Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Presentation (September 2023)
43 slides from Zentalis Pharmaceuticals's investor presentation, Sep 13, 2023
Slide 1: Corporate Presentation September 2023
Corporate Presentation September 2023 Nasdaq: ZNTL
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: Positioned to Execute and Deliver
3 • Deep oncology experience • Veteran scientific, clinical advisors • Partnerships with Pfizer, GSK • Cash runway into 2026 Positioned to Execute and Deliver Transforming the Treatment Paradigm in Gynecologic Cancers and Beyond • Compelling clinical monotherapy activity • Synergistic anti-tumor act
Slide 4: Pipeline Addresses Difficult to Treat Cancers with Large Commercial Opportunities
4 Pipeline Addresses Difficult to Treat Cancers with Large Commercial Opportunities COMPOUND INDICATION + DEVELOPMENT APPROACH PRECLINICAL Phase 1 Phase 1b Phase 2 Phase 3 STATUS / EXPECTED MILESTONES Azenosertib WEE1 Inhibitor Platinum Sensitive Ovarian Cancer + Paclitaxel or Carboplatin Initiate Q
Slide 5: Azenosertib WEE1 Inhibitor with Potential to Address Large Unmet Need Across Array of Cancers
Azenosertib WEE1 Inhibitor with Potential to Address Large Unmet Need Across Array of Cancers
Slide 6: Azenosertib Targets WEE1, a Critical Protein for Cancer Cell Survival
6 • WEE1 phosphorylates CDK/Cyclin complexes to engage cell cycle checkpoints, allowing DNA repair to occur • Azenosertib inhibits WEE1: • Inactivates CDK1 and 2 • WEE1 has important roles during S-phase and at G2/M checkpoint • Cell cycle progresses without sufficient DNA repair leading to mitotic
Slide 7: Tumors with High Genomic Instability are Sensitive to Azenosertib
7 Tumors with High Genomic Instability are Sensitive to Azenosertib *OVCAR3 Cyclin E1 positive cells, 16-hour treatment Cyclin E1 0 0.1 0.3 1 µM Azenosertib p-CHK1 Cleaved Caspase-3 γH2AX p-H3 Azenosertib induces markers of DNA damage, replicative stress, and apoptosis* High genomic instability can
Slide 8: Azenosertib Monotherapy Potentially Addresses 88% Of High Grade Serous Ovarian Cancer
8 Potential to Transform Treatment Paradigm for Patients and Capture Significant Market Share in Ovarian Cancer Cyclin E1+ HRP Cyclin E1+ HRD Cyclin E1 low HRDOthers 30% 24% 12% 34% High Grade Serous Ovarian Cancer Patient Segments • Ongoing clinical programs will evaluate Cyclin E1+ and HRD+ as pat
Slide 9: Addressable Patient Population More than Doubles as Franchise Expands
9 Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC 2L+ USC 2L+ USC 2L+ USC 2L+ USC 2L
Slide 10: Azenosertib Clinical Data Shows Efficacy as Monotherapy in Gynecologic Malignancies
Azenosertib Clinical Data Shows Efficacy as Monotherapy in Gynecologic Malignancies with Favorable Safety and Tolerability Profile
Slide 11: Azenosertib Monotherapy Activity Supports Advancement into Multiple Difficult-to-Treat Tumor Types
11 Three ongoing Phase 2 monotherapy trials have the potential to support rapid paths to registration in ovarian cancer and USC Monotherapy RP2D established: 400 mg 5:2 Doubled steady state drug exposure compared to continuous dosing 37% Objective Response Rate with durable responses using intermitt
Slide 12: Zentalis Study Enabled Rapid and Efficient Approach to Dose Optimization
12 Zentalis 001 Study Enabled Rapid and Efficient Approach to Dose Optimization Primary objectives: Safety, PK (Steady State Exposure (AUC0-24) & Concentration Maximum (Cmax)) Phase 1b expansion Intermittent Dosing Dose finding (CRM) Total daily dose, 5:2 or 4:3 schedule Phase 1a Dose Escalation Pha
Slide 13: Azenosertib Intermittent Dosing Schedule Doubles Objective Response Rate
13 Azenosertib Intermittent Dosing Schedule Doubles Objective Response Rate In Ovarian/USC Populations Data cut-off: June 2, 2023 *Response evaluable: have baseline measurable disease by RECIST 1.1, at least one post baseline scan, and received at least one dose of drug Patients who received ≥300 mg
Slide 14: 89% of Ovarian and USC Patients Had Target Lesion Reductions
14 Azenosertib Monotherapy Intermittent Dosing: 89% of Ovarian and USC Patients Had Target Lesion Reductions from their Baseline Scans + + ++ + ++ + + + + + Baseline Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 PD PR -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 Be st P
Slide 15: Azenosertib Monotherapy Demonstrates Favorable Safety Profile
15 Azenosertib Monotherapy Demonstrates Favorable Safety Profile Continuous (n=67) Intermittent (n=27) Total* (n=94) Treatment Related AEs, N (%) All Grade Grade 3/4 All Grade Grade 3/4 All Grade Grade 3/4 Gastrointestinal Nausea 46 (68.7) 2 (3.0) 9 (33.3) - 55 (58.5) 2 (2.1) Diarrhea 31 (46.3) 4 (6
Slide 16: Intermittent Schedules Reduce Dose Modifications And Serious Adverse Events
16 *Safety Evaluable Population: Received at least one dose of drug; Continuous 300, 350, 400; Intermittent 350 5:2 and 400 5:2 Abbreviations: SAEs, serious adverse events Azenosertib At Intermittent Schedules Reduces Dose Modifications And Serious Adverse Events Continuous N = 67 Intermittent N = 2
Slide 17: Azenosertib Monotherapy Multiple Ongoing Studies Generating Potentially Registrational Data
Azenosertib Monotherapy Multiple Ongoing Studies Generating Potentially Registrational Data
Slide 18: TETON: Azenosertib Monotherapy in Advanced Uterine Serous Carcinoma
18 Zentalis 004 (TETON): Azenosertib Monotherapy In Women With ≥2L Advanced Uterine Serous Carcinoma Endpoints NCT04814108 Patients (N=130) Azenosertib 400 mg QD 5:2 Key Eligibility: Recurrent or persistent USC; ≥1 prior platinum-based chemotherapy regimen; Prior HER-2 directed therapy for known HER
Slide 19: DENALI: CCNE1 Amplification and Cyclin E1+ in Platinum-Resistant HGSOC
19 Zentalis 005 (DENALI): Evaluating Impact of CCNE1 Amplification and Cyclin E1+ in Platinum-Resistant High-Grade Serous Ovarian Cancer Endpoints (ICR) Cohort 2B (N=80) CCNE1 Non-Amplified & Cyclin E1+ Cohort 2C (N=40) CCNE1 Non-Amplified & Cyclin E1- Cohort 2A (N=60) CCNE1 Amplified NCT05128825 Co
Slide 20: MAMMOTH: Azenosertib With or Alternating With Niraparib in PARP-Resistant Ovarian Cancer
20Abbreviations: PARPi, poly-ADP ribose polymerase inhibitor; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; PFS, progression free survival; ORR, objective response rate Zentalis 006 (MAMMOTH): Revised Phase 1/2 Study Of Azenosertib In Combination With Niraparib Or Altern
Slide 21: Azenosertib Combination with Chemotherapy Clinical Data
Azenosertib Combination with Chemotherapy Clinical Data Shows Strong Efficacy and Favorable Safety Profile Across Several Chemotherapy Backbones Enable Advancement into Phase 3 in Ovarian Cancer
Slide 22: Addition of Azenosertib to Chemotherapies Increases Response Rates and Durability
22 Addition of Azenosertib to Chemotherapies Increases Response Rates and Durability of Response in Ovarian Cancer Compared to Chemotherapy Alone Cyclin E1+ status associated with superior Objective Response Rate and longer Progression Free Survival across response-evaluable patient population Regis
Slide 23: Zentalis 002: Phase 1b Combination Study To Define RP2D Dosing
23 Zentalis 002: Phase 1b Combination Study To Define RP2D Dosing Azenosertib + Paclitaxel 200 mg QD 5:2 2 dose levels 300 mg QD 5:2 Azenosertib + Gemcitabine Azenosertib + PLD 200 mg QD 3 dose levels Cohort assignment by availability and investigator preference Paclitaxel: 80 mg/m2 on D1, D8, D15 (
Slide 24: Encouraging Efficacy and Durability in Azenosertib + Full Dose Chemotherapy Doublets
24 Encouraging Efficacy and Durability in Azenosertib + Full Dose Chemotherapy Doublets Endpoint Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib + Gemcitabine (N=18) Azenosertib + PLD (N=35) Total (N=115) Response-Evaluable* (N) 22 28 13 31 94 ORR (confirmed), N (%) 11 (
Slide 25: Azenosertib Combo Safety Profile Across Chemotherapy Backbones
25 Abbreviations: C, Continuous azenosertib dosing; I, Intermittent azenosertib dosing; MTD, maximum tolerated dose; PLD, pegylated liposomal doxorubicin *All doses were at or below the MTD **A MTD for Gemcitabine + Azenosertib has not been determined, further dose cohorts are ongoing. Azenosertib C
Slide 26: Cyclin E1 is a Hallmark of Certain Cancers and Associated with Poor Outcomes
26 Cyclin E1 is a Hallmark of Certain Cancers and Associated with Poor Outcomes Zentalis evaluating CCNE1 amplification and / or Cyclin E1 over-expression as a potential marker for the enrichment of patient populations for treatment with azenosertib Cyclin E1 is encoded by the CCNE1 gene and forms a
Slide 27: CCNE1 Amplified and/or Cyclin E1 Positive Cancers Have a Worse Outcome
27*Timing of tissue collection was not disclosed. Abbreviations: PFS: progression free survival, OS; overall survival Ovarian Cancer Patients with CCNE1 Amplified and/or Cyclin E1 Positive Cancers have a Worse Outcome Following Platinum-Based Chemotherapy Treatment Independent of Platinum-Sensitivit
Slide 28: Zentalis 002: Majority of Ovarian Cancers are Cyclin E1+
28 Zentalis 002: Majority of Ovarian Cancers are Cyclin E1+ IHC H-Score* >150 ≤ 150 to > 50 ≤ 50 CCNE1 Amplified 5 0 0 CCNE1 Not Amplified 25 15 6 Tissue Not Evaluated for Amplification 16 21 6 • H-score > 50 includes all CCNE1 amplified tumors • Prevalence of Cyclin E1-IHC+, H-score > 50 of all saf
Slide 29: Durability Triples in Patients with Cyclin E1+ Tumors
29 *Response evaluable patients (having received at least one scan) Abbreviations: IHC, immunohistochemistry ; CI, confidence interval Liu, J., et al. “Correlation of Cyclin E1 expression and clinical outcomes in a Phase 1b dose-escalation study of Azenosertib (ZN-c3), a WEE1 inhibitor, in combinati
Slide 30: Data Supports Advancement into Platinum-Sensitive Ovarian Cancer & Earlier Line Therapy
30 *Gemcitabine + Azenosertib has exciting and durable activity-a MTD has not been determined, further dose cohorts are ongoing. Abbreviations: RP2D, recommended phase 2 dose; PLD pegylated liposomal doxorubicin; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; D, day; AUC,
Slide 31: Azenosertib Programs Investigating Post-PARPi Treatment and Post-BEACON BRAF mCRC
Azenosertib Advancing Programs Investigating Post-PARPi Treatment and Post-BEACON BRAF mCRC, Supported by Strong Body of Preclinical Data
Slide 32: Azenosertib +/- PARP Inhibitor Combinations Active in Ovarian CDX and TNBC PDX Models
321. Chen X Cancers (Basel). 2021 Apr 1;13(7). Abbreviations: PARP, poly (ADP-ribose) polymerase; CDX, cell line derived xenograft; TNBC, triple-negative breast cancer; PDX, patient derived xenograft; TGI, tumor growth inhibition Monotherapy Azenosertib +/- PARP Inhibitor Combinations are Active in
Slide 33: Preclinical Data Supports Azenosertib with Encorafenib and Cetuximab
33Source: Zentalis Data on File Preclinical Data Supports the Combination of Azenosertib 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 a
Slide 34: BRAF mCRC Study in Collaboration with Pfizer
34 BRAF mCRC Study in Collaboration with Pfizer Key Eligibility: 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 regime
Slide 35: ZN-d5 BCL-2 Inhibitor with Potential Best-in-Class Profile
ZN-d5 BCL-2 Inhibitor with Potential Best-in-Class Profile
Slide 36: BCL-2: A Clinically Validated Oncology Target
36 BCL-2: A Clinically Validated Oncology Target • BCL-2 is an anti-apoptotic protein involved in tumor survival and resistance to chemotherapy 1 • The intrinsic apoptotic pathway is controlled by the BCL-2 protein family on outer mitochondrial membrane2, 3 • BCL-2 inhibitors may restore the normal
Slide 37: ZN-d5: A Potent BCL-2 Inhibitor Designed with Improved Selectivity
37 ZN-d5: A Potent BCL-2 Inhibitor Designed with Improved Selectivity for BCL-2 ZN-d5 has 10x 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
Slide 38: ZN-d5 in AL (Primary) Amyloidosis
38 ZN-d5 in AL (Primary) Amyloidosis • 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 worl
Slide 39: Acute Myeloid Leukemia (AML) is an Aggressive Heme Malignancy
39 • AML is an aggressive malignancy of myeloid precursor cells with suppression of normal hematopoiesis & resulting in pancytopenia • Incidence/mortality in US is approximately 20k/10k per year; 30% 5-year survival1 • Venetoclax + low-dose Ara-C or HMAs is approved for newly diagnosed AML in patien
Slide 40: ZN-d5 + Azenosertib Combination Results in Decreased Levels of DDR Proteins
40 ZN-d5 + Azenosertib Combination Treatment Also Results in Decreased Levels of DDR Proteins ZN-d5 at subtherapeutic doses activates caspases leading to: • DNA damage (increased in γH2AX) • Degradation or decrease of DDR related proteins (Wee1 and RRM2) • These effects are increased when combined w
Slide 41: Combination of ZN-d5 and Azenosertib Results in Synergistic Anti-Tumor Activity in AML
41 Combination of ZN-d5 and Azenosertib Results in Synergistic Anti-Tumor Activity in AML 1. Izadi H et al. AACR 2022 Cancer Res (2022) 82 (12_supplement):2591; Data / Report On File, Zentalis Pharmaceuticals • Significant enhancement of activity vs. use of either agent alone in several indications,
Slide 42: 2023 is a Catalyst Rich Year – Key Milestones
42 2023 is a Catalyst Rich Year – Key Milestones Azenosertib WEE1 Inhibitor ZN-d5 BCL-2 Inhibitor Discovery 1Q 2023 Initiate enrollment in the BRAF mutant colorectal cancer BEACON regimen combination clinical trial in collaboration with Pfizer 1H 2023 Provide preclinical rationale for Cyclin E1 enri
Slide 43: Contact
zentalis.com 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 801 New York, NY 10018 Science Center 10275 Science Center Drive Suite 200 San Diego,
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