- Fecal Incontinence
|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
J Crohns Colitis. 2023 Aug 21;17(8):1235-1251.doi: 10.1093/ecco-jcc/jjad047.
Matthieu Allez 1, Bruce E Sands 2, Brian G Feagan 3, Geert D'Haens 4, Gert De Hertogh 5, Charles W Randall 6, Bin Zou 7, Jewel Johanns 7, Christopher O'Brien 8, Mark Curran 9, Rory Rebuck 8, Mei-Lun Wang 8, Nina Sabins 10, Thomas Baker 8, Taku Kobayashi 11
1Department of Gastroenterology, Hôpital Saint-Louis, AP-HP, INSERM U1160, Université Paris Cité, Paris, France.
2Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3Western University and Alimentiv Inc., Department of Medicine, London, Ontario, Canada.
4Inflammatory Bowel Disease Center, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
5University Hospitals Leuven, Lab of Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
6Gastroenterology Research of America and University of Texas, San Antonio, TX, USA.
7Janssen Research & Development, Statistics, Spring House, PA, USA.
8Janssen Research & Development, Immunology, Spring House, PA, USA.
9Janssen Research & Development, Immunology, Raritan, NJ, Japan.
10Janssen Research & Development, Translational Science, Spring House, PA, USA.
11Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
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.