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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-05, Vol.64 (5), p.1579-1588
• Main Authors: Bengtsson, Anders A., Sturfelt, Gunnar, Lood, Christian, Rönnblom, Lars, van Vollenhoven, Ronald F., Axelsson, Bengt, Sparre, Birgitta, Tuvesson, Helén, Öhman, Marie Wallén, Leanderson, Tomas
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Biological and medical sciences; Clinical Medicine; Disease Models, Animal; Diseases of the osteoarticular system; Double-Blind Method; Drug therapy; Female; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney - metabolism; Kidney - pathology; Klinisk medicin; Lupus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred MRL lpr; Middle Aged; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - therapeutic use; Prednisolone - therapeutic use; Quinolines - adverse effects; Quinolines - chemistry; Quinolines - pharmacokinetics; Quinolines - therapeutic use; Reumatologi och inflammation; Rheumatology and Autoimmunity; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Severity of Illness Index; Treatment Outcome; Young Adult
• ISSN: 0004-3591; 2326-5191; 1529-0131; 1529-0131; 2326-5205
• DOI: 10.1002/art.33493

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 human SLE support the future clinical development of paquinimod.