A phase II study of laquinimod in Crohn's disease

Abstract

ObjectiveLaquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD.DesignMulticentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF).Results117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses.ConclusionsLaquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD.Trial registration numberNCT00737932.

Next generation of small molecules in inflammatory bowel disease

“…In a recent phase III study, laquinimod displayed clear efficacy in relapsing-remitting multiple sclerosis94 and also has been evaluated for the treatment of CD95 and other chronic inflammatory diseases (such as lupus nephritis and arthritis).…”

“…In a phase IIa multicentre, randomised, placebo-controlled study, d'Haens et al 95 evaluated the safety and efficacy of 8 weeks of induction therapy with laquinimod in patients with active, moderate-to-severe CD (defined as a Crohn's disease activity index (CDAI) of 220–450 and either a serum C reactive protein level >5 mg/L or endoscopic evidence of mucosal ulcerations). Overall, 117 patients were randomised to laquinimod 0.5, 1, 1.5 or 2 mg/day, and 63 patients were randomised to placebo.…”

A Thorough QT/QTc Study With Laquinimod, a Novel Immunomodulator in Development for Multiple Sclerosis and Huntington Disease

“…The most common AEs reported in this study, including headache, pain in an extremity, and abdominal pain, are consistent with the known AE profile of laquinimod. 10,12,13,27 Elevations in liver enzymes occurred in subjects treated with laquinimod and were either transient or considered not clinically significant.…”

Where are we heading to in pharmacological IBD therapy?

“…Laquinimod was successfully tested in patients with multiple sclerosis. In a phase 2 trial in patients with active CD clinical remission was achieved in 48.3, 26.7, 13.8, and 17.2 % of patients receiving 0.5, 1, 1.5, and 2 mg laquinimod versus 15.9 % in the placebo group [104]. Treatment with laquinimod caused headache, abdominal pain, nausea, vomiting, and musculoskeletal pain as the most common adverse effects [104].…”