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Every BreathYouTake:Everything youneedtoknow about

Alpha-1Antitrypsin Deficiency

DebbieMahoney,PhD,APRN,FNP-BC&

DebbieWaldrop,MSN,RN,CCRC

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Special Thanks To:

•Alpha-1 Foundation•CSLBehring•James Stocks,MD

NoDisclosures

Objectives

1. DescribethegeneticetiologyandprevalenceofAAT.2. Listthepulmonaryandextrapulmonary clinicalmanifestationsof

AAT.3. DiscusstreatmentoptionsforAAT

OverviewofAATD• WhatisAlpha-1AntitrypsinDeficiency?• History&Inheritance• LungDisease• LiverDisease• Diagnosis• Treatment• Future• Summary• Alpha1Foundation

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WhatisAATDeficiency?

• Genetic/HereditaryconditioncausingdecreasedlevelsofAATinbloodandtissues

• Affectsanestimated100,000peopleintheUSandasimilarnumberinEurope

• Approximately25millioncarriersoftheAlpha-1geneintheUS• Predisposestolung,liver,otherdiseases

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WhatisAlpha-1Antitrypsin(AAT)?

• NormalAATproteinphenotype“M”• 95%ismadeintheliver&transportedtoalltissuesbyblood• Foundinlargequantitiesinserum(90-200mg/dl)• Maineffect:inactivatingproteases• Primarytarget:neutrophilelastase

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α1-antitrypsin

Neutrophilelastase

Asn46

Asn247

Asn83

Asn95

Asn144As p88

Ser173His 41

ILe356Pro357

Met358

Ser359

ILe360

Pro361

Adapted from Crystal et al

Alpha-1AntitrypsinandElastase

Alpha-1-antitrypsin– ZProtein

•PiZ resultsfromamutationinthegene•Zproteinmisfolds &accumulatesintheliver

• secretion from liverisimpaired.•Lowsecretionresultsin“deficient”serumlevel.

Zphenotype accountsfor95%ofclinicalillness.

Other Deficient Variants

• Sallele:

• Variant isassociated withmilderdeficiency

• Nullallele:– NoAATproduction

• Zeroserumlevel• Morethan100otherraremutationsexist

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Phenotype PedigreeAATCo-dominant Inheritance

MZ ZZMZ

MZ MZ

MM

CarrierofZ CarrierofZ

Normal CarrierCarrier Severely affectedAATD

0

60

40

20

MM MS SS MZ SZ ZZ Null

53 5248

42

23

3.4

7

0

Serum level ofalpha1-antitrypsinin µMol

Genetic PI TypeRisk of lung disease “normal” low low low moderate high high

50

30

10

20 18 2015

10

Inheritance– DiagnosticLevels

80 mg% ~ 11 µMolAbove 130 - normal

11µMthreshold

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History ofAAT

• 1962:Dr.Carl-Bertil Laurell (1919-2001)attheUniversityofLund,Swedendiscoveredtheabsenceofthealpha-1bandin2serumelectrophoresisgels.

• FurtherinvestigationbyDr.Sten Eriksson

• 4ofthe6patientshademphysema.

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Agarose gel electrophoresis

α1-band

+ –

PI*ZZ

PI*MM

(Normal plasma level 0.9-1.7 g/l)

0.2 g/l

~1.3 g/l

History Identification of Deficiency

History

• 1963-DrsCarlLaurell &Sten Eriksson• AATDidentifiedascauseof‘familialemphysema’

• 1969• AATDidentifiedascauseofnewbornliverfailure

• Early1970s• AATidentifiedasimportantproteaseinhibitor• Proteasesrole ininflammationandinjury

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History• Late1970s

• Neutrophilelastase likelymediatoroflungdestructioninAlpha-1• CigarettesmokecapableofdestroyingAATfunction

• 1980s• PlasmadeficiencyduetoblockageofreleaseofAATfromliverandliverinjurylikelyduetothisaccumulation

• Prolastin® approvedinUS,Germany,andSpain

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Population Screening Studies

• 200,000neonatesscreenedinSweden• Pi*ZZin127,or1 in1575

• 20,000blooddonorstestedinSt.Louis• Pi*ZZ:1in2857

• 965consecutiveemphysemapatients• 1.9%werePi*ZZ• 8.0%werePi*MZ

PrevalenceofAlpha-1

ThemostprevalentpotentiallyfatalgeneticdisorderofadultCaucasiansintheUnitedStates.

- Anestimated25million individualscarrydeficientgenes

- Over100,000AmericanshavesevereAATD

- Lessthan10%yetdiagnosed

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ComparisonofPI*ZZPrevalence

Disorder PrevalenceAAT deficiency (PI*ZZ) Over 100,000

Cystic Fibrosis 30,000

Huntington’s Disease 30,000

Spina Bifida 166,000

Idiopathic Pulmonary Fibrosis 128,000

Testicular Cancer 196,000

Ovarian Cancer 177,000

Hodgkin’s Lymphoma 164,000

Cervical Cancer 243,884

Clinical PresentationofAlpha-1

Why dothose with Alpha-1 getLung Disease?

• Uncontrolledproteolytic attackonlungtissuebecauseoflowcirculatinglevelsofAAT.

• TheZproteinislesseffectiveatinhibitingneutrophilelastase thantheMprotein.

• Cigarettesmokecaninactivatethepatient’sownAAT inthelungs.

• NormalAAT levels functiontosuppressinflammation

LungDisease• ChronicObstructivePulmonaryDisease(COPD),primarilyemphysema• Bronchiectasis• Ofteninyoungeradultsandoutofproportiontosmokinghistory• Riskfactors:

• Smoking• 2nd handsmoke• Occupationalexposures• Lunginfections

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Clinical Pulmonary Presentation

Resultsfrom2patientregistriesregardingpriordiagnosisbeforeAlpha-1:

• 54%hademphysema• ThemeanFEV1 among1129participantsintheNHLBIregistrywas43%of predictedwithameanageof 45.

• 72%hadrespiratorysymptoms• 42-46%withchronicbronchitis• 35%hadadiagnosisofasthma.

• 30%of NHLBIpatientshadFEV1 reversibilitywhentestedwithspirometry.

ClinicalpresentationdoesNOTIDAATD!

Elastase Burden

Elastase

AAT (MM)

Elastase protection

NormalBalanceofNeutrophilElastase&AAT

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Breakdown of lung tissue

Elastase

AAT (not MM)

Elastase protection

Elastase Burden

Balance ofNeutrophil Elastase &AAT inaDeficient Patient Radiology

• Areview ofchestradiographsfrom165ZZpts:• 15%werenormal• Only20%showedthe“classic” findingofemphysemaatthebases

• Areview of102CTsofZZpts:• 64%showedbasalpredominance• 36%hadpredominantapicaldisease

•HRCToftenfindsbronchiectasis

Chestx-raysandCTscanscanNOTidentifyAATD.

Average Age at Diagnosis

Based on 302 patients with PiZZ out of 26,520 patients tested.M Brantly, U of Florida

47%

4

15

46

76

94

31

122

22

0

10

2030

40

5060

70

80

90100

0"10 11"20 21"30 31"40 41"50 51"60 61"70 71"80 81"90Age (Years)

Nu

mb

er o

f P

atie

nts

Not just “young” with COPD

AATDandSurvival

• Mediansurvivalinsmokers=49years• Innon-smokers=69years

notdifferentfromgeneralpopulation• Innon-smokerslungdiseaseoften

developsafterage50

Missed Clinical Recognition

• AverageAlpha-1patienthassymptomsfor7.2to8.3yearsbeforediagnosisismade.

• 44%ofAlpha-1patientsseeatleast3doctorsbeforeadiagnosisismade.

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Whydomanyphysicians presume thatSOB,cough,andwheezing isasthmaorcaused bysmoking….

Butgastroenterologist s never presume that liverdysfunction isdue toalcohol?

Alpha-1 Liver Disease

LiverDisease• Canoccurinneonates,children,andadults• Neonatals oftenneedlivertransplantation• Inadults,amajorityofpatientswhodiewithAlpha-1havehistologicevidenceofliverdisease

• Potentialcontributionofriskfactorsisnotwellunderstood(alcohol?,drugs?,virus?)

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Liver Management

• Regularcontactwithadoctorwhoisfamiliarwithalpha-1liverdisease.

• Acombinationofaskingaboutnewsymptoms,physicalexaminationmonitoring,bloodtests,andx-ray/ultrasoundexams.

Treatment• Therearenospecifictreatmentsto

preventalpha-1liverdamage.• Thereareeffectivetreatmentsused

forliverdiseaseingeneral.• Augmentationtherapyhasnoeffectonliverdisease.• Livertransplantation:tradingonediseaseforanother?

Other extrapulmonary manifestations ofAATdeficiency• Panniculitis

• (hot,painful, rednodulesorplaqueson thethighorbuttocks)andpossiblyvasculitis,

• Inflammatoryboweldisease,• Intracranialandintra-abdominalaneurysms,• Fibromusculardysplasia• Glomerulonephritis

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Timeto TestDiagnosis

• Lung• EarlyonsetCOPD• COPDinnon-smoker• Unexplainedbronchiectasis• Predominanceofbasilaremphysema

• Familyhistoryofemphysemaand/orAlpha-1

• Unremittingasthmainadult

• Liver• Unexplainedchildhoodliverdisease• Unexplainedcirrhosis inadult• FamilyhistoryofAlpha-1

•Vasculitis• Wegener’sGranulomatosis• NecrotizingPanniculitis

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When to suspect Alpha-1

Diagnosis

• Carefulfollow-upofindividualswithoutsymptoms• Lifestylechanges

• Smokingcessation• Exercise• Nutrition• Stressreduction• Environmentalmodifications

• Alpha-1specifictherapy

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Advantages of Early Diagnosis

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Whyshouldwedetect individuals withAATD?

• Assistinsmokingcessation• Assistinoccupationaldecisions• Meaningfulgeneticdatatofamilymembers• Diseasespecificsupport• AllowtherapyspecificforAATD• Becauseit’stherightthingtodoforyourpatients.

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• Simple to diagnose– Tube of blood– Finger stick

Alpha-1 is a laboratory diagnosis,not a clinical diagnosis

– Level– Phenotyping– Genotypingg

How Can We Test for AATD? Testing viaFinger Stick

• TestingforAATlevels&genotypeviaasinglefinger-stickofblood

• Canbemailedintoacentrallab

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alphaone@musc.edu1-(877)-886-2383

FreeConfidential testingavailable:

ACTStudy atMUSC

www.alphaoneregistry.org

SoyoufoundanAlpha.

NowWhat?!!?!

Treatment

•StandardTherapiesinCOPDTreatment• Smokingcessation• PulmonaryRehab• Bronchodilators• Inhaledsteroids• Oxygen• Lungtransplant• Earlytreatmentofrespiratoryinfections• Fluandpneumoniavaccination

Treatment

• Management/EvaluationofLiverdisease• ConsiderationofAugmentationTherapy

Augmentation therapy

• CheckbaselineHIV,HBVtiters• ImmunizeforHBVasindicated• Annualcostsforpatientsreceivingaugmentationtherapyareuptoapproximately$80,000peryear,

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HealthEffectsfromSmokingMen

oImpotenceoSpermdensityoInfertility

WomenoLowerbonedensity inpostmenopausalwomenoStillbirthoMiscarriageoInfertilityoEctopicpregnancyoPre-termdeliveryoSeverevaginalbleedingduringpregnancy

www.cdc.gov/tobacco. dat a_st atistic s/FActsheets/health_effects. htm

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ChildhoodHealthEffects

• SIDSincreased3.5fold• Respiratoryinfections• Earinfections• Asthma• Learningdifficulties• Behavioralproblems• Childhoodcancers• HighBloodPressure

TheToll ofTobaccoonTexas

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CosttoTexans

TobaccorelateddiseasecostTexas$12billionannually• 5.8billiondirectmedicalcosts• 6.8billiononlostproductivityduetoprematuredeaths• Householdtaxburden

$570

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Augmentation Therapy

• Augmentationtherapyisusedtoincreaseserumandlungepithelialliningfluid(ELF)levelsofAAT

• PlasmaderivedtreatmentforadultswithAATDandemphysema

Augmentation Therapy

• Augmentationtherapywasfirstapproved25yearsago.

• Fourapproveddrugs– Prolastin C(Grifols)Aralast &Glassia(Baxalta/Shire),Zemaira (CSL)

• Originalapprovalbasedonpharmacokineticandbiochemicaldata.

• Subsequentapprovalsamecriteria.• Nonebasedontherapeuticefficacy.

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AATDImbalanceofNeutrophilElastase&AAT

Breakdown of lung tissue

Elastase

AAT

Elastase protection

Elastase Burden

Elastaseburden

Elastaseprotection

Lung Tissue Protected

Elastase

AAT +AAT Augmentation

+

Role of Augmentation Therapy

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LungFunctionDeclines

100%

75

50

25

025 7550

AGE

Smoker

Nonsmoker

disability

death

Alpha 1LungFunctionFEV1%

__________________________________

___________________________________

Why Augmentation Therapy?

Wewers inNEJM1987;316:1055

Does Augmentation Clinically Work?

History

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NIH Alpha-1 Registry1987-1995

37 Registry Sites in US

1129 individuals enrolled51 from UT Health NortheastOne of top 5 most successful sites

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USNHLBIRegistry ‘87-95• Prospective,non-controlled,non-randomized

• Comparisonoflungfunction&mortalityintreatedversusuntreatedpatients

• Inclusioncriteria-AATlevel≤ 11µM

• n:277treatedvs 650untreated

MeanFEV1Decline

ml/yr

<10 <20 <30 <40 <50 <60 <70 <80

-20-40-60-80

-100-120-140

FEV1 % Predicted

Augmentation

No Augmentation

NHLBIRegistry- Mortality Seersholm etal.ERJ.1997

• Numberofpatients• n=295;97control,198treated

• Mainfindings• Declineinlung functionintreatedgroupwas

lower (FEV1=53vs75mL/yr,p=0.02)• EffectbestseenwithFEV1=31- 65%

predicted

DanishStudyGroup•Double-blind, randomized, prospective

multicenter study (N=56 ex-smokers)

•Comparison of250mg/kgmonthly foratleast3yearsinpatientswith Pi*Z.

• Endpoints – PFT and CTdensitometry

•No significant difference indecline oflung function expressed inFEV1per yearbetween both arms

Changes inLungCTDensity

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4

Cha

nge

in lu

ng d

ensi

ty

(15t

h pe

rcen

tile

-g/L

)

Years

PlaceboActive

P = 0.07

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CanadianRegistry2005

• Patients receivingAlpha-1vsuntreatedmatchedcontrolpatients

• N:21patients receivingAlpha-1,42controls

• Medianobservation was5.6years.

• Medianduration ofaugmentationwas4.4years.

CanadianRegistry

-70

-60

-50

-40

-30

-20

-10

0

Change in FEV1

(mL/Year)

With AugmentationTherapy

Control

-29.9

-63.6

P=0.019

MetaAnalysis - AATD•5studieswithatotalof1509patients

• 4non-randomizedtrials• 1randomizedtrial

•Results• FEV1 declinewasslowerby23%

withaugmentationtherapy• MainlywithFEV1 30%-65%ofpredicted

benefited(thosewith fastestdecline)

CTdensitometrymaybeamoresensitivemeasurementofemphysemaanditsprogression.

Future•Newformsofaugmentationtherapy

• Inhalation- AATproducedinsheepmilk•Oralneutrophilelastase inhibitors(pills)•Agentsthatmoveproteinfromliver

•Genetherapy•Generepair•Genereplacement

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Summary

• Alpha-1AntitrypsinDeficiencyismorecommonthanpreviouslythought

• Itcausesmorethanjustemphysema.• TestingforAlpha-1isquickandeasy.• Augmentationtherapyisavailable

anditiseffective.

TheAlpha-1Foundation

Alphaone.org

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The Alpha-1 Foundation is committed to finding a cure for

Alpha-1 Antitrypsin Deficiency and to improving the lives of people affected by Alpha-1 worldwide.

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Alpha-1 Foundation Programs

Abo ut th is pro ject

Abo ut th is pro ject

Abo ut th is pro ject

Abo ut th is pro ject

Abo ut th is pro ject

EducationalScho larsh ip s

Advocacyand

Pub licPo licy

C lin ical Re source Ce n te rs

Re se arch P rograms

Education Daysand

NationalCon fe re nce

Alpha-1 Global

In itiative

Bu ild ingFrie nds fo r

aCu re

FamilyTe sting

Ge ne ticCounse ling

SupportGroupNe twork

E-EducationAlpha-1 K id sP rogram

Scie n tificMe e tings and Con fe re nce s

Patie n tIn fo rmation Line

Pe e rGu ide P rogram

and muchmore !

AlphaNet

Comprehensive Health Management

serving the entire Alpha-1 Community

Over 7,000 PATIENTS ENROLLED

$47M IN REVENUE TO THE ALPHA-1 FOUNDATION

COMPLETED 13 STUDIES

SGRQ AND SF36 COMPLETED BI-ANNUALLY

48 ALPHANET COORDINATORS

Engaging the Community Advocacy•Access

•Specialtytier•Marketplaceaccess•Oxygen•Coverage

•Research•PlasmaSafety•TrialDesign•ActionPlanforCOPD•Biomarkers•Newborn Screening•Transplant

Progress Towards a Cure

GeneTherapy StemCellTherapy

StopPolymerizationor theProteinBeing Made

Delivery

Aerosolized Therapy

SmallMolecule CRISPR

$60M TO WORLDWIDE RESEARCH

NORTH AMERICA

EUROPE

MIDDLEEAST

AUSTRALIA

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Be Part of the Cure

www.copdpprn.org

https://alphaoneregistry.org/research_registry

Be Part of Liver Studies

Clinical Resource Centers

• New Recruitment Process• Proficiency Exam• CRC AccessProgram• CRC Recruitment Brochure• CRC Forum

SpecialThanks to:James Stocks, MD

UTHealthNortheast,Tyler,TexasTheAlpha-1Foundation

Formoreinformationcontact:JanHoeft,RN,CCRC

UTHealthNortheast(903)877-5518Jan.hoeft@uthct.edu

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