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KYNAMRO is a novel, first-in-class, apo-B synthesis inhibitor for the reductionof LDL-C. It is a second-generation
antisense drugwe discovered and licensed toGenzyme in 2008. KYNAMRO acts bydecreasing the productionof apo-B. Apo-B
provides the structural core for atherogenic lipids, includingLDL-C, which carry cholesterol through the bloodstream. KYNAMRO
reducesLDL-C andother key atherogenic lipids linked to cardiovascular disease bypreventing their formation. Togetherwith
Genzyme, we completed the largest randomized, double-blind, placebo-controlled trial conducted todate inHoFHpatients. In this
multi-center trial, KYNAMRO significantly further reducedLDL-C and all othermeasured endpointswhen added to a treated
baseline. In this trial, four patients (11percent) treatedwithKYNAMROwithdrewdue to adverse events. Consistentwithother
studies evaluatingKYNAMRO, commonly observed adverse events includedmild tomoderate injection site reactions and flu-like
symptoms, aswell as elevations in liver transaminases.
FamilialHypercholesterolemia
Physicians diagnose patients as havingFH if theyhave veryhigh cholesterol, are at high cardiovascular risk and cannot
reduce their LDL-C sufficientlywith currently available lipid-lowering therapies. FH is a genetic disease that causes elevatedLDL-C
levels and familypatterns of premature heart disease andheart disease-related death. FHpatients have inherited abnormalities in liver
cells that are responsible for clearingLDLparticles from the blood. FH is autosomal dominant, whichmeans that all first-degree
relatives of FHpatients have a 50percent chance of having the disease aswell,making early detection through early screening
critically important. Patientswithuntreatedheterozygous FHhave a 50percentmortality rate by age 60.
HoFH is a severe formof FH. PeoplewithHoFHhave inheritedmutations that limit the body’s ability to clear cholesterol.
HoFH is extremely rare: it is believed tooccur inonlyone out of everyonemillion persons. Aswithother rare diseases, the true
prevalence ofHoFHmaybe underestimated because of inadequate data andunder-diagnosis. Today, it is estimated thatHoFH affects
about 6,000people globally. Medical literature includes different criteria formaking the diagnosis ofHoFH. There aremultiple
diagnostic criteria, whichmay include:
DNA evidence confirming the presence of specific genemutations associatedwith a genetic diagnosis ofHoFH. However,
DNA evidence is generallynot necessary for diagnosis andgenetic analysismaybe inconclusive;
Familyhistory, if known, of premature coronaryheart disease andhypercholesterolemia;
Presence of premature heart disease;
Elevatedplasma levels of total cholesterol andLDL-C;
Physical examination for signs of cholesterol deposits, includingxanthomas on the backs of hands, fingers, face andother
areas of the skin. Xanthomasmaynot be present in everypatient; and
Suboptimal response to lipid lowering therapy.
In addition to lipid-loweringmedications, current standard-of-care forHoFHpatients can include apheresis, a two to four
hour process administered two to four times amonth. Apheresismechanically removesLDL-C from the blood anduntil recently it
has been the primary therapy available on topofmaximally tolerated lipid-lowering therapy.
Clinical Development
In conjunctionwithGenzyme, we evaluatedKYNAMRO in aPhase 3 study inpatientswithHoFH. The randomized,
double-blind, placebo-controlled,multi-center study enrolled51HoFHpatients age 12 to53 years, including sevenpatients age12 to
16years, whoweremaintaining a regimen ofmaximally tolerated lipid-loweringmedications. TreatmentwithKYNAMRO further
reducedLDL-C levels by an average of 113mg/dL, or 25percent, from a treatedbaseline of 439mg/dL, and further reduced all
measured endpoints for atherogenic particles. InMarch2010, these datawere published inTheLancet byProfessorRaal of the
University of theWitwatersrand inSouthAfrica.
TogetherwithGenzymewe also conducted three additional Phase 3 studies inpatientswith severe hypercholesterolemia, in
patientswithheterozygous familial hypercholesterolemia, orHeFH, and inpatientswithhigh cholesterol at high risk for
cardiovascular disease. In all threePhase 3 studies, treatmentwithKYNAMRO loweredLDL-C and reducedother atherogenic lipids,
including apo-B, total cholesterol, non-HDL-C, and lipoprotein a, or Lp(a). These key lipids are generally accepted risk factors for
cardiovascular disease. Data from these studieswere published inCirculation, PLoSOne and the Journal of theAmericanCollege of
Cardiology.
Safety data forKYNAMRO are based onpooled results from the four Phase 3 studies noted abovewith a total of 390
patients. In these four Phase 3 studies, 261patients receivedweekly subcutaneous injections of 200mg ofKYNAMRO and 129
patients receivedplacebo for amedian treatment durationof 25weeks. Eighteenpercent of patients onKYNAMRO and twopercent
of patients onplacebodiscontinued treatment due to adverse reactions. Themost common adverse reactions inpatients treatedwith
KYNAMRO that led to treatment discontinuation andoccurred at a rate greater thanplacebowere: injection site reactions of five
percent, alanine aminotransferase increase of 3.4percent, flu-like symptoms of 2.7percent, aspartate aminotransferase increase of 2.3
percent and abnormal liver function test of 1.5percent.
