NTRC 12026-0 is a non-covalent BTK inhibitor with a covalent-like binding profile for both BTK wild-type as well as all clinically relevant BTK mutant variants. It not only inhibits signaling of the BTKC481S mutant variant associated with CLL resistance to covalent BTK inhibitors (which for their binding on the cysteine at position 481), but also BTK mutant variants that arise following treatment with non-covalent BTK inhibitors like pirtobrutinib. NTRC 12026-0 is in preclinical development, showing high selectivity, good manufacturability and promising PK/PD properties.
We are planning to develop NTRC 12026-0 in CLL patients (and potentially other B-cell malignancy patients) that have acquired a C481S mutation, in combination with a covalent BTK inhibitor, like Imbruvica or Calquence. Preclinical testing has shown synergistic effects for these combinations and might result in prolonged tumor regression. The overlapping mutant BTK binding profiles might even prevent relapse induced by BTK mutations, while maintaining the favorable safety profile associated with BTK inhibitors in general.
A First in Human (FIH) trial with NTRC 12026-0 is expected to be initiated the second half of 2024.