On April 17, 2023 ZentalisTM Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, reported preclinical data that supports CCNE1 amplification and / or Cyclin E1 expression as a potential marker for the enrichment of patient populations for treatment with azenosertib, the Company’s potentially first-in-class Wee1 inhibitor product candidate (Press release, Zentalis Pharmaceuticals, APR 17, 2023, View Source [SID1234630182]). These new preclinical data demonstrate that azenosertib drives cancer cell death in Cyclin E1-high tumor cells in vitro and substantially inhibits the growth of Cyclin E1-high, patient-derived, in vivo tumor models.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The findings are being presented today at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, in a poster entitled "Cyclin E1 protein overexpression sensitizes ovarian cancer cells to azenosertib (ZN-c3), a novel, selective and orally bioavailable inhibitor of Wee1." The poster can be found on the Company’s website at this link. The poster presentation details are below.

Session Category: Clinical Research Excluding Trials
Session Title: Biomarkers of Therapeutic Benefit 2
Session Date and Time: Monday, April 17, 2023, 9:00 AM ET – 12:30 PM ET
Location: Section 39
Poster Board Number: 27
Abstract Presentation Number: 2153

"We are excited to present new preclinical data demonstrating the utility of Cyclin E1 as a predictive marker to identify patients likely to respond to azenosertib," said Mark Lackner, Ph.D., Chief Translational Officer of Zentalis. "Our findings suggest that Cyclin E1 expression via gene amplification or independent mechanisms sensitizes ovarian cancer cells to azenosertib alone or in combination with chemotherapy. These data confirm and build upon our prior preclinical work, and the published research of others, and provide additional evidence that supports our ongoing clinical trial studying azenosertib as a monotherapy in patients with Cyclin E1-driven ovarian cancer. These data also support the potential development of companion diagnostics for azenosertib."
The study analyzed data from a panel of patient-derived ovarian cancer cell lines in vitro and in vivo models of ovarian cancer. The results show that high Cyclin E1 protein expression is significantly associated with sensitivity to azenosertib, and that artificial overexpression of Cyclin E1 in cell lines with low endogenous Cyclin E1 expression sensitizes those cells to azenosertib. In addition, the study provides foundational details on the mechanistic basis of Cyclin E1 sensitization to Wee1 inhibition, including that Cyclin E1 overexpression results in accumulation of replication stress biomarkers and that azenosertib sensitivity is mediated by CDK2 activity.

The study also provides supportive data for several relevant standard of care chemotherapy combinations based on in vitro synergy assays and suggests that Cyclin E1 expression is a relevant clinical predictive marker. The Company is conducting an analysis of CCNE1 copy number and Cyclin E1 protein expression in its Phase 1b study of azenosertib in combination with chemotherapy in patients with platinum-resistant ovarian cancer. The Company now anticipates sharing these clinical data in the first half of 2023, in advance of original guidance.

"These encouraging translational results support the use of CCNE1 copy number and / or Cyclin E1 protein expression as predictive markers that have the potential to significantly improve patient outcomes by enabling us to select the right patients for treatment with azenosertib," said Gordon Mills, M.D., Ph.D., Professor of Cell, Developmental and Cancer Biology, Oregon Health and Science University School of Medicine. The Company is collaborating with Dr. Mills on preclinical and clinical studies related to the effects of Wee1 inhibition on replicative stress, cell cycle modulation and DNA repair.
Another poster being presented at AACR (Free AACR Whitepaper) by the Ivy Brain Tumor Center at Barrow Neurological Institute entitled "Tumor Pharmacokinetics, Pharmacodynamics and Efficacy Analysis of Wee1 inhibitor, Azenosertib in Patient-Derived Xenograft Models of Glioblastoma," demonstrates that azenosertib can achieve pharmacologically-relevant intracerebral free-drug concentrations, and that pharmacodynamic activity is observed in a preclinical glioblastoma model. This research underscores the potential of azenosertib as a therapy for a more extensive range of tumor types than those presently under clinical investigation. Once presented, the poster can be found on the Company’s website using this link. The poster presentation details are below.
Session Category: Experimental and Molecular Therapeutics, Chemistry
Session Title: Pharmacokinetics, Pharmacodynamics, and Molecular Pharmacology
Session Date and Time: Monday, April 17, 2023, 1:30 PM ET – 5:00 PM ET
Location: Section 18
Poster Board Number: 19
Abstract Presentation Number: 2796

About Azenosertib

Zentalis’ azenosertib (ZN-c3) has been designed to be a highly potent and selective Wee1 inhibitor.
Azenosertib is currently being evaluated in the clinic for advanced solid tumors and hematological malignancies in the following three therapeutic settings of high unmet medical need: (1) as a monotherapy, (2) in combination with traditional chemotherapy and DNA damaging agents, and (3) in combination with molecularly targeted agents. As a monotherapy, azenosertib is currently being evaluated in a Phase 2 clinical trial in adult women with uterine serous carcinoma (USC), an aggressive form of endometrial cancer that accounts for approximately 10-15% of all endometrial cancers. We are also evaluating azenosertib as a monotherapy in a Phase 2 clinical trial in patients with Cyclin E1 driven high-grade serous ovarian cancer (HGSOC). The Company is evaluating azenosertib as a monotherapy in a Phase 1 dose optimization clinical trial in patients with advanced solid tumors, and plans to declare the recommended Phase 2 monotherapy dose and provide an update on dose optimization activities in the first half of 2023. In chemotherapy combinations, azenosertib is currently being evaluated in combination with each of paclitaxel, carboplatin, pegylated liposomal doxorubicin (PLD) and gemcitabine in four cohorts in a Phase 1b clinical trial in patients with advanced platinum-resistant ovarian, peritoneal or fallopian tube cancer. The Company plans to disclose results from this study in the first half of 2023, in advance of original guidance. Azenosertib is also currently being evaluated in combination with gemcitabine in a Phase 1/2 clinical trial in adult and pediatric patients with relapsed or refractory osteosarcoma. In combination with molecularly targeted agents, the Company is studying azenosertib in combination with GlaxoSmithKline plc’s (GSK’s) PARP inhibitor, niraparib (ZEJULA), in a Phase 1/2 clinical trial in platinum-resistant ovarian cancer patients who have failed PARP inhibitor maintenance treatment as part of a clinical collaboration with GSK. The Company is also collaborating with Pfizer Inc. to evaluate azenosertib in combination with encorafenib and cetuximab, an FDA-approved standard of care known as the BEACON regimen, in patients with BRAF V600E mutant metastatic colorectal cancer in a Phase 1/2 clinical trial.