BTK inhibition provides clinically active and durable platelet response

Oral rilzabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, demonstrated a clinically active and durable platelet response and was well tolerated in patients with heavily pretreated immune thrombocytopenia (ITP). This was found in an open-label phase 1/2 study evaluating rilzabrutinib in adults with relapsed ITP who had at least 2 platelet counts <30 × 10⁹/L in the 14 days prior to the first dose of rilzabrutinib [1].

BTK inhibition targets both adaptive and innate drivers of immune-mediated disease [2]. “BTK inhibition prevents antibody production in B cells, blocks phagocytosis in macrophages, and has additional effects on basophils and neutrophils,” Dr David J. Kuter (Massachusetts General Hospital & Harvard Medical School, USA) said. “There is no effect on T cells.”

Rilzabrutinib is an oral, reversible, covalent inhibitor of BTK targeting underlying disease mechanisms of platelet destruction. As opposed to ibrutinib, rilzabrutinib does not inhibit platelet aggregation. Completion of the dose-escalation study phase determined that the minimally-effective dose was rilzabrutinib 400 mg given twice daily [3].

The current study included patients who had inadequate response to prior corticosteroids and/or thrombopoietin receptor agonists (TPO-RA) but were allowed to continue receiving stable doses of these medications. The primary endpoint was ≥2 consecutive platelet counts of ≥50 × 10⁹/L and an increase of ≥20 × 10⁹/L from baseline without requiring rescue medication.

Overall, 14/32 patients (44%) achieved the primary endpoint, and responders maintained platelet counts ≥50 × 10⁹/L for a median of 71% of weekly counts (range 33-100%). Primary endpoint responses were achieved despite prior splenectomy or lack of response to prior ITP therapies. Independent of the primary response, 67% of all patients were able to achieve clinically meaningful benefit of platelet counts ≥30 × 10⁹/L. Nine responding patients continued rilzabrutinib 400 mg twice daily into the long-term extension period for an additional median of 20 weeks of treatment. In these patients treated beyond 6 months, responses remained consistently reliable for 97% of weeks at ≥30 × 10⁹/L and 89% of weeks at ≥50 × 10⁹/L platelet counts.

Rilzabrutinib was well tolerated with only grade 1/2 treatment-related treatment-emergent adverse events overall. There were only 2 related grade 1 events observed in the long-term extension period. Pivotal ITP studies are enrolling to further demonstrate the magnitude and durability of clinical benefit of rilzabrutinib.

1. Kuter DJ, et al. Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 22.
2. López-Herrera G, et al. J Leukoc Biol. 2014;95:243-50.
3. Kuter DJ, et al. Phase I/II, Open-Label, Adaptive Study of Oral Bruton Tyrosine Kinase Inhibitor PRN1008 in Patients with Relapsed/Refractory Primary or Secondary Immune Thrombocytopenia. 61^st ASH Annual Meeting, 7-10 December 2019. Abstract 87.

Posted on 18 February 202118 February 2021