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

Abstract

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.

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

“…This inhibitor has been granted orphan medicinal product status in Europe and the US for the indication of systemic sclerosis. Importantly, ABR-215757 has been reported to have few side effects and encouraging pharmacokinetics in early-phase trials in people with systemic lupus erythematosus (68). Importantly, we now show that this molecule inhibited atherogenesis in a preclinical model of diabetes, providing a potential new therapeutic approach to reduce the cardiovascular burden in diabetes.…”

The quinoline-3-carboxamide paquinimod (ABR-215757) reduces leukocyte recruitment during sterile inflammation: Leukocyte- and context-specific effects

“…Recently, the S100A9 protein was identified as one molecular target of the Q-compound paquinimod (ABR-215757) [40]. We have previously shown that paquinimod interferes with development of disease both in mouse models of multiple sclerosis [40,41] and systemic lupus erythematosus [42]. Further, our previous work indicated that this compound interfered with the accumulation of myeloid cells during inflammation [43].…”

Plasma S100A8/A9 Correlates With Blood Neutrophil Counts, Traditional Risk Factors, and Cardiovascular Disease in Middle-Aged Healthy Individuals

“…S100A8/A9 is of particular interest as a possible therapeutic target for the prevention of acute CV events because compounds that block the binding of S100A8/A9 to its receptors have been developed and are already approved for clinical testing in humans. 39,40 …”