Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Presentation (June 2024)
61 slides from Zentalis Pharmaceuticals's investor presentation, Jun 3, 2024
Slide 1: Corporate Presentation
Corporate Presentation Nasdaq: ZNTL June 2024 Exhibit 99.1
Slide 2: Forward Looking Statements and Disclaimer
2 Forward Looking Statements and Disclaimer 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 Securi
Slide 3: First-in-class WEE1 Inhibitor with Broad Franchise Potential
3 First-in-class WEE1 Inhibitor with Broad Franchise Potential Abbreviations: PROC, platinum resistant ovarian cancer; USC, uterine serous carcinoma; ORR, objective response rate; NDA, New Drug Application; mPFS, median progression free survival Statements comparing azenosertib to other agents, not
Slide 4: Building Azenosertib Franchise in Gynecologic Cancers and Beyond
4 Building Azenosertib Franchise in Gynecologic Cancers and Beyond INDICATION TRIAL NAME + DEVELOPMENT APPROACH Phase 1 Phase 1b Phase 2 Phase 3 EXPECTED MILESTONES Azenosertib WEE1 Inhibitor G Y N EC O LO G IC M A LI G N A N C IE S Platinum Sensitive Ovarian Cancer Planned trial in 1L maintenance s
Slide 5: Clinical Programs Position Zentalis for Multiple Datasets with Value-creating Potential
5 2024 2025 2026 Multiple Tumor Types (Includes Ovarian and Uterine Serous Carcinoma) Platinum Resistant Ovarian Cancer Platinum Sensitive Ovarian Cancer Uterine Serous Carcinoma Abbreviations: 1H, first half; 2H, second half Clinical Programs Position Zentalis for Multiple Datasets with Value-creat
Slide 6: Azenosertib Mechanism of Action – Inhibitor of WEE1
6 Normal Cell Cycle Regulation • In cancer cells, oncogene induced replication stress (e.g. Cyclin E1 activation or a driver mutation) leads to high levels of DNA damage and genomic instability • Cancers with high levels of replication stress are sensitized to WEE1 inhibition via azenosertib • Inhib
Slide 7: Azenosertib Treatable Patient Population More Than Doubles as Franchise Expands
7 ‘Drug treatable’ estimates from DRG Clarivate. For ‘Other Cyclin E1+ tumors’ used incidence reported by SEER and ECIS. HRD Post PARPi tumor types: Prostate, Pancreas and Breast; Other Cyclin E1+ Tumor Types include bladder, stomach, esophageal, lung, and breast cancer Abbreviations: PROC, platinum
Slide 8: Azenosertib Monotherapy Results
Azenosertib Monotherapy Results Monotherapy Anti-tumor Activity in Gynecologic Malignancies with Favorable Safety and Tolerability Profile
Slide 9: Strong Safety and Tolerability of Azenosertib Monotherapy
Established monotherapy RP2D of 400 mg 5:2 Median follow up has increased by nearly 5 months and mPFS has increased to 6.5 months 37% Objective Response Rate using intermittent dosing in ovarian and USC patients Maintained excellent safety and tolerability with intermittent dosing CORPORATE CALL Jun
Slide 10: Intermittent Monotherapy Patient Population Was Heavily Pretreated and Treatment Refractory
10 Intermittent Monotherapy Patient Population Was Heavily Pretreated and Treatment Refractory USC and HGSOC subjects who received at least one dose of azenosertib with intermittent dosing schedule, have baseline measurable disease by RECIST 1.1, and at least one post-baseline scan. *Platinum Resist
Slide 11: Monotherapy Azenosertib Results in a 37% Confirmed Response Rate
11Subjects who received at least one dose of azenosertib with intermittent dosing schedule, have baseline measurable disease by RECIST 1.1, and at least one post-baseline scan. Abbreviations: +, patients remain on therapy at the time of data cut-off; CR, complete response; PR, partial response; SD,
Slide 12: Monotherapy Azenosertib Has Meaningful and Durable Benefit
12 Monotherapy Azenosertib Has Meaningful and Durable Benefit to Platinum Resistant Ovarian Cancer/USC Patients * Subjects who received at least one dose of azenosertib with intermittent dosing schedule, have baseline measurable disease by RECIST 1.1, and at least one post-baseline scan. Abbreviatio
Slide 13: Progression-Free Survival with Monotherapy Azenosertib
13 P ro gr e ss io n -F re e Su rv iv al P ro b ab ili ty 1.0 – 0.8 – 0.6 – 0.4 – 0.2 – 0.0 – 0 1 2 3 4 5 6 7 8 Months – – – – – – – – – Monotherapy Azenosertib Has Meaningful and Durable Benefit to Platinum Resistant Ovarian Cancer/USC Patients * Subjects who received at least one dose of azenosert
Slide 14: Azenosertib Monotherapy Continues to Demonstrate Excellent Safety Profile
14 ALL GRADES GRADE 3/4 Fatigue 18 (39.1) 5 (10.9) Hematologic Anemia 11 (23.9) 5 (10.9) Thrombocytopenia 9 (19.6) 4 (8.7) Neutropenia 9 (19.6) 7 (15.2) ALL GRADES GRADE 3/4 Gastrointestinal Nausea 20 (43.5) 2 (4.3) Diarrhea 22 (47.8) 4 (8.7) Vomiting 8 (17.4) 1 (2.2) Decreased appetite 4 (8.7) 1 (2
Slide 15: Azenosertib is Well Tolerated Compared to Other Gynecologic Malignancy Therapies
15 24% 35% 0% 28% 52% 12% 20% 39% 11% 54% 72% 5% 51% 50% 15% 0% 10% 20% 30% 40% 50% 60% 70% 80% Reductions Interruptions Discontinuations Azenosertib is Well Tolerated with Similar or Better Tolerability Compared to Other Gynecologic Malignancy Therapies Safety Evaluable Population (All tumor types;
Slide 16: Data Supports Ongoing Potentially Registrational Studies
16 Data Supports Ongoing Azenosertib Monotherapy Potentially Registrational Studies in Ovarian Cancer and Uterine Serous Carcinoma Monotherapy Conclusions EXCELLENT TOLERABILITY & SAFETY MONOTHERAPY EFFICACY 37% confirmed ORR mPFS of 6.5 MONTHS Supports differentiation from other clinical WEE1 inhib
Slide 17: Phase 2 Trials of Azenosertib
Phase 2 Trials of Azenosertib Potential Paths to Registration in Platinum Resistant Ovarian Cancer and Uterine Serous Carcinoma
Slide 18: Platinum Resistant Ovarian Cancer: High Unmet Need
18 Platinum Resistant Ovarian Cancer: High Unmet Need Provides Opportunity for Monotherapy Approval 1 Figures represent Company estimates of U.S. and EU5 patients with conditions covered by the Company’s targeted indications; Source: IQVIA, DRG Clarivate; 2 Matulonis U. JCO 2023 41:13:2436-2445; Abb
Slide 19: DENALI (ZN-c3-005) Trial Design
19Note: Cyclin E1+ refers to protein overexpression determined by immunohistochemistry Abbreviations: QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; ORR, objective response rate; DOR, Duration of Response; 1H, first half DENALI (ZN-c3-005): Prospective Evaluation of CCNE
Slide 20: MAMMOTH (ZN-c3-006) Trial Design
20 Abbreviations: PARP, poly-ADP ribose polymerase; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; ORR, objective response rate DOR, duration of response; PFS, progression-free survival; 2H, second half MAMMOTH (ZN-c3-006): Phase 1/2 Study of Azenosertib in Combination wi
Slide 21: New Treatment Options Needed in 2L+ Uterine Serous Carcinoma
211 Figures represent Company estimates of U.S. patients with conditions covered by the Company’s targeted indications and are dependent upon regulatory approvals; Source: IQVIA, DRG Clarivate, Kantar Health; Abbreviations: 2L+, second line maintenance plus; USC, uterine serous carcinoma; 1L, first
Slide 22: TETON (ZN-c3-004) Azenosertib Monotherapy in Uterine Serous Carcinoma
22 CURRENTLY ACCRUING - FDA Fast Track Designation Abbreviations: 2L, two lines; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; ORR, objective response rate; DOR, duration of response; 2H, second half; The FDA granted Fast Track designation in November 2021 to azenosertib
Slide 23: Azenosertib in Platinum Sensitive Ovarian Cancer 1L Maintenance
Azenosertib in Platinum Sensitive Ovarian Cancer 1L Maintenance Opportunity to Provide Prolonged Benefit for a Larger Number of Patients
Slide 24: Opportunity for Azenosertib in First Line Maintenance in HRP PSOC
PFI<6m Second Line Therapy Combination Chemotherapy Platinum Doublet PFI>6m PFI<6m Platinum Resistant Single Agent Chemotherapy or Mirvetuximab (~35% pts)3 Opportunity for Azenosertib in First Line Maintenance in Homologous Repair Proficient (HRP) Platinum Sensitive Ovarian Cancer 1 Ray-Coquard I. N
Slide 25: Azenosertib in 1L Maintenance Setting for Platinum Sensitive Ovarian Cancer
25 Abbreviations: 1L, one line; PFS, progression free survival; OS, overall survival; 2H, second half Azenosertib in 1L Maintenance Setting for Platinum Sensitive Ovarian Cancer Azenosertib + Bevacizumab Platinum Sensitive Ovarian Cancer Bevacizumab alone • Advanced Ovarian Cancer following 6 cycles
Slide 26: Potential to Impact the Greatest Number of Ovarian Cancer Patients in 1L Maintenance
26 Potential for Azenosertib to Impact the Greatest Number of Ovarian Cancer Patients in the 1L Maintenance Setting 1 Figures represent Company estimates of U.S. and EU5 patients with conditions covered by the Company’s targeted indications; Source: IQVIA, DRG Clarivate Kantar and DRG; 2 Ray-Coquar
Slide 27: Azenosertib as 1L Maintenance Therapy: Investigator Perspectives
27 Additional trial details in 2H 2024 Azenosertib as 1L Maintenance Therapy in Platinum Sensitive Ovarian Cancer Patients Professor Alexandra Leary, MD, PhD Deputy Chair of Medical Oncology, Institut de Cancérologie Gustave Roussy, France GINECO and ENGOT Investigator “Zentalis’ frontline maintenan
Slide 28: Azenosertib Combination with Chemotherapy Clinical Data
Azenosertib Combination with Chemotherapy Clinical Data Shows Strong Efficacy and Favorable Safety Profile in Platinum Resistant Ovarian Cancer
Slide 29: ZN-c3-002: Phase 1b Combination Study in Platinum Resistant Ovarian Cancer
29 Azenosertib + Paclitaxel Azenosertib + Gemcitabine Azenosertib + PLD Azenosertib + Carboplatin Liu JF, et al. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 5513-5513; Abbreviations: CRM, continuous reassessment model; QD, once daily; D, day; AUC, area under the curve; PLD, pegylat
Slide 30: Encouraging Efficacy and Durability with Azenosertib in Combination with Chemotherapy
30 *Response-evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one post-baseline assessment. All objective responses were confirmed per RECIST v 1.1. Data include patients on all schedules of azenosertib plus chemotherapy. Liu JF, et al. J
Slide 31: Azenosertib in Combination with Chemotherapy Demonstrates Favorable Safety Profile
31*All doses were at or below MTD and were intermittent; **A MTD for gemcitabine + azenosertib has not been determined, further dose cohorts are ongoing. Liu JF, et al. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 5513-5513; Abbreviations: MTD, maximum tolerated dose; PLD, pegylate
Slide 32: Addition of Azenosertib Increases Response Rates and Durability Versus Chemotherapy Alone
32 Liu JF, et al. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 5513-5513; Abbreviations: SOC, standard of care; PLD, pegylated liposomal doxorubicin Addition of Azenosertib to Single Agent Chemotherapy Increases Response Rates and Durability of Response in Ovarian Cancer Compared t
Slide 33: Azenosertib in Osteosarcoma
Azenosertib in Osteosarcoma
Slide 34: ZN-c3-003: Phase 1 Study Design and Subject Flow
34 ZN-c3-003: Phase 1 Study Design and Subject Flow 4:3, 4 days on, 3 days off; 5:2, 5 days on, 2 days off; A, azenosertib; AE, adverse event; DL, dose level; ECOG, Eastern cooperative Oncology Group; F/U, follow-up; G, gemcitabine; IV, intravenous; MTD, maximum tolerated dose; PS, performance statu
Slide 35: Doses Evaluated and Dose-Limiting Toxicities
35 Doses Evaluated and Dose-Limiting Toxicities No evidence of a drug-drug interaction between azenosertib and gemcitabine was observed Pharmacokinetic results were consistent with those seen in azenosertib monotherapy and other chemotherapy combination studies with azenosertib Osteosarcoma, ZN-c3-0
Slide 36: Percent Change From Baseline in Sum of Longest Diameters
36• Percentage is based on total number of treated subjects with baseline and at least 1 post baseline tumor assessments Percent Change From Baseline in the Sum of Longest Diameters for Target Lesions Osteosarcoma, ZN-c3-003 Data cut-off: January 9, 2024 Avutu et al, Phase 1 Results of the WEE1 Inhi
Slide 37: Event-Free Survival Among Patients Receiving Azenosertib + Gemcitabine
37 Event-Free Survival Among Patients Receiving Azenosertib + Gemcitabine Osteosarcoma, ZN-c3-003 Data cut-off: January 9, 2024 Avutu et al, Phase 1 Results of the WEE1 Inhibitor, Azenosertib, in Combination With Gemcitabine in Adult and Pediatric Patients With Relapsed or Refractory Osteosarcoma. A
Slide 38: Adverse Events in Osteosarcoma Study
38 Adverse Event All Cohorts All Grades [n(%)] N=31 All Cohorts Grade > 3 [n(%)] N=31 MTD All Grades [n(%)] n=6 MTD Grade > 3 [n (%)] n=6 Thrombocytopenia (combined) 25 (80.6%) 13 (41.9%) 3 (50%) 2 (33.3%) Anemia (combined) 15 (48.4%) 6 (19.4%) 2 (33.3%) 1 (16.7%) Fatigue 15 (48.4%) 4 (12.9%) 4 (66.
Slide 39: Targeting Tumors with High Genomic Instability Using Azenosertib
Targeting Tumors with High Genomic Instability Using Azenosertib
Slide 40: Multiple Mechanisms Leading to Genomic Instability Enhance Sensitivity to Azenosertib
40 CDK2/Cyclin E S G1 1 Fagundes R, et al. Front Cell Dev Biol. 2021; 2 Stewart MD, Oncologist. 2022; 3 Zhang, J, et al. Genes 2016; Abbreviations: BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; KRAS, Kirsten rat sarcoma viral oncogene homolog Multiple Mechanisms Leading to Genomic Instability
Slide 41: Azenosertib Results in Higher DNA Damage and Tumor Growth Inhibition in Cyclin E1 Positive Tumors
41 1800 1500 12009 00 600 300 0 0 4 8 12 16 20 24 28 • Azenosertib treatment results in 88% Tumor Growth Inhibition (TGI) in xenografted Cyclin E1 positive OVCAR3 tumors Ma, et al. Cancer Res (2023) 83 (7_Supplement): 2153; Abbreviations: PO, orally; QD, daily Azenosertib Results in Higher Levels of
Slide 42: Cyclin E1 Amplification Particularly Prevalent in Gynecologic Malignancies
42 Cyclin E1 Amplification Particularly Prevalent in Gynecologic Malignancies But Occurs in Many Other Tumor Types TCGA Pan Cancer Analysis (6547 samples)1 Frequency of CCNE1 Amplification Across Tumor Types2 0 5 10 15 20 25 Frequency of Amplification (%) Ovarian Serous Bladder Urothelial Stomach Ad
Slide 43: CCNE1 Amplification and Cyclin E1 Outcomes Across Tumor Types
43 1 Shariat SF, et al. Human Path. 2006; 2 Matsushita R, et al. British J Cancer 2015; 3 Lotan Y, et al. Euro Assoc Urology 2013; 4 Stronach E, et al. Mol Cancer Res 2018; 5 Pils D, et al. Euro J Cancer 2014; 6 Petersen S, et al. Gynecol Oncol 2020; 7 Nakayama N, et al. Cancer 2010; 8 Kang E, et al
Slide 44: Ovarian Cancer Patients with CCNE1 Amplified and/or Cyclin E1+ Cancers Have Worse Outcome
441 Stronach, et al. Mol Cancer Res 2018;16:1103-11; 2 Pils, et al. Eur J Cancer 2014;50:99-110; 3 Peterson, et al. Gynecol Oncol 2020;157:405-10; 3 Nakayama, et al. Cancer 2010;116:2621-34; 5 Kang, et al. Cancer 2023;129:697-713; 6 Chan, et al. J Pathol Clin Res 2020;6:252-62; *Timing of tissue col
Slide 45: Progression Free Survival Triples in Patients with Cyclin E1+ Tumors
45H-scores calculated by multiplying the percentage of cells (0 to 100%) with intensity of Cyclin E1 expression (0 to 3); Liu JF., et al. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 5513-5513; Abbreviations: CI, confidence interval; PFS, progression free survival Progression Free S
Slide 46: Cyclin E1 Protein Expression is High in Majority of Ovarian Cancers
46 *H-scores calculated by multiplying the percentage of cells (0 to 100%) with intensity of Cyclin E1 expression (0 to 3). Harismendy, et al. Presented at the AACR Special Conference in Cancer Research: Ovarian Cancer. October 5 - 7, 2023 - Boston, MA; Abbreviations: HGSOC, high-grade serous ovaria
Slide 47: Azenosertib +/- PARP Inhibitor Combinations Active in HRD Tumors
47Zentalis data on file; Abbreviations: PARP, poly-ADP ribose polymperase; HRD, homologous recombination repair deficient; PARPi, PARP inhibitor; CDX, cell line derived xenograft; PDX, patient derived xenograft; TNBC, triple-negative breast cancer Monotherapy Azenosertib +/- PARP Inhibitor Combinati
Slide 48: Preclinical Data Supports Azenosertib with Encorafenib and Cetuximab
48 • Oncogene-induced replication stress in mutationally driven cancers leads to DNA damage and genomic instability1 • Azenosertib further increases replication stress and DNA damage, providing mechanistic basis for synergy with EGFR/BRAF inhibition • Addition of azenosertib to the BEACON regimen is
Slide 49: ZN-c3-016: Phase 1/2 Trial in BRAF mCRC in Collaboration with Pfizer
49Abbreviations: BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; mCRC, metastatic colorectal cancer; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose; ORR, objective response rate; DOR, duration of response; DCR, disease control rate; PFS, prog
Slide 50: Azenosertib with KRASG12C Inhibitor Sotorasib Demonstrates Tumor Regressions in NSCLC Model
50 The Combination of Azenosertib with the KRASG12C Inhibitor Sotorasib Demonstrates Tumor Regressions in a NSCLC Model Source: Zentalis AACR poster 2024, Jameson, et al Abbreviations: TV, tumor volume; SEM, standard error of the mean; TGI, tumor growth inhibition; TV, change in tumor volume; NSCLC
Slide 51: Azenosertib with KRASG12C Inhibitors Drives Regression in CRC and PDAC Models
51 Combination of Azenosertib with KRASG12C Inhibitors Improves Efficacy and Drives Tumor Regression in Colorectal (CRC) and Pancreatic (PDAC) Models Source: Zentalis AACR poster 2024, Jameson, et al KRAS Abbreviations: TV, change in tumor volume
Slide 52: Strong Rationale Supports Ongoing Clinical Development in High Genomic Instability Cancers
52 3 2 1 Abbreviations: IHC, immunohistochemistry; PARP, poly-ADP ribose polymerase; BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; EGFR, epidermal growth factor receptor; HRD, homologous recombination repair deficient Strong Rationale Supports Ongoing Clinical Development of Azenosertib in Ca
Slide 53: BCL-2 Inhibitor (ZN-d5) in Combination with Azenosertib in AML
BCL-2 Inhibitor (ZN-d5) in Combination with Azenosertib Represents Opportunity to Address Acute Myeloid Leukemia Patients with Known Poor Prognosis and High Unmet Need
Slide 54: Relapsed/Refractory AML Remains a Major Unmet Medical Need
1. American Cancer Society. Cancer Facts & Figures 2023, SEER and ECIS. 2 Figures represent company best estimates based on US patients with conditions covered by the companies target indication. Sources DRG Clarivate, Kantar Health 3 Shimony, S, et al. Am J Hematol. 2023; 98(3): 502-526; 4 Maiti A,
Slide 55: ZN-d5 and Azenosertib Combination Enhances Apoptosis and Anti-Tumor Activity in AML Model
55 HL-60 (in vitro)HL-60 (in vitro) Izadi H, et al. AACR 2022 Cancer Res (2022) 82 (12_supplement):2591; Data / Report On File, Zentalis Pharmaceuticals Combination of ZN-d5 and Azenosertib Results in Enhanced Apoptosis, DNA Damage and Synergistic Anti-Tumor Activity in an AML Model - - + - + - + +
Slide 56: Many AML Patients Still Lack Treatment Options After Relapse
56 Adapted from Heuser, Y. et. Al. Annals of Oncology 31 (6) 697-712 2020; Abbreviations: AML, acute myeloid leukemia; SCT, stem cell transplant Despite Recent Progress and Evolving Treatment Paradigm in AML, Many Patients Still Lack Treatment Options After Relapse 1st Relapse Chemo/SCT Ineligible:
Slide 57: ZN-d5-004C: Phase 1/2 Study of ZN-d5 and Azenosertib in R/R AML
57 ZN-d5-004C: Enrolling Phase 1/2 Study of ZN-d5 and Azenosertib in R/R AML Abbreviations: R/R, relapsed/refractory; AML, acute myeloid leukemia; RP2D, recommended Phase 2 dose; PK, pharmacokinetics; ORR, objective response rate; CR, complete response; CRi: complete response with incomplete count r
Slide 58: Executing on the Franchise Potential of Azenosertib
Executing on the Franchise Potential of Azenosertib
Slide 59: Upcoming Clinical Milestones
59 Initial data from Phase 1 azenosertib + BEACON regimen trial in BRAF mutant mCRC with Pfizer (ZN-c3-016) Topline data from niraparib + azenosertib cohorts in Phase 2 trial in post-PARPi PROC (MAMMOTH, ZN-c3-006) Initial data from Phase 1 azenosertib + ZN-d5 trial in R/R AML (ZN-d5-004C) 2H Abbrev
Slide 60: Zentalis is Positioned for Success with Azenosertib Franchise
60 1 Figures represent Company estimates of U.S. and EU5 patients with conditions covered by the Company’s targeted indications; Source: IQVIA, DRG Clarivate Abbreviations: mPFS: median progression free survival; ORR, objective response rate; USC, uterine serous carcinoma; 1L, first line NDA, New Dr
Slide 61: Contact
zentalis.com Kyle Rasbach Chief Business Officer krasbach@zentalis.com (212) 433-3787 Corporate Office 1359 Broadway Suite 801 New York, NY 10018 Science Center 10275 Science Center Drive Suite 200 San Diego, CA 92121 Kimberly Blackwell, M.D. Chief Executive Officer kblackwell@zentalis.com (212) 433
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