INTERLEUKIN-2 DIPHTHERIA FUSION PROTEIN (DAB(486)IL-2) IN REFRACTORY RHEUMATOID-ARTHRITIS - A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL WITH OPEN-LABEL EXTENSION

Objective, This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleuk in-2 diphtheria fusion protein (DAB(486)IL-2) in refractory rheumatoid arthritis (RA). Methods, Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirhe umatic drug washout, to receive a daily intravenous dose of either DAB (486)IL-2 or placebo (saline) for 5 days, A blinded, third-party obser ver evaluated arthritis activity, Clinical response was defined as gre ater than or equal to 25% improvement in swollen and tender joints and greater than or equal to 25% improvement in at least 2 of 6 additiona l parameters, The double-blind phase was 4 weeks; placebo patients cou ld cross over to receive open-label treatment for a maximum bf 3 month ly DAB(486)IL-2 cycles. Results, In the double-blind phase, 4 of 22 pa tients (18%) in the treated group and none in the placebo group (P = 0 .05) met the criteria for clinical response, During the open-label tre atment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB(486)IL-2, respectively, Adverse events included transient fever/chills (45%), na usea/vomiting (50%), elevated (less than or equal to 3x normal) transa minases (55%), and increased joint pain (45%), Twelve patients (8 plac ebo, 4 DAB(486)IL-2) did not complete 3 treatment cycles, No apparent differences were noted in CD4+ CD25+ cells of responders versus nonres ponders, or of DAB(486)IL-2-treated versus placebo-treated patients. C onclusion, Clinical responses were noted in patients treated with DAB( 486)IL-2 (18%) compared with placebo (0%) in the double-blind phase, I n the open-label phase, 33% of patients completing 3 monthly DAB(486)I L-2 cycles had improvement in arthritis activity. Further studies of I L-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.