A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND AND AIMS: Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. METHODS: TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. RESULTS: In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. CONCLUSIONS: Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. CLINICALTRIALS.GOV IDENTIFIER: NCT02877134.

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.

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.