Zentalis Pharmaceuticals, Inc. · NASDAQ:ZNTL
Zentalis Pharmaceuticals — Corporate Update (June 2021)
44 slides from Zentalis Pharmaceuticals's corporate update, Jun 28, 2021
Slide 1: Mid-Year Update June 2021
Mid-Year Update June 2021 Creating Differentiated Therapies to Improve the Lives of Cancer Patients
Slide 2: Forward-Looking Statements and Disclaimer
Forward-Looking Statements and Disclaimer 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 Private Securities
Slide 3: Mid-Year Update: Executive Summary
Mid-Year Update: Executive Summary • Since AACR 2021, ZN-c3 has generated new clinical responses, further depth of responses, increased durability and improved hematological tolerability; representing one of the most promising clinical advances in DNA Damage Response (DDR) and synthetic lethality to
Slide 4: ZN-c3
4 ZN-c3
Slide 5: ZN-c3 WEE1 Inhibitor - Executive Summary
ZN-c3 WEE1 Inhibitor - Executive Summary Since AACR 2021, ZN-c3 has generated new clinical responses, further depth of responses, increased durability and improved hematological tolerability; representing one of the most promising clinical advances in DNA Damage Response (DDR) and synthetic lethalit
Slide 6: ZN-c3: Clinical Development Plan Overview
ZN-c3: Clinical Development Plan OverviewOngoing and Planned Clinical Programs • Initial Phase 1 monotherapy dose escalation and expansion data (1) – ZN-c3 was well-tolerated as a single agent – RP2D for ZN-c3 determined – ZN-c3 showed Exceptional Responses in heavily pre- treated subjects with adva
Slide 7: ZN-c3: Expanding Indications through Investigator Initiated Studies
ZN-c3: Expanding Indications through Investigator Initiated Studies • New IITs to start: ‒ Glioblastoma Multiforme: Preclinical study completed. Clinical study to commence in 2021 planned ‒ Triple Negative Breast Cancer: Combination with anti-PDL1 and chemotherapy. Clinical study to commence in 2022
Slide 8: ZN-c3 has the Potential to be Both First-in-Class and Best-in-Class
ZN-c3 has the Potential to be Both First-in-Class and Best-in-Class • Key attributes to ZN-c3’s Proof of Concept (POC) success: 1. Target biology known and validated 2. Clinical results shown with monotherapy • ZN-c3’s POC includes: A. Determination of RP2D B. Evidence of relevant clinical activity
Slide 9: Target Biology Known and Validated (Lancet)
1. Target Biology Known and Validated 9 • Publication in Lancet, Jan 23, 2021 • The inhibition of WEE1 has already been shown in a randomized double- blind, placebo-controlled study to exhibit a statistically significant overall survival advantage • Rare for oncology drugs to show a survival advanta
Slide 10: Target Biology Known and Validated (JCO)
1. Target Biology Known and Validated 10 • Publication in JCO March 12, 2021 • A third party WEE1 inhibitor exhibited a 29% ORR in a Phase 2 study in very sick endometrial cancer patients with USC subtype (most of these women die within 5 years upon diagnosis) • AZ has just started a registrational
Slide 11: Evidence of Strong Clinical Activity Shown by ZN-c3
2. Evidence of Strong Clinical Activity Shown by ZN-c3 11 • Clinically relevant responses seen in a refractory solid tumor untargeted all-comer population as monotherapy. Responses seen across four different tumor types signaling potential for broad oncology applicability • We believe this is the fi
Slide 12: Exceptional Responder Clinical Update: Additional Scans Since AACR 2021
2. Exceptional Responder Clinical Update: Additional Scans Since AACR 2021 (Ovarian Cancer Exceptional Responder) 12
Slide 13: Exceptional Responder Clinical Update: Additional Scans Since AACR 2021
13 2. Exceptional Responder Clinical Update: Additional Scans Since AACR 2021 (Ovarian Cancer Exceptional Responder)
Slide 14: RP2D Selected: Interim Plasma Pharmacokinetics
• Greater than dose proportional exposure up to 450 mg (not plotted) • 1.87 to 2.50-fold accumulation at 200- 350 mg dose • No additional increase of exposure occurs beyond Day 15 (up to Cycle 6) • 300 mg dose chosen as RP2D because it exhibited the highest mean AUC between 25-400 mg • 300 mg dose w
Slide 15: RP2D Selected (Cont.): WEE1 Target Engagement in Surrogate Tissue
1. A. RP2D Selected (Cont.) Hair bulb Basal epidermis WEE1 CDK1 Y15 ZN-c3 p-CDK1 = Brown Staining (subject with cPR) Baseline On Treatment Basal epidermis Hair bulb 40x -100% -99% 1. CDK1 phosphorylation by WEE1 2. p-CDK1 inhibition 3. Skin Biopsy 15 Source: Drawing adapted from Servier Medical Art
Slide 16: RP2D Selected (Cont.): WEE1 Target Engagement
A. RP2D Selected (Cont.) 16 M or e W EE 1 Ta rg et E ng ag em en t Higher Drug Exposure 0 5000 10000 15000 20000 -100 -50 0 50 100 Average drug exposure at RP2D of 300mg QD AUC0-24 hr (ng*h/mL) p- CD K1 (% in hi bi tio n) WEE1 Target Engagement • Inhibition of p-CDK1 demonstrated WEE1 target engagem
Slide 17: Strong Comparative Efficacy Data of ZN-c3 vs AZD1775
17 B. Strong Comparative Efficacy Data of ZN-c3 vs AZD1775 • Early study published in JCO Oct 20, 2015, enabling comparison head-to-head with ZN- c3’s monotherapy refractory solid tumor study • Due to tolerability issues for AZD1775 as monotherapy, MTD was established as 225 mg BID for 5 days per 21
Slide 18: Predictive Biomarker Driven Settings
Predictive Biomarker Driven Settings 18 Uterine Serous Carcinoma PARP Combo Chemo Combos Immunotherapy Combo Proprietary Combos Biomarker Identified “Exceptional Responders” Across Tumor Types Representative Indication(s) Orphan Setting ZN-c3 ORR 43% (3/7)1 Clinical Studies Initiated in PARP and Che
Slide 19: Tolerability Profile of ZN-c3
C. Tolerability Profile of ZN-c3 Adverse Events (%) 1.5 1.5 7.6 1.5 1.5 6 9 4.5 1.5 4.5 1.5 6 9 4.5 7.6 7.6 3 7.6 3 7.6 7.6 18.2 42.4 42.4 39.4 63.6 10.6 12.1 13.6 13.6 13.6 13.6 13.6 28.8 45.4 50 51.5 72.7 -100 -75 -50 -25 0 25 50 75 100 Dizziness Dehydration Edema peripheral Weight decreased Dyspn
Slide 20: Safety/Tolerability vs AZD1775
C. Safety/Tolerability vs AZD1775 (1) Adverse Events (%)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-c3 and
Slide 21: Safety/Tolerability vs AZD1775 (Cont.)
C. Safety/Tolerability vs AZD1775 (Cont.) 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-c3 and the Adavos
Slide 22: Path to Potential Accelerated Approvals
• Conducted EOP1 Mtg with FDA re: study ZN-c3-004, a monotherapy trial planned with registrational intent in women with recurrent or persistent USC ‒ Proposed study for ZN-c3-004 designed with registrational intent for potential accelerated approval • In 2H 2021, Zentalis expects to approach FDA wit
Slide 23: Commercial Opportunity
Predictive Biomarker Driven Settings 23 Uterine Serous Carcinoma PARP Combo (e.g., Ovarian) Chemo Combo (e.g., CRC, NSCLC or GBM) Immunotherapy Combos (e.g., TNBC or CRC) Biomarker Identified “Exceptional Responders” Across Tumor Types Representative Indication(s) Orphan Setting Addressable Patient
Slide 24: ZN-c5
24 ZN-c5
Slide 25: ZN-c5 Executive Summary
ZN-c5 Executive Summary • New interim clinical data from Phase 1/2 monotherapy studies suggest ZN- c5 has the potential to be best-in-class with favorable safety/tolerability data in mono and combo settings • New interim clinical data rival other oral SERD efficacy data; awaiting completion of study
Slide 26: ZN-c5: Clinical Development Plan
ZN-c5: Clinical Development Plan 26 Monotherapy Dose Escalation ZN-c5(1) Monotherapy Expansion ZN-c5 (2) Enrolled Combination Dose Escalation ZN-c5 + palbociclib (2) Enrolling Combination Phase 2 ZN-c5 + palbociclib Expected Initiation 2021 Monotherapy Phase 2 ZN-c5 Enrolling Combination Dose Escala
Slide 27: ZN-c5-001: First-in-Human Study - Design & Endpoints
ZN-c5-001: First-in-Human Study - Design & Endpoints • Monotherapy Dose escalation (3+3 design) → Maximum tolerated dose/Recommended Phase 2 Dose • Monotherapy Expansion → Safety and tolerability • Monotherapy Phase 2 → Clinical Benefit Rate (CBR) • Combination with Palbociclib Dose escalation (3+3)
Slide 28: ZN-c5-001: Key Inclusion Criteria
ZN-c5-001: Key Inclusion Criteria 28 Protocol Portion N Prior therapies allowed for advanced/met disease Endocrine-based therapies Chemotherapies Phase 1 Monotherapy Dose Escalation unlimited 0 – 2 Phase 1 Combination Dose Escalation unlimited 0 – 1 Phase 1 Monotherapy Expansion 0 – 2 0 – 1 Phase 2
Slide 29: ZN-c5-001: Baseline Demographics - ZN-c5 Monotherapy
ZN-c5-001: Baseline Demographics - ZN-c5 Monotherapy 29 Patient Characteristics ZN-c5 Monotherapy N = 56 Median age, years (range) 58.5 (38 – 89) ECOG status, n (%) 0 1 2 30 (55%) 25 (45%) 0 N (range) prior lines of therapy (adv/mt) N (range) endocrine-based N (range) chemotherapy N prior CDK4/6i N
Slide 30: New Clinical Data: ZN-c5-001 Monotherapy Efficacy Summary by Dose
New Clinical Data: ZN-c5-001 Monotherapy Efficacy Summary by Dose 30 * Patients with measurable disease Dose (mg) 50 75 100 150 300 Overall N (enrolled) 16 3 3 21 13 56 CBR 2/5 (40%) 0/3 (0%) 1/3 (33%) 4/21 (19%) 7/13 (54%) 14/42 (33%) ORR* 0/14 0/2 0/3 1/13 (8%) 1/8 (13%) 2/40 (5%) Data cut-off 11
Slide 31: ZN-c5-001 Monotherapy 50-100 mg Treatment Duration
PD PD PD SD SD+ SD SD+ SD+ SD+ SD+ SD+ SD SD SD SD24 SD24 PD PD SD PD PD SD24 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 1903-101 102-108 1002-102 102-107 102-109 104-002 (50 mg : M) 109-101 1003-105 1902-101 1902-102 1901-101 1003-103 109-103 1003-104 101-004 (50 mg : M) 104-005 (50 mg
Slide 32: ZN-c5-001 Monotherapy Treatment Duration
SD SD SD SD SD+ SD PD PD PD SD PD SD SD SD SD SD SD SD24 SD24+ SD24+ PR+ SD SD24+ SD24+ NE PD SD SD SD SD24 PR+ SD24 SD24+ SD24+ 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 105-003 (75 mg BID : NM) 107-001 (75 mg BID: M) 105-001 (75mg BID : M) 104-016 (75 mg BID : M) 106-018 (75 mg BID :
Slide 33: ZN-c5-001 Monotherapy Target Lesion Size Change
-100 -80 -60 -40 -20 0 20 40 60 80 100 Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Target Lesion size - % Change from Baseline 101-004 (50 : SD24) 104-002 (50 : SD) 104-006 (75 : PD) 106-007 (75 : PD) 106-009 (100 : SD24) 104-010 (100 : SD) 107-001 (75 BID : SD) 105-001 (75 BID : SD) 104
Slide 34: ZN-c5 Plasma PK Parameters in Combo Arms
New Interim Clinical Data: ZN-c5 Plasma PK Parameters in Combo Arms Confidential34 ZN-c5 Dose (mg) ZN-c5 on Day 1 ZN-c5 on Day 15 ZN-c5 Accum by AUC Cmax (ng/mL) Tmax (hr) AUC0-24hr (ng*h/mL) Cmax (ng/mL) Tmax (hr) AUC0-24hr (ng*h/mL 25 (n=3/2) Mean 2,230 2 26,800 2,360 2 26,500 1.2 SD 447 2-2 7,040
Slide 35: ZN-c5 Window of Opportunity Initial Biomarker Study
35 New Interim Clinical Data: ZN-c5 Window of Opportunity Initial Biomarker Study N Mean STD All doses 21 -17% 22% 25 BID 3 -23% 21% 50 QD 9 -15% 26% 50 mg* 12 -17% 24% 150 mg* 6 -20% 16% 300 QD 3 -8% 29% *total daily dose Linear Regression %H-score change from baseline = intercept + slope*total dai
Slide 36: ZN-c5 Monotherapy – Related AEs in ≥ 10%
New Interim Clinical Data: ZN-c5 Monotherapy – Related AEs in ≥ 10% 36 AEs in N 50 mg QD N = 16 75 mg QD N = 3 100 mg QD N = 3 75 mg BID N = 6 150 mg QD N = 15 150 mg BID N = 3 300 mg QD N = 10 Total N = 56 Grade 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 All N (%) Any AE 6 2 0 1 0 0 0 0 0 2 2
Slide 37: ZN-c5 Combination with Palbociclib – Related TEAEs ≥ 10%
New Interim Clinical Data: ZN-c5 Combination with Palbociclib – Related TEAEs ≥ 10% 37 25 mg QD N = 6 25 mg BID N = 5 50 mg QD N = 13 50 mg BID N = 2 100 mg QD N = 12 150 mg QD N = 3 Total N = 41 Grade 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 Any AE 4 1 1 2 2 1 7 5 1 1 5 2 5 3 9 16 14
Slide 38: ZN-d5
38 ZN-d5
Slide 39: ZN-d5: Clinical Development Plan
ZN-d5: Clinical Development Plan 39 Ongoing and Planned Clinical Programs AML and Non-Hodgkin’s Lymphoma: Monotherapy Dose Escalation Initiated 4Q 2020 Phase 1 Phase 2 Undisclosed Indication: Phase 1b Combination Study Expected Initiation 1H 2022 Monotherapy Phase 2 Study Expected Initiation 1Q 2022
Slide 40: ZN-d5 Update
ZN-d5 Update • ZN-d5 is a highly selective, oral BCL-2 inhibitor • In internal preclinical studies, ZN-d5 is 14x more selective for BCL-2 over BCL-xL than venetoclax, potentially yielding less thrombocytopenia • Entered the clinic in October 2020 in a dose-escalation study in relapsed/ refractory no
Slide 41: ZN-e4
41 ZN-e4
Slide 42: ZN-e4 Update
ZN-e4 Update • ZN-e4 is a potent, third generation EGFR inhibitor • Lack of active metabolite binding to wild type EGFR provides potential for better tolerability than osimertinib • First-in-human dose escalation study in EGFR-mutant non-small cell lung cancer is ongoing • Enrolled 26 subjects, both
Slide 43: Milestones
Milestones 2 zentalis
Slide 44: Updated Key Milestones
44 Updated Key Milestones Event Expected Timing ZN-c3 (WEE1 Inhibitor) Initiate Phase 2 monotherapy in uterine serous carcinoma Initiate Phase 1/2 chemotherapy combo in osteosarcoma Initiate Phase 1/2 niraparib combo in ovarian cancer Initiate Phase 1/2 tumor agnostic, predictive biomarker s
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