Pharmacodynamic marker modulation of the selective WEE1 inhibitor Debio 0123 in patient biopsies from phase 1 clinical trial

Poster presented at ESMO 2022

Hans Gelderblom1, Noemie Luong2, Jourik A. Gietema3, Ingrid Desar4, Omar Saavedra Santa Gadea5, Judith R Kroep1, Mathilde Jalving3, Anne Bellon2, Justyna Nowakowska2,6, Maud Jonnaert2, Esteban Rodrigo Imedio2

1 Leiden University Medical Center, Leiden, The Netherlands
2 Debiopharm International SA, Lausanne, Switzerland
3 University Medical Center Groningen, Groningen, The Netherlands
4 Radboud Universitair Medisch Centrum, Nijmegen, The Netherlands
5 Vall d’Hebron Institute of Oncology, Barcelona, Spain
6 Current address: Lonza AG, Visp, Switzerland


Debio 0123 is an investigational, orally bioavailable, highly selective, adenosine triphosphate (ATP)-competitive inhibitor of the WEE1 tyrosine kinase. WEE1 is a key regulator of cell cycle progression at both the G2/M and S phases of the cell cycle. At G2/M WEE1 influences entry into mitosis by modulating activity of cyclin-dependent kinase 1 (CDK1, also referred to as cell division cycle 2 [CDC2]). Inhibition of WEE1 presents an opportunity as a therapeutic strategy in cancer, either as monotherapy or in combination with other therapies1, by inducing a reduction of phosphorylated CDC2 (pCDC2) and driving cancer cells prematurely into mitosis leading to mitotic catastrophe and apoptosis. Here we present data on modulation of pharmacodynamic marker pCDC2 upon treatment with Debio 0123 in tumor and skin biopsies from patients in Arm A of the Debio 0123-101 (NCT03968653) study (after 3 days of treatment), across all dose levels explored so far. In paired skin biopsies, a consistent reduction in pCDC2 was observed starting at the dose level 150 mg, becoming more pronounced with increasing doses. A correlation could be observed between Debio 0123 plasma exposure and pCDC2 reduction. Currently, a more intense dosing schedule is also being tested in Arm B. Overall, these data suggest Debio 0123 target engagement from a dose of 150mg onwards when administered for 3 days, being more pronounced at higher doses.