Model‐Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti–Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease

Abstract Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double‐blind, placebo‐controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof‐of‐concept part I of the study demonstrated significant treatment effects, part II (dose‐ranging) revealed an unexpected lack of dose‐response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure‐response (E‐R) analyses were planned and performed. A 1‐compartment PopPK model with first‐order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E‐R relationship; however, this was driven by data from part I. Part II–only analysis did not show an apparent efficacy E‐R relationship. No important covariates were identified in efficacy E‐R analyses, overall, and in various subpopulations. No apparent E‐R relationships were observed for the investigated safety end points. The PopPK and E‐R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement.