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KYNAMRO
In January2013, theFDA approved themarketing application forKYNAMRO in theUnitedStates for patientswithHoFH.
Genzyme has alsoobtainedmarketing approval inother countries, includingMexico, Argentina andSouthKorea, and is pursuing
marketing approval forKYNAMRO inother countries. Apheresis andmaximally tolerated lipid-lowering therapies, including statins,
have been the standardof care for homozygous FHpatients. Apheresis is a two to four hour process administered two to four times a
month thatmechanically separates LDL-C from the blood. Because apheresis is an invasive, time-consuming procedure conducted
only in specialty centers, it canbe difficult for patients to receive this treatment.
We believe that of the drugs that are indevelopment or on themarket, KYNAMRO’s closest competitor is lomitapide.
Lomitapide is a smallmolecule drug thatAegerionPharmaceuticals developed and commercialized to limit secretionof cholesterol
and triglycerides from the intestines and the liver. TheFDA andEuropeanMedicinesAgency, or EMA, have approved lomitapide as
anoral, once-a-day treatment for patientswithHoFH. TheFDA approval for lomitapide is supportedby a Phase 3 study in 29patients
withHoFH. Aegerion states that themost common adverse reactions in thePhase 3 studywere gastrointestinal, reportedby27of 29
patients, or 93%. In earlier studies evaluating lomitapide, patients discontinueduse of lomitapide at a high rate due togastrointestinal
adverse events, such as diarrhea, nausea andvomiting. In addition, some patients experienced elevations in liver enzymes and
increasedmean levels of fat in the liver, or hepatic fat, bothofwhichAegerion states it observed in its Phase 3 clinical trial of
lomitapide. LikeKYNAMRO, lomitapide is available only through aREMS program that restricts the access of lomitapide toonly
patientswith a clinical or laboratorydiagnosis consistentwithHoFH andboth theKYNAMRO and lomitapide labels contain aBoxed
Warning citing the riskof liver toxicity.
In our clinical experiencewithKYNAMRO, we have seen substantial reductions inLDL-C and reductions in other
atherogenic lipids linked to cardiovascular disease. Inour Phase 3 studies that evaluatedKYNAMRO inmore than250patients, the
most common adverse events patients observedwere injection site reactions and flu-like symptoms. We alsoobserved elevations in
liver transaminases andmoderatemedian increases in liver fat that appeared to be associatedwith greater reductions in apoB. We
believe that this safetyprofile supports our initialmarket opportunity in patientswho cannot currently reach their recommendedLDL-
C goal. KYNAMRO is administeredby injectiononceweekly at homewith a prefilled syringewhile patients take lomitapide orally
once daily. In addition, to avoidgastrointestinal events, patients on lomitapide are required tomaintain a low fat diet of less than 20%
fat andpatients are gradually titrated to amaximally tolerateddose. In the lomitapide label, concurrent use of lomitapide and common
medications forHoFHpatientswhohave cardiovascular disease, including simvastatin andwarfarin, need tobe closelymonitoreddue
to drug-drug interactionswith potentially harmful outcomes. KYNAMROhas no restrictionswith thesemedications, whichmaybe
advantageous forHoFHpatientswho are on a broad range of therapies due to the severityof their disease. KYNAMRO sales couldbe
affected ifKYNAMRO’s product profile is not advantageouswhen compared to anoral drug, as some patientsmayprefer the oral
drugoverKYNAMRO. Factors affecting a product’s profilemay include, efficacy, side effects, pricing and reimbursement.
Aegerionhas stated that it is charging in excess of $300,000 for lomitapide per patient per year, which is significantlyhigher
thanKYNAMRO. Our partner, Genzyme, has extensive experience inbringingmedicines topatientswith severe and rare diseases. In
theUnitedStates, Genzyme intends to capitalize on its existing sales andmarketing infrastructurewithin specializedmedical
communities. In addition, with an existingglobal commercial infrastructure in the cardiovascular community, we believe that Sanofi
and its global presencewill aid in the rapid expansion ofKYNAMRO intomarkets throughout theworld.
ISIS-TTR
Rx
InFebruary2013, we began aPhase 3 study evaluating ISIS-TTR
Rx
in patientswithFAP, a severe and rare disease. Patients
withFAPhave very limited therapeutic options and liver transplantation is themost common treatment used to reduce the production
of the plaque-causingprotein. Liver transplantation is a very complicated and expensivemedical procedure performedonly inmajor
medical centers. Patientswho receive a liver transplant are often required to take immunosuppressive drugs for the rest of their lives.
In addition, due to the previous accumulationof plaques innerve andheartmuscle, normal TTR protein from a normal liver can still
aggregate andprogress the disease.
We believe that of the drugs that are indevelopment or on themarket, ISIS-TTR
Rx
’s closest competitor is anoral drug,
tafamadis, which is onlymarketed inEurope under the brandnameVyndaqel. InMay2012, theFDA rejected tafamadis for use in the
UnitedStates stating that thePhase 3 studydata didnot show that tafamadis is effective in directly slowing the progressionof FAP.
We believe that basedon themechanismof our drug andour preclinical data, that ISIS-TTR
Rx
couldhave a significantlybetter
therapeutic profile than tafamadis andother drugs that are earlier indevelopment. Tafamadiswas designed to stabilize theTTR
tetramer structure andprohibit plaque formation. Another oral drug, diflunisal, has been shown to stabilize theTTR tetramer structure
and could alsooffer benefit topatientswithTTR amyloidosis. Diflunisal is anoral generic drug that is available in theUnitedStates
andEurope for use as a non-steroidal anti-inflammatory drug. Diflunisal was tested in aPhase 3 study inpatientswithFAP. In this
studymore thanhalf of the patients discontinued treatment and although a clinicallymeaningful change indisease progressionwas
