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An investigational oral Bruton's tyrosine kinase (BTK) inhibitor was tolerable and yielded rapid and durable responses in pretreated patients with immune thrombocytopenia (ITP), according to results of an open-label phase I/II trial.

In the 60-patient study, 40% (95% CI 28-53) had a platelet response to rilzabrutinib at a median 167.5 days of treatment, reported David Kuter, MD, of Massachusetts General Hospital in Boston, and colleagues.

Response -- defined as two consecutive platelet counts of ≥50 × 10³/mm³ plus an increase of ≥20 × 10³/mm³ from baseline without rescue medication -- was similarly 40% (95% CI 26-56) among those who received the highest dose of the reversible, potent BTK inhibitor (400 mg twice daily), which was the dose identified during dose-escalation for further development.

"BTK inhibition with rilzabrutinib was effective at suppressing immune-mediated platelet destruction in patients with immune thrombocytopenia, thus providing evidence of a new mechanism for targeting the underlying pathologic characteristics," the group wrote in the .

In the overall group, the median time to a first platelet response of ≥50 × 10³/mm³ was 11.5 days, and patients who responded spent 65% of the time with a platelet count at this target. Among the responders, 71% (overall) and 78% (400 mg twice-daily group) had platelet counts at this level on at least four of their last eight assessments.

While from the American Society of Hematology recommend thrombopoietin-receptor agonists, the anti-CD20 antibody rituximab (Rituxan), or splenectomy for ITP lasting 3 months or more, no standard treatment currently exists for those with multiple relapses, according to Kuter and colleagues.

"Although the percentage of patients with durable remission is high with splenectomy (approximately 60 to 70%), this treatment is generally viewed less favorably than nonsurgical therapies owing to potential surgical complications, higher risks of infection or thromboembolic events, and a lifelong increased risk of sepsis with capsuled microorganisms," the group wrote.

According to background information in the study, rilzabrutinib has two mechanisms of action, "decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies."

"The covalent binding of rilzabrutinib contributes to long BTK-target engagement and durable inhibition with limited drug exposure, a clinical advantage that is accompanied by rapid systemic clearance, which reduces the potential for off-target toxic effects," Kuter's group explained.

Rilzabrutinib as a potential drug in ITP has received from the FDA and is currently being tested at the 400 mg twice-daily dose against placebo in , an ongoing phase III trial of persistent or chronic ITP in individuals ages 12 and up.

Treatment-related adverse events (TRAEs) occurred in 52% of patients, all of which were low-grade and transient. Common events included diarrhea (32%), nausea (30%), fatigue (10%), abdominal distention (7%), and vomiting (5%). No grade 3 TRAEs were reported and there was one death in a patient with preexisting Evans syndrome, which was deemed by investigators to be unrelated to treatment.

Rescue medication to avoid serious AEs or platelet deterioration was used in 12% of patients.

"There was no evidence of infections, thrombotic events, cardiac arrhythmias, liver-related toxic effects, or increased bleeding typically associated with BTK inhibitors and thrombopoietin-receptor agonists, although the follow-up was limited," the authors noted.

Starting in March 2018, the international enrolled 60 patients with ITP who had an inadequate response to prior treatment, testing four different starting doses of rilzabrutinib given for 24 weeks: 200 mg once daily (n=9), 400 mg once daily (n=1), 300 mg twice daily (n=5), and 400 mg twice daily (n=45). Primary endpoints were platelet response and safety.

Patients in the study were a median age of 50, and 57% were women. Platelet count was a median 15 × 10³/mm³ (range, 2-33 × 10³/mm³) at baseline, and they had their disease for a median 6.3 years.

The cohort had received a median of four prior therapies, including prior glucocorticoids in 92%, thrombopoietin-receptor agonists in 58%, IV immune globulin in 43%, rituximab in 40%, and fostamatinib in 13%. A fourth had also undergone splenectomy.

Platelet response rates were similar across various subgroups, including for those with chronic ITP (40%), those who received four or more prior therapies (36%), those on rilzabrutinib alone (45%) or with simultaneous ITP therapy (38%), and those with (33%) or without (42%) prior splenectomy.

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