^
    2d
    Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations. (PubMed, Blood Cancer J)
    Covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are effective but alterations in the kinase domain at C481 or BTK gatekeeper residue T474 mutations result in development of resistance...We evaluated the efficacy of a new ncBTKi, docirbrutinib (AS-1763), against 14 BTK mutants, including C481S, T474x, and L528x, as well as gatekeeper and kinase domain double mutants, using biochemical assays, cell-line models, and primary CLL lymphocytes. Docirbrutinib potently inhibited BTK autophosphorylation and mutant BTK-driven cell proliferation, with greater effects than ibrutinib and pirtobrutinib against certain mutants. In treatment-naïve and relapsed/refractory CLL samples, docirbrutinib disrupted B-cell receptor signaling and sensitized cells to apoptosis induced by venetoclax and AZD5991. In a dose-escalation trial (NCT05602363), docirbrutinib decreased CCL3/CCL4 biomarkers and inhibited the B-cell receptor pathway signaling in longitudinal samples from patients with relapsed/refractory CLL. These findings establish docirbrutinib as a pan-mutant ncBTKi with potential to improve outcomes for CLL patients, including those with disease resistant to cBTKi and other ncBTKi.
    Preclinical • Journal
    |
    CCL3 (C-C Motif Chemokine Ligand 3)
    |
    BTK C481S
    |
    Venclexta (venetoclax) • Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib) • AZD5991 • docirbrutinib (AS-1763)
    over2years
    AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov)
    P1, N=110, Recruiting, Carna Biosciences, Inc. | Phase classification: P1b --> P1
    Phase classification
    |
    PLCG2 (Phospholipase C Gamma 2)
    |
    PLCG2 mutation
    |
    docirbrutinib (AS-1763)
    almost3years
    AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov)
    P1b, N=110, Recruiting, Carna Biosciences, Inc. | Not yet recruiting --> Recruiting
    Enrollment open
    |
    docirbrutinib (AS-1763)