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Model-based dose selection to inform translational clinical oncology development of WNT974, a first-in-class
Yan Ji1, Pai-Hsi Huang1, Steve Woolfenden2
1Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Abstract:
WNT974 is a potent, selective, and orally bioavailable first-in-class inhibitor of Porcupine, a membrane-bound O-acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose-escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5-45 mg WNT974 were studied, however, the protocol-defined maximum tolerated dose (MTD) was not established based on dose-limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model-based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure-response analyses of a target-inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure-response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model-based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.
Insights
A model-based approach using pharmacokinetics, biomarkers, and safety data identified an optimal dose for WNT974, a Porcupine inhibitor, in advanced cancer patients. This method aids early oncology trial dose selection.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- WNT974 is a first-in-class Porcupine inhibitor targeting Wnt secretion, under clinical development for advanced solid tumors.
- A Phase I trial investigated WNT974 dosing, but a maximum tolerated dose (MTD) was not established due to lack of dose-limiting toxicity.
Purpose of the Study:
- To utilize a model-based approach to determine the recommended dose for expansion (RDE) for WNT974.
- To integrate pharmacokinetic, biomarker, and safety data for optimal dose selection in early oncology trials.
Main Methods:
- Population pharmacokinetic (PK) modeling was employed.
- Exposure-response analyses integrated a target-inhibition biomarker (skin AXIN2 mRNA) and adverse event (dysgeusia) data.
- The RDE was selected based on predicted exposure within a target range balancing inhibition and tolerability.
Main Results:
- The model-based approach successfully estimated a target exposure range for WNT974.
- A dose yielding exposure within this target range was identified as the RDE.
- This approach provided an alternative to the conventional MTD for selecting an optimal biological dose.
Conclusions:
- Model-based dose selection integrating PK, biomarker, and safety data is effective for early oncology trials.
- This strategy can inform translational clinical oncology drug development.
- WNT974 dose selection was optimized using an integrated PK/PD/safety model.
