Can HDL Infusions Significantly Quicken Atherosclerosis Regression?
A phase II, Multi-center, double-blind, ascending dose, placebo-controlled, dose-finding trial of CER-001 or placebo in subjects with acute coronary syndrome.

Cardiovascular disease remains the most pressing healthcare issue for developed
countries and is becoming so for developing countries. There are a number of
chronic therapies available for long-term management of risk. Short term
therapies for subjects with an acute event, such as an episode of acute
coronary syndrome (ACS), are focused on reperfusion and removing thrombus but
most subsequent events are caused by ahterosclerotic plaque rupture at a
different sit. There are no approved therapies that can rapidly reduce the
burden of unstable, inflamed plaque in the overall coronary vascular bed. HDL
has multiple actions that could lead to atherosclerotic plaque stabilization,
such as rapid removal of large quantities of cholesterol from the vasculature,
improvement in endothelial function, protection against oxidative damage and
reduction in inflammation. This study will asses the effects of CER-001, an
ApoA-I- based HDL mimetic, on indices of atherosclerotic plaque progression and
regression as assessed by intravascular ultrasound (IVUS) measurements in
patients with ACS.

To assess the impact of six IV infusions of 3, 6, or 12 mg/kg of CER-001 or
placebo, given at weekly intervals, on atherosclerotic plaque volume, as
measured by coronary IVUS.

Subjects presenting with symptoms of ACS will be eligible to be screened for
this
study. At the time of baseline catheterization, subjects need to have an
adequate IVUS
evaluation of one *target* artery for IVUS which is not influenced by prior or
present PCI, and
the proximal 4 cm of the target artery should have a diameter stenosis between
0 and 50% by
visual angiographic assessment, a reference diameter *2.5 mm and be free of
filling defects
suggestive of thrombus. Once the baseline IVUS has been evaluated by the IVUS
Core
Laboratory for overall quality, the presence of a suitable target vessel and
the absence of
technical factors which can preclude accurate reading of the IVUS images, the
subject will be
randomized to receive an intravenous, given over one hour, of placebo or one of
three
doses of CER-001 (3, 6, or 12 mg/kg). Randomized subjects will return at weekly
intervals (i.e.,
every 7 to 11 days) for five additional infusions. End-of-treatment labs will
be drawn one week
(5 to 9 days) after the last infusion. A follow-up IVUS will be conducted
approximately 3 weeks
(14 to 35 days) after the last infusion. A follow-up visit will occur
approximately 6 months (+/- 2 weeks) after the last infusion to collect
samples for Anti-ApoA1 antibody testing and lipid profile and to monitor for
MACE endpoints. The total study duration from randomization to follow up IVUS
for a completed study subject can therefore range from approximately 7 to 8
months.

Primary study parameters/outcome of the study
The primary endpoint for this study is the nominal change in total plaque
volume (TPV) in a 30 mm segment of the target coronary artery assessed by
3-dimensional (3D) IVUS.

Subjects enrolled in this study will have a second coronary catheterization
performed
approximately 8-10 weeks following their initial catheterization and will
therefore be exposed to the risks associated with the second catheterization
procedure. Cardiac catheterization is a common medical procedure that rarely
causes serious problems, however, complications can include:
* Bleeding, infection, and pain where the catheter was inserted.
* Damage to blood vessels. Rarely, the catheter may scrape or poke a hole in a
blood
vessel as it's threaded to the heart.
* An allergic reaction to the dye used.
Other, less common complications of the procedure include:
* Arrhythmias (irregular heartbeats). These often go away on their own, but may
need
treatment if they persist.
* Damage to the kidneys caused by the dye used.
* Blood clots that can trigger stroke, heart attack, or other serious problems.
* Low blood pressure.
* A buildup of blood or fluid in the sac that surrounds the heart. This fluid
can prevent the
heart from beating properly.
Subjects will receive six infusions of CER-001 (3, 6, or 12 mg/kg) or placebo
during the study. In single-dose studies of CER-001 up to 45 mg/kg adverse
events were rare, mild in nature, and self-limiting. No adverse effects on the
liver, kidney or red blood cells were observed in humans, however these effects
have been seen in animals treated with higher doses (50 mg/kg and above dosed
every second day for 4 weeks) in toxicology studies. Liver toxicity has been
observed with the use of other HDL mimetics in humans. Minor adverse events
such as headache, nausea, vomiting, abdominal pain or injection site reactions
would also be reasonable o expect. Subjects in this trial will be allowed to
be treated with all required medication to treat new or existing medical
conditions, including their qualifying ACS event, and to maintain health and
well-being. Subjects treated with placebo (25% chance) will receive no
additional therapeutic benefit, however those treated with active drug (75%
chance) are expected to derive therapeutic benefit from the removal of
cholesterol from peripheral tissues including the vascular bed. The estimated
treatment effect ranges from a reduction in total plaque volume of 4 mm3 (3
mg/kg) to 7 mm3 (12 mg/kg) beyond that seen in placebo-treated subjects under
post-ACS standard-of-care treatment.