Trial in progress: Study design of a randomized, phase 3 trial evaluating the efficacy and safety of mezagitamab (TAK-079) compared with placebo in adults with chronic primary immune thrombocytopenia

Abstract Background and significance: Immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder characterized by severe thrombocytopenia, risk of bleeding, and reduced quality of life. Use of current therapies may be limited in some patients due to poor response or medication intolerance, resulting in a need for effective novel therapeutic options. Mezagitamab is a fully human anti-CD38 monoclonal antibody, a novel class of potential therapies that deplete the plasma cells which produce anti-platelet autoantibodies as well as other immune effector cells. A Phase II study (NCT04278924) demonstrated that weekly doses of mezagitamab 600 mg for 8 weeks had promising signs of efficacy: 10/11 participants treated with mezagitamab 600 mg achieved a platelet response compared with 3/13 participants treated with placebo. Responses were observed as early as two days after the first dose. Mezagitamab was delivered subcutaneously and had favorable safety and tolerability, with no Grade 2 or higher infusion-related reactions. This abstract reports the design of a Phase III study assessing the efficacy and safety of subcutaneous mezagitamab 600 mg compared with placebo in adult participants with chronic primary ITP and an insufficient response or intolerance to prior therapies. Study Design and Methods: This is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study (NCT06722235) involving approximately 20 countries and >100 study sites. Participants will be ≥18 years, with primary ITP for ≥12 months, evidence of an insufficient response or intolerance to ≥1 first-line and ≥1 second-line treatment for ITP, and a mean platelet count <30,000/μL. Patients will not be included if they have received anti-CD20 treatment during the last 6 months. Participants will be randomized (2:1) to mezagitamab 600 mg or placebo. Study treatment will be administered subcutaneously once weekly for 8 weeks, followed by 8 weeks off treatment, then once weekly treatment for a further 8 weeks, for a total study duration of 24 weeks. Steroid premedication (methylprednisolone 40 mg) is only required for the first dose of mezagitamab. Use of additional, stable background ITP therapy is permitted, including corticosteroids, thrombopoietin receptor agonists, and fostamatinib, as is use of rescue therapy (corticosteroids, intravenous immunoglobulin, platelet transfusion) when indicated. Participants can enter the long-term safety follow-up trial (NCT06948318) at study end, or at Week 16 if they are deemed to be early non-responders. The primary endpoint will be durable platelet response through Week 24, defined as a platelet count ≥50,000/μL on at least 4 of the 6 weekly platelet measurements between Weeks 19 and 24, and the response will be compared between treatment arms using the Cochran-Mantel Haenszel test. Secondary efficacy endpoints include: cumulative number of weeks through Week 24 with platelet count ≥50,000/μL; time to first platelet count ≥50,000/μL; cumulative number of weeks through Week 24 with platelet count ≥30,000/μL and at least double that of baseline; complete platelet response (platelet count ≥100,000/μL on ≥2 visits through Week 24); platelet response at Week 16 (platelet count ≥50,000/μL before study treatment administration at the Week 16 visit); change from baseline in the Symptoms scale score of the ITP Patient Assessment Questionnaire; occurrence of the use of rescue therapy; time to first rescue therapy; and bleeding events based on the ITP-specific Bleeding Assessment Tool. Safety will be assessed by incidences of treatment-emergent adverse events, treatment-related adverse events, Grade ≥3 treatment-emergent adverse events, and by clinically significant abnormal laboratory test results and vital signs. Exploratory pharmacodynamic analyses will include evaluation of immunoglobulin levels and lymphocyte subsets. Results: This study began in February 2025, is due to complete in 2028, and will enroll approximately 171 participants.Conclusions: Given promising, early-stage results for anti-CD38 treatment in patients who have been difficult to manage on current therapies, this global study will evaluate the efficacy and safety of subcutaneous mezagitamab as a potential novel therapy for patients with ITP who have had an insufficient response or intolerance to prior therapy.