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DOP059. Reduction of fecal calprotectin levels and relationship to clinical parameters in the phase 2 study of laquinimod for the treatment of active moderate to severe Crohn's disease

G. D'Haens1, W.J. Sandborn2, P. Rutgeerts3, J.F. Colombel4, K. Brown5, A. Haviv6, H. Barkay7, A. Sakov7, B. Feagan8, 1University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 2University of California, UCSD Inflammatory Bowel Disease Center, San Diego CA, United States, 3Catholic University of Leuven, Department of Internal Medicine and Endoscopy, Leuven, Belgium, 4Icahn School of Medicine at Mount Sinai, Gastroenterology, New York, United States, 5Teva Pharmaceuticals, Clinical Development Research and Development, Frazer, United States, 6Chiasma Pharm, Formerly of Teva Pharmaceuticals, Jerusalem, Israel, 7Teva Pharmaceuticals, Biostatistics Research and Development, Netanya, Israel, 8University of Western Ontario, Robarts Clinical Trials Robarts Research Institute, Ontario, Canada

Background

Laquinimod is an oral therapy in development for the treatment of Crohn's disease (CD). An exploratory multicenter double-blind dose-ranging phase 2 study (NCT00737932) found that laquinimod at doses of 0.5 mg and 1.0 mg safely induced clinical remission in patients with active moderate-to-severe CD. The study also explored whether laquinimod which has been shown to have anti-inflammatory properties in other disease states, reduced fecal calprotectin concentrations, an objective measure of intestinal inflammation in patients with CD in addition to improving clinical symptoms.

Methods

Patients (N = 180) with active moderate-to-severe CD were randomly assigned to one of 4 laquinimod doses (0.5, 1.0, 1.5, 2 mg/day, n = 29 or 30 per dose) or placebo (n = 16 per dose) in sequential dose-escalating cohorts. Treatment was administered for 8 weeks with a 4-week follow-up visit. Stable concomitant therapies and prior anti-TNF medications were allowed. Efficacy analyses included the proportions of patients in clinical remission (CDAI < 150 and no treatment failure [TF]) and with a clinical response (70 or 100 point CDAI reduction or remission and no TF) and measures of fecal calprotectin. Patients with fecal calprotectin concentrations ≥250 µg/g at baseline were assessed to determine if there was a shift in fecal calprotectin levels to <250 µg/g and reduction by at least 50%.

Results

Doses of 0.5 mg and 1.0 mg laquinimod increased the proportion of patients in clinical remission and with clinical response 100 and 70. There were increased proportions of patients with reduced fecal calprotectin levels for all laquinimod dose groups compared to the pooled placebo group at Week 8. Likewise, the proportions of patients who showed both a reduction in fecal calprotectin and an improvement in clinical remission or response were greater in the laquinimod dose groups than in the pooled placebo group (Table 1).

Table 1 (abstract DOP059)
LaquinimodPooled placebo
0.5 mg (n = 29)1.0 mg (n = 30)1.5 mg (n = 29)2.0 mg (n = 29)(n = 63)
Proportion of patients in clinical remission at Week 8*48%27%14%17%16%
Proportion of Responders 100 at Week 8*55%40%28%28%32%
Proportion of Responders 70 at Week 8*62%53%31%28%35%
Patients with fecal calprotectin level ≥250 µg/g at baseline (% of treatment arm)18 (62%)18 (60%)15 (51.7%)11 (37.9%)44 (69.8%)
Reduction of calprotectin**7 (38.9%)7 (38.9%)4 (26.7%)4 (36.4%)6 (13.6%)
Reduction of calprotectin and clinical remission**5 (27.8%)3 (16.7%)1 (6.7%)2 (18.2%)1 (2.3%)
Reduction of calprotectin and Response 100**5 (27.8%)3 (16.7%)3 (20.0%)4 (36.4%)3 (6.8%)
Reduction of calprotectin and Response 70**6 (33.3%)5 (27.8%)2 (20.0%)4 (36.4%)4 (9.1%)
*Proportion of patients per treatment arm and **proportion of patients per treatment arm with fecal calprotectin concentrations ≥250 µg/g at baseline.

Conclusion

This dose-ranging study suggests that laquinimod at the lower doses of 0.5 mg and 1.0 mg improved clinical symptoms in patients with CD. All doses of laquinimod were found to have an effect on reducing intestinal inflammation using the threshold of ≥250 µg/g fecal calprotectin levels as a marker of inflammation in active CD. The lowest dose of laquinimod 0.5 mg appears to have the most robust and consistent effect on reducing inflammation and improving clinical symptoms relative to the higher laquinimod doses and to placebo.