UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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FORM 8-K
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CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of report (Date of earliest event reported): November 9, 2022
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(Exact name of registrant as specified in its charter)
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(State or other jurisdiction of incorporation or organization) | (Commission File Number) | (I.R.S. Employer Identification No.) | ||||||||||||
(Address of principal executive offices) (Zip Code)
(212 ) 433-3791
(Registrant’s telephone number, include area code)
N/A
(Former name or former address, if changed since last report)
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) | |||||
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) | |||||
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) | |||||
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) | |||||
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbol(s) | Name of each exchange on which registered | ||||||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 2.02 Results of Operations and Financial Condition.
On November 9, 2022, Zentalis Pharmaceuticals, Inc. (the “Company”) announced its financial results for the quarter ended September 30, 2022 and commented on certain business updates. The full text of the press release issued in connection with the announcement is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
Item 7.01 Regulation FD Disclosure.
Beginning on November 9, 2022, spokespersons of the Company plan to present the information in the Corporate Presentation attached hereto as Exhibit 99.2 at conferences and in meetings with investors and analysts.
The information contained in Items 2.02 and 7.01 of this Current Report on Form 8-K (including Exhibits 99.1 and 99.2 attached hereto) shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, except as expressly provided by specific reference in such a filing.
By providing the information in Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.2 hereto, the Company is not making an admission as to the materiality of any information herein. The information contained in this Current Report on Form 8-K is intended to be considered in the context of more complete information included in the Company’s filings with the U.S. Securities and Exchange Commission (the "SEC") and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this Current Report on Form 8-K, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
The following exhibits relating to Items 2.02 and 7.01 shall be deemed to be furnished, and not filed:
Exhibit No. | Description | |||||||
| 104 | Cover Page Interactive Data File (embedded within the inline XBRL document) | |||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| ZENTALIS PHARMACEUTICALS, INC. | ||||||||||||||
| Date: November 9, 2022 | By: | /s/ Kimberly Blackwell, M.D. | ||||||||||||
| Kimberly Blackwell, M.D. | ||||||||||||||
| Chief Executive Officer | ||||||||||||||
Zentalis Pharmaceuticals Reports Third Quarter 2022 Financial Results and Operational Updates
Six sponsored studies with potentially first-in-class Wee1 inhibitor, ZN-c3, ongoing and continuing dose optimization work, as drug continues to show improved tolerability in initial safety data from monotherapy Phase 2 USC trial announced today
Identified Cyclin E driven high-grade serous ovarian cancer patients as initial expansion population for ZN-c3 biomarker monotherapy trial
Announced first ZN-c3 clinical development collaboration with Pfizer BRAF-mutant mCRC;
Expanded ZN-c3 clinical development collaboration with GSK in PARP resistant ovarian cancer
Declared BCL-xL protein degrader candidate and initiated IND-enabling studies; Molecule has broad potential across multiple tumor types and in combination
Strengthened Board and management team with appointments of Chief Medical Officer, Chief Scientific Officer and Chief Translational Officer
$422 million cash balance as of September 30, 2022, with projected cash runway into 2025
NEW YORK and SAN DIEGO—November 9, 2022 — 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, today announced financial results for the third quarter ended September 30, 2022 and highlighted recent corporate accomplishments.
“During the third quarter, we made tremendous progress advancing our clinical strategy and corporate capabilities. We have established a three-pronged development plan for ZN-c3, our potentially first-in-class Wee1 inhibitor investigation as a monotherapy, in combination with chemotherapy and in combination with targeted therapies,” said Kimberly Blackwell, MD, Chief Executive Officer of Zentalis. “Building on ZN-c3's favorable safety profile in the monotherapy setting across tumor types, we are pleased to announce Cyclin E gene amplification and protein overexpression as our biomarker strategy in high grade serous ovarian cancer. This biomarker defined trial in ovarian cancer will allow us to demonstrate potential efficacy in an enriched patient population that has shown evidence of clinical sensitivity to Wee1 inhibition. This trial also has the potential to show initial proof of concept for Wee1 inhibition in Cyclin E driven cancers, which have higher levels of chemotherapy and targeted therapy resistance. On the combination front, there is strong data demonstrating Wee1 inhibition’s synergy with DNA-damaging therapies, such as PARP inhibitors, and with targeted agents in mutationally driven cancers. There is significant interest in these approaches, and we currently have collaborations with Pfizer, GSK and the Dana-Farber Cancer Institute to explore these combinations in the clinic.”
Dr. Blackwell continued, “Our development of ZN-c3 includes ongoing dose optimization activities across the clinical program. Although we have demonstrated a favorable safety profile and monotherapy efficacy when ZN-c3 was given on a continuous daily dosing schedule, data show that higher doses delivered on an intermittent schedule have the potential to lead to higher pharmacokinetic exposures and a more favorable therapeutic index. We believe our dose optimization work will allow us to benefit the broadest range of cancer patients and maximize value for all of our stakeholders. With our strong cash position and strengthened management team, we believe we are well-positioned to execute on our clinical development plans and further our mission to improve the lives of cancer patients.”
Wee1 Inhibitor (ZN-c3)Program Highlights
•Monotherapy in USC safety and enrollment update: As of a data cutoff on September 14, 2022, a total of 43 patients were enrolled and dosed in the Phase 2 monotherapy uterine serous carcinoma (USC) trial. ZN-c3 was well tolerated and the safety profile was similar or improved relative to previously disclosed data, exhibiting a better hematological and gastrointestinal tolerability profile. The U.S. Food and Drug Administration has granted Fast Track designation to ZN-c3 in this setting.
•Cyclin E biomarker strategy in high-grade serous ovarian cancer: The Company announced that Cyclin E overexpression and/or amplification in high-grade serous ovarian cancer will become the focus of its ongoing Phase 1/2 clinical study examining biomarker-driven enrichment strategies for ZN-c3. Cyclin E overexpression acts at the G1-S checkpoint by driving premature entry into S-phase resulting in replicative stress and significantly increases sensitivity to ZN-c3. The Company has generated preclinical data showing that Cyclin E overexpression sensitizes cancer cells to the anti-tumor effects of ZN-c3 as well as preliminary retrospective clinical data that Cyclin E protein levels may be associated with clinical benefit from ZN-c3. The Company plans to present the preclinical data in the first half of 2023. The two new cohorts of patients will be given monotherapy, which will potentially generate meaningful data sets in patients with Cyclin E gene amplification and patients with Cyclin E protein overexpression independent of gene amplification.
•Dose optimization: The Company highlighted that it continues to optimize dosing across the ZN-c3 clinical portfolio to maximize exposure, improve normal tissue tolerability and enable maximum probability of success. The Company anticipates that the Phase 2 USC trial dose will be modified based on these ongoing dose optimization studies and that, as a result, the timeline of the USC study will be extended. The Company anticipates providing an update on ZN-c3 dosing in the first half of 2023, including expected program timelines and potential paths to registration.
•Pfizer collaboration in mCRC: Zentalis and Pfizer are collaborating on a Phase 1/2 dose escalation study of ZN-c3 in combination with encorafenib and cetuximab (BEACON regimen) in BRAF V600E-mutated metastatic colorectal cancer (mCRC) patients. In preclinical studies, Wee1 inhibition has shown synergy with many targeted agents in mutationally driven cancers and the addition of ZN-c3 to the BEACON regimen enhanced anti-tumor activity in a cell-line-derived xenograft model. Additional information on this clinical development collaboration is available here.
•GSK collaboration in ovarian cancer: Zentalis and GSK are expanding their ongoing collaboration looking at the clinical synergy of ZN-c3 and niraparib in PARP resistant ovarian cancer. The Phase 1/2 dose escalation study, currently enrolling with concurrent dosing of the two drugs, will be expanded to include a cohort that will be given ZN-c3 and niraparib on a dose escalating, alternating schedule of one week of ZN-c3 followed by one week of niraparib.
•Chemotherapy combination in platinum-resistant ovarian cancer: The Company continues to enroll its dose escalation trial of standard chemotherapy (paclitaxel, gemcitabine, and carboplatin) in platinum-resistant ovarian cancer.
•Chemotherapy combination in osteosarcoma: The Company will be presenting initial data from its Phase 1/2 combination trial of ZN-c3 and chemotherapy in osteosarcoma in a poster session at the upcoming Connective Tissue Oncology Society (CTOS) 2022 Annual Meeting, being held November 16-19 in Vancouver. Details for the CTOS poster presentation are as follows:
oTitle: Preliminary Data from a Phase 1 Dose Escalation Study of ZN-c3 Plus Gemcitabine in Relapsed/Refractory Osteosarcoma (NCT04833582)
oSession: Medical & Pediatric Oncology and Trials
oDate/Time: November 17, 2022 from 5:00pm to 7:00pm ET
oPresenter: Viswatej Avutu, MD, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center
•Dana-Farber combination study in platinum-resistant pancreatic cancer: Zentalis announced an investigator-initiated trial with Dana-Farber Cancer Institute, funded by Stand Up To Cancer and the Lustgarten Foundation, to explore the combination of ZN-c3 with gemcitabine in platinum-resistant advanced pancreatic adenocarcinoma. James Cleary, MD, PhD, Director, Clinical Research, Division of Gastrointestinal Oncology at the Dana-Farber Cancer Institute and Brandon Huffman, MD, Adult Medical Oncology Fellow at the Dana-Farber Cancer Institute, will be running this trial. "We are pleased to announce this important trial which builds on the growing body of clinical evidence supporting the use of ZN-c3 across a range of tumor types," said Dr. Cleary. "Pancreatic cancer continues to be area of high unmet patient need, and we look forward to understanding the potential role of ZN-c3 in helping these patients."
BCL-2 Inhibitor (ZN-d5) Update
•Monotherapy dose optimization continues in NHL and amyloidosis: Dosing with food is ongoing in patients in non-Hodgkin lymphoma (NHL) and amyloidosis, and the combination study of ZN-d5 and ZN-c3 in acute myeloid leukemia (AML) is scheduled to initiate in the fourth quarter of 2022.
BCL-xL Degrader Update
•Declared candidate and initiated IND-enabling studies: BCL-xL degrader candidate demonstrates potent anti-cancer activity in several preclinical models and has the potential to have platelet sparing benefits over clinical-stage BCL-xL targeted inhibitors.
Corporate Highlights
•In September, Zentalis appointed Jan Skvarka, PhD, MBA, to its Board of Directors. Dr. Skvarka is an accomplished biopharmaceutical executive bringing over three decades of extensive operational, strategic and financial expertise to Zentalis. Dr. Skvarka was formerly Chief Executive Officer of Trillium Therapeutics, Inc., which was acquired by Pfizer under his leadership.
•In October, the Company promoted co-founder Kevin Bunker, PhD, to Chief Scientific Officer. In this new role, Dr. Bunker will focus on leading Research and Development, advancing the preclinical pipeline with the Company’s Integrated Discovery Engine.
•In October, Zentalis appointed Carrie Brownstein, MD, as Chief Medical Officer. Dr. Brownstein, a leading oncologist and hematologist, joins Zentalis with over two decades of medical and biopharmaceutical experience, successfully executing clinical program strategies across all phases of product development.
•In October, the Company appointed Mark Lackner, PhD, as Chief Translational Officer, Head of Biomarker Strategy. Dr. Lackner, a recognized and respected cancer biologist, joins Zentalis with over two decades of oncology-focused drug development expertise, including significant experience in biomarker discovery and clinical biomarker strategies.
Third Quarter 2022 Financial Results
•Cash and Marketable Securities Position: As of September 30, 2022, Zentalis had cash, cash equivalents and marketable securities of $421.7 million. The Company believes that its existing cash, cash equivalents and marketable securities as of September 30, 2022 will be sufficient to fund its operating expenses and capital expenditure requirements into the first quarter of 2025.
•Research and Development Expenses: Research and development, or R&D, expenses for the three months ended September 30, 2022 were $42.2 million, compared to $54.0 million for the three months ended September 30, 2021. The decrease of $11.8 million was primarily due to non-recurring R&D impairments and licensing milestones of $8.8 million and $5.0 million, respectively, recorded during the three months ended September 30, 2021. Other decreases in R&D expenses included $4.6 million in decreased manufacturing and collaborative expenses and $0.3 million of additional reimbursement from Zentera under our cost sharing arrangement. These decreases were offset by increases of $3.4 million, $3.1 million and $0.4 million of clinical trial related costs, personnel and consulting costs and overhead allocations, respectively.
•General and Administrative Expenses: General and administrative expenses for the three months ended September 30, 2022 were $12.0 million, compared to $8.9 million during the three months ended September 30, 2021. This increase of $3.1 million was primarily attributable to an increase in non-cash stock based compensation expense of $1.8 million and $0.3 million related to other compensation expense. Increases of $1.9 million, $0.6 million and $0.5 million were seen in rent and depreciation expense, external consulting expense and legal expense, respectively. These amounts were partially offset by a decrease in permits and fees and allocation of overhead expenditures to R&D of $1.6 million and $0.4 million, respectively.
About Zentalis Pharmaceuticals
Zentalis Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers. The Company is developing a focused pipeline of potentially best-in-class oncology candidates, all internally discovered, which include ZN-c3, a potentially first-in-class Wee1 inhibitor for advanced solid and liquid tumors, ZN-d5, a BCL-2 inhibitor for hematologic malignancies and related disorders and a heterobifunctional degrader of BCL-xL for solid and hematological malignancies. The Company has licensed ZN-c3 and ZN-d5 to its joint venture, Zentera Therapeutics, Ltd. to develop and commercialize these candidates in Greater China, but otherwise retains full economic ownership and control of ZN-c3 and ZN-d5. Zentalis has operations in both New York and San Diego.
For more information, please visit www.zentalis.com. Follow Zentalis on Twitter at @ZentalisP and on LinkedIn at www.linkedin.com/company/zentalis-pharmaceuticals.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements relating to the potential for a product candidate to be first-in-class and/or best-in-class; the potential benefits of our dose optimization work, including the potential benefit of higher doses delivered on an intermittent schedule; projected cash runway; potential benefits of our product candidates; potential benefits of the Cyclin E biomarker defined trial; our belief we are well-position to execute on our clinical development plans and further our mission to improve the lives of cancer patients; plans to expand our clinical trials, including our Phase 1/2 dose escalation study in ovarian cancer in collaboration with GSK; plans to present preclinical data relating to Cyclin E and the timing thereof; potentially modifying the Phase 2 USC trial dose and the impact of that modification on the timeline of the Phase 2 USC trial; the timing of providing an update on ZN-c3 dosing and the content of that update; the timing of initiation of our clinical trials; and the potential of ZN-c3 to help pancreatic cancer patients. The terms “believe,” “look forward,” “may,” “opportunity,” “optimize,” “plans,” “potential,” “scheduled,” “will” and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our substantial dependence on the success of our lead product candidates; the outcome of preclinical testing and early trials may not be predictive of the success of later clinical trials; failure to identify additional product candidates and develop or commercialize marketable products; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; failure to obtain U.S. or international marketing approval; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel, and risks relating to management transitions; significant costs as a result of operating as a public company; the COVID-19 pandemic has adversely impacted and may continue to adversely impact our business, including our preclinical studies and clinical trials; and the other important factors discussed under the caption “Risk Factors” in our most recently filed periodic report on Form 10-K or 10-Q and subsequent filings with the U.S. Securities and Exchange Commission (SEC) and our other filings with the SEC. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.
ZENTALIS™ and its associated logos are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release.
Investor Contacts:
Adam D. Levy, PhD, MBA
Adam D. Levy, PhD, MBA
alevy@zentalis.com
Alexandra Roy
Solebury Strategic Communications
Solebury Strategic Communications
aroy@soleburystrat.com
Media Contact:
Julia Deutsch
Solebury Strategic Communications
jdeutsch@soleburystrat.com
Julia Deutsch
Solebury Strategic Communications
jdeutsch@soleburystrat.com
| Zentalis Pharmaceuticals, Inc. | |||||||||||||||||||||||
| Condensed Consolidated Statements of Operations | |||||||||||||||||||||||
| (Unaudited) | |||||||||||||||||||||||
| (In thousands, except per share amounts) | |||||||||||||||||||||||
| Three Months Ended September 30, | Nine Months Ended September 30, | ||||||||||||||||||||||
| 2022 | 2021 | 2022 | 2021 | ||||||||||||||||||||
| Operating Expenses | |||||||||||||||||||||||
| Research and development | $ | 42,181 | $ | 53,998 | $ | 132,118 | $ | 137,162 | |||||||||||||||
| General and administrative | 12,012 | 8,872 | 43,415 | 31,187 | |||||||||||||||||||
| Total operating expenses | 54,193 | 62,870 | 175,533 | 168,349 | |||||||||||||||||||
| Operating loss | (54,193) | (62,870) | (175,533) | (168,349) | |||||||||||||||||||
| Other Income (Expense) | |||||||||||||||||||||||
| Investment and other income, net | 1,905 | 99 | 2,755 | 313 | |||||||||||||||||||
| Gain on deconsolidation of Zentera | — | 51,582 | — | 51,582 | |||||||||||||||||||
| Net loss before income taxes | (52,288) | (11,189) | (172,778) | (116,454) | |||||||||||||||||||
| Income tax expense (benefit) | (159) | (697) | (109) | (456) | |||||||||||||||||||
| Loss on equity method investment | 2,371 | — | 9,460 | — | |||||||||||||||||||
| Net loss | (54,500) | (10,492) | (182,129) | (115,998) | |||||||||||||||||||
| Net loss attributable to noncontrolling interests | (99) | (6,301) | (294) | (7,332) | |||||||||||||||||||
| Net loss attributable to Zentalis | $ | (54,401) | $ | (4,191) | $ | (181,835) | $ | (108,666) | |||||||||||||||
| Net loss per common share outstanding, basic and diluted | $ | (0.96) | $ | (0.09) | $ | (3.56) | $ | (2.59) | |||||||||||||||
| Common shares used in computing net loss per share, basic and diluted | 56,807 | 44,609 | 51,098 | 41,918 | |||||||||||||||||||
| Zentalis Pharmaceuticals, Inc. | ||||||||||||||
| Selected Condensed Consolidated Balance Sheet Data | ||||||||||||||
| (Unaudited) | ||||||||||||||
| (In thousands) | ||||||||||||||
| As of June 30, | As of December 31, | |||||||||||||
| 2022 | 2021 | |||||||||||||
| Cash, cash equivalents and marketable securities | $ | 421,726 | $ | 339,887 | ||||||||||
Working capital (1) | 379,829 | 306,826 | ||||||||||||
| Total assets | 529,193 | 454,507 | ||||||||||||
| Total liabilities | 100,455 | 90,025 | ||||||||||||
| Total Zentalis equity | $ | 428,738 | $ | 364,482 | ||||||||||
(1) The Company defines working capital as current assets less current liabilities. | ||||||||||||||
1 CORPORATE PRESENTATION November 2022
2 Zentalis Pharmaceuticals, Inc. (“we,” “us,” “our,” “Zentalis” or the “Company”) cautions that this presentation (including oral commentary that accompanies this presentation) contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding potential for our product candidates to be first-in-class and/or best-in-class; potential for accelerated approval paths; potential for our product candidates to be developed as monotherapies and in combination; potential for ZN-c3 to address large populations with significant unmet need; our development approach for our product candidates, including ZN- c3; plans for and potential benefits of dose optimization, and the anticipated timing of updates on dosing optimization; timing of preclinical and clinical program updates; the potential unmet need in a particular indication and/or patient population; potential for combinations including our product candidates and the potential benefits thereof; the target profiles and potential benefits of our product candidates and their mechanisms of action, including as a monotherapy and/or in combination; our belief that we have strengthen our clinical development plans, including for ZN-c3; timing of discontinuation activities for ZN-c5 and ZN- c4; clinical and regulatory progress of our product candidates, including the estimated timing of IND-enabling studies, enrollment, initiation of clinical trials and data announcements; the market opportunities for and market potential of our product candidates; our anticipated milestones; and the potential of our collaborations, as well as statements that include the words “anticipate,” “design,” “estimate,” “expect,” “may,” “plan,” “opportunity,” “potential,” “strategy,” “to come,” “will” and similar statements of a future or forward-looking nature. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the outbreak of the novel coronavirus disease, COVID-19, has adversely impacted and may continue to adversely impact our business, including our preclinical studies and clinical trials; our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our substantial dependence on the success of our lead product candidate; failure to identify additional product candidates and develop or commercialize marketable products; the early stage of our development efforts; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; failure to obtain U.S. or international marketing approval; our product candidates may cause serious adverse side effects; interim, initial, “topline”, and preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures that could result in material changes in the final data; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel; and significant costs as a result of operating as a public company. Other risks and uncertainties include those identified under the caption “Risk Factors” in our most recently filed periodic reports on Forms 10-K and 10-Q and subsequent filings with the U.S. Securities and Exchange Commission in the future could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management’s estimates as of the date of this presentation. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. While we may elect to update these forward-looking statements at some point in the future, we assume no obligation to update or revise any forward-looking statements except to the extent required by applicable law. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about our industry. These data involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such data and estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Neither we nor our affiliates, advisors or representatives makes any representation as to the accuracy or completeness of that data or undertake to update such data after the date of this presentation. ZENTALISTM and its associated logos are trademarks of Zentalis and/or its affiliates. All other trademarks, trade names and service marks appearing in this presentation are the property of their respective owners. All website addresses given in this presentation are for information only and are not intended to be an active link or to incorporate any website information into this document. Zentalis’ product candidates are investigational drugs and have not yet been approved by the U.S. Food and Drug Administration or any other regulatory authority. Forward-Looking Statements and Disclaimer
3 Company Overview Lead Program: Wee1i (ZN-c3) potentially first- and best-in-class • Potential accelerated approval paths for monotherapy in multiple biomarker enriched populations • Enriched patient populations including Uterine Serous Carcinoma (USC), Cyclin E driven and post-PARP progression • Investigating highly synergistic concurrent combinations, including BRAF/MEK inhibitors in BRAF mutant mCRC and PARP inhibitors in high grade serous ovarian cancer • Fast Track designation granted in USC BCL-xL heterobifunctional degrader for liquid and solid tumors (preclinical) BCL-2 inhibitor (ZN-d5): broad applicability as anti-apoptotic target; potential as monotherapy and in combination, including with ZN-c3 Additional discovery programs against validated cancer targets Integrated Discovery Engine: 4 FDA-cleared INDs within 5 years
4 Q3 2022 Highlights ZN-d5 efforts focused on amyloidosis monotherapy and combination with ZN-c3 study Expanded relationship with Pfizer, building on equity investment and SAB appointment earlier this year Broad progress across ZN-3 program as we optimize dosing across exposure, efficacy and tolerability in both monotherapy and combination settings Cyclin E overexpression / amplification as our biomarker strategy for enriching patient populations for ZN-c3 Advanced preclinical pipeline Cash position of $422 million Multiple dose optimization studies ongoing; USC trial enrolled 43 patients as of September 2022; consistently demonstrating favorable tolerability; osteosarcoma safety and efficacy update to be presented at CTOS Conference Operating runway into 2025 enabling achievement of multiple data readouts and catalysts Declared development candidate for BCL-xL protein degrader; IND enabling studies initiated Enrollment in dose optimization, first-in-class indication for amyloidosis and ZN-c3 combination in AML studies Strategic collaboration now includes ZN-c3 combination study in BRAF mutant colorectal cancer Potential to address large populations with significant unmet need with accelerated monotherapy path to registration
5 COMPOUND INDICATION DEVELOPMENT APPROACH PRECLINICAL EARLY CLINICAL DEVELOPMENT LATE CLINICAL DEVELOPMENT STATUS / EXPECTED MILESTONES ZN-c3 Wee1 Inhibitor Uterine Serous Carcinoma Monotherapy FDA Fast Track Designation Solid Tumors Monotherapy Update on ZN-c3 dosing 1H 2023 Cyclin E Driven Ovarian Cancer Monotherapy Enrolling, preclinical update to come in 1H 2023 PARP Resistant Ovarian Cancer Monotherapy alternating with niraparib or concurrent with niraparib Enrolling, opened alternating cohort in 4Q 2022 Ovarian Cancer + Multiple Chemotherapy Backbones Enrolling; Phase 1 dose escalation results in 2023 Osteosarcoma + gemcitabine Presenting data CTOS Conf Nov 2022 BRAF Mutant Colorectal Cancer + encorafenib and cetuximab Plan patient initiation Q1 2023 Pancreatic Cancer + gemcitabine Dana Farber Cancer Institute, funded by SU2C/Lustgarten ZN-d5 BCL-2 Inhibitor AL Amyloidosis Monotherapy Continues to enroll NHL Monotherapy Continues to enroll AML + ZN-c3 Anticipate trial initiation 4Q 2022 BCL-xL Degrader Solid Tumors and Heme Malignancies Declared development candidate; IND enabling activities initiated Advancing Focused Pipeline with Multiple Clinical Opportunities Footnotes Here New/Revised Disclosure
Wee1 Inhibitor ZN-c3
7 Wee1: A Critical Cell Cycle Regulation Target • Wee1 is a protein kinase that inhibits the activity of both CDK1 and CDK2 kinases and is involved in the regulation of G1/S, G2/M, and M phase cell cycle checkpoints • Wee1 plays an important role during normal cell cycle progression but also in response to DNA damage and interacts with DNA damage response (DDR) pathways ZN-c3: Wee1 Inhibitor G1G2 P Wee1 CDK1 Cyclin B1 P G2/M Checkpoint P Wee1 CDK2 Cyclin A/E P G1/S Checkpoint S M P Wee1 CDK1 Cyclin B1 P Mitosis Exit
8 Wee1 Inhibition by ZN-c3 Forces Cancer Cells to Proceed into Mitosis • Wee1 inhibition causes cancer cells to proceed into mitosis without being able to repair damaged DNA, resulting in premature mitotic entry and apoptosis 1 • Wee1 inhibition also increases replication stress by inducing aberrant firing of replication origins and depletion of nucleotide pools 1 ZN-c3: Wee1 Inhibitor G1G2 S M 1. Kok, et al. Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors. Oncogenesis 9, 88 (2020) P Wee1 CDK1 Cyclin B1 G2/M Checkpoint Wee1 CDK1 Cyclin B1 Mitosis Exit P Wee1 CDK2 Cyclin A/E G1/S Checkpoint P
9 Structure-Based Drug Design (SBDD) Led to the Discovery of a Highly Potent and Selective Wee1 Inhibitor ZN-c3 with Improved ADME Properties Asn376 Tyr378 Cys379 Phe310 Ile305 ZN-c3 potency and ADME Wee1 IC50 3.8 nM H23 IC50 103 nM A427 IC50 75 nM Log D 2.4 hPPB 66% hHep <18 mL/min/kg solubility > 2000 µM CYP3A4 7 µM hERG > 30 µM Huang, PQ; et al. J. Med. Chem. 2021, 64, 13004-13024 Hydrogen bonding with the Wee1 gatekeeper Asn376 Ethyl CH-π interactions with Phe310 of the G- loop Effective bidentate hydrogen-bond interactions with the hinge element Electron-deficient pyrimidine interacts with Phe433 via π−π stacking Sandwiched between Gly382 and Ile305 (CH- π). Additional π−π interactions with Tyr378 Hydrogen bonding to the Ile305 backbone carbonyl. Important for ADME properties Chiral OH engaged in polar interactions with Asn431 and Ser430 Allyl occupying a lipophilic pocket formed by Ala326, Ile327, Lys328, and Asn376 ZN-c3: Wee1 Inhibitor
10 Indication Incidence Estimates (US+EU) Development Approach Ovarian Cancer 46,700 1 Strategic commitment to patients with multiple ongoing studies in monotherapy and combination settings High Grade Serous Ovarian Cancer (HGSOC) (75% of Ovarian Cancer) 35,000 2 Initial ongoing studies combining ZN-c3 with both common chemotherapy backbones and PARP inhibitor in platinum resistant populations as part of GSK development partnership Cyclin E Driven Ovarian Cancer (~25% of HGSOC) 8,800 3 Ongoing Biomarker study with monotherapy regimen exploring Cyclin E protein overexpression and gene amplification Other Cyclin E Driven Solid Tumors 80,000+ 3 Potential follow-on opportunities including prostate, lung, breast, etc. Uterine Serous Carcinoma 10,100 4 Fast track designation monotherapy program Colorectal (BRAF mutant) 36,300 5 Anticipate initiation of ZN-c3 + BEACON regimen in Q1 2023 as part of Pfizer development partnership Osteosarcoma 4,300 6 ZN-c3 + gemcitabine combination. Initial data readout at 2022 CTOS Conference Pancreatic Cancer 108,000 7 ZNc3 + gemcitabine combination. Demonstrate POC via investigator sponsored trial at Dana Farber AML 25,600 8 Combine ZN-c3 with ZN-d5, BCL-2 inhibitor ZN-c3: Significant Market Opportunity Across a Broad Range of Solid and Liquid Tumors ZN-c3: Wee1 Inhibitor 1. Cancer of the Ovary - Cancer Stat Facts. (n.d.). SEER. Retrieved November 2, 2022, from https://seer.cancer.gov/statfacts/html/ovary.html and ECIS - European Cancer Information System 2. Ovarian Cancer Research Alliance. Retrieved November 4, 2022. https://ocrahope.org/2021. 3. Chen at al Mol Cell Proteomics. 2019 Aug 9;18(8 suppl 1):S15-S25 4. Trastuzumab for Rare Form of Endometrial Cancer. (2020, August 13). National Cancer Institute. https://www.cancer.gov/news-events/cancer-currents-blog/2020/endometrial-cancer-usc-her2-trastuzumab 5. Cancer of the Colon and Rectum - Cancer Stat Facts. (n.d.). SEER. Retrieved November 2, 2022, from https://seer.cancer.gov/statfacts/html/colorect.html and ECIS - European Cancer Information System 6. Cancer of the Bones and Joints - Cancer Stat Facts. (n.d.). SEER. Retrieved November 2, 2022, from https://seer.cancer.gov/statfacts/html/bones.html and Annals of Oncology, VOLUME 32, ISSUE 12, P1520-1536, DECEMBER 01, 2021 7. Cancer of the Pancreas - Cancer Stat Facts. (n.d.). SEER. Retrieved November 2, 2022, from https://seer.cancer.gov/statfacts/html/pancreas.html and ECIS - European Cancer Information System 8. Acute Myeloid Leukemia - Cancer Stat Facts. (n.d.). SEER. Retrieved November 2, 2022, from https://seer.cancer.gov/statfacts/html/amyl.html and Acute Myeloid Leukaemia: Mapping the Policy Response to an Acute Cancer in France, Germany, Italy, Spain, and the UK. (2019). The Economist Intelligence Unit.
Uterine Serous Carcinoma ZN-c3
12 • USC is molecularly distinct from endometrial cancer with frequent alterations in p53 (90%), CCNE1 (25%) and HER2 (25%) 4 • High amounts of oncogene-driven replicative stress • Wee-1 is a validated target in USC with reported ORR of 29.4% and a PFS6 rate of 47.1% with adavosertib 5 • USC is an aggressive form of endometrial cancer that accounts for 10-15% of all endometrial cancers 1 • The 5-year survival for late-stage is approx. 41% compared to 75% in women with the most common form of endometrial cancer 2 • USC is responsible for ~40% of endometrial cancer deaths 3 Unmet Need in Uterine Serous Carcinoma is Significant ZN-c3’s emerging efficacy and tolerability profile show promise in addressing unmet need in USC 0% 50% 100% New Cases Deaths USC Endometrial • Current standards of care for USC: - First line: Platinum based chemotherapy - Second line: Pembro + Lenvatinib - Third Line: No specific recommendations, single-agent chemotherapy (4-9%) and some limited use of bevacizumab 6 • There is a high need for a therapeutic option in later line patients after prior platinum containing chemotherapy and pembrolizumab + lenvatinib treatment • ZN-c3 is potentially a first-in-class treatment option for USC 1. https://www.cancer.gov/news-events/cancer-currents-blog/2020/endometrial-cancer-usc-her2-trastuzumab 2. Boruta DM II, Cancer 101:2214-2221, 2004. 3. McGunigal M. Int J Gynecol Cancer 27:85-92, 2017. 4. Cancer Genome Atlas Research Network, Kandoth C. Nature 497:67-73, 2013. 5. Liu J. J Clin Oncol 39, 14:1531-1539, 2021. 6. CancerMPact, Future Trends and Insights Endometrial cancer June 2021; data on file. ZN-c3: USC UNMET NEED UNIQUE BIOLOGY COMPETITIVE LANDSCAPE
13 ZN-c3-001: Summary of Clinical Activity – Meaningful and Durable Responses Seen in USC Best Overall Response N = 11†; n (%) Complete Response (unconfirmed)* 1 (9.1) Partial Response (confirmed) 2 (18.2) Stable Disease 7 (63.6) ≥ 12 weeks 4 (36.3) < 12 weeks 3 (27.3) Progressive Disease 1 (9.1) Overall Response Rate (95% CI = 6.0%, 61.0%) 3 (27.3) DCR (CR + PR + SD) (95% CI = 58.7%, 99.8%) 10 (90.9) Median Duration of Response 5.6 months mPFS 4.2 months Best Overall Response and Reduction of Target Lesions ** Prior pembrolizumab + lenvatinib use 4.3% 2.9% -2.9% -3.1% -3.3% -4.7% -6.7% -14.4% -43.3% -48.9% -100.0%-100% -80% -60% -40% -20% 0% 20% 40% 60% 80% 100% PD PR SD PD SD SD SD SD SD SD PR PR uCR ** ** ** ** ** ** ** * Best overall response for this subject is PR. † N=11 subjects with measurable disease and at least 1 post-baseline tumor assessment. At time of data cutoff 2 SDs were ongoing on study DCR=disease control rate; uCR=unconfirmed complete response. Meric-Bernstam et al. Presentation at American Association for Cancer Research 2022 Meeting. Safety and clinical activity of single-agent ZN-c3, an oral Wee1 inhibitor, in a Phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC). Data cutoff January 21, 2022. ZN-c3: USC
14 85.7 64.3 42.9 42.9 28.6 28.6 21.4 14.3 14.3 14.3 14.3 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 14.3 020406080100 Nausea Vomiting Fatigue Diarrhea Decreased Appetite Dehydration Anaemia Thrombocytopenia Weight Decreased Dizziness Headache Neutropenia Leukopenia Dysgeusia Abdominal pain Rash Hypoalbuminaemia Oedema Peripheral Blood Alkaline Phosphatase Increased Constipation Chills Hepatic Enzyme Increased Tachycardia Onychomadesis Dyspepsia All Grades (All AEs) Grade ≥ 3 (All AEs) 60.5 32.6 46.5 37.2 14.0 7.0 9.3 7.0 7.0 4.7 2.3 7.0 4.7 4.7 4.7 2.3 2.3 2.3 7.0 9.3 7.0 9.3 7.0 4.7 2.3 2.3 2.3 2.3 20 40 60 80 100 All Grades (Related AEs) Grade ≥ 3 (Related AEs) ZN-c3 Continues to Show Favorable Tolerability Profile in Monotherapy USC Setting 1. Data as of 21 Jan 2022, Presented at AACR 2022 by F. Meric-Bernstam 2. Data as of 14 Sep 2022 ZN-c3: USC New dataset Treatment Related Adverse Events 2 n=43 Previously reported dataset Treatment Related Adverse Events 1 n=14 Patients with Adverse Events (%)
Dose Optimization ZN-c3
16 ZN-c3: Multiple PRs Across Tumor Types as Monotherapy AmVate 300 Ovar 300 Panc 350 Pros 350 Panc 450 CRC 350 SCLC 450 RCC 300 Ovar 300 Brea 350 CRC 350 CRC 300 USC 300 CRC 350 USC 300 CRC 300 NSCLC 300 Gast 350 Panc 400 450 CRC 300 Ovar 350 CRC 300 USC 300 USC 300 LeiS 350 CRC 350 LeiS 300 CRC 300 USC 300 USC 350 USC 350 NSCLC 450 CRC 350 Ovar 70% 60% 50% 40% 30% 20% 10% 0% -10% -20% -30% -40% -50% -60% -70% PD PR PD, 63 PD, 46 PD, 32 PD, 31 PD, 27 PD, 25 PD, 23 PD,17 PD, 13 PD, 10 PD, 8 SD, 5 SD4, 0 CPD, 4 PD, 3 SD+, 2 PD, 0 PD, -1 SD, -1 SD, -2 SD+, -5 SD+, -5 SD, -10 SD, -18 SD+, -22 PD, -24 uPR+, -33 cPR+, -43 cPR+, -49 cPR, -49 cPR, -51 cPR+, -69 Inv Dec, 0 SD, 0 Waterfall as of 05/15/2021; 3 subjects with no treatment scans (CRC, USC, Pancreas), and experienced clinical progressive disease (CPD) + denotes treatment ongoing. Newly reported uPR in USC is included. ORR based on radiographic responses. Both uPRs reported at AACR 2021 as of 03/15/2021 in USC were confirmed. ZN-c3-001 Dose Escalation and Expansion – 300mg QD and Above Dose Cohorts Best % Change in Target Lesion Size and Best Overall Response ZN-c3: Wee1 Inhibitor
17 Optimizing the Therapeutic Index of ZN-c3 • Only set dose of ZN-c3 has been in the USC (004 trial) at 300mg QD continuous daily dosing • Monotherapy activity demonstrated • Well tolerated safety profile • From 300mg QD dosing, we will examine pushing the therapeutic index for monotherapy dosing across three trials as this represents the fastest path to regulatory approval considerations and meaningful clinical evidence • Our experience to date (>200 patients) is that exposure and maintenance of exposure drives efficacy (both response and duration of response) • Alternative dosing to date (>60 patients): • Less dose interruptions and modifications Dosing update planned 1H 2023 Minimal Effective Dose Maximum Well- Tolerated Dose Therapeutic Index A m o u n t o f D ru g in B lo o d ZN-c3: Wee1 Inhibitor
18 • Preclinical and clinical evidence demonstrates that exposure drives activity, which is key to addressing as many patients and dosing regimens as possible • Large clinical data set (n>200 treated patients to date) with established activity as a continuous dose and ongoing studies examining combination regimens and dose optimization • Patients already treated form strong basis for ongoing work • Strategy is to demonstrate strong monotherapy efficacy in high unmet need tumors, optimizing for activity and maintaining or improving tolerability • Three monotherapy trials, including a two-arm trial with Cyclin E biomarker • Anticipate providing update on dosing in H1 2023 Accelerating Our Approach to Optimizing Dosing Establishing the optimal monotherapy dose will lead to broadest benefit across tumor types, shortest path to registration and strongest clinical profile ENCOURAGING DEMONSTRATION OF CLINICAL ACTIVITY PLAN TO ESTABLISH OPTIMAL DOSING ZN-c3: Wee1 Inhibitor
19 ZN-c3: Intermittent Dosing Increases Efficacy and Maintains Tolerability in Ovarian Cancer Models ZN-c3: Wee1 Inhibitor -1 2 5 8 11 14 17 20 23 26 0 400 800 1200 1600 2000 Days Post Treatment Initiation T u m o r V o lu m e ( m m 3 ) Vehicle qd × 24 ZN-c3 60 mg/kg qd × 24 ZN-c3 80 mg/kg (qd × 5, 2 d off) ZN-c3 100 mg/kg (qd × 4, 3 d off) ZN-c3 90 mg/kg (qd × 4, 3 d off) Continuous dosing 5d on, 2d off 4d on, 3d off 4d on, 3d off OVCAR3 Model 2 5 8 11 14 17 20 23 26 -30 -20 -10 0 10 20 30 Days Post Treatment Initiation B o d y W e ig h t C h a n g e ( % ) Vehicle qd × 24 ZN-c3 60 mg/kg qd × 24 ZN-c3 80 mg/kg (qd × 5, 2 d off) ZN-c3 90 mg/kg (qd × 4, 3 d off) ZN-c3 100 mg/kg (qd × 4, 3 d off)
20 3. Skin Biopsy Decreases in p-CDK1 Show Target Engagement for Wee1 Inhibition Confirmation of Wee1 Target Engagement in Surrogate Tissue 1 1. CDK1 phosphorylation (p-CDK1) is mediated by Wee1 2. Inhibition of Wee1 will lead to inhibition of p-CDK1 3. Skin biopsies were performed at baseline and on treatment to verify p-CDK1 levels and level of target engagement of Wee1 1. Chalasani, P; et al. 526P Pharmacodynamic evidence for WEE1 target engagement in surrogate and tumor tissues from a phase I study of the WEE1 inhibitor ZN-c3. Annals of Onc. 2021, 526P 1. CDK1 phosphorylation by Wee1 2. p-CDK1 inhibition 1 1 CDK1 Wee1 Y15 ZN-c3 p-CDK1 = Brown Staining (subject with cPR) Baseline On Treatment Decreases in p-CDK1 at Baseline vs on Treatment 40xHair bulb -99% -100% Basal epidermis ZN-c3: Wee1 Inhibitor
21 ZN-c3: PK/PD Correlation Shows Active Target Engagement • Inhibition of p-CDK1 demonstrated Wee1 target engagement • Increase in dose / drug exposure directly related to Wee1 target engagement • ≥300 mg QD showed highest AUC, with excellent target engagement and p-CDK1 levels decreased at least by 50% Wee1 Target Engagement AUC0-24 hr (ng*h/mL) p -C D K 1 (% in h ib it io n ) M o re W e e 1 Ta rg et E n g a g e m e n t 0 5000 10000 15000 20000 -100 -50 0 50 100 Average drug exposure at 300 mg QD Higher Drug ExposureSubjects with PR Target engagement (50%) ZN-c3: Wee1 Inhibitor 1. Chalasani, P; et al. 526P Pharmacodynamic evidence for WEE1 target engagement in surrogate and tumor tissues from a phase I study of the WEE1 inhibitor ZN-c3. Annals of Onc. 2021, 526P
Biomarker Approach: Cyclin E Driven Cancers ZN-c3
23 Cyclin E Cyclin E Overexpressing Cancer Cells are Highly Sensitive to Wee1 Inhibition • Cyclin E overexpression accelerates G1/S signaling, which cause high levels of replicative stress 1 • Wee1 inhibition further drives replicative stress, causing mitotic catastrophe and cell death G1G2 S M 1. Kok, et al. Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors. Oncogenesis 9, 88 (2020) P Wee1 CDK1 Cyclin B1 G2/M Checkpoint Wee1 CDK1 Cyclin B1 Mitosis Exit P Wee1 CDK2 Cyclin E G1/S Checkpoint P Cyclin E Overexpression Cyclin E Cyclin E Cyclin E Cyclin E Cyclin E Cyclin E ZN-c3: Cyclin E
24 Cyclin E Amplification is Associated with Poor Prognosis and Chemotherapy Response Across Tumor Types 1. Liu, J. et al., Cell, 2018, 173, 400-416; (figure generated using cBioPortal.org, see Cerami et al. Cancer Discovery. 2012 2; 401 and Gao et al. Sci. Signal. , 2013, 6, pl1). 2. Huang, X. et al., Frontiers in Oncology, 2020, 10, Article 583314, 1-16 3. Stronach, E., et al., Molecular Cancer Research, 2018, 1103-1111. TCGA Pan Cancer Atlas 1 Triple Negative Breast Cancer (TNBC) 2 Carboplatin-treated Ovarian Cancer 3 CCNE1 amplified (N=410) CCNE1 not amplified (N=10,305) Log-rank test p-value=1.06 10-13 CCNE1 amplified (N=4) CCNE1 not amplified (N=50) CCNE1 amplified (N=47) CCNE1 not amplified (N=201) ZN-c3: Cyclin E
25 Cyclin E Overexpression is Associated to Increased Sensitivity to ZN-c3 in Ovarian Cell Lines 1. ZN-c3 sensitivity is assessed by CellTiter Glo after 96 hours of culture. Data represent an average of at least 2 independent studies. Protein expression was assessed by Western Blot and is representative of 2 independent experiments. 2. CCNE1 was overexpressed in SKOV3 by lentivirus transduction followed by puromycin selection. Empty vector control was generated simultaneously. ZN-c3 Sensitivity and Cyclin E Protein Expression 1 ZN-c3 Sensitivity in SKOV3 Overexpressing Cyclin E 2 • Ovarian cell lines overexpressing Cyclin E are more sensitive to ZN-c3 • Cyclin E overexpression sensitizes the low-sensitive cell line SKOV-3 to ZN-c3 P ro te in e xp re ss io n (a rb it ra ry u n it s) 0 1 2 3 4 5 6 7 OV90 KURAMOCHI TYK-nu OVCAR3 ZN-c3 sensitivity Protein expression ZN -c 3 s en si ti vi ty - IC 5 0 ( m M ) ZN-c3: Cyclin E
26 Cyclin E Amplification is Associated with Poor Prognosis and Chemotherapy Response Across Tumor Types Carboplatin-treated Ovarian Cancer 3 SKOV3 CCNE1 not amplified, TP53 mut HCC1806 CDX CCNE1 amp (CN=7), TP53 mut OVCAR3 CDX CCNE1 amp (CN=14) TGI(80 mpk, Day 28) = 88%TGI(80 mpk, Day 28) = 63.5%TGI(80 mpk, Day 28) = 51.5% 2 5 8 11 14 17 20 23 -30 -20 -10 0 10 20 30 Days Post Treatment Initiation B o d y W e ig h t C h a n g e ( % ) Vehicle qd × 21 ZN-c3 80 mg/kg qd × 21 Days Post Treatment Initiation -1 2 5 8 11 14 17 20 23 0 400 800 1200 1600 Days Post Treatment Initiation T u m o r V o lu m e ( m m 3 ) Vehicle qd × 21 ZN-c3 80 mg/kg qd × 21 Days Post Tr ent Initiation Days Post Grouping (Day) Days Post Treatment Initiation Days Post Grouping (Day) Days Post Grouping (Day) ZN-c3: Cyclin E
27 Moving Forward with CCNE1 in HGSOC: Revised ZN-c3-005 Study Design CCNE1 Amp ZN-c3 monotherapy at doses and schedules deemed well tolerated in ZN-c3-001 ZN-c3 monotherapy ZN-c3: Cyclin E Cohort A CCNE1 Amp PH 1b / SAFETY LEAD-IN PH 2 EXPANSION Cohort B CCNE1 Non-amp Cyclin E Overexpressed Platinum-resistant HGSOC 1-3 prior lines (prior bevacizumab required)
28 • In 2022, the total number of drug- treatable second line platinum-resistant ovarian cancer patients is estimated to be >14,000 in the United States, EU5 and Japan 2 • Platinum-resistant and -refractory ovarian cancer represents a high unmet need • It is associated with a poor prognosis and limited treatment options - ORR of 11.8% with standard of care 1 for platinum resistant patients • Improvement in efficacy with acceptable safety profile would make a meaningful difference for patients Platinum-Resistant/Refractory Ovarian Cancer Remains an Unmet Need • Current standard of care for second line platinum-resistant ovarian patients is single-agent chemotherapy ± bevacizumab 3 • Ongoing pivotal trials focus on novel MOAs, including ADCs, and combinations with either PARPi or chemotherapy. 3 • ZN-c3 is potentially a first-in-class treatment option that works synergistically with other anticancer therapies UNMET NEED PATIENT POPULATION COMPETITIVE LANDSCAPE 1. Pujade-Lauraine et al. J Clin Oncol 2014; 32:1302-1308; AURELIA study 2. Decision Resources Group; data on file. 3. CancerMPact Treatment Architecture Ovarian cancer July 2021; data on file. 0 4,000 8,000 Drug-Treatable Patients by Region: 2022 U.S. EU5 Japan ZN-c3: Ovarian ZN-c3’s efficacy and tolerability profile are well-positioned for the platinum-resistant/refractory ovarian population
29 ZN-c3-002: Summary of Clinical Activity Summary of Clinical Activity (All Cohorts) Group N Evaluable* (n) PR/uPR (n) SD (n) PD (n) DCR (%) ORR (%) ZN-c3 + Paclitaxel 9 8 5 3 – 100 62.5 ZN-c3 + Carboplatin 17 11 5 4 2 81.8 45.5 ZN-c3 + PLD 30 24 3 17 4 83.3 12.5 Total 56 43 13 24 6 86.0 30.2 Pasic, et al. Poster Presented at American Association for Cancer Research Annual Meeting (2022): Abstract CT148: A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 * Patients with measurable disease and at least one post-baseline scan Of evaluable subjects, ORR is percentage with PR/uPR; DCR = disease control rate, percentage of ORR + SD; uPR = unconfirmed partial response Data cutoff January 28, 2022 ZN-c3: Ovarian
30 55.4 48.2 41.1 37.5 35.7 35.7 28.6 21.4 19.6 17.9 16.1 14.3 14.3 14.3 12.5 8.9 8.9 8.9 8.9 7.1 7.1 7.1 7.1 5.4 5.4 5.4 5.4 5.4 5.4 5.4 5.4 7.1 35.7 17.9 8.9 8.9 5.4 3.6 1.8 7.1 5.4 5.4 10.7 5.4 3.6 1.8 3.6 1.8 5.4 1.8 020406080100 Nausea Neutropenia Thrombocytopenia Anaemia Vomiting Fatigue Diarrhoea Hypoalbuminaemia Leukopenia Abdominal pain Hypokalaemia Alanine Aminotransferase Increased Lymphopenia Hypomagnesaemia Pain (any) Gamma-glutamyltransferase Increased Aspartate Aminotransferase Increased Pyrexia Headache Ascites Weight Decreased Blood Alkaline Phosphatase Increased Dyspnoea Small Intestinal Obstruction Decreased Appetite Muscle Spasms Face Oedema Dyspepsia Hyponatraemia Cough COVID-19 All Grades (All AEs) Grade ≥ 3 (All AEs) 48.2 41.1 37.5 26.8 30.4 23.2 16.1 5.4 16.1 3.6 1.8 14.3 3.6 3.6 3.6 7.1 5.4 3.6 1.8 1.8 1.8 3.6 3.6 3.6 3.6 1.8 1.8 5.4 32.1 17.9 7.1 7.1 3.6 1.8 7.1 1.8 10.7 1.8 1.8 1.8 1.8 20 40 60 80 100 All Grades (Related AEs) Grade ≥ 3 (Related AEs) ZN-c3-002: TEAEs ≥5% for All Patients (N=56) Adverse Events January 28, 2022 data cutoff. Pasic, et al. Poster Presented at American Association for Cancer Research Annual Meeting (2022): Abstract CT148: A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer ZN-c3: Ovarian Related AEsTEAEs
PARP-Refractory Ovarian Cancer ZN-c3
32 • Combination of PARP and Wee1 inhibitors in TNBC results in synergistic cell killing in preclinical models with either BRCA1 mutations or high levels of cyclin E 1 • The combination of ZN-c3 and niraparib shows efficacy in both ovarian and TNBC in vivo models • Sequential administration of PARP and ZN-c3 is efficacious but is better tolerated than concurrent based on body weight loss • Wee1 inhibition may broaden the application range of PARP inhibitors in ovarian cancer and TNBC, consistent with results from the EFFORT 2 and STAR trials 3 ZN-c3 + PARP Inhibitor Combinations are Active in both Ovarian CDX and TNBC PDX Models OVCAR3 Model TGI Body Weight TNBC Model TGI Body Weight 1. Chen X Cancers (Basel). 2021 Apr 1;13(7):1656 2. Westin, S.; J Clinical Oncology, 39, N15 (Supplement). 2021, 5505. 3. Yap T. Eur J Cancer. Vol 174 (Supplement 1), S7: 2022. Days Post Treatment Initiation Days Post Treatment Initiation Days Post Treatment Days Post Treatment ZN-c3: PARP Combinations
33 Key Eligibility: • Recurrent high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer (serous, clear cell or endometrioid). • Prior therapy: 1 – 5 prior lines for advanced/metastatic disease • Disease progression while taking a PARPi as maintenance treatment (minimum of 3 months of treatment required). Primary Endpoint • Determine MTD/RP2D and optimal administration schedule 3+3 dose escalation design ZN-c3-006: Phase 1/2 Study of ZN-c3 in combination with niraparib in patients with platinum-resistant ovarian cancer KEY ELIGIBILITY PHASE 1: SAFETY LEAD-IN ZN-c3 + niraparib administered concurrently ZN-c3 + niraparib administered in an alternating schedule ZN-c3: PARP Combinations
BRAF Metastatic Colorectal Cancer ZN-c3
35 Preclinical Data Supports the Combination of ZN-c3 with Encorafenib and Cetuximab: BEACON REGIMEN • Oncogene-induced replication stress in mutationally driven cancers such as BRAF mutant colorectal cancer leads to DNA damage and genomic instability • Oncogene activation disrupts replication regulation leading to slow and stalled replication forks and other defects and leads to DNA damage • Dependency of cancers with replication stress on Wee1 signaling provides a mechanistic basis for synergy with EGFR/BRAF inhibition • Addition of ZN-c3 to the BEACON regimen is well tolerated and provides superior efficacy in an in vivo model of BRAF mutant CRC LS411N -1 2 5 8 11 14 17 20 0 250 500 750 1000 1250 1500 Days Post Treatment Initiation T u m o r V o lu m e ( m m 3 ) SOC Vehicle A qd × 21 Encorafenib 20 mg/kg qd × 21 Cetuximab 15 mg/kg BIW × 3 ZN-c3 60 mg/kg qd × 21 Cetuximab 15 mg/kg BIW × 3 + Encorafenib 20 mg/kg qd × 21 ZN-c3 60 mg/kg qd × 21 + Encorafenib 20 mg/kg qd × 21 + Cetuximab 15 mg/kg BIW × 3 Days Post Treatment Initiation 2 5 8 11 14 17 20 -30 -20 -10 0 10 20 30 B o d y W e ig h t C h a n g e ( % ) Days Post Treatment InitiationDays Post Treatment Initiation LS411N (BRAF mutant CRC) ZN-c3: BRAF mCRC
36 PHASE 2: DOSE EXPANSION N: Up to 80 patients • Phase 1 Endpoints: Safety, tolerability, MTD, RP2D • Phase 2 Endpoint(s): ORR; DOR, DCR, PFS, TTP Encorafenib + Cetuximab + Escalating Dose Levels of ZN-c3 PHASE 1: DOSE FINDING BRAF mCRC Study in Collaboration with Pfizer • Patients with mCRC and documented BRAFV600E mutation • Disease progression after 1 or 2 previous regimens for metastatic disease • Prior therapy may include BRAF and/or EGFR directed therapy (e.g. may have progressed after BEACON regimen) Phase 1/2, Open-Label, Multi-center Study Of ZN-c3 In Adults With Metastatic Colorectal Cancer Large Patient Population… • Up to 21% of mCRC patients have BRAF mutations (~15,000 patients per year, U.S.) with over 90% V600E1 • Testing for BRAF mutations is routine, providing opportunity to identify patients With Significant Unmet Need • Median OS in BRAF mutant CRC patients <1 year, vs. BRAF WT >2 years2 • While targeted BRAF inhibition (e.g., vemurafenib) has been successful in melanoma with response rates >80%, this strategy has failed in CRC (OR ~5%) due to innate resistance3 • Encorafenib in combination with cetuximab (BEACON) was approved for BRAF V600E mCRC in April 2020 and is now the standard of care 1 Sorbye H, Dragomir A, Sundström M, et al. High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort. PLoS One. 2015;10(6):e0131046. 2 Corcoran et al. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600–Mutant Colorectal Cancer. J Clin Oncol (2015) Dec 1; 33(34): 4023-4031 3 Kopetz et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. NEJM (2019) 381: 1632-1643 Zentalis maintains full economic ownership and control of ZN-c3, apart from Greater China rights (Zentara). ZN-c3: BRAF mCRC
BCL-2 Inhibitor ZN-d5
38 BCL-2: A Clinically Validated Oncology Target • BCL-2 is an anti-apoptotic protein involved in tumor survival and chemo resistance 1 • The intrinsic apoptotic pathway is controlled by the BCL-2 protein family on the mitochondrial outer membrane 2, 3 • BCL-2 inhibitors may restore the normal apoptosis process, making it an important target for cancer treatments Mechanism of Action of BCL-2 Inhibitors 1 BAXBIM BCL2 BCL2 BCL-2i BAX BCL-XL MCL1 BIM BCL2 BCL2 BIM BAX BAX BAX Cytochrome c Apoptosis 1. Konopleva M et al. Cancer Discov. 2016 Oct;6(10):1106-1117 2. Konopleva M and Letai A. Blood. 2018 Sep 6;132(10):1007-1012 3. Bhola PD and Letai A. Mol Cell. 2016;61(5):695-704 ZN-d5: BCL-2 Inhibitor
39 ZN-d5: A Potent BCL-2 Inhibitor Designed with Improved Selectivity for BCL-2 ZN-d5 has >14x Improved Selectivity for BCL-2 vs BCL-xL and Binds With Higher Affinity to BCL-2 Mutants than Venetoclax Compound ID Affinity (Kd, nM) IC50 (nM) BCL-2 Type BCL-2 BCL-xL MCL-1 WT G101V F104L D103Y Venetoclax 0.41 28 >30000 1.3 7.3 8.4 18.3 ZN-d5 0.29 190 >30000 1.4 3.7 1.4 5.0 Compound ID CTG (24 h) IC50 (mM) Venetoclax 0.6 ZN-d5 2.4ZN-d5 Exhibits Potent In Vitro Activity Across Multiple Tumor Cell Lines Compound ID CTG IC50 (nM) ALL MCL DLBCL AML RS4;11 Mino-1 Granta- 519 DOHH-2 Toledo HL-60 Molm-13 MV4-11 Venetoclax 2.9 1.1 161 43 191 26 18 3.8 ZN-d5 5.1 0.1 89 50 92 21 39 5.1 0.0010.010.1110 0 20 40 60 80 Compound [mM] In h ib it io n ( % ) Venetoclax ZN-d5 ZN-d5: Less Human Platelet Toxicity Compared to Venetoclax in an In Vitro Assay • ZN-d5 shows activity in preclinical models of ALL, NHL and AMLZN-d5 shows activity in preclinical models of ALL, NHL and AML Venetoclax data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmaceutical company developing the compound ZN-d5: BCL-2 Inhibitor
40 ZN-d5: May Bind with Higher Affinity to BCL-2 Mutants than Venetoclax Compound ID IC50 (nM) BCL-2 Type WT G101V F104L D103Y Venetoclax 1.3 7.3 8.4 18.3 ZN-d5 1.4 3.7 1.4 5.0 Mutations in BCL-2 May be Driving Sub-Clonal Pockets of Resistance to Venetoclax in CLL 55% (16/29) patients acquired mutations in BCL-2 family members • 41% (14/29) with mutations in BCL-2 • 21% (6/29) with mutations in PMAIP1 (NOXA), BAX or BAD Majority (9/14) were detected with BCL-2 mutations after 24 months on venetoclax • 55% (16/29) of patients with CLL progression CLL Progression on Venetoclax Acquired post-therapy No mutation detected Note: Competition assay for displacing BAK peptide bound to BCL-2 Source: Chyla, B. ASH Presentation (2019) Venetoclax data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmaceutical company developing the compound ZN-d5: BCL-2 Inhibitor
41 ZN-d5 Clinical Development Plan • Improved in vitro potency and has 10x improved selectivity for BCL-2 vs BCL-xL compared to venetoclax • Observed to bind with higher affinity to BCL-2 mutants than venetoclax in in vitro assay - Mutations in BCL-2 may be driving sub-clonal pockets of resistance to venetoclax • Preclinical combination data of ZN-d5 + ZN-c3 utilizing novel biology showed synergistic an additive activity across multiple indications in both solid and liquid tumors, often at subtherapeutic doses Ongoing and Planned Clinical Programs Indication Treatment Trial Updates Non-Hodgkin’s Lymphoma ZN-d5 Continues to enroll AL Amyloidosis ZN-d5 Continues to enroll AML ZN-d5 & ZN-c3 Anticipate trial initiation in 4Q 2022 ZN-d5: BCL-2 Inhibitor
42 ZN-d5: Favorable Early Comparison to Venetoclax in NHL ZN-d5: NHL Upper respiratory tract infections • ZN-d5 100-1200mg, empty stomach • Venetoclax 200-1200mg with food • Early toxicity profile in NHL favorable vs. published venetoclax data 1 - Fewer AEs of any Grade, Grade ≥3 - No TLS observed - Venetoclax AEs not dose-dependent 1. Davids et al, J Clin Oncol 2017;35:826-833; emergent AEs reported in ≥15% of subjects. ZN-d5 results as of 03 Nov 2021 data cutoff.
43 ZN-d5 in AL (Primary) Amyloidosis 1. Zhang et al. Clin Lymphoma Myeloma Leuk. 2019;19(suppl 10):e339 2. Kyle et al, Mayo Clin Proc. 2019;94:465-471 3. Premkumar et al, Blood Cancer J 2021;11:10; hematologic response rate in 38 evaluable patients. AL Amyloidosis study is currently enrolling patients • AL Amyloidosis: Deposition of immunoglobulin light chains - Clonal plasma cell population secretes misfolding light chain - Progressive systemic amyloid accumulation causes widespread organ damage - High morbidity and mortality • Orphan disease - Estimated worldwide prevalence is 75,000 1 - About 4k new cases/year in the US 2 • Not a cancer, but treated like one - Agents active in multiple myeloma used in first-line and relapsed/refractory settings - Daratumumab only approved therapy, for first-line use with CyBorD • Relapsed/refractory setting is a high unmet medical need 63% VGPR/CR 3 ZN-d5: AL Amyloidosis
44 BCL-2 Inhibition has Shown Robust Clinical Activity in AL Amyloidosis • Patients with the t(11;14) translocation have a worse prognosis than the general AL amyloidosis population 1 • BCL-2 inhibition showed an improved response rate in the t(11;14) cohort with a trend towards better survival Best Response in Evaluable Patients 1. Premkumar et al, Blood Cancer J 2021;11:10; hematologic response rate in 38 evaluable patients. OS for All Patients ZN-d5: AL Amyloidosis
Potential Combination of ZN-c3 and ZN-d5
46 The Combination of BCL-2 and Wee1 Inhibitors Results in Synergy in Several Tumor Models Including AML • ZN-d5 and ZN-c3 combination represents a novel therapeutic approach • Significant enhancement of activity than single agent in several indications, including AML • Combination regimen was well-tolerated in mice • Zentalis is the only company known to have both inhibitors in clinical development HL-60 AML Model ZN-d5 + ZN-c3 0 3 6 9 12 15 18 0 300 600 900 1200 1500 1800 2100 2400 2700 Vehicle ZN-d5 50 mg/kg, qd ZN-c3 60 mg/kg, qd Days Post Treatment T u m o r V o lu m e ( m m 3 ) ZN-d5 50 mg/kg + ZN-c3 60 mg/kg, qd. Regression: 94% Presented at AACR 2022 by Izadi, H.; et. al. Cancer Res (2022) 82 (12_supplement): 2591.
47 Antitumor Activity in Solid Tumor Models with the ZN-d5 + ZN-c3 Combination Represents Market Expansion Opportunities 1. Izadi, H. et. al. Cancer Res (2022) 82 (12_Supplement): 2605. 0 3 6 9 12 15 18 21 0 200 400 600 800 1000 1200 1400 Vehicle ZN-d5 50 mg/kg ZN-c3 80 mg/kg ZN-d5 50 mg/kg + ZN-c3 80 mg/kg Days Post Treatment T u m o r V o lu m e ( m m 3 ) SCLC Model (DMS53)1 Days t t ent TNBC Model (MDA-MB-436) Days Post Treatment NSCLC Model (H146) Days Post Treatment Neuroendocrine Prostate Model (H660) Days Post Treatment ZN-d5 + ZN-c3
BCL-xL Protein Degrader
49 Declared development candidate and initiated IND enabling activities BCL-xL Degrader Background and Rationale Background, Clinical Relevance, and Approach Therapeutic Hypothesis • BCL-xL is a member of the anti-apoptotic BCL-2 proteins and is clinically validated. 1, 2 • Expression of BCL-xL contributes to therapeutic resistance mechanisms. 3, 4, 5 • Degrading BCL-xL will induce cell death and overcome resistance mechanisms in multiple cancer types, while reducing the possibility of on- target thrombocytopenia. Patient Selection • Heme malignancies. • Solid tumors. Internal Combination Opportunities • ZN-c3 (Wee1 inhibitor) and ZN-d5 (BCL-2 inhibitor) Therapeutic Window • BCL-xL is required for platelet viability and BCL-xL inhibitors (e.g. navitoclax) are dose limited in the clinic due to on-target thrombocytopenia. 6 • A degradation approach with a E3 ligase low expressed in platelets could help mitigate thrombocytopenia. 7, 8 • Efficacy may be achieved at lower doses and frequencies due to the catalytic MOA of degraders, further reducing the chance of thrombocytopenia and increasing TI. Chemical Modality • Heterobifunctional degrader linking BH3-binding moiety. Competitive Landscape • Multiple inhibitors and one degrader in the clinic (Ph1/2). 1. Bhola PD and Letai A. Mol Cell. 2016;61(5):695-704 2. Konopleva M and Letai A. Blood. 2018 Sep 6;132(10):1007-1012 3. Rahman SFA et al., Future Oncology, 2020, 16(28) 4. Yue et al., Cnacer Cell Int., 2020, 20(254) 5. cbioportal.org 6. Wilson WY et al., Lancet Oncol., 2010; 11(12):1149-1159 7. Khan et al. Nature Med 12, 1938-1947 (2019) 8. He et al. Nature Comm 11, (2020) Figure from: Delbridge, A. R. D., et. al. Nat Rev Cancer 16, 99-109 (2016) BCL-xL Degrader
50 BCL-xL IV Degrader is More Efficacious than BCL-xL Inhibitor (Navitoclax) in MOLT4 (T-ALL) Models Navitoclax data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmaceutical company developing the compound • BCL-xL Degrader demonstrates excellent efficacy in the MOLT4 tumor model (T-ALL) and is well-tolerated at efficacious doses • BCL-xL degrader is more efficacious than Navitoclax -1 2 5 8 11 14 17 20 0 200 400 600 800 1000 1200 1400 Days Post Treatment Initiation T u m o r V o lu m e ( m m 3 ) Navitoclax 100 mg/kg PO QD Navitoclax 100 mg/kg PO QW Navitoclax 20 mg/kg IV QW ZN Degrader 4, 20 mg/kg IV QW ZN Degrader 4, 40 mg/kg IV QW Vehicle i ti Days Post Treatment Initiation BCL-xL Degrader
51 ZN-c3 Combined with a Low Dose of Navitoclax (BCL-xL Inhibitor) Results in Synergistic Anti-tumor Activity in the ALL model MOLT-4 1 1. Izadi, H.; et. al. Cancer Res (2022) 82 (12_Supplement): 2605. TGI: Tumor Growth Inhibition ALL: Acute Lymphoblastic Leukemia MOLT-4 model is BCL-xL dependent, but is not on BCL-2 Navitoclax data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmaceutical company developing the compound • The MOA of the combination of the BCL-xL therapeutic and ZN-c3 represents a novel approach which results in synergistic anti-tumor activity. • Development of the BCL-xL degrader offers an opportunity to combine with other anti-cancer agents, such as ZN-c3. ZN-c3 + BCL-xL Days Post Treatment Days Post Treatment
Conclusions
53 4 ZENTALIS DRUGS Utilizing the Highly Efficient Integrated Discovery Engine to Generate Potentially Best-In-Class Drugs PATIENTS1 ZENTALIS DISCOVERY ENGINE2 3 Genomic FeaturesPathways Functional Screens Preclinical Models Chemistry Machine Learning • CRISPR screens • BH3 profiling • Genomics • 2D • 3D • Organoids • CDX • PDX • Enzymatic and allosteric inhibitors • Heterobifunctional Degraders and Molecular Glues • Crystallography and SBDD IDENTIFY1 ANALYZE2 CREATE3 GENERATE4
54 Company focused on generating clinical evidence that creates value and delivers new therapies to cancer patients Organizational Accomplishments and Progress Since May 2022 PRIORITY ACCOMPLISHMENTS / PROGRESS Strengthen organizational talent and complete executive team build-out New Board Member and 6 Executive Hires or Promotions including CMO, CSO, CTO, SVP Portfolio Management, General Counsel and President Prioritize and strengthen clinical development plans for ZN-c3 Expanded / continued near-term registrational opportunities in populations most likely to benefit: 6 ongoing sponsored and 2 newly announced studies (one with Pfizer and one with Dana Farber) Evolve ZN-d5 program Establishing clear clinical strategy around pro-apoptotic asset Advance BCL-xL degrader program Declared development candidate and initiated IND enabling studies Deprioritize non-strategic assets Discontinue all activity around SERD (ZN-c5) and EGFR (ZN-d4) by end of 2022 Strengthen balance sheet to fund development activities through key catalysts Successfully completed capital raise in May 2022; cash runway into 2025 1 2 3 4 5 6
55 2022 Key Milestones 1H 2022 ZN-c3 Wee1 Inhibitor ZN-d5 BCL-2 Inhibitor Integrated Discovery Engine Zentera Initial readout on Phase 1 USC expansion cohort Initial readout on Phase 1b ovarian chemotherapy combo Initial enrollment/safety update on Phase 2 USC trial 1 Initial readout on Phase 1/2 chemotherapy combo in osteosarcoma 1H 2022 1H 2022 1H 2022 1Q 2022 Initiate Phase 1 / 2 monotherapy study in amyloidosis Initiate Phase 1 / 2 combination study of ZN-d5 + ZN-c3 in AML Updated results from Phase 1 dose escalation in AML and NHL 1H 2022 1H 2022 2022 Initiate IND enabling studies for an internal program 2022 Maximize value from investment in and partnership with Zentera 1. FDA Fast Track designation
56 Kimberly Blackwell, M.D. Chief Executive Officer kblackwell@zentalis.com (212) 433-3787 Melissa Epperly Chief Financial Officer mepperly@zentalis.com (215) 290-7271 Corporate Office 1359 Broadway Suite 1710 New York, NY 10018 Science Center 10275 Science Center Drive Suite 200 San Diego, CA 92121