Two-species toxicology for Silexion’s siRNA candidate SIL204 reported no systemic organ toxicity, clearing a key preclinical gate and keeping the program on track for a Phase 2/3 trial in locally advanced pancreatic cancer with first patient in targeted for Q2 2026.
The company has completed the toxicology package supporting regulatory submissions in Israel and Germany and has locked in a CRO partner for execution. SIL204 is a next-generation RNA interference therapy designed to silence mutant KRAS, with preclinical data showing growth inhibition across KRAS-mutant lines and anti-tumor activity in pancreatic models after systemic dosing. The planned clinical regimen is notable: a combined intratumoral plus systemic administration strategy intended to maximize local and systemic exposure. Silexion previously tested a first-generation construct in a Phase 2a study that showed a positive trend versus chemotherapy, and is now advancing the optimized successor into an adaptive, later-stage program.
Strategically, this is an expansion move using an OUS-first regulatory route and a seamless Phase 2/3 design to compress timelines and conserve capital. The choice of Israel’s Ministry of Health and Germany’s BfArM suggests a focus on jurisdictions with established pathways for RNA therapeutics and greater flexibility to start mid-stage studies when supportive human data exist on a related construct. Positioning a KRAS-targeted siRNA against a field dominated by small-molecule inhibitors also hedges against the allele-specific limits seen with G12C agents and the still-maturing G12D landscape in pancreatic cancer. The integrated intratumoral plus systemic approach raises the probability of hitting heterogeneous tumor compartments, but it also raises the operational burden and regulatory scrutiny around procedural safety and class effects like innate immune activation.
For sites, practical implications are immediate. Centers will need interventional endoscopy or IR capability for intratumoral delivery—likely EUS-guided—alongside systemic administration, with associated training, credentialing, and scheduling coordination across specialties. Eligibility workflows will hinge on reliable KRAS genotyping and repeat tissue access for pharmacodynamic and biomarker reads. Handling requirements for oligonucleotide products and any delivery vehicles will add to pharmacy SOP complexity, cold-chain vigilance, and IMP accountability. CROs will have to stand up an adaptive protocol with a safety run-in, DMC oversight, a rigorous imaging charter, and harmonized submissions across two regulators, while ensuring consistency in procedure technique to limit site-level variability that can erode signal. Regulators will focus on off-target effects, complement activation, cytokine profiles, and dose-exposure relationships across the dual routes, and will expect clear bridging logic from the first-generation construct to SIL204.
The near-term watchlist is specific: the design choices embedded in the initial protocol, including whether the primary endpoint emphasizes conversion to resection, PFS, or OS; the mutation spectrum included (G12D dominant versus broader KRAS variants); the dosing sequence and schedule across intratumoral and systemic arms; and the size and objectives of the safety run-in that will govern the transition to the Phase 3 component. CMC maturity will be a gating factor, particularly around siRNA manufacturing scale, impurity control, and any lipid or polymer delivery systems. Competitive pressure will intensify as G12D inhibitors and combination regimens move into pancreatic settings; Silexion will need a clear differentiation story on tolerability and operational feasibility, not just mechanistic breadth. Execution risk centers on site activation timelines in two countries, reproducibility of intratumoral administration, and early safety signals typical for oligonucleotides. If the company can lock regulatory alignment in early 2026 and demonstrate a clean, procedurally manageable safety profile in the run-in, the seamless design could carry momentum into an efficacy read that matters.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
