Cypherpunk Technologies Inc. · NASDAQ:CYPH
Cypherpunk Technologies — Leap Therapeutics — Investor Presentation (January 2024)
44 slides from Cypherpunk Technologies's investor presentation, Jan 23, 2024
Slide 1: Company presentation
company presentation LEAP THERAPEUTICS January 23, 2024
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 tri
Slide 3: Developing biomarker-targeted antibody therapies for cancer patients
Developing biomarker-targeted antibody therapies for cancer patients 3 Two clinical stage antibody programs – DKN-01 targeting DKK1 FL-301 targeting CLDN18.2 Upcoming multiple milestones from two randomized clinical trials Biomarker strategy, focus on GI cancers Cash runaway to Q2 2025 with $70M at
Slide 4: Pipeline
Pipeline 4 Indication: Treatment: Preclinical Phase 1 Phase 2 Phase 3 Partners: DKN-01 Anti-DKK1 antibody tislelizumab + chemotherapy bevacizumab + chemotherapy pembrolizumab FL-302 (NBL-016) Anti-CLDN18.2/CD137 bispecific antibody FL-301 (NBL-015) Anti-CLDN18.2 antibody Gastric cancer Gastric cance
Slide 5: DKN-01 Anti-DKK1 monoclonal antibody
DKN-01 Anti-DKK1 monoclonal antibody
Slide 6: The role of DKK1 in cancer
The role of DKK1 in cancer 6 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 i
Slide 7: Activity of DKN-01 to treat cancer
Activity of DKN-01 to treat cancer 7 CKAP4 Angiogenesis Akt PI3K Cancer cell Cancer cells Tumor Cancer cell DKK1 DKN-01 treatment neutralizes DKK1 and stimulates an immune mediated anti-tumor response. DKN-01 DKN-01 activates NK cells, reprograms macrophagesinto the tumor-attacking M1 subtype and pr
Slide 8: DKN-01 and anti-PD-1 cooperativity
DKN-01 and anti-PD-1 cooperativity 8 Anti-PD1 Anti-PD1 PD1 DKN-01 targets innate immunity by activating NK cells, reprogramming Macrophages and inhibiting MDSCs, thus setting the stage for an enhanced adaptive immune response by anti-PD-1. Promotes a pro-inflammatory M1 macrophage phenotype. DKN-01
Slide 9: DKN-01 Gastric cancer development
DKN-01 Gastric сancer development
Slide 10: DKK1-high levels are associated with poor survival in gastric cancer
DKK1-high levels are associated with poor survival in gastric cancer 10 Strata 21 34 7 1 1 20 4 0 0 100 200 300 time to treatment discontinuation (days) High levels of DKK1 correlate with shorter overall survival In gastric cancer TCGA STAD dataset DKK1-high is associated with poor response to first
Slide 11: DKN-01 single agent activity in heavily pretreated esophagogastric cancer patients
DKN-01 single agent activity in heavily pretreated esophagogastric cancer patients 11 Baseline 4-month scan On Study 1 Year, Reduction -33.9% Failed Prior anti-PD-L1 + IDOi Best Overall Response of 20 Evaluable Patients* Partial Response 2 Stable Disease 6 Progressive Disease 12 *By Blinded Independ
Slide 12: Clinical activity of DKN-01 plus paclitaxel or anti-PD-1 antibody
*DKK1-high ≥ upper tertile (35) Clinical activity of DKN-01 plus paclitaxel or anti-PD-1 antibody 12 PD PD PD PD PD PDPD PD PD PD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD PD PD PD PD PD PD PD PD PD PD PR PR PR PR PR PR PR PR PR PR PR PR PR PD PD PD PD PD PD PD PD PD PD PD PD SD SD SD
Slide 13: Response by DKK1 expression in first-line patients
mITT* population N=22 DKK1-high N=10 DKK1-low N=9 DKK1-unknown N=3 CR - complete response 1 (5%) 0 1 (11%) 0 PR - partial response 15 (68%) 9 (90%) 5 (56%) 1 (33%) SD - stable disease 5 (23%) 0 3 (33%) 2 (67%) PD - progressive disease 0 0 0 0 NE - non-evaluable 1 (5%) 1 (10%) 0 0 Response by DKK1 ex
Slide 14: Response by PD-L1 expression
Response by PD-L1 expression 14 86% ORR in PD-L1 low patients Best % change in sum of diameters vCPS: visually-estimated combined positive score; PD-L1: programmed death-ligand 1 *Includes one pathologic CR As presented at ASCO 2023 1L GEJ/GC DKN-01 + tislelizumab + chemotherapy CR - complete respon
Slide 15: Progression-free survival
Progression-free survival 15 Overall Population DKK1-high: H-score ≥35; | DKK1-low: H-score <35 | PD-L1: Programmed Death-Ligand 1 | vCPS: Visually-Estimated Combined Positive Score As presented at ASCO 2023 ≥5 <5 Unknown 6 5 4 3 2 2 16 15 13 12 10 10 8 7 7 6 4 3 0 3 3 2 2 2 2 2 2 2 1 1 1 0 12 12 3
Slide 16: Overall survival
Overall survival 16 DKK1-high: H-score ≥35; | DKK1-low: H-score <35 | PD-L1: Programmed Death-Ligand 1 | vCPS: Visually-Estimated Combined Positive Score As presented at ASCO 2023 Overall Population ≥5 <5 Unknown Obverall 25 24 21 20 19 9 7 6 3 0 6 6 5 5 5 4 4 4 3 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Slide 17: DKK1 and PD-L1 expression are not correlated
DKK1 and PD-L1 expression are not correlated 17 This population had low overall PD-L1 expression 1L GEJ/GC DKN-01 + tislelizumab + chemotherapy 200 300 100 10 20 30 40 50 60 70 80 90 100 0 DKK1 expression (H-score) 0-300 PD-L1 expression (CPS) 0 - 100 DKK1 0 Spearman correlation r = 0.061 p-value (t
Slide 18: Competitive benchmarks for anti-PD-1 + chemotherapy in 1L GEJ/GC patients
Competitive benchmarks for anti-PD-1 + chemotherapy in 1L GEJ/GC patients 18 Nivolumab Checkmate-649 ORR (%) (95% CI) 50.4% (44.3%, 56.4%) 50% (46%, 55%) 47% (43%, 50%) 9.0 (8.2, 19.4) 9.6 (8.2, 12.4) 8.5 (7.7, 9.9) 8.3 (7.0, 9.3) 7.7 (7.1, 8.6)) 8.6 (7.9, 11.1) DOR months (95% CI) PFS months (95% C
Slide 19: DisTinGuish Part C randomized study
DisTinGuish Part C randomized study 1L GEJ/GC DKN-01 + tislelizumab + chemotherapy 19 DKN-01 + tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) Tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) N=85 N=85 Stratification factors: • DKK1 expression (TPS ≥ 20% vs < 20%) • PD-L1 (CPS ≥5 vs < 5) Key
Slide 20: DKN-01 Colorectal cancer development
DKN-01 Colorectal cancer development
Slide 21: Rationale for targeting colorectal cancer with DKN-01
Rationale for targeting colorectal cancer with DKN-01 DKK1 expression is the highest in metastatic rectum 21 • CRC is characterized by hyperactivation of the Wnt pathway, often believed to be the initiating and driving event • Consensus Molecular Subtype 2 primarily in left-sided tumors • DKK1 highe
Slide 22: DKN-01 has activity in CRC models in combination with bevacizumab or 5FU
DKN-01 has activity in CRC models in combination with bevacizumab or 5FU HCT116 • DKN-01 has efficacy in CRC syngeneic models including HCT116 • Additive activity was seen with bevacizumab • In a 5FU chemotherapy-resistant model, DKN-01 demonstrates significant inhibition of tumor growth alone and w
Slide 23: DeFianCe study design: advanced colorectal cancer
DeFianCe study design: advanced colorectal cancer 23 Randomized phase 2 study of FOLFIRI/FOLFOX and bevacizumab +/- DKN-01 as second-line treatment of advanced colorectal cancer 2L CRC DKN-01 + bevacizumab + chemotherapy Primary objective: PFS Secondary objectives: – ORR – DoR – OS DKN-01 + SOC chem
Slide 24: Overall response rate exceeded 20% target with high disease control rate
Overall response rate exceeded 20% target with high disease control rate 24 ORR in RE patients: 8/27 = 30% DCR in RE patients: 25/27 = 93% Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) Overall, n=27 30 93 8 (30) 17 (63) 2 (
Slide 25: Greater activity in left-sided tumors subgroup
Greater activity in left-sided tumors subgroup 25 • 9 patients who remain on study therapy are left-sided, 6 of whom are rectal/rectosigmoid patients Treatment ongoing Overall, n=27 Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n
Slide 26: Enriched responses in rectal/rectosigmoid cancer patients
Enriched responses in rectal/rectosigmoid cancer patients 26 Overall, n=13 Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) Rectal 46 100 6 (46) 7 (54) 0 (0) 6 of the 8 responding patients were in the rectal/rectosigmoid subgr
Slide 27: Duration of clinical benefit
27 Duration of clinical benefit Tumor sidedness subgroup As presented at ASCO GI 2024
Slide 28: Progression-free survival
Progression-free survival 28 Median PFS: 6.3 months 6-month PFS rate: 55.2% • Heterogeneous population included many unfavorable subgroups • 9 patients remain on therapy at a minimum of 8.5 months on therapy As presented at ASCO GI 2024
Slide 29: PFS still maturing with patients continuing on therapy
PFS still maturing with 6 patients continuing on therapy Rectal/rectosigmoid cancer subgroup 29 Preliminary median PFS: 9.4 months 6-month PFS rate: 57.1% As presented at ASCO GI 2024
Slide 30: Baseline circulating DKK1 correlates with improved responses
Baseline circulating DKK1 from rectal cancer patients demonstrates higher expression in partial responders (n=6) as compared to stable disease or progressive disease patients (n=7). DKK1 plasma levels were analyzed using the SomaScan platform (SomaLogic; Boulder, CO). Data shown as median plasma val
Slide 31: DKN-01 Endometrial cancer development
DKN-01 Endometrial cancer development
Slide 32: DKN-01 monotherapy - overall response by DKK1 tumoral expression
Status Total CR PR SD PD NE ORR DCR DKK1-high (≥18)* n=8 1 1 3 3 0 25% 63% DKK1-low (<18) n=15 0 0 1 11 3 0% 7% Unknown n=6 0 0 5 1 0 0% 83% DKN-01 monotherapy - overall response by DKK1 tumoral expression 32 CR PR SD SD PD PD PD PD PD PD PD PD PD PD PD PD PD SD SD SD — PD — PD SD SD SD SD — *H-scor
Slide 33: Complete response in endometrial cancer patient on DKN-01 monotherapy
Complete response in endometrial cancer patient on DKN-01 monotherapy 33 Maximum percent ecrease -100% -60% -20% -80% -40% 0% 37.5% 56% tumor reduction CR Treatment: DKN-01 monotherapy Patient: 60 yo female with recurrent endometrial cancer Prior treatment: radiation and chemotherapy poorly tolerate
Slide 34: DKN-01 plus pembrolizumab endometrial cancer study
DKN-01 plus pembrolizumab endometrial cancer study 34 * Move to Stage II based on ORR in Stage I 2-3L EEC DKN-01 + pembrolizumab Key eligibility criteria: • > 18 years of age • Pathology-confirmed advanced or recurrent endometrial carcinoma • Non-endometrioid histologies included with a Wnt activati
Slide 35: FL-301 and FL-302 Anti-Claudin18.2 antibodies
FL-301 (NBL-015) FL-302 (NBL-016) Anti-Claudin18.2 antibodies
Slide 36: The role of Claudin18.2
The role of Claudin18.2 36 Normal epithelial cells • Regulates barrier properties and contributes to cell-to-cell adhesion. • Expression very limited in normal tissue. • Typically buried in the tight junction complex of gastric mucosal cells. Cancer cells • In cancer, cells lose their polarity and s
Slide 37: FL-301 is a potential best-in-class anti-Claudin18.2 antibody
FL-301 (NBL-015) is a potential best-in-class anti-Claudin18.2 antibody with enhanced tumor killing efficacy 37 FL-301 CLDN18.2 Efficacy could extend to patients with lower CLDN18.2 expression that other currently used anti-CLDN18.2 antibodies. Engineered Fc High affinity Fab Higher affinity Fully h
Slide 38: FL-302 Claudin18.2-CD137 bispecific antibody program
FL-302 (NBL-016) Claudin18.2-CD137 bispecific antibody program 38 FL-302 CLDN18.2-CD137 0 30 3000 2000 1000 0 Tumor volume (mm3 ) Days post implantant Control Tumor free: 0% 5 mg/kg Tumor free: 67% Tetravalent construct СLDN18.2-CD137 High affinity to claudin18.2 СLDN18.2 CD137 CLDN18.2 dependent T
Slide 39: FL-501 Anti-GDF15 monoclonal antibody
FL-501 Anti-GDF15 monoclonal antibody
Slide 40: The role of GDF15 in cancer
The role of GDF15 in cancer 40 Cancer cells GDF15 expression leads to a reduction in T cell infiltration and increase in Treg function. Cancer cell GDF15 GDF15 experessed by tumors is also able to drive cancer progression by promoting an immunosuppressive tumor microenvironment. Tumor
Slide 41: FL-501 mechanism of action
FL-501 mechanism of action Cancer cells Inhibition of GDF15 by FL-501 may promote immune stimulation in a broad range of cancers. T T reg FL Tumor -501 is designed to block the immune inhibitory activity of GDF15. Cancer cell FL-501 GDF15
Slide 42: Corporate
CORPORATE La. 3 om. + . ~ Rs Ay sstttees leaptherapeutics
Slide 43: Management team
Management team 43 Christine Granfield Vice president, head of regulatory affairs and quality Cyndi Sirard, MD Chief medical officer Jason Baum, PhD Chief scientific officer Walter Newman, PhD Senior research fellow Douglas Onsi President & chief executive officer Mark O’Mahony Chief manufacturing o
Slide 44: DKN-01 clinical milestones
DKN-01 clinical milestones 44 Indication: Treatment: tislelizumab + chemotherapy bevacizumab + chemotherapy pembrolizumab Gastric cancer 1L Colorectal cancer 2L Endometrial cancer 2L Q4 2023 2024 Q1 Q2 Q3 Q4 ORR PFS Initial Data Part A PFS Part B LPI ORR Part C LPI DisTinGuish DeFianCe
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