On November 6, 2023 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, reported financial results for the quarter ended September 30, 2023, and highlighted recent corporate accomplishments (Press release, Zentalis Pharmaceuticals, NOV 6, 2023, View Source [SID1234637049]).

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"We are executing on our fast-to-market strategy for our potentially first-in-class and best-in-class WEE1 inhibitor, azenosertib, while also laying the groundwork for the franchise opportunity we see for azenosertib across multiple tumor types," said Kimberly Blackwell, M.D., Chief Executive Officer of Zentalis. "Azenosertib continues to show very encouraging monotherapy anti-tumor activity, safety and tolerability in both ovarian cancer and uterine serous carcinoma. We are executing our clinical strategy to advance this high-potential asset to patients with ovarian cancer and uterine serous carcinoma as quickly as possible and expand into additional indications where WEE1 inhibition has the potential to improve outcomes for patients. By focusing our team and resources on the advancement of azenosertib, Zentalis is targeting the submission of the first NDA for azenosertib in a gynecologic malignancy in 2026."

"This quarter we are also executing on our succession plan for Chief Scientific Officer, which will see our Chief Translational Officer, Mark Lackner, succeed our co-founder, Kevin Bunker, at the end of the year" said Dr. Blackwell. "Kevin’s passion for discovering promising oncology drugs is a cornerstone of our culture and led to four of our product candidates advancing into the clinic, including azenosertib. I want to thank Kevin for his immense contributions to Zentalis and to the cancer patients we serve."

"Since joining Zentalis last year, Mark has put together a talented translational team and has spearheaded our biomarker enrichment strategies for azenosertib," continued Dr. Blackwell. "Mark’s appointment as Chief Scientific Officer sees our translational and discovery efforts brought under a single umbrella, which puts us in a strong position as we continue to advance azenosertib through the clinic while supporting robust preclinical drug discovery efforts."

Program Updates and Highlights

•Azenosertib monotherapy program. Today, the Company announced an updated analysis of the ongoing Phase 1 clinical trial of azenosertib as a monotherapy in solid tumors (ZN-c3-001), which continued to show anti-tumor activity with intermittent dosing. In the same population of 19 platinum resistant or refractory ovarian cancer and uterine serous carcinoma (USC) patients that were included in the data reported on June 6, 2023, the objective response rate (ORR) was 37%.

Median follow-up has increased by nearly 5 months and the median progression free survival (mPFS) has increased to 6.5 months. With additional safety-evaluable patients and follow-up since June, azenosertib continues to demonstrate a favorable safety and tolerability profile that is similar to or better than approved ovarian cancer products, supporting its continued advancement

•Azenosertib development strategy. Azenosertib is currently being evaluated in more than 10 ongoing and planned clinical trials as a monotherapy and in combinations with compelling scientific rationales across a broad array of tumor types. The Company is on track to submit its first New Drug Application (NDA) for azenosertib in a gynecologic malignancy in 2026. The Company has revised its strategy in platinum sensitive ovarian cancer (PSOC) and plans to evaluate azenosertib in PSOC in the first-line (1L) maintenance setting in the clinic. This strategy allows for the opportunity to benefit a larger segment of patients with ovarian cancer and fill a gap in the treatment paradigm since the standard of care in the 1L maintenance setting is evolving and fewer options are available. The Company plans to provide additional details on this trial in the second half of 2024, and anticipates initiating enrollment in 2025.

•Presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference: Ovarian Cancer. In October, the Company presented a poster presentation titled "Cyclin E1 Positive Staining Is Frequent and Independent of Prior Platinum Treatment in High Grade Serous Ovarian Cancer" at the AACR (Free AACR Whitepaper) Special Conference: Ovarian Cancer in Boston. To review the data in more detail, click here.

•ZN-d5 + azenosertib in relapsed or refractory acute myeloid leukemia (R/R AML). Zentalis is the only company known to have both a WEE1 inhibitor, azenosertib, and a BCL-2 inhibitor, ZN-d5, in clinical development. The Company is evaluating the combination of these promising product candidates in a Phase 1/2 trial in heavily pretreated patients with R/R AML based on strong preclinical data demonstrating highly synergistic anti-leukemia activity of this combination. The Company updated guidance for sharing initial data from this trial to the second half of 2024.

•ZN-d5 in relapsed or refractory light chain amyloidosis (R/R AL amyloidosis). Dose escalation is complete in the Phase 1 trial of ZN-d5 as a monotherapy in R/R AL amyloidosis. A preliminary efficacy signal was observed in patients with R/R AL amyloidosis with a hematologic response rate of 40% in patients treated with at least 400 mg daily of ZN-d5. ZN-d5 was well tolerated with few treatment-related adverse events. The proposed monotherapy dose has been identified as 800 mg daily. The Company does not plan to develop ZN-d5 further for this indication in order to focus its resources on the azenosertib franchise opportunity, including the azenosertib + ZN-d5 combination.

Corporate Highlight

•Today, the Company announced that Mark Lackner, Ph.D., Chief Translational Officer, Head of Biomarker Strategy, will succeed co-founder, Kevin Bunker, Ph.D., as Chief Scientific Officer at the end of the year. Dr. Bunker will continue his service to the Company as an advisor following the transition. Dr. Lackner joined Zentalis in October 2022. Prior to Zentalis, Dr. Lackner served as Senior Vice President, Head of Biology and Translational Sciences at IDEAYA Biosciences, where he successfully led biology efforts contributing to three small molecule development candidates and established a strong translational team that led to the discovery of a novel combination biomarker strategy. Previously, Dr. Lackner worked at Genentech for over a decade, holding multiple roles of increasing responsibility that culminated in serving as the Head of Genentech Oncology Early Stage Biomarker Group. During this tenure, he led multiple

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research teams in developing and incorporating predictive biomarker strategies across all phases of clinical trials and managed a diverse biomarker portfolio spanning targeted therapies, immuno-oncology agents and antibody drug conjugates.

Anticipated Upcoming Milestones

•1H 2024
◦Final results of Phase 1 azenosertib + chemotherapy (gemcitabine) trial in osteosarcoma (ZN-c3-003)
•2H 2024
◦Final results of Phase 1b azenosertib monotherapy trial in solid tumors (ZN-c3-001)
◦Topline data from Phase 1/2 azenosertib + PARP inhibitor (niraparib) and azenosertib monotherapy trial in platinum resistant ovarian cancer in partnership with GSK (MAMMOTH, ZN-c3-006)
◦Initial data from Phase 1 azenosertib + BEACON regimen (encorafenib + cetuximab) trial in BRAF mutant metastatic colorectal cancer in partnership with Pfizer (ZN-c3-016)
◦Initial data from Phase 1 of azenosertib + ZN-d5 trial in R/R AML (ZN-d5-004C)
◦Additional details on planned clinical trial of azenosertib in PSOC in the 1L maintenance setting
•1H 2025
◦Topline data from Phase 2 azenosertib monotherapy trial in platinum resistant high-grade serous ovarian cancer (DENALI, ZN-c3-005)
•2H 2025
◦Topline data from Phase 2 azenosertib monotherapy trial in recurrent or persistent USC (TETON, ZN-c3-004)
•2025
◦Initiate clinical trial of azenosertib in PSOC in the 1L maintenance setting.
•2026
◦First NDA for azenosertib in a gynecologic malignancy

Third Quarter 2023 Financial Results

•Cash and Marketable Securities Position: As of September 30, 2023, Zentalis had cash, cash equivalents and marketable securities of $516.6 million. The Company believes that its existing cash, cash equivalents and marketable securities as of September 30, 2023 will be sufficient to fund its operating expenses and capital expenditure requirements into 2026.

•Research and Development Expenses: Research and development (R&D) expenses for the quarter ended September 30, 2023 were $46.8 million, compared to $42.2 million for the quarter ended September 30, 2022. The increase of $4.6 million was primarily attributable to $3.2 million of costs shared with Zentera in the prior period, a $2.6 million increase related to personnel expenses, of which $1.4 million related to non-cash stock-based compensation expense, and $0.8 million related to consulting costs. These increases were partially offset by decreases of $1.3 million and $0.7 million in facility expenses and clinical expenses, respectively.

•General and Administrative Expenses: General and administrative (G&A) expenses for the quarter ended September 30, 2023 were $16.0 million, compared to $12.0 million during the quarter ended September 30, 2022. This increase of $4.0 million was primarily attributable to a $2.9 million increase in personnel expenses, of which $2.2 million related to non-cash stock-based compensation expense, and a $1.1 million increase related to facilities and outside services.

About Azenosertib
Azenosertib is a potentially first-in-class and best-in-class small molecule WEE1 inhibitor in development for the treatment of cancer. Inhibition of WEE1, a DNA damage response kinase, drives cancer cells into mitosis without being able to repair damaged DNA, resulting in cell death. Currently, there are no FDA-approved WEE1 inhibitors, and azenosertib has been designed for superior selectivity and pharmacokinetic properties. Azenosertib is being developed in therapeutic areas of high unmet need and is being evaluated as a monotherapy, in combination with chemotherapy, and in combination with molecularly targeted agents.