Platelet Response to Lusutrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease and Thrombocytopenia Undergoing Non-Emergency Invasive Procedures: Results from a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Abstract

Thrombocytopenia is a common complication of chronic liver disease (CLD), which may be caused by multiple factors including decreased production of thrombopoietin (TPO). The presence of thrombocytopenia may complicate the conduct of routine invasive procedures that are commonly performed in CLD patients, leading to delayed or cancelled procedures. Lusutrombopag (formerly S-888711) is an orally available, small molecule agonist of human TPO receptor. Here we report the platelet response data from a confirmatory global phase 3, randomized, double-blind, placebo-controlled study (L-PLUS 2 study) evaluating lusutrombopag for the treatment of thrombocytopenia in patients with CLD who were undergoing non-emergency invasive procedures.Key eligibility criteria included 18 years of age or older, platelet count < 50 × 109/L at baseline, Child-Pugh Class A or Class B, and expecting to undergo a non-emergency invasive procedure. Patients with existing or history of portal vein thrombosis (PVT), or with past or present thrombosis or prothrombotic conditions were excluded. Patients were randomized 1:1 to receive oral lusutrombopag 3 mg once daily or placebo for up to 7 days. Stopping criteria based upon platelet count measurement on days 5, 6 and 7 were used to prevent platelet overshoot. Invasive procedures were performed between Day 9 and Day 14. Platelet transfusion was mandated by the study protocol if a patient's platelet count prior to the invasive procedure was < 50×109/L. The primary efficacy endpoint was proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomization to 7 days after the primary procedure. Safety assessment included adverse events, physical exams, laboratory tests and imaging for detection of PVT.A total of 215 patients were randomized, constituting the ITT population (lusutrombopag 108, placebo 107). Baseline patient characteristics were similar between the two treatment groups. The most common invasive procedures included endoscopic variceal ligation (28%), endoscopy with or without polypectomy/biopsy (27%), dental extraction (11%), and transarterial chemoembolization (9%). The study met its primary efficacy endpoint: 64.8% of patients in lusutrombopag group required no platelet transfusion prior to their procedures and no rescue therapy for bleeding up to 7 day after the procedure, compared to 29.0% of patients in the placebo group (p<0.0001). The proportion of patients who met the definition of platelet responder (platelet count ≥ 50×109/L and an increase from baseline of ≥ 20×109/L at least once during the study) was 64.8% in lusutrombopag group and 13.1% in placebo group (p<0.0001). Figure 1 shows the median platelet count over the study period for both treatment groups. Among patients in the lusutrombopag group who did not receive platelet transfusion, the mean peak platelet count was 86.9×109/L (mean increase from baseline 47.1×109/L) which occurred on average around Day 12, and the median duration of platelet count maintained at ≥ 50×109/L was 19 days. Treatment-emergent adverse events (TEAEs) were reported for 47.7% of patients in lusutrombopag group and 48.6% in placebo group, with serious TEAEs at 6.5% in each treatment group. Three PVT events were observed, 1 in lusutrombopag group and 2 in placebo group; all were incomplete occlusion considered not clinically significant and all events resolved with therapy. Bleeding-related TEAEs occurred in 3 patients of lusutrombopag group and 6 patients in placebo group.In conclusion, oral lusutrombopag 3 mg once daily demonstrated superiority over placebo as treatment for thrombocytopenia in patients with CLD undergoing invasive procedures in this global phase 3 study, meeting all pre-specified primary and secondary endpoints. Lusutrombopag was well tolerated, with a safety profile similar to that of placebo. [Display omitted] DisclosuresAfdhal:Shionogi: Consultancy; Merck: Consultancy; Ligand: Consultancy; Jansen: Consultancy; Gilead: Consultancy; Echosens: Consultancy; Spring Bank Pharmaceuticals: Employment, Equity Ownership; Allurion: Equity Ownership; TRIO Healthcare: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Duggal:Shionogi: Consultancy. Ochiai:Shionogi: Employment. Motomiya:Shionogi: Employment. Kano:Shionogi: Employment. Nagata:Shionogi: Employment. Peck-Radosavljevic:Shionogi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jansen: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Research Funding.