The safety and efficacy of pirtobrutinib in adults with immune thrombocytopenia: A phase 1/2 dose-finding study in progress

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by reduced platelet counts and increased risk of bleeding. Although current treatment options, including thrombopoietin-receptor agonists and immunosuppressive agents, typically result in an initial response, lack of long-term durable remission and significant side effects limit their use. Advances in understanding ITP pathogenesis have highlighted Bruton tyrosine kinase (BTK) as a promising therapeutic target. Pirtobrutinib (LY3527727), a highly selective, non-covalent, reversible BTK inhibitor, may offer advantages for patients with ITP due to its optimized pharmacokinetic properties, once-daily dosing, and specificity for BTK. Preclinical studies in ITP models demonstrated that pirtobrutinib effectively modulates B-cell activity and reduces autoantibody production, supporting its potential as a therapeutic agent. This phase 1/2 study (NCT06721013) aims to optimize the dosing of pirtobrutinib in adults previously treated for primary ITP. Methods:This study consists of 2 parts: phase 1 dose escalation and phase 2 dose optimization. Phase 1 is an open-label portion where dose escalation will be driven by the BOIN method. Approximately 9-18 participants will be enrolled into sequential dose levels, starting at the lowest dose level of oral pirtobrutinib, given once daily for 12 weeks. The primary objective for phase 1 is to assess the safety and tolerability of pirtobrutinib and select doses for phase 2. Secondary objectives will assess the preliminary efficacy by platelet response rate, the extent of disease control, and describe the PK of pirtobrutinib. Phase 2 is a randomized, double-blind dose optimization design where approximately 10 participants will be equally randomized to evaluate at least two dose levels of pirtobrutinib versus placebo. Patients will be treated for 12 weeks, followed by a 12-week period of visits to assess the durability of response. In phase 2, the primary objective is to assess the efficacy of pirtobrutinib versus placebo, by stable platelet response rate (platelet count ≥50 k/μL on ≥4 of 6 consecutive biweekly visits between weeks 14-24, without rescue therapy and prohibited concomitant medications affecting efficacy). Secondary objectives will evaluate the safety, PK, and additional efficacy endpoints of pirtobrutinib. Eligibility criteria include age ≥18, confirmed diagnosis of primary ITP for at least 3 months prior to enrollment, and history of response to ≥1 prior line of therapy. Exclusion criteria include treatment other than corticosteroids or TPO-RA for ITP within 2 weeks of visit 1, use of anticoagulants or antiplatelet therapy, history of any thrombotic or embolic event within 12 months before screening, hematologic malignancy, and significant cardiovascular disease. Results: This study is a Trial in Progress, and enrollment is ongoing.