Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study

Abstract

Objective: Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC.

Design: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement.

Results: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 μg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events.

Conclusions: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted.

Clinical trial registration number: ClinicalTrials.gov NCT00656890.

Keywords: Antibody Targeted Therapy; Ulcerative Colitis.

Figure 1

Patient disposition. *Two patients randomised to the placebo group were not treated.

Figure 2

Clinical response, remission and healing rates at Day 57. Prespecified Mayo scoring method (intent-to-treat population). Mayo score re-derived after unblinding the data and by following conventional rules in the literature. Error bars represent 95% CIs. A clinical response was defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Remission was defined as a total Mayo score of ≤2 with no individual subscore exceeding 1 point and no blood in stools. Mucosal healing was defined as an absolute subscore for endoscopy of ≤1.

Figure 3

Clinical response by pharmacokinetic trough concentration at Day 57. (A) Post hoc analysis by trough concentration tertiles. Clinical response was defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Remission was defined as a total Mayo score of ≤2 with no individual subscore exceeding 1 point and no blood in stools. Mucosal healing was defined as an absolute subscore for endoscopy of ≤1. (B) Post hoc logistic regression analysis of clinical response by trough concentration. Patients from the placebo group were not included in this model fitting. Analysis demonstrated that by increasing BMS-936557 exposure by a factor of 2, the odds of achieving a clinical response increases by 3.77. Horizontal line denotes response rate of the placebo arm. (C) Post hoc logistic regression analysis of clinical remission by trough concentration. Patients from the placebo group were not included in this model fitting. Horizontal line denotes remission rate of the placebo arm. For all analyses, the Mayo score was re-derived after unblinding the data and by following conventional rules in the literature.

Figure 4

Histological analyses at Day 57. (A) Proportion of patients in histological remission (Geboes Index score <2) at Day 57. (B) Proportion of patients in histological remission (Geboes Index score <1) at Day 57. (C) Improvement across histological categories for BMS-936557-treated patients with C_minss ≥100 μg/ml (n=15); C_minss =steady-state trough serum concentration; Error bars represent 95% CI. (D) Improvement across histological categories for placebo-treated patients (n=32). (E) Histological improvement in the presence of clinical improvement in a patient who achieved BMS-936557 C_minss ≥100 μg/ml. Baseline Mayo score was 8 and endoscopy subscore was 3; Day 57 Mayo score was 2 and endoscopy subscore was 1. Baseline Geboes Index score was 5, and H&E staining shows mucosa of the colon with moderate architectural abnormalities: crypts are shortened, not reaching the muscularis mucosae; variable intercryptal distance. Epithelial cells are not well differentiated. The cellular infiltrate in the lamina propria is severely increased with basal accumulation; composition is mixed, with mild cryptitis. Day 57 Geboes Index score was 0, and H&E staining shows mucosa of the colon with moderate architectural abnormalities; variable intercryptal distance. Epithelial cells are well differentiated (surface loss is due to artefact) and cellular infiltrate in the lamina propria is within normal limits. (F) Histological improvement in the absence of clinical improvement in a patient who achieved BMS-936557 C_minss ≥100 μg/ml. Baseline Mayo score was 8 and endoscopy subscore was 2; Day 57 Mayo score was 7 and endoscopy subscore was 2. Baseline Geboes Index score was 5. H&E staining shows mucosa of the colon with moderate architectural abnormalities: crypts are shortened, not reaching the muscularis mucosae; variable intercryptal distance. Epithelial cells are less well differentiated – surface epithelial cells are flattened and partially lost: at the edge of the loss, the cells are flattened indicating restitution (part of the healing process). The cellular infiltrate in the lamina propria is severely increased with basal accumulation; composition is mixed, with mild cryptitis. At Day 57, Geboes Index score was 0. H&E staining shows colon with normal architecture: surface is smooth and crypts run parallel. Internal diameter of crypts is constant and distance between crypts is normal and constant. Mucin secretion is well preserved and the lamina propria infiltrate is borderline normal in distribution and intensity. Epithelial cells are well differentiated. In the ×100 magnification, there is some lifting of surface epithelial cells, which can be explained as an artefact as the cells are well differentiated. All analyses were performed post hoc. Access the article online to view this figure in colour.