Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Investor Day (April 2022)
55 slides from Zentalis Pharmaceuticals's investor day presentation, Apr 8, 2022
Slide 1: AACR 2022 Investor Event
A A C R 2 0 2 2 I n v e s t o r E v e n t A p r i l 8 , 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 Private Securities Li
Slide 3: Today's Agenda
Today’s Agenda • Phase 1 monotherapy update from USC cohort • Phase 1b chemotherapy combination data in ovarian cancer | 3 ZN-c3 (Wee1 inhibitor) Updates ZN-c5 (oral SERD) Updates 1 2 ZN-d5 (Bcl-2 inhibitor) Updates Summary and Catalysts 3 4
Slide 4: Company Overview
Lead Program: Wee1i (ZN-c3) potentially first- and best-in-class • Monotherapy responses in 4 solid tumor types, with 3 Exceptional Responders & additional responses in USC • Promising data in ovarian cancer when combined with chemotherapy • Potential accelerated approval paths for USC* and biomarke
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 is currently evaluating ZN-c5 in combination with palbociclib (Ibrance®), as part of a clinical research collaboration with Pfizer, evaluating ZN-c5 in combination with abemaciclib (Ver
Slide 6: ZN-c3: Wee1 Inhibitor Background
Z N - c 3 : We e 1 I n h i b i to r B a c k g r o u n d
Slide 7: Wee1 Inhibition: Clinically Proven DDR Target for Cancer
Wee1 Inhibition: Clinically Proven DDR Target for Cancer M S G2 G1 CDK1 Cyclin B1 P Tyr15 WEE1i MITOSIS EXIT CDK1 Cyclin B1 P Tyr15 WEE1i G2/M CHECKPOINT CDK2 Cyclin A/E P Tyr15 WEE1i INTRA S CHECKPOINT Wee1 inhibition causes cancer cells to proceed to mitosis without repairing DNA damage, resulting
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) Asn376 Tyr378 Cys379 Phe310 Ile305 Effective bidentate hydrogen-bond interactions with the hinge element Hydrogen bonding with the Wee1 gatekeeper Asn376 Eth
Slide 9: ZN-c3: Differentiated Selectivity Profile
ZN-c3: Differentiated Selectivity Profile(1) (1) Illustrations reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) % Inhibition (@ 1µM) 90+ 5 kinases 75-89 5 kinases ZN-c3 | 9 % Inhibition (@ 1µM) 90+ 13 kinases 75-89 24 kinases Adavosertib >470 kinases ZN-c3: Wee1 Inhibitor
Slide 10: ZN-c3: Phase 1 USC Monotherapy Update
Z N - c 3 : P h a s e 1 U S C M o n o t h e ra p y U p d a te
Slide 11: 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 12: Safety and Clinical Activity of Single-Agent ZN-c3 in USC
Safety and clinical activity of single-agent ZN-c3, an oral Wee1 inhibitor, in a Phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC) F. Meric-Bernstam1, P. Chalasani2, H. Mamdani3, C. Zheng4, M. Viana4, R. Lambersky4, P. Pultar4, A. Tolcher5 1MD Anderson Cancer Center
Slide 13: ZN-c3: Chemo Combination in Ovarian Cancer
ZN-c3: Chemo Combinat ion in Ovar ian Cancer
Slide 14: 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 15: ZN-c3 Combined with Chemotherapy is Highly Active in vitro
ZN-c3 Combined with Chemotherapy is Highly Active in vitro Against OVCAR3 Ovarian Cancer Cells ZN-c3: WEE1 InhibitorZN-c3: Ovarian • Inhibition of Wee1, combined with DNA-damaging agents (doxorubicin and carboplatin) or inducers of replication stress (paclitaxel and gemcitabine), causes mitotic entr
Slide 16: ZN-c3-002: Study Design
ZN-c3-002: Study Design ZN-c3: Ovarian MTD= maximum tolerated dose; N= number of subjects; RP2D= recommended Phase 2 dose; CRM= continual reassessment method; PLD= liposomal doxorubicin | 16
Slide 17: ZN-c3-002: Baseline Characteristics
ZN-c3-002: Baseline Characteristics Baseline Characteristics (All Cohorts) (1) No subjects have been enrolled in the gemcitabine arm as of January 28, 2022. (2) Full patient genetic background analysis ongoing. ZN-c3: Ovarian Characteristic ZN-c3 + PLD (n = 30) ZN-c3 + Carboplatin (n = 17) ZN-c3 + P
Slide 18: Expectations for Efficacy in Recurrent Ovarian Cancer Patients
Expectations for Efficacy in Recurrent Ovarian Cancer Patients | 18 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 19: Maximum Reduction in Sum of Target Lesion Diameters, All Patients
ZN-c3-002: Maximum Reduction in Sum of Target Lesion Diameters All Patients (n=43*)(1) ZN-c3: Ovarian PLD 250 PLD 200 PR PD PR/uPR+SDPDBest Overall Response: -100 -80 -60 -40 -20 0 20 40 60 80 100 M a x im u m c h a n g e ( % ) in s u m o f ta rg e t le s io n d ia m e te rs Subjects CAR 200 + PLD 3
Slide 20: Robust Disease Control Rate Observed Across All Cohorts
ZN-c3-002: Robust Disease Control Rate Observed Across All Cohorts | 20 ZN-c3: Ovarian Responders experienced a meaningful duration of response P e rc e n t C h a n g e f ro m B a s e li n e (B e s t R e s p o n s e ) Weeks Data cutoff January 28, 2022. -25 8.338 -12.31 -79.49 -66.3 -2.04 1.56 -21.0
Slide 21: ZN-c3-002: Responder #1 Background
ZN-c3-002: Responder #1 Background | 21 ZN-c3: Ovarian Ovarian Cancer – Platinum-resistant • 52-year-old female, Stage III Ovarian Cancer, metastases to the liver, abdomen, mesentery (lymph node). ECOG PS 0 • Two prior lines of therapy in the advanced/ metastatic setting • ZN-c3 starting dose: 200 m
Slide 22: Responder #1 Baseline and Follow-up (Liver Lesion)
ZN-c3-002: Responder #1 Baseline and Follow-up (Liver Lesion) 4th Assessment (Jan 2022)Baseline (July 2021) | 22 ZN-c3: Ovarian
Slide 23: ZN-c3-002: Responder #2 Background
ZN-c3-002: Responder #2 Background | 23 ZN-c3: Ovarian Ovarian Cancer – Platinum-resistant • 72-year-old female, Stage IV Ovarian Cancer, metastases to the greater omentum, spleen capsule, pararectal, Liver capsule, peritoneum. ECOG PS 0 • Two prior lines of therapy in the advanced/ metastatic setti
Slide 24: Responder #2 Baseline and Follow-up (Liver Lesion)
ZN-c3-002: Responder #2 Baseline and Follow-up (Liver Lesion) 2nd Assessment (December 2021)Baseline (October 2021) | 24 ZN-c3: Ovarian Complete disappearance
Slide 25: 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 26: Maximum Reduction in Target Lesion Diameters: PLD Patients
ZN-c3-002: Maximum Reduction in Sum of Target Lesion Diameters PLD Patients(1) ZN-c3: Ovarian Confidential Draft - Work In Progress -100 -80 -60 -40 -20 0 20 40 60 80 100 M a x im u m c h a n g e ( % ) in s u m o f ta rg e t le s io n d ia m e te rs 200 200 250 300 + + 300 200 300 + + ++ 350I 300 20
Slide 27: Maximum Reduction in Target Lesion Diameters: Carboplatin Patients
ZN-c3-002: Maximum Reduction in Sum of Target Lesion Diameters Carboplatin Patients(1) ZN-c3: Ovarian -100 -80 -60 -40 -20 0 20 40 60 80 100 M a x im u m c h a n g e ( % ) in s u m o f ta rg e t le s io n d ia m e te rs 200 PR PD 200 200 300 300 200 200 ++ 200 200 200 200 ++ + Subjects SDPDBest Over
Slide 28: Maximum Reduction in Target Lesion Diameters: Paclitaxel Patients
ZN-c3-002: Maximum Reduction in Sum of Target Lesion Diameters Paclitaxel Patients(1) ZN-c3: Ovarian -100 -80 -60 -40 -20 0 20 40 60 80 100 M a x im u m c h a n g e ( % ) in s u m o f ta rg e t le s io n d ia m e te rs PR PD 200^ 200 200 ++ + 200 200 + 200^ 200 + + 200 + SDPDBest Overall Response: S
Slide 29: Clinically Feasible Response Rates for ZN-c3 and Competitors in Ovarian Cancer
ZN-c3-002 ZN-c3 + Chemotherapy 11.8% 23.0% 33.3% 16.7% 30.4% 66.7% 28.9% 11.1% 12.5% 45.5% 62.5% 0% 10% 20% 30% 40% 50% 60% 70% 80% AURELIA study Chemotherapy Gemcitabine + Adavosertib PLD + Adavo low dose PLD + Adavo high dose Carboplatin + Adavo low dose Carboplatin + Adavo high dose Paclitaxel +
Slide 30: 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 31: ZN-c3 Exhibits Lower Hematologic Toxicity vs Adavosertib
ZN-c3 Exhibits Lower Hematologic Toxicity vs Adavosertib When Combined with Chemotherapy – Grade ≥ 3 TRAEs* • Target ZN-c3 dosing was QD continuously throughout the treatment cycle across all chemotherapy cohorts • Adavosertib’s dosing schedule was intermittent to manage expected tolerability concer
Slide 32: ZN-c3 GI Tolerability Profile is Better than Adavosertib
ZN-c3 GI Tolerability Profile is Better than Adavosertib When Combined with Chemotherapy – Grade ≥ 3 TRAEs* | 32 ZN-c3: Ovarian Nausea 0% 5% 10% 15% ZN-c3-002 Lheureux, Lancet Moore, Clin Can Res Vomiting 0% 5% 10% 15% ZN-c3-002 Lheureux, Lancet Moore, Clin Can Res Diarrhea 0% 5% 10% 15% ZN-c3-002 L
Slide 33: ZN-c3 Oral Dosing Regimen is Convenient and in Dose Escalation
ZN-c3 Oral Dosing Regimen is Convenient and Currently in Dose Escalation ZN-c3: Ovarian (1) ZN-c3 January 28, 2022 data cutoff. (2) Moore KM et al. Clin Cancer Res 2022;28:36–44 Note: Non-head-to-head comparison. Results of a head-to-head comparison may differ significantly from those set forth here
Slide 34: ZN-c3 Demonstrates Superior Efficacy with Greater Safety/Tolerability
0% 10% 20% 30% 40% 50% 60% 70% 80% 0%10%20%30%40%50%60%70%80% ZN-c3 Demonstrates Superior Efficacy with Greater Safety/ Tolerability in Patients with a Worse Prognosis* | 34 ZN-c3: Ovarian ZN-c3 + Carboplatin (QD Regimen): ORR: 45.5% Neutropenia Grade ≥3: 23.5% ZN-c3 + Paclitaxel (QD Regimen): ORR:
Slide 35: Summary of Chemotherapy Combination in Ovarian Cancer
ZN-c3-002: Summary of Chemotherapy Combination in Ovarian Cancer CLINICAL ACTIVITY SAFETY PROFILE REGULATORY PATH ZN-c3: Ovarian ZN-c3 is well-tolerated with chemotherapy and supports potential use in additional indications (1) Moore KM et al. Clin Cancer Res 2022;28:36–44 (2) Lheureux S et al. Lanc
Slide 36: ZN-c5: Oral SERD Data Update
2 zentalis ZN-c5: Oral SERD Data Update
Slide 37: ZN-c5 Combination with CDK 4/6i – Efficacy Data
ZN-c5 Combination with CDK 4/6i – Efficacy Data | 37 ZN-c5: CDK4/6i Combo Palbociclib Combination Phase 1 Dose (mg/day) N ORR CBR mPFS (months) 25 mg QD + Palbo 10 1/7* (14%) 2/7*(29%) ** 50 mg QD + Palbo 18 2/13 (15%) 6/18 (33%) 3.6 >50 mg + palbo (includes 25 BID) 22 0/14 8/22 (36%) 3.7 Overall 50
Slide 38: ZN-c5 Combination with CDK 4/6i – Tolerability Profile
ZN-c5 Combination with CDK 4/6i – Tolerability Profile (TEAE ≥20%) | 38 ZN-c5: CDK4/6i Combo Palbociclib Combination (N=50) Data as of Jan 31, 2022 ClinicalTrials.gov Identifier: NCT03560531 Data as of Jan 11, 2022 ClinicalTrials.gov Identifier: NCT04514159 Abemaciclib Combination (N=10) Treatment E
Slide 39: ZN-c5 is not Expected to have DDI with Commonly Used Medicines
ZN-c5 is not Expected to have DDI with Commonly Used Medicines at Relevant Doses Example: For subjects taking atovarstatin, Cholesterol remains well-controlled regardless of ZN-c5 dose ZN-c5: PK | 39(1) Ibrance™ Clin Pharmacology Review 2014 Aug 13. Weighted average from Pfizer studies-1001c and 100
Slide 40: ZN-c5 Safety Profile and Bone Protective Activity vs Other Oral SERDs
Bone Mineral Density in Ovariectomized Mice (Interim Look, 9 weeks) Micro-CT of Trabecular Bone ZN-c5 Safety Profile and Bone Protective Activity Versus Other Oral SERDs Supports Use in Adjuvant Settings 8 weeks – on-going study Sham Vehicle OVX Vehicle OVX ZN-c5 10mpk OVX Fulvestrant 12 weeks; Femu
Slide 41: ZN-d5: BCL2 Inhibitor
2 zentalis ZN-d5: BCL2 Inhibitor
Slide 42: 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 43: BCL-2 Inhibition Has Shown Robust Clinical Activity in AL Amyloidosis
BCL-2 Inhibition has Shown Robust Clinical Activity in AL Amyloidosis ZN-d5: BCL-2 Inhibitor (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
Slide 44: ZN-d5 + ZN-c3: Activity in Hematologic Malignancies and Solid Tumors
Z N - d 5 + Z N - c 3 : A c t i v i t y i n H e m a to l o g i c M a l i g n a n c i e s a n d S o l i d t u m o r s
Slide 45: BH3 Mimetics Synergize with Wee1 Inhibitor ZN-c3
BH3 mimetics synergize with the Wee1 inhibitor ZN-c3 by activating caspases which induce DNA damage and degrade key proteins Hooman Izadi, Noah Ibrahim, Tiffany Hoang, Jianhui Ma, Petrus R. De Jong, Joseph Pinchman, Kevin D. Bunker, Ahmed A. Samatar, Fernando Doñate Combination of the BCL-2 inhibito
Slide 46: 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) | 46 ZN-d5 + ZN-c3 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 tu
Slide 47: 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 gH2AX) • Degradation or decrease of DDR related proteins (Wee1 and RRM2) • These effects are increased when combined with ZN-
Slide 48: BCL-2 and Wee1 Inhibitor Combination Results in Synergism in Tumor Models
The Combination of BCL-2 and Wee1 Inhibitor Results in Synergism in Several Tumor Models Including AML 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 T u m o r V o lu m e ( m m 3 ) ZN-d5 50 mg/kg + ZN-c3
Slide 49: 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 V eh ic le ZN -d 5 20 0 m g/k g ZN -c 3 80 m g/k g ZN -d 5 +ZN -c 3 0 10000 20000 30000 40000 50000 60000 AML PDX model Bone Marrow Analysis h u C D 4 5 + M e a n C e ll N u m b e r Vehicle ZN-d5 200 mg/
Slide 50: 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 T u m o r V o lu m e ( m m 3 ) DMS53 -1
Slide 51: ZN-c3 Combined with Low Dose Navitoclax Enhances Anti-tumor Activity
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 52: Summary
2 zentalis Summary
Slide 53: Summary
Summary ZN-d5 Bcl-2 Inhibitor ZN-c5 Oral SERDZN-c3 Wee1 Inhibitor: A Potential Cornerstone Treatment • ZN-c3 showed strong clinical activity and good tolerability in USC and in combination with chemotherapy in ovarian cancer • Observed overall potential superior profile compared to adavosertib(1-3)
Slide 54: Key Milestones
Key Milestones ZN-c3: Wee1 Inhibitor ZN-c5: Oral SERD 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+ Initial readout on Phase 1/2 chemotherapy combo in osteosarcoma* 1H 2022 1H 2022 2H 2022
Slide 55: Contact
Anthony Sun, M.D., CEO and Chairman asun@zentalis.com (212) 433-3780 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