Brukinsa (zanubrutinib)

First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.

P2, N=50, Not yet recruiting, Azienda Ospedaliera di Padova

P1, N=24, Active, not recruiting, BeOne Medicines | Recruiting --> Active, not recruiting

P3, N=394, Recruiting, Guangzhou Lupeng Pharmaceutical Company LTD.

P=N/A, N=50, Not yet recruiting, The First Affiliated Hospital of Soochow University; The First Affiliated Hospital of Soochow University

P4, N=25, Not yet recruiting, People‘s Hospital of Xinjiang Uygur Autonomous Region; People‘s Hospital of Xinjiang Uygur Autonomous Region

P2, N=43, Not yet recruiting, Institute of Hematology, Chinese Academy of Medical Sciences (Chinese Academy of Medical Sciences Hematology Hospital); Institute of Hematology, Chine

P2, N=34, Not yet recruiting, The FIrst Affiliated Hospital, College of Medicine, Zhejiang University; The FIrst Affiliated Hospital, College of Medicine, Zhejiang University

P2, N=50, Recruiting, Beijing Tongren Hospital

P2, N=96, Completed, BeiGene | Active, not recruiting --> Completed

Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies.