A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of 2 Doses of RO4905417 (R1512) Administered to Patients with Non ST-Elevation Myocardial Infarction (Non-STEMI) Undergoing Percutaneous Coronary Intervention (PCI)

Cardiovascular disease (CVD) is the leading cause of death according to the
American Heart Association*s 2010 Heart Disease and Stroke statistics and
coronary artery disease (CAD) is the most common form of CVD. As CAD
progresses, narrowing and obstruction of the lumen of coronary blood vessels
occurs, restricting the flow of oxygenated blood to the myocardium. Blockages
of the arteries to the heart may lead to angina pectoris, and ultimately
myocardial infarction. The two primary interventions for patients with
multivessel CAD are coronary artery bypass graft (CABG) surgery and
percutaneous coronary intervention (PCI).
Percutaneous coronary intervention has become a standard revascularization
procedure for patients with coronary artery disease. Since its introduction
into clinical practice in 1977, remarkable technological advances have rendered
PCI a safe procedure used to treat increasingly complex lesions in patients
with both stable and unstable coronary artery disease. Nevertheless,
periprocedural myocardial damage has been estimated to occur in between 4 % and
50 % of patients and importantly, can even occur after seemingly uneventful PCI
procedures. PCI may result in myocardial infarction, need for emergent or
urgent repeat revascularization, or even death.
The pathophysiology of post-PCI myocardial damage is multifactorial, but
inflammation appears to play a pivotal role. Hyperplasia of the arterial intima
at the site of intervention remains one of the major causes of late failure of
PCI. Damage to the vascular wall during intervention leads to activation of
leukocytes, endothelial cells, and smooth muscle cells. Importantly,
inflammatory and cellular changes after PCI are not restricted to the injured
arterial intima and the proximal adventitia but are also present in
perivascular tissue extending several millimeters away from the artery wall.
Following angioplasty of porcine coronary arteries, neutrophils and macrophages
have been detected deep within the myocardium. Adhesion molecules such as
P-selectin, VCAM-1 and E-selectin are expressed by endothelial cells of the
myocardial microvessel. These animal studies are consistent with clinical
observations that activated neutrophils are present in the coronary sinus after
PCI. Release of proteolytic enzymes and generation of reactive oxygen species
by these activated neutrophils may in turn aggravate endothelial damage during
PCI. Concentrations of various inflammatory markers including tumor
necrosis-factor alpha, C-reactive protein, and IL-6 also rise in response to
PCI and PCI has also been associated with platelet activation as demonstrated
by increased soluble P-selectin (sP-selectin) concentrations.
Cumulatively, these data suggest that PCI stimulates an extensive inflammatory
and proliferative response in the vasculature that may ultimately result in
injury to the myocardium and/or later restenosis.
Restenosis has also remained a major limitation of the clinical usefulness of
PCI. Despite primary success rates as high as 90 %, the incidence of chronic
restenosis after PCI has been reported to be as high as 40 % within 6 months.
Migration of leukocytes across the endothelium, platelet aggregation and
thrombus formation seem to be major reasons for restenosis after PCI. Heider et
al. observed that patients that developed restenosis after PCI by six months,
had significantly higher concentrations of the adhesion molecules P-selectin,
E-selectin, and VCAM-1 up to 30 days following PCI than patients who did not
develop restenosis.
P-selectin, a cell adhesion molecule expressed on activated endothelial cells
and platelets plays a critical role in leukocyte tethering and rolling on the
vessel wall and subsequent diapedesis. Following activation of endothelial
cells, P-selectin can be rapidly translocated from Weibel-Palade bodies to the
membrane surface to mediate leukocyte rolling by interacting with sialylated,
fucosylated ligands such as P-selectin glycoprotein ligand 1 (PSGL-1). When
expressed on the endothelial surface, P-selectin affects hemostasis and
thrombosis. P-selectin also promotes platelet rolling and adhesion to
stimulated vessel walls, supports leukocyte recruitment to thrombi and enhances
fibrin formation. Furthermore, P-selectin induces formation of procoagulation
microparticles and mediates microparticle recruitment to thrombi, which
promotes thrombus growth and stabilization. The vessel is transformed into a
proinflammatory, hypercoagulable state, which contributes to lesion growth and
instability. On activated platelets, P-selectin facilitates the adhesion of
monocytes to injured endothelium or subendothelial matrix.
Recent studies in apolipoprotein E-deficient mice have suggested that transient
inhibition of P-selectin with either anti-P-selectin antibodies or anti-PSGL-1
antibodies significantly decreased macrophage content of atherosclerotic plaque
as well as neointima formation after arterial injury. These data indicate that
inhibition of P-selectin can reduce vascular injury in an animal model of
atherosclerosis and may also decrease myocardial injury following PCI.

The primary efficacy objective of this study is:
• To evaluate the efficacy of RO4905417 in reducing the procedural damage
during PCI
The secondary efficacy and safety objectives of this study are:
• To evaluate the changes in other cardiac and renal biomarkers
• To evaluate the safety of RO4905417 by monitoring of adverse events and the
incidence of MACEs at 30 and 120 days after PCI after a single dose of study
drug

Three arms, multi-center, randomized, double-blind, placebo-controlled, study
comparing 5 mg/kg dose and 20 mg/kg dose of RO4905417 versus a matching placebo.
Patients will be randomized to receive either:
-Placebo administered as at least 1 hour infusion prior to PCI
-5 mg/kg of RO4905417 administered as at least 1 hour infusion prior to PCI
-20 mg/kg of RO4905417 administered as at least 1 hour infusion prior to PCI

The infusion should be completed at least one hour and not more than 24 hours
before the planned PCI procedure. The patients will be assessed at 8 hours
post-PCI, 16 hours post-PCI, and 24 hours post-PCI (or time of discharge,
whichever is earlier). Baseline will correspond to assessments and blood
sampling performed before the infusion (before the procedure). The patients
will have a safety visit at 30 and 120 days after the infusion. Patients who
receive infusion, but do not undergo the planned PCI procedure will be followed
for assessment of safety only.

Patients who are eligible for the study will be treated with RO4905417
according to the schedule of assessments, outlined on page 8 and 9 in the
protocol.

Risks in other studies:

RO4905417 was well tolerated up to the highest dose administered (20 mg/kg) and
for up to 3-month treatment (once monthly administration) in both healthy
volunteers and PAD patients.
Eight serious adverse events (SAEs) have been reported in phase I studies;
rhabdomyolysis (possibly related to study medication) in a healthy subjects
treated with 0.1 mg/kg, hypopharyngeal cancer (unrelated to the study
medication) in a PAD patient treated with 3 mg/kg, acute hepatitis B leading to
death (unrelated to the study medication) in a PAD patient treated with 0.3
mg/kg and five SAEs in patients treated with placebo, including four
cardiovascular SAEs (transient ischemic attack, acute myocardial infarction,
angina pectoris and intermittent claudication) and one major thrombocytopenia
Most other adverse events (AEs) were of mild/moderate intensity and resolved
without sequelae. The most frequently reported AEs were headache and upper
respiratory tract infection in healthy volunteers, diarrhea, hypoaesthesia and
fatigue in PAD patients. Overall, the pattern and nature of AEs were similar in
the placebo and the active treated groups.
No clinically significant or dose-related abnormalities were reported on ECG
and vital signs. No dose-related abnormalities were reported in laboratory
parameters. Elevated CPK values were the most commonly reported laboratory
abnormality, but without showing dose related pattern.
Bleeding time and platelet aggregation were not affected by treatment with
RO4905417, in healthy subjects as well as in PAD patients treated with aspirin
or clopidogrel.
Out of 114 subjects and patients treated with RO4905417, two healthy subjects
tested positive for antibodies against RO4905417. The presence of HAHA had
however no impact on their safety, pharmacokinetic and pharmacodynamic profiles


Risks of research procedures:

The research procedures can also entail risks and discomfort. There is a slight
chance of pain or bruising from blood samples. Some people faint when a blood
sample is taken. See also a list of all study activities on pages 8 and 9 of
the Protocol or the answers to question E4, E6 and E9 of this form