Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Corporate Update (January 2025)
45 slides from Zentalis Pharmaceuticals's corporate update, Jan 29, 2025
Slide 1: Corporate Event January 29, 2025
Corporate Event January 29, 2025 Nasdaq: ZNTL Exhibit 99.2
Slide 2: Forward-looking statements
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 st
Slide 3: Agenda for Today
3 Opening Remarks Julie Eastland, Chief Executive Officer Azenosertib/WEE1 Biology and Cyclin E1 Overview Mark Lackner, PhD, Chief Scientific Officer 001 and MAMMOTH Results Ingmar Bruns, MD, Chief Medical Officer DENALI Part 1b Results Dave O’Malley, MD, The Ohio State University Comprehensive Canc
Slide 4: Azenosertib Potential Best-in-Class Therapy for Cyclin E1+ PROC
4 Azenosertib Potential Best-in-Class Therapy for Cyclin E1+ PROC ➢ Recent launch of approved therapy in biomarker selected PROC demonstrates the large commercial opportunity ➢ Cyclin E1+ PROC, ~21,500 patients*, linked to poorer outcomes; no approved, targeted therapies ➢ SOC: mono chemo 4-13% ORR1
Slide 5: Similar Results Seen Across Studies in Cyclin E1+ PROC
5 ORR^ mDOR SAFETY Solid Tumors ZN-c3-001 (Dose Escalation) Monotherapy, ≥300mg total daily dose, intermittent schedules 34.8%* (8/23) 5.2 mos Well tolerated across active doses and tumor types PARPi Resistant Ovarian Cancer MAMMOTH (ZN-c3-006) Monotherapy arm 400mg 5:2 31.3% (5/16) 4.2 mos Well tol
Slide 6: Cyclin E1 Overexpression Sensitizes Cancer Cells to Azenosertib
6 • Cyclin E1 overexpression increases CDK2 activity and accelerates G1-S transition, rendering cells more dependent on the DNA repair at the G2-M checkpoint • Inhibition of WEE1 activates CDKs, accelerates G1-S and G2-M transitions, and increases DNA damage to intolerable levels, resulting in mitot
Slide 7: Cyclin E1+ Tumors Comprise a Significant Portion of the PROC Population
7 * Cyclin E1 IHC+ based on Zentalis proprietary IHC cutoff and Cyclin E1 IHC assay developed from the existing clinical data † Cyclin E1 IHC+% based on literature (~20% CCNE1 amplification) and the unbiased CCNE1 amp & Cyclin E1 overlapping data generated from Zentalis clinical trial samples ‡ Sour
Slide 8: Azenosertib Initial Focus in Cyclin E1+ PROC
8 INDICATION TRIAL NAME + DEVELOPMENT APPROACH Solid Tumors ZN-c3-001 Dose-escalation monotherapy 274 Patients dosed 19 Study sites Fully enrolled PARPi Resistant Ovarian Cancer MAMMOTH (ZN-c3-006) Azenosertib monotherapy and in combination with niraparib 117 Patients dosed 22 Study sites Fully enro
Slide 9: ZN-c3-001 Dose-Escalating Monotherapy Study in Solid Tumors
ZN-c3-001 Dose-Escalating Monotherapy Study in Solid Tumors NCT04158336
Slide 10: First-in-Human Phase Dose and Schedule Optimization in Solid Tumors
10 Total Enrollment First-in-Human Phase 1 Dose and Schedule Optimization in Solid Tumors: Therapeutic Window Established N=274 across all tumor types and dose* N=193 at total daily dose ≥ 300mg; evaluated for safety and anti-tumor activity ZN-c3-001 * Total enrollment (N=274) included cohorts for f
Slide 11: Heavily Pre-Treated Patient Population with Multiple Tumor Types
11 Heavily Pre-Treated Patient Population with Multiple Tumor Types; Patients with PROC had a Median of Five Prior Lines of Therapy PROC N = 69 USC N = 35 Other Solid Tumors* N = 89 Age (years) Median 66 66 64 Range (Min-Max) (48 – 83) (53 – 78) (26 – 81) ECOG PS (n, %) ECOG 0 19 (28%) 8 (23%) 32 (3
Slide 12: Tolerable at Active Dose Levels Across Tumor Types
12 Tolerable at Active Dose Levels Across Tumor Types Treatment Related AEs, n (%) Treatment-Related SAE 19 (9.8%) TRAE leading to dose reduction 76 (39.4%) TRAE leading to dose interruption 78 (40.4%) TRAE leading to discontinuation 10 (5.2%) TRAE leading to death 1 (0.5%) Treatment Related AEs*, n
Slide 13: Clinical Activity Overview
13 Clinical Activity Overview - Total Daily Doses ≥ 300 mg - Continuous and Intermittent (N=193) Azenosertib Demonstrated Encouraging ORR and DOR at ≥300mg total daily dose, intermittent in PROC Tumor Type PROC USC Other Solid Tumors Dose Schedule Intermittent Continuous Intermittent Continuous Inte
Slide 14: Key Takeaways from Azenosertib studied across multiple tumor types
14 Key Takeaways from 001 Azenosertib studied in a large patient population across multiple tumor types Platinum-resistant ovarian cancer (PROC) identified as an indication particularly susceptible to WEE1 inhibition Cyclin E1 identified as predictive biomarker for response to azenosertib Meaningful
Slide 15: MAMMOTH (ZN-c3-006)
MAMMOTH (ZN-c3-006) NCT05198804
Slide 16: MAMMOTH: Two Clinically-active Monotherapy Doses Studied in PARPi-resistant PROC
16 MAMMOTH: Two Clinically-active Monotherapy Doses Studied in Heavily Pre-treated, PARPi-resistant PROC Patient Population Study Design ✓ 1-5 prior lines of therapy ✓ Platinum-resistant, progressed while receiving an approved PARP inhibitor ✓ Mandatory sufficient tissue for biomarker analysis Key E
Slide 17: Heavily Pre-Treated PARPi-resistant PROC Population
17 Heavily Pre-Treated PARPi-resistant PROC Population 300 mg 5:2 (N=25) 400 mg 5:2 (N=36) Age (years) Median 71.0 63.0 Range (Min-Max) 45 – 80 31 - 84 ECOG PS (n, %) ECOG 0 7 (28%) 16 (44%) ECOG 1 18 (72%) 20 (56%) Prior Lines of Treatment (n, %) 1-3 15 (60%) 20 (56%) ≥4 10 (40%) 16 (44%) PARP 25 (
Slide 18: Well-characterized Safety and Tolerability in PROC Monotherapy Cohorts
18 Well-characterized Safety and Tolerability in PROC Monotherapy Cohorts at 300mg QD and 400mg QD (5:2) Doses Neutropenia: Neutropenia, neutrophil count decreased, neutrophil percentage decreased; Thrombocytopenia: platelet count decreased and thrombocytopenia; Anemia: hematocrit decreased, hemoglo
Slide 19: Azenosertib Monotherapy 300mg & 400mg QD (5:2)
19 Azenosertib Monotherapy 300 mg & 400mg QD (5:2) Azenosertib Demonstrated Clinically Meaningful Responses in PARPi-resistant Monotherapy Cohorts Dose and Schedule 300mg 5:2 400mg 5:2 Cyclin E1 IHC Status All Cyclin E1+ All Cyclin E1+ Number of Patients 25 14 36 16 ORR, (%), n (95% CI) 20.0% (5/25)
Slide 20: Key Takeaways from MAMMOTH Monotherapy Cohort
20 Key Takeaways from MAMMOTH Monotherapy Cohort Consistent antitumor activity in PARPi-resistant patients Tolerability and toxicity consistent with 001 study and similar between the assessed doses 400mg QD 5:2 showed numerically higher response rates than 300mg QD 5:2 MAMMOTH Learnings continue to
Slide 21: DENALI Part 1b (ZN-c3-005)
DENALI Part 1b (ZN-c3-005) NCT05198804
Slide 22: David M O'Malley, MD
22 David M O'Malley, MD Director & Professor, Division of Gynecologic Oncology in Obstetrics and Gynecology John G. Boutselis Chair in Gynecologic Oncology The Ohio State University and the James Comprehensive Cancer Center
Slide 23: Platinum Resistant Ovarian Cancer: High Unmet Need Provides Opportunity
23 PARP Inhibitor or Bevacizumab + Olaparib Bevacizumab Combination Chemotherapy Platinum Doublet HRP PFI>6m PFI<6m PFI<6m Carboplatin + Paclitaxel High Unmet Need in Cyclin E1+ PROC Patients (2L+) Approved 2L+ Therapy Chemo Mono ORR 4 – 13%1 Mirvetuximab (FRα+ ~35% of PROC) ORR 32% - 42%2 No approv
Slide 24: Standard of Care Single-Agent Chemotherapy has Low Efficacy in PROC
24 Standard of Care Single-Agent Chemotherapy has Low Efficacy in PROC New Options with Greater Efficacy Needed bev, bevacizumab; FRα, folate receptor alpha; mo, months; ORR, objective response rate; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PROC, platinum-resistant ovari
Slide 25: DENALI Part 1b Evaluated 400mg 5:2 QD and Confirmed Cyclin E1 Biomarker
25 Study Design ✓ Platinum-resistant ovarian cancer ✓ 1-5 prior lines of therapy ✓ Tissue mandatory for biomarker assessment Key Eligibility DENALI Part 1b Evaluated 400mg 5:2 QD and Confirmed Cyclin E1 Biomarker DENALI Abbreviations: QD, once daily; 5:2, 5-days of treatment followed by 2-days off t
Slide 26: DENALI Part 1b Patient Demographics and Clinical Characteristics
26 DENALI Part 1b Evaluated 400mg 5:2 QD and Confirmed Cyclin E1 Biomarker Prior Therapies (n, %) Bevacizumab 93 (91%) PARPi 57 (56%) Cyclin E1 Status (n, %) Positive 48 (47%) Negative 46 (45%) Unknown 8 (8%) Age (years) Median 66 Range (Min-Max) 34 - 82 ECOG PS (n, %) ECOG 0 53 (52%) ECOG 1 49 (48%
Slide 27: Safety and Tolerability Profile Remains Favorable Compared to Standard of Care
27 Consistent with Prior Studies, Safety and Tolerability Profile Remains Favorable Compared to Standard of Care Azenosertib 400mg QD 5:2 (N=102) Treatment Related AEs, N (%) Treatment Related SAE 22 (21.6%) TRAE leading to dose reduction 43 (42.2%) TRAE leading to dose interruption 60 (58.8%) TRAE
Slide 28: Cyclin E1+ Is a Strong Predictive Biomarker for Response
28 Cyclin E1+ Is a Strong Predictive Biomarker for Response to Azenosertib Abbreviations: IHC, immunohistochemistry; ORR, confirmed objective response rate; ITT, intent-to-treat † IHC+ based on proprietary IHC cutoff developed from Zentalis clinical data, non-Cyclin E1 IHC+ includes Cyclin E- (N=46)
Slide 29: ORR ~35% in Response Evaluable Patients with Cyclin E1+ PROC
29 ORR ~35% in Response Evaluable Patients with Cyclin E1+ PROC - ORR in response evaluable* pts - 34.9% (15/43) (95% CI, 21.0-50.9) *Includes patients who received at least one post-treatment scan Abbreviations: CI, confidence interval; cPR, confirmed partial response; ORR, objective response rate;
Slide 30: mDOR ~5.5 months, Still Maturing at Data Cutoff
30 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Treatment Duration (Months) B es t O ve ra ll R es p o n se mDOR ~5.5 months, Still Maturing at Data Cutoff Abbreviations: CI, confidence interval; cPR, confirmed partial response; mDOR, median duration of response; mPFS, median progression-free survival;
Slide 31: Key Takeaways from DENALI
31 Key Takeaways from DENALI DENALI DENALI Part 1b demonstrates azenosertib has the potential to provide greater benefit for patients with Cyclin E1+ PROC over available therapies* Cyclin E1 established as highly selective and predictive biomarker for response to azenosertib Favorable toxicity with
Slide 32: Integrated Data and Path to Registration in PROC
Integrated Data and Path to Registration in PROC
Slide 33: Azenosertib Monotherapy Studies Support the PROC Registration-intent Study
33 Azenosertib Monotherapy Studies Provide Large Amount of Safety Data and Meaningful Antitumor Activity to Support the PROC Registration-intent Study Well characterized safety profile in 356 patients Including PROC patients at 400mg 5:2 (N=165) and 300mg 5:2 (N=38) First-in-human in solid tumors do
Slide 34: Safety and Tolerability at 300mg and 400mg 5:2 Broadly Comparable
34 Safety and Tolerability at 300 and 400 mg 5:2 Broadly Comparable Neutropenia: Neutropenia, neutrophil count decreased, neutrophil percentage decreased; Thrombocytopenia: platelet count decreased and thrombocytopenia; Anemia: hematocrit decreased, hemoglobin decreased, RBC count decreased Abbrevia
Slide 35: 400mg 5:2 Shows Meaningful Response Rates >30% and mDOR >5 mos
35 Abbreviations: CI, confidence interval; cPR, confirmed partial response; mDOR, median duration of response; PD, progressive disease; SD, stable disease; NE, not estimable due to small number of subjects and events. 400mg 5:2 Shows Meaningful Response Rates >30% and mDOR >5 mos 300 mg 5:2 400 mg 5
Slide 36: Azenosertib Has Potential to be the First and Best-in-Class WEE1 Inhibitor
36 Clinically meaningful ORR > 30%, mDOR ~5.5 months Consistent efficacy across multiple monotherapy studies in heavily pre-treated patients Azenosertib Has Potential to be the First and Best-in-Class WEE1 Inhibitor in Cyclin E1+ PROC 1 Well characterized safety profile, favorable to SOC chemo1 Addi
Slide 37: Registration-Intent Studies for Azenosertib Monotherapy in PROC
37 Randomized Study vs. Standard of Care Same Patient Population Initiation Planned Post-Dose Confirmation Detail Design to be Discussed with FDA Abbreviations: 5:2 schedule = 5 days once-daily administration of azenosertib, followed by 2 days without azenosertib; IHC= immunohistochemistry; MIRV, mi
Slide 38: Closing
Closing
Slide 39: Azenosertib Opportunity: Studies and Milestones
39 INDICATION TRIAL NAME + DEVELOPMENT APPROACH PHASE 1 PHASE 2 PHASE 3 MILESTONE* Studies for Lead Indication PROC Monotherapy DENALI Part 1b Updated Data at 1H 2025 Medical Meeting DENALI Part 2a + Part 2b Registration-intent Cyclin E1+ FDA Fast Track Designation Part 2a initiation 1H25 Topline Da
Slide 40: Azenosertib Potential Best-in-Class Therapy for Cyclin E1+ PROC
40 Azenosertib Potential Best-in-Class Therapy for Cyclin E1+ PROC ➢ Recent launch of approved therapy in biomarker selected PROC demonstrates the large commercial opportunity ➢ Cyclin E1+ PROC, ~21,500 patients*, linked to poorer outcomes; no approved, targeted therapies ➢ SOC: mono chemo 4-13% ORR
Slide 41: Q&A
Q&A Julie Eastland Chief Executive Officer, President and Director Ingmar Bruns, MD Chief Medical Officer Mark Lackner, PhD Chief Scientific Officer David M O'Malley, MD Director & Professor, Division of Gynecologic Oncology in Obstetrics and Gynecology Liz Hickin VP, IR
Slide 42: ZN-c3-016 (BRAF+EGFR Combo in BRAF Mutant CRC)
ZN-c3-016 (BRAF+EGFR Combo in BRAF Mutant CRC)
Slide 43: ZN-c3-016: Phase 1/2 Trial in BRAF mCRC in Collaboration with Pfizer
43 ZN-c3-016: Phase 1/2 Trial in BRAF mCRC in Collaboration with Pfizer Data Cutoff Nov 25 2024 Active database; subject to further change Abbreviations: BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; mCRC, metastatic colorectal cancer; EGFR, epidermal growth factor receptor; MTD, maximum tole
Slide 44: Integrated Safety Analysis
Integrated Safety Analysis
Slide 45: Integrated Safety Analysis in All Patients
45 Integrated Safety Analysis in All Patients Total Daily Dose ≥300mg (N=356) Neutropenia: Neutropenia, neutrophil count decreased, neutrophil percentage decreased; Thrombocytopenia: platelet count decreased and thrombocytopenia; Anemia: haematocrit decreased, haemoglobin decreased, RBC count decrea
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