Related Experiment Video
Updated: Jun 23, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia
David J Kuter1, Merlin Efraim1, Jiri Mayer1
1From the Hematology Division, Massachusetts General Hospital, and Harvard Medical School - both in Boston (D.J.K.); the Multiprofile Hospital for Active Treatment Sveta Marina EAD, Varna (M.E.), and the Clinic of Hematology, University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski" EAD, Pleven (N.T.) - both in Bulgaria; the Department of Internal Medicine, Hematology, and Oncology, Masaryk University Hospital, Brno (J.M.), the First Department of Medicine and the Department of Hematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague (M.T.), the Fourth Department of Internal Medicine and Hematology, Faculty of Medicine, University Hospital of Hradec Kralove, Hradec Kralove (M.K.), and the Department of Hemato-oncology, University Hospital Ostrava, and the Faculty of Medicine, University of Ostrava, Ostrava (J.G.) - all in the Czech Republic; Barts Health NHS Trust, the Royal London Hospital (V.M.), and the Department of Immunology and Inflammation, Imperial College London (N.C.), London, and Leicester Royal Infirmary, Leicester (M.G.) - all in the United Kingdom; Princess Alexandra Hospital, Woolloongabba, QLD (R. Bird), Monash Medical Centre, Clayton, VIC (Z.K.), Canberra Hospital, Garran, ACT (P.Y.C.), Perth Blood Institute, Murdoch University, Perth, WA (R. Baker), Concord Repatriation General Hospital, Concord, NSW (I.C.), and Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC (I.G.) - all in Australia; MidMichigan Health, Midland, MI (T.R.); Erasmus MC-University Medical Center, Rotterdam, the Netherlands (A.J.G.J.); NewYork-Presbyterian Hospital and Weill Cornell Medical Center, New York (E.-J.L.); McGill University Health Centre, Montreal (M.W.); the Center for Cancer and Blood Disorders, Bethesda, MD (R. Boccia); the University of Washington Medical Center, Seattle (T.G.); Ostfold Hospital Foundation, Gralum, and the Institute of Clinical Medicine, University of Oslo, Oslo - both in Norway (W.G.); and Principia Biopharma (a Sanofi company), South San Francisco, CA (O.B., R. Burns, A.N., D.T., P.A., B.Z.).
Background:
Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies.
Methods:
In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication).
Results:
Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%.
Conclusions:
Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).
