Zentalis Pharmaceuticals (ZNTL) Study Update summary

Clinical hold and safety update

• FDA placed a partial clinical hold on azenosertib monotherapy studies (ZN-c3-001, DENALI, TETON) after two patient deaths from presumed sepsis in early 2024; ongoing patients may continue, but new enrollment is paused while the company works with the FDA to resolve the hold.

• The hold affects monotherapy studies but not combination studies; over 500 patients have received monotherapy, with more than 200 at the 400 mg 5-2 dose.

• Eight Grade 5 (fatal) treatment-related events have occurred in solid tumor trials since 2019, mostly linked to infection in the setting of neutropenia; Grade 5 events included sepsis, neutropenia, pancytopenia, hypovolemic shock, and bowel perforation.

• Two additional deaths occurred in non-Zentalis studies, including one in China and one in a non-solid tumor patient.

• Neutropenia and related infections are recognized on-target effects of WEE1 inhibition; supportive care and close monitoring are emphasized.

Study status and enrollment

• ZN-c3-001 (solid tumors), DENALI (PROC), and MAMMOTH (PROC, PARPi-resistant) studies are fully enrolled, with DENALI Cohort 1b over 100 patients; TETON (USC) accrual is paused.

• Over half of all monotherapy enrollment occurred in the past 12 months, reflecting strong investigator and patient interest.

• Nearly 800 patients have been treated with azenosertib across multiple studies since 2019.

• Extensive biomarker work in DENALI Cohort 1b aims to clarify patient populations most likely to benefit.

• Mammoth (PARP-resistant, platinum-resistant ovarian cancer) is fully enrolled; top-line data from all three cohorts expected this year.

Data disclosure and future plans

• Final and topline data from ZN-c3-001, DENALI Cohort 1b, and MAMMOTH studies are expected in the second half of 2024.

• Denali data will allow analysis of Cyclin E as a predictive biomarker in platinum-resistant ovarian cancer.

• Mammoth will provide insights into azenosertib monotherapy and combination with PARP inhibitors in PARP-resistant settings.

• Data disclosures are independent of regulatory updates; future guidance on development plans will follow resolution of the partial hold.

• Zentalis is also advancing research on protein degraders in cancer therapy.