Slide 1: Sirexatamab (DKN-01) Clinical Development: Initial Data from DeFianCe Part B and DisTinGuish Part C
company presentation LEAP THERAPEUTICS Sirexatamab (DKN - 01) Clinical Development Initial Data from Part B of the DeFianCe Study and Part C of the DisTinGuish Study January 28, 2025
Slide 2: Forward looking statements
Forward looking statements 2 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 operations, clinical t
Slide 3: Sirexatamab (DKN-01) Anti-DKK1 monoclonal antibody
SIREXATAMAB (DKN - 01) Anti - DKK1 monoclonal antibody
Slide 4: The role of DKK1 in cancer
The role of DKK1 in cancer 4 Tumor CKAP4 Angiogenesis Akt PI3K Cancer cell Cancer cells DKK1 is produced and secreted by cancer cells, and functions on several tumor pathways and nearby immune cells. Enhances the suppressive activity of MDSCs and M2 macrophages. Reduces NK cell activity and T - cell
Slide 5: DKK1 production from multiple sources can drive tumor growth
DKK1 production from multiple sources can drive tumor growth 5 Tumor DKK1 DKK1 Bone DKK1 low DKK1 high Blood vessel ELISA Enzyme - Linked Immunosorbent Assay DKK1 RNA from the tumor is measured by RNAscope DKK1 protein in circulation is measured by ELISA
Slide 6: Activity of sirexatamab (DKN-01) to treat cancer
Activity of sirexatamab (DKN - 01) to treat cancer 6 CKAP4 Angiogenesis Akt PI3K Cancer cell Cancer cells Tumor Cancer cell DKK1 Sirexatamab ( DKN - 01 ) treatment neutralizes DKK1 and stimulates an immune mediated anti - tumor response. sirexatamab ( DKN - 01 ) A ctivates NK cells, reprograms macro
Slide 7: Sirexatamab (DKN-01) Colorectal cancer development
SIREXATAMAB (DKN - 01) Colorectal cancer development
Slide 8: DeFianCe study design
DeFianCe study design 8 Randomized phase 2 study of FOLFIRI/FOLFOX and b evacizumab +/ - sirexatamab ( DKN - 01 ) as second - line treatment of advanced colorectal cancer Primary : PFS overall and in left - sided mCRC (Investigator A ssessed ) Secondary: • PFS overall and in left - sided mCRC (BICR)
Slide 9: Bevacizumab benchmark studies demonstrate need for new options in second-line
Bevacizumab benchmark studies demonstrate need for new options for today’s heterogeneous second - line patient population ML18147 409 5.4% E3200 286 22.7% SLAVE 228 25.7% Bevacizumab + Chemo Bevacizumab + Chemo Bevacizumab + Chemo * *SLAVE included N=198 left sided CRC patients. This subgroup has an
Slide 10: DeFianCe Part B: patient disposition as of January 3, 2025
• Mean duration on treatment: • Experimental Arm 6.00 months • Control Arm 5.75 months • Experimental Arm • 49% of subjects off therapy • Control Arm • 59% of subjects off therapy DeFianCe Part B: As of January 3, 2025 1 0 *Data cutoff 01/03/25 N=235 Screened N=94 Randomized (Control) n=47 Not Rando
Slide 11: Part B: Population demographics
Part B: Population demographics 11 Control Arm N=94 n (%) Experimental Arm N=94 n (%) N=188 52 (55) 64 (68) Male 42 (45) 30 (32) Female 58.7 (29, 84) 59.6 (33, 84) Age, mean (min, max) Geography 40 (43) 41 (44) United States 45 (48) 50 (53) South Korea 9 (10) 3 (3) Germany Tumor Sidedness 21 (22) 23
Slide 12: Part B: Overall safety summary
Part B: Overall safety summary 12 * SAEs assessed as related to sirexatamab (DKN - 01) occurred in 5 subjects and include diarrhea (n=2), vomiting (n=1), anal fistula (n=1), enterovesical fistula (n=1), infusion related reaction (n=1), and confusional state (n=1). + Unrelated to siexatamab (DKN - 01
Slide 13: Intent-to-Treat Population
INTENT - TO - TREAT POPULATION January 2025
Slide 14: Sirexatamab improved ORR by 12% (35% vs. 23%)
Sirexatamab improved ORR by 12% (35% vs. 23%) Intent - to - Treat (ITT) population 14 Bevacizumab + (FOLFOX/FOLFIRI) N= 94 DKN - 01 + bevacizumab + (FOLFOX/FOLFIRI) N= 94 n (%) n (%) Response 2 (2) 0 (0) CR 20 (21) 33 (35) PR 23% 35% ORR 57 (61) 48 (51) SD 84% 86% DCR 7 (7) 6 (6) PD 8 (9) 7 (7) No a
Slide 15: Progression-free survival not yet mature
Progression - free survival not yet mature ITT population 15 • 75 PFS events • 37 Experimental Arm • 38 Control Arm • 82 Patients still on therapy • 46 Experimental Arm • 36 Control Arm
Slide 16: DKK1 correlates with increasing sirexatamab clinical benefit
DKK1 correlates with increasing sirexatamab clinical benefit ITT population by DKK1 levels 16 Bev + (FOLFOX/ FOLFIRI), Upper quartile N=18 DKN - 01 + Bev + (FOLFOX/ FOLFIRI), Upper quartile N= 25 Bev + (FOLFOX/ FOLFIRI), Median N= 36 DKN - 01 + Bev + (FOLFOX/ FOLFIRI), Median N= 49 n (%) n (%) n (%)
Slide 17: High DKK1 levels correlated with enhanced responses on sirexatamab therapy
High DKK1 levels correlated with enhanced responses on sirexatamab therapy 17 75% Cut 50% Cut Responders (CR, PR) Non - Responders • DKK1 levels corresponded with Experimental Arm ORR advantage across 2L CRC • Enhanced improvement at 50% Median Level, that continues to expand at the 75% Upper Quarti
Slide 18: Tumor Sidedness Subgroup
TUMOR SIDEDNESS SUBGROUP January 2025
Slide 19: Sirexatamab improved ORR in both left and right sided tumors
Sirexatamab improved ORR in both left and right sided tumors Tumor sidedness subgroup 19 SOC Right N=21 DKN - 01 + SOC Right N=23 SOC Left N=73 DKN - 01 + SOC Left N=71 n (%) n (%) n (%) n (%) Response 0 (0) 0 (0) 2 (3) 0 (0) CR 4 (19) 6 (26) 16 (22) 27 (38) PR 19% 26% 25% 38% ORR 13 (62) 13 (57) 44
Slide 20: Sirexatamab improved ORR by 13% (38% vs. 25%) in left-sided subgroup
Sirexatamab improved ORR by 13% (38% vs. 25%) Left - sided subgroup 20 No Assessment PD DCR ORR Left - sided 7% 6% 87% 38% Experimental Arm 7% 8% 85% 25% Control Arm
Slide 21: DKK1 correlates with clinical benefit in left-sided subgroup
DKK1 correlates with increasing sirexatamab clinical benefit Left - sided subgroup by DKK1 levels 21 SOC Left - sided, Upper Quartile N=13 DKN - 01 + SOC Left - sided, Upper Quartile N=21 SOC Left - sided, Median DKK1 N=28 DKN - 01 + SOC Left - sided, Median DKK1 N=37 n (%) n (%) n (%) n (%) Respons
Slide 22: Anti-VEGF Exposure Subgroup
ANTI - VEGF EXPOSURE SUBGROUP January 2025
Slide 23: Sirexatamab improved ORR in VEGF-naïve patients by 22%
Sirexatamab improved ORR in VEGF - naïve patients by 22% Anti - VEGF exposure subgroup 23 SOC Prior anti - VEGF N=49 DKN - 01 + SOC Prior anti - VEGF N=45 SOC No prior anti - VEGF N=45 DKN - 01 + SOC No prior anti - VEGF N=49 n (%) n (%) n (%) n (%) Response 0 (0) 0 (0) 2 (4) 0 (0) CR 9 (18) 8 (18)
Slide 24: Sirexatamab improved ORR by 22% (51% vs. 29%) in no prior anti-VEGF subgroup
Sirexatamab improved ORR by 22% (51% vs. 29%) No prior anti - VEGF subgroup 24 No Assessment PD DCR ORR No Prior anti - VEGF 6% 0% 94% 51% Experimental Arm 7% 9% 84% 29% Control Arm
Slide 25: DKK1 correlates with clinical benefit in anti-VEGF exposure subgroup
DKK1 correlates with increasing sirexatamab clinical benefit Anti - VEGF exposure subgroup by DKK1 levels 25 SOC Anti - VEGF Exposure, Upper Quartile N=7 DKN - 01 + SOC Anti - VEGF Exposure, Upper Quartile N=9 SOC Anti - VEGF Exposure, DKK1 Median N=15 DKN - 01 + SOC Anti - VEGF Exposure, DKK1 Media
Slide 26: Anti-EGFR Exposure Subgroup
ANTI - EGFR EXPOSURE SUBGROUP January 2025
Slide 27: Sirexatamab improved ORR by 27% (54% vs. 27%) in anti-EGFR exposure subgroup
Sirexatamab improved ORR by 27% (54% vs. 27%) Anti - EGFR exposure subgroup 27 No Assessment PD DCR ORR Prior anti - EGFR 11% 0% 89% 54% Experimental Arm 0% 18% 82% 27% Control Arm
Slide 28: RAS Mutational Status Subgroup
RAS MUTATIONAL STATUS SUBGROUP January 2025
Slide 29: Sirexatamab improved ORR in both RAS-wt and RAS-mut patients
Sirexatamab improved ORR in both RAS - wt and RAS - mut patients RAS mutational status subgroup 29 SOC RAS mut N=52 DKN - 01 + SOC RAS mut N=43 SOC RAS wt N=25 DKN - 01 + SOC RAS wt N=35 n (%) n (%) n (%) n (%) Response 0 (0) 0 (0) 2 (8) 0 (0) CR 10 (19) 11 (26) 6 (24) 15 (43) PR 19% 26% 32% 43% ORR
Slide 30: Sirexatamab improved ORR by 11% (43% vs. 32%) in RAS wildtype subgroup
Sirexatamab improved ORR by 11% (43% vs. 32%) RAS wildtype subgroup 30 No Assessment PD DCR ORR RAS Wildtype 3% 0% 97% 43% Experimental Arm 0% 12% 88% 32% Control Arm
Slide 31: Sirexatamab enhanced ORR in patients with high DKK1
Sirexatamab enhanced ORR in patients with high DKK1 31 DKK1 high (top quartile) DKK1 high (median) All Patients Control Experimental Control Experimental Control Experimental Group 11% 48% 22% 39% 23% 35% ITT 8% 52% 25% 43% 25% 38% Left - sided 20% 25% 13% 25% 18% 18% Right - sided 18% 56% 33% 56% 2
Slide 32: Summary of preliminary results
Summary of preliminary results 32 • In this 188 patient randomized controlled trial, sirexatamab (DKN - 01) plus bevacizumab and chemotherapy is demonstrating higher ORR as 2L therapy for MSS CRC than bevacizumab and chemotherapy alone • The PFS data is not mature, however early separation in the K
Slide 33: Potential Phase 3 Trial: 2nd Line Metastatic CRC
Potential Phase 3 Trial: 2 nd Line Metastatic CRC 33 Primary Endpoint • BICR assessed Objective Response Rate (Accelerated Approval) • Overall Survival (Confirmatory Endpoint) Potential patient populations • DKK1 - high • A nti - VEGF naïve • EGFR experienced • RAS wildtype Chemo + bev + placebo Pat
Slide 34: Sirexatamab (DKN-01) Gastric cancer development
SIREXATAMAB (DKN - 01) Gastric с ancer development
Slide 35: Part C: DisTinGuish Study First Line GEJ/Gastric Cancer
Part C: DisTinGuish Study FIRST LINE GASTROESOPHAGEAL JUNCTION / GASTRIC CANCER
Slide 36: DisTinGuish Part C randomized study
DisTinGuish Part C randomized study 36 Sirexatamab ( DKN - 01 ) + tislelizumab + SOC chemotherapy ( CAP OX or mFOLFOX6) Tislelizumab + SOC chemotherapy ( CAP OX or mFOLFOX6) N=8 5 N=8 5 Stratification factors: • DKK1 expression (TPS ≥ 20% vs < 20%) • PD - L1 (CPS ≥5 vs < 5) Key eligibility criteria:
Slide 37: Rationale-305 study: tislelizumab + chemotherapy in 1L GEJ/GC
OR R (%) (95 % CI) DO R mo n ths (95% CI) P F S mo n ths (95% CI) O S mo n ths (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) All Patients 40.5 % ( 36.2 % , 45.0 %) 47 .3 % (4 2.9 % , 5 1.8 %) 6.2 (5.6, 6.9 ) 6.9 (5.7, 7.2 ) 12.9 ( 12.1, 14.1 ) 15.0 (1 3.6 , 16.5 ) 8.6 ( 7.9, 11.0 ) 7.2 ( 6.0, 8.5 ) C
Slide 38: DisTinGuish Trial: Consort Diagram
DisTinGuish Trial: Consort Diagram *Data extraction 12/16/24 38 • More Control Arm patients discontinued for patient decision (10 vs 1) • More Control Arm patients have withdrawn consent or are lost to follow - up, affecting OS and PFS endpoints (15 vs. 4) N=298 Screened n=128 Not Randomized • Patie
Slide 39: Demographics: Intent-to-Treat Population (ITT)
Demographics: Intent - to - Treat Population (ITT) 39 Tislelizumab + (CAPOX/FOLFOX) (N=85)[ n, %] DKN - 01 + tislelizumab + (CAPOX/FOLFOX) (N=85) [n, %] Description 64 (75) 59 (69) Male Gender 21 (25) 26 (31) Female 60 59 Mean (Std) Age (yrs) 51 (60) 49 (58) South Korea Region 30 (35) 30 (35) United
Slide 40: Summary of Safety Events
Summary of Safety Events Safety Population 40 tislelizumab + (CAPOX/FOLFOX) N=85 n (%) DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=84 + n (%) 84 (99) 84 (100) Treatment Emergent Adverse Events 34 (40) 38 (45) Serious Treatment Emergent Adverse Events 51 (60) 54 (64) Severe Treatment Emergent Adverse
Slide 41: Confirmed ORR in ITT Population by BICR and Investigator
Confirmed ORR in ITT Population by BICR and Investigator 41 tislelizumab + (CAPOX/FOLFOX) N=85 DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=85 n (%) n (%) Response 11 (13) 9 (11) CR 25 (29) 35 (41) PR 36 (42) [31.7, 53.6] 44 (52) [40.7, 62.7] ORR 95% CI 23 (27) 18 (21) SD 20 (24) 15 (18) Non - CR / No
Slide 42: Confirmed ORR in DKK1-high Population by BICR and Investigator
Confirmed ORR in DKK1 - high Population by BICR and Investigator 42 • Experimental Arm has a higher confirmed ORR by BICR: 59% vs. 36% • C onfirmed ORR by Investigator Assessment are the same in both arms: 64% vs. 64% • Investigator Assessment identified 6 additional confirmed responses in the Contr
Slide 43: Confirmed ORR in PD-L1 Negative Population
Confirmed ORR in PD - L1 Negative Population 43 • Experimental Arm has a higher confirmed ORR by BICR: 44% vs. 32% • Confirmed ORR by Investigator Assessment favors Experimental Arm: 50% vs. 37% Blinded Independent Central Review Investigator Assessment tislelizumab + (CAPOX/FOLFOX) N=19 DKN - 01 +
Slide 44: ITT Population PFS by BICR and Investigator Assessment
ITT Population PFS by BICR and Investigator Assessment 44 Blinded Independent Central Review Investigator Assessment • Median PFS for the Control Arm is 3.5 months longer by Investigator Assessment and 5.1 months longer by BICR than the median PFS for tislelizumab in Rationale - 305 of 6.9 months (9
Slide 45: DKK1-high Population (TPS > 20) PFS by BICR and Investigator Assessment
DKK1 - high Population (TPS > 20) PFS by BICR and Investigator Assessment Blinded Independent Central Review Investigator Assessment 45 • PFS HR by BICR favors the Experimental Arm: 0.68 • PFS HR by Investigator Assessment favors the Control Arm: 1.5 (BICR disagreed with PD in 43% of the Investigato
Slide 46: PD-L1 Negative Population PFS by BICR and Investigator Assessment
PD - L1 Negative Population PFS by BICR and Investigator Assessment 46 Blinded Independent Central Review Investigator Assessment • PFS HR by Investigator Assessment favors the Experimental Arm: 0.55 (Experimental median 9.82 months vs. Control 7.46 months) • PFS HR by BICR shows no benefit: 0.96 (e
Slide 47: Summary of preliminary results
Summary of preliminary results The BICR results demonstrate improved Confirmed ORR favoring the Experimental Group in: 47 Control Experimental n Group 42% 52% 170 Intent - to - treat 36% 59% 44 DKK1 - high TPS > 20 32% 44% 37 PD - L1 Negative • The BICR results demonstrate improved PFS trends favori
Slide 48: Conclusions
CONCLUSIONS leaptherapeutics
Slide 49: Summary of preliminary results – DeFianCe 2L CRC study
Summary of preliminary results – DeFianCe 2L CRC study 49 • ORR benefit observed across multiple potential Phase 3 CRC populations • DKK1 levels highly correlated with clinical activity in 2L CRC • Preparations will begin for a registrational Phase 3 study in 2L CRC patients while follow - up contin