A PILOT STUDY OF LJP 394, A NOVEL THERAPEUTIC AGENT FOR THE TREATMENT
OF SYSTEMIC LUPUS ERYTHEMATOSUS
Weisman MH, and Bluestein HG-University of California, San Diego
LJP 394, a novel synthetic oligonucleotide conjugate, has been
shown to lower anti-dsDNA and increase survival in the male BXSB
mouse. We conducted this Phase 2 pilot study in patients with
systemic lupus erythematosus (SLE) to examine the tolerability
of LJP 394 and its effects on anti-dsDNA.
Four female patients aged 31-56 years (1 white, 1 black, 2 Hispanic)
were studied. Two were receiving prednisone (13-20 mg daily),
and 3 hydroxychloroquine (200-400 mg daily). Mean duration of
SLE was 2.3±2.6 years (range 6 months-5 years). Mean baseline
serum creatinine was 0.7±0.2 mg/dL (range 0.5-0.9 mg/dL), mean
C3 complement was 63±44.5 IU/L (range 19-850 IU/L).
Each patient received a single 100 mg dose of LJP 394, either
as a 2-hour infusion (n=2) or as an intravenous bolus (n=2). Vital
signs, electrocardiograms, routine laboratory tests, and serological
evaluation of anti-dsDNA, circulating immune complexes, complement
levels, and complement split products were performed pre- and
post-dosing.
Following administration of LJP 394, there were no drug-related
changes in vital signs, electrocardiograms, or routine laboratory
tests. We observed slight, transient complement activation at
2 hours post-dosing, which was not manifested clinically. LJP
394 significantly reduced anti-dsDNA levels in all subjects with
gradual return to baseline by 2 to 4 weeks. The mean percent reduction
from baseline in anti-dsDNA was (% reduction ±SE):
|
Hour
1
|
Hour
2
|
Hour
4
|
Hour
6
|
Hour
8
|
Day
1
|
Day
7
|
Day
14
|
Day
28
|
|
51.7
|
53.8
|
47.4
|
47.4
|
51.8
|
42.0
|
25.2
|
17.6
|
12.0
|
|
±12.0
|
±12.5
|
±13.1
|
±12.1
|
±11.8
|
±6.8
|
±6.7
|
±6.3
|
±16.7
|
There was no difference in response between infused and bolus
patients, or between patients with low and high baseline levels
of anti-dsDNA.
We conclude that in patients with SLE, a single 100 mg dose of
LJP 394 can safely reduce the level of circulating anti-dsDNA.
Longer-term Phase 2 studies to examine the tolerability of repeated
doses and to explore the most suitable dosage regimens are ongoing.
Presented at the
American College of Rheumatology Conference
October 24, 1995
|