CFON-026 / Crossfire Oncology - LARVOL DELTA

CFON-026 is a macrocycle that disrupts the BTK protein scaffold thereby inhibiting all clinically relevant BTK resistance mutations (AACR 2025) - "The first generation BTK inhibitors bind covalently to Cys481 and include ibrutinib, acalabrutinib and zanubrutinib...Pirtobrutinib was developed as a second generation non-covalent BTK inhibitor, though resistance has emerged via the acquisition of BTK mutant variants BTKT474I and BTKL528W...CFON-026 disrupts the BTK kinase structure, abrogating both kinase activity and scaffold functions. CFON-026 can overcome resistance mutations emerging from all existing covalent and non-covalent BTK inhibitor therapies."

Clinical • Oncology

CFON-026, a best-in-class macrocyclic non-covalent inhibitor of BTK(WT) and all clinically relevant BTK resistance mutations (EORTC-NCI-AACR 2024) - "The first generation BTK inhibitors, including ibrutinib, acalabrutinib and zanubrutinib, bind covalently but are prone to acquired resistance...Pirtobrutinib is a second generation non-covalent BTK inhibitor designed to bind both BTKWT and BTKC481S but is prone to novel resistance inducing BTK mutant variants including BTKT474I and BTK V416L resulting in a relatively short progression free survival in the clinic...CFON-026 induces complete tumour regression in a TMD8 xenograft model. ConclusionCFON-026 is an EPriL-based best-in-class non-covalent BTK inhibitor that can overcome resistance mutations emerging from existing covalent and non-covalent BTK inhibitor therapies."

Clinical • Oncology

CFON-026 is a potent non-covalent BTK inhibitor suitable for combination therapy with covalent BTK inhibitors for early eradication of resistance mutations (AACR 2024) - "Frequently observed mutations include BTKC481S, which abrogates covalent binding of irreversible drugs such as acalabrutinib, ibrutinib and zanubrutinib, and BTKT474I and BTKV416L which both abrogate binding of the non-covalent inhibitor drug pirtobrutinib [1, 2]. [1] Woyach et al., J Clin Oncol (2017). [2] Wang et al., N. Eng J Med (2022)."

Combination therapy • Oncology