Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Co-Administration of the Oral S1P-Lyase Inhibitor LX2931 with Methotrexate Was Well Tolerated Over 14 Days in Patients with Stable Rheumatoid Arthritis
Fleischmann1, Roy, Frazier2, Kenny S., Freiman2, Joel, Brooks2, Barbara, Oravecz2, Tamas, Augeri3, David, Kelly2, Michael
Sphingosine-1-phosphate (S1P) is a lipid metabolite affecting lymphocyte trafficking; the major route of S1P degradation is via S1P lyase (S1PL). Mice with reduced S1PL activity have significantly reduced circulating lymphocytes as a consequence of increased S1P content in lymphoid tissues. LX2931 (LX3305), an oral small molecule inhibitor of S1PL, is being developed as a potential therapeutic for autoimmune and inflammatory disorders. LX2931 exhibited significant activity in reducing the inflammatory response in preclinical arthritis models in the mouse and rat. In addition, co-administration of LX2931 with methotrexate (MTX) in the rat model revealed improved pharmacology over monotherapy alone.
LX2931 (120 mg po QD) was evaluated in a randomized, double-blind, placebo controlled, study in 15 subjects (12 active, 3 placebo) diagnosed with stable rheumatoid arthritis (RA) to evaluate the PK, PD, safety and tolerability of co-administration with MTX. The study was conducted at a single center with all subjects receiving MTX at a stable dose between 7.525 mg per week.
Co-administration of MTX with LX2931 was well tolerated over 14 days of dosing in patients with stable RA. The most commonly occurring adverse events included headache (26.7%), abdominal pain (20.0%), and nausea (20.0%). Among the abdominal pain events, one was mild and occurred while on study drug, two were mild to moderate and occurred after the last study dose. There were no clinically significant trends observed in laboratory values, vital signs, or electrocardiograms. No clinically significant changes in either MTX or LX2931 kinetics were observed (Figure). Slight increases in MTX AUC(0-last), and Cmax were observed at Day 15 with no changes in 7-OH-MTX or LX2931 PK.
Co-administration of LX2931 with MTX in patients with stable RA over 14 days was well tolerated with no clinically significant PK, PD, or safety interaction. These observations combined with preclinical and Phase 1 studies in healthy volunteers indicate that inhibition of S1PL by LX2931 may represent a new mechanism for immune modulation and justify further clinical development of LX2931 as a potential small molecule therapy for RA and other autoimmune and inflammatory disorders.
To cite this abstract, please use the following information:
Fleischmann, Roy, Frazier, Kenny S., Freiman, Joel, Brooks, Barbara, Oravecz, Tamas, Augeri, David, et al; Co-Administration of the Oral S1P-Lyase Inhibitor LX2931 with Methotrexate Was Well Tolerated Over 14 Days in Patients with Stable Rheumatoid Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :426