Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis

Andersen, Oluf; Lycke, Jan; Po, Tollesson; Svenningsson, Anders; Runmarker, Björn; As, Linde; Åström, Mikael; Gjörstrup, P.; Ekholm, Sven

doi:10.1177/135245859600100613

Cited by 21 publications

(19 citation statements)

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“…Potent disease-inhibitory effects in experimental models of autoimmune diseases (3)(4)(5)(6)(7) and proof of concept in clinical studies have been demonstrated for compounds within this class. Linomide, the predecessor compound, exhibited clinical efficacy in juvenile type 1 diabetes (8) and in multiple sclerosis (MS) in phase II studies (9,10). The phase III clinical testing of linomide in MS patients was, however, terminated due to unexpected cardiovascular effects (11)(12)(13), with a few cases of myocardial infarction.…”

mentioning

confidence: 99%

Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR‐215757), a new quinoline‐3‐carboxamide derivative: Studies in lupus‐prone mice and a multicenter, randomized, double‐blind, placebo‐controlled, repeat‐dose, dose‐ranging study in patients with systemic lupus erythematosus

Bengtsson

Sturfelt

Lood

et al. 2012

Arthritis & Rheumatism

105

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Objective. To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose.Methods. The efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared with that of established SLE treatments. Dose-response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double-blind, placebo controlled, dose-ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks.Results. Paquinimod treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid-sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once-daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported.Conclusion. Paquinimod effectively inhibited disease and had a steroid-sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and EudraCT database no. 2005-002526-55.

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mentioning

confidence: 99%

Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR‐215757), a new quinoline‐3‐carboxamide derivative: Studies in lupus‐prone mice and a multicenter, randomized, double‐blind, placebo‐controlled, repeat‐dose, dose‐ranging study in patients with systemic lupus erythematosus

Bengtsson

Sturfelt

Lood

et al. 2012

Arthritis & Rheumatism

105

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“…It is well absorbed in humans after oral administration and has a mean plasma half life of 28±62 h. The dose-response curve appears bell-shaped with, maximal immunostimulation at a daily dose of 0.2±0.4 mg/kg in man [39,41], a dose 2±10 times higher than used in the present trial. In placebo-controlled trials, preliminary results at 6 months indicated that a dose of 2.5 mg/day of linomide reduces active lesions in the relapsing remitting form of multiple sclerosis [42] and tends to inhibit the progression of its secondary progressive form [43].…”

Section: Discussionmentioning

confidence: 99%

Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial

et al. 1998

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The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

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“…Promising results with linomide were demonstrated in EAE and preliminary clinical trials. 33 However, a phase 3 trial of linomide was terminated shortly after enrollment completion owing to unanticipated toxicity, including pericarditis, pleural effusion, myocardial infarction, possible pulmonary embolism, pancreatitis, and death. 34 Other common adverse effects included arthralgia, myalgia, bursitis, and edema.…”

Section: Laquinimodmentioning

confidence: 99%

Emerging Therapies for Relapsing Multiple Sclerosis

Cohen¹

2009

Arch Neurol

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Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis

Cited by 21 publications

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Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial

Emerging Therapies for Relapsing Multiple Sclerosis

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