Sepsis deaths halt Zentalis' azenosertib cancer trials

Zentalis Pharmaceuticals recently announced that the FDA has implemented a partial clinical hold on three of their monotherapy studies involving their leading drug candidate, azenosertib (ZN-c3). This decision comes in the wake of two patient deaths suspected to be due to sepsis. The announcement led to a significant drop in the company's shares, plummeting more than 45% on Tuesday.

The partial hold affects three specific trials: the Phase I dose-escalation study ZN-c3-001 in solid tumors, the Phase II DENALI trial in platinum-resistant ovarian cancer (PROC), and the Phase II TETON study in uterine serous carcinoma. Both sepsis-related deaths were reported in the DENALI study.

Kimberly Blackwell, CEO of Zentalis Pharmaceuticals, emphasized the company's commitment to patient safety. "Patient safety is our top priority, and any deaths occurring in clinical trials are deeply unfortunate," she remarked. Blackwell also mentioned that the company is actively collaborating with the FDA to lift the partial clinical hold as swiftly as possible. Despite this setback, she expressed confidence in azenosertib's therapeutic potential, highlighting that over 500 patients have been treated with the WEE1 inhibitor across various studies. The DENALI trial's Cohort Ib alone has enrolled over 100 patients suffering from PROC. "We look forward to sharing the results along with comprehensive efficacy and safety data from DENALI Cohort Ib later this year," Blackwell added.

Earlier data from Phase Ib, reported last year, showed promising results when azenosertib was combined with paclitaxel for PROC patients, yielding a confirmed overall response rate of 50% and a median progression-free survival of 7.4 months. Azenosertib is considered a potentially first-in-class WEE1 inhibitor aimed at tumors with genomic instability, such as PROC and uterine serous carcinoma. By inhibiting WEE1, the drug facilitates the accumulation of DNA damage in cancer cells, thereby inducing replication stress and apoptosis.

While addressing the clinical hold, Zentalis also announced plans to release Phase I/II data later this year from the MAMMOTH study, which evaluates azenosertib in combination with GSK's PARP inhibitor, Zejula (niraparib), in patients with PROC. The pharmaceutical company reiterated its commitment to advancing this potentially groundbreaking therapy for patients with gynecological cancers.

Overall, Zentalis remains steadfast in its mission to bring innovative and effective cancer treatments to patients, despite the recent challenges posed by the clinical hold. The forthcoming data from various studies, including DENALI and MAMMOTH, will be pivotal in determining the future course of azenosertib and its potential impact on the treatment landscape for gynecological malignancies.