A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SEQUENTIAL-DOSE STUDY OF THE SAFETY OF APRATASTAT (TMI-005), A NOVEL ORAL DUAL INHIBITOR OF TNF-ALPHA-CONVERTING ENZYME/METALLOPROTEINASE, IN PATIENTS WITH RHEUMATOID ARTHRITIS ON A BACKGROUND OF METHOTREXA

Background: Apratastat (TMI-005, APS) is a novel, oral small-molecule dual inhibitor of tumor necrosis factor-alpha (TNF-α)-converting enzyme and matrix metalloproteinases (MMPs) that has been advanced into clinical development for the treatment of rheumatoid arthritis (RA). APS blocks secretion of soluble TNF-α and downregulates multiple MMPs implicated in cartilage destruction and bone erosions.In the treatment of RA, TNF-α antagonism reliably improves signs and symptoms, and slows radiographic progression. Concurrent inhibition of MMPs may further retard cartilage destruction. Although TNF-α blocking agents are highly effective disease-modifying agents, safety concerns and parenteral route of administration limits their use in a larger RA population. Data from studies that support the evaluation of APS for the treatment of RA include improvement of symptoms and histology in adjuvant and collagen-induced arthritis and safety that is comparable with placebo in three phase 1 trials in healthy subjects. APS may fulfill a significant unmet need for an oral TNF-blocker in the treatment of RA.Objectives: To determine the safety of two sequential doses of APS in patients with RA on a stable regimen of methotrexate (MTX).Methods: Subjects aged 18 years or older with known RA on a stable dose of MTX (7.5-20 mg/week) were included. Patients were not required to have current active disease. Other DMARDs and anti-TNF-α agents were not permitted. Sixteen (16) subjects (8 in each cohort) were sequentially randomized to 50 or 150 mg APS (n=6) or placebo (n=2) for 4 weeks. Laboratory safety evaluations, adverse events (AEs), and clinical parameters were recorded weekly.Results: Demographic and baseline characteristics were similar among all groups. The majority of subjects were white women, mean age 58.76±7.26 years and mean weekly dose of MTX 16.41±4.08 mg. Twelve subjects (75%) were on concomitant folic acid therapy.APS was well tolerated at both dose levels (50 or 150 mg twice daily) evaluated. No serious AEs or deaths were reported. Thirteen (13) of the total of 16 (81.3%) subjects reported 1 or more AEs. All AEs were either mild or moderate in severity. The majority of treatment-emergent-AEs (Table) were thought to be probably not related or definitely not related to test article by the investigator.No clinically significant elevations of laboratory parameters including hepatic aminotransferases, were observed. One subject in the 150-mg TMI-005 group discontinued treatment on day 15 because of worsening of RA symptoms. Number (%) Of Patients Reporting Selected Treatment-Emergent Adverse Events Body System AE Placebo (n=4) 50mg APS (n=6) 150mg APS (n=6) Total (n=16) Any AE 3 (75.0) 4 (66.7) 6 (100) 13 (81.3) Arthralgia 2 1 3(18.7) Peripheral edema 0 1 1 2(12.5) Headache 1 0 0 1(6.3) Nausea 0 1 0 1(6.3) Lymphadenopathy 0 1 0 1(6.3) Insomnia 0 1 1 1(6.3) Sinusitis 0 1 0 1(6.3) Urinary Tract Infection 0 0 1 1(6.3) AEs are listed by frequency. Some patients had more than 1 AE. Not all AEs are listed AEs are listed by frequency. Some patients had more than 1 AE. Not all AEs are listedConclusion: APS, either 50 mg or 150 mg twice daily, was well tolerated for 4 weeks with an acceptable safety profile. There were no clinically significant AEs or significant changes in hepatic aminotransferases. The data from this study support the concomitant use of APS with MTX in the ongoing proof-of-concept study.Citation: Ann Rheum Dis, volume 64, supplement III, year 2005, page 132Session: Cytokines and inflammatory mediators