Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials

Abstract

Due to an unexpected increase in serious cardiovascular events in MS patients treated with Linomide, a synthetic immunomodulator, two phase-III multinational relapsing remitting (RR) and secondary progressive (SP) MS trials had to be discontinued. MRI results of 413 patients who participated for at least 3 months were analysed. Patients received placebo, 2.5 or 5 mg Linomide. Scans were performed at pre-enrolment, month 3 and termination. The number and volume of enhancing lesions (ELV), and the number of active scans were evaluated. At month 3, the decrease in the number of enhancing lesions in the placebo group was 11%, compared with 15% in the 2.5 mg group (P=0.027) and 23% in the 5 mg group (P=0.057). Using the percentage of active scans as outcome parameter, the odds ratio for improvement between placebo and 2.5 mg group was 1.62 (P=0.14); between placebo and 5 mg Linomide group 3.58 (P=0.003). At termination, a rebound effect was noted in the 2.5 mg group (P=0.01). Analysis of the ELV showed no significant difference between placebo and treatment groups. Although Linomide has unacceptable side effects, it seems to have a modest effect on MS disease activity, as measured by MRI. Multiple Sclerosis (2000) 6, 99 - 104

Cytochrome P450 3a4 Is the Major Enzyme Responsible for the Metabolism of Laquinimod, a Novel Immunomodulator

“…Laquinimod (ABR-215062, N-ethyl-N-phenyl-5-chloro-1,2-dihydroxy-1-methyl-2-oxo-3-quinoline-carboxamide) represents a novel orally active immunomodulator similar in structure to the previously clinically evaluated analog, roquinimex (Linomide) (Andersen et al, 1996;Karussis et al, 1996;Noseworthy et al, 2000;Tan et al, 2000;Tuvesson et al, 2000). Both roquinimex and laquinimod have been found to effectively inhibit disease in both acute experimental autoimmune encephalomyelitis and chronic relapsing experimental autoimmune encephalomyelitis, two mouse models for the study of multiple sclerosis (MS) (Karussis et al, 1993a,b;Brunmark et al, 2002;Jönsson et al, 2004).…”

Treatment of multiple sclerosis: current concepts and future perspectives

“…The structurally related predecessor compound roquinimex (linomide) was effective in suppressing MRI activity in RRMS. However, a phase III trial of roquinimex was prematurely terminated due to severe adverse events (myocardial infarction, pericarditis, and serositis) [80]. The immunomodulator laquinimod is supposed to be pharmacologically and chemically distinct from roquinimex [81].…”

Regulation of human glia by multiple sclerosis disease modifying therapies

“…The clinical development of the latter was stopped due to concerns regarding cardiac toxicity [95]. As a small molecule, laquimimod has been shown to diffuse across the BBB, where it accumulates in the parenchyma and exerts direct effects on resident CNS cells [96][97][98].…”