Zentalis Pharmaceuticals Stock

Zentalis Pharmaceuticals, Inc. (Zentalis) operates as a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers.

The company’s lead product candidate, azenosertib (ZN-c3), is a potentially first-in-class and best-in-class WEE1 inhibitor for advanced solid tumors and hematological malignancies. Azenosertib is being evaluated as a monotherapy and in combination across multiple ongoing clinical trials. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types and in combination with several chemotherapy backbones. As part of the company’s azenosertib clinical development program, the company is exploring enrichment strategies targeting tumors with high levels of replication stress, such as Cyclin E1 positive tumors, homologous recombination deficient tumors, and tumors with oncogenic driver mutations. The company is also developing a BCL-2 inhibitor, ZN-d5, in combination with azenosertib, and the company is the only company that has both a WEE1 inhibitor and a BCL-2 inhibitor in clinical development. The company exclusively in-licenses or solely owns worldwide development and commercialization rights to azenosertib and ZN-d5.

The company also continues to use its extensive drug discovery experience and capabilities across cancer biology and medicinal chemistry, which the company refers to as its Integrated Discovery Engine, to advance the company’s ongoing research on protein degraders of undisclosed targets. The company’s product candidates are differentiated from current programs targeting similar pathways and, if approved, have the potential to significantly impact clinical outcomes of patients with cancer.

Strategy

The company’s strategy includes the following key components: rapidly advancing the clinical development of the company’s potentially best-in-class and first-in-class WEE1 inhibitor, azenosertib, as a monotherapy toward first regulatory approval; executing on the company’s azenosertib clinical development strategy to build the azenosertib franchise; executing on the company’s patient enrichment strategy for azenosertib targeting tumors with high levels of replication stress; advancing the clinical development of the company’s potentially best-in-class BCL-2 inhibitor in combination with azenosertib; leveraging the company’s deep expertise and capabilities across cancer biology and medicinal chemistry to advance the company’s preclinical programs; and collaborating under the company’s existing strategic partnerships and evaluate additional strategic opportunities to maximize the value of the company’s pipeline.

Development Programs

Azenosertib (WEE1 Inhibitor)

Azenosertib is an oral, small molecule WEE1 inhibitor. The inhibition of WEE1, a DNA damage response kinase, drives cancer cells into mitosis without being able to repair damaged DNA, resulting in cell death and thereby preventing tumor growth and potentially causing tumor regression. There are no WEE1 inhibitors approved by the FDA. The company has designed azenosertib to have advantages over other investigational therapies targeting WEE1, including superior selectivity and PK properties. Azenosertib is being evaluated in the clinic for advanced solid tumors and hematological malignancies as a monotherapy, in combination with traditional chemotherapy and other DNA damaging agents, and in combination with molecularly targeted agents. The company is targeting the submission of the company’s first NDA for azenosertib in a gynecologic malignancy in 2026.

The following clinical trials are part of the azenosertib clinical development program:

Clinical Trial of Azenosertib in Platinum Sensitive Ovarian Cancer (PSOC). The company is planning to initiate a clinical trial evaluating azenosertib in PSOC patients in the first-line maintenance setting. The company expects to disclose additional details with respect to this trial in the second half of 2024, and to initiate this trial in 2025.

Monotherapy - Phase 2 Clinical Trial in Cyclin E1 Driven High-Grade Serous Ovarian Cancer, Fallopian Tube, or Primary Peritoneal Cancer (HGSOC) (DENALI - ZN-c3-005). The company is evaluating azenosertib as a monotherapy in a Phase 2 clinical trial in patients with Cyclin E1 positive platinum resistant HGSOC. The company’s Cyclin E1 positive enrichment strategy is supported by preclinical data that showed that high Cyclin E1 protein expression sensitized cancer cells to the anti-tumor effects of azenosertib as well as preliminary retrospective clinical data that Cyclin E1 protein levels may be associated with clinical benefit from WEE1 inhibition. In addition, in April 2023, the company announced preclinical data at the 2023 American Association for Cancer Research, or AACR, Annual Meeting that demonstrated that azenosertib drove cancer cell death in Cyclin E1-high tumor cells in vitro and substantially inhibited growth of Cyclin E1-high, patient derived, in vivo tumor models. The company expects to disclose topline data from this trial in the first half of 2025.

Monotherapy/Combination - Phase 1/2 Clinical Trial of Azenosertib as a Monotherapy and with PARP Inhibitor (PARPi) in Platinum Resistant Ovarian Cancer (PROC) (MAMMOTH - ZN-c3-006). The company is evaluating azenosertib as a monotherapy and in combination with GSK's PARP inhibitor, niraparib (ZEJULA), in a Phase 1/2 clinical trial in PROC patients who have failed PARPi treatment as part of a clinical collaboration with GSK. This clinical study is supported by preclinical data that showed that combining azenosertib and niraparib resulted in synergistic cell killing in ovarian cancer in vivo models. The company expects to disclose topline data from this trial in the second half of 2024.

Monotherapy - Phase 2 Clinical Trial in Recurrent or Persistent Uterine Serous Carcinoma (USC) (TETON - ZN-c3-004). Azenosertib is being evaluated as a monotherapy in a Phase 2 clinical trial in patients with USC. Azenosertib was well tolerated. The FDA granted Fast Track designation in November 2021 to azenosertib in patients with advanced or metastatic USC who have received at least one prior platinum-based chemotherapy regimen for management of advanced or metastatic disease. The study design in this patient population has the potential to support registration in the United States. The company expects to disclose topline data from this trial in the second half of 2025.

Combination - Phase 1b Clinical Trial of Azenosertib and Chemotherapy in PROC (ZN-c3-002). Azenosertib is being evaluated in combination with each of paclitaxel, carboplatin, PLD, and gemcitabine in four separate cohorts in a Phase 1b clinical trial in patients with PROC. On May 25, 2023, the company announced positive data from this Phase 1b clinical trial. Azenosertib was well tolerated in combination with multiple types of chemotherapy and demonstrated encouraging clinical activity, with noteworthy objective response rates, or ORRs, and median progression free survival, or mPFS, in all patients, but especially in those patients with Cyclin E1 positive tumors, a subgroup recognized to have a poor prognosis and to show relatively poor outcomes following treatment with chemotherapy. A total of 115 patients were enrolled in the study across all chemotherapy combination groups.

Monotherapy - Phase 1b Dose Finding Clinical Trial in Solid Tumors (ZN-c3-001). The company is evaluating azenosertib as a monotherapy in a Phase 1b dose finding clinical trial for the treatment of solid tumors. On June 6, 2023, the company announced positive data from this clinical trial. Across all tumor types, 74 patients received azenosertib on a continuous dosing schedule and 53 patients received azenosertib on an intermittent dosing schedule. When evaluating continuous versus intermittent at comparable clinically meaningful dose levels, the data were the following: intermittent dosing maintained safety and improved tolerability of azenosertib as compared to continuous dosing. Gastrointestinal, fatigue, and hematologic Grade 3 and 4 TRAEs were comparable or favorable versus continuous dosing. On November 6, 2023, the company announced updated data from this trial. As of September 27, 2023, azenosertib continued to demonstrate a favorable safety and tolerability profile with additional safety-evaluable patients and longer follow-up. The company expects to disclose the final results from this trial in the second half of 2024.

Combination - Phase 1 Clinical Trial of Azenosertib and Chemotherapy in Relapsed or Refractory Osteosarcoma (ZN-c3-003). The company completed the dose escalation portion of the Phase 1 clinical trial of azenosertib in combination with gemcitabine in adult and pediatric patients with R/R osteosarcoma. The company has identified a proposed recommended Phase 2 dose of azenosertib in combination with gemcitabine in this patient population and have seen clinically meaningful activity. The company expects that azenosertib in combination with gemcitabine will continue to be evaluated in osteosarcoma in an investigator-initiated trial. The company received orphan drug designation and rare pediatric disease designation from the FDA for azenosertib in osteosarcoma. The company expects to disclose the final results from this trial in the first half of 2024.

Combination - Phase 1/2 Clinical Trial of Azenosertib with Encorafenib and Cetuximab (BEACON Regimen) in BRAF V600E Mutant Metastatic Colorectal Cancer (mCRC) (ZN-c3-016). The company is collaborating with Pfizer 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 mCRC in a Phase 1/2 clinical trial. In preclinical studies, WEE1 inhibition has shown synergy with many targeted agents in mutationally driven cancers, and the addition of azenosertib to the BEACON regimen enhanced anti-tumor activity in a cell-line-derived xenograft model. The company initiated enrollment in this clinical trial in the first quarter of 2023, and expects to disclose the initial data from this trial in the second half of 2024.

Combination - Phase 1/2 Clinical Trial of Azenosertib and Chemotherapy in Pancreatic Cancer. The company has agreed to support the Dana Farber-sponsored Phase 1/2 clinical trial evaluating azenosertib and chemotherapy (gemcitabine) in pancreatic cancer patients.

Combination – Phase 1/2 Clinical Trial of Azenosertib, Chemotherapy and Pembrolizumab, in Triple Negative Breast Cancer (TNBC). The company has agreed to support the Dana Farber-sponsored Phase 1/2 clinical trial evaluating azenosertib, chemotherapy (carboplatin) and pembrolizumab, in patients with TNBC.

ZN-d5 (BCL-2 Inhibitor)

ZN-d5 is a selective, oral small molecule inhibitor of BCL-2. BCL-2 is a protein that plays a critical role in the regulation of cell death, known as apoptosis. The overexpression of BCL-2 is frequently detected in numerous cancer types, which prevents apoptosis of cancer cells. Utilizing the company’s medicinal chemistry expertise, the company has designed ZN-d5 to have best-in-class potency, selectivity and PK properties. ZN-d5 is being evaluated in combination with azenosertib in a Phase 1/2 dose escalation clinical trial in patients with R/R AML (ZN-d5-004C). The Phase 1 portion of this trial will escalate the doses of both drugs to identify the dose for the combination, which will be assessed in Phase 2 expansion cohort(s). This study is expected to enroll up to approximately 100 patients. This clinical trial is supported by preclinical models that showed that the combination of ZN-d5 with azenosertib yielded a significant enhancement of activity in several indications, including R/R AML, as compared to activity shown with either of these product candidates as a single agent. Preclinical models also showed that the combination of ZN-d5 with azenosertib was well tolerated in mice. The company is the only company to have both a WEE1 inhibitor and a BCL-2 inhibitor in clinical development. The company expects to disclose the initial data from this trial in the second half of 2024.

Integrated Discovery Engine

The company is also advancing its research on protein degraders and other undisclosed targets utilizing the company’s Integrated Discovery Engine. The company’s Integrated Discovery Engine has enabled the company to take each of its clinical-stage product candidates from initial discovery to Investigational New Drug application, or IND, submission in less than three years, with a total of four FDA-cleared INDs in a span of five years. The company begins its process of drug discovery by identifying fundamental biological pathways of cancers based upon a number of factors, including validation of the pathway through prior clinical outcomes and ability to impact large patient populations. The company then analyzes existing marketed products and compounds in development that target these cancer pathways and assess their limitations, efficacy, safety, tolerability, PK, patient convenience and potential to be used in combination with other therapies. Next, the company uses its medicinal chemistry expertise and extensive understanding of structure based drug design and target-structure activity relationships to design product candidates with properties that can address observed limitations and suboptimal drug characteristics of marketed products or other compounds in development, including potency, solubility, route of administration and PK properties.

Overcoming these limitations may also allow the company to develop these product candidates for use in combination with other therapies, including with the company’s internally-developed product candidates, if approved. Finally, the company strives to generate preclinical data to support that such candidates could have a differentiated product profile in the company’s expected lead indications before advancing a compound into clinical development.

Intellectual Property

In-licensed Patents and Patent Applications

The company’s wholly owned subsidiary, Zeno Management, Inc., or ZMI, has exclusively in-licensed or is the owner/assignee of issued patents and patent applications directed to the company’s technology across the company’s pipeline in the United States and many other major jurisdictions worldwide, including Europe, Japan and China. Certain issued patents and patent applications directed to azenosertib and ZN-d5 have been exclusively in-licensed from Recurium IP Holdings, LLC, or Recurium IP.

The expected expiration dates for issued patents, or patents that may issue from any patent applications, directed to the company’s WEE1 inhibitor program, including azenosertib, are between 2038 and 2044 plus any extensions or adjustments of term available under national law. The expected expiration dates for the patents, or patents that may issue from any patent applications, directed to the company’s BCL-2 inhibitor program, including ZN-d5, are between 2039 and 2044 plus any extensions or adjustments of term available under national law. However, there can be no assurance that any of the pending patent applications will issue. Furthermore, there can be no assurance that the company will benefit from any patent term extension or favorable adjustments to the term of any of the issued patents or patents that may issue from any pending patent applications in the future.

The applicable authorities, including the FDA in the United States and the U.S. Patent and Trademark Office, or USPTO, may not agree with the company’s assessment of whether such patent term extensions or adjustments should be granted, and, if granted, they may grant more limited extensions or adjustments than the company request.

Trademarks

The company’s trademark portfolio includes the ZENTALIS mark and the stylized ‘Z’ mark, both of which are registered in the United States, as well as in major foreign markets, including the EU, the United Kingdom, Japan, and China.

License Agreements and Strategic Collaborations

Recurium IP Holdings, LLC License Agreement

In December 2014, the company’s wholly owned subsidiary, Zeno Pharmaceuticals, Inc., entered into a license agreement, or the Recurium Agreement, with Recurium IP, which was subsequently amended, under which Zeno Pharmaceuticals, Inc. was granted an exclusive worldwide license to certain intellectual property rights owned or controlled by Recurium IP to develop and commercialize pharmaceutical products for the treatment or prevention of disease, other than for providing pain relief. The intellectual property rights exclusively licensed by ZMI under the Recurium Agreement include certain intellectual property covering azenosertib and ZN-d5.

Pfizer Development Agreement

In April 2022, the company entered into a development agreement with Pfizer to collaborate to advance the clinical development of azenosertib. The company did not grant Pfizer any economic ownership or control of azenosertib or the rest of the company’s pipeline. In October 2022, the company announced its first clinical development collaboration with Pfizer to initiate a Phase 1/2 dose escalation study of azenosertib, in combination with encorafenib and cetuximab (an FDA-approved standard of care known as the BEACON regimen) in patients with BRAF V600E mutant mCRC.

GSK Clinical Trial Collaboration and Supply Agreement

In April 2021, the company entered into a clinical trial collaboration and supply agreement with GSK under which the company was evaluating the combination of azenosertib and niraparib, GSK’s poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with PROC.

Immunome License Agreement

On January 5, 2024, the company entered into an exclusive, worldwide license agreement with Immunome, under which Immunome licensed from the company ZPC-21 (now known as IM-1021), a preclinical ROR1 ADC, with best-in-class potential, and the company’s proprietary ADC platform technology.

Government Regulation and Product Approval

Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon the company and its third-party manufacturers.

Research and Development

The company’s research and development expenses were $189.6 million for the year ended December 31, 2023.

History

The company, a Delaware corporation, was founded in 2014. It was incorporated in 2014. The company was formerly known as Zentalis Pharmaceuticals, LLC and changed its name to Zentalis Pharmaceuticals, Inc. in 2020.