Isis Pharmaceuticals, Inc. Form 10K - page 19

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ISIS-GSK3Rx — ISIS-GSK3Rx is an antisense drugwe designed to anundisclosed target to treat a viral infection. ISIS-
GSK3Rx is the thirddrug to enter development under our collaborationwithGSK. We are eligible to receivemilestone payments from
GSK as ISIS-GSK3Rx advances indevelopment, andwe are responsible for developing the drugup toPhase 2proof-of-concept, at
which timeGSKhas the option topayus a license fee and license ISIS-GSK3Rx fromus. We are also eligible to receive double-digit
royalties on sales of ISIS-GSK3Rx.
We are currently evaluating ISIS-GSK3Rx in aPhase 1/2 study inhealthyvolunteers andpatients and expect to complete this
study in2014.
ISIS-GSK4Rx — ISIS-GSK4Rx is an antisense drugwe designed to anundisclosed target to treat anocular disease.We are
developing ISIS-GSK4Rx as part of our collaborationwithGSK.We are eligible to receivemilestone payments fromGSK as ISIS-
GSK4Rx advances indevelopment, andwe are responsible for developing the drugup toPhase 2proof-of-concept, atwhich timeGSK
has the option topay us a license fee and license ISIS-GSK4Rx fromus.We are also eligible to receive double-digit royalties on sales
of ISIS-GSK4Rx.
We plan to initiate preclinical studies to support an investigational newdrug application for ISIS-GSK4Rx in2014.
RG-101 —RG-101 is a preclinical drug that Regulus Therapeutics Inc., a companywe co-founded focusedonmicroRNA
therapeutics, is developing. Anoligonucleotide that inhibitsmicroRNA, RG-101 is an anti-miR that targetsmicroRNA-122, ormiR-
122. Researchers believe thatmiR-122 is essential for the replicationof hepatitisC virus, orHCV, suggesting that an anti-miR-122
drugmay reduceHCV infection and improveHCV-associated pathologies like fatty liver.
MicroRNAs are small RNAmolecules that donot encode proteins, but insteadwork as natural antisense sequences that
scientists believe regulate the expressionof approximatelyone-thirdof all human genes.
Regulus currentlyplans todevelopRG-101 as a key component of anHCV combination regimen for patientswhohave
failed, or are intolerant of, the current standardof care and for specific patient populations, such as patientswithHCV/HIV co-
infections. Regulus plans to initiate aPhase 1 study forRG-101 inhealthyvolunteers in2014.
RG-012 —RG-012 is a preclinical drug candidateRegulus is developing,which is an anti-miR that targetsmicroRNA-21, or
miR-21. Regulus reports that subcutaneous administration of RG-012 significantlydecreased the rate of renal fibrosis and increased
the lifespanofmice treatedwithRG-012up to 50percent in amousemodel ofAlport Syndrome. Alport Syndrome is a life-
threateningdisease inwhichpatients experience progressive loss of kidney function.
Regulus currentlyplans todevelopRG-012 toproof-of-concept. At that stage of development, Regulus’ partner Sanofi has
an exclusive option to license. We are eligible to receive a portionof allmilestone payments and royaltiesRegulus receives from
Sanofi if Sanofi chooses to exercise its option to licenseRG-012 fromRegulus andRG-012 advances indevelopment.
AntisenseTechnology
Our core technologyplatform can supportmultiple target-based antisense researchprogramswithout significantly increasing
costs.We candesignour antisense drugs to target a broad range of diseases, efficientlyproducing a proprietaryportfolioof drugs that
can interrupt the productionof disease-causingproteinswithout disruptingother proteins that are necessary for the body’s normal
functions.We are currentlypursuing antisense drugdiscoveryprograms focusedonvarious severe and rare, cardiovascular,
neurologic andmetabolic diseases and cancer.
Genes contain the informationnecessary toproduce proteins. Agene ismade upof nucleoside bases:Adenine, Thymine,
Guanine, andCytosine, commonlyknown asA, T, G andC, which are linked together to form a two-stranded structure that resembles
a twisted ladder, known as deoxyribonucleic acid, orDNA. The nucleotides onone side of the ladder bindweakly to complementary
nucleotides on the other strand according to specific rules; for example, ApairswithT andGpairswithC, creating the ladder’s rungs.
Scientists call this highly specific nucleotide pairinghybridization. The sequence or order of these nucleotides establishes the cell’s
recipes formakingproteins. Eachprotein’s instructions reside in a corresponding segment ofDNAknown as a gene.