Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Presentation (August 2023)
47 slides from Zentalis Pharmaceuticals's investor presentation, Aug 9, 2023
Slide 1: Corporate Presentation August 2023
Corporate Presentation August 2023 Nasdaq: ZNTL Exhibit 99.1
Slide 2: Forward Looking Statement and Disclaimer
2 Forward Looking Statement 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 Securit
Slide 3: Clinical-Stage Oncology Company Focused on Difficult-to-Treat Cancers
3 • Deep oncology experience • Veteran scientific, clinical advisors • Partnerships with Pfizer, GSK • Cash runway into 2026 Positioned to Execute and Deliver We Are a Clinical-Stage Oncology Company Focused on Difficult-to-Treat Cancers • High levels of monotherapy anti-tumor activity • Best-in-cla
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
Azenosertib WEE1 Inhibitor with Potential to Address Large Unmet Need Across Array of Cancers
Slide 6: Three ongoing monotherapy trials could support rapid paths to registration
6 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 intermitte
Slide 7: Azenosertib Targets WEE1, a Critical Protein for Cancer Cell Survival
7 • WEE1 phosphorylates CDK/Cyclin complexes to engage cell cycle checkpoints, allowing DNA repair to occur • Azenosertib inhibits WEE1: • Leads to inactivation of CDK 1 and 2 • Removes 2 cell cycle checkpoints: G1/S and G2/M • Cell cycle progresses without sufficient DNA repair • Cancer cells accum
Slide 8: Tumors with High Genomic Instability are Sensitive to Azenosertib
8 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* *OVCAR3 Cyclin E1 positive cells, 16-hour treatment High genomic instability can be caused by: Cyclin E1+ Tumors • Cyclin E1+ drives accelerated en
Slide 9: Monotherapy Potentially Addresses 88% Of High Grade Serous Ovarian Cancer
9 Potential to Transform Treatment Paradigm for Patients and Capture Significant Market Share in Ovarian Cancer Cyclin E1+ HRP Cyclin E1+ HRD Cyclin E1 low HRD Others 30% 24% 12% 34% High Grade Serous Ovarian Cancer Patient Segments • Ongoing clinical programs address Cyclin E1+ and HRD+ patient pop
Slide 10: Addressable Patient Population More than Doubles as Franchise Expands
10 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 2
Slide 11: Intermittent Monotherapy Dose Substantially Improves Antitumor Activity and Tolerability
Azenosertib Azenosertib Intermittent Monotherapy Dose Substantially Improves Antitumor Activity and Tolerability
Slide 12: 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: Intermittent Dosing Significantly Increases Steady State Exposure
13Patients who received ≥300 mg; Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; AUC, area under the curve Intermittent Dosing Resulted In A Significant Increase In Steady State Exposure With intermittent dosing, more patients reach the projected target efficacious steady s
Slide 14: Intermittent Dosing Doubles Objective Response Rate in Ovarian/USC
14 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 15: 89% of Ovarian and USC Patients Had Target Lesion Reductions
15 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 B e st
Slide 16: Intermittent Dosing Maintains Safety And Tolerability
16 Intermittent Dosing Maintains Safety And Tolerability 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 (6.0) 11 (
Slide 17: Azenosertib: Improved Tolerability Compared To Other Agents
17 Azenosertib: Improved Tolerability Compared To Other Agents 1 4 .8 % 3 3 .3 % 0 .0 % 5 5 .0 % 5 7 .0 % 1 5 .0 % 5 4 .0 % 7 2 .0 % 5 .0 % 2 0 .0 % 3 3 .0 % 9 .0 % Reduction Interruption Discontinuation Azenosertib-Intermittent (ZENTALIS001) Adavosertib (ADAGIO) Adavosertib (EFFORT) Mirvetuximab (S
Slide 18: Monotherapy Paving Path to Registration with Three Ongoing Trials
Azenosertib Monotherapy Paving Path to Registration with Three Ongoing Trials Accruing at New Intermittent Dose
Slide 19: TETON: Azenosertib Monotherapy in Advanced Uterine Serous Carcinoma
19 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 20: DENALI: CCNE1 Amplification and Cyclin E1+ in Platinum-Resistant HGSOC
20 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 21: MAMMOTH: Azenosertib With Niraparib in PARP-Resistant Ovarian Cancer
21Abbreviations: 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 22: Azenosertib Combination with Chemotherapy
Azenosertib Combination with Chemotherapy Strong and Durable Efficacy Signals and Favorable Safety Profile Across Chemotherapy Backbones Enable Advancement into Phase 3 in Ovarian Cancer
Slide 23: Addition of Azenosertib Increases Response Rates and Durability
23 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 24: Zentalis 002: Phase 1b Combination Study To Define RP2D
24 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 25: Encouraging Efficacy and Durability in Chemotherapy Doublets
25 Encouraging Efficacy and Durability in Azenosertib 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 (50.0) 10 (35
Slide 26: Activity of Azenosertib + Paclitaxel is Robust and Competitively Favorable
26 Activity of Azenosertib + Paclitaxel is Robust and Competitively Favorable References: 1. Markman et al. Gynecol Oncol 2006;101:436-40. 2. AURELIA: Avastin USPI 3. MITO11: Pignata et al. Lancet Oncol 2015;16:561-68. 4. OCTOPUS: Banerjee et al. ESMO 2019. 5. GYN49: Moore et al. Clin Cancer Res 202
Slide 27: Azenosertib Combination Benchmarks and References
27 References: 1. Leitao et al. Gynecol Oncol 2003;91:123-9. 2. CARTAXHY: Lortholary et al. Ann Oncol 2012;23:346-52. 3. Pectasides et al. Gynecol Oncol 2010;118:52-7. 4. Brewer et al. Gynecol Oncol 2006;103:446-50. 5. MK- 1775-009: Leijen et al. J Clin Oncol 2016;34:4354-61. 6. GYN-49: Moore et al.
Slide 28: Cyclin E1 Positive Cancers Have a Worse Outcome Following Platinum Chemotherapy
28*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 29: Zentalis 002: Majority of Ovarian Cancers are Cyclin E1+
29 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 30: Durability Triples in Patients with Cyclin E1+ Tumors
30 *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 31: Intermittent Dosing Across Chemotherapy Backbones Has Favorable Safety Profile
31 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. Intermittent
Slide 32: Data Supports Advancement into Platinum-Sensitive Ovarian Cancer
32 *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 33: Advancing Post-PARPi and Post-BEACON BRAF mCRC Programs
Azenosertib Advancing Programs Investigating Post-PARPi Treatment and Post-BEACON BRAF mCRC, Supported by Strong Body of Preclinical Data
Slide 34: Azenosertib +/- PARP Inhibitor Active in Ovarian CDX and TNBC PDX Models
34 1. 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 35: Preclinical Data Supports Combination with Encorafenib and Cetuximab
35 Source: 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
Slide 36: BRAF mCRC Study in Collaboration with Pfizer
36 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 37: ZN-d5 BCL-2 Inhibitor with Potential Best-in-Class Profile
ZN-d5 BCL-2 Inhibitor with Potential Best-in-Class Profile
Slide 38: BCL-2: A Clinically Validated Oncology Target
38 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 39: ZN-d5: Potent BCL-2 Inhibitor with Improved Selectivity
39 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 40: ZN-d5 in AL (Primary) Amyloidosis
40 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 41: BCL-2 Inhibition Shown Robust Clinical Activity in AL Amyloidosis
41 BCL-2 Inhibition has Shown Robust Clinical Activity in AL Amyloidosis Best Response in Evaluable Patients 5% 20% 26% 40% 19% 5% 10% 4% 29% 10% 37% 34% 20% 41% ALL PATIENTS (N=38) N ON-T(11;14) PATIENTS (N=10) T(11;14) PATIENTS (N =2 7 ) PROGRESSION SD/NR PR VGPR CR 30% VGPR/CR 63% GPR/CR 78% VGPR
Slide 42: ZN-d5-003: Phase 1/2 Trial in R/R AL Amyloidosis
42 ZN-d5-003: Phase 1 Multicenter International Clinical Trial in R/R AL Amyloidosis Part A: Safety Recommended Phase 2 Dose Key Eligibility: AL amyloidosis ; R/R to 1-3 prior lines of therapy; dFLC ≥20 mg/L; ECOG PS ≤2; Adequate hematologic and organ function Part A: Bayesian Optimal Interval Dose
Slide 43: BCL-xL Protein Degrader Discovery Program
BCL-xL Protein Degrader Compelling Discovery Program
Slide 44: BCL-xL Degrader Background and Rationale
44 BCL-xL Degrader Background and Rationale Declared development candidate and initial IND enabling activities 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
Slide 45: BCL-xL Degrader More Efficacious than Navitoclax in MOLT4 Model
45 BCL-xL Degrader is More Efficacious than BCL-xL Inhibitor (Navitoclax) in MOLT4 (T-ALL) Model MOLT4 tumor model (T-ALL) • 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 Navitocl
Slide 46: 2023 is a Catalyst Rich Year – Key Milestones
46 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 47: 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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