Key Takeaways

  • In an international phase 1–2 clinical trial of patients with immune thrombocytopenia, an oral investigational drug called rilzabrutinib was active and associated with only low-level toxic effects at all dose levels.
  • Additional clinical trials are underway to verify that rilzabrutinib can safely boost platelet levels in patients with this autoimmune disease characterized by an increased risk of bleeding.

We hypothesized that rilzabrutinib would be effective in both reducing the antibody attacking the platelets as well as minimizing the rate of platelet destruction by the macrophages.

David J. Kuter, MD, DPhil
Program Director, Hematology, Mass General Cancer Center

BOSTON – In people with immune thrombocytopenia (ITP), the body produces destructive antibodies against platelets in the blood, which increases the risk of bruising, bleeding, hospitalization, death, fatigue, and an impaired quality of life. A drug called rilzabrutinib has generated promising safety and efficacy results in a recent international multi-center phase 1–2 ITP trial led by investigators at Massachusetts General Hospital (MGH).  The findings, which are published in the New England Journal of Medicine, pave the way for more advanced clinical trials.

Research has shown that cells called macrophages are primarily responsible for destroying antibody-coated platelets in ITP, and an enzyme called Bruton kinase is critical to their function. Although an inhibitor of Bruton kinase that was approved to treat a common form of leukemia decreases macrophage activity and raises platelets counts in patients with both leukemia and ITP, the drug, called ibrutinib, also inhibits the function of platelets, which reduces its efficacy in ITP. 

Oral rilzabrutinib was developed as a new type of Bruton kinase inhibitor that reduces macrophage activity and the production of anti-platelet antibodies but does not affect the function of platelets.  “We hypothesized that rilzabrutinib would be effective in both reducing the antibody attacking the platelets as well as minimizing the rate of platelet destruction by the macrophages,” says lead author David J. Kuter, MD, DPhil, who is the program director of Hematology at MGH and a professor of Medicine at Harvard Medical School.

In the 60-patient trial that involved a range of rilzabrutinib doses, all treatment-related adverse events were minor and transient. At a median follow-up of approximately 5.5 months of treatment, 24 of the 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose experienced a significant platelet response. The median time to develop a healthy platelet count was 10.5 days. Among patients who experienced a platelet response, the average percentage of weeks in which they had a healthy platelet count was 65%. The dose of 400 mg twice daily was identified as the dose for further testing.

Importantly, the patients in this study had already tried multiple therapies, and their disease were considered highly refractory to treatment. A major phase 3 clinical trial is currently underway at many sites, including MGH, to test the effectiveness of rilzabrutinib in patients with ITP that is less refractory to other medications.

“If the findings of our study are borne out in other studies, rilzabrutinib may provide a rapid rise in platelet count and a sustained increase to a safe platelet count number, which could thereby minimize bleeding, and the drug could conceivably make the antibody causing the disease to disappear,” says Kuter. “What is impressive is that this drug lacks major negative effects that have been historically associated with this class of medications. We saw no increased risk of bleeding, infection, liver dysfunction, or intolerance by patients.”

Additional study authors include Merlin Efraim, MD, Jiri Mayer, MD, Marek Trněný, MD, Vickie McDonald, MD, Robert Bird, MB, BS, Thomas Regenbogen, MD, Mamta Garg, MD, Zane Kaplan, MD, Nikolay Tzvetkov, MD,
Philip Y. Choi, MD, A.J. Gerard Jansen, MD, Milan Kostal, MD,
Ross Baker, MD, Jaromir Gumulec, MD, Eun-Ju Lee, MD,
Ilona Cunningham, MD, Isaac Goncalves, MD, Margaret Warner, MD, Ralph Boccia, MD, Terry Gernsheimer, MD, Waleed Ghanima, MD, Olga Bandman, MD, Regan Burns, BA, Ann Neale, BS, Dolca Thomas, MD, Puneet Arora, MD, Beiyao Zheng, PhD, and Nichola Cooper, MD.

This work was supported by Sanofi.

 About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham health care system.