Efficacy and safety results of linperlisib in adult patients with primary immune thrombocytopenia (ITP)

Abstract Introduction: Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by continuous thrombocytopenia and an increased risk of bleeding. A proportion of patients couldn't continuously benefit from current therapies and some of their needs remain unmet. PI3K signaling pathways promote the loss of B cells tolerance, whose downstream signaling pathways, including AKT and BTK-mediated pathways, are activated. Inhibitors of PI3K can significantly reduce the platelet apoptosis induced by anti-GPIbα antibodies, while linperlisib is a small molecule inhibitor of PI3Kδ. This article reports the initial phase II results of linperlisib in adult patients with persistent or chronic ITP that has failed second-line treatment in the study ChiCTR2400083875. Methods: This is a single-arm, single-center, and exploratory phase II clinical study, aiming to evaluate the efficacy and safety of linperlisib. Adult patients with relapsed/refractory ITP who had the duration of more than 6 months and have received ≥2 prior standard care of ITP therapy, with an average of 2 baseline platelet counts of < 30×109/L in the 2 months before baseline, were eligible for the study. The patients received a single oral dose of linperlisib 40mg QD for 24 weeks. The primary endpoint was the percentage of subjects with the platelet count of ≥ 50×109/L within 12 weeks of treatment (the platelet counts should be tested at least twice consecutively, with an interval of at least 7 days). Results: As of July 1st, 2025, 12 patients were enrolled, among whom 75% (9/12) were female. The median age of these patients was 33.5 y (range, 18-70) and median duration of ITP was 19 months (range, 6-144). 66.7%(8/12) of patients received prior rhTPO treatment and 58.3% (7/12) of patients were treated with TPO-RAs. The median platelet count at baseline was 11.5×109/L (range, 5-27). Overall, 50.0% (6/12) of patients had the platelet count of ≥ 50×109/L within 12 weeks of treatment (the platelet counts should be tested at least twice consecutively, with an interval of at least 7 days). 66.7% (8/12) of patients had response. Response was defined as the platelet count of at least 30×109/L (the platelet counts should be tested at least twice consecutively, with an interval of at least 7 days), at least doubling of the baseline count, and absence of bleeding. 33.3% (4/12) of patients had complete response. Complete response was defined as the platelet count of at least 100×109/L (the platelet counts should be tested at least twice consecutively, with an interval of at least 7 days), at least doubling of the baseline count, and absence of bleeding. Median time to the first platelet counts of ≥50×109/L among responding patients was 14 days (3-56). Among primary responders, platelet counts of ≥50×109/L were maintained for 83.3% (5/6) of visits. Analysis on subgroups demonstrated that the response rate and the durable response rate were 57.1% and 42.9% for patients with prior TPO-RAs treatment, and 50.0% and 37.5% for patients with rhTPO treatment, respectively. Treatment-related adverse events (TRAEs) occurred in 83.3% of patients, all of which were classified into grade 1-2. The most common TRAEs included decreased neutrophil count (50%), oral ulcer (41.7%), increased levels of alanine aminotransferase (ALT) (25.0%), hypercholesterolemia (25.0%), decreased white blood cells count (16.7%), and diarrhea (16.7%), thereby supporting the safety of linperlisib 40mg QD. No related thrombotic events or deaths were observed. Conclusions: Linperlisib was well tolerated in adult patients with relapsed/refractory ITP. Linperlisib 40mg QD demonstrated durable, and clinically significant platelet responses in all subgroups with pretreated ITP. A randomized phase 3 study will be continued to further assess the durable clinical benefits of linperlisib in adult patients with relapsed/refractory ITP.