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* = Presenting author

P379. Safety and efficacy of laquinimod in inducing clinical and biochemical improvement in active Crohn's disease: Results of an exploratory trial

G. D'Haens1, J.-F. Colombel2, W. Sandborn3, P. Rutgeerts4, B. Feagan5, 1University of Amsterdam, Amsterdam, Netherlands, 2Centre Hospitalier Universitaire (CHU) de Lille, Lille, France, 3University of California San Diego, United States, 4Catholic University of Leuven, Belgium, 5University of Western Ontario, Canada

Background

Laquinimod (LAQ) is a novel oral immunomodulator in development for the treatment of Crohn's disease (CD). LAQ has an immune modulatory effect on antigen presenting cells (mainly M2 monocytes), directing T cells towards an antiinflammatory phenotype & resulting in down regulation of proinflammatory cytokines. This study evaluated the safety & efficacy of LAQ in patients with active moderate-severe CD & assessed the impact of the drug on fecal calprotectin as an objective biomarker of intestinal inflammation.

Methods

Phase IIa, multicenter, sequential-cohorts RCT with LAQ doses of 0.5, 1, 1.5, or 2 mg/day or placebo (45 patients per cohort randomized 2:1) for 8 weeks with 4-weeks follow-up. CD patients with a CD Activity Index (CDAI) of 220–450 & serum CRP >5 mg/L or mucosal ulcerations evident on endoscopy were included. Stable concomitant therapies (corticosteroids, immunosuppressive drugs [AZT, 6MP, MTX], 5-ASA, antibiotics) & prior anti-TNF use were allowed. Elevated fecal calprotectin was not required. Comprehensive safety monitoring & assessments were performed. Efficacy analyses included the proportions of patients in remission (CDAI <150 & no treatment failure [TF]), those with a response 100 (100 point CDAI reduction & no TF) and those who had a reduction in fecal calprotectin defined as a decrease from ≥250 µg/g to below 250 µg/g & ≥50% reduction. This study was exploratory & no hypothesis testing was planned.

Results

117 patients received LAQ & 63 pts received placebo. AEs occurred in 86–97% of LAQ groups vs. 83% in pooled placebo group; most common AEs were headache, abdominal pain, nausea & vomiting, and musculoskeletal pain. For pooled LAQ and placebo groups, mean (SD) baseline CDAI were 298 (58) & 311 (75), and median (IQR) fecal calprotectin levels were 389 (749) & 475 (802) µg/g, respectively. At week 8, effects on remission and response were observed with the 0.5 mg LAQ dose; 1 mg dose showed lower magnitude effects and higher LAQ doses showed similar effects to placebo.

All doses reduced fecal calprotectin.

 Pooled placebo0.5 mg LAQ1 mg LAQ1.5 mg LAQ2 mg LAQ
Number of patients*6329302929
Number of patients with calprotectin ≥250 µg/g at Baseline and non-missing calprotectin level at Week 84418181511
Clinical remission15.9%48.3%26.7%13.8%17.2%
Clinical response 10031.7%55.2%40.0%27.6%27.6%
Calprotectin decrease from ≥250 µg/g to below 250 µg/g & ≥50% reduction13.6%38.9%38.9%26.7%36.4%

Conclusion

This study indicates that treatment with LAQ is well tolerated and the 0.5 and 1 mg doses may have clinically relevant effects on remission & response. All doses (LAQ 0.5–2 mg) were found to reduce objective measures of intestinal inflammation in active CD.