesity. These biomarkers predict drug efficacy and weight loss in humans, aiding clinical trial decisions.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Development
Background:
- Methionine aminopeptidase 2 (MetAP2) is a target for obesity treatment.
- Current MetAP2 inhibitors require improved safety profiles.
- Pharmacodynamic (PD) biomarkers are crucial for evaluating novel drug candidates.
Purpose of the Study:
- To identify a PD biomarker for selecting potent MetAP2 inhibitors.
- To predict clinical efficacy of MetAP2 inhibitors.
- To develop a pharmacokinetic-pharmacodynamic-efficacy model for MetAP2 inhibitors.
Main Methods:
- Treatment of primary human cells and diet-induced obese mice with MetAP2 inhibitors.
- Measurement of NMet14-3-3γ levels as a PD biomarker.
- Development of predictive models for efficacy in mice and humans.
Main Results:
- MetAP2 inhibition increased NMet14-3-3γ levels in human cells and mouse adipose tissue.
- Compounds reduced body weight in obese mice.
- Developed models accurately predicted efficacy based on target engagement and compound concentration.
Conclusions:
- NMet14-3-3γ is a valid target engagement biomarker for MetAP2 inhibitors.
- Biomarkers aid in selecting efficacious compounds and predicting weight loss.
- This approach supports decision-making in early clinical trials for obesity treatment.
