Leap Therapeutics Reaches FDA Alignment on Phase 3 Trial for Sirexatamab in DKK1-High Metastatic Colorectal Cancer
核心洞察
Leap Therapeutics reached FDA alignment on a registrational Phase 3 trial of sirexatamab in DKK1 (搜索)-high, second-line metastatic colorectal cancer (搜索) (mCRC), with objective response rate supporting accelerated approval and overall survival supporting full approval.
The randomized Phase 2 DeFianCe study, published in Clinical Cancer Research, showed sirexatamab's benefit increases with rising baseline plasma DKK1 (搜索) levels, defining DKK1-high mCRC as a biologically distinct population with high unmet need.
Sirexatamab received FDA Fast Track designation in May 2026 for DKK1 (搜索)-high mCRC patients whose disease has progressed following one prior systemic therapy.
Leap Therapeutics, a subsidiary of Cypherpunk Technologies Inc. (搜索), has reached alignment with the U.S. Food and Drug Administration (FDA) on a registrational Phase 3 trial design for sirexatamab (DKN-01), an anti-DKK1 (搜索) monoclonal antibody, in patients with DKK1-high, second-line metastatic colorectal cancer (搜索) (mCRC). The announcement, made as part of Cypherpunk's second quarter 2026 financial results, marks a pivotal regulatory milestone for a biomarker-defined patient population with significant unmet medical need.
Douglas E. Onsi, President and CEO of Cypherpunk Technologies, stated: "Our Leap Therapeutics subsidiary reached alignment with the FDA on a proposed Phase 3 trial in a DKK1 (搜索)-high, second-line, metastatic colorectal cancer (搜索) population, with objective response rate as the primary endpoint to support accelerated approval and overall survival to support full approval in the United States and registration globally."
Phase 2 DeFianCe Study Establishes DKK1 Biomarker Rationale
The regulatory path is grounded in the randomized Phase 2 DeFianCe study (NCT05480306), whose results were published in Clinical Cancer Research. The publication, titled "Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial," reported complete efficacy, safety, and biomarker analyses.
While the prespecified primary endpoint was not met in the intent-to-treat population, the peer-reviewed analyses established that the benefit of sirexatamab increases as a patient's baseline plasma DKK1 (搜索) level rises. This relationship was confirmed by independent statistical approaches and reinforced by the observation that high DKK1 predicts poorer outcomes on standard of care alone. Together, these findings define DKK1-high mCRC as a biologically distinct population with high unmet need.
Registrational Phase 3 Trial Design
Leap Therapeutics held a Type C meeting with the FDA to discuss the DeFianCe results and the proposed registrational path for sirexatamab in DKK1 (搜索)-high, second-line mCRC. The FDA provided feedback supporting key elements of the proposed design, including the use of a DKK1 biomarker-selected patient population and a dual-endpoint structure intended to support both accelerated and full approval.
The aligned Phase 3 trial is a randomized, controlled study evaluating sirexatamab in combination with investigator's-choice fluoropyrimidine-based chemotherapy (FOLFIRI or mFOLFOX6) plus bevacizumab, compared with chemotherapy and bevacizumab alone. Approximately 270 patients with mCRC whose disease has progressed following one prior line of systemic therapy, prospectively identified as DKK1 (搜索)-high using a baseline plasma DKK1 assay cut point, are expected to be enrolled and randomized 1:1.
Potential accelerated approval in the United States could be determined by objective response rate (ORR) in an initial group of approximately 160 patients, while overall survival (OS) will be evaluated in the full study population to support a filing for full approval in the United States and registration in markets outside the United States. A blood-based companion diagnostic would be developed in parallel to identify DKK1 (搜索)-high patients in routine clinical practice.
Fast Track Designation
In May 2026, the FDA granted Fast Track designation to sirexatamab in combination with fluoropyrimidine plus oxaliplatin- or irinotecan-based chemotherapy and bevacizumab, for the treatment of patients with DKK1 (搜索)-high mCRC whose disease has progressed following one prior systemic therapy. The Fast Track program is intended to facilitate development and expedite review of drug candidates that treat serious conditions and fill an unmet medical need, and may confer benefits including frequent communication with the FDA and a rolling submission of the marketing application.
Strategic Process for Advancing Sirexatamab
Leap Therapeutics has initiated a strategic process to identify the best path forward for sirexatamab and to secure the resources required to advance the program into Phase 3 development. The process is expected to consider a range of alternatives, which may include financing the program as an independent entity, or a strategic transaction with a pharmaceutical or biotechnology company, including a partnership, license, collaboration, sale, or other business combination.
The Company has not set a timetable for the conclusion of the process and does not intend to disclose developments unless and until it determines that further disclosure is appropriate or required. There can be no assurance that the strategic process will result in any transaction or financing on terms favorable to the Company or its stockholders.
Financial Context
The biotechnology program operates within Cypherpunk Technologies, a privacy technology company whose primary strategies involve accumulating Zcash (ZEC) and investing in privacy technologies. For the second quarter of 2026, Cypherpunk reported net income of $39.4 million, or $0.18 per diluted share, compared to a net loss of $16.6 million in the second quarter of 2025, driven primarily by a $46.0 million unrealized gain on the fair value of its ZEC treasury holdings. Research and development expenses declined to $0.2 million for the quarter, from $10.5 million in the prior-year period, reflecting the completion of clinical trials and a 2025 reduction in force.