Jaypirca (pirtobrutinib)

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2025 --> Jun 2026

P1/2, N=56, Not yet recruiting, Fondazione Italiana Linfomi Ets

P1, N=30, Recruiting, National Heart, Lung, and Blood Institute (NHLBI)

P2, N=24, Recruiting, Zhejiang Cancer Hospital

P1, N=22, Recruiting, F. Hoffmann-La Roche AG

P1/2, N=82, Not yet recruiting, French Innovative Leukemia Organization

P2/3, N=196, Recruiting, BeOne Medicines AG

P1/2, N=195, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting | N=424 --> 195

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=87, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

P3, N=600, Active, not recruiting, Loxo Oncology, Inc. | Trial primary completion date: Apr 2026 --> Oct 2026 | Trial completion date: Jan 2027 --> Oct 2027

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.