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P465 Efficacy of ustekinumab for induction and maintenance of histological healing in patients with Crohn's disease

Li K.*1, Chan D.1, Pollack P.1, Jacobstein D.1, Brodmerkel C.1, Gasink C.1, Feagan B.G.2, Sandborn W.3, Rutgeerts P.4, De Hertogh G.5

1Janssen Research & Development, LLC, Spring House, United States 2Robarts Clinical Trials, Robarts Research Institute, Western University, London, Ont, Canada 3University of California San Diego, La Jolla, United States 4University Hospital, Gasthuisberg, Leuven, Belgium 5University Hospital Gasthuisberg, Leuven, Belgium

Background

Ustekinumab (UST) has been shown to induce & maintain clinical response & remission & to produce clinically meaningful endoscopic improvement in patients (pts) with moderate-severe Crohn's disease (CD). Effects of UST on histologic CD activity were evaluated in a substudy of the induction (UNITI-1&2) & maintenance (IM-UNITI) Phase 3 studies.

Methods

At endoscopy, 2 biopsies were collected at induction baseline (I-Wk0), Wk8 (I-Wk8), & maintenance Wk44 (M-Wk44) from 3 anatomical regions (ileum, splenic flexure, rectum). One expert GI pathologist (GDH) blindly scored all biopsies using the Global Histology Activity Score (GHAS [1] for each region. At I-Wk0, pts received a single IV dose (UST 130 mg, UST ∼6 mg/kg, or PBO). At maintenance Wk0 (i.e. I-Wk8), UST induction responders (R, CDAI decrease ≥100 [CR]) were re-randomized to SC PBO, UST 90mg q12w or UST 90mg q8w; UST induction non-responders (NR) received SC UST 90mg → SC UST 90mg q8w if in CR after 8wks; PBO induction NR received UST IV 130mg → SC UST 90mg q12w if in CR after 8wks; and PBO induction R received PBO. Histology data from 251 substudy pts with simple endoscopic score for CD (SES-CD) ≥3 (i.e. ulceration in any segment) at I-Wk0 were eligible for analysis. The relationship between GHAS & SES-CD was evaluated by Spearman correlation. Histologic improvements (i.e. change in GHAS from I-Wk0 at I-Wk8, M-Wk44) were assessed within each group (UST, PBO) & between groups (UST vs PBO, among pts with evaluable data at both I-Wk0 & I-Wk8, M-Wk44).

Results

Regional & overall GHAS were moderately correlated with SES-CD at all timepoints (r=0.6, p<0.001). GHAS was significantly reduced at I-Wk8 in pts treated with UST (from 10.4 to 7.1, p<0.001) but not PBO (from 9.2 to 7.8). At M-Wk44 in the randomized maintenance population, a continued reduction in GHAS from I-Wk8 was observed with UST 90mg SC q8w (from 7.39 to 6.07, p=0.07) but not UST 90mg SC q12w (from 5.29 to 8.67) or PBO (from 9.19 to 10.85). In the pooled maintenance population (randomized & non-randomized), continued histologic improvement from I-Wk8 was observed with UST 90mg q8w (7.14 to 5.19, p<0.0001), but not UST 90mg q12w (from 6.14 to 7.18) or PBO (from 8.19 to 8.85). Consistent results are observed in between-group (UST vs. PBO) analyses, numerically greater GHAS reduction was observed for UST.

Conclusion

Histologic & endoscopic disease activities were moderately correlated. Consistent with previously reported endoscopic results, statistically significant histologic improvements were observed in pts induced with UST, but not PBO. Trends for greater & continued histologic improvement were observed in pts who received UST 90mg q8w maintenance.

References:

[1] D'Haens GR, Geboes K, Peeters M, et al. Gastroenterology. 1998;114(2):262–267