TheValueofPCSK9Inhibitors:AMatterofPerspective

DavidHuggar,PharmDMastersofPharmacotherapyCandidate

TheUniversityofTexasatAustinCollegeofPharmacyPharmacotherapyEducationandResearchCenter

UniversityofTexasHealthScienceCenteratSanAntonio

LearningObjectives1. Summarizetheepidemiologyandpathophysiologyofatheroscleroticcardiovascular

disease(ASCVD)2. SummarizerecommendationsforpreventionofASCVD3. ReviewthePCSK9inhibitordrugclass,includingrelevantclinicalandeconomicanalyses4. IdentifyappropriatepatientpopulationforPCSK9inhibitoruse

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CardiovascularDisease&Hyperlipidemia

1. AtheroscleroticCardiovasculardisease(ASCVD)a. AmericanCollegeofCardiology/AmericanHeartAssociation(ACC/AHA)definitionsinclude1,2:

i. Myocardialinfarction(MI)ii. Coronaryheartdisease(CHD)iii. Unstableangina

b. OveralldeathrateattributabletoASCVD3

i. 230deaths/100,000Americansperyearii. Morethan2,150AmericansdieofASCVDeachday;1deathevery40secondsiii. 34%ofASCVD-associateddeathsoccurbeforeageof75years

c. CostsofASCVD3,4

i. EstimatedannualcostsforASCVD(2011)—$320.1billionii. Projectedtoincreasetomorethan$818billionannuallyby2030iii. Averagehospitalcharge(in2012)

1. Cardiac/vascularsurgery—$78,8972. Cardiacrevascularization—$149,4803. Percutaneousintervention—$70,027

Table1:RiskfactorsofASCVD2Modifiable Non-Modifiable

Smoker AgeObesity(BMI>30kg/m2) FamilyhistoryofearlyCVDHypertension MalesexDiabetesmellitus Race(AfricanorAsianorigin)Hyperlipidemia

2. Hyperlipidemia(HLD)a. Cholesterolisanessentialcomponentoflife5

i. Buildingblockofcellmembranesii. Componentofsteroidhormonesynthesisiii. Requiredforproductionofbileacids

b. RoleinASCVD6

i. Circulatingcholesterolpenetratesandaccumulatesinarterialwalls1. Initiatesinflammatoryresponse2. Enhancesfoamcell/plaqueformationleadingtopartialorcompleteocclusion

ii. AtherosclerosisincreasesriskofCHD,stroke,andperipheralvasculardiseasec. Lipidstransportedthroughoutbodyascomplexeswithproteins5,6

i. Low-densitylipoproteins(LDL)1. ElevatedlevelsareassociatedwithincreasedriskofCVD2. TakenupbyliverviamembraneLDL-receptors3. LDLparticlesizeinfluencesatherogenicpotential

ii. High-densitylipoproteins(HDL)1. Removescholesterolfromperipheraltissueandtransportstoliverforexcretion2. LowserumconcentrationsassociatedwithincreasedriskofCVDevents

iii. Triglycerides(TGs)1. Serumlevelsstronglyinfluencedbyrecentdietaryintake2. UnclearroleinASCVDdevelopment

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Fig.1—Cholesterolsynthesispathways

EncyclopediaBritannica.www.britannica.com/science/cholesterol.2007.

Hyperlipidemia(HLD)continuedd. FamilialHypercholesterolemia(FH)7-12

i. Geneticdefectsthatresultinhypercholesterolemia1. Autosomaldominantinheritancepattern2. MostmutationsoccurintheLDL-receptorgene—onchromosome193. MutationstoApolipoproteinB(ApoB)accountfor~5%ofFHcases4. Mutationstoproproteinconvertasesubtilisintype-9(PCSK9)accountfor~1%ofFHcases

ii. HeterozygousFH(HeFH)1. AssociatedwithLDLlevels250-350mg/dL2. ~1:500peopleglobally;500,000-1,300,000casesinUS3. SevereHeFHassociatedwithsignificantlyincreasedriskofCVD

iii. HomozygousFH(HoFH)1. AssociatedwithLDLlevels>500mg/dL2. ~1:1,000,000peopleglobally;300-500diagnosedcasesinUS3. Highlevelsofplasmacholesteroloftenprevalentatbirth4. UntreatedpatientsoftenexperiencefirstmajorCVeventduringadolescence

iv. Clinicalpresentation1. Strongfamilyhistoryofelevatedcholesterollevelsorearlycardiovascularevents2. Cholesterollevelsresistanttotreatmentinparent(s)3. Xanthomas—cholesteroldepositsinskinortendons4. Xanthelasmas—cholesteroldepositsintheeyelids5. Elevatedlevelsofinflammatorymarkersreflectearlyatherogenesis6. CoronarycalcificationsignificantlymoreprominentinadolescentswithFH

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Hyperlipidemia(HLD)continuede. SupplementalpredictorsofCVrisk6,14-16

i. Apolipoprotein-B(ApoB)1. Primaryproteincomponent

ofnon-HDL2. Necessaryforlipidtransport

andLDLuptake3. Elevatedlevelsassociated

withincreasedriskofASCVDii. High-sensitivityC-reactiveprotein(hs-CRP)

1. Acutephasereactantusedtomeasureinflammation

2. ElevatedlevelsconsideredpredictiveoffutureCVDeventrisk

iii. Lipoprotein(a)1. Lipoprotein(a)transportslipidsand

reducesfibrinolysis2. Hasstructuralsimilaritiestoplasminogen3. Levelsaregeneticallydeterminedandremainrelativelyconstant

iv. Lipoprotein-associatedphospholipaseA21. Aninflammatoryenzymeassociatedwithatherosclerosis2. ElevatedlevelsshowntodoubleriskofCVevents3. Higherpredictivevaluewhenelevatedinconcertwithhs-CRP

v. Coronarycalciumscore1. Calciumdepositsinarterialwallsasresponsetoinflammation2. Calcificationstiffensarterialwallsandreduceselasticity3. SignificantlymoreprominentinadolescentswithFHthanthosewithout

Fig.3—TreatmentoptionsforHLD

Statins

•Atorvastatin•Fluvastatin•Lovastatin•Pravastatin•Rosuvastatin•Simvastatin

Niemann-PickInhibitor

•Ezetimibe

PCSK9Inhibitors

• Alirocumab• Evolocumab

FibricAcids

•Fenofibrate•Gemfibrozil

Fig.2—AHAFHDiagnosis13

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TreatmentGuidelines

Fig.4—AmericanCollegeofCardiology/AmericanHeartAssociationguidelinesfortheuseofstatintherapyinat-riskpatients17

Fig.5—NationalLipidAssociationguidelinesformanagementofhyperlipidemia2

3. Controversiessurroundinglipidgoalsa. ACC/AHA—treatment-drivenguidelines18,19

i. 4S—simvastatinreducesall-causemortalityinpatientswithpriorMIandhyperlipidemiaii. WOSCOPS—pravastatinreducedincidenceofMIanddeathinpatientswithmoderate

hyperlipidemiaandnohistoryofCVDb. NLA—LDLgoal-drivenguidelines20

i. PROVEIT-TIMI22—HigherdosestatinresultedinLDL<70mg/dLandbetteroutcomesc. Dearthofstudiescomparingtreatmentandgoal-drivenapproaches

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LDLGoal-DrivenTherapy

MurphySA,CannonCP,BlazingMA,etal.Reductionintotalcardiovasculareventswithezetimibe/simvastatinpost-acutecoronarysyndrome:TheIMPROVE-ITtrial.JAmColl

Cardiol.2016;67(4):353-61.Objective • ToidentifywhetheradditionalLDL-loweringaddingezetimibetostatintherapyis

clinicallybeneficialDesign • Multicenter,double-blind,randomizedcontrolledtrial

• n=18,144• Medianfollow-up:6years

InclusionCriteria

• Age≥50years• RecenthospitalizationforACS• LDL-C≥50mg/dL

ExclusionCriteria

• StrokeorTIA• Useofstatinmorepotentthansimvastatin40mg• UntreatedLDL≥125mg/dL,treatedLDL≥100mg/dL• PlannedCABGforACSevent

PrimaryOutcome

• Compositeof:CVmortality,majorCVevent,ornonfatalstroke

Interventions • Simvastatin40mg+ezetimibe10mgdaily,or• Simvastatin40mg+placebodaily

Results Primaryoutcome:• CompositeofCVmortality,majorCVevent,ornonfatalstroke:32.7%vs.34.7%[HR0.94;CI0.89-0.99;p=0.016]

Secondaryoutcomes:• Compositeofall-causemortality,majorCVevent,ornonfatalstroke:38.7%vs.40.3%[HR0.95;CI0.9-1.0;p=0.03]

• CompositeofCVmortality,nonfatalMI,urgentrevascularization:17.5%vs.18.9%[HR0.91;CI0.85-0.98;p=0.02]

• All-causemortality:15.3%vs.15.4%[HR0.99;CI0.91-1.07;p=0.78]• MortalityfromCVcauses,MI,orstroke:20.4%vs.22.2%[HR0.9;CI0.84-0.96;p=0.003]• Stroke:4.2%vs.4.8%[HR0.86;CI0.73-1.0;p=0.05]• MI:13.1%vs.14.8%[HR0.87;CI0.8-0.95;p=0.002]• LDLat1-yearfollow-up:53.2vs.69.9mg/dL(p<0.001)

Safety • Nodifferenceinpre-specifiedsafetyendpointsAuthor’sConclusion(s)

• Lipid-loweringtherapywithezetimibeplussimvastatinimprovedclinicaloutcomes,supportingintensivelipid-loweringtherapyafteraninitialCVevent.

ReviewerCritique

• Useofmoderate-intensitystatininhigh-riskpopulationisnotstandardofcare• LowerserumLDLassociatedwithsignificantdecreasesinMI,stroke,andCV-relatedmortality

• Establishesaroleforadditionofnon-statintherapyinhigh-riskpatients

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ProproteinConvertaseSubtilisin/KexinType-9(PCSK9)

4. PhysiologicfunctionofPCSK922a. DegradeshepaticLDLreceptorsb. FewerLDLreceptorsresultsinhigherserumLDLconcentrationsc. Sterolreceptorelementbindingproteins(SREBP-2s)regulatePCSK9andLDL-receptorproductiond. StatinsinduceproductionofPCSK9e. PCSK9functioncanbeinhibitedwithmonoclonalantibodies(mAbs)

i. Bindtheepidermalgrowthfactor-likeA(EGF-A)domainii. EGF-AisthecatalyticdomainwherePCSK9bindsandinitiatesLDL-Rdegradation

Fig.6—TheroleofPCSK9inlipidmetabolism

5. PCSK9roleinCVD

a. Gain-of-function(GOF)mutationstoPCSK9promoteLDL-receptordegradationandresultinhighserumLDLconcentrations,earlystrokeandMI22,23

i. ThreegenerationsofFrenchfamilywithGOFmutationhadserumLDLconcentrationsof466mg/dLb. Loss-of-function(LOF)mutationstoPCSK9inhibitLDL-receptorbreakdownandresultinlowserumLDL

concentrations22,24i. TwowomenwithLOFmutationsresultedinserumLDLconcentrationsmeasured~15mg/dLii. IncreasedratesofLOFmutationsinblacksfoundtoresultin28%lowerserumLDLconcentrations

andnearly90%lowerriskofCAD6. PCSK9Inhibitors25,26

a. Alirocumab(Praluent®)[Regeneron/Sanofi]—fullyhumanmAbapprovedJuly24th,2015i. 75mg,150mgsqinjectionevery2weeksii. AWP~$14,600/year

b. Evolocumab(Repatha™)[Amgen]—fullyhumanmAbapprovedAugust27th,2015i. 140mgsqinjectionevery2weeks,or420mgsqinjectionevery4weeksii. AWP~$14,100/year

c. Investigationali. RN316(bococizumab)[Pfizer]—humanizedmAbii. LY3015014[EliLilly]—fullyhumanmAb

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Fig.7—TimelineofPCSK9inhibitordiscoveryanddevelopment

GearingME.Apotentialnewweaponagainstheartdisease:PCSK9inhibitors.HarvardUniversity.2015.

7. Currentlitigationa. AmgencontendsRegeneron/Sanofiinfringedonevolocumabpatentsb. Regeneron/Sanofiarguethepatentswereinvalidc. UScourtsruledinfavorofAmgeninMarchd. Praluent™maybetakenoffthemarket

8. FDAapprovedindications25,26a. AdditionalloweringofLDLinpatientsunabletocontrolserumlevelswithcurrenttreatmentoptionsb. Asanadjuncttodietandmaximally-toleratedstatintherapyinselectpatientgroups

Table3:FDAapprovedindicationsforPCSK9inhibitorsDrug Adjunctive

therapyforHeFH

AdjunctivetherapyforHoFH

Adjunctivetherapyinpatientsw/clinicalASCVDrequiringadditionalLDL-lowering

Alirocumab √ √Evolocumab √ √ √

9. Safety25-27

a. Adverseeffects:i. Diarrhea,increasedserumtransaminases,injection-sitereactions,hypersensitivityreactions,

infection,myalgiaii. Neurocognitiveimpairment

1. 2ndmostcommonpatient-reportedadverseeffectofstatins2. Mechanismofdevelopmentisunclear,orevenrelatedtocholesterollevels

a. Decreasedratesofneuronalre-myelinationduetodecreasedcholesterolb. Decreasedcholesteroldeliverytoneuronscausingimpairedsynapticfiring

3. FDAhasmandatedfurtherassessmentinphaseIVstudies

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PreliminaryOutcomes

Title ODYSSEYLONGTERM27 OSLER28

OSLER-1 OSLER-2Objective • Toobtainlonger-termdataon

alirocumab’ssafetyandLDLcholesterolreduction

• Toobtainlonger-termdataonevolocumab’ssafety,side-effectprofile,andLDLcholesterolreduction

Design • Multicenter,double-blind,parallel-group,randomized,controlledtrial

• n=2,310• ITTanalysis

• Twoopen-label,randomized,controlledtrialso OSLER-1:PhaseIIo OSLER-2:PhaseIII

• Eachtrialcomposedof5-7smallertrials• n=4,465

InclusionCriteria • ≥18years• Highriskforcardiovascularevent:

o HeFHo CHDorriskequivalent

• LDL-C≥70mg/dL• Receivinghigh-dosestatintherapyormaxtolerated≥4weeks

• 18-80years• Highriskofcardiovascularevent• LDL75-189mg/dL• Stableonstatintherapy≥4weeks

ExclusionCriteria • LDL<70mg/dLorTG>400mg/dL• Recentorfutureplasmaexchange• ACS,stroke,orPVDinterventioninprevious3mos.

• NYHAclassIIIorIV• HoFH

• ClinicaldiagnosisofHoFH• Lipoproteinapheresisinpreceding4months• Malignancy• RecentMIorstroke• 10-YearFraminghamriskscore>10%

Interventions • Statin+alirocumab150mgsqQ2W• Statin+placebosqQ2W• Randomized2:1

• Standardtherapy+evolocumabo Evolocumab140mgQ2W,oro Evolocumab420mgQ4W

• Standardtherapy+placebo• Randomized2:1

MeanAge 60.4vs.60.6years 57.8vs.58.2yearsHxofCHD 68%vs.70% 19.8%vs.20.6%MedianTClevel 153vs.152mg/dL 202vs.205mg/dL

MedianLDLlevel 123vs.122mg/dL 120vs.121mg/dLPrimaryOutcomes • ChangeinLDL-Cfrombaselinetoweek24:

-74.2vs.-3.6mg/dL(p<0.001)• Incidenceofadverseevents:69.2%vs.64.8%(p=NR)

SecondaryOutcomes

• LDL-C<70mg/dL:79.3%vs.8.0%(p<0.001)• LDL-CΔfrombaseline-week78:-52.4mg/dLvs.+3.6mg/dL(p<0.001)

• Post-hocmajorCVevents:1.7%vs.3.3%(p=0.02)

• NonfatalMI:0.9%vs.2.3%(p=0.01)

• %changeinLDL-Cfrombaseline:61%(CI59-63%,p<0.001)

• LDL<70mg/dLat12weeks:73.6%vs.3.8%• Cardiovasculareventrates:0.95%vs.2.18%[HR0.47,CI0.28-0.78(p=0.003)]

AnyAE 81%vs82.5%(p=0.4) 69.2%vs.64.8%(p=NR)SeriousAE 18.7%vs.19.5%(p=0.66) 7.5%vs.7.5%(p=NR)Myalgia 5.4%vs.2.9%(p=0.006) 6.4%vs.6.0%(p=NR)NeurocognitiveAE 1.2%vs.0.5%(p=0.17) 0.9%vs.0.3%(p=NR)

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Pharmacoeconomics

10. Sowhat?30-32a. Americansspent~$310billiononallmedicationsin2015

i. $18.7billionspentoncholesterol-loweringmedicationsb. PCSK9inhibitorsprojectedtobethecostliestdrugclassever

i. Estimated$16B-$150billionadditionalspendannuallyintheUSc. Anestimated3in5bankruptciesareduetomedicalbillsd. Hospitalandhealth-systempharmaciestraditionallyviewedascost-centers

11. ACC/AHAeconomicanalysis33a. Publishedformalrecommendationsforinclusionofcostinassessingthevalueofcareb. Valueisdefinedasafunctionofresults(eg.safety,outcomes)andcostc. Summaryofimplementationrecommendations

i. Analysesshouldbeundertakenfromthesocietalperspectiveii. AnalysesshouldbelimitedtouseofdatarelevanttotheUnitedStatesorNorthAmericaiii. Thresholdsforvalueshouldincludeanupperandlowerboundaryiv. Performancemeasuresshouldconsidercostanalysesresults

12. Pharmacoeconomicanalysis34-38a. Subsetofoutcomesresearchintendedtoprovideobjectivemeasuresofvalueb. Valueisassumedfromtheperspectiveofeithersociety,payers,providers,orpatientsc. Fourbasictypesofanalysescomparecostsinputsofaproduct/servicewithoutcomes

Table3:PharmacoeconomicanalysesMethodology CostMeasurementUnit OutcomeMeasurementUnit

Cost-minimizationanalysis $orothermonetaryunit N/A;assumedequivalentCost-benefitanalysis $orothermonetaryunit $orothermonetaryunitCost-effectivenessanalysis $orothermonetaryunit AcommonnaturalunitCost-utilityanalysis $orothermonetaryunit Quality-adjustedlifeyear(QALY)or

otherutilityAnalysesshouldemployoneof:societal,payer,provider,orpatientperspective

Adaptedfrom:RascatiKL.Essentialsofpharmacoeconomics.2nded.Baltimore,MD.LippincottWilliams&Wilkins.2014.

d. Cost-effectivenessanalysis(CEA)i. Comparesrelativecostsandoutcomesof≥2products/servicesii. Cannotcompareproducts/serviceswithdifferentoutcomemeasuresiii. Doesnotaccountfordifferencesinside-effectprofiles

e. Cost-utilityanalysis(CUA)i. Comparesrelativecostsandutility-weightedoutcomesof≥2products/servicesii. Utilityweightsarea0.0(death)to1.0(perfecthealth)measureofoutcomepreferenceiii. Incorporatespatientorsocietalpreferencesintovaluemeasures

f. Measuringvaluei. Willingness-to-pay(WTP):Howmuchpeoplearewillingtopaytoreducethechanceofanadverse

healthoutcomeii. Incrementalcost-effectratio(ICER):(CostA–CostB)/(OutcomeA–OutcomeB)iii. Quality-adjustedlifeyears(QALYs):Outcomesinyearsoflifegained,adjustedforpatientpreferenceiv. Budgetaryimpact:theestimatedoverallcostofaddingaproducttotheformulary

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Pharmacoeconomicanalysiscontinued34-38

g. Historicvaluebenchmarksi. Regularlycited$50,000/QALYthresholdstemsfromacongressionalmandatethatdialysisbe

coveredforMedicarerecipientsii. TheWorldHealthOrganization(WHO)valuesQALYsat3xGDPpercapita

h. Recentvaluebenchmarksi. NewtreatmentoptionsforhepatitisCwereevaluatedashigh-to-reasonablevalueat

≤$20,000/QALYii. Meta-analysesofcurrentdialysisvaluereportsICERsbetween$65,496-$488,360perQALY

EconomicLiterature

TiceJA,OllendorfDA,CunninghamC,PearsonSD,KaziDS,etal.PCSK9inhibitorsfortreatmentofhighcholesterol:effectiveness,valueandvaluebasedpricebenchmarks.ICERNovember2015.

Purpose • ToevaluatethecomparativeclinicaleffectivenessandcomparativevalueofPCSK9inhibitorsasaclassforpatientswithelevatedLDL

Design • Cost-utilityanalysiso Carevalueo Budgetaryimpact

ScenariosModeled

• Familialhypercholesterolemia(FH)• ClinicalCVD—secondaryprevention

o Statin-intolerant(assumed10%)o Statin-tolerant,notatLDLgoal(<70mg/dL)

• Willingness-to-paythresholdso $50,000/QALYo $100,000/QALYo $150,000/QALY

PopulationsModeled

Outcomes • Costperquality-adjustedlife-year(QALY)Methods • UsedCVDpolicymodel

o EntireUSadultpopulationage35-74yearsin2015o Assumedhealthsystemperspectiveforbothanalyses

• Definedfamilialhypercholesterolemiaas:o LDL>250mg/dLwithoutstatinuseo LDL≥200mg/dLwithstatinuse

• Stratified10%ofthepopulationwithhistoryofCVDtomodelstatin-intolerance• Appliedlifetimehorizonof95-yearsold• Discountedfuturecostsandbenefitsby3%eachsuccessiveyear

Assumptions • Costsfromthehealthsystemperspective• DrugeffectsonoutcomesaredirectlyproportionaltodegreeofLDLreduction

Abletotoleratestatin?

Yes-Treatmentwithstatinalone-Treatmentwithstatinplusezetimibe-TreatmentwithastatinplusPCSK9inhibitor

No-Notreatment-Treatmentwithezetimibealone-TreatmentwithaPCSK9inhibitor

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• PCSK9inhibitorshavenoeffectonriskofstroke• Tenpercentofpersonsexposedtostatinsareintolerant• Ageandsexspecificcostswereextrapolatedfromnationaldata• Annualcostbasedonwholesaleacquisitioncost

o Ezetimibe—$2,828/yro PCSK9inhibitors(class)—$14,350/yr

• ~2.6millionpersonswouldreceiveaPCSK9inhibitorinthefollowing5years• Budgetimpactthresholdis$904million

Results Value-basedpricebenchmarksforPCSK9inhibitortherapy

Population CareValuePrice:$100K/QALY

CareValuePrice:$150K/QALY

MaxPriceatPotentialBudgetImpactThreshold

Value-BasedPriceBenchmark

FH(n=453,443) $5,700/yr $8,000/yr $10,278/yr $5,700-$8,000/yrCVDstatin-intolerant(n=364,948)

$5,800/yr $8,300/yr $12,896/yr $5,800-$8,300/yr

CVDnotatLDLgoal(n=1,817,788)

$5,300/yr $7,600/yr $2,976/yr $2,976/yr

Total(n=2,636,179)

$5,404/yr $7,735/yr $2,177/yr $2,177/yr

FH:familialhypercholesterolemia;CVD:cardiovasculardisease;LDL:low-densitylipoprotein;QALY:quality-adjustedlifeyearAuthor’sdiscussion

• PCSK9inhibitorsmaysubstantiallyreducenon-fatalMIs,non-fatalstrokes,andcardiovasculardeathoveralifetime

• PCSK9inhibitorsgeneratedICERsthatexceedcommonly-acceptedthresholds• An85%reductioninlistpricewouldbenecessarytoavoidaddingexcessivecostburdenstothe

healthcaresystemReviewer’scritique

• CVDmodelnotapplicabletopatients<35yearsold• FHdiagnosisnotin-linewithcurrentrecommendationsfordiagnosis• UsedhistoricLDLtreatmentgoalvaluesnolongerstandardofcare• Tenpercentstatinintolerancerateisanoverestimation• Outcomeeventreductiondoesnotreflectresultsfromrecentstudies• DrugeffectsonCVDwerebasedonLDLreductionalone• Sensitivityanalysesofbasecasesconsistentlysensitivetolowerpriceandlongeranalysishorizon• Usedarbitrarybudgetimpactthresholdthatdoesnotreflectrealworldpolicy

13. ICERreportsummary39

a. ICERmodeledPCSK9useinstatintolerantandintolerantpatientsi. Comparedtoezetimibeuseii. Baselinestatinuse

b. Utilizedacost-benefitanalysistocomparevalueofezetimibeandPCSK9inhibitorsasadd-ontherapiesc. ICERfindsPCSK9inhibitorsonlyviableastreatmentoptionswithoutrestrictionatapriceof$2,177—aprice

lessthanthecurrentAWPofezetimibed. Findingsarebasedonquestionablemodelingofpopulationandeventratese. Costsmisspotentiallysignificanteventsavoided

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Conclusion14. Clinicalsummary40,41

a. PCSK9inhibitorssignificantlydecreaseserumLDLcholesteroli. EvolocumabdecreasedLDLby~61%at48-weeksii. AlirocumabdecreasedLDLby61%at24weeks,and58%at78weeks

b. LDLcholesterollevelsbelow70mg/dLmayresultinfurtherimprovedCVDoutcomesi. MeanabsoluteLDLlevelwas48mg/dLat24weeksoftherapyinODYSSEY

c. Interimanalysesindicateadditional48-53%eventreductionwhenaddedtostatintherapyd. Studiesofsafetyconcludeneitherdrugpossessesasignificantadverseeffectprofile

i. Similarratesofadverseeventsleadingtodiscontinuationwereobservedbetweenalirocumabandplacebo,respectively:

ii. SlightlyhigherratesofneurocognitiveeventswithPCSK9inhibitorscomparedtoplacebo(notstatisticallysignificant)

e. Interimoutcomesanalysestrendingtowardssignificanteventreduction

15. Costsummary39a. PCSK9inhibitorsprojectedtobecostliestdrugclassinhistoryatcurrentaveragewholesaleprices(AWPs)

i. PraluentAWP:$14,600/yearii. RepathaAWP:$14,100/year

b. ICERfindings:i. ICERsatlistpricerangefrom$274,00-$302,00perQALYformodeledpopulationsii. Limitingusetoonlypost-MIpatientsstillresultsincosts>$150,000/QALYiii. ConcludedclassisviableatalowerpricethancurrentAWPforZetia®iv. Markedflawsinmodelingandcostassumptions

c. Emergingpay-for-performancedealscompensatepayersforunmetclinicaloutcomes

16. Clinicalrecommendationsa. Reserveasadd-onagentsinpatientswithgenetically-confirmedFHafterinitiatingstatintherapy

i. PrimarypreventioninpatientswithHoFHii. Primarypreventioninpatientswithhigher-riskHeFHiii. SecondarypreventioninmostpatientswithHeFH

b. Reserveasadd-onagentsforsecondarypreventioninhigh-riskpatientswithoutFHc. Keepawatchfuleyeonoutcomesdatalikelytobemadeavailableby2017

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AppendixAppendix1:Selectstudiesassessingstatin-inducedLDL-loweringandCVDoutcomes18-20,45-53

Trial N Intervention MeanbaselineLDL(mg/dL)

MeanLDLreduction

CVDeventreductionrate

NNT

Placebocontrolled4S(1994) 4444 Simvastatin20mg 188 35% 34%(p<0.0001) 15WOSCOPS(1996) 6595 Pravastatin40mg 192 26% 31%(p<0.001) 42AFCAPS/TEXCAPS(1998)

6605 Lovastatin20-40mg 150 25% 37%(p<0.001) 24

MIRACL(2001) 3086 Atorvastatin80mg 124 58% 16%(p=0.048) 39ALLHAT-LLT(2002) 3638 Pravastatin40mg 146 28% 9%(p<0.96) 43HPS(2002) 20536 Simvastatin40mg 131 30% 23%(p<0.0001) 19CARDS(2004) 2838 Atorvastatin10mg 117 40% 37%(p<0.001) 24ASPEN(2006) 2410 Atorvastatin10mg 113 30% 10%(NS) 4MEGA(2006) 8214 Pravastatin10-20mg 157 18% 33%(p=0.01) 6SPARCL(2006) 4731 Atorvastatin80mg 133 42% 26%(p<0.001) 15JUPITER(2008) 17802 Rosuvastatin20mg 108 50% 44%(p<0.00001) 82StatincomparativeefficacyPROVEIT-TIMI22(2004)

4162 Atorvastatin40mgvs.pravastatin40mg

106vs.106 95vs62mg/dL

16%(p<0.005) 2

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