Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Presentation (August 2022)
44 slides from Zentalis Pharmaceuticals's investor presentation, Aug 9, 2022
Slide 1: Corporate Presentation August 2022
C O R P O R AT E P R E S E N TAT I O N A u g u s t 2 0 2 2
Slide 2: Forward-Looking Statements and Disclaimer
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 Securiti
Slide 3: Company Overview
| 3 Lead Program: Wee1i (ZN-c3) potentially first- and best-in-class • Partial responses seen in four tumor types to date • Potential accelerated approval paths for USC and biomarker-driven trials • Fast Track designation granted in USC • Orphan drug and rare pediatric disease designations granted i
Slide 4: Integrated Discovery Engine
Utilizing the Highly Efficient ‘Integrated Discovery Engine’ to Generate Potentially Best-In-Class Drugs | 4 IDENTIFY ANALYZE CREATE GENERATE • CRISPR screens • BH3 profiling • Genomics Image reproduced from: https://blog.f1000.com/2017/02/01/f1000prime-f1000prime-faculty-launch-bioinformatics-biome
Slide 5: Broad Oncology Pipeline Designed to Improve Patient Outcomes
Broad Oncology Pipeline Designed to Improve Patient Outcomes PHASE 1 PHASE 2 COLLABORATORS (1)PHASE 3 (1) Zentalis intends to evaluate ZN-c3 in combination with niraparib (ZEJULA®), as part of a clinical research collaboration with GlaxoSmithKline. Zentalis maintains full ownership of ZN-c5 and ZN-c
Slide 6: ZN-c3 Wee1 Inhibitor
2 zentalis ZN-c3 Wee! Inhibitor
Slide 7: Wee1 Inhibition: Clinically Proven DDR Target for Cancer
Wee1 Inhibition: Clinically Proven DDR Target for Cancer ZN-c3 ATR CHK1 Wee1 PP DNA X Source: Drawing based on Targeting WEE1 Kinase in Cancer. Matheson CJ, et al. Trends Pharmacol Sci. 2016 • Wee1 is a protein kinase expressed at high levels in many cancer types that prevents entry into mitosis in
Slide 8: Structure-Based Drug Design Led to Discovery of ZN-c3
Structure-Based Drug Design (SBDD) Led to the Discovery of a Highly Potent and Selective Wee1 Inhibitor ZN-c3 with Improved ADME Properties(1) | 8 N N N N O N H N OH ZN-c3 N N Asn376 Tyr378 Cys379 Phe310 Ile305 Effective bidentate hydrogen-bond interactions with the hinge element Hydrogen bonding wi
Slide 9: ZN-c3: Differentiated Selectivity Profile
ZN-c3: Differentiated Selectivity Profile | 9 % Inhibition (@ 1µM) 90+ 13 kinases 75-89 24 kinases % Inhibition (@ 1µM) 90+ 5 kinases 75-89 5 kinases (1) Adavosertib data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmac
Slide 10: ZN-c3 Clinical Development Plan
ZN-c3 Clinical Development Plan: Cornerstone of Multiple Treatments in Many Indications • Potentially best-in-class/first-in-class profile; efficacy observed in hematologic and solid tumors • Targeting superior selectivity and tolerability profile supports combination therapies across multiple indic
Slide 11: Platinum-Resistant/Refractory Ovarian Cancer Remains an Unmet Need
Platinum-Resistant/Refractory Ovarian Cancer Remains an Unmet Need UNMET NEED PATIENT POPULATION COMPETITIVE LANDSCAPE ZN-c3: Ovarian ZN-c3’s efficacy and tolerability profile are well-positioned for the platinum-resistant/refractory ovarian population • Platinum-resistant and -refractory ovarian ca
Slide 12: Expectations for Efficacy in Recurrent Ovarian Cancer Patients
Expectations for Efficacy in Recurrent Ovarian Cancer Patients | 12 ZN-c3: Ovarian (1) Pujade-Lauraine E et al. [AURELIA study] J Clin Oncol 2014; 32:1302-1308. (2) Moore KM et al. Clin Cancer Res 2022;28:36–44 (3) Lheureux S et al. Lancet 2021; 397: 281–92 (4) Platinum refractory population of 7% i
Slide 13: ZN-c3-002: Summary of Clinical Activity
ZN-c3-002: Summary of Clinical Activity Summary of Clinical Activity (All Cohorts) ZN-c3: Ovarian Group N Evaluable* (n) PR/uPR+ (n) SD/SD+ (n) PD (n) DCR (%) ORR (%) Total 56 43 13 24 6 86.0 30.2 ZN-c3 + PLD 30 24 3 17 4 83.3 12.5 ZN-c3 + Carboplatin 17 11 5 4 2 81.8 45.5 ZN-c3 + Paclitaxel 9 8 5 3
Slide 14: ZN-c3-002: TEAEs ≥5% for All Patients
ZN-c3-002: TEAEs ≥5% for All Patients (N=56)(1) 48.2 41.1 37.5 26.8 30.4 23.2 16.1 5.4 16.1 1.8 3.6 1.8 10.7 14.3 1.8 3.6 0 3.6 1.8 3.6 7.1 5.4 3.6 0 1.8 1.8 1.8 1.8 0 1.8 3.6 3.6 3.6 3.6 1.8 1.8 0 5.4 32.1 17.9 7.1 7.1 3.6 1.8 7.1 55.4 48.2 41.1 37.5 35.7 35.7 28.6 21.4 19.6 17.9 16.1 14.3 10.7 14.
Slide 15: The Unmet Need in Uterine Serous Carcinoma is Significant
The Unmet Need in Uterine Serous Carcinoma is Significant UNMET NEED PATIENT POPULATION COMPETITIVE LANDSCAPE ZN-c3: USC • USC results in ~40% of endometrial cancer deaths despite comprising only 10% of cases - Prior to pembro+len approval, ORR of 9.5% with PLD was chemo SOC for third-line USC(1) -
Slide 16: ZN-c3-001: Summary of Clinical Activity – Complete Response Seen
ZN-c3-001: Summary of Clinical Activity – Complete Response Seen | 16 ZN-c3: USC Best Overall Response N = 11; n (%) Complete Response (unconfirmed)* 1 (9) Partial Response (confirmed) 2 (18) Stable Disease 7 (63.6) ≥ 12 weeks 4 (36.3) < 12 weeks 3 (27.3) Progressive Disease 1 (9) Overall Response R
Slide 17: ZN-c3 Compares Favorably in Efficacy and Tolerability to Adavosertib
ZN-c3 Compares Favorably in Efficacy and Tolerability to Adavosertib • ZN-c3 demonstrated a higher DCR and on par ORR to adavosertib in a sicker patient population • ZN-c3-001 USC cohort had 57% prior pembrolizumab + lenvatinib use • Oral continuous dosing regimen for ZN-c3 is enabled by its best-in
Slide 18: ZN-c3: Exceptional Responders with Single Agent Treatment
ZN-c3: Exceptional Responders with Single Agent Treatment | 18 Patient Prior lines of therapy Tumor reduction (%) Duration on study CRC, Stage IV 5 51% 169 days Ovarian cancer, Stage IV 19 68% 221 days and remains on study NSCLC, Stage IV 5 50% 154 days Overview of Confirmed Exceptional Responders (
Slide 19: ZN-c3: Displayed Multiple PRs Across Tumor Types
ZN-c3: Displayed Multiple PRs Across Tumor Types | 19 3 subjects with no treatment scans (CRC, USC, Pancreas), and experienced clinical progressive disease (CPD) + denotes treatment ongoing (1) Waterfall as of 05/15/2021; both uPRs reported at AACR 2021 in USC are confirmed PRs. Newly reported uPR i
Slide 20: ZN-c3: Well Tolerated in Comparison to Adavosertib
2.2 2.2 6.6 2.2 8.9 2.2 2.2 8.9 13.3 6.6 8.8 11.8 2.9 8.8 8.8 32.3 2.9 8.8 17.6 23.5 2.9 2.9 2.9 5.8 5.9 23.5 8.8 26.5 20.6 35.3 20.6 20.6 29.4 38.2 32.4 44.1 32.4 26.5 61.8 32.4 67.6 26.5 44.1 38.2 32.4 41.2 85.3 64.7 61.8 0 0 0 2.2 2.2 4.5 4.5 4.5 4.5 6.6 6.6 8.9 11.1 11.1 13.3 15.5 15.5 31.1 60 6
Slide 21: ZN-c3: Meaningfully Reduced Hematological Toxicities
ZN-c3: Meaningfully Reduced Hematological Toxicities (1) | 21 Source: Liu JF et al. J Clin Oncol. 2021 Mar 11:JCO2003167 (1) Non-head-to-head comparison. Results of a head-to-head comparison may differ significantly from those set forth herein. In addition, because our Phase 1 clinical trial for ZN-
Slide 22: Exceptional Responders Exhibit Unique Biological Features
Exceptional Responders Exhibit Unique Biological Features | 22 • Observed multiple Exceptional Responses with single agent ZN-c3 (1) • Activity in tumor types (e.g., CRC) not previously seen by other Wee1i • Approach to confirm unique, novel and predictive profile • Clear path for the development of
Slide 23: Decreases in p-CDK1 Show Target Engagement for Wee1 Inhibition
Decreases in p-CDK1 Show Target Engagement for Wee1 Inhibition | 23 p-CDK1 = Brown Staining (subject with cPR) Baseline On Treatment 40x -100% -99% Decreases in p-CDK1 at Baseline vs on Treatment Basal epidermis Hair bulb 1. CDK1 phosphorylation (p-CDK1) is mediated by Wee1 2. Inhibition of Wee1 wil
Slide 24: ZN-c3: PK/PD Correlation Shows Active Target Engagement at RP2D
ZN-c3: PK/PD Correlation Shows Active Target Engagement at RP2D | 24 M or e W ee 1 Ta rg et E ng ag em en t 0 5000 10000 15000 20000 -100 -50 0 50 100 Average drug exposure at RP2D AUC0-24 hr (ng*h/mL) p- CD K1 (% in hi bi tio n) Wee1 Target Engagement Higher Drug Exposure • Inhibition of p-CDK1 dem
Slide 25: ZN-c3 in Combination with Gemcitabine in Osteosarcoma Model
ZN-c3 in Combination with Gemcitabine Shows Strong Activity in an Osteosarcoma Cancer Model • Approximately 1,000 new cases in the U.S.(1) • Up to 90% have sequence mutations or structural variants in TP53 and are often enriched in relapsed or refractory cases, portending resistance to chemotherapy(
Slide 26: Wee1 Inhibition Shows Strong Preclinical Activity in Colorectal Cancer
Wee1 Inhibition as a Monotherapy and in Combination Shows Strong Preclinical Activity in Colorectal Cancer | 26 ZN-c3: Colorectal (1) Sotorasib (AMG510, KRAS G12C inhibitor) (2) Seligmann JF et al. J Clin Oncol. 2021 Sep 18 -1 5 11 17 23 29 35 41 0 100 200 300 400 500 600 Vehicle qd ZN-c3 60 mg/kg q
Slide 27: ZN-c3 + PARP Inhibitor Combination in a TNBC PDX Model
ZN-c3 + PARP Inhibitor Combination Induces Regressions and is Well Tolerated in a TNBC PDX Tumor Model • Tumors with Cyclin E amplification have enhanced sensitivity to Wee1 inhibition (1) • Combination of PARP and Wee1 inhibitors in TNBC: - Results in synergistic cell killing in preclinical models
Slide 28: ZN-d5 BCL-2 Inhibitor
2 zentalis ZN-d5 BCL-2 Inhibitor
Slide 29: BCL-2: A Clinically Validated Oncology Target
BAX BCL-2: A Clinically Validated Oncology Target • BCL-2 is an anti-apoptotic protein involved in tumor survival and chemo resistance (1) • The intrinsic apoptotic pathway is controlled by the BCL-2 protein family on the mitochondrial outer membrane (2, 3) • BCL-2 inhibitors may restore the normal
Slide 30: ZN-d5: A Potent BCL-2 Inhibitor with Improved Selectivity
ZN-d5: A Potent BCL-2 Inhibitor Designed with Improved Selectivity for BCL-2 | 30 Compound ID Affinity (Kd, nM) IC50 (nM) BCL-2 Type BCL-2 BCL-xL MCL-1 WT G101V F104L D103Y Venetoclax 0.41 28 >30000 1.3 7.3 8.4 18.3 ZN-d5 0.29 190 >30000 1.4 3.7 1.4 5.0 Compound ID CTG IC50 (nM) ALL MCL DLBCL AML RS
Slide 31: ZN-d5: May Bind with Higher Affinity to BCL-2 Mutants than Venetoclax
ZN-d5: May Bind with Higher Affinity to BCL-2 Mutants than Venetoclax | 31 Note: Competition assay for displacing BAK peptide bound to BCL-2 Compound IC50 (nM) BCL-2 Type WT G101V F104L D103Y Venetoclax 1.3 7.3 8.4 18.3 ZN-d5 1.4 3.7 1.4 5.0 CLL Progression on Venetoclax Mutations in BCL-2 May be Dr
Slide 32: ZN-d5 Clinical Development Plan
ZN-d5 Clinical Development Plan • Improved in vitro potency and has 10x improved selectivity for BCL-2 vs BCL-xL compared to venetoclax • Observed to bind with higher affinity to BCL-2 mutants than venetoclax in in vitro assay - Mutations in BCL-2 may be driving sub-clonal pockets of resistance to v
Slide 33: ZN-d5: Favorable Early Comparison to Venetoclax in NHL
ZN-d5: Favorable Early Comparison to Venetoclax in NHL • ZN-d5 100-1200 mg, empty stomach • Venetoclax 200-1200 mg with food • Early toxicity profile in NHL favorable vs. published venetoclax data(1) - Fewer AEs of any Grade, Grade ≥3 - No TLS observed - Venetoclax AEs not dose-dependent (1) Davids
Slide 34: ZN-d5 in AL (Primary) Amyloidosis
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 worldwi
Slide 35: BCL-2 Inhibition Has Shown Robust Clinical Activity in AL Amyloidosis
BCL-2 Inhibition has Shown Robust Clinical Activity in AL Amyloidosis (1) Premkumar et al, Blood Cancer J 2021;11:10; hematologic response rate in 38 evaluable patients. (1) OS for All Patients Best Response in Evaluable Patients All patients (n=38) Non-t(11;14) patients (n=10) t(11;14) patients (n=
Slide 36: Novel Biology Supports Synergy of BCL-2 and Wee1 Inhibition – CAMPRO
Novel Biology Supports Synergy of BCL-2 and Wee1 Inhibition – CAMPRO (CAspase Mediated PROteolysis) | 36 This novel synergistic finding supports the use of ZN-d5 + ZN-c3 in both sensitive and less sensitive tumor cells, opening a large market opportunity across both solid and liquid tumors Treatment
Slide 37: ZN-d5 + ZN-c3 Combination Decreases Levels of DDR Proteins
ZN-d5 + ZN-c3 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 with ZN-
Slide 38: BCL-2 and Wee1 Inhibitors Show Synergism in Several Tumor Models Including AML
The Combination of BCL-2 and Wee1 Inhibitors Results in Synergism in Several Tumor Models Including AML | 38 HL-60 AML model 0 3 6 9 12 15 18 0 300 600 900 1200 1500 1800 2100 2400 2700 Vehicle ZN-d5 50 mg/kg, qd ZN-c3 60 mg/kg, qd Days Post Treatment Tu m or V ol um e (m m 3 ) ZN-d5 50 mg/kg + ZN-c
Slide 39: ZN-d5 Combined with ZN-c3 is Active in Patient-Derived AML Samples
ZN-d5 Combined with ZN-c3 is Active in Patient-Derived AML Samples n= 6 or 10, qd x 17 treatment Veh icl e ZN-d5 2 00 m g/kg ZN-c3 80 m g/kg ZN-d5 + ZN-c3 0 10000 20000 30000 40000 50000 60000 AML PDX model Bone Marrow Analysis hu CD 45 + M ea n Ce ll Nu m be r Vehicle ZN-d5 200 mg/kg ZN-c3 80 mg/kg
Slide 40: Antitumor Activity in Solid Tumor Models with ZN-d5 + ZN-c3
Antitumor Activity in Solid Tumor Models with the ZN-d5 + ZN-c3 Combination Represents Market Expansion Opportunities 0 3 6 9 12 15 18 21 0 200 400 600 800 1000 1200 1400 Vehicle ZN-d5 50 mg/kg ZN-c3 80 mg/kg ZN-d5 50 mg/kg + ZN-c3 80 mg/kg Days Post Treatment Tu m or V ol um e (m m 3 ) DMS53 -1 5 1
Slide 41: ZN-c3 Combined with Low Dose Navitoclax in ALL Model MOLT-4
ZN-c3 Combined with a Low Dose of Navitoclax (BCL-xL Inhibitor) Results in Enhanced Anti-tumor Activity in the ALL model MOLT-4 The MOA of the combination of ZN-d5 and ZN-c3 represents a novel therapeutic approach which also applies to combinations of ZN-c3 with other inhibitors of anti-apoptotic pr
Slide 42: Conclusions
2 zentalis Conclusions
Slide 43: Key Milestones
Key Milestones ZN-c3: Wee1 Inhibitor Initial readout on Phase 1 USC expansion cohort Initial readout on Phase 1b ovarian chemotherapy combo Initial enrollment/safety update on Phase 2 USC trial(1) Initial readout on Phase 1/2 chemotherapy combo in osteosarcoma(2) 1H 2022 1H 2022 2H 2022 2H 2022 ZN-d
Slide 44: Contact
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 1710 New York, NY 10018 Science Center 10275 Science Center Drive Suite 200 San Diego, CA 92121
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