Zentalis Pharmaceuticals (ZNTL) Study Update summary

Clinical Data Highlights and Study Results

• Azenosertib demonstrated consistent objective response rates above 30% in cyclin E1 positive platinum-resistant ovarian cancer (PROC) patients across multiple studies, with a median duration of response around 5.5 months and a favorable safety profile at 300 mg and 400 mg intermittent dosing schedules.

• Cyclin E1 overexpression was established as a predictive biomarker, identifying about 50% of PROC patients, and a companion diagnostic is being developed to enhance patient selection and treatment outcomes.

• Safety data showed manageable hematologic and gastrointestinal toxicities, with most adverse events being low grade, low rates of high-grade events, and minimal treatment discontinuations; mitigation strategies are being refined to further improve tolerability.

• Efficacy and safety were consistent across studies, supporting the advancement of azenosertib as a first-in-class oral option for PROC patients with significant unmet need.

• Azenosertib is also being explored in other Cyclin E1+ tumor types, including breast, endometrial, and bladder cancers.

Regulatory and Development Strategy

• FDA alignment was achieved for a seamless DENALI Part 2 trial design, enabling dose confirmation and potential accelerated approval if data remain supportive, with topline data expected by end of 2026.

• DENALI Part 2 will enroll less heavily pretreated, healthier patients, with improved supportive care and monitoring expected to enhance efficacy and duration of response.

• Dose confirmation in Part 2A will compare 300 mg and 400 mg, with ongoing enrollment and a plan to initiate a phase 3 confirmatory study concurrently with Part 2B.

• Regulatory discussions confirmed no need for dose modification at 400 mg, and the FDA supported rapid progression to the next trial phase based on the totality of safety and efficacy data.

• Corporate restructuring and streamlined operations extend cash runway into late 2027, supporting execution through anticipated DENALI Part 2 topline data.

Key Clinical Insights and Future Outlook

• Cyclin E1 positive PROC patients, a group with poor prognosis and limited benefit from chemotherapy, showed marked improvement with azenosertib, with response rates in the mid-30% range.

• Early and ongoing mitigation strategies for adverse events are expected to further improve patient outcomes and trial retention.

• The trial design leverages a proprietary immunohistochemistry assay for cyclin E1, ensuring precise patient selection and efficient enrollment.

• Lessons learned from prior studies and other oral agents are being applied to optimize supportive care and reduce early discontinuations.

• The company is focused on rapid execution of registration studies, with a clear path to potential first approval in PROC and plans to update the market as data matures.