Cypherpunk Technologies Inc. · NASDAQ:CYPH
Cypherpunk Technologies — Leap Therapeutics — Investor Day (July 2022)
50 slides from Cypherpunk Technologies's investor day presentation, Jul 12, 2022
Slide 1: Leap Therapeutics DKN-01 R&D Day July 12, 2022
company presentation LEAP THERAPEUTICS DKN - 01 R&D Day July 12, 2022
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: Agenda
Agenda 3 DKK1 Biology and DKN - 01 Mechanism of action Colorectal cancer: Zev Wainberg , MD UCLA Prostate cancer: David Wise, MD, PhD New York University Gastric cancer : Samuel Klempner , MD Massachusetts General Hospital Endometrial cancer: Rebecca Arend , MD University of Alabama at Birmingham
Slide 4: Overview
DKN - 01 Overview 4 Important milestones in 2022 and 2023 Single agent activity in three indications Biomarker - targeted development Combinations with checkpoint inhibitors and chemotherapy Strategic partnership with BeiGene T C Cancer cell DKN - 01 DKK1
Slide 5: The role of DKK1 in cancer
The role of DKK1 in cancer 5 Cance r cell DKK1 is produced and secreted by cancer cells, functions on several tumor pathways and nearby immune cells DKK1 V E GFR2 CKAP4 Angiogenesis A kt β - ca t enin DKK1 DKK1 PI3K Cance r cell T umor Cancer cells Myeloid - derived suppressor cell WNT F ZD LRP 5/6
Slide 6: DKN-01 - an anti-DKK1 antibody
DKN - 01 - an anti - DKK1 antibody 6 Tumor Cancer cell DKN - 01 Single agent and combination activity demonstrated in three different tumor types. Well - tolerated as monotherapy and in combination with chemotherapy or checkpoint inhibitors. Reduces cell proliferation Blocks signaling through CKAP4
Slide 7: DKN-01 + anti-PD-1 combination
DKN - 01 + anti - PD - 1 combination 7 Enhances tumor microenvironment for immune cells to target and clear the tumor Activates CD8 T cells Stimulates activity of NK cells Induces pro - inflammatory tumor microenvironment Upregulates PD - L1 (the target for anti - PD - 1 antibodies) Anti - PD - 1 st
Slide 8: Pipeline
Pipeline 8 DKN - 01 + anti - PD - 1 pembrolizumab DKN - 01 + docetaxel DKN - 01 DKN - 01 + anti - PD - 1 tislelizumab + chemotherapy (1L) DKN - 01 + anti - PD - 1 tislelizumab (2L) 1L PFS d ata, 2L initial data Q1 2022 Final 1L data expected in Q3 2022 1L Randomized Controlled Trial FPI Q4 2022 Inve
Slide 9: Gastric cancer development
DKN - 01 Gastric cancer development
Slide 10: DKK1-high levels are associated with poor survival
DKK1 - high levels are associated with poor survival 10 Strata 21 34 7 1 1 20 4 0 300 200 100 0 time to treatment discontinuation (days) High l evels of DKK1 c orrelate with s horter o verall s urvival In g astric c ancer TCGA STAD d ataset DKK1 - high i s a ssociated with p oor r esponse to first -
Slide 11: DKK1 expression determined using RNAscope
DKK1 expression determined using RNAscope 11 * H - s core cut - off at 35 (equating to TPS 20) was identified for gastric cancer from our study of DKN - 01 + pembrolizumab 0 50 100 150 200 250 300 DKK 1 - l o w DKK 1 - high DKK1 - low p atient (H - score = 4) DKK1 - high p atient (H - score = 108) C
Slide 12: DKN-01 single agent activity in esophagogastric cancer
DKN - 01 single agent activity in heavily pretreated esophagogastric cancer patients 12 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
Slide 13: 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 13 PD PD PD PD PD PD PD PD 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
Slide 14: DisTinGuish study design: advanced GEJ/Gastric cancer
DisTinGuish study design: advanced GEJ/Gastric cancer Assess the safety and anti - tumor activity of DKN - 01 in combination with tislelizumab +/ - chemo therapy DKN - 01 + t islelizumab/XELOX DKN - 01 + t islelizumab Overall Response Rate Progression - Free Survival Duration of Response Overall Res
Slide 15: DisTinGuish Part A consort diagram
DisTinGuish Part A consort diagram 15 DKK1 - high: H - score ≥35; DKK1 - low: H - score <35 1L GEJ/GC DKN - 01 + t islelizumab + chemotherapy 25 patients enrolled in ITT DKK1 - low ( ITT) DKK1 unknown expression C ompleted at least a full cycle of therapy (mITT) 1 unable to complete a full cycle of
Slide 16: Best overall response by DKK1 expression
Best overall response by DKK1 expression 16 68.2% ORR in the mITT p opulation (1 CR; 14 PR) * mITT population includes all patients who received > 1 dose of DKN - 01 As presented at ASCO GI 2022 mITT * population N=22 DKK1 - high N=10 DKK1 - low N=9 DKK1 - unknown N=3 CR - complete response 1 (4.5%)
Slide 17: Durable response by DKK1 expression
Durable response by DKK1 expression 17 90 % ORR in DKK1 - high patients Best % cha n ge in sum of diameters Best Response Tumor Type GEJ GC DKK1 RNAscope H - score status High (≥35) Low (<35) Unknown Time since first dose (months) 2 3 4 5 9 12 14 PR - partial response SD - stable disease 10 6 7 8 11
Slide 18: PFS longer in DKK1-high patients
PFS longer in DKK1 - high patients Median PFS all: 10.7 mo Median PFS for DKK1 - high: 11.9 mo Median PFS from Checkmate - 649 (nivolumab + chemo): 7.7 months Median 95% Cl High ≥35 11.9 1.12 12.0 Low <35 10.7 4.07 NA Unknown 8.38 1.31 NA Progression - free survival by DKK1 status (N=25) 12 High ≥35
Slide 19: Overall survival not reached
Overall survival not reached 19 Median 95% Cl High ≥35 NA 1.12 NA Low <35 NA 4.83 NA Unknown NA 1.31 NA Overall survival by DKK1 status (N=25) 12 High ≥35 9 Low <35 4 Unknown 11 9 6 7 5 7 Kaplan - Meier estimate 1 0.6 0 0.8 0.4 0.2 Overall survival (months) 2 3 4 5 9 12 14 10 6 7 8 11 13 0 1 DKK1 RN
Slide 20: Best overall response by PD-L1 expression
Best overall response by PD - L1 expression 20 79 % 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 GI 2022 CR - complete response 1 (50%) PR - p ar
Slide 21: DKK1 and PD-L1 expression are not correlated
DKK1 and PD - L1 expression are not correlated 21 This population had low overall PD - L1 expression 200 300 100 40 10 50 80 20 60 90 30 70 100 0 DKK1 expression (H - score) 0 - 300 PD - L1 expression (CPS) 0 - 100 DKK1 0 Spearman correlation r = 0.061 p - value (two - sides) = 0.804 CR - complete r
Slide 22: DKN-01 plus tislelizumab and chemotherapy safety profile
DKN - 01 plus tislelizumab and chemotherapy safety profile 22 1L GEJ /GC DKN - 01 + t islelizumab + chemotherapy Preferred terms: Part A (N=25) No. Patients (%) TEAEs leading to death within 30 days of last dose 3 (12%) Any adverse event 25 (100%) Grade ≥ 3 events 14 (56%) DKN - 01 - related 5 (20%)
Slide 23: DisTinGuish Part C randomized study
DisTinGuish Part C randomized study 1L GEJ/GC DKN - 01 + t islelizumab + chemotherapy 23 DKN - 01 + tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) Tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) N=80 N=80 Stratification factors: • DKK1 expression (TPS ≥ 20% vs < 20%) • PD - L1 (CPS ≥5 vs <
Slide 24: Highlights in gastric cancer
DKN - 01 highlights in gastric cancer 24 DKK1 is an important new therapeutic target in gastric cancer DKK1 - high is associated with aggressive biology, poor response to standard 5 - FU therapy, and shorter survival 56% ORR 10.7m PFS 90% ORR 11.9m PFS Response is correlated with DKK1 expression and
Slide 25: Colorectal cancer development
DKN - 01 Colorectal cancer development
Slide 26: Rationale for targeting colorectal cancer
Rationale for targeting colorectal cancer DKK1 elevated in advanced CRC (Tempus) • CRC is characterized by hyperactivation of the Wnt pathway, often believed to be the initiating and driving event • DKK1 drives resistance to 5FU; DKN - 01 has demonstrated prior synergy with 5FU - based regimen in GE
Slide 27: DKN-01 activity with 5-FU chemotherapy in colorectal models
DKN - 01 activity in combination with 5 - FU chemotherapy in colorectal cancer models 27 • DKN - 01 has efficacy in CRC syngeneic models including HCT116 • Additive activity was seen with 5FU chemotherapy • In a 5FU chemotherapy - resistant model, DKN - 01 demonstrates significant inhibition of tumo
Slide 28: DKN-01 activity with 5-FU chemotherapy in colorectal models
DKN - 01 activity in combination with 5 - FU chemotherapy in colorectal cancer models 28 • DKN - 01 has efficacy in CRC syngeneic models including SW480 • Additive activity was seen with 5FU chemotherapy • In a 5FU chemotherapy - resistant model, DKN - 01 demonstrates significant inhibition of tumor
Slide 29: DKN-01 activity with PD-1 antibody in colorectal model
DKN - 01 activity in combination with PD - 1 antibody in colorectal cancer model 29 • DKN - 01 has efficacy in CRC syngeneic models including CT26 • Additive activity was seen with an anti - PD - 1 antibody Tumor size (mm 3 ) 2000 1000 0 Days (post - inoculation) 500 lgG2a mDKN - 01 + Anti - PD - 1
Slide 30: DKN-01 activity with PI3 kinase inhibitor in colorectal models
DKN - 01 activity in combination with PI3 kinase inhibitor in colorectal cancer models 30 • DKN - 01 has efficacy in CRC xenograft models, including with PIK3CA mutation • Additive activity was seen with an PI3 kinase inhibitor HCT116 parental HCT116 + PIK3CA H1047R mutation 3000 2000 1000 0 1500 50
Slide 31: Colorectal cancer study
DKN - 01 colorectal cancer study 31 Randomized phase 2 study of FOLFIRI/FOLFOX and b evacizumab +/ - DKN - 01 as second - line treatment of advanced colorectal cancer 2L CRC DKN - 01 + bevacizumab + chemotherapy Primary objective: PFS (SOC: mPFS 5.7 mos ) Secondary objectives: – ORR (SOC: ORR 5%) –
Slide 32: Endometrial cancer development
DKN - 01 Endometrial cancer development
Slide 33: Endometrial Cancer
Endometrial Cancer 33 Most common gynecological cancer in the western world High DKK1 i s associated with poor response to anti - VEGF therapy in endometrioid endometrial cancer patients Anti - VEGF treatment: 81% 95% 69% 17% 20% 80% 60% 40% O v e r all Regional (70%) Localized (67%) Metastatic (9%)
Slide 34: Single agent activity in endometrial cancer
Single agent activity in endometrial cancer 34 Single agent activity is very low, ranging from 3 - 20% 13% 6% 3% 9% 13.5% 14.3% 36% 63.5% 26% 20% 50% 25% pembrolizumab 1.8 0% mPFS (months) dostarlimab durvalumab lenvatinib everolimus bevacizumab avelumab Anti - PD(L) - 1: MSS/refractory PD - L1+ mTO
Slide 35: Phase 2 study design in advanced gynecologic malignancies
Eligible p a tie n ts • Recurrent EEC • Recurrent platinum - resistant /refractory EOC • Recurrent MMMT • ≥ 1 prior therapy • Measurable disease • 50% in each group with Wnt signaling alteration Phase 2 study design evaluating DKN - 01 monotherapy and in combination in advanced gynecologic malignanc
Slide 36: DKN-01 monotherapy 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 36 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 —
Slide 37: Complete response in endometrial cancer patient on DKN-01 monotherapy
Complete response in endometrial cancer patient on DKN - 01 monotherapy 37 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 poor
Slide 38: Pembrolizumab + lenvatinib in second-line endometrial cancer
Pembrolizumab + lenvatinib in second - line endometrial cancer 1 KEYNOTE - 775 data presented at SGO 2021 2 FDA Approves LENVIMA® ( lenvatinib ) plus KEYTRUDA® (pembrolizumab) Combination Treatment for Patients with Certain Types of Endometrial Carcinoma. https://www.eisai.com/news/2019/news201967.h
Slide 39: DKN-01 plus pembrolizumab endometrial cancer study
DKN - 01 plus pembrolizumab endometrial cancer study 39 * Move to Stage II based on ORR in Stage I 2 - 3 L E E C DKN - 01 + pembrolizumab Key eligibility criteria: • > 18 years of age • P athology - confirmed advanced or recurrent endometrial carcinoma • Non - endometrioid histologies included with
Slide 40: Prostate cancer development
DKN - 01 Prostate cancer development
Slide 41: DKK1 and DKN-01 in prostate cancer
DKK1 and DKN - 01 in prostate cancer 41 David Wise ASCO 2017 DKK1 expression is regulated by AR in CRPC tumor biopsies CIBERSORT analysis shows DKK1 expression associated with reduced inflammatory infiltrate DKN - 01 has efficacy in a PC3 SCID xenograft p< 0.0001 10 5 0 - 5 - 10 DKK1 mRNA expression
Slide 42: Investigator-initiated study in mCRPC
Investigator - initiated study in advanced metastatic castration - resistant prostate cancer ( mCRPC ) 42 DKN - 01 delays prostate cancer growth in pre - clinical models in an NK - cell dependent manner. DKK1 is upregulated in prostate cancers with low Androgen Receptor (AR) expression. DKK1 AR P r
Slide 43: Investigator-initiated study in mCRPC: patient characteristics
DKK1 expression N=2 4 H - score 0 15 ( 58.3 %) H - score ≥1 10 ( 41.7 %) H - score ≥10 5 ( 20.8 %) H - score ≥35 3 ( 12.5 %) DKN - 01 + Doc e ta x el 300mg N/A N=4 600mg N/A N=3 300mg 75mg/m 2 N=3 600mg 75mg/m 2 N=3 Age 64.5 74 66 68 Adenocarcinoma , n (%) 4 (100%) 3 (100%) 3 (100%) 1 (33%) Neuroend
Slide 44: DKN-01 activity in advanced mCRPC patients
DKN - 01 activity in advanced mCRPC patients Monotherapy N= 7 Combination N= 6 PR - p artial response 0 5 ( 83.3 %) S D - s table disease 2 ( 28.6 %) 0 PD - p rogressive disease 3 (42.9%) 0 NE - non - evaluable 2 ( 28 . 6 %) * 1 (1 6.7 %) * 1 NE patient in each group had no measurable disease at bas
Slide 45: DKN-01 activity in combination with docetaxel
DKN - 01 activity in combination with docetaxel PFS Best PSA Response Best PSA Response (%) 100 50 0 - 50 - 100 mPFS, 6.4 months 100 75 50 25 0 Months 0 2 4 6 8 10 rPFS (n=6) pts treated with DKN - 01 plus Docetaxel. rPFS (%) DKN - 01 600mg plus Docetaxel DKN - 01 300mg plus Docetaxel 45 2L+ mCRPC D
Slide 46: Confirmed partial response with deepening of response on monotherapy
-0.75 -0.5 -0.25 0 0 65 130 195 260 % Change from Baseline Days on Treatment Confirmed partial response with deepening of response on monotherapy 46 Docetaxel plus DKN - 01 DKN - 01 Monotherapy * * Docetaxel discontinued due to toxicity Continued tumor regression with DKN - 01 treatment observed aft
Slide 47: Highlights in prostate cancer
DKN - 01 highlights in prostate cancer 47 Non - clinical studies identified DKK1 as being upregulated in prostate cancers with low Androgen Receptor expression and that inhibition of DKK1 delayed prostate cancer growth DKN - 01 in combination with docetaxel showed promising clinical responses in uns
Slide 48: Development Strategy 2022-2023 Milestones
DKN - 01 DEVELOPMENT STRATEGY 2022 - 2023 Milestones
Slide 49: Leap 2022-2023 clinical milestones
Leap 2022 - 2023 clinical milestones Prostate cancer + docetaxel Part A: First - line patients combination with chemotherapy Part B: Second - line patients DKK1 - high Part C: First - line patients Randomized Controlled Trial Gastric cancer + tislelizumab 49 Colorectal cancer + bevacizumab + chemoth
Slide 50: Questions & Answers
QUESTIONS & ANSWERS