Disclosures: Sanofi funded this study. Kuter reports research fees from and/or consultant roles with Alexion (Syntimmune), Amgen, Argenx, BioCryst, Bristol Myers Squibb, Caremark, Cellularity, Cellphire, CRICO, Daiichi Sankyo, Hengrui, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp & Dohme, Momenta, Novartis, Pfizer, Platelet Biogenesis, Platelet Disorder Support Association, Rigel, Sanofi (Principia), Sanofi (Genzyme), Sobi (Dova), Takeda (Bioverativ), UCB and Up-To-Date; and stock ownership with Rubius. Please see the study for all other authors' relevant financial disclosures.
April 13, 2022
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Rilzabrutinib active, safe in immune thrombocytopenia

Disclosures: Sanofi funded this study. Kuter reports research fees from and/or consultant roles with Alexion (Syntimmune), Amgen, Argenx, BioCryst, Bristol Myers Squibb, Caremark, Cellularity, Cellphire, CRICO, Daiichi Sankyo, Hengrui, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp & Dohme, Momenta, Novartis, Pfizer, Platelet Biogenesis, Platelet Disorder Support Association, Rigel, Sanofi (Principia), Sanofi (Genzyme), Sobi (Dova), Takeda (Bioverativ), UCB and Up-To-Date; and stock ownership with Rubius. Please see the study for all other authors' relevant financial disclosures.
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Rilzabrutinib induced rapid and durable clinical activity in previously treated patients with immune thrombocytopenia, according to results of a phase 1/phase 2 clinical trial published in The New England Journal of Medicine.

Additionally, the oral Bruton tyrosine kinase inhibitor demonstrated a low-grade safety profile.

Primary study endpoint of platelet response.
Data derived from Kuter DJ, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2110297.

“Prior research with ibrutinib [Imbruvica; Pharmacyclics, Janssen] had shown that patients with chronic lymphocytic leukemia and immune thrombocytopenia [ITP] had improvement in their ITP, suggesting that Bruton tyrosine kinase [BTK] inhibition might play a role in ITP therapy. Unfortunately, ibrutinib has a substantial risk of worsening platelet function and cannot be widely used in thrombocytopenic disorders such as ITP,” David J. Kuter, MD, DPhil, hematology program director at Massachusetts General Hospital and professor of medicine in the division of hematology at Harvard Medical School, told Healio. “With the development of a BTK inhibitor that lacked the antiplatelet effect and did not promote cardiac arrhythmias, we sought to explore the use of BTK inhibition in ITP.”

Methodology

The analysis included 60 patients (median age, 50 years; range, 19-74; 57% women) with platelet counts of less than 30 × 103/mm3 on two occasions no less than 7 days apart within 15 days before trial entry. Patients received a median four previous immune thrombocytopenia therapies and had a history of a response to at least one of those therapies, but not to the previous or concomitant therapy maintained at baseline.

Patients had a median platelet count of 15 × 103/mm3 at baseline and median disease duration of 6.3 years.

Kuter and colleagues used intrapatient dose escalation of oral rilzabrutinib (Sanofi) over 24 weeks, with a lowest starting dose of 200 mg (once daily) and higher starting doses of 400 mg (once daily), 300 mg (twice daily) and 400 mg (twice daily). Safety and platelet response served as primary endpoints.

Key findings

Results showed that after a median 167.5 days of treatment (range, 4-293), 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) starting rilzabrutinib treatment at the highest dose met the primary endpoint of platelet response.

Researchers reported a median time of 11.5 days to the first platelet count of at least 50 × 103/mm3. Additionally, they noted a 65% mean percentage of weeks with a platelet count of at least 50×103/mm3 among patients with a primary platelet response.

David J. Kuter, MD, DPhil
David J. Kuter

“More than half the patients responded within 2 weeks and the responses were maintained with the platelet count over 50,000/mm3 on nearly two-thirds of study visits in the 24-week study,” Kuter told Healio. “The therapy was well-tolerated with very few significant adverse side effects. Bleeding was not increased and there were no cardiac arrhythmias.”

Kuter added that he was surprised by the rapid and dramatic response in such a high proportion of patients who had failed a median of four other therapies, and that the therapy showed few significant adverse events in this relatively short study. Treatment-related adverse events were all transient and grade 1 or grade 2.

“An ongoing long-term, open-label, extension study has confirmed the durability of the treatment effect and the paucity of major adverse events,” he said. “There is no apparent increased risk [for] infection, but obviously longer drug exposure needs to be obtained to confirm that.”

Implications

Further research is underway, including a large, placebo-controlled randomized study of rilzabrutinib vs. standard of care among patients with less refractory forms of ITP and another in autoimmune hemolytic anemia, which also is mediated by B cells and macrophage activation.

“A wide range of other autoimmune conditions have a similar pathophysiology, and future use of BTK inhibition for these may play a major role in the treatment of disorders of the kidney, nerves and muscles,” Kuter said.

For more information:

David J. Kuter, MD, DPhil, can be reached at Hematology Division, Massachusetts General Hospital, Suite 118, Room 110, Zero Emerson Place, Boston, MA 02114-2603; email: kuter.david@mgh.harvard.edu.