Slide 1: DKN-01 in Gynecologic Cancers
DKN-01 in Gynecologic Cancers March 22, 2021
Slide 2: Forward Looking Statements
2 Leap Therapeutics | Forward Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future oper
Slide 3: Agenda
3 Leap Therapeutics Cynthia Sirard, MD Chief Medical Officer Jay Baum, PhD Vice President and Head of Translational Medicine On Behalf of the P204 Investigators Rebecca Arend, MD, MSPH AGENDA Associate Professor University of Alabama at Birmingham O’Neal Comprehensive Cancer Center Q&A
Slide 4: DKN-01 in Gynecologic Malignancies
4 DKN-01 in Gynecologic Malignancies
Slide 5: DKK1 in Cancer
5 DKK1 in Cancer • Overexpression of DKK1 linked to poor prognosis • Tumor cells secrete DKK1 promoting proliferation, metastasis and angiogenesis • DKK1 suppresses anti-tumor immune responses • Neutralizing DKK1 activates an innate immune response in oncology models
Slide 6: DKK1 is an Important Target Regulating Key Signaling Pathways
6 DKK1 is an Important Target Regulating Key Signaling Pathways DKK1 inhibits canonical DKK1 indirectly activates DKK1 activates Wnt signaling Figure 2 Figure 2 Figure 2 noncanonical signaling PI3K/AKT signaling A DKK1Ainhibition DKK1A inhibition of DKK1 of B inhibition DKK1 DKK1Bactivation Bofactiv
Slide 7: Wnt/ß-Catenin Activation is Associated With Poor Outcomes in EEC
7 Wnt/ß-Catenin Activation is Associated With Poor Outcomes in EEC Liu et al; 2014 Natl Cancer Inst Kurnit et al; 2017 Mod Pathol • CTNNB1 exon 3 mutations characterize an • Recurrence-free survival for endometrioid endometrial aggressive subset of low-grade and low-stage cancer patients, grade 1-2
Slide 8: Activation of Wnt/ß-catenin-Dependent Signaling Results in Increased Expression of DKK1
8 Activation of Wnt/ß-catenin-Dependent Signaling Results in Increased Expression of DKK1 Stabilizing CTNNB1 Mutant TCGA data. Real World Evidence (RWE) in endometrioid endometrial cancer patients (Tempus) Alterations to S33, *Wnt activating mutations include CTNNB1, AXIN1/2, APC, ZNRF3, RNF43, RSPO
Slide 9: DKN-01: A Humanized Monoclonal Antibody [IgG4] Targeting DKK1
9 DKN-01: A Humanized Monoclonal Antibody [IgG4] Targeting DKK1 • Humanized monoclonal antibody [IgG4] against DKK1 • DKN-01 Mechanism of Action: (1) Direct anti-tumor effects (2) Activates innate immune response (3) Acts as an anti-angiogenic agent • GEJ/GC tumors with DKK1-high expression have dem
Slide 10: Endometrial Cancer
10 Endometrial Cancer • Most common gynecological cancer in the western world 5-Year Overall and Relative Survival • ~62,000 annual cases in the United 100% States and the incidence is increasing 90% 80% 70% • Fourth most common cancer in 60% women in the US 50% 95% 40% 81% 70% • Clinical risk facto
Slide 11: Endometrial Cancer – Four molecular subtypes
11 Endometrial Cancer (EC) – Four molecular subtypes<br />(Integrated genomic, transcriptomic and proteomic characterization) GOG 210 Endometrioid (Cosgrove 2018) Incidence: 49% CNS, 4% POLE mutant, 39% MMR deficient, 8% copy number altered (CNA). Cancer-specific mortality: 5%=CNS ; 2.6% =POLE tumor
Slide 12: Treatment Paradigm for Advanced Endometrial Cancer
12 Treatment Paradigm for Advanced Endometrial Cancer Diagnosis Advanced or Recurrent Endometrial Cancer 1st Line Chemo Regimen Systemic (Carboplatin + Paclitaxel Therapy preferred) Not MSI-H or dMMR Lenvatinib/Pembrolizumab ORR 30% ~50-60% Biomarker Directed MSI-H /TMB-H 2nd Line Pembrolizumab or O
Slide 13: Single Agent Activity in Endometrial Cancer
13 Single Agent Activity in Endometrial Cancer Class Drug name ORR (%) DCR (%) mPFS (mos) Anti-PD(L)-1: MSS/refractory PD-L1+ pembrolizumab 13 26 1.8 dostarlimab 20 - - durvalumab 6 - - avelumab 3 - - Anti-angiogenic bevacizumab 13.5 63.5 4.2 lenvatinib 14.3 - 5.4 mTOR everolimus 9 36 2.8 Cytotoxic
Slide 14: Pembrolizumab + Lenvatinib Data
14 Pembrolizumab + Lenvatinib Data Most common AE’s with Including gastrointestinal disorders: 1.2%, 6% LENVIMA + KEYTRUDA treated patients: 89% 100% hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), vomiting (36.7%), weight decrease cardiac
Slide 15: High DKK1 Is Associated With Poor Response to anti-VEGF and anti-PD-(L)1
15 High DKK1 Is Associated With Poor Response to anti-VEGF and anti-PD-(L)1 in Endometrioid Endometrial Cancer Patients Anti-VEGF treatment PD-(L)1 treatment • TTD: Time to treatment discontinuation • Threshold for DKK1 high vs low mRNA expression devised using an optimal cutoff to maximize hazard r
Slide 16: DKN-01 Phase 2 Study Design
16 DKN-01 Phase 2 Study Design EEC N=29 DKN-01 300 mg Primary objective: Eligible Patients EOC Monotherapy N=14 Objective response • Recurrent EEC • Recurrent platinum- N=52 rate (ORR) resistant/refractory MMMT Secondary objectives: EOC N=9 Exploring genetic • Recurrent MMMT mutations in the Wnt EEC
Slide 17: Wnt Genetic Groups
17 Wnt Genetic Groups Wnt Signaling Alterations Wnt Activating Mutations Genes that are associated with the Wnt A well defined subgroup of the genes associated signaling pathway, either directly or tangentially with Wnt Signaling Alterations Genes: CTNNB1, APC, AXIN1/2, RNF43, ZNRF3, • Alterations t
Slide 18: DKK1 High Expression Is Associated with Wnt Activating Mutations
18 DKK1 High Expression Is Associated with Wnt Activating Mutations • Overall, 21% had Wnt Activating Mutations; most common mutation CTNNB1 (16%) • Tumors with Wnt activating mutations have 14.4 times higher DKK1 expression Distribution of DKK1 RNAscope H-Scores by DKK1 RNAscope Wnt Activating Muta
Slide 19: Endometrial Cancer Patients have Higher DKK1 Expression than Ovarian Cancer Patients
19 Endometrial Cancer Patients have Higher DKK1 Expression than Ovarian Cancer Patients DKK1 Expression 150 RNAscope (H-score) 125 100 Median H-scores EEC: 14 75 EOC: 5 50 25 0 H-score = 115 H-score = 11 CTNNB1(S37F) No mutation 2) 9) =4 =2 (n (n C C EE EO
Slide 20: DKN-01 Was Well Tolerated as Monotherapy and in Combination with Paclitaxel
20 DKN-01 Was Well Tolerated as Monotherapy and in Combination with Paclitaxel • Related SAEs: Most Common DKN-01 Related TEAEs ‒ DKN-01 monotherapy: 5.8% Monotherapy: Combination therapy: • Nausea (28.8%) • Fatigue (30.5%) ‒ DKN-01 + paclitaxel combination: 6.8% • Fatigue (26.7%) • Anemia (27.1%) •
Slide 21: Endometrial Cancer
21 Endometrial Cancer
Slide 22: Demographics & Baseline Tumor Characteristics
22 Demographics & Baseline Tumor Characteristics Patient Characteristics EEC Mono (n=29) EEC Combo (n=24) All EEC (n=53) Tumor Genetics EEC Mono ( n=29) EEC Combo (n=24) All EEC (n=53) Age (yrs), median 63.0 64.5 63.0 Wnt Altered, n (%) 21 (72%) 16 (67%) 37 (70%) White, n 27 (93%) 21 (88%) 48 (91%)
Slide 23: Endometrial Cancer: DKN-01 Monotherapy
23 Endometrial Cancer DKN-01 Monotherapy
Slide 24: DKN-01 Monotherapy - Endometrial Cancer Overall Response
24 DKN-01 Monotherapy - Endometrial Cancer Overall Response • Endometrial cancers with alterations in the Wnt signaling pathway had greater clinical activity than in those without Wnt pathway alterations (ORR: 10% vs 0%, DCR: 48% vs 13%) 220% 20% increase 30% decrease PD 180% 140% 100% PD (%) Change
Slide 25: DKN-01 Monotherapy - Endometrial Cancer Durable Clinical Benefit
25 DKN-01 Monotherapy - Endometrial Cancer Durable Clinical Benefit • Endometrial cancers with alterations in the Wnt signaling pathway had more durable clinical benefit than in those without Wnt pathway alterations 220 20% increase 30% decrease 180 % change in sum of target lesions 140 100 60 20 0
Slide 26: Monotherapy Complete Response in Endometrial Cancer Patient
26 Monotherapy Complete Response in Endometrial Cancer Patient • Resection followed by vaginal cuff brachytherapy. Recurred in right psoas Monotherapy Complete Response in EEC muscle and received local XRT, then 100% carboplatin and paclitaxel which was 75% poorly tolerated with neuropathy % Change
Slide 27: Monotherapy Partial Response in Endometrial Cancer Patient
27 Monotherapy Partial Response in Endometrial Cancer Patient • Resection followed by local vaginal brachytherapy then systemic Monotherapy Partial Response in EEC chemotherapy (carboplatin/paclitaxel) 100% to which she experienced substantial toxicity 80% • Tumor growth within 1 month of 60% % Chan
Slide 28: Endometrial Cancer: Tumoral DKK1 as a Biomarker
28 Endometrial Cancer: Tumoral DKK1 as a Biomarker
Slide 29: DKN-01 Monotherapy - Overall Response by DKK1 Tumoral Expression
29 DKN-01 Monotherapy - Overall Response by DKK1 Tumoral Expression • Endometrial cancer with DKK1-high* tumoral expression have better ORR (14% vs 0%) and clinical benefit (57% vs. 7%) after DKN-01 treatment compared with low DKK1 tumors • 7 patients with unknown DKK1 expression had an additional c
Slide 30: DKN-01 Monotherapy - Durable Clinical Benefit in DKK1-high Tumors
30 DKN-01 Monotherapy - Durable Clinical Benefit in DKK1-high Tumors • High tumoral DKK1 expression have more durable clinical benefit after DKN-01 monotherapy compared with DKK1- low tumors
Slide 31: DKN-01 Monotherapy - Improved PFS with High Tumoral DKK1 Expression
31 DKN-01 Monotherapy - Improved PFS with High Tumoral DKK1 Expression • Tumors with high DKK1 have longer PFS (3.0 vs 1.8 mo [HR 0.39; 95% CI: 0.14, 1.1]) after DKN-01 monotherapy compared with DKK1-low tumors
Slide 32: DKN-01 Monotherapy Sensitivity Analysis
32 DKN-01 Monotherapy Sensitivity Analysis • Sensitivity analysis reflecting 3 patients with known Wnt activating mutations considered to be DKK1-high • Strengthens PFS compared to DKK1 low to 5.8 mos vs 1.8 mos (HR 0.565, 95% CI: 0.25, 1.28)
Slide 33: DKN-01 + Paclitaxel - Durable Clinical Benefit with High DKK1 Tumoral Expression
33 DKN-01 + Paclitaxel - Durable Clinical Benefit with High DKK1 Tumoral Expression • Endometrial cancer with DKK1 high tumoral expression have more durable clinical benefit after DKN-01 + paclitaxel compared with DKK1-low tumors
Slide 34: DKN-01 + Paclitaxel - Improved PFS with High Tumoral DKK1 Expression
34 DKN-01 + Paclitaxel - Improved PFS with High Tumoral DKK1 Expression • Tumors with high DKK1 have longer PFS (5.4 vs 1.8 mo [HR 0.34; 95% CI: 0.12, 0.97]) after DKN-01 + paclitaxel compared with DKK1-low tumors
Slide 35: DKK1 Expression is Higher in Endometrioid Endometrial Carcinoma
35 DKK1 Expression is Higher in Endometrioid Endometrial Carcinoma DKK1 Expression (EEC Histologies) 150 125 RNAscope (H-score) 100 75 Median H-score Endometrioid: 18 Non Endometrioid: 11 50 25 0 5) 7) =1 =2 Endometrioid (n (n id id rio ri o et et m m do do En En on N Non Endometrioid histologies ar
Slide 36: Pooled Endometrial Cancer - Overall Response in Endometrioid Histology by Tumoral DKK1 Expression
36 Pooled Endometrial Cancer - Overall Response in Endometrioid Histology by Tumoral DKK1 Expression • Tumors with high DKK1 have better ORR (7% vs. 0 %) and DCR (57% vs 15%) after DKN-01 treatment compared with DKK1-low tumors DKK1 Expression and BOR 140 120 RNAscope (H-score) 100 PR (n=1) 80 SD (n
Slide 37: Pooled Endometrial Cancer - Durable Clinical Benefit in Endometrioid Histology
Pooled Endometrial Cancer - Durable Clinical Benefit in Endometrioid 37 Histology by DKK1 Tumoral Expression • Endometrial cancer with DKK1 high tumoral expression have more durable clinical benefit after DKN-01 treatment compared with low DKK1 tumors
Slide 38: Pooled Endometrial Cancer - PFS in Endometrioid Histology by Tumoral DKK1 Expression
38 Pooled Endometrial Cancer - PFS in Endometrioid Histology by Tumoral DKK1 Expression • Tumors with high DKK1 have better PFS (4.1 vs 1.8 mo [HR 0.34; 95% CI: 0.14, 0.81]) after treatment compared with low DKK1 tumors
Slide 39: Conclusions
39 Conclusions ► DKN-01 (anti-DKK1 antibody) is safe and well tolerated as either a monotherapy or in combination with paclitaxel ► DKN-01 monotherapy demonstrated clinical activity in unselected heavily-pretreated endometrial cancer patients including a complete response ► High tumoral DKK1 express
Slide 40: Q&A
40 Q&A