Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Corporate Update (June 2023)
53 slides from Zentalis Pharmaceuticals's corporate update, Jun 6, 2023
Slide 1: Azenosertib Clinical Update
Azenosertib Clinical Update Dose Selection, Monotherapy and Chemotherapy Combinations Efficacy and Safety and Ongoing Development June 2023 Nasdaq: ZNTL
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: Today's Agenda
3 Today’s Agenda 1 Review of Azenosertib Monotherapy Trial Results: Declaration of New Azenosertib Monotherapy Dose 2 Currently Accruing Trials in Ovarian Cancer and USC Review of Azenosertib + Chemotherapy in Platinum-Resistant Ovarian Cancer (Presented Yesterday: ASCO Abstract 5513)3 Proposed Phas
Slide 4: Joining the Call Today
Joining the Call Today 4 Kimberly Blackwell, MD Chief Executive Officer Zentalis Pharmaceuticals Carrie Brownstein, MD Chief Medical Officer Zentalis Pharmaceuticals Funda Meric-Bernstam, MD Chair of the Department of Investigational Cancer Therapeutics -- the Phase 1 Program at The University of Te
Slide 5: Zentalis' Clinical Transformation Has Yielded Significant Progress
5 Zentalis’ Clinical Transformation Has Yielded Significant Progress • To develop first in class and best in class therapies against known cancer targets Purpose Positioned to Execute and Deliver • Management team with deep oncology experience • Respected scientific and clinical advisors • Establish
Slide 6: Today's Call: Four Critical Take Home Messages Around Azenosertib
6 Today’s Call - Two Large Phase 1 Data Sets: Four Critical Take Home Messages Around Azenosertib Combination With Single Agent Chemotherapy Improves Response Rates And Durability Over Chemotherapy Alone In Platinum-resistant/Refractory Ovarian Cancer: • 50% ORR, 5.6 month DOR and a 7.4 month mPFS w
Slide 7: Azenosertib New Intermittent Monotherapy Dose
AZENOSERTIB NEW INTERMITTENT MONOTHERAPY DOSE
Slide 8: Azenosertib Intermittent Monotherapy Dose Substantially Improves Antitumor Activity and Tolerability
8 Azenosertib Intermittent Monotherapy Dose Substantially Improves Antitumor Activity and Tolerability Compared to prior dosing regimen (300 mg continuous), intermittent dosing led to: • More than a doubling of exposures • A near doubling of response in both USC and HGSOC • Confirmed ORR of 36.8% in
Slide 9: Azenosertib Targets WEE1, a Critical Protein for Cancer Cell Survival
9 • WEE1 phosphorylates CDK/Cyclin complexes to engage cell cycle checkpoints, allowing DNA repair to occur • Azenosertib inhibits WEE1: • Leads to dephosphorylation of CDK 1 and 2, activating the cdk/cyclin complexes • Removes 2 cell cycle checkpoints: G1/S and G2/M • Cell cycle progresses without
Slide 10: Finding The Optimal Dose of Azenosertib
10 Increased exposures at steady state Maintained or improved tolerability Finding The Optimal Dose of Azenosertib A m o u n t o f D ru g in B lo o d 300 mg continuous dose demonstrated favorable safety profile and antitumor activity, but preclinical models and clinical data suggested that intermitt
Slide 11: Zentalis Study: From First In Human to Dose Optimization
11 Zentalis 001 Study: From First In Human 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 Phase 1b Expansion
Slide 12: Zentalis 001: Heavily Pretreated Patients With Advanced Solid Tumors
12 Zentalis 001: Heavily Pretreated Patients With Advanced Solid Tumors Continuous N = 74 Intermittent N = 53 Total N = 127 Age Median 67 64 65 Range (Min-Max) (41 - 81) (35 - 83) (35 – 83) Measurable Disease (N, %) 70 (94.6) 53 (100) 123 (96.9) ECOG PS (N, %) ECOG 0 20 (27.0) 18 (34.0) 38 (29.9) EC
Slide 13: Zentalis 001: Multiple Tumor Types, No Biomarker Stratification
13 Zentalis 001: Multiple Tumor Types, No Biomarker Stratification N=127 • Clear Cell RCC • NSCLC • Gastric Cancer • Head and Neck SCC • Anal SCC • Melanoma • SCLC • Uterine stromal sarcoma • Small cell ovarian • Carcinosarcoma • Adenoid cystic carcinoma • Appendiceal (includes N ≤ 2) No biomarker,
Slide 14: Intermittent Dosing Resulted In A Significant Increase In Steady State Exposure
14 Patients who received ≥300 mg; Collected at Day 12 after 3 consecutive days of dosing 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 (AUC0-24 ) With intermittent do
Slide 15: Intermittent Dosing Achieves Higher Maximal Concentration (Cmax) Levels
15Data cut-off: April 24, 2023 Patients who received ≥300 mg; Collected at Day 12 after 3 consecutive days of dosing Intermittent Dosing Achieves Higher Maximal Concentration (Cmax) Levels
Slide 16: Azenosertib Monotherapy Efficacy in Ovarian and Uterine Serous Carcinoma
AZENOSERTIB MONOTHERAPY EFFICACY IN OVARIAN AND UTERINE SEROUS CARCINOMA
Slide 17: Zentalis 001: Patients With Uterine Serous Carcinoma And Ovarian Cancer
17 Zentalis 001: Patients With Uterine Serous Carcinoma And Ovarian Cancer After Multiple Prior Therapies 51 Patients Enrolled with Uterine Serous Carcinoma or High-Grade Serous Ovarian Cancer • Continuous and Intermittent dosing schedules • Heavily Pretreated Group of Patients: USC N = 26 HGSOC N =
Slide 18: Intermittent Dosing Schedule Doubles Objective Response Rate In Ovarian/USC
18 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 o ne dose of drug Patients who received ≥300 m
Slide 19: 89% of Ovarian and USC Patients Had Target Lesion Reductions
19 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 20: Patient Profile: Durable cPR In Cyclin E Amplified Platinum Resistant Ovarian Cancer
20 Abbreviations: cPR, confirmed partial response; HGSOC, high-grade serous ovarian cancer; SD, stable disease; PD, progressive disease; PR, partial response. Azenosertib Patient Profile: Durable cPR In Cyclin E Amplified Platinum Resistant Ovarian Cancer Screening Timepoint 2 Prior lines of therapy
Slide 21: Patient Profile: Durable cPR In HRD+ PARPi Platinum Resistant Ovarian Cancer
21 Azenosertib Patient Profile: Durable cPR In HRD+ PARPi Platinum Resistant Ovarian Cancer Screening Screening Timepoint 2 Target Lesion No Longer Visualized Prior lines of therapy 1. Carbo/taxol/abraxane/bev/Olaparib (PD) 2. Pembrolizumab (PD) 3. NaPi2b targeting-ADC (XMT-1536) (PD) 4. Carbo/gem/b
Slide 22: Azenosertib Monotherapy Safety in Patients From Zentalis
AZENOSERTIB MONOTHERAPY SAFETY IN PATIENTS FROM ZENTALIS 001
Slide 23: Intermittent Dosing Maintains Safety And Improves Tolerability Over Continuous Dosing
23 Intermittent Dosing Maintains Safety And Improves Tolerability Over Continuous Dosing 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)
Slide 24: Intermittent Schedules Reduce Dose Modifications And Serious Adverse Events
24 *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 25: Azenosertib: Tolerability Compared To Adavosertib and Mirvetuximab
25 Azenosertib: Tolerability* Compared To Adavosertib and Mirvetuximab 14 .8 % 33 .3 % 0. 0% 55 .0 % 57 .0 % 15 .0 % 5 4 .0 % 72 .0 % 5. 0% 2 0 .0 % 3 3 .0 % 9. 0 % Reduction Interruption Discontinuation Azenosertib-Intermittent (ZENTALIS001) Adavosertib (ADAGIO) Adavosertib (EFFORT) Mirvetuximab (S
Slide 26: Azenosertib Monotherapy Ongoing Studies in USC and Ovarian Cancer
AZENOSERTIB MONOTHERAPY ONGOING STUDIES IN USC AND OVARIAN CANCER
Slide 27: Monotherapy Dose and Biomarker Enrichment Is Foundational To Our Clinical Strategy
27 Monotherapy Dose and Biomarker Enrichment Is Foundational To Our Clinical Strategy 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 genomi
Slide 28: Zentalis (TETON): Azenosertib Monotherapy in Advanced Uterine Serous Carcinoma
28 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 29: Zentalis (DENALI): CCNE1 Amplification and Cyclin E1+ in Ovarian Cancer
29 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 30: Zentalis 006 (MAMMOTH): Azenosertib With Niraparib in PARP-resistant Ovarian Cancer
30 Abbreviations: 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 Alter
Slide 31: Azenosertib is Highly Active Agent in Ovarian Cancer and USC
31 • Recommended Phase 2 dose of 400 mg at 5:2 schedule selected based on clinical safety and efficacy • Update on monotherapy efficacy data, and clinical trial timelines in 2H23 36.8% Confirmed Response Rate in Ovarian and Uterine Serous Carcinomas with intermittent dosing* Majority of patients rem
Slide 32: Azenosertib Chemotherapy Combinations
AZENOSERTIB CHEMOTHERAPY COMBINATIONS
Slide 33: Cyclin E1 Expression and Outcomes in Phase 1b Azenosertib Chemotherapy Study
33 Correlation of Cyclin E1 expression and clinical outcomes in a Phase 1b dose-escalation study of Azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum- resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EO
Slide 34: Main Takeaways: Strong and Durable Efficacy Across Chemotherapy Backbones
34 *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 35: Phase 1b Combination Study to Define RP2D Dosing
35 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 (28-day cycles)
Slide 36: Patient Characteristics
36 *Safety Evaluable Population: Received at least one dose of drug. Abbreviations: PLD, pegylated liposomal doxorubicin; NR, not reported; ECOG, Eastern Cooperative Oncology Group Patient Characteristics* Characteristic Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib +
Slide 37: High Response of Azenosertib Doublets
37 High Response of Azenosertib 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 (35.7) 5 (38.5) 6 (19.4) 32 (34.0) Med
Slide 38: Kaplan-Meier Curves of Progression-Free Survival: Durable Responses
38 Abbreviations: PLD, pegylated liposomal doxorubicin; PFS, progression free survival; m, months. Kaplan-Meier Curves of Progression-Free Survival: Durable Responses 0 0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25 P ro gr es si o n -F re e Su rv iv al P ro b ab ili ty Median PFS (months) Azenosertib combin
Slide 39: The Activity of Azenosertib + Paclitaxel is Robust and Durable
39 21 30 25 29 29 32 42 50 0 10 20 30 40 50 O R R ( % ) The Activity of Azenosertib + Paclitaxel is Robust and Durable Compared to Historical Reports of Single Agent Paclitaxel, Adavosertib + Paclitaxel and Mirvetuximab in Platinum-Resistant Ovarian Cancer 3.9 3.5 4.1 5.5 5.5 5.6 7.4 0 2 4 6 8 Pacli
Slide 40: The Activity of Azenosertib + Carboplatin is Robust and Durable
40 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 41: Patients With Cyclin E1+ Tumors Consistently Have Worse Outcomes On Chemotherapy
41 Abbreviations: RFS, recurrence free survival, CSS; cancer specific survival, OS; overall survival; PFS, Progression free survival; DMFS; distant metastasis free survival, Patients With Cyclin E1+ Tumors Consistently Have Worse Outcomes On Chemotherapy Hazard Ratio Worse outcome Chappuis PO (2005)
Slide 42: CCNE1 Amplified and/or Cyclin E1+ Cancers Have a Worse Outcome Following Platinum Chemotherapy
42 *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 + Cancers have a Worse Outcome Following Platinum-Based Chemotherapy Treatment Independent of Platinum- Sensitivity Sta
Slide 43: Zentalis 002: Majority of Ovarian Cancers are Cyclin E1+
43 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 sa
Slide 44: Progression Free Survival Significantly Improved in Cyclin E1+ Cohort
44 Progression Free Survival is Significantly Improved in Cyclin E1+, Cohort compared to Cyclin E1- Independent of Chemotherapy Backbone *Response evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one pos t-baseline assessment. Abbreviations
Slide 45: Treatment-related Adverse Events: All Doses Moving Forward Involve Intermittent Dosing
45 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. *** Safety ev
Slide 46: Proposed Randomized Phase 3 Trial Design of Azenosertib + Chemotherapy
46 Proposed Randomized Phase 3 Trial Design of Azenosertib + Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer that is Cyclin E1+ Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG performance status 0-1; ≥1L Prior Line of Platinum-based chemotherapy; Platinum-Sensitive (Platinum-free
Slide 47: Conclusions: Data Supports Advancement of Azenosertib-Chemotherapy Combination
47 *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 48: Potential to Transform Treatment Paradigm and Capture Market Share in Ovarian Cancer
48 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 po
Slide 49: Addressable Patient Population More than Doubles as Franchise Expands
49 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 50: Today's Conclusions: Great Progress in Advancing Azenosertib's Potential
50 Today’s Conclusions: Great Progress in Advancing Azenosertib’s Potential to Transform Cancer Care Solid efficacy with multiple chemotherapy combinations • Significant improvements in ORR and mPFS over chemotherapy alone or chemotherapy + adavosertib • Opportunity to use Cyclin E+ as biomarker to
Slide 51: Our Thanks And Deepest Appreciation To All Patients, Caregivers, Families, And Investigators
51 Our Thanks And Deepest Appreciation To All Patients, Caregivers, Families, And Investigators KBC Bežanijska kosa A hospital you can trust.
Slide 52: Question & Answer Session
Question & Answer Session 52 Kimberly Blackwell, MD Chief Executive Officer Zentalis Pharmaceuticals Carrie Brownstein, MD Chief Medical Officer Zentalis Pharmaceuticals Funda Meric-Bernstam, MD Chair of the Department of Investigational Cancer Therapeutics -- the Phase 1 Program at The University o
Slide 53: Backup: Data Breakdown for ASCO Disclosures
Backup: Data Breakdown for ASCO Disclosures N, ORR (%) Azenosertib + Paclitaxel Azenosertib + Carboplatin Azenosertib + Gemcitabine Azenosertib + PLD Total Efficacy Evaluable in Abstract* 9/18 (50.0) 9/27 (33.3) 2/14 (14.3) 5/35 (14.3) 25/94 (26.6) Efficacy Evaluable ASCO Poster Data Cut** 11/26 (42
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