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ISIS-FXI
Rx
— ISIS-FXI
Rx
is an antisense drugwe designed to treat clotting disorders. It targets FactorXI, a clotting factor
produced in the liver that is an important component of the coagulationpathway. High levels of FactorXI increase the riskof
thrombosis, a process involving aberrant blood clot formation responsible formanyheart attacks and strokes. Elevated levels of Factor
XI also increase the riskof venous thrombosis, a common problem after surgery, particularlymajor orthopedic procedures, such as
knee or hip replacement. Peoplewho are deficient inFactorXI have a lower incidence of thromboembolic eventswithminimal
increase inbleeding risk. Although currently available anticoagulants reduce the riskof thrombosis, physicians associate these
anticoagulantswith increasedbleeding, which canbe fatal.
Inpreclinical studies, ISIS-FXI
Rx
demonstrated potent antithrombotic activitywith no increase in bleeding comparedwith
standard anti-clotting agents, including lowmolecularweight heparin, warfarin andFactorXa inhibitors, all ofwhich increase
bleeding.We have completed aPhase 1 study evaluating the safety and activityof ISIS-FXI
Rx
inhealthyvolunteers. In this
study, ISIS-FXI
Rx
produceddose-dependent statistically significant reductions of greater than 80percent inFactorXI protein. In this
study, subjects tolerated ISIS-FXI
Rx
well withno increase inbleeding.
In2012, we initiated a Phase 2 study evaluating ISIS-FXI
Rx
inpatients undergoingknee replacement surgery, also referred to
as total knee arthroplasty, or TKA. This study is a comparator-controlled study, inwhichwewill compare the safety and activity of
ISIS-FXI
Rx
to a commonly used anti-coagulant, enoxaparin. In this study,we are evaluating the effectiveness of ISIS-FXI
Rx
in
reducing the number of thrombotic events inpatients followingTKAwithout increasing bleeding. Given themechanismof FactorXI
inhibition, we believe that doctors coulduse our drugbroadly as an anti-thrombotic inmanydifferent therapeutic settings forwhich
additional safe andwell tolerated anti-thrombotic drugs are needed. We plan to report data on ISIS-FXI
Rx
from the Phase 2 study in
patients undergoingTKA in2014.
ISIS-CRP
Rx
—
ISIS-CRP
Rx
is an antisense drugwe designed to reduceC-reactive protein, or CRP, a protein produced in the
liver. CRP levels increase dramaticallyduring inflammatorydisorders, and scientists have linked excessive amounts ofCRP to
coronary artery disease. Furthermore, a growingbodyof evidence from clinical trials implicatesCRP in cardiovascular disease
progression. These results suggest that itmay be therapeutically beneficial to significantly decreaseCRP levels inpatientswho are at
risk for coronary events. In addition, clinicians have associated elevatedCRP levelswith aworseningof overall outcomes in
conditions such as end-stage renal disease andmultiplemyeloma, suggesting that loweringCRP couldhelp these patients. CRP
elevation is also evident inmanyothermajor inflammatorydiseases.
In preclinical studies, we observed that our antisense inhibitor of CRP suppressed liver and serumCRP levels.We evaluated
ISIS-CRP
Rx
in aPhase 1 study inwhich ISIS-CRP
Rx
produced statistically significant reductions inCRP in the cohort of subjects that
entered the studywith elevated levels of CRP.We also evaluated ISIS-CRP
Rx
inhealthyvolunteerswhowere subjected to an
endotoxin challenge, which caused an increase inCRP andother inflammatorymarkers. In this study,we showed that pretreatment
with ISIS-CRP
Rx
was able toblunt the acute increase inCRP. Inour Phase 2program, we are evaluating ISIS-CRP
Rx
indifferent
disease settingswhere elevated levels of CRP are associatedwith aworseningof disease symptoms. The first of these Phase 2 studies
evaluated ISIS-CRP
Rx
inpatientswith rheumatoid arthritis, or RA, with chronically elevatedCRP. In this study, patients treatedwith
ISIS-CRP
Rx
achieved rapid, dose-dependentmean reductions of up to67percent inCRP. Patients also showed improvements in signs
and symptoms ofRA, which correlatedwith reductions inCRP, butwere not sufficientlygreater than improvements observed in the
placebogroup to justify further development of ISIS-CRP
Rx
for RA.
We are also evaluating ISIS-CRP
Rx
in aPhase 2 study inpatientswith atrial fibrillation, orAF. AF involves an irregular heart
rate that commonly causes poor blood flow to the body. In this study, we are evaluating the effect of loweringCRPon the frequency
anddurationofAF. We plan to report data on ISIS-CRP
Rx
from the Phase 2 study inpatientswithAF in2014.
ISIS-APO(a)
Rx
— ISIS-APO(a)
Rx
is an antisense drugwe designed to reduce apolipoprotein(a) in the liver to offer a direct
approach for reducingLp(a), an independent risk factor for cardiovascular disease. Scientists associate high levels of Lp(a)with an
increased riskof atherosclerosis, coronaryheart disease, heart attack and stroke. Lp(a) levels inblood canvarygreatlybetween
individuals due primarily to genetic variations between individuals. Lp(a) levels are geneticallydetermined, reachedby the age of two
and remain constant throughout the life of the individual. Diet and lifestyle changes have little impact onLp(a) levels and current
therapies donot adequately reduceLp(a) to acceptable levels inpatientswith elevatedLp(a). As a general guideline for ideal
Lp(a) levels, theEuropeanAtherosclerosis Society recommends that Lp(a) be less thanor equal to50mg/dL. Evenpatientswho can
control their LDL-C remain at high-riskof cardiovascular events if theyhave high levels of Lp(a). There is a significant need for a
highly specific drug that can lower Lp(a).
We completed aPhase 1 study evaluating ISIS-APO(a)
Rx
inhealthyvolunteerswith incomingLp(a) levels ranging from10
mg/dL to 98mg/dL. In this study, we reporteddose-dependent reductions of up to95percent inLp(a). In addition toLp(a) activity,
subjects treatedwith300mgof ISIS-APO(a)
Rx
experienced anup to59percent reduction inoxidizedphospholipids, lipids that play
an important role inproinflammatory andproatherogenic processes believed tobe associatedwithLp(a). In this study, ISIS-APO(a)
Rx
demonstrated a good safetyprofile andwas generallywell tolerated.
