Zentalis Pharmaceuticals Announces First Patient Dosed in DENALI Part 2 Clinical Trial of Azenosertib in Patients With Cyclin E1+ PROC

Zentalis Pharmaceuticals, Inc. recently announced the first patient has been dosed in Part 2 of the Phase 2 DENALI clinical trial (NCT05128825) of azenosertib in patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC).

As previously disclosed, the Company aligned with the US FDA on the design of DENALI Part 2, which allows for seamless enrollment in the two parts of the trial:

• Part 2a is designed to confirm the primary dose-of-interest with a target enrollment of approximately 30 patients at each of two dose levels: 400mg QD 5:2 and 300mg QD 5:2 (intermittent daily dosing on a five days on, two days off dosing schedule).
• Part 2b is designed to enroll approximately 70 additional patients at the selected dose, which will be informed by the Part 2a results, subject to FDA feedback.

The Company expects to disclose topline data from DENALI Part 2 by year end 2026 and if successful, this trial has the potential to support an accelerated approval, subject to FDA review.

“Dosing the first patient in Part 2 of the DENALI study is an important milestone for Zentalis as we continue the clinical development of azenosertib,” said Ingmar Bruns, M.D., Chief Medical Officer of Zentalis. “We are proud that azenosertib is one step closer to our goal of addressing a tremendous unmet need. We are grateful to our patients and their families for participating in this trial, which has the potential to result in a treatment option for thousands of women diagnosed with Cyclin E1+ PROC.”

Previously disclosed clinical data from Part 1b of the DENALI study showed clinically meaningful results in patients with Cyclin E1+ PROC. As of the January 13, 2025 data cutoff, patients who were response-evaluable (n=43) had an objective response rate (ORR) of 34.9% and a median duration of response (mDOR) of 6.3 months. The mDOR is subject to change as there were patients with ongoing responses as of the cutoff date.

The data also established Cyclin E1 protein overexpression, regardless of CCNE1 gene amplification, as a sensitive and specific predictive biomarker that can be used to identify patients who could potentially derive benefit from azenosertib. Zentalis estimates that about half of PROC patients overexpress Cyclin E1 protein based on its proprietary immunohistochemistry cutoff.

Azenosertib is a novel, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated as a monotherapy and combination clinical studies in ovarian cancer and additional tumor types. WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death.

Zentalis Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing azenosertib (ZN-c3), a potentially first-in-class and best-in-class WEE1 inhibitor for patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC). Azenosertib is being evaluated as a monotherapy and in combination across multiple tumor types in clinical trials and has broad franchise potential. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types. The Company is also leveraging its extensive experience and capabilities to translate its science to advance research on additional areas of opportunity for azenosertib outside PROC. Zentalis has operations in San Diego. For more information, visit www.zentalis.com.