CYPH 8-K
Cypherpunk Technologies Inc. (CYPH)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
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| Item 8.01. | Other Events |
On January 28, 2025, Leap Therapeutics, Inc. (the “Company”) issued a press release entitled “Leap Therapeutics Reports Initial Clinical Data from Part B of DeFianCe Study and Part C of the DisTinGuish Study.” The full text of the press release is filed as Exhibit 99.1 to this Current Report on Form 8-K and incorporated herein by reference; provided, however that information on or connected to our website referenced in the Company’s press release is expressly not incorporated by reference into or intended to be filed as a part of this Current Report on Form 8-K.
Also on January 28, 2025, the Company posted an updated corporate presentation on its website, www.leaptx.com. A copy of the presentation is filed as Exhibit 99.2 to this Current Report on Form 8-K and incorporated herein by reference. The information contained on, or that can be accessed from, the Company’s website is not incorporated into, and does not constitute a part of, this Current Report on Form 8-K.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit Number |
Description | |
| 99.1 | Press Release dated January 28, 2025 | |
| 99.2 | Leap Corporate Presentation | |
| 104 | Cover Page Interactive Data File. (Embedded within the Inline XBRL document.) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| LEAP THERAPEUTICS, INC. | ||
| Dated: January 28, 2025 | By: | /s/ Douglas E. Onsi |
| Name: | Douglas E. Onsi | |
| Title: | Chief Executive Officer and President | |
Exhibit 99.1
Leap Therapeutics Reports Initial Clinical Data from Part B of the DeFianCe Study and
Part C of the DisTinGuish Study
35% objective response rate (ORR) in second-line colorectal cancer (CRC) patients treated with sirexatamab (DKN-01) plus bevacizumab and chemotherapy, compared to 23% ORR in the control arm
DKK1 levels highly correlated with clinical activity in CRC population
ORR benefit with sirexatamab observed across multiple potential Phase 3 CRC populations
Preparations will begin for a registrational Phase 3 study in second-line CRC patients
DisTinGuish Part C study in gastric cancer demonstrates activity in biomarker populations,
but not the signal necessary to advance into Phase 3
Leap to host a conference call to present clinical data today, January 28, 2025, at 8:00 a.m. ET
Cambridge, MA – January 28, 2025 – Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, today announced positive initial data from Part B of the DeFianCe study evaluating sirexatamab (DKN-01) in combination with bevacizumab and chemotherapy as a second-line treatment for patients with advanced colorectal cancer (CRC), and initial data from Part C of the DisTinGuish study evaluating sirexatamab in combination with tislelizumab and chemotherapy in first-line patients with advanced gastroesophageal junction (GEJ) and gastric cancer.
Key Findings from Part B of the DeFianCe study:
“Data from Part B of the DeFianCe study closely mirror the findings from Part A, and together they demonstrate the potential of sirexatamab to provide a compelling treatment option for second-line CRC patients who do not benefit from current standard of care,” said Cynthia Sirard, M.D., Chief Medical Officer of Leap. “Along with consistently achieving higher response rates than the control arm, the data also point to a favorable safety profile. While not yet fully mature, we are encouraged by the progression-free survival data thus far across key subgroups in the study. We look forward to reporting additional data from Part B as it matures over the coming months and beginning our planning for Phase 3 registrational studies.”
“The patient population in second-line CRC is heterogeneous, and there is a true unmet need for new treatment options that are safe and effective. The latest findings from DeFianCe Part B are highly encouraging, as sirexatamab combination therapy is outperforming bevacizumab and chemotherapy alone in ORR in the intent-to-treat analysis and across key subgroups of interest,” said Zev Wainberg, M.D., Professor of Medicine and Co-Director of the GI Oncology Program at UCLA. “Initial results also show increased response rates in patients with high DKK1 levels, directly correlating with sirexatamab’s novel mechanism of action. These data support moving forward into Phase 3 registrational studies to further explore a unique treatment option for patients in need.”
The DeFianCe study (NCT05480306) is a Phase 2, open-label, global study of sirexatamab in combination with bevacizumab and chemotherapy in patients with advanced microsatellite stable (MSS) CRC who have received one prior systemic therapy for advanced disease. Part B of the study is a 188 patient randomized controlled trial, with the primary objective being progression-free survival (PFS) in patients with left-sided cancers and in all patients. Key secondary and exploratory objectives include objective response rate (ORR), duration of response, and overall survival across tumor, treatment, and biomarker subgroups.
| · | Across the intent-to-treat (ITT) population with second-line MSS CRC (n=188): |
| o | Patients treated with sirexatamab plus bevacizumab and chemotherapy (Experimental Arm, n=94) had ORR of 35% and disease control rate (DCR) of 86%, compared to an ORR of 23% and DCR of 84% in patients treated with bevacizumab and chemotherapy alone (Control Arm, n=94) |
| · | Across the population with left-sided primary tumors (n=144): |
| o | Patients treated in the Experimental Arm (n=71) had an ORR of 38%, compared to an ORR of 25% in the Control Arm (n=73) |
| · | Plasma DKK1 highly correlated with clinical activity: |
| o | Patients in the Experimental Arm with DKK1 levels above the median (n=49) had an ORR of 39%, compared to 22% ORR in the Control Arm (n=36) |
| o | Patients in the upper-quartile of DKK1 levels in the Experimental Arm (n=25) had an ORR of 48%, compared to 11% ORR in the Control arm (n=18) |
| · | Key patient subgroups demonstrated higher ORR in the Experimental Arm: |
| o | No prior anti-VEGF therapy: Patients in the Experimental Arm (n=49) had an ORR of 51%, compared to 29% ORR in the Control arm (n=45) |
| o | Prior anti-EGFR therapy: Patients in the Experimental Arm (n=28) had an ORR of 54%, compared to 27% ORR in the Control arm (n=22) |
| o | RAS wildtype (RAS-wt) tumors: Patients in the Experimental Arm (n=35) had an ORR of 43%, compared to 32% ORR in the Control Arm (n=25) |
| · | With only 3 months follow-up on the final patients enrolled and mean duration on study of approximately 6 months, PFS is not yet mature. Eighty-two patients are still on study, 46 in the Experimental Arm and 36 in the Control Arm. Early separation in the Kaplan-Meier PFS curves is being seen in many of the key patient subgroups, including DKK1 biomarker, anti-VEGF-naïve, anti-EGFR-experienced, and RAS-wt patients. Leap expects to report additional data as it matures in 2025. |
| · | Sirexatamab plus bevacizumab and chemotherapy was well-tolerated, without additive toxicity to the standard of care. |
The strong signal in CRC from the DeFianCe study supports Leap moving forward to plan a registrational Phase 3 clinical trial to evaluate sirexatamab plus bevacizumab and chemotherapy in second-line MSS CRC patients with high unmet need, subject to regulatory discussions. Potential Phase 3 patient populations include: DKK1 biomarker-selected, anti-VEGF naïve, anti-EGFR experienced, or RAS-wt patients. While the data matures, Leap intends to conduct global commercial and regulatory strategic analysis to select the optimal population.
Key Findings from Part C of the DisTinGuish study:
Leap also reported data from Part C of the DisTinGuish study evaluating sirexatamab in combination with tislelizumab, BeiGene’s anti-PD-1 antibody, and chemotherapy in first-line patients with advanced GEJ and gastric cancer. While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer.
“Sirexatamab plus tislelizumab and chemotherapy demonstrated improved confirmed response rates compared to the control arm in the ITT, DKK1-high, and PD-L1 negative patients by Blinded Independent Central Review (BICR). However, gastric cancer is a difficult tumor to assess radiologically, and unfortunately, there was a high level of discordance between investigator assessment (IA) and BICR,” said Dr. Sirard. “Therefore, we have decided to focus our internal effort and resources on advancing sirexatamab in CRC and will explore strategic partnership opportunities to advance sirexatamab plus anti-PD-1 antibodies in gastric cancer and other indications where there is high DKK1 expression.”
Part C of the DisTinGuish study (NCT0436380) is a Phase 2, randomized, open-label, multicenter study of sirexatamab in combination with tislelizumab and chemotherapy in first-line patients with advanced GEJ and gastric cancer. Part C enrolled 170 first-line, HER2-negative patients. Patients were randomized 1:1 to evaluate sirexatamab in combination with tislelizumab and chemotherapy, compared to tislelizumab and chemotherapy alone. The primary objective is PFS by IA in all patients and in DKK1 TPS > 20 (DKK1-high) patients. Secondary objectives include ORR, duration of response, and overall survival as measured by BICR and IA in all patients and in DKK1-high patients.
| · | Across the ITT population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (Experimental Arm, n=85) had a confirmed ORR of 52% by both IA and BICR, while patients treated with tislelizumab and chemotherapy alone (Control Arm, n=85) had a confirmed ORR of 56% by IA and 42% by BICR. |
| · | Based on BICR: |
| o | Patients in the Experimental Arm with DKK1-high tumors (n=22) had a confirmed ORR of 59%, compared to 36% in the Control Arm (n=22) |
| o | Patients in the Experimental Arm with PD-L1-negative tumors (n=18) had a confirmed ORR of 44%, compared to 32% in the Control Arm (n=19) |
| · | In the ITT population, preliminary median PFS in the Experimental Arm was 9.72 months by BICR and 7.66 months by IA compared to 11.99 months by BICR and 10.41 months by IA in the Control Arm. The median PFS for tislelizumab plus chemotherapy in the Phase 3 Rationale-305 study was 6.9 months (95% CI: 5.7, 7.2). |
| · | In the DKK1-high population, preliminary median PFS in the Experimental Arm was 7.72 months by BICR and 7.43 months by IA compared to 7.79 months by BICR and 11.14 months by IA in the Control Arm. The hazard ratio for PFS by BICR was 0.68, representing a trend in favor of the Experimental Arm in the overall time to event analysis. |
| · | Sirexatamab plus tislelizumab and chemotherapy was well tolerated, without additive toxicity to the standard of care. |
Conference Call:
Leap’s management team will host a conference call today, January 28, 2025 at 8:00 a.m. Eastern Time to further discuss the data. The conference call will be broadcast live in listen-only mode and can be accessed via the webcast URL: https://edge.media-server.com/mmc/p/t93pn2ke. A replay of the event will be available for a limited time on the Investors page of the Company’s website at https://investors.leaptx.com/.
About Leap Therapeutics
Leap Therapeutics (Nasdaq: LPTX) is focused on developing targeted and immuno-oncology therapeutics. Leap's most advanced clinical candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody targeting the Dickkopf-1 (DKK1) protein. Sirexatamab is being studied in patients with colorectal, esophagogastric, and gynecological cancers. Leap's pipeline also includes FL-501, a humanized monoclonal antibody targeting the growth and differentiation factor 15 (GDF-15) protein, in preclinical development. For more information about Leap Therapeutics, visit http://www.leaptx.com or view our public filings with the SEC that are available via EDGAR at http://www.sec.gov or via https://investors.leaptx.com/.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within the meaning of the federal securities laws. Such statements are based upon current plans, estimates and expectations of the management of Leap that are subject to various risks and uncertainties that could cause actual results to differ materially from such statements. The inclusion of forward-looking statements should not be regarded as a representation that such plans, estimates and expectations will be achieved. Words such as "anticipate," "expect," "project," "intend," "believe," "may," "will," "should," "plan," "could," "continue," "target," "contemplate," "estimate," "forecast," "guidance," "predict," "possible," "potential," "pursue," "likely," and words and terms of similar substance used in connection with any discussion of future plans, actions or events identify forward-looking statements.
All statements, other than historical facts, including statements regarding the potential safety, efficacy, and regulatory and clinical progress of Leap's product candidates; the anticipated timing for initiation or completion of clinical trials and release of clinical trial data and the expectations surrounding the outcomes thereof; Leap's future clinical or preclinical product development plans for any of Leap's product candidates; Leap's estimations of projected cash runway; and any assumptions underlying any of the foregoing, are forward-looking statements. Important factors that could cause actual results to differ materially from Leap's plans, estimates or expectations could include, but are not limited to: (i) the results of Leap's clinical trials and pre-clinical studies, including whether the final data from Part B of the DeFianCe study or Part C of the DisTinGuish study are the same as the initial data reported, (ii) Leap's ability to successfully finance or enter into new strategic partnerships for sirexatamab or any of its other programs; (iii) any regulatory feedback that Leap may receive from U.S. Food and Drug Administration (FDA) or equivalent foreign regulatory agency with respect to the registrational Phase III clinical trials that Leap proposes to conduct using sirexatamab for the treatment of patients with second-line CRC or with respect to any other pre-clinical or clinical development activities that Leap will be required to conduct in order to obtain regulatory approval of sirexatamab for the treatment of second-line CRC; (iv) whether any Leap products will receive approval from the FDA or equivalent foreign regulatory agencies; and (v) exposure to inflation and interest rate fluctuations, as well as fluctuations in the market price of Leap's traded securities. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Leap may not actually achieve the forecasts disclosed in such forward-looking statements, and you should not place undue reliance on such forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption "Risk Factors" in Leap's most recent Annual Report on Form 10-K filed with the SEC, as well as discussions of potential risks, uncertainties, and other important factors in its subsequent filings with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither Leap, nor any of its affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing Leap's views as of any date subsequent to the date hereof.
CONTACT:
Douglas E. Onsi
President & Chief Executive Officer
Leap Therapeutics, Inc.
617-714-0360
Matthew DeYoung
Investor Relations
Argot Partners
212-600-1902
Exhibit 99.2
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
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 trials, collaborations and partnerships, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward - looking statements within the meaning of U.S. securities laws. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward - looking statements, although not all forward - looking statements contain these identifying words. Forward - looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward - looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. We may not actually achieve the plans, intentions or expectations disclosed in our forward - looking statements, and you should not place undue reliance on our forward - looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward - looking statements we make. These and other risk factors are listed from time to time in reports filed with the Securities and Exchange Commission, including, but not limited to, our Annual Reports on Form 10 - K and our Quarterly Reports on Form 10 - Q. We assume no obligation to update any forward - looking statements, except as required by applicable law. This presentation does not constitute an offer to sell, or the solicitation of an offer to buy, any securities.
SIREXATAMAB (DKN - 01) Anti - DKK1 monoclonal antibody
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 infiltration. Promotes angiogenesis by increasing the number and size of blood vessels. Promotes activation of Akt by direct signaling through CKAP4 and PI3 kinase. Cancer cell DKK1
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
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 macrophages into the tumor - attacking M1 subtype and promotes T cell infiltration. R educes MDSCs and tumor suppressive M2 macrophages in the TME. R educes angiogenesis and inhibits pro - oncogenic PI3K/AKT signaling.
SIREXATAMAB (DKN - 01) Colorectal cancer development
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) • ORR • DoR • OS Sirexatamab ( DKN - 01 ) + SOC chemotherapy (FOLFIRI or mFOLFOX6) + bevacizumab SOC chemotherapy (FOLFIRI or mFOLFOX6) + bevacizumab N= 94 N= 94 Key eligibility criteria: • One prior 5 - FU based therapy for advanced colorectal adenocarcinoma • RECIST v1.1 measurable disease • MSS and absence of BRAFV600 mutation N=1 88* 1:1 S a f e ty run in IA s a f e ty review Sirexatamab ( DKN - 01 + SOC + bevacizumab N= 33 OBJECTIVES *Right - sided mCRC capped at 45 Key Exploratory P opulations : – DKK1 biomarker high/median – VEGF - naive – EGFR - experienced – RAS wildtype
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 ORR of 22.7% Bevacizumab - experienced Bevacizumab - naïve EGFR - experienced Treatment Study ORR Population PFS OS 11.2 5.7 7.3 7.1 16.2 12.9 Significant unmet needs in 2L patients 9
• 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 Randomized • Other: 1 • Screen failure: 46 N=94 Randomized (Experimental) n=3 Did not start treatment n=6 Did not start treatment n=3 Discontinued study • Other: 2 • With drawal of consent: 1 n=5 Discontinued study • Other: 4 • Withdrawal of consent: 1 N=91 Started treatment N=88 Started treatment n=45 Discontinued treatment • Adverse Event: 1 • Death: 1 • Objective disease progression: 31 • Other: 1 • Physician decision: 4 • Withdrawal by subject: 7 n= 23 Discontinued study: • Death: 9 • Withdrawal of con sent: 14 n=24 Discontinued study: • Death: 9 • Other: 1 • Withdrawal of con sent: 14 N=68 Study ongoing N=65 Study ongoing n=46 Treatment ongoing n=36 Treatment ongoing n=52 Discontinued treatment • Adverse Event: 1 • Death: 1 • Initiation or alternative treatment: 1 • Objective disease progression: 34 • Other: 1 • Physician decision: 6 • Withdrawal by subject: 8
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 (25) Right 73 (78) 71 (76) Left ECOG PS 44 (47) 41 (44) 0 50 (53) 53 (56) 1 Race 45 (48) 55 (59) Asian 4 (4) 4 (4) Black/African American 42 (45) 31 (33) White 3 (3) 4 (4) Other • Demographics were well balanced across study arms • 77% subjects with left - sided tumors • 51% enrolled from South Korea
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), cardiac arrest • Overall TEAE profile is similar between the Experimental and Control Arms suggesting the addition of sirexatamab (DKN - 01) does not adversely impact the safety profile of the combinatorial agents. Control Arm N=88 n (%) Experimental Arm N=91 n (%) N=179 88 (100) 91 (100) Any TEAE 86 (98) 90 (99) Regimen - related TEAE 50 (57) 50 (55) ≥ Grade 3 TEAE 44 (50) 48 (53) Regimen - related ≥ Grade 3 TEAE 14 (16) 17 (19) Any SAE 4 (5) 11 (12) Regimen - related SAEs * 0 (0) 1 (1) AEs leading to death + 11 (13) 12 (13) AEs leading to discontinuation of any regimen N/A 3 (3) AEs leading to discontinuation of DKN - 01 34 (39) 32 (35) AEs leading to dose reduction of any regimen 54 (61) 60 (66) AEs leading to dose interruption of any regimen
INTENT - TO - TREAT POPULATION January 2025
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 assessment
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
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 (%) n (%) Response 0 (0) 0 (0) 0 (0) 0 (0) CR 2 (11) 12 (48) 8 (22) 19 (39) PR 11% 48% 22% 39% ORR 12 (67) 10 (40) 24 (67) 25 (51) SD 78% 88% 89% 90% DCR 3 (17) 3 (12) 3 (8) 4 (8) PD 1 (6) 0 (0) 1 (3) 1 (2) No assessment Median Upper Quartile Median DKK1
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 Quartile Level
TUMOR SIDEDNESS SUBGROUP January 2025
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 (60) 35 (49) SD 81% 83% 85% 87% DCR 1 (5) 2 (9) 6 (8) 4 (6) PD 3 (14) 2 (9) 5 (7) 5 (7) No assessment
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
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 (%) Response 0 (0) 0 (0) 0 (0) 0 (0) CR 1 (8) 11 (52) 7 (25) 16 (43) PR 8% 52% 25% 43% ORR 8 (62) 7 (33) 17 (61) 18 (49) SD 69% 86% 86% 92% DCR 3 (23) 3 (14) 3 (11) 3 (8) PD 1 (7) 0 (0) 1 (4) 0 (0) No assessment Median DKK1 Upper Quartile DKK1 Control Control Experimental Experimental
ANTI - VEGF EXPOSURE SUBGROUP January 2025
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) 11 (24) 25 (51) PR 18% 18% 29% 51% ORR 32 (65) 27 (60) 25 (56) 21 (43) SD 84% 78% 84% 94% DCR 3 (6) 6 (13) 4 (9) 0 (0) PD 5 (10) 4 (9) 3 (7) 3 (6) No assessment
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
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 Median N=22 n (%) n (%) n (%) n (%) Response 0 (0) 0 (0) 0 (0) 0 (0) CR 0 (0) 3 (33) 1 (7) 4 (18) PR 0% 33% 7% 18% ORR 4 (57) 3 (33) 11 (73) 13 (59) SD 57% 67% 80% 77% DCR 2 (29) 3 (33) 2 (13) 4 (18) PD 1 (14) 0 (0) 1 (7) 1 (5) No assessment Median DKK1 Upper Quartile DKK1 Control Experimental
ANTI - EGFR EXPOSURE SUBGROUP January 2025
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
RAS MUTATIONAL STATUS SUBGROUP January 2025
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 36 (69) 25 (58) 14 (56) 19 (54) SD 88% 84% 88% 97% DCR 3 (6) 5 (12) 3 (12) 0 (0) PD 3 (6) 2 (5) 0 (0) 1 (3) No assessment
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
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% 29% 51% VEGF - naïve 0% 33% 7% 18% 18% 18% VEGF - experienced 0% 63% 29% 62% 27% 54% EGFR - experienced 0% 55% 22% 47% 32% 43% RAS wildtype 15% 38% 18% 25% 19% 26% RAS mutant 14% 48% 27% 38% 26% 35% Liver mets 0% 50% 13% 36% 11% 36% Lung mets • In the ITT and each subgroup explored, patients with high DKK1 levels above the median or upper quartile demonstrate enhanced ORR . • Early separation in PFS curves driven by DKK1 levels.
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 - M curves favoring the Experimental Arm is seen in several targetable indications: DKK1 biomarker, VEGF - naïve, RAS wildtype, and EGFR - experienced. • Sirexatamab should advance rapidly into Phase 3 CRC registrational studies. Control ORR Sirexatamab (DKN - 01) Experimental ORR n Group 23% 35% 188 Intent - to - treat 25% 38% 144 Left - sided tumors 29% 51% 94 VEGF - naïve 27% 54% 50 EGFR - experienced 32% 43% 60 RAS wildtype 26% 35% 136 Liver metastases 11% 36% 89 Lung metastases 11% 48% 43 Upper quartile DKK1 levels 22% 39% 85 Upper half DKK1 levels
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 Patient Enrollment Chemo + bev + sirexatamab (DKN - 01) Randomized 1:1 Trial Design: Global, randomized, 2 - arm, placebo - controlled Phase 3 Patient Population: 2 nd Line metastatic CRC progressed on front - line therapy
SIREXATAMAB (DKN - 01) Gastric с ancer development
Part C: DisTinGuish Study FIRST LINE GASTROESOPHAGEAL JUNCTION / GASTRIC CANCER
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: • No prior therapy for unresectable locally advanced or metastatic gastric/GEJ adenocarcinoma • RECIST v1.1 measurable disease • Her2 negative N=1 7 0 1:1 Primary : PFS, DKK - high and all Secondary: • OS, DKK1 - high and all • DOR, DKK1 - high and all • ORR, DKK1 - high and all OBJECTIVES
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 ) Control Tislelizumab + Chemo Rationale - 305 study: tislelizumab + chemotherapy in 1L GEJ/GC patients N= 501 N= 496 0.80 ( 0.69, 0.92 ) 0.78 ( 0.67, 0.90 ) 31.5% (23.4%, 40.4%) 5.0 (3.9, 6.7) 7.5 (4.4, 12.0) North America & Europe N= 125 10.5 (8.1, 12.1) 11.0 (8.4, 13.9) 5.4 (4.3, 5.9 ) 5.6 (4.4, 7.0) 36.0% (27.6%, 45.1%) Control Tislelizumab + Chemo 34.9% (21%, 50.9%) 18 (2.8, NA) 11.8 (4.3, NA) N= 69 N= 43 13.8 (10.2, 17.8) 15.4 (8.4, 16.5) 6.9 (5.6, 15 ) 7.9 (5.6, 9.7) 44.9% (32.9%,57.4%) CP S < 1 PD - L1 Control Tislelizumab + Chemo 0.71 (0.54, 0.94) 0.84 (0.63, 1.11) 0.87 (0.54, 1.41) 0.98 (0.64, 1.50) N= 124 All patients and PD - L1 < TAP 1 from September 26, 2024 FDA Briefing Document North American & Europe as presented at ASCO GI 2024 37
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 • Patient withdrawal of consent: 3 • Screen failure: 125 N=85 Randomized n=1 Did not start treatment n=0 Did not start treatment n=1 Discontinued study n=0 Discontinued study N=84 Started treatment N=85 Started treatment n=68 Discontinued treatment • Adverse Event: 7 • Concurrent anticancer therapy: 1 • Death: 1 • Disease progression per RECIST: 52 • Investigator decision: 5 • Other: 1 • Patient decision: 1 n=44 Discontinued study: • Death: 40 • Patient withdrawal of con sent: 4 n=67 Discontinued treatment • Adverse Event: 2 • Concurrent anticancer therapy: 1 • Disease progression per RECIST: 50 • Investigator decision: 3 • Other: 1 • Patient decision: 10 n=47 Discontinued study: • Death: 32 • Lost to follow - up: 1 • Patient withdrawal of con sent: 14 N=40 Study ongoing N=38 Study ongoing n=16 Treatment ongoing n=18 Treatment ongoing N=85 Randomized
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 States 4 (5) 6 (7) Germany 57 (67) 67 (79) Gastric Tumor type 28 (33) 18 (21) GEJ 22 (26) 22 (26) TPS≥20% DKK1 63 (74) 63 (74) TPS<20% 20 (24) 18 (21) CPS < 1 PD - L1 49 (58) 55 (65) CPS 1 - < 10 16 (19) 12 (14) CPS ≥ 10 3 (4) 3 (4) MSI - H + 42 (49) 44 (52) CAPOX Chemotherapy on Study 43 (51) 41 (48) FOLFOX 25 (29) 25 (29) Yes Ascites 29 (34) 30 (35) Yes Liver Metastasis 54 (64) 47 (55) Yes SOC chemotherapy during screening 82 (97) 80 (94) Yes BICR evaluation 57 (67) 60 (71) Target lesion at baseline 25 (29) 20 (24) No target disease at baseline • 27% patients overall with GEJ type tumors • 26% patients with DKK1 high expressing tumors • 71% patients with low PD - L1 expression (CPS <5) • 27% patients without measurable disease at baseline per BICR • 59% patients had screening chemotherapy *Data extraction 12/16/24. + FMI ctDNA
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 Events ( ≥Grade 3) 28 (33) 16 (19) Infusion Related Reactions 79 (93) 79 (94) Regimen Related Treatment Emergent Adverse Events 18 (21) 16 (19) Regimen Related Serious Treatment Emergent Adverse Events 36 (42) 39 (46) Regimen Related Severe Treatment Emergent Adverse Events (Grade ≥ 3) 3 (4) 4 (5) Treatment Emergent Adverse Events Leading to Death 0 (0) 1 (1) # Regimen Related Treatment Emergent Adverse Events Leading to Death 24 (28) 26 (31) Immune Related Treatment Emergent Adverse Events *Data extraction 12/16/24. + one subject never dosed. # oxaliplatin related • Overall TEAEs, ≥ G3 TEAEs, SAEs and Deaths occur at similar rates across treatment arms suggesting no added toxicity with sirexatamab (DKN - 01)
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 / Non - PD 79 (93) 77 (91) DCR 2 (2) 3 (4) PD 4 (5) 5 (6) NE Blinded Independent Central Review Investigator Assessment • Experimental A rm has a higher Confirmed ORR by BICR: 52% vs. 42% • Control A rm has a higher Confirmed ORR by Investigator Assessment: 56% vs. 52% • Investigator Assessment identified 12 additional confirmed responses in the Control A rm, 0 in the Experimental A rm • Non - CR/Non - PD non - measurable disease by BICR higher in Control Arm: 20 vs. 15 tislelizumab + (CAPOX/FOLFOX) N=85 DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=85 n (%) n (%) Response 4 (5) 6 (7) CR 44 (52) 38 (45) PR 48 (56) [45.3, 67.2] 44 (52) [40.7, 62.7] ORR 95% CI 29 (34) 34 (40) SD 77 (91) 78 (92) DCR 4 (5) 3 (4) PD 4 (5) 4 (5) NE
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 Control Arm, 1 in the Experimental Arm tislelizumab + (CAPOX/FOLFOX) N=22 DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=22 n (%) n (%) Response 2 (9) 1 (5) CR 6 (27) 12 (55) PR 8 (36) [17.2, 59.3] 13 (59) [36.4, 79.3] ORR 95% CI 6 (27) 3 (14) SD 4 (18) 3 (14) Non - CR / Non - PD 18 (82) 19 (86) DCR 2 (9) 2 (9) PD 2 (9) 1 (5) NE Blinded Independent Central Review Investigator Assessment tislelizumab + (CAPOX/FOLFOX) N=22 DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=22 n (%) n (%) Response 2 (9) 2 (9) CR 12 (55) 12 (55) PR 14 (64) [40.7, 82.8] 14 (64) [40.7, 82.8] ORR 95% CI 6 (27) 6 (27) SD 20 (91) 20 (91) DCR 0 (0) 1 (5) PD 2 (9) 1 (5) NE
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 + tislelizumab + (CAPOX/FOLFOX) N=18 n (%) n (%) Response 3 (16) 1 (6) CR 3 (16) 7 (39) PR 6 (32) [11.89, 54.28] 8 (44) [21.53, 69.24] ORR 95% CI 7 (37) 4 (22) SD 5 (26) 6 (33) Non - CR / Non - PD 18 (95) 18 (100) DCR 1 (5) 0 (0) PD 0 (0) 0 (0) NE tislelizumab + (CAPOX/FOLFOX) N=19 DKN - 01 + tislelizumab + (CAPOX/FOLFOX) N=18 n (%) n (%) Response 1 (5) 3 (17) CR 6 (32) 6 (33) PR 7 (37) [15.39, 59.22] 9 (50) [26.02, 73.98] ORR 95% CI 11 (58) 8 (44) SD 18 (95) 17 (94) DCR 1 (5) 1 (6) PD 0 (0) 0 (0) NE
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 (95% CI: 5.7, 7.2) • PFS HR by Investigator Assessment favors the Control Arm: 1.4 (24 patients censored prior to PD: 17 Control Arm vs. 7 Experimental Arm) • PFS HR by BICR shows no benefit: 1.01 (BICR disagreed with PD in 52% of the Investigator Assessed PD and only agreed with the PD time point in 31% of patients)
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 Investigator Assessed PD and only agreed with the PD time point in 37% of patients; earlier PD by BICR on 6 Control Arm and 2 Experimental Arm patients) • Median PFS for the Control Arm by BICR is 3.35 months shorter than by 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 (effect of censoring following discordance favoring the Control Arm) • Median PFS for the Control Arm is 5.4 months longer by BICR than the median PFS for tislelizumab in Rationale - 305 of 7.9 months (95% CI: 5.6, 9.7)
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 favoring the Experimental Arm in DKK1 - high TPS > 20 (Hazard Ratio 0.68). • Very high level of discordance between Blinded Independent Central Review and Investigator Assessment. • Significant number of patient discontinuations without PFS events and early withdrawals, primarily in the Control Arm. • The Investigator Assessment results are less favorable to the Experimental Arm and more favorable to the Control Arm (and as compared to Rationale - 305) resulting in a study that will not be successful for its primary endpoint of PFS by Investigator Assessment when the study completes. • DKK1 - high and PD - L1 negative biomarker populations demonstrated positive signal, with potential for strategic partnership opportunities.
CONCLUSIONS
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 continues • CRC prioritized over gastric cancer as the larger market opportunity with clear path into Phase 3 development Control ORR Sirexatamab (DKN - 01) Experimental ORR n Group 23% 35% 188 Intent - to - treat 25% 38% 144 Left - sided tumors 29% 51% 94 VEGF - naïve 27% 54% 50 EGFR - experienced 32% 43% 60 RAS wildtype 26% 35% 136 Liver metastases 11% 36% 89 Lung metastases 11% 48% 43 Upper quartile DKK1 plasma levels 22% 39% 85 Upper half DKK1 plasma levels