Isis Pharmaceuticals, Inc. Form 10K - page 11

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ISIS-PKKRx — ISIS-PKKRx is an antisense drugwe designed toprevent hereditary angioedema, orHAE, attacks. ISIS-
PKKRx inhibits the productionof prekallikren, or PKK, a proteinproduced in the liver that plays an important role in the activationof
inflammatorymediators associatedwith acute attacks ofHAE. HAE is a rare genetic disease that is characterized by rapid andpainful
attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea. HAE affects approximately 20,000patients in the
UnitedStates andEurope and canbe fatal if swellingoccurs in the larynx. Inpatientswith frequent or severe attacks, doctorsmay use
prophylactic treatment approaches toprevent and reduce the severity ofHAE attacks.However, current prophylactic treatment
approaches are very limited and havemajor tolerability issues due to challenging administration requirements leavingpatientswith
few therapeutic options. By inhibiting the productionof PKK, ISIS-PKKRx couldbe an effective prophylactic approach topreventing
HAE attacks.
In 2014, we plan to initiate aPhase 1/2 clinical study evaluating ISIS-PKKRx inhealthyvolunteers and in patientswith
hereditary angioedema. We plan to report data from this study in late 2014or early2015.
ISIS-DMPKRx — ISIS-DMPK Rx is an antisense drugwe designed to correct the underlyinggenetic defect that causes
MyotonicDystrophyType 1, orDM1. DM1 is themost common formofmuscular dystrophy in adults. It is causedby a genetic defect
in the dystrophiamyotonica-proteinkinase, orDMPK, gene inwhich a sequence of three nucleotides, CTG, repeats extensively. This
DNA expansionproduces an abnormally large toxicRNA that accumulates in cells, includingmuscle cells, andprevents productionof
proteins essential for normal cellular function. In addition todisablingmuscle spasms andprogressivemusclewasting andweakness,
DM1 also affectsmanyother organswithin the body. PatientswithDM1 can experience insulin insensitivity, cataracts and infertility.
DM1 is estimated to affect approximately150,000patients in theUnitedStates, Europe and Japan. The severity and age of onset of
DM1 correlateswith the number of times the three nucleotides repeat, which increases fromone generation to the next. Currently,
there are nodisease-modifying therapies for patientswithDM1 and treatments are intendedonly tomanage symptoms.
In2012, we andBiogen Idec entered into an alliance that providesBiogen Idec anoption todevelop and commercialize
ISIS-DMPKRx. Under the agreement, we received anupfront fee and are responsible for developing ISIS-DMPKRx. Biogen Idec has
the option to license ISIS-DMPKRx up through completionof thePhase 2 study.Wewill receivemilestone payments fromBiogen
Idec as ISIS-DMPK Rx advances throughdevelopment.
ISIS-DMPKRx targetsDMPK to reduce the toxicRNA in the cells. Inpreclinical studies, we showed that an antisense
compound targeting theDMPKmessenger RNA, ormRNA, enteredmuscle cells and significantly reduced the toxicRNA. Effective
reductionof toxicRNA led to a reversal of the disease symptoms that was sustained for up to one year after treatment in amouse
model ofDM1. By removing toxicRNA, ISIS-DMPKRx couldbe an effective approach to treatingpatientswithDM1.
In 2014, we plan to initiate aPhase 1/2 clinical study evaluating ISIS-DMPKRx inhealthyvolunteers and inpatientswith
DM1.
CardiovascularFranchise
Cardiovascular disease is the leading cause of death in theUnitedStates. A common cause of cardiovascular disease is
atherosclerosis, or premature plaque buildup, whichoccurswhen cholesterol and inflammatory cells accumulate in bloodvessels.
Researchers have shown a strong correlationbetweenhigh cholesterol levels and subsequent cardiovascular diseases. As such,
lowering cholesterol is a key component inpreventing andmanaging cardiovascular disease.
Cardiovascular disease is an area of focus for us. We have created a cardiovascular disease franchise comprised of drugs that
target all the key components of cardiovascular disease, includingvarious atherogenic lipids, inflammation and thrombosis, an
aberrant blood clot formation responsible formost heart attacks and strokes. For example, we are developing a drug that lowers apoC-
III and triglycerides, which are both independent risk factors for cardiovascular disease. A recent addition toour cardiovascular
franchise is our drug that lowers Lp(a), another independent risk factor for cardiovascular disease. Currently available lipid-lowering
therapies donot significantly lower apoC-III, triglycerides, or Lp(a).We believe that targeting apoC-III andLp(a) couldprovide a
complementary approach to lipid-lowering therapies, includingKYNAMRO.
ISIS-APOCIIIRx — ISIS-APOCIIIRx is an antisense drugwe designed to reduce apoC-III proteinproduction and lower
triglycerides. In2014, we plan to initiate aPhase 3program that will include evaluating ISIS-APOCIIIRx in patientswithFCS and in
patientswith severelyhigh triglyceride levels of greater than880mg/dL. Formore information on ISIS-APOCIIIRx, please refer to
the ISIS-APOCIIIRx sectionunder the subheading “Severe andRareDisease Franchise”.