Isis Pharmaceuticals, Inc. Form 10K - page 13

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We plan to initiate a Phase 2program for ISIS-APO(a)Rx inpatientswithhigh riskof cardiovascular disease andhigh
Lp(a) levels in2014.
ISIS-FVIIRx — ISIS-FVII Rx is an antisense drugwe designed to reduceFactorVII, a key component of the tissue factor
coagulationpathway, for the treatment or preventionof thrombotic diseases. Clinicians have linked elevated levels of FactorVII
activitywith poor prognosis in several thrombotic diseases, such as heart attacks, andwith cancer-associated thrombosis, which is the
second leading cause of death in cancer patients.
Inpreclinical studies, antisense inhibitionof FactorVII rapidly reducedFactorVII activitybymore than90percent in three
days, suggesting that physicians coulduse ISIS-FVIIRx in acute clinical settings, such as following surgery, toprevent patients from
developingharmful blood clots. In addition, we observedno increase inbleedingwith ISIS-FVIIRx, which is a common side effect of
currently available anti-thrombotic drugs. ISIS-FVIIRx is the seconddrug to enter development as part of our strategy to createmore
potent and safer anti-thrombotic drugs that donot increase bleeding.
We plan to complete our preclinical evaluationof ISIS-FVIIRx in2014.
ISIS-ANGPTL3Rx — ISIS-ANGPTL3Rx is an antisense drugwe designed to reduce angiopoietin-like 3protein, or
ANGPTL3, an independent risk factor for cardiovascular disease. ANGPTL3 is produced in the liver and regulates lipid, glucose and
energymetabolism. Humanswith elevated levels ofANGPTL3have hyperlipidemia that is associatedwith an increased riskof
premature heart attacks, increased arterial wall thickness aswell asmultiplemetabolic abnormalities, such as insulin resistance. In
contrast, humanswith lower levels ofANGPTL3have lower LDL-C and triglyceride levels and a lower riskof cardiovascular disease.
Inpreclinical studies, antisense inhibitionofANGPTL3 resulted in robust reductions ofmultiple lipidparameters, including total-
cholesterol, LDL-C and triglycerides.
We plan to initiate a Phase 1 study for ISIS-ANGPTL3Rx in2014with the potential to report data from this study in late 2014
or early2015.
MetabolicFranchise
Metabolic disorders are chronic diseases that affectmillions of people. There is still a significant need for new therapies for
these patients. According to theCenters forDiseaseControl andPrevention, diabetes affectsmore than 25millionpeople in the
UnitedStates, or eight percent of the population, with type 2diabetes constituting 90 to95percent of those cases.
Metabolic disease is a very large area ofmedical need and is another area inwhichwe focus our drugdiscovery efforts. Our
approach is todevelop antisense drugs that doctors can add to existing therapies to treat diabetes. One hurdle for traditional drug
development is thatmost traditional drugs cannot selectively target a disease-causingproteinwithout also affecting closely related
proteins, whichoften results in unwanted side effects.We designour antisense drugs to target the gene responsible for producing the
disease-causingproteinwhile avoidingunwanted effects on closely relatedproteins, thereby reducing the riskof side effects.
We nowhave three drugs inPhase 2 studies inour pipeline to treat type 2diabetes, eachofwhich acts upon targets in the
liver or fat tissue through a distinctmechanism to improve insulin sensitivity, reduce glucose production, or affect othermetabolic
aspects of this complex disease.
ISIS-GCGRRx — ISIS-GCGRRx is an antisense drug that targets the glucagon receptor, orGCGR, to reduce the effects of
glucagon. Glucagon is a hormone that opposes the actionof insulin and stimulates the liver toproduce glucose, particularly in type 2
diabetes. Inpatientswith advanceddiabetes, uncontrolledglucagon action leads to a significant increase inblood glucose levels.
Therefore, attenuatingglucagon action couldhave a significant glucose lowering effect inpatientswith severe diabetes. In addition,
reducingGCGRproducesmore active glucagon-like peptide, orGLP-1, a hormone that preserves pancreatic function and enhances
insulin secretion.
We are developing ISIS-GCGRRx tohelpprovide better glucose control for patientswith type 2diabetes. Inpreclinical
studies using themost insulin-resistantmodels of type 2diabetes, antisense reductionofGCGRdecreased excessive liver glucagon
action, produced robust glucose control, reduced levels of triglycerides andhelpedpreserve the pancreaswithout producing
hypoglycemia. Although researchers have developed and evaluated smallmolecule inhibitors ofGCGR andobservedglucose-
lowering effects, treatmentwith these smallmolecule inhibitors alsoproduced side effects, including increases in lipids andblood
pressure, limiting their potential use as drugs.