A DOSE-RANGING STUDY OF LJP 394, A NOVEL THERAPEUTIC AGENT FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS.

Cash J, The Cleveland Clinic Foundation, Cleveland OH; Cronin M, Medical College of Wisconsin, Milwaukee, WI; Katz R, Rheumatology Asociates, Chicago, IL; Furie R, North Shore University Hospital, Manhasset NY; Aranow C, State University of New York-Health Science Center at Brooklyn, Brooklyn NY; Hudson P, The Ohio State University, Columbus OH; Liebling M, Harbor-UCLA Medical Center, Torrance CA; Weisman M, University of California San Diego Medical Center, San Diego CA; Berner C, La Jolla Pharmaceutical Co., San Diego CA

A pilot study has shown that a single 100 mg intravenous dose of LJP 394, a novel synthetic oligonucleotide conjugate, safely lowered levels of circulating anti-dsDNA by 20-80% in four women with systemic lupus erythematosus (Weisman M and Bluestein H, 1995). We conducted this Phase 2, placebo-controlled, double-blind dose-ranging study in men and women with SLE to examine the tolerablilty of repeated doses of LJP 394, and to study the effects of multidose regimens on levels of circulating serum anti-dsDNA and SLE-related disease activity and quality of life.

Fifty-eight patients (53 F, 5 M) meeting 1982 ARA critiera for SLE received placebo (9), or 1mg (13), 10mg (18), or 50mg (18) of LJP 394 at intervals of 1, 2, or 4 weeks for a total of 4 months. All patients were clinically stable and had anti-dsDNA > 15 IU/mL (Farr assay) at entry. The population ranged in age from 18-66 years and consisted of 30 Whites, 17 Blacks, and 11 patients of other races. Patients were followed for 2 months prior to randomization, and for 2 months after cessation of therapy. Anti-dsDNA, routine clinical assessments, Lupus Activity Index, and SF-36TM Health Survey were monitored. Mean daily prednisone use was similar in all groups and ranged between 2 and 10 mg.

Data will be presented which demonstrate that LJP 394 reduced levels of circulating dsDNA in a dose/frequency dependent manner for up to eight weeks after cessation of therapy, an effect consistent with modulation of B-cell function. Of 6 patients who experienced serious adverse events, 3 were related to lupus flares, and 2 of these patients withdrew from the study; an additional 4 withdrawals were attributed to exacerbations of lupus. The remaining 3 serious adverse events were related to the underlying disease, or remotely related to therapy. However, no relationship was seen between the development of an adverse event and the dose or the frequency of administration. For those patients who completed the study, disease activity remained stable during treatment and follow-up.

Multiple doses of LJP 394 safely reduced anti-dsDNA concentrations in patients with SLE and may prove to be a valuable therapeutic intervention.

Presented at The 26th Scandinavian Congress of Rheumatology Conference, May 31 - June 3, 1996, Reykjavik, Iceland.