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SAN DIEGO, Feb. 18 /PRNewswire-FirstCall/ -- La Jolla
Pharmaceutical Company (Nasdaq: LJPC) today announced preliminary
findings from a Phase III clinical trial evaluating Riquent(TM),
previously known as LJP 394, for the treatment of lupus renal disease.
The Company continues to analyze the results from the trial.
The objective of the study was to determine Riquent's
ability to delay the following: renal flare, treatment with HDCC
(high-dose corticosteroids and/or cyclophosphamide) or other immunosuppressive
drugs, hospitalization, or death due to lupus (Major SLE flare);
reduce antibodies to double-stranded DNA (dsDNA); and to assess
safety compared with placebo in the intent-to-treat population and
in patients with impaired renal function at baseline. The intent-to-treat
population was defined as patients with high-affinity antibodies
to Riquent. The trial was designed to compare the effect of drug
or placebo treatment in two well-balanced groups of lupus patients
with a history of renal disease. Additional information follows
in the section titled Trial Design.
Summary of Results
Intent-to-treat analysis: Riquent appeared to be well
tolerated with no apparent differences in the overall incidence
of serious adverse events or adverse events between Riquent-treated
and placebo-treated patients. However, an initial assessment of
the trial data indicates that treatment with Riquent did not increase
length of time to renal flare, the primary endpoint, in a statistically
significant manner when compared with placebo through the end of
the study. There were 298 patients in the intent-to-treat population,
145 on Riquent and 153 on placebo. Patients were treated for as
long as 92 weeks with a median of 46 weeks.
There was a statistically significant reduction in
antibodies to dsDNA in the Riquent-treated group compared with the
placebo-treated group (p<0.001). Antibodies to dsDNA are believed
to result in renal flares and other clinical manifestations of lupus.
Riquent was designed to reduce antibodies to dsDNA and this effect
has been demonstrated in all clinical studies of Riquent.
In this study, changes in antibodies to dsDNA strongly
correlated with changes in complement levels in an inverse relationship
(p < 0.001). Complement C3 levels below normal at baseline (hypocomplementemia)
strongly correlated with an increased risk of renal flare (p< 0.001).
Similar correlations between antibody levels and complement C3 were
observed in the previous Phase II/III study. Together, these data
confirm the pathogenic nature of these antibodies to dsDNA in lupus
patients.
In the intent-to-treat population, there were fewer
renal flares, treatments with HDCC and Major SLE (systemic lupus
erythematosus) flares in Riquent-treated patients compared with
placebo-treated patients. The estimated median time to renal flare
was 123 months in the Riquent-treated group and 89 months in the
placebo-treated group. There were 41 renal flares, 17 (12%) in Riquent-treated
patients and 24 (16%) in placebo-treated patients. There were 68
treatments with HDCC, 32 (22%) in the Riquent-treated group and
36 (24%) in the placebo-treated group. There were 82 Major SLE flares
in the trial, 35 (24%) in patients on Riquent and 47 (31%) in patients
on placebo. None of these differences were statistically significant.
Reviewing a graph of the results showed that the Riquent
and placebo lines for time to renal flare and for the changes in
antibody levels were separating until weeks 46 to 48. In the first
46 weeks, 90% or 22 of 24 renal flares occurred in the study in
the placebo patients compared with 59% or 10 of 17 in the Riquent-treated
patients. At weeks 44, 46, and 48, the incidence of renal flares
was 20:10 (p = 0.085), 22:10 (p = 0.041) and 22:11 (p = 0.067),
respectively, in favor of Riquent. At weeks 44, 46 and 48, the incidence
of renal and/or Major SLE flares was 43:27 (p=0.057), 46:28 (p=0.033)
and 46:29 (p=0.061), respectively, in favor of Riquent. More discussion
follows in the section titled Other Observations.
In addition, the results from this trial appear to
support the use of the Company's high-affinity assay to identify
patients who may respond to Riquent and also to confirm the high-affinity
analysis approach used in the previous Phase II/III study. As the
baseline affinity of patients' antibodies for Riquent increased,
the number of renal flares declined in the Riquent-treated group
compared with the placebo-treated group.
Patients with Impaired Renal Function analysis: In
a prospectively defined subpopulation with impaired renal function
at baseline, defined as a serum creatinine > 1.5 mg/dl at baseline,
there were 43 patients, 20 on Riquent and 23 on placebo. Riquent-treated
patients had fewer renal flares, treatments with HDCC and Major
SLE flares compared with patients on placebo, but the number of
patients was small and the differences were not statistically significant.
There were 8 renal flares, 2 (10%) in patients on Riquent and 6
(26%) in patients on placebo. There were 9 treatments with HDCC,
3 (15%) in patients on Riquent and 6 (26%) in patients on placebo.
There were 11 Major SLE flares, 4 (20%) in patients on Riquent and
7 (30%) in patients on placebo. There were 14 renal flares and/or
Major SLE flares, 5 (25%) in patients on Riquent and 9 (39%) in
patients on placebo. Similar results in the same group were observed
for renal flares in a previous Phase II/III study: no renal flares
(0%) were observed in the 11 Riquent- treated high-affinity patients
compared with 6/11 (55%) of the placebo-treated high-affinity patients.
Experts believe a delay in time to or a decrease in the incidence
of renal flares and/or Major SLE flares in this high-risk population
would be considered medically meaningful.
Next Steps
The Company plans to complete its analysis of the
Phase III data and meet with regulatory agencies. The analysis of
data from the health-related quality of life survey and patient
self-assessment is ongoing. The Company will continue to collect
data in the ongoing open-label follow-on trial. Based on the observed
reduction in antibodies to dsDNA, which the Company believes confirms
LJP's Tolerance Technology(R) approach, the Company plans at this
time to continue its antibody-mediated thrombosis program and evaluate
the use of the technology for other diseases, which will depend
on the availability of additional funding.
Other Observations
Several observations may help to explain the results
from the study. These observations are preliminary and they will
all require review by appropriate regulatory agencies and medical
experts.
Changes in medical practice: There appears to have
been changes in medical practice since the completion of the Phase
II/III study as evidenced by a difference in prescribing regimens
for immunosuppressive drugs. In particular, it appears there were
differences in baseline treatments in the patient population in
the Phase III study compared with the previous trial. A higher percentage
of patients were receiving immunosuppressive treatments at study
entry: 73/145 (50%) in the Riquent-treated group versus 63/153 (41%)
in the placebo-treated group in the Phase III study, compared with
35/114 (31%) in the Riquent-treated group versus 40/116 (34%) in
the placebo-treated group in the Phase II/III trial. The sample
size selected for the Phase III study was based on the Phase II/III
study.
The definition of HDCC may not have captured all of
the potential events in this study, as HDCC did not include some
of the newer immunosuppressive drugs that are increasingly used
instead of cyclophosphamide. While these newer drugs have a better
side effect profile than cyclophosphamide, they are still broadly
immunosuppressive. The definition of Major SLE flare included increases
in corticosteroid doses as well as any new or increased dose of
immunosuppressive agents, hospitalization or death, provided they
were associated with active SLE.
To account for these observed changes in medical
practice, a combined analysis of all patients with either a renal
flare and/or a Major SLE flare was performed. In this combined analysis,
there were 88 events, 37 (26%) in Riquent-treated patients and 51
(33%) in placebo-treated patients. Thus, changes in medical practice
may have resulted in fewer renal flares because patients were being
treated before a renal flare could have been observed or documented.
Depletion of susceptible patients in placebo group:
It appears that "sicker" patients in the Riquent group stayed in
the trial longer than "sicker" patients in the placebo group even
though a comparable number of patients discontinued in each group
before they met a predefined endpoint in the study (a depletion
of susceptible patients). Reviewing a graph of the results showed
that the Riquent and placebo lines for time to renal flare and for
the changes in antibody levels were separating until weeks 46 to
48. Upon reviewing patient laboratory values, placebo patients remaining
in the study past weeks 44 to 48 appeared to have better renal function
than the placebo group who dropped out or flared prior to these
weeks, as measured by creatinine clearance at baseline (p = 0.024
at week 48). In the placebo- treated group, those who remained in
the study after weeks 44 to 48 showed no mean changes in antibodies
to dsDNA from baseline.
Trial Design
Treatment: Patients were treated with weekly doses
of 100 mg of Riquent or with placebo. Patients were also permitted
to receive other treatments including immunosuppressive drugs. This
randomized, double-blind, placebo- controlled study was conducted
at more than 70 major medical centers in North America and Europe.
Patients could remain in the study for up to 92 weeks.
Analysis groups: The prospectively defined analysis
groups were the intent-to-treat population and patients with impaired
renal function. Patients with impaired renal function were defined
as having a serum creatinine level of 1.5 mg/dL to 3.5 mg/dL at
baseline. In general, patients with impaired renal function are
at greater risk of progressing to renal flare, kidney failure, and
dialysis.
Endpoints: The primary endpoint was time to renal
flare. A renal flare was defined as a significant, reproducible
increase in serum creatinine, urine protein or blood in the urine.
The secondary endpoint was time to treatment with HDCC. HDCC was
defined as any dose of cyclophosphamide or an increase in prednisone
of 15 mg/day or higher resulting in a final dose greater than 20
mg/day.
Other prospectively defined secondary outcomes included
time to Major SLE flare, treatment associated maintenance and/or
improvement in health-related quality of life, decreases in antibodies
to dsDNA and associated increases in complement C3 levels. A Major
SLE flare was defined as the occurrence of any one of the following
due to manifestations of active SLE: treatment with HDCC or initiation
or increase in treatment with other immunosuppressive agents, including
azathioprine, mycophenolate mofetil, methotrexate, cyclosporin and
leflunomide; or hospitalization or death. This definition of Major
SLE flare was designed to capture serious events where patients
were treated for manifestations of active SLE as well as renal disease
or where treatment, hospitalization or death could have preceded
the occurrence of a documented renal flare.
Complement changes were evaluated by determining the
mean change from baseline in the complement protein C3 that indicates
overall complement consumption due to active inflammation. Antibody
changes were evaluated by determining the mean percent change of
antibodies to dsDNA from baseline. Patients' assessments of disease
activity and health-related quality of life were measured on a regular
basis as well as at the time of, and 30 days following, a documented
renal flare.
Discussion of Preliminary Results
"Based on preliminary results, Riquent appears to
be well tolerated in patients over a relatively long study period
of up to 92 weeks and LJP plans to continue the ongoing open-label
follow-on study to collect additional information," said Steve Engle,
CEO of La Jolla Pharmaceutical Company. "Although the prospectively
defined primary efficacy analysis in the intent- to-treat population
did not demonstrate the level of efficacy expected, we believe the
study shows a clear correlation between treatment with drug and
improvements in complement that are associated with a reduced risk
of renal flares in the trial. Lupus trials conducted with Riquent
have consistently demonstrated the ability to reduce these pathogenic
antibodies."
"Many of the preliminary results in this trial appear
consistent with the previous Phase II/III study," said Engle. "We
observed a larger difference between Riquent- and placebo- treated
patients earlier in the trial, at weeks 44 to 48, and we still see
this treatment difference in patients with impaired renal function
who remained on treatment during the entire study. We believe the
statistically significant reduction in antibodies to dsDNA seen
in Riquent-treated patients compared with placebo further demonstrates
Riquent's mechanism of action, confirms our core Tolerance Technology(R)
platform and supports its potential application in other autoimmune
diseases with disease- causing antibodies."
"It appears that several issues may have prevented
us from attaining statistical significance," said Engle. "Unfortunately,
changes in medical practice and interference from concomitant medications
are difficult issues in drug development. Moving forward, our clinical
development pathway cannot be fully defined until the study results
are completely analyzed and we discuss the results with regulatory
agencies."
"We appreciate the patients, physicians and others
who helped make this trial possible and remain dedicated to the
search for less harmful therapies for lupus patients," said Engle.
"We appreciate our investors' critical support. We will continue
to analyze the data from the trial and then we plan to discuss these
results with the regulatory agencies. Our guidance to investors
and others will be limited during this time."
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