Jaypirca (pirtobrutinib)

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.

P3, N=306, Recruiting, Newave Pharmaceutical Inc | Not yet recruiting --> Recruiting

P2, N=25, Not yet recruiting, University of Utah

A stem-like malignant B cell population enriched in resistant samples exhibited features of metabolic reprogramming and epithelial-mesenchymal transition. Together, our findings highlight heterogeneous, multi-layered mechanisms of PBN resistance and suggest chromatin regulators as potential therapeutic targets to overcome PBN resistance in MCL.

P4, N=150, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P2, N=13, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P2, N=50, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P=N/A, N=40, Not yet recruiting, Ou Bai, MD/PHD

P3, N=620, Not yet recruiting, Nurix Therapeutics, Inc.

Aberrant B cell receptor signaling occurs in several B cell neoplasms including follicular lymphoma (treated with zanubrutinib, a BTK inhibitor), mantle cell lymphoma (acalabrutinib, pirtobrutinib, zanubrutinib), marginal zone lymphoma (zanubrutinib), chronic lymphocytic leukemia and small lymphocytic lymphoma (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), and Waldenström macroglobulinemia (ibrutinib, zanubrutinib)...Pirtobrutinib fails to form a covalent bond and is a reversible BTK inhibitor. The FDA-approvals of rilzabrutinib and remibrutinib (2025) represent the first nononcologic authorizations for BTK antagonists.

Noncovalent BTK inhibitors, particularly pirtobrutinib, has shown impressive activity in patients who have progressed on covalent BTKi. The FDA approval of lisocabtagene maraleucel represents a significant milestone in the treatment of double refractory CLL, providing a potentially curative option for eligible patients. The development of effective treatments for double refractory CLL represents an urgent unmet clinical need and the promising results from emerging therapies offer hope for improved outcomes in this challenging patient population.