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Antibody-mediated thrombosis
Current
status
Antibody-mediated
Thrombosis Candidate in Human Clinical
Trials
In November 2001, La Jolla Pharmaceutical
initiated a Phase I/II clinical trial
of LJP 1082, for the treatment of stroke,
deep-vein thrombosis and other conditions
associated with antibody-mediated thrombosis.
The objective of the trial is to evaluate
the safety and activity of a single
dose of LJP 1082 in patients with antibody-mediated
thrombosis.
Initial results from Phase I/II
clinical trial presented at the American
College of Rheumatology Annual Meeting
October 27, 2002
Based on an initial assessment of
the trial data, the drug was well-tolerated
at all five dose levels. LJP 1082 had
an elimination half-life of at least
12 hours following intravenous administration.
Following treatment with a single 50
mg or 200 mg dose, antibodies to LJP
1082 were reduced in some patients.
In total, 20 patients with a history
of antibody-mediated thrombosis participated
in the trial period. All adverse events
observed were categorized as mild to
moderate and deemed to have no or an
unlikely relationship to study drug.
The adverse event profiles appeared
similar between drug-treated and placebo-treated
groups. There were no serious adverse
events. No significant increase in circulating
immune complexes, changes in complement
protein C3 or activation of patient
T cells was observed following drug
treatment.
Even though there were a small number
of patients in the study, there was
an apparent dose-dependent response
following drug treatment. Patients receiving
higher doses of LJP 1082 had larger
reductions in antibodies to LJP 1082.
In the 50 and 200 mg treatment groups,
there was an apparent correlation between
the level of reduction and the affinity
of the patient's antibodies for drug.
Most patients had antibodies that were
specific for the first domain of the
target protein, beta 2 GP1, which is
the epitope presented on LJP 1082.
This study is the first of several
that may be required to establish appropriate
dose regimens and the observed reductions
may not be large enough to affect patient
health or reduce antibodies to beta
2 GP1in a majority of patients. Additional
analyses are ongoing. Potential drug
interference in some of the antibody
assays is also being evaluated. This
study was not designed to evaluate the
ability of LJP 1082 to tolerize B cells
that produce antibodies to beta 2 GP1
and additional studies will be needed.
Trial Design
In the Phase I/II trial, five different
groups, each consisting of four or five
patients, were treated with a single
intravenous dose of LJP 1082 of 1, 3,
10, 50 or 200 mg and then monitored
for 30 days. One patient in each group
received placebo. In order to participate
in the trial, patients were required
to have elevated levels of antibodies
to beta 2 GP1, the target of the antibodies
involved in antibody-mediated thrombosis.
Standard safety assessments including
physical exams, lab values and vital
signs, and immunology specific measurements
were taken over 30 days following a
single dose of LJP 1082.
Pre-Clinical Results
Through its pioneering research in
the area of antibody-mediated thrombosis,
La Jolla Pharmaceutical discovered the
specific region on ß2 GP1 targeted by
disease-causing antibodies. These results
were published in the Proceedings of
the National Academy of Science (PNAS)
in 1998. It was this discovery that
enabled the Company to build LJP 1082,
a Toleragen that is designed to shut
down the B cells that produce antibodies
to ß2 GP1.
In a pre-clinical rat model, LJP 1082
drug treatment reduced the level of
antibodies and the number of B cells
producing these antibodies by up to
90%. These findings suggest that the
drug candidate effectively shut down,
or tolerized, the targeted B cells responsible
for producing these disease-associated
antibodies. LJP hopes to advance LJP
1082 as a potential therapeutic that
specifically targets the underlying
cause of antibody-mediated thrombosis
and avoids unwanted serious side effects.
Background
Antibody-mediated thrombosis, also
called antiphospholipid syndrome (APS),
is a blood clotting disorder that afflicts
up to two million people in the U.S.
and Europe (*1).
Patients with high levels of anticardiolipin
antibodies (ACA) have an increased risk
of stroke, heart attack, deep vein thrombosis,
and recurrent fetal loss. Current therapy
relies on anticoagulants, which are
difficult to manage, may cause serious
side effects - such as an increased
risk of life-threatening bleeding episodes
- and are not effective in many patients.
Our discovery of the target of these
disease-causing antibodies is enabling
La Jolla Pharmaceutical scientists to
design a drug candidate that may reduce
the risk of inappropriate blood-clot
formation. The target of these clot-promoting
antibodies is a small region on a key
blood protein called beta 2-glycoprotein
I. To date, our scientists have shown
that approximately 90% of patients studied
with antibody-mediated thrombosis have
antibodies that bind to this region.
The identification of a disease target
for antibody-mediated thrombosis has
allowed us to begin building new drug
candidates that bind to these antibodies
with high-affinity and are designed
to tolerize, or shut down, the B cells
that produce them.
Anticardiolipin antibodies occur in approximately 10% to 15%
of all stroke and heart attack patients (*2,*3)
and in approximately 25% of all deep-vein thrombosis and recurrent-fetal-loss
patients (*4,*5).
People who experience antibody-mediated thrombotic events are
typically younger than the majority of stroke or heart attack
patients and have clotting events affecting several organ systems.
Anticardiolipin antibodies are believed to prolong the duration
of clot formation. We have observed that antibodies from APS patients
inhibited the inactivation of clotting Factor Va, increasing the
likelihood of inappropriate blood clot formation. Because these
antibodies can prevent Factor Va inactivation, APS patients may
be at risk of larger or more numerous blood clots.
The antigenic target for anticardiolipin
antibodies is the phospholipid-binding
plasma protein beta 2-glycoprotein I
(b2GPI), rather than the phospholipid
itself. By identifying the primary antibody
binding site on the b2GPI molecule,
we have discovered the key component
needed to build a treatment Toleragen
(*6,*7).
Current treatment options
APS patients are typically treated with anticoagulants: heparin,
warfarin, and low-dose aspirin. Although these therapies inhibit
clot formation, none suppress the production of pathogenic antibodies.
Long-term warfarin anticoagulation appears to be the most effective
prophylaxis for both venous and arterial antibody-mediated thrombosis
patients (*8). However,
adverse reactions to warfarin include serious bleeding episodes,
necrosis, fever, nausea, and vomiting. Patients are often put
on lifelong therapy, and must be monitored frequently. The cessation
of warfarin treatment carries a high risk of recurrent thrombosis
during the first six months after the discontinuation of therapy
(*8).
Stroke
Elevated anticardiolipin antibodies are an independent risk
factor for a recurrent stroke. These antibodies can lead to a
much higher risk of recurrence and a shorter interval between
thrombotic events, as compared to the general stroke population(*9).
There were 731,100 first or recurrent strokes in U.S. in 1996,
according to the American Heart Association, and over 4.4 million
Americans are estimated to be living stroke victims. The prevalence
of ACA in the general stroke population is 10% to 15%, while the
prevalence in the stroke population under the age of 50 approaches
50% (*10). The occurrence
of these antibodies in the general population is only 1% to 3%.
Deep Vein Thrombosis
Anticardiolipin antibodies are the most common blood abnormality
in deep vein thrombosis (DVT) patients. The prevalence of ACA
in DVT is about 24%(*4).
Approximately two million people suffer from DVT each year in
the U.S. (*11) DVT
can lead to pulmonary embolism, with a high fatality rate. The
U.S. incidence of ACA-mediated DVT may be as high as 480,000 each
year. Antibody-positive patients have a recurrence rate more than
twice that of DVT patients without ACA (*12).
Current anticoagulation treatment for DVT with heparin or warfarin
carries a significant risk of bleeding complications.
Myocardial Infarction
There is a high prevalence of ACA in the young myocardial infarction
(MI) patient population who lack other apparent cardiovascular
risk factors. Over 1.5 million people suffer from heart attacks
each year in the U.S. The prevalence of ACA in MI patients is
estimated to be 10% (*3).
ACA are more common in younger patients, and are a risk factor
for recurrent cardiovascular thromboembolic events. The prevalence
of ACA in MI patients under the age of 50 may be as high as 20%
(*13). The treatment
of antibody-mediated coronary artery disease also involves long-term
use of warfarin anticoagulation.
Other Indications
ACA increase a patient's risk of subsequent generalized thrombosis,
and increase the rate of graft reocclusion following cardiovascular
surgery. In one study, 84% of ACA-positive cardiovascular surgery
patients suffered postoperative complications (*14),
and 53% of antibody-positive patients undergoing coronary arterial
bypass grafts experienced occlusion of the vein graft following
surgery, despite warfarin therapy (*15).
One quarter of all recurrent fetal
loss (RFL) may be antibody-mediated.
There are between 120,000 and 300,000
women who suffer from RFL each year
in the U.S. An 82% rate of fetal loss
in next pregnancies has been measured
for women with high levels of ACA (*16).
Current therapy has limited efficacy
and is typically aspirin plus heparin.
Delay in Factor Va inactivation
Activated by thrombin, Factor Va (5a)
plays a key role in blood coagulation.
Factor Va acts as a co-factor to accelerate
clot formation, giving rise to the nickname
"accelerin." Factor Va has a strong
procoagulant effect, prolonging the
duration of clot formation. The inactivation
of Factor Va is fundamental in controlling
the clotting process. Factor Va helps
accelerate clotting in the event of
an injury, but Factor Va then needs
to be rapidly inactivated by the body
to prevent the clot from expanding.
In normal individuals Factor Va generation
and inactivation is regulated by activated
protein C. It has been proposed that
anticardiolipin antibodies impair the
normal functioning of protein C.
Work in our laboratories has confirmed
the observations of Galli, et al. (*17)
that anticardiolipin antibodies from
APS patients can delay the inactivation
of Factor Va, leading to a prolongation
of the clotting process. ACA can be
isolated from patients, added to normal
human serum and the levels of Factor
Va monitored over time. While in the
absence of ACA the normal serum levels
of Factor Va rapidly return to baseline
after clotting is initiated, the presence
of ACA causes the Factor Va levels to
remain elevated. At 20 minutes ACA from
a typical patient cause the levels of
Factor Va to be 50% higher than normal.
We believe that these significantly
higher levels of the procoagulant Factor
Va may lead to an increased tendency
to form blood clots. Removal of the
ACA by our Tolerance Technology may
correct the delay in Factor Va seen
in APS patients and prevent the inappropriate
blood clot formation seen with these
patients.
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