On September 11, 2023 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported updated preclinical data supporting development of the Company’s WEE1 inhibitor candidate, ATRN-1051, for the treatment of ovarian cancer (Press release, Aprea, SEP 11, 2023, View Source [SID1234635055]).

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The preclinical and in vitro data suggest that the selective properties of ATRN-1051 may make it a more efficacious cancer therapy than the other WEE1 inhibitors in development. Importantly, ATRN-1051 is a highly potent and selective inhibitor of WEE1 that does not significantly affect off-target PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle. Such off-targeting of the PLK family has been a challenge to other WEE1 inhibitors in the class. Evidence generated by Aprea suggests that off-target inhibition of PLK1 substantially limits the ability of WEE1 inhibitors to cause genotoxicity, the proposed mechanism by which WEE1 inhibitors act as cancer therapeutics.

The preclinical research of ATRN-1051 in ovarian cancer also shows an increased expression of cyclin E1, or CCNE1. CCNE1 amplification, which is associated with platinum resistance and poor survival, has been shown to be a reliable predictive biomarker of response to WEE1 inhibition. As part of the preclinical studies with ATRN-1051, the Company conducted cell culture and CDX mouse model studies using the CCNE1-normal and CCNE1-amplified ovarian cancer cell lines to show that low doses of ATRN-1051 completely suppress the growth of CCNE1-amplified ovarian cancer cells and tumors. In addition to the anti-tumor activity, the preclinical studies of ATRN-1051 indicate improved AUC pharmacokinetic properties compared to other WEE1 inhibitors, with the low dose of ATRN-1051 showing a similar AUC as higher doses of other WEE1 inhibitors.

Table 1
ATRN 1051 (1) Zentalis AstraZeneca
ZN-c3 (2) AZD-1775 (2)
Dose (mg/kg/d) 10 20 40 80 20 40 80
Cmax ng/ml 1,460 1,167 1,997 5,100 635 2,460 4,703
Tmax hr 3 1 1 1 1 1 1
AUC0-24, ng*hr/ml 16,739 4,863 17,088 39,722 1,494 6,313 13,408

Note: Head-to-head studies have not been conducted
(1) Data from an exploratory formulation of ATRN-1051 administered to fasted Balb/c mice
(2) Data from study in A-427 NSCLC xenograft model as reported in Zentalis Corporate Overview, March 2022

"We are very excited and encouraged by these positive findings that demonstrate ATRN-1051’s promise as a clinical agent based on its preclinical in vivo activity and safety profile," said Dr. Oren Gilad, President and CEO of Aprea. "We look forward to presenting the full data set at an upcoming 2023 scientific conference and to filing an IND for ATRN-1051 by the end of 2023. We believe these findings support the further development of this potentially substantial and clinically important agent. We also look forward to hosting a key opinion leader (KOL) event this fall highlighting these exciting data and outlining our development plan."

WEE1 kinase is a key regulator of multiple phases of the cell cycle, most prominently in progression from G1 to S phase and S to M phase through inhibitory phosphorylation of CDK2 and CDK1, respectively. Thus, when WEE1 is inhibited, both G1-S and S-M checkpoints are abrogated, leading to premature S-phase and M-phase entry. Notably, the replication stress caused by CCNE1 overexpression is transformed into toxic levels of double stranded breaks and cancer cell death when WEE1 is inhibited. The Company believes that CCNE1 gene amplification or high CCNE1 protein expression is a potential predictive biomarker of ATRN-1051 efficacy.

About ATRN-1051
The Company is targeting the WEE1 kinase, a key regulator of multiple phases of the cell cycle, with its lead WEE1 inhibitor product candidate, ATRN-1051. ATRN-1051 is an orally bioavailable small molecule inhibitor of WEE1 that is highly potent and selective. ATRN-1051 is distinct from other WEE1 inhibitors based on its potentially superior pharmacokinetic properties and selectivity. The company anticipates filing an IND for ATRN-1051 by the end of 2023.