A PHASE I, DOSE ESCALATION STUDY TO EVALUATE THE TOLERABILITY OF ABR-215757 IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Background: ABR-215757 is a small molecule compound intended for chronic oral treatment of systemic lupus erythematosus (SLE). The compound belongs to the quinoline 3-carboxamides, a group of immunomodulators interacting with a defined target expressed on myeloid cells. These compounds cause reduction of autoreactive T cell proliferation without general immune suppression. ABR-215757 effectively inhibits disease in MRLlpr/lpr mice, an experimental model for SLE. Multiple disease parameters including serological disease markers and histopathological manifestations are affected by ABR-215757. A previous clinical Phase I dose escalation study in healthy volunteers demonstrated tolerability of ABR-215757 at doses up to at least 3.0 mg/day. The present study involved assessment of safety parameters in SLE and RA patients following 12 weeks of treatment with ABR-215757. Objectives: To establish the maximum tolerable dose (MTD) and to determine the tolerability of ABR-215757 in SLE and rheumatoid arthritis (RA) patients during 12 weeks of daily treatment. Methods: A randomized, double-blind, placebo-controlled, repeat dose, multi centre, phase-I, dose-escalation study in patients with SLE and RA. Cohorts of 8 patients (stratified; 4 SLE and 4 RA) were to receive escalating doses (1.5, 3.0, 4.5 and 6.0 mg) of ABR-215757 (3 patients/group) or placebo (one patient/group) in addition to standard maintenance treatment. The primary endpoint was to determine MTD which was the highest dose where not more than 1 patient out of 6 experienced dose limiting toxicity (DLT). Safety assessments involved analysis of haematology and clinical chemistry, ECG measurements and recording of adverse events (AEs). In addition, the effect on interferon-inducible gene expression was studied. Results: The most frequently reported AEs considered as possibly/probably related to study drug were respiratory tract infections, arthralgia, myalgia, elevated liver enzymes, fever and nausea/vomiting. The majority of the AEs were mild or moderate and transient. At 4.5 mg and higher some AEs of severe intensity, considered possibly/probably related, were reported. Eight serious adverse events (SAEs) considered as possibly/probably related were reported, all of them in the 4.5 and 6.0 mg dose groups. No specific pattern of changes in ECG measurements was observed. Further, ABR-215757 treatment induced significant changes of the gene profile including decreased expression of a number of IFN regulated genes. Conclusion: The MTD of ABR-215757 in SLE patients was concluded to be 4.5 mg/day, and safety data support treatment with ABR-215757 up to at least 3 mg/day in future clinical studies. Furthermore, the results indicated that ABR-215757 could normalize pathways that are central in the pathogenesis of SLE. Disclosure of Interest: None declared.Citation: Annals of the Rheumatic Diseases, volume 68, supplement 3, year 2009, page 244Session: SLE, Sjgren's and APS Treatment (Poster Presentations )