The Value of PCSK9 Inhibitors: A Matter of Perspective

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The Value of PCSK9 Inhibitors: A Matter of Perspective
TheValueofPCSK9Inhibitors:
AMatterofPerspective
DavidHuggar,PharmD
MastersofPharmacotherapyCandidate
TheUniversityofTexasatAustinCollegeofPharmacy
PharmacotherapyEducationandResearchCenter
UniversityofTexasHealthScienceCenteratSanAntonio
LearningObjectives
1. Summarizetheepidemiologyandpathophysiologyofatheroscleroticcardiovascular
disease(ASCVD)
2. SummarizerecommendationsforpreventionofASCVD
3. ReviewthePCSK9inhibitordrugclass,includingrelevantclinicalandeconomicanalyses
4. IdentifyappropriatepatientpopulationforPCSK9inhibitoruse
CardiovascularDisease&Hyperlipidemia
1.
AtheroscleroticCardiovasculardisease(ASCVD)
a. AmericanCollegeofCardiology/AmericanHeartAssociation(ACC/AHA)definitionsinclude1,2:
i. Myocardialinfarction(MI)
ii. Coronaryheartdisease(CHD)
iii. Unstableangina
b. OveralldeathrateattributabletoASCVD3
i. 230deaths/100,000Americansperyear
ii. Morethan2,150AmericansdieofASCVDeachday;1deathevery40seconds
iii. 34%ofASCVD-associateddeathsoccurbeforeageof75years
c. CostsofASCVD3,4
i. EstimatedannualcostsforASCVD(2011)—$320.1billion
ii. Projectedtoincreasetomorethan$818billionannuallyby2030
iii. Averagehospitalcharge(in2012)
1. Cardiac/vascularsurgery—$78,897
2. Cardiacrevascularization—$149,480
3. Percutaneousintervention—$70,027
Table1:RiskfactorsofASCVD2
Modifiable
Smoker
Obesity(BMI>30kg/m2)
Hypertension
Diabetesmellitus
Non-Modifiable
Age
FamilyhistoryofearlyCVD
Malesex
Race(AfricanorAsianorigin)
Hyperlipidemia
2.
Hyperlipidemia(HLD)
a. Cholesterolisanessentialcomponentoflife5
i. Buildingblockofcellmembranes
ii. Componentofsteroidhormonesynthesis
iii. Requiredforproductionofbileacids
b. RoleinASCVD6
i. Circulatingcholesterolpenetratesandaccumulatesinarterialwalls
1. Initiatesinflammatoryresponse
2. Enhancesfoamcell/plaqueformationleadingtopartialorcompleteocclusion
ii. AtherosclerosisincreasesriskofCHD,stroke,andperipheralvasculardisease
c. Lipidstransportedthroughoutbodyascomplexeswithproteins5,6
i. Low-densitylipoproteins(LDL)
1. ElevatedlevelsareassociatedwithincreasedriskofCVD
2. TakenupbyliverviamembraneLDL-receptors
3. LDLparticlesizeinfluencesatherogenicpotential
ii. High-densitylipoproteins(HDL)
1. Removescholesterolfromperipheraltissueandtransportstoliverforexcretion
2. LowserumconcentrationsassociatedwithincreasedriskofCVDevents
iii. Triglycerides(TGs)
1. Serumlevelsstronglyinfluencedbyrecentdietaryintake
2. UnclearroleinASCVDdevelopment
Huggar|2
Fig.1—Cholesterolsynthesispathways
EncyclopediaBritannica.www.britannica.com/science/cholesterol.2007.
Hyperlipidemia(HLD)continued
d. FamilialHypercholesterolemia(FH)7-12
i. Geneticdefectsthatresultinhypercholesterolemia
1. Autosomaldominantinheritancepattern
2. MostmutationsoccurintheLDL-receptorgene—onchromosome19
3. MutationstoApolipoproteinB(ApoB)accountfor~5%ofFHcases
4. Mutationstoproproteinconvertasesubtilisintype-9(PCSK9)accountfor~1%ofFHcases
ii. HeterozygousFH(HeFH)
1. AssociatedwithLDLlevels250-350mg/dL
2. ~1:500peopleglobally;500,000-1,300,000casesinUS
3. SevereHeFHassociatedwithsignificantlyincreasedriskofCVD
iii. HomozygousFH(HoFH)
1. AssociatedwithLDLlevels>500mg/dL
2. ~1:1,000,000peopleglobally;300-500diagnosedcasesinUS
3. Highlevelsofplasmacholesteroloftenprevalentatbirth
4. UntreatedpatientsoftenexperiencefirstmajorCVeventduringadolescence
iv. Clinicalpresentation
1. Strongfamilyhistoryofelevatedcholesterollevelsorearlycardiovascularevents
2. Cholesterollevelsresistanttotreatmentinparent(s)
3. Xanthomas—cholesteroldepositsinskinortendons
4. Xanthelasmas—cholesteroldepositsintheeyelids
5. Elevatedlevelsofinflammatorymarkersreflectearlyatherogenesis
6. CoronarycalcificationsignificantlymoreprominentinadolescentswithFH
Huggar|3
Hyperlipidemia(HLD)continued
e. SupplementalpredictorsofCVrisk6,14-16
Fig.2—AHAFHDiagnosis13
i. Apolipoprotein-B(ApoB)
1. Primaryproteincomponent
ofnon-HDL
2. Necessaryforlipidtransport
andLDLuptake
3. Elevatedlevelsassociated
withincreasedriskofASCVD
ii. High-sensitivityC-reactiveprotein(hs-CRP)
1. Acutephasereactantusedtomeasure
inflammation
2. Elevatedlevelsconsideredpredictiveof
futureCVDeventrisk
iii. Lipoprotein(a)
1. Lipoprotein(a)transportslipidsand
reducesfibrinolysis
2. Hasstructuralsimilaritiestoplasminogen
3. Levelsaregeneticallydeterminedandremainrelativelyconstant
iv. Lipoprotein-associatedphospholipaseA2
1. Aninflammatoryenzymeassociatedwithatherosclerosis
2. ElevatedlevelsshowntodoubleriskofCVevents
3. Higherpredictivevaluewhenelevatedinconcertwithhs-CRP
v. Coronarycalciumscore
1. Calciumdepositsinarterialwallsasresponsetoinflammation
2. Calcificationstiffensarterialwallsandreduceselasticity
3. SignificantlymoreprominentinadolescentswithFHthanthosewithout
Fig.3—TreatmentoptionsforHLD
Statins
•Atorvastatin
•Fluvastatin
•Lovastatin
•Pravastatin
•Rosuvastatin
•Simvastatin
Niemann-Pick
Inhibitor
PCSK9
Inhibitors
•Ezetimibe
• Alirocumab
• Evolocumab
•Fenofibrate
•Gemfibrozil
FibricAcids
Huggar|4
TreatmentGuidelines Fig.4—AmericanCollegeofCardiology/AmericanHeartAssociationguidelinesfortheuseof
statintherapyinat-riskpatients17
Fig.5—NationalLipidAssociationguidelinesformanagementofhyperlipidemia2
3.
Controversiessurroundinglipidgoals
a. ACC/AHA—treatment-drivenguidelines18,19
i. 4S—simvastatinreducesall-causemortalityinpatientswithpriorMIandhyperlipidemia
ii. WOSCOPS—pravastatinreducedincidenceofMIanddeathinpatientswithmoderate
hyperlipidemiaandnohistoryofCVD
b. NLA—LDLgoal-drivenguidelines20
i. PROVEIT-TIMI22—HigherdosestatinresultedinLDL<70mg/dLandbetteroutcomes
c. Dearthofstudiescomparingtreatmentandgoal-drivenapproaches
Huggar|5
LDLGoal-DrivenTherapy MurphySA,CannonCP,BlazingMA,etal.Reductionintotalcardiovascularevents
withezetimibe/simvastatinpost-acutecoronarysyndrome:TheIMPROVE-ITtrial.JAmColl
Cardiol.2016;67(4):353-61.
Objective
Design
Inclusion
Criteria
Exclusion
Criteria
Primary
Outcome
Interventions
Results
Safety
Author’s
Conclusion(s)
Reviewer
Critique
• ToidentifywhetheradditionalLDL-loweringaddingezetimibetostatintherapyis
clinicallybeneficial
• Multicenter,double-blind,randomizedcontrolledtrial
• n=18,144
• Medianfollow-up:6years
• Age≥50years
• RecenthospitalizationforACS
• LDL-C≥50mg/dL
• StrokeorTIA
• Useofstatinmorepotentthansimvastatin40mg
• UntreatedLDL≥125mg/dL,treatedLDL≥100mg/dL
• PlannedCABGforACSevent
• Compositeof:CVmortality,majorCVevent,ornonfatalstroke
• Simvastatin40mg+ezetimibe10mgdaily,or
• Simvastatin40mg+placebodaily
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%[HR
0.91;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)
• Nodifferenceinpre-specifiedsafetyendpoints
• Lipid-loweringtherapywithezetimibeplussimvastatinimprovedclinicaloutcomes,
supportingintensivelipid-loweringtherapyafteraninitialCVevent.
• Useofmoderate-intensitystatininhigh-riskpopulationisnotstandardofcare
• LowerserumLDLassociatedwithsignificantdecreasesinMI,stroke,andCV-related
mortality
• Establishesaroleforadditionofnon-statintherapyinhigh-riskpatients
Huggar|6
ProproteinConvertaseSubtilisin/KexinType-9(PCSK9)
4.
PhysiologicfunctionofPCSK922
a. DegradeshepaticLDLreceptors
b. FewerLDLreceptorsresultsinhigherserumLDLconcentrations
c. Sterolreceptorelementbindingproteins(SREBP-2s)regulatePCSK9andLDL-receptorproduction
d. StatinsinduceproductionofPCSK9
e. PCSK9functioncanbeinhibitedwithmonoclonalantibodies(mAbs)
i. Bindtheepidermalgrowthfactor-likeA(EGF-A)domain
ii. EGF-AisthecatalyticdomainwherePCSK9bindsandinitiatesLDL-Rdegradation
Fig.6—TheroleofPCSK9inlipidmetabolism
5.
6.
PCSK9roleinCVD
a. Gain-of-function(GOF)mutationstoPCSK9promoteLDL-receptordegradationandresultinhighserumLDL
concentrations,earlystrokeandMI22,23
i. ThreegenerationsofFrenchfamilywithGOFmutationhadserumLDLconcentrationsof466mg/dL
b. Loss-of-function(LOF)mutationstoPCSK9inhibitLDL-receptorbreakdownandresultinlowserumLDL
concentrations22,24
i. TwowomenwithLOFmutationsresultedinserumLDLconcentrationsmeasured~15mg/dL
ii. IncreasedratesofLOFmutationsinblacksfoundtoresultin28%lowerserumLDLconcentrations
andnearly90%lowerriskofCAD
PCSK9Inhibitors25,26
a. Alirocumab(Praluent®)[Regeneron/Sanofi]—fullyhumanmAbapprovedJuly24th,2015
i. 75mg,150mgsqinjectionevery2weeks
ii. AWP~$14,600/year
b. Evolocumab(Repatha™)[Amgen]—fullyhumanmAbapprovedAugust27th,2015
i. 140mgsqinjectionevery2weeks,or420mgsqinjectionevery4weeks
ii. AWP~$14,100/year
c. Investigational
i. RN316(bococizumab)[Pfizer]—humanizedmAb
ii. LY3015014[EliLilly]—fullyhumanmAb
Huggar|7
Fig.7—TimelineofPCSK9inhibitordiscoveryanddevelopment
GearingME.Apotentialnewweaponagainstheartdisease:PCSK9inhibitors.HarvardUniversity.2015.
7.
Currentlitigation
a. AmgencontendsRegeneron/Sanofiinfringedonevolocumabpatents
b. Regeneron/Sanofiarguethepatentswereinvalid
c. UScourtsruledinfavorofAmgeninMarch
d. Praluent™maybetakenoffthemarket
8.
FDAapprovedindications25,26
a. AdditionalloweringofLDLinpatientsunabletocontrolserumlevelswithcurrenttreatmentoptions
b. Asanadjuncttodietandmaximally-toleratedstatintherapyinselectpatientgroups
Table3:FDAapprovedindicationsforPCSK9inhibitors
Drug
9.
Adjunctive Adjunctive
therapyfor therapy
HeFH
forHoFH
Alirocumab
√
Evolocumab
√
Adjunctivetherapyinpatients
w/clinicalASCVDrequiring
additionalLDL-lowering
√
√
√
Safety25-27
a. Adverseeffects:
i. Diarrhea,increasedserumtransaminases,injection-sitereactions,hypersensitivityreactions,
infection,myalgia
ii. Neurocognitiveimpairment
1. 2ndmostcommonpatient-reportedadverseeffectofstatins
2. Mechanismofdevelopmentisunclear,orevenrelatedtocholesterollevels
a. Decreasedratesofneuronalre-myelinationduetodecreasedcholesterol
b. Decreasedcholesteroldeliverytoneuronscausingimpairedsynapticfiring
3. FDAhasmandatedfurtherassessmentinphaseIVstudies
Huggar|8
PreliminaryOutcomes
Title
OSLER28
ODYSSEYLONGTERM27
Objective
Design
InclusionCriteria
ExclusionCriteria
Interventions
MeanAge
HxofCHD
MedianTClevel
• Toobtainlonger-termdataon
alirocumab’ssafetyandLDLcholesterol
reduction
• Multicenter,double-blind,parallel-group,
randomized,controlledtrial
• n=2,310
• ITTanalysis
• ≥18years
• Highriskforcardiovascularevent:
o HeFH
o CHDorriskequivalent
• LDL-C≥70mg/dL
• Receivinghigh-dosestatintherapyormax
tolerated≥4weeks
• LDL<70mg/dLorTG>400mg/dL
• Recentorfutureplasmaexchange
• ACS,stroke,orPVDinterventionin
previous3mos.
• NYHAclassIIIorIV
• HoFH
• Statin+alirocumab150mgsqQ2W
• Statin+placebosqQ2W
• Randomized2:1
60.4vs.60.6years
68%vs.70%
153vs.152mg/dL
MedianLDLlevel
123vs.122mg/dL
PrimaryOutcomes • ChangeinLDL-Cfrombaselinetoweek24:
-74.2vs.-3.6mg/dL(p<0.001)
Secondary
• LDL-C<70mg/dL:79.3%vs.8.0%(p<0.001)
Outcomes
• 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)
AnyAE
81%vs82.5%(p=0.4)
SeriousAE
18.7%vs.19.5%(p=0.66)
Myalgia
5.4%vs.2.9%(p=0.006)
NeurocognitiveAE
1.2%vs.0.5%(p=0.17)
•
•
•
•
•
•
OSLER-1
OSLER-2
Toobtainlonger-termdataonevolocumab’s
safety,side-effectprofile,andLDLcholesterol
reduction
Twoopen-label,randomized,controlledtrials
o OSLER-1:PhaseII
o OSLER-2:PhaseIII
Eachtrialcomposedof5-7smallertrials
n=4,465
18-80years
Highriskofcardiovascularevent
LDL75-189mg/dL
Stableonstatintherapy≥4weeks
•
•
•
•
•
ClinicaldiagnosisofHoFH
Lipoproteinapheresisinpreceding4months
Malignancy
RecentMIorstroke
10-YearFraminghamriskscore>10%
•
•
• Standardtherapy+evolocumab
o Evolocumab140mgQ2W,or
o Evolocumab420mgQ4W
• Standardtherapy+placebo
• Randomized2:1
57.8vs.58.2years
19.8%vs.20.6%
202vs.205mg/dL
•
•
•
•
120vs.121mg/dL
Incidenceofadverseevents:69.2%vs.64.8%
(p=NR)
%changeinLDL-Cfrombaseline:61%(CI5963%,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)]
69.2%vs.64.8%(p=NR)
7.5%vs.7.5%(p=NR)
6.4%vs.6.0%(p=NR)
0.9%vs.0.3%(p=NR)
Huggar|9
Pharmacoeconomics
10. Sowhat?30-32
a. Americansspent~$310billiononallmedicationsin2015
i. $18.7billionspentoncholesterol-loweringmedications
b. PCSK9inhibitorsprojectedtobethecostliestdrugclassever
i. Estimated$16B-$150billionadditionalspendannuallyintheUS
c. Anestimated3in5bankruptciesareduetomedicalbills
d. Hospitalandhealth-systempharmaciestraditionallyviewedascost-centers
11. ACC/AHAeconomicanalysis33
a. Publishedformalrecommendationsforinclusionofcostinassessingthevalueofcare
b. Valueisdefinedasafunctionofresults(eg.safety,outcomes)andcost
c. Summaryofimplementationrecommendations
i. Analysesshouldbeundertakenfromthesocietalperspective
ii. AnalysesshouldbelimitedtouseofdatarelevanttotheUnitedStatesorNorthAmerica
iii. Thresholdsforvalueshouldincludeanupperandlowerboundary
iv. Performancemeasuresshouldconsidercostanalysesresults
12. Pharmacoeconomicanalysis34-38
a. Subsetofoutcomesresearchintendedtoprovideobjectivemeasuresofvalue
b. Valueisassumedfromtheperspectiveofeithersociety,payers,providers,orpatients
c. Fourbasictypesofanalysescomparecostsinputsofaproduct/servicewithoutcomes
Table3:Pharmacoeconomicanalyses
Methodology
Cost-minimizationanalysis
Cost-benefitanalysis
Cost-effectivenessanalysis
Cost-utilityanalysis
CostMeasurementUnit
$orothermonetaryunit
$orothermonetaryunit
$orothermonetaryunit
$orothermonetaryunit
OutcomeMeasurementUnit
N/A;assumedequivalent
$orothermonetaryunit
Acommonnaturalunit
Quality-adjustedlifeyear(QALY)or
otherutility
Analysesshouldemployoneof:societal,payer,provider,orpatientperspective
Adaptedfrom:RascatiKL.Essentialsofpharmacoeconomics.2nded.Baltimore,MD.LippincottWilliams&Wilkins.2014.
d.
e.
f.
Cost-effectivenessanalysis(CEA)
i. Comparesrelativecostsandoutcomesof≥2products/services
ii. Cannotcompareproducts/serviceswithdifferentoutcomemeasures
iii. Doesnotaccountfordifferencesinside-effectprofiles
Cost-utilityanalysis(CUA)
i. Comparesrelativecostsandutility-weightedoutcomesof≥2products/services
ii. Utilityweightsarea0.0(death)to1.0(perfecthealth)measureofoutcomepreference
iii. Incorporatespatientorsocietalpreferencesintovaluemeasures
Measuringvalue
i. Willingness-to-pay(WTP):Howmuchpeoplearewillingtopaytoreducethechanceofanadverse
healthoutcome
ii. Incrementalcost-effectratio(ICER):(CostA–CostB)/(OutcomeA–OutcomeB)
iii. Quality-adjustedlifeyears(QALYs):Outcomesinyearsoflifegained,adjustedforpatientpreference
iv. Budgetaryimpact:theestimatedoverallcostofaddingaproducttotheformulary
Huggar|10
Pharmacoeconomicanalysiscontinued34-38
g. Historicvaluebenchmarks
i. Regularlycited$50,000/QALYthresholdstemsfromacongressionalmandatethatdialysisbe
coveredforMedicarerecipients
ii. TheWorldHealthOrganization(WHO)valuesQALYsat3xGDPpercapita
h. Recentvaluebenchmarks
i. NewtreatmentoptionsforhepatitisCwereevaluatedashigh-to-reasonablevalueat
≤$20,000/QALY
ii. Meta-analysesofcurrentdialysisvaluereportsICERsbetween$65,496-$488,360perQALY
EconomicLiterature
TiceJA,OllendorfDA,CunninghamC,PearsonSD,KaziDS,etal.PCSK9inhibitorsfortreatmentofhigh
cholesterol:effectiveness,valueandvaluebasedpricebenchmarks.ICERNovember2015.
Purpose
Design
Scenarios
Modeled
• ToevaluatethecomparativeclinicaleffectivenessandcomparativevalueofPCSK9inhibitorsasa
classforpatientswithelevatedLDL
• Cost-utilityanalysis
o Carevalue
o Budgetaryimpact
• Familialhypercholesterolemia(FH)
• ClinicalCVD—secondaryprevention
o Statin-intolerant(assumed10%)
o Statin-tolerant,notatLDLgoal(<70mg/dL)
• Willingness-to-paythresholds
o $50,000/QALY
o $100,000/QALY
o $150,000/QALY
Populations
Modeled
-Treatment withstatinalone
-Treatmentwithstatinplusezetimibe
Yes
-TreatmentwithastatinplusPCSK9inhibitor
Ableto
tolerate
statin?
-Notreatment
-Treatmentwithezetimibealone
No
-TreatmentwithaPCSK9inhibitor
Outcomes
Methods
Assumptions
• Costperquality-adjustedlife-year(QALY)
• UsedCVDpolicymodel
o EntireUSadultpopulationage35-74yearsin2015
o Assumedhealthsystemperspectiveforbothanalyses
• Definedfamilialhypercholesterolemiaas:
o LDL>250mg/dLwithoutstatinuse
o LDL≥200mg/dLwithstatinuse
• Stratified10%ofthepopulationwithhistoryofCVDtomodelstatin-intolerance
• Appliedlifetimehorizonof95-yearsold
• Discountedfuturecostsandbenefitsby3%eachsuccessiveyear
• Costsfromthehealthsystemperspective
• DrugeffectsonoutcomesaredirectlyproportionaltodegreeofLDLreduction
Huggar|11
PCSK9inhibitorshavenoeffectonriskofstroke
Tenpercentofpersonsexposedtostatinsareintolerant
Ageandsexspecificcostswereextrapolatedfromnationaldata
Annualcostbasedonwholesaleacquisitioncost
o Ezetimibe—$2,828/yr
o PCSK9inhibitors(class)—$14,350/yr
• ~2.6millionpersonswouldreceiveaPCSK9inhibitorinthefollowing5years
• Budgetimpactthresholdis$904million
Value-basedpricebenchmarksforPCSK9inhibitortherapy
Population
CareValue
CareValuePrice: MaxPriceat
Value-Based
Price:
$150K/QALY
PotentialBudget PriceBenchmark
$100K/QALY
ImpactThreshold
FH(n=453,443) $5,700/yr
$8,000/yr
$10,278/yr
$5,700-$8,000/yr
CVDstatin$5,800/yr
$8,300/yr
$12,896/yr
$5,800-$8,300/yr
intolerant
(n=364,948)
CVDnotatLDL $5,300/yr
$7,600/yr
$2,976/yr
$2,976/yr
goal
(n=1,817,788)
Total
$5,404/yr
$7,735/yr
$2,177/yr
$2,177/yr
(n=2,636,179)
•
•
•
•
Results
FH:familialhypercholesterolemia;CVD:cardiovasculardisease;LDL:low-densitylipoprotein;QALY:quality-adjustedlifeyear
Author’s
discussion
Reviewer’s
critique
• PCSK9inhibitorsmaysubstantiallyreducenon-fatalMIs,non-fatalstrokes,andcardiovasculardeath
overalifetime
• PCSK9inhibitorsgeneratedICERsthatexceedcommonly-acceptedthresholds
• An85%reductioninlistpricewouldbenecessarytoavoidaddingexcessivecostburdenstothe
healthcaresystem
• CVDmodelnotapplicabletopatients<35yearsold
• FHdiagnosisnotin-linewithcurrentrecommendationsfordiagnosis
• UsedhistoricLDLtreatmentgoalvaluesnolongerstandardofcare
• Tenpercentstatinintolerancerateisanoverestimation
• Outcomeeventreductiondoesnotreflectresultsfromrecentstudies
• DrugeffectsonCVDwerebasedonLDLreductionalone
• Sensitivityanalysesofbasecasesconsistentlysensitivetolowerpriceandlongeranalysishorizon
• Usedarbitrarybudgetimpactthresholdthatdoesnotreflectrealworldpolicy
13. ICERreportsummary39
a. ICERmodeledPCSK9useinstatintolerantandintolerantpatients
i. Comparedtoezetimibeuse
ii. Baselinestatinuse
b. Utilizedacost-benefitanalysistocomparevalueofezetimibeandPCSK9inhibitorsasadd-ontherapies
c. ICERfindsPCSK9inhibitorsonlyviableastreatmentoptionswithoutrestrictionatapriceof$2,177—aprice
lessthanthecurrentAWPofezetimibe
d. Findingsarebasedonquestionablemodelingofpopulationandeventrates
e. Costsmisspotentiallysignificanteventsavoided
Huggar|12
Conclusion
14. Clinicalsummary40,41
a. PCSK9inhibitorssignificantlydecreaseserumLDLcholesterol
i. EvolocumabdecreasedLDLby~61%at48-weeks
ii. AlirocumabdecreasedLDLby61%at24weeks,and58%at78weeks
b. LDLcholesterollevelsbelow70mg/dLmayresultinfurtherimprovedCVDoutcomes
i. MeanabsoluteLDLlevelwas48mg/dLat24weeksoftherapyinODYSSEY
c. Interimanalysesindicateadditional48-53%eventreductionwhenaddedtostatintherapy
d. Studiesofsafetyconcludeneitherdrugpossessesasignificantadverseeffectprofile
i. Similarratesofadverseeventsleadingtodiscontinuationwereobservedbetweenalirocumaband
placebo,respectively:
ii. SlightlyhigherratesofneurocognitiveeventswithPCSK9inhibitorscomparedtoplacebo(not
statisticallysignificant)
e. Interimoutcomesanalysestrendingtowardssignificanteventreduction
15. Costsummary39
a. PCSK9inhibitorsprojectedtobecostliestdrugclassinhistoryatcurrentaveragewholesaleprices(AWPs)
i. PraluentAWP:$14,600/year
ii. RepathaAWP:$14,100/year
b. ICERfindings:
i. ICERsatlistpricerangefrom$274,00-$302,00perQALYformodeledpopulations
ii. Limitingusetoonlypost-MIpatientsstillresultsincosts>$150,000/QALY
iii. ConcludedclassisviableatalowerpricethancurrentAWPforZetia®
iv. Markedflawsinmodelingandcostassumptions
c. Emergingpay-for-performancedealscompensatepayersforunmetclinicaloutcomes
16. Clinicalrecommendations
a. Reserveasadd-onagentsinpatientswithgenetically-confirmedFHafterinitiatingstatintherapy
i. PrimarypreventioninpatientswithHoFH
ii. Primarypreventioninpatientswithhigher-riskHeFH
iii. SecondarypreventioninmostpatientswithHeFH
b. Reserveasadd-onagentsforsecondarypreventioninhigh-riskpatientswithoutFH
c. Keepawatchfuleyeonoutcomesdatalikelytobemadeavailableby2017
Huggar|13
Appendix
Appendix1:Selectstudiesassessingstatin-inducedLDL-loweringandCVDoutcomes18-20,45-53
Trial
N
Intervention
Meanbaseline
LDL(mg/dL)
MeanLDL
reduction
CVDevent
reductionrate
NNT
Placebocontrolled
4S(1994)
4444
Simvastatin20mg
188
35%
34%(p<0.0001)
15
WOSCOPS(1996)
6595
Pravastatin40mg
192
26%
31%(p<0.001)
42
AFCAPS/TEXCAPS
(1998)
MIRACL(2001)
6605
Lovastatin20-40mg
150
25%
37%(p<0.001)
24
3086
Atorvastatin80mg
124
58%
16%(p=0.048)
39
ALLHAT-LLT(2002)
3638
Pravastatin40mg
146
28%
9%(p<0.96)
43
HPS(2002)
CARDS(2004)
20536 Simvastatin40mg
2838 Atorvastatin10mg
131
117
30%
40%
23%(p<0.0001)
37%(p<0.001)
19
24
ASPEN(2006)
2410
Atorvastatin10mg
113
30%
10%(NS)
4
MEGA(2006)
8214
Pravastatin10-20mg
157
18%
33%(p=0.01)
6
SPARCL(2006)
JUPITER(2008)
4731 Atorvastatin80mg
17802 Rosuvastatin20mg
133
108
42%
50%
26%(p<0.001)
44%(p<0.00001)
15
82
106vs.106
95vs62
mg/dL
16%(p<0.005)
2
Statincomparativeefficacy
PROVEIT-TIMI22
(2004)
4162
Atorvastatin40mgvs.
pravastatin40mg
Huggar|14
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