Fast track — ArticlesEffect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
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and clinical phase I studies revealed a gain in the benefit and risk profile of laquinimod compared with roquinimex (unpublished data).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.
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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
References (35)
- et al.
The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental allergic encephalomyelitis
J Neuroimmunol
(2002) - et al.
Suppression of experimental auto-immune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue
Neuropharmacol
(2002) - et al.
Modelling MRI enhancing lesion counts in multiple sclerosis using a negative binomial model: implications for clinical trials
J Neurol Sci
(1999) - et al.
Short-term evolution of new multiple sclerosis lesions enhancing on standard and triple dose gadolinium-enhanced brain MRI scans
J Neurol Sci
(1999) - et al.
Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study
Blood
(2000) - et al.
A pilot trial of Cop-1 in exacerbating-remitting multiple sclerosis
N Engl J Med
(1987) - et al.
Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial
Neurology
(1995) - et al.
Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability
Neurology
(1998) - et al.
European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis
Ann Neurol
(2001) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. clinical results of a multicenter, randomized, double blind, placebo-controlled trial
Neurology
(1993)
Intramuscular interferon beta-1a for disease progression in exacerbating-remitting multiple sclerosis
Ann Neurol
Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing-remitting multiple sclerosis
Lancet
A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis
N Engl J Med
Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomized multicentre study of active disease using MRI and clinical criteria
J Neurol Neurosurg Psychiatry
Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome
J Neurol
Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis
Neurology
Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation
Neurology
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