Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Presentation (March 2023)
53 slides from Zentalis Pharmaceuticals's investor presentation, Mar 1, 2023
Slide 1: Corporate Presentation March 2023
1 CORPORATE PRESENTATION March 2023
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: Company Overview
3 Company Overview Lead Program: Wee1i azenosertib (ZN-c3), potentially first- and best-in-class • Potential accelerated approval paths for monotherapy in multiple biomarker enriched populations • Enriched patient populations including Uterine Serous Carcinoma (USC), Cyclin E1 driven and post-PARP p
Slide 4: Development pipeline and expected milestones
4 COMPOUND INDICATION DEVELOPMENT APPROACH PRECLINICAL EARLY CLINICAL DEVELOPMENT LATE CLINICAL DEVELOPMENT STATUS / EXPECTED MILESTONES Azenosertib (ZN-c3) Wee1 Inhibitor Uterine Serous Carcinoma Monotherapy FDA Fast Track Designation Solid Tumors Monotherapy Update on azenosertib dosing 1H 2023 in
Slide 5: Wee1 Inhibitor Azenosertib (ZN-c3)
Wee1 Inhibitor Azenosertib (ZN-c3)
Slide 6: Wee1: A Critical Cell Cycle Regulation Target
6 Wee1: A Critical Cell Cycle Regulation Target • Wee1 is a protein kinase that inhibits the activity of both CDK1 and CDK2 kinases and is involved in the regulation of G1/S, G2/M, and M phase cell cycle checkpoints • Wee1 plays an important role during normal cell cycle progression but also in resp
Slide 7: Wee1 Inhibition by Azenosertib Forces Cancer Cells into Mitosis
7 Wee1 Inhibition by Azenosertib Forces Cancer Cells to Proceed into Mitosis • Wee1 inhibition causes cancer cells to proceed into mitosis without being able to repair damaged DNA, resulting in premature mitotic entry and apoptosis 1 • Wee1 inhibition also increases replication stress by inducing ab
Slide 8: Structure-Based Drug Design Led to Discovery of Azenosertib
8 Structure-Based Drug Design (SBDD) Led to the Discovery of a Highly Potent and Selective Wee1 Inhibitor Azenosertib with Improved ADME Properties Asn376 Tyr378 Cys379 Phe310 Ile305 azenosertib potency and ADME Wee1 IC50 3.8 nM H23 IC50 103 nM A427 IC50 75 nM Log D 2.4 hPPB 66% hHep <18 mL/min/kg s
Slide 9: Indication incidence estimates and development approach
9 Indication Incidence Estimates (US+EU) Development Approach Ovarian Cancer 46,700 1 Strategic commitment to patients with multiple ongoing studies in monotherapy and combination settings High Grade Serous Ovarian Cancer (HGSOC) (75% of Ovarian Cancer) 35,000 2 Ongoing study combining azenosertib w
Slide 10: Uterine Serous Carcinoma Azenosertib (ZN-c3)
Uterine Serous Carcinoma Azenosertib (ZN-c3)
Slide 11: Unmet Need in Uterine Serous Carcinoma is Significant
11 • USC is molecularly distinct from endometrial cancer with frequent alterations in p53 (90%), CCNE1 (25%) and HER2 (25%) 4 • High amounts of oncogene-driven replicative stress • Wee-1 is a validated target in USC with reported ORR of 29.4% and a PFS6 rate of 47.1% with adavosertib 5 • USC is an a
Slide 12: ZN-c3-001: Summary of Clinical Activity in USC
12 ZN-c3-001: Summary of Clinical Activity – Meaningful and Durable Responses Seen in USC Best Overall Response N = 11†; n (%) Complete Response (unconfirmed)* 1 (9.1) Partial Response (confirmed) 2 (18.2) Stable Disease 7 (63.6) ≥ 12 weeks 4 (36.3) < 12 weeks 3 (27.3) Progressive Disease 1 (9.1) Ov
Slide 13: Azenosertib Favorable Tolerability Profile in Monotherapy USC
13 85.7 64.3 42.9 42.9 28.6 28.6 21.4 14.3 14.3 14.3 14.3 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 14.3 020406080100 Nausea Vomiting Fatigue Diarrhea Decreased Appetite Dehydration Anaemia Thrombocytopenia Weight Decreased Dizziness Headache Neutropenia Leukopenia Dysgeusia Abdomi
Slide 14: Dose Optimization Azenosertib (ZN-c3)
Dose Optimization Azenosertib (ZN-c3)
Slide 15: Multiple PRs Across Tumor Types as Monotherapy
15 Azenosertib: Multiple PRs Across Tumor Types as Monotherapy AmVate 300 Ovar 300 Panc 350 Pros 350 Panc 450 CRC 350 SCLC 450 RCC 300 Ovar 300 Brea 350 CRC 350 CRC 300 USC 300 CRC 350 USC 300 CRC 300 NSCLC 300 Gast 350 Panc 400 450 CRC 300 Ovar 350 CRC 300 USC 300 USC 300 LeiS 350 CRC 350 LeiS 300
Slide 16: Optimizing the Therapeutic Index of Azenosertib
16 Optimizing the Therapeutic Index of Azenosertib • Only set dose of azenosertib has been in USC (004 trial) at 300mg QD continuous daily dosing • Monotherapy activity demonstrated • Well tolerated safety profile • From 300mg QD dosing, we will examine pushing the therapeutic index for monotherapy
Slide 17: Intermittent Dosing Increases Efficacy in Ovarian Cancer Models
17 Azenosertib: Intermittent Dosing Increases Efficacy and Maintains Tolerability in Ovarian Cancer Models -1 2 5 8 11 14 17 20 23 26 0 400 800 1200 1600 2000 Days Post Treatment Initiation T u m o r V o lu m e ( m m 3 ) Vehicle qd × 24 ZN-c3 60 mg/kg qd × 24 ZN-c3 80 mg/kg (qd × 5, 2 d off) ZN-c3 1
Slide 18: Skin Biopsy Decreases in p-CDK1 Show Target Engagement
18 3. Skin Biopsy Decreases in p-CDK1 Show Target Engagement for Wee1 Inhibition Confirmation of Wee1 Target Engagement in Surrogate Tissue 1 1. CDK1 phosphorylation (p-CDK1) is mediated by Wee1 2. Inhibition of Wee1 will lead to inhibition of p-CDK1 3. Skin biopsies were performed at baseline and o
Slide 19: PK/PD Correlation Shows Active Target Engagement
19 Azenosertib: PK/PD Correlation Shows Active Target Engagement • Inhibition of p-CDK1 demonstrated Wee1 target engagement • Increase in dose / drug exposure directly related to Wee1 target engagement • ≥300 mg QD showed highest AUC, with excellent target engagement and p-CDK1 levels decreased at l
Slide 20: Biomarker Approach: Cyclin E1 Driven Cancers
Biomarker Approach: Cyclin E1 Driven Cancers Azenosertib (ZN-c3)
Slide 21: High Cyclin E1 Cells are Highly Sensitive to Wee1 Inhibition
21 Cyclin E1 High Cyclin E1 Expressing Cancer Cells are Highly Sensitive to Wee1 Inhibition • High cyclin E1 protein expression accelerates G1/S signaling, which cause high levels of replicative stress 1 • Wee1 inhibition further drives replicative stress, causing mitotic catastrophe and cell death
Slide 22: CCNE1 Amplification and Poor Prognosis Across Tumor Types
22 CCNE1 Gene Amplification is Associated with Poor Prognosis and Chemotherapy Response Across Tumor Types 1. Liu, J. et al., Cell, 2018, 173, 400-416; (figure generated using cBioPortal.org, see Cerami et al. Cancer Discovery. 2012 2; 401 and Gao et al. Sci. Signal. , 2013, 6, pl1). 2. Huang, X. et
Slide 23: High Cyclin E1 Expression Increases Sensitivity to Azenosertib
23 High Cyclin E1 Protein Expression is Associated with Increased Sensitivity to Azenosertib in Ovarian Cell Lines 1. Azenosertib sensitivity is assessed by CellTiter Glo after 96 hours of culture. Data represent an average of at least 2 independent studies. Protein expression was assessed by Wester
Slide 24: CCNE1 Amplification and Azenosertib Tumor Growth Inhibition
24 CCNE1 Gene Amplification is Associated with Poor Prognosis and Chemotherapy Response Across Tumor Types Carboplatin-treated Ovarian Cancer 3 SKOV3 CCNE1 not amplified, TP53 mut HCC1806 CDX CCNE1 amp (CN=7), TP53 mut OVCAR3 CDX CCNE1 amp (CN=14) TGI(80 mpk, Day 28) = 88%TGI(80 mpk, Day 28) = 63.5%
Slide 25: Revised ZN-c3-005 Study Design
25 Moving Forward with Cyclin E1 patient enrichment in HGSOC: Revised ZN-c3- 005 Study Design CCNE1 Amp azenosertib monotherapy at doses and schedules deemed well tolerated in ZN-c3-001 azenosertib monotherapy Cohort A CCNE1 Amp PH 1b / SAFETY LEAD-IN PH 2 EXPANSION Cohort B CCNE1 Non-amp High Cycli
Slide 26: Platinum-Resistant/Refractory Ovarian Cancer Remains an Unmet Need
26 • In 2022, the total number of drug- treatable second line platinum-resistant ovarian cancer patients is estimated to be >14,000 in the United States, EU5 and Japan 2 • Platinum-resistant and -refractory ovarian cancer represents a high unmet need • It is associated with a poor prognosis and limi
Slide 27: ZN-c3-002: Summary of Clinical Activity
27 ZN-c3-002: Summary of Clinical Activity Summary of Clinical Activity (All Cohorts) Group N Evaluable* (n) PR/uPR (n) SD (n) PD (n) DCR (%) ORR (%) Azenosertib + Paclitaxel 9 8 5 3 – 100 62.5 Azenosertib + Carboplatin 17 11 5 4 2 81.8 45.5 Azenosertib + PLD 30 24 3 17 4 83.3 12.5 Total 56 43 13 24
Slide 28: Adverse events in chemotherapy combination study
28 55.4 48.2 41.1 37.5 35.7 35.7 28.6 21.4 19.6 17.9 16.1 14.3 14.3 14.3 12.5 8.9 8.9 8.9 8.9 7.1 7.1 7.1 7.1 5.4 5.4 5.4 5.4 5.4 5.4 5.4 5.4 7.1 35.7 17.9 8.9 8.9 5.4 3.6 1.8 7.1 5.4 5.4 10.7 5.4 3.6 1.8 3.6 1.8 5.4 1.8 020406080100 Nausea Neutropenia Thrombocytopenia Anaemia Vomiting Fatigue Diarr
Slide 29: PARP-Refractory Ovarian Cancer Azenosertib (ZN-c3)
PARP-Refractory Ovarian Cancer Azenosertib (ZN-c3)
Slide 30: Azenosertib + PARP Inhibitor Combinations Active in Preclinical Models
30 • Combination of PARP and Wee1 inhibitors in TNBC results in synergistic cell killing in preclinical models with either BRCA1 mutations or high levels of cyclin E1 1 • The combination of azenosertib and niraparib shows efficacy in both ovarian and TNBC in vivo models • Preclinically, sequential a
Slide 31: ZN-c3-006: Azenosertib with Niraparib Study Design
31 Key Eligibility: • Recurrent high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer (serous, clear cell or endometrioid). • Prior therapy: 1 – 5 prior lines for advanced/metastatic disease • Disease progression while taking a PARPi as maintenance treatment (minimum of 3 month
Slide 32: BRAF Metastatic Colorectal Cancer Azenosertib (ZN-c3)
BRAF Metastatic Colorectal Cancer Azenosertib (ZN-c3)
Slide 33: Preclinical Support for Azenosertib with Encorafenib and Cetuximab
33 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 activation disrupts replication
Slide 34: BRAF mCRC Study in Collaboration with Pfizer
34 PHASE 2: DOSE EXPANSION N: Up to 80 patients • Phase 1 Endpoints: Safety, tolerability, MTD, RP2D • Phase 2 Endpoint(s): ORR; DOR, DCR, PFS, TTP Encorafenib + Cetuximab + Escalating Dose Levels of azenosertib PHASE 1: DOSE FINDING BRAF mCRC Study in Collaboration with Pfizer • Patients with mCRC
Slide 35: ZN-d5 BCL-2 Inhibitor
” zentalis ZN-d5 BCL-2 Inhibitor
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 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 apopt
Slide 37: ZN-d5: Potent BCL-2 Inhibitor 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 Binds BCL-2 Mutants with Higher Affinity than Venetoclax
38 ZN-d5: May Bind with Higher Affinity to BCL-2 Mutants than Venetoclax Compound ID 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 Mutations in BCL-2 May be Driving Sub-Clonal Pockets of Resistance to Venetoclax in CLL 55% (16/29) patients acquired mutat
Slide 39: ZN-d5 Clinical Development Plan
39 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 t
Slide 40: ZN-d5: Early Comparison to Venetoclax in NHL
40 ZN-d5: Favorable Early Comparison to Venetoclax in NHL ZN-d5: NHL Upper respiratory tract infections • ZN-d5 100-1200mg, empty stomach • Venetoclax 200-1200mg with food • Early toxicity profile in NHL favorable vs. published venetoclax data 1 - Fewer AEs of any Grade, Grade ≥3 - No TLS observed -
Slide 41: ZN-d5 in AL (Primary) Amyloidosis
41 ZN-d5 in AL (Primary) Amyloidosis 1. Zhang et al. Clin Lymphoma Myeloma Leuk. 2019;19(suppl 10):e339 2. Kyle et al, Mayo Clin Proc. 2019;94:465-471 3. Premkumar et al, Blood Cancer J 2021;11:10; hematologic response rate in 38 evaluable patients. AL Amyloidosis study is currently enrolling patien
Slide 42: BCL-2 Inhibition Clinical Activity in AL Amyloidosis
42 BCL-2 Inhibition has Shown Robust Clinical Activity in AL Amyloidosis • Patients with the t(11;14) translocation have a worse prognosis than the general AL amyloidosis population 1 • BCL-2 inhibition showed an improved response rate in the t(11;14) cohort with a trend towards better survival Best
Slide 43: Potential Combination of Azenosertib and ZN-d5
Potential Combination of Azenosertib (ZN-c3) and ZN-d5
Slide 44: BCL-2 and Wee1 Inhibitors Synergy in Tumor Models Including AML
44 The Combination of BCL-2 and Wee1 Inhibitors Results in Synergy in Several Tumor Models Including AML • ZN-d5 and azenosertib combination represents a novel therapeutic approach • Significant enhancement of activity than single agent in several indications, including AML • Combination regimen was
Slide 45: Antitumor Activity in Solid Tumor Models with ZN-d5 + Azenosertib
45 Antitumor Activity in Solid Tumor Models with the ZN-d5 + Azenosertib Combination Represents Market Expansion Opportunities 1. Izadi, H. et. al. Cancer Res (2022) 82 (12_Supplement): 2605. 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 +
Slide 46: BCL-xL Protein Degrader
” zentalis BCL-xL Protein Degrader
Slide 47: BCL-xL Degrader Background and Rationale
47 Declared development candidate and initiated IND enabling activities BCL-xL Degrader Background and Rationale Background, Clinical Relevance, and Approach Therapeutic Hypothesis • BCL-xL is a member of the anti-apoptotic BCL-2 proteins and is clinically validated. 1, 2 • Expression of BCL-xL cont
Slide 48: BCL-xL Degrader More Efficacious than Navitoclax in MOLT4 Models
48 BCL-xL IV Degrader is More Efficacious than BCL-xL Inhibitor (Navitoclax) in MOLT4 (T-ALL) Models Navitoclax data based on evaluation of comparable proxy chemical compound purchased from commercial sources rather than obtained from the pharmaceutical company developing the compound • BCL-xL degra
Slide 49: Azenosertib with Low-Dose Navitoclax Synergistic in T-ALL Model
49 Azenosertib Combined with a Low Dose of Navitoclax (BCL-xL Inhibitor) Results in Synergistic Anti-tumor Activity in the T-ALL model MOLT-41 1. Izadi, H.; et. al. Cancer Res (2022) 82 (12_Supplement): 2605. TGI: Tumor Growth Inhibition ALL: Acute Lymphoblastic Leukemia MOLT-4 model is BCL-xL depen
Slide 50: Conclusions
” zentalis Conclusions
Slide 51: Integrated Discovery Engine to Generate Best-In-Class Drugs
51 4 ZENTALIS DRUGS Utilizing the Highly Efficient Integrated Discovery Engine to Generate Potentially Best-In-Class Drugs PATIENTS1 ZENTALIS DISCOVERY ENGINE2 3 Genomic FeaturesPathways Functional Screens Preclinical Models Chemistry Machine Learning • CRISPR screens • BH3 profiling • Genomics • 2D
Slide 52: 2023 Key Milestones
52 2023 Key Milestones 1H 2023 Azenosertib (ZN-c3) Wee1 Inhibitor ZN-d5 BCL-2 Inhibitor Integrated Discovery Engine Initiate enrollment in the BRAF mutant colorectal cancer BEACON regimen combination clinical trial in collaboration with Pfizer Provide preclinical rationale for Cyclin E1 enrichment s
Slide 53: Contact
53 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
Zentalis Pharmaceuticals — Investor Presentation (March 2023) on 6ix