Elsevier

The Lancet

Volume 371, Issue 9630, 21–27 June 2008, Pages 2085-2092
The Lancet

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Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

https://doi.org/10.1016/S0140-6736(08)60918-6Get rights and content

Summary

Background

A 24-week phase II trial has shown that 0·3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0·3 and 0·6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study.

Methods

The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18–50 years, were randomly assigned to placebo (n=102), laquinimod 0·3 mg a day (n=98), or 0·6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week −4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov, number NCT00349193.

Findings

Compared with placebo, treatment with laquinimod 0·6 mg per day showed a 40·4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4·2 [SD 9·2] vs 2·6 [5·3], p=0·0048); treatment with 0·3 mg per day showed no significant effects (3·9 [5·5] vs placebo, p=0·6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome—ie, a thrombotic venous outflow obstruction of the liver—occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0·6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation.

Interpretation

In patients with relapsing-remitting multiple sclerosis, 0·6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated.

Funding

Teva Pharmaceutical Industries.

Introduction

Multiple sclerosis is an immune-mediated disease of the central nervous system, affecting predominantly the white matter. Available treatments include glatiramer acetate,1, 2, 3, 4 interferon β,5, 6, 7 natalizumab,8 and mitoxantrone.9, 10 The common target of all these treatments are the inflammatory aspects of multiple sclerosis, which predominate in the relapsing-remitting phase of the disease. Because all the approved treatments are injectable drugs, the availability of an oral agent is assumed to present a major advantage for patients, in terms of convenience.

Laquinimod is a novel immunomodulatory agent developed as a potential disease-modifying treatment for multiple sclerosis. A structurally-related drug, roquinimex (linomide), has been found to significantly reduce the clinical and MRI activity of multiple sclerosis in phase II–III clinical trials. Phase III clinical trials were interrupted because of severe adverse events (myocardial infarction, pericarditis, and serosistis).11, 12, 13, 14, 15 Preclinical and clinical phase I studies revealed a gain in the benefit and risk profile of laquinimod compared with roquinimex (unpublished data). Laquinimod is likely to exert its anti-inflammatory activity via a Th1–Th2 shift16, 17 and, in a 24-week double-blind phase II study, 0·3 mg of laquinimod given daily was well tolerated and effective in suppressing the formation of MRI-active lesions in relapsing-remitting multiple sclerosis (41% reduction vs placebo).18 In view of the dose-related beneficial effects of laquinimod in both preclinical and clinical studies, we wished to test the efficacy, safety, and tolerability of two doses of laquinimod versus placebo—ie, the already explored dose of 0·3 mg and a double dose of 0·6 mg, in a multicentre, multinational, double-blind, placebo-controlled study.

Section snippets

Patients

The study was done in 51 centres in nine countries. Enrolment started in March, 2005, and was completed in October, 2005. Eligible patients were diagnosed as having multiple sclerosis according to the McDonald criteria,19 and a relapsing-remitting disease course,20 with at least one documented relapse within the year before study entry. Participants were aged 18–50 years, were ambulatory with an expanded disability status scale (EDSS) score between 1 and 5, and had at least one gadolinium

Results

The trial profile for the study is shown in figure 1. Of 720 patients screened for eligibility, 306 patients with relapsing-remitting multiple sclerosis were randomly assigned to receive placebo (n=102), laquinimod 0·3 mg per day (n=98), or laquinimod 0·6 mg per day (n=106). The most common reason for screening failure was the absence of GdE lesions on the screening MRI (400 of 414). 283 patients completed the study (92·5%). Early termination was related to adverse events in nine patients, two

Discussion

This phase II clinical trial showed a significant effect of oral daily laquinimod 0·6 mg in reducing the MRI-measured disease activity in patients with relapse-remitting multiple sclerosis. No significant treatment effects were seen with the lower dose of laquinimod. The decrease of MRI activity during the last part of the study was evident for both GdE lesions and new T2 lesions, indicating that laquinimod reduces not only the extent of blood-brain barrier opening, but also the accrual of

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