Model-based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti- Natural Killer Group 2 Member D (NKG2D) Monoclonal Antibody, in Moderately to Severely Active Crohn's Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevent 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's disease (CD). While the proof-of-concept Part I of the study demonstrated significant treatment effects, Part II (dose-ranging) revealed 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 one-compartment PopPK model with first-order absorption and parallel linear and non-linear elimination pathways was established for tesnatilimab in CD patients. No clinically significant covariates were identified and overall consistent PK was observed between Part I and Part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood NKG2D 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 endpoints. The PopPK and E-R analysis indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement. This article is protected by copyright. All rights reserved.