medwireNews: Early results for the oral Bruton tyrosine kinase (BTK) inhibitor rilzabrutinib support its use in patients with relapsed or refractory immune thrombocytopenia (ITP).

David Kuter, from Massachusetts General Hospital in Boston, USA, reported the findings of the phase 1/2 dose-escalation study at the at the virtual 62nd American Society of Hematology Annual Meeting and Exposition.

“Rilzabrutinib, previously called PRN1008, has been specifically designed to inhibit BTK in autoimmune diseases,” the presenter said, highlighting the agent’s precise, reversible, and prolonged binding properties.

The trial was open to patients aged 18–80 years who had previously responded to one or more treatments for primary or secondary ITP and had at least two platelet counts below 30 x 10⁹/L.

Over 24 weeks, 53 patients were given rilzabrutinib at a dose of 200 mg or 400 mg once daily, or 300 mg or 400 mg twice daily, with a stable dose of corticosteroids and/or thrombopoietin receptor agonist therapy also permitted.

Kuter focused on results for the 38 patients who received what was determined to be the minimal effective dose of 400 mg twice daily; these patients were aged a median of 50 years, 55% were women, and the majority (97%) had primary ITP, lasting a median 6 years. Their median baseline platelet count was 17 x 10⁹/L and they had received a median of six prior treatments for ITP. Approximately a quarter (24%) had undergone splenectomy.

The study’s primary endpoint of two or more consecutive platelet counts of at least 50 x 10⁹/L without rescue medication was met by 42% of the patients given rilzabrutinib 400 mg twice daily, including 33% of those who had previously undergone splenectomy.

And the proportion of patients responding to rilzabrutinib was not predicted by prior response or nonresponse to a thrombopoietin receptor agonist (n=26; 25 vs 43%), rituximab (n=17; 40 vs 25%), or fostamatinib (n=6; 50 vs 50%).

Kuter said there was a “remarkable and rapid response” to treatment, with 53% of patients achieving a “clinically meaningful” platelet count of at least 30 x 10⁹/L by day 8 of the study.

Moreover, he noted that primary endpoint responses were durable in 16 patients, so that over 19.6 weeks of follow-up, patients had a platelet count of at least 20 x 10⁹/L on 85% of weeks, of at least 50 x 10⁹/L on 70% of weeks, and of 100 x 10⁹/L or higher on 29% of weeks.

Eleven patients given rilzabrutinib 400 mg twice daily achieved a platelet count of 50 x 10⁹/L or higher for at least half of the prior 8 weeks (median, 98 x 10⁹/L) and were eligible to enter a long-term extension (LTE) study designed to further examine the safety of the drug.

The LTE patients were comparable to the full 400 mg twice daily cohort in terms of age (median, 49 years), sex (62% female), median baseline platelet count (17 x 10⁹/L), number of prior treatments (five), and splenectomy (23%), but had a shorter median duration of treatment, at 3.8 years versus 6.0 years in the whole cohort, the investigator observed.

During up to 43.6 weeks of treatment, these patients maintained “consistently reliable” responses, he said, with the group achieving a platelet count of at least 30 x 10⁹/L for 97% of study weeks, of at least 50 x 10⁹/L for 89% of weeks, and of at least 100 x 10⁹/L for 45% of weeks.

One patient who had completed treatment experienced a platelet count drop but responded when treatment with rilzabrutinib was restarted, the presenter noted.

Kuter reported that almost half (47%) of patients given the 400 mg twice daily dose experienced treatment-related adverse events but these were transient and occurred at grade 1 or 2, most commonly diarrhea or nausea, with less frequent reports of vomiting, fatigue, abdominal pain or distension, and vulvovaginal dryness.

In the LTE study cohort, there was just one report of grade 1 diarrhea and another of grade 2 vulvovaginal dryness.

“The safety profile showed a clear benefit over risk for this medication,” the presenter said, emphasizing that there were no treatment-related serious adverse events or bleeding and thrombotic events.

“Pivotal ITP studies are enrolling to further demonstrate the magnitude and durability of rilzabrutinib’s clinical benefit,” Kuter concluded, adding that the agent received FDA FastTrack status in October 2020.

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62nd ASH Annual Meeting and Exposition; 5–8 December 2020

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