On April 8, 2022 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported initial efficacy and safety data from the ongoing Phase 1b trial of ZN-c3 in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian cancer (Press release, Zentalis Pharmaceuticals, APR 8, 2022, View Source [SID1234611712]). Data were reviewed as a clinical poster during the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in New Orleans, Louisiana on April 8-13, 2022.

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"The initial combination clinical activity reported from our ongoing trial supports ZN-c3’s potential best-in-class efficacy and safety profile and for the first time, showcases its synergistic combinability with various chemotherapies," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis. "Utilizing a continuous dosing regimen in patients with advanced disease, ZN-c3 demonstrated an Objective Response Rate of 30.2% across all cohorts – achieving up to 62.5% with one cohort – and a markedly better tolerability profile within the Wee1 inhibitor class. Based on these promising initial results, we believe the data support the development of a Phase 3 trial to further investigate this combination’s effect in ovarian cancer patients. We look forward to announcing our future development plans for this program before year-end and are motivated by the opportunity to potentially deliver an improved and best-in-class treatment option to patients."

Initial Efficacy and Safety Data

The ongoing Phase 1b dose-escalation trial is evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics and pharmacodynamics of ZN-c3 in combination with standard chemotherapies in platinum-resistant or -refractory ovarian cancer. The study consists of four combination dose cohorts: ZN-c3 + PLD, ZN-c3 + carboplatin, ZN-c3 + paclitaxel, and ZN-c3 + gemcitabine, and is enrolling a more advanced patient population, with the inclusion of platinum-refractory patients and higher prior rates of bevacizumab treatment, than similar trials that included a Wee1 inhibitor.

At the time of the data cutoff on January 28, 2022, 56 patients – which were enrolled across three of the cohorts – were evaluated for safety, the primary endpoint, and 43 were response-evaluable. The fourth cohort, ZN-c3 + gemcitabine, had not begun enrollment at the time of the data cutoff. The evaluation of the recommended Phase 2 dose remains ongoing, with the key efficacy data presented at AACR (Free AACR Whitepaper) included in the table below.

Summary of Clinical Activity

ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile in comparison to the Wee1 inhibitor class. As of the cutoff date, the most common treatment-related adverse events at all grades included nausea (48.2% of patients), neutropenia (41.1% of patients), thrombocytopenia (37.5% of patients), vomiting (30.4% of patients) and anemia (26.8% of patients).

"Platinum-resistant and -refractory ovarian cancer are associated with poor prognoses and limited treatment options, with standard of care having an Overall Response Rate of less than 12%," commented Kathleen Moore, MD, Director of the Oklahoma TSET Phase I Program for the Stephenson Cancer Center at the University of Oklahoma College of Medicine. "A treatment option that could elicit a clinically meaningful improvement in efficacy, while being well-tolerated, would make a meaningful difference for patients. In this initial cut of data, ZN-c3 in combination with standard chemotherapies has surpassed this goal, achieving an improved efficacy and tolerability profile in a sicker patient population within the Wee1 inhibitor class. Wee1 inhibition remains a promising therapeutic approach to treating an array of solid tumors, including advanced ovarian cancer, and these results further support the class’ potential in changing the treatment paradigm."

Update on Additional AACR (Free AACR Whitepaper) Presentations

Interim data from the Phase 1 monotherapy USC expansion cohort receiving ZN-c3 ≥300mg QD were also released today. ZN-c3 is potentially a best-in-class Wee1 inhibitor and is in an ongoing potentially registrational Phase 2 trial for USC patients​ (NCT04814108). Updated data from the USC expansion cohort of the Phase 1 monotherapy trial will be presented at the mini symposium on April 11, 2022 at 2:50 p.m. CT.

In addition, Zentalis has three preclinical posters demonstrating the broad potential of ZN-c3 in multiple settings including AML (Abstract #2591), overcoming PARP resistance (Abstract #2606), and in novel biology when combined with our BCL-2 inhibitor, ZN-d5 (Abstract #2605). These findings further support ZN-c3 as a potential cornerstone treatment, creating a significant market opportunity across a broad range of solid and liquid tumors.

The clinical poster, two clinical abstracts and three preclinical posters are currently available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website at View Source

Updates on ZN-c5

Initial clinical data of ZN-c5 in combination with CDK 4/6 inhibitors demonstrated excellent safety and tolerability. Drug-drug interactions were seen with ZN-c5 doses; however, ZN-c5 is not expected to have DDIs with commonly used medicines or ZN-c3 at relevant doses.

Uniquely among the leading oral SERDs, ZN-c5 demonstrated meaningful bone protectant activity in ovariectomized mice, highlighting a further point of differentiation within the oral SERD class, along with excellent tolerability. Zentalis believes this profile positions ZN-c5 well for an adjuvant setting.

Zentalis plans to initiate a combination study of ZN-c5 + ZN-c3 in ER+/HER2- CDK 4/6i-resistant breast cancer patients in 2022.

KOL Webcast Event:

Zentalis will host a webcast event with key opinion leader, Kathleen Moore, MD, today, Friday, April 8, 2022 at 4:00 p.m. EDT. Dr. Moore is the Associate Professor in the Section of Gynecologic Oncology; the Jim and Christy Everest Endowed Chair in Cancer Research; and the Director of the Oklahoma TSET Phase I Program for the Stephenson Cancer Center at the University of Oklahoma College of Medicine. She has a clinical research interest in drug development and Phase I trials and is a leading expert in gynecological oncology.

To register and access the event, the webcast link is available on the Investors & Media section of the Zentalis website at www.zentalis.com.

About ZN-c3

ZN-c3 is a potentially first-in-class and best-in-class oral inhibitor of Wee1 in development for the treatment of advanced solid tumors. The inhibition of Wee1, a DNA damage response protein, aims to generate sufficient DNA damage in cancer cells, causing cell death, thereby preventing tumor growth and potentially causing tumor regression. ZN-c3 has broad potential as a monotherapy and in combination. We are currently evaluating this candidate in several ongoing and planned studies, including two potentially registrational monotherapy trials in USC and a biomarker-driven setting, as well as combination studies, including in combination with chemotherapy in patients with advanced ovarian cancer. We also received orphan drug and rare pediatric disease designations from the FDA for pediatric osteosarcoma and have initiated a Phase 1/2 trial in combination with chemotherapy.