RANDOMIZED, PLACEBO CONTROLLED, DOUBLE-BLIND PHASE III CLINICAL TRIAL FOR THE EVALUATION OF LJP 394 (ABETIMUS SODIUM) IN THE TREATMENT OF PATIENTS WITH SLE WHO ARE AT RISK FOR RENAL FLARE

Mario Cardiel for the LJP 394-90-09 Study Investigators Group

Background:
LJP 394 is an immunomodulatory agent that was designed to delay SLE renal disease and prevent renal flares by selectively inducing B cell tolerance in anti-dsDNA B cells and reducing circulating levels of anti-dsDNA antibodies. Anti-dsDNA antibodies are believed to contribute to the development of lupus nephritis, a major cause of morbidity and mortality in SLE patients. In a previous study of LJP 394 approximately 90% of enrolled patients were noted to have high affinity antibodies to the oligonucleotide epitope of LJP 394 at baseline. Of these 189 patients, those treated with LJP 394 experienced significantly longer time to renal flare, fewer renal flares, and longer time to initiation of high-dose corticosteroids or cyclophosphamide when compared with placebo. The present study was designed to assess these preliminary findings and further evaluate the safety of LJP 394.

Objectives:
The primary objective was to determine whether LJP 394 100 mg weekly was more effective than placebo in delaying renal flares in patients with high-affinity antibodies and a history of SLE renal disease. A secondary objective was to determine if LJP 394 was more effective than placebo in delaying time to initiation of treatment with cyclophosphamide and/or high-dose corticosteroids.

Methods:
Patients were eligible for participation if they had had a documented renal flare within the past four years, had no evidence of active SLE renal disease within the past three months and had a Farr level of > 15 IU/mL. Patients were randomized in a 1:1 ratio to receive either LJP 394 100 mg IV or placebo weekly for a period of up to 22 months.

Outcome measurements:
A protocol-defined renal flare required that it be attributed to SLE and that it satisfied one or more of the following three criteria: (1) a reproducible increase in serum creatinine of > 20% or at least 0.3 mg/dL, whichever is greater, and accompanied by significant proteinuria and/or hematuria and/or red cell casts, (2) a reproducible increase in 24-hr urine protein, or (3) new reproducible hematuria or a reproducible 2-grade increase in hematuria compared to baseline, with > 25% dysmorphic red blood cells, and either an 800 mg increase 24-hr protein or new red cell casts. All renal flares were blindly adjudicated by an independent Renal Events Committe. In addition, incidence of renal flare, incidence of cyclophosphamide and/or high-dose corticosteroid use, and time to, and incidence of, major SLE flares were also measured. Quality of life assessments included SF-36 and patient self-assessments.

Results:
The trial ended in December 2002. Seventy-two clinical sites in North America and Europe enrolled a total of 317 patients of whom 298 (94%) were determined to have had high affinity antibodies to LJP 394 at baseline. There were 41 renal flares in patients with high-affinity antibodies and five renal flares in patients with low-affinity antibodies. The average time in study for patients was approximately 11 months. At the time this abstract was prepared, the study remained blinded.

Conclusion:
This recently completed phase III study will assess the safety and effectiveness of LJP 394, a potential new treatment for patients with SLE who are at risk for renal flare.

Presented at the
Annual European Congress of Rheumatology "EULAR 2003"
Lisbon, Portugal
June 18-21, 2003