Leap Therapeutics Announces Publication of DeFianCe Study Results in Clinical Cancer Research
Rhea-AI Summary
Cypherpunk Technologies (Nasdaq: CYPH), via its oncology subsidiary Leap Therapeutics, reported peer-reviewed Phase 2 DeFianCe results of sirexatamab (DKN-01) in second-line metastatic colorectal cancer in Clinical Cancer Research.
The randomized Part B enrolled 188 patients to sirexatamab plus FOLFIRI or mFOLFOX6 and bevacizumab versus chemotherapy and bevacizumab alone. Analyses showed that baseline plasma DKK1 is a continuous biomarker, with sirexatamab benefit increasing as DKK1 levels rise. In DKK1-high patients above the median (n=88), objective response rate was 38.0% versus 23.7%, median PFS 9.0 vs 7.1 months (HR 0.61), and overall survival not reached vs 14.4 months (HR 0.42). In the upper DKK1 quartile (n=44), ORR was 44.0% vs 15.8%, PFS 9.4 vs 5.9 months (HR 0.46), and OS not reached vs 9.5 months (HR 0.17).
The prespecified primary PFS endpoint in the intent-to-treat population was not met (HR 0.84). Safety was generally comparable between arms, with grade ≥3 adverse events in 59.3% vs 67.0%. According to the company, these data support a biomarker-selected Phase 3 trial and follow the May 2026 FDA Fast Track designation for sirexatamab in DKK1-high mCRC.
Positive
- DKK1-high above median subgroup: ORR 38.0% vs 23.7%, PFS 9.0 vs 7.1 months, OS HR 0.42
- Upper DKK1 quartile subgroup: ORR 44.0% vs 15.8%, PFS 9.4 vs 5.9 months, OS HR 0.17
- Statistically significant treatment-by-DKK1 interaction for PFS (p=0.0129) and OS (p=0.0027)
- Safety profile comparable or better: grade ≥3 TEAEs 59.3% vs 67.0%; serious TEAEs ~20% in both arms
- Practical blood-based biomarker: plasma DKK1 detectable in 100% of patients, ~8-fold range, cross-platform concordance r=0.77
- FDA Fast Track designation granted in May 2026 for sirexatamab in DKK1-high mCRC
Negative
- Primary endpoint not met: ITT PFS HR 0.84, with 9.2 vs 8.3 months and no statistical significance
- ITT analysis underpowered versus plan, with 119 PFS events vs 145 planned in a heterogeneous population
Market reaction after Phase 2 clinical data: CYPH +5.93%
Following this news, CYPH has gained 5.93%, reflecting a notable positive market reaction. Our momentum scanner has triggered 3 alerts so far, indicating moderate trading interest and price volatility. The stock is currently trading at $0.72. Trading volume is exceptionally heavy at 9.6x the average, suggesting very strong buying interest.
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Key Figures
Historical Context
| Date | Event | Sentiment | 24h Move | Catalyst |
|---|---|---|---|---|
| May 14 | Q1 earnings report | Positive | +15.4% | Positive DeFianCe data and Fast Track designation accompanied the quarterly results. |
| Apr 15 | Zcash investment update | Positive | -5.3% | The company increased its Zcash holdings and launched an investor dashboard. |
| Mar 16 | Full-year earnings report | Positive | +12.6% | Full-year results included net income, Zcash holdings, and positive Phase 2 data. |
| Mar 09 | Zcash investment | Positive | +5.7% | The company invested in ZODL and expanded its Zcash holdings. |
24h Move is the share-price change in the day after each event; other market factors may also have contributed.
Historical events produced positive 24-hour reactions in three of four cases, while the April 15 company news event diverged with a negative reaction.
Key Terms
dkk1 medical
monoclonal antibody medical
progression-free survival medical
overall survival medical
intent-to-treat technical
fast track regulatory
AI-generated analysis. How Rhea-AI works. Not financial advice.
- Peer-reviewed analyses establish baseline plasma
DKK1 as a continuous quantitative biomarker predicting deepening sirexatamab benefit in 2L mCRC patients - In
DKK1 -high 2L mCRC patients, sirexatamab improved response, progression-free survival, and overall survival when added to bevacizumab and chemotherapy
The publication, "Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial," reports the complete efficacy, safety and biomarker analyses from the study and details the statistical basis for the
The peer-reviewed analyses establish that the benefit of sirexatamab increases as a patient's baseline plasma
"In second-line colorectal cancer, we urgently need novel biomarkers that inform patients' treatment options. The final data from the DeFianCe study show that baseline plasma
"Microsatellite-stable colorectal cancer remains one of the most difficult settings in gastrointestinal oncology, as patients whose disease progresses after first-line therapy have quite limited options. We need new liquid biopsy biomarkers that tell us effectively which patients will benefit from which therapy. These data support the utility of baseline plasma
Key Findings from the Publication
DeFianCe (NCT05480306) was a two-part, randomized, open-label, multicenter Phase 2 study. Part B randomized 188 patients 1:1 to sirexatamab plus FOLFIRI or mFOLFOX6 and bevacizumab (Sirexatamab Arm) or to chemotherapy and bevacizumab alone (Control Arm). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Baseline plasma
Sirexatamab benefit increased as baseline plasma
- Three independent analyses — a continuous treatment-by-DKK1 interaction model, a permutation-tested Biomarker Adaptive Threshold (BAT) analysis, and median- and upper-quartile subgroup analyses — converged on the same conclusion: benefit rises with baseline plasma
DKK1 . - The treatment-by-DKK1 interaction was statistically significant for both PFS (p=0.0129) and OS (p=0.0027), with
DKK1 modeled as a continuous variable. - The BAT analysis with permutation testing reached the same conclusion (PFS p=0.018; OS p<0.001), and the data-driven cut points aligned with the median and upper quartile of baseline plasma
DKK1 .
- ORR was
38.0% in the Sirexatamab Arm compared with23.7% in the Control Arm. - Median PFS was 9.0 months versus 7.1 months; HR 0.61 (
95% CI, 0.37–1.00); p=0.0255. - Median OS was not reached versus 14.4 months; HR 0.42 (
95% CI, 0.19–0.91); p=0.0118.
- ORR was
44.0% in the Sirexatamab Arm compared with15.8% in the Control Arm; p=0.0149. - Median PFS was 9.4 months versus 5.9 months; HR 0.46 (
95% CI, 0.22–0.96); p=0.0168. - Median OS was not reached versus 9.5 months; HR 0.17 (
95% CI, 0.05–0.53); p<0.001.
Higher baseline
- In the Control Arm, median OS declined as
DKK1 rose — not reached in the overall population, 14.4 months above the median, and 9.5 months in the upper quartile — consistent with published evidence linking elevatedDKK1 to more aggressive disease. DKK1 -high patients therefore represent a population with both poor prognosis on standard therapy and the greatest observed benefit from sirexatamab.
Plasma
- Baseline plasma
DKK1 was detectable in100% of patients across an approximately eight-fold dynamic range. - Levels were concordant across two orthogonal platforms — an aptamer-based SomaScan assay and an antibody-based Meso Scale Discovery (MSD) assay (Spearman r=0.77).
- Tumoral
DKK1 mRNA expression was low in most tissue samples, reinforcing that plasma — not tissue — reflects the systemicDKK1 burden relevant to colorectal cancer biology, and supporting a blood-based patient-selection test.
Results in the overall intent-to-treat (ITT) population
- The prespecified primary endpoint of PFS in the ITT population was not met. Median PFS was 9.2 months in the Sirexatamab Arm versus 8.3 months in the Control Arm; HR 0.84 (
95% CI, 0.58–1.21). ORR was35.1% versus26.6% , and median OS was not reached in either arm; HR 0.83 (95% CI, 0.46–1.48). - The final analysis included 119 investigator-assessed PFS events against the 145 events planned, leaving the ITT analysis underpowered in a biologically heterogeneous population.
Safety
- Sirexatamab in combination with chemotherapy and bevacizumab was generally well tolerated. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in
59.3% of patients in the Sirexatamab Arm compared with67.0% in the Control Arm, and serious TEAEs were comparable between arms (19.8% versus19.3% ). - TEAEs leading to discontinuation of sirexatamab occurred in
4.4% of patients, indicating that adding sirexatamab did not meaningfully change the tolerability of standard of care.
About Sirexatamab (DKN-01)
Sirexatamab (DKN-01) is a humanized monoclonal antibody that binds and neutralizes Dickkopf-related protein 1 (
About Leap Therapeutics
Leap Therapeutics, Inc. is the biotechnology research and development subsidiary of Cypherpunk Technologies Inc. (Nasdaq: CYPH), developing novel therapies for patients with cancer, including sirexatamab (DKN-01) and FL-501. For more information, visit www.leaptx.com.
About Cypherpunk Technologies
Cypherpunk Technologies is a privacy technology company. The Company's mission is to advance technologies that guarantee privacy for humans on the internet. Cypherpunk pursues this mission through two primary strategies: accumulating Zcash (ZEC); and investing in, acquiring, and building technologies that push the frontier of privacy forward. Additionally, through its subsidiary Leap Therapeutics, Inc., the Company is developing novel therapies for patients with cancer, continuing the development of sirexatamab and FL-501. For more information about the Company, visit our websites at http://www.cypherpunk.com and http://www.leaptx.com or view our public filings with the SEC that are available via EDGAR at http://www.sec.gov.
FORWARD-LOOKING STATEMENTS
This press release includes forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally can be identified by the use of words such as "anticipate," "expect," "plan," "could," "may," "will," "believe," "estimate," "forecast," "goal," "intend," "project," and other words of similar meaning. Forward-looking statements in this release include, without limitation, statements regarding the potential clinical benefit of sirexatamab; the role of baseline plasma DKK1 as a predictive biomarker and the development of a companion diagnostic; the Company's plans for and the design, initiation, timing, conduct and potential results of a Phase 3 clinical trial of sirexatamab; the potential for objective response rate to support a filing for accelerated approval in the United States and for overall survival to support full approval in the United States and registration in other markets; the significance of the Company's Type C meeting with the FDA and any alignment reached with the Agency; the definition, validation and prevalence of the DKK1-high patient population and the anticipated size and enrollment of the Phase 3 trial; and the Company's strategic process and the potential for a financing, partnership, license, collaboration, sale or other transaction.
These statements are based on the Company's current expectations and are subject to substantial risks and uncertainties that could cause actual results to differ materially. Important factors include, among others: (i) the DeFianCe study did not meet its prespecified primary endpoint of progression-free survival in the intent-to-treat population; (ii) the DKK1 biomarker subgroup and interaction analyses were exploratory, were based on a limited number of patients, were not adjusted for multiplicity, and may not be replicated in a prospective clinical trial; (iii) the impact of imbalances between treatment arms in the DKK1 subgroups; (iv) the risk that alignment with the FDA on trial design does not constitute agreement that any trial will succeed or that any marketing application will be accepted or approved, and the FDA may change its position at any time; (v) accelerated approval, if pursued, requires that the surrogate endpoint be reasonably likely to predict clinical benefit and is subject to confirmatory trial requirements and possible withdrawal if such requirements are not satisfied; (vi) the Company's ability to initiate or complete the Phase 3 trial on the anticipated timeline or at all; (vii) the Company's ability to obtain additional capital to advance sirexatamab on acceptable terms or at all; (viii) that risk that the strategic process may not result in any transaction or financing, may be terminated at any time, and any resulting transaction may not be on terms favorable to the Company or its stockholders; (ix) the Company's ability to develop and validate a companion diagnostic; (x) the success of competing therapies; (xi) the Company's ability to secure manufacturing capacity for sirexatamab; and (xii) the Company's ability to maintain and protect its intellectual property rights.
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. The Company 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 the Company's most recent Annual Report on Form 10-K filed with the SEC, or as may be included in other reports or information we file 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 the Company, 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 the Company's views as of any date subsequent to the date hereof.
CONTACT:
Douglas E. Onsi
President & Chief Executive Officer
Leap Therapeutics, Inc. / Cypherpunk Technologies Inc.
617-714-0360
donsi@leaptx.com
For Investors:
Matthew DeYoung
Investor Relations
Argot Partners
212-600-1902
leap@argotpartners.com
For Media:
Jacqueline Ortiz Ramsay
It Factor Strategies
954-294-3249
jacqueline@itfactorstrategies.com
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SOURCE Cypherpunk Technologies Inc.