AMAP102, AN ORALLY AVAILABLE 5-HT2 RECEPTOR ANTAGONIST DEVELOPED FOR THE TREATMENT OF RA, IS SAFE AND WELL TOLERATED IN HEALTHY SUBJECTS

Background: AMAP102 is a 5-HT2B/5-HT2C receptor antagonist with anti-inflammatory properties, developed for the treatment of rheumatoid arthritis (RA). The concept of using a 5-HT2 antagonist for the treatment of RA is new and unique. The 5-HT2 antagonism leads to a reduction of IL-6 and TNF-α, two important mediators of joint inflammation and cartilage/bone destruction. Previously, the novel, orally bioavailable, small molecule AMAP102 has been demonstrated to decrease the production of TNF-α and IL-6 in macrophages and primary synoviocytes. The beneficial effects of orally administered AMAP102 have been shown in several animal models highly relevant to the RA indication, e.g., antigen-induced arthritis and collagen-induced arthritis. In addition, AMAP102 suppressed inflammatory pain in a formalin-induced pain model. The objective of the current study was to assess the safety, tolerability and pharmacokinetics of AMAP102 in healthy subjects. Methods: The safety, tolerability and pharmacokinetics of AMAP102 were assessed in healthy subjects in a double-blind, placebo-controlled, single and multiple ascending oral dose Phase I study. AMAP102 was given to healthy male subjects at single oral doses of 5 mg, 25 mg, 100 mg and 150 mg. A group with female healthy subjects received a single oral dose of 100 mg. AMAP102 was given orally to healthy male subjects at 50 mg bid and 75 mg bid for 6 days and once on day 7. Two out of 8 subjects per group received placebo randomized and double-blinded. The safety and tolerability of the compound was addressed by recording of adverse events, physical examination, neurological examination, vital signs, electrocardiography, telemetry (in single doses in males), abbreviated mini mental test score and body weight. Blood samples were collected and assessed for plasma drug levels and clinical laboratory parameters. Results: There were no serious adverse events, and no adverse events that implicated a stopped dose escalation. There were no clinically significant findings in physical or neurological examinations, abbreviated mini mental test score, vital signs, weight, electrocardiography or clinical laboratory evaluations. No clinically significant arrhythmias were noted on telemetry. AMAP102 was rapidly absorbed following single and multiple oral doses, with Cmax being attained within 0.5 to 3 hours in all subjects. Steady-state was reached after 3 to 6 days of dosing. There was no gender difference in the safety or in the pharmacokinetics. Conclusions: In this single and multiple oral dose Phase I study, AMAP102 was safe and well tolerated. The safety and pharmacokinetic profile of AMAP102 supports its further development. A Phase II study in patients with RA is planned. Disclosure of Interest: A.-C. Ryde Employee of: AnaMar AB, A. Boman Shareholder of: Acure Pharma AB, Employee of: Acure Pharma AB, N. Palmqvist Employee of: AnaMar AB, C. Wenglén Employee of: AnaMar AB, M. Siller Employee of: AnaMar AB, A. Sjödin Employee of: AnaMar AB, C. Klint Employee of: AnaMar AB, A. Pramhed Employee of: AnaMar AB, E. Seifert Shareholder of: Acure Pharma AB, Employee of: Acure Pharma AB, P. Lek Shareholder of: Acure Pharma AB, Employee of: Acure Pharma AB, T. Lundstedt Shareholder of: Acure Pharma AB, Employee of: Acure Pharma AB, G. Ekström Employee of: AnaMar AB, H. Arozenius Employee of: AnaMar ABCitation: Annals of the Rheumatic Diseases, volume 70, supplement 3, year 2011, page 601Session: Rheumatoid arthritis – non-biologic treatment (Poster Presentations )