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THE B-CELL TOLERAGEN LJP-394 REDUCES
RENAL FLARES IN PATIENTS WITH LUPUS
NEPHRITIS: A PROSPECTIVE DOUBLE-BLINDED,
PLACEBO CONTROLLED TRIAL
J.A. Tumlin1, M. D. Linnik2 and G. B.
Appel3, and, Div. Nephrology, Emory
Univ. Atlanta GA1., Div. Nephrology,
La Jolla Pharmaceutical Co., San Diego,
CA2 and Columbia Presbyterian Med. Center,
NY3
Introduction: High avidity double-stranded
DNA autoantibodies (ds-DNA-Ab) are specific
markers of SLE and contribute to the
glomerular injury in lupus nephritis.
LJP 394 is a novel, immunomodulatory
drug comprised of 4 ds-oligonucleotides
that reduce ds-DNA antibody titers through
B cell tolerance. To determine whether
LJP-394 prevents recurrent lupus nephritis,
we conducted a randomized, double blind,
placebo (PBO) controlled trial in 189
patients with high-affinity ds-DNA antibodies
and known renal disease secondary to
SLE.
Primary Objective: To determine
whether LJP-394 1) reduces the incidence
of recurrent lupus nephritis at 18 months;
2) reduces ds-DNA antibody titers, and
3) reduces treatment with cyclophosphamide
(CX) and high-dose corticosteroids (HDCC).
Methods: Patients were randomized
to receive weekly PBO or LJP-394 (100
mg) for 15 weeks, followed by intermittent
dosing with 50 mg for 60 weeks. Patients
were allowed to continue immunosuppressive
medications previously prescribed if
below protocol requirements.
Definitions: A renal flare was
defined as a 1) >0.3mg/dL rise in
serum creatinine (or 20% rise above
baseline); 2) a 1-2gm increase in urinary
protein (or a two-fold increase, above
baseline) in two 24hr urine collections;
or a 25% increase in dysmorphic red
cells over baseline.
Results: WHO class III/IV was
present in 70 and 69% in the LJP-394
and PBO groups respectively. LJP-394
reduced the incidence of renal flares
by 67% (P<0.008) and prolonged the
time to renal flare compared to placebo
(P<0.008).
[^ = P<0.05, * = P<0.004]
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Table
1: Clinical Outcome
|
LJP
394 |
Placebo
(N=97) |
| %
Reduction ds-DNA AB/16 weeks |
30+or
minus 4% |
5+or
minus 6% |
| #
Renal Flares/18 months |
7/92
(8%)^ |
21/97
(22%) |
| #
Renal Flares (Cr 1.5-2.5 mg/dl) |
0/11
(0%)* |
6/10
(60%) |
Major SLE flares were observed in 18/91
(20%) of the LJP-394 group compared
to 37/95 (39%) in PBO (P<0.01). Patients
receiving LJP-394 received 41% fewer
courses of high dose immunosuppression
(P<0.03)
Conclusion: LJP-394 reduces
ds-DNA Ab titers, recurrent nephritis
and need for immunosuppression in patients
with high-affinity ds-DNA-Ab
Presented by Dr.
James A. Tumlin at the
ASN / ISN World Congress of Nephrology
2001
San Francisco, CA., October 10-17, 2001.
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