Idiopathic Pulmonary Fibrosis in the Era of Antifibrotic Therapy: Searching for New Opportunities Grounded in Evidence

www.revportpneumol.org

SPECIAL

ARTICLE

Idiopathic

pulmonary

fibrosis

in

the

era

of

antifibrotic

therapy:

Searching

for

new

opportunities

grounded

in

evidence

C.

Robalo-Cordeiro

_,

_P.

_Campos

_,

_L.

_Carvalho

_,

_A.

_Borba

_,

_S.

_Clemente

_,

_S.

_Freitas

_,

S.

Furtado

_,

_J.M.

_Jesus

_,

_C.

_Leal

_,

_A.

_Marques

_,

_N.

_Melo

_,

_C.

_Souto-Moura

_,

_S.

_Neves

_,

V.

Sousa

_,

_A.

_Santos

_,

_A.

_Morais

a_{PulmonologyDepartment,CoimbraUniversityHospital,FacultyofMedicineofCoimbra,Coimbra,Portugal}

b_{ImagiologyDepartment,SantaMariaHospital,NorthernLisbonHospitalCentre,Lisbon,Portugal}

c_{PathologyDepartment,FacultyofMedicineoftheUniversityofCoimbra,Coimbra,Portugal}

d_{PulmonologyDepartment,SantaMartaHospital,CentralLisbonHospitalCentre,Lisbon,Portugal}

e_{PulmonologyDepartment,BeatrizÂngeloHospital,Loures,Portugal}

f_{PulmonologyDepartment,CoimbraUniversityHospitalCentre,Coimbra,Portugal}

g_{RadiologyDepartment,SãoJoãoHospitalCentre,Oporto,Portugal}

h_{RadiologyDepartment,SantaMartaHospital,CentralLisbonHospitalCentre,Lisbon,Portugal}

i_{PulmonologyDepartment,SãoJoãoHospitalCentre,Oporto,Portugal}

j_{PathologyDepartment,SãoJoãoHospitalCentre,FacultyofMedicineofPortoUniversity,Oporto,Portugal}

k_{PulmonologyDepartment,VilaNovadeGaia/EspinhoHospitalCentre,VilaNovadeGaia,Portugal}

l_{PrimeFocus,Lisbon,Portugal}

Received12May2017;accepted29May2017 Availableonline28June2017

KEYWORDS Idiopathicpulmonary fibrosis; Interstitiallung disease; Nintedanib; Pirfenidone

Abstract Idiopathicpulmonaryfibrosis(IPF)isaprogressiveandfatallungdisease thatup tonowhasbeenassociated withapoorprognosis.However,theresultsoftheINPULSISand ASCENDtrialsandtheapprovalofnintedanibandpirfenidonehavemarkedthebeginningof anew erafor IPFpatients. Questionsremain, however.Shouldthesedrugs beusedearlier? What effectwillthey haveonmore severe disease?Willtheir effectslastbeyond thetrial period?Thismanuscriptistheoutcomeofamultidisciplinarymeetingbetweenpulmonology, radiology,andpathologycliniciansontheuseofantifibroticagentsinIPF.Inouropinion,the existing data show thatpirfenidone andnintedanib slow functional declinein earlystages

∗_{Correspondingauthor.}

E-mailaddress:carlos.crobalo@gmail.com(C.Robalo-Cordeiro). http://dx.doi.org/10.1016/j.rppnen.2017.05.005

2173-5115/©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ofdisease. Thesedrugs also appear toresult intherapeutic benefitswhen administered to patientswithadvanceddisease atdiagnosisandmaintaineffectiveovertime.Thedata also suggestthatcontinuingantifibrotictherapyafterdiseaseprogressionmayconferbenefits,but more evidenceisneeded.Earlydiagnosis andtreatmentarecrucial for reducingfunctional decline,slowingdiseaseprogression,andimprovingqualityoflife.

©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive and deadlydiseasewithameansurvivalof3---5yearsfromthe timeofdiagnosis.Itismorecommoninmen,smokers,and peopleover50yearsold.1,2_{Theconditionischaracterized} bydyspneaonexertion,non-productivecough,crackleson auscultation,and digital clubbing.It is diagnosed usinga specificcombination ofradiologicand/orhistopathological patternsofusualinterstitialpneumonia(UIP)andexclusion ofotherknowncausesofUIP.1,3_{Generalphysiciansmustbe} abletorecognizethesymptomsofIPFtoensurethetimely referral of suspectedcases, and it is essential thatthese arethenevaluatedbyamultidisciplinaryteamwith expe-rience in interstitial lung diseases to ensure an accurate diagnosis.1,4---8

This manuscript is the outcome of a multidisciplinary meeting in which pulmonology, radiology, and pathology clinicianscametogethertodebatetopicsrelatedtotheuse ofantifibroticdrugsinthetreatmentofIPF.

IPF

treatment:

a

recent

(r)evolution

IPF was initially considered to be a chronic inflamma-tory process and therefore early treatment strategies aimed to eliminate or suppress the inflammatory com-ponent. In 2000, the first international guidelines on IPFdiagnosis and treatment recommendedcorticosteroids and immunosuppressive/cytotoxic agents (azathioprine or cyclophosphamide)as ‘‘standard treatment’’,despite the weak evidence available.9 _{This targeting of inflammatory} pathways,however,produceddisappointingresults.4,10---12

UnderstandingofIPFpathobiologyimprovedsignificantly followingthepublicationofthe2000IPFguidelinesandit wasproposedthatthediseasemightbetheresultofan aber-ranthealing responsetorecurrent alveolar epithelial cell injury.13,14_{Guidelinespublishedin2011concludedtherewas} insufficient evidence to continue to recommend corticos-teroid andimmunomodulatoryagents asstandard therapy forIPF.15 _{The resultsoftheIFIGENIA study,adouble-blind} clinical trial designed to investigate the potentialrole of antioxidantpathways in IPF, were published in 2005. The trial,whichcomparedprednisoloneplusazathioprine with prednisoloneplusazathioprineplusN-acetylcysteine(NAC), showedasignificantlyreduceddeclineinforcedvital capac-ity(FVC) (p=0.02) and diffusion capacity of the lung for carbonmonoxide(DLCO)(p=0.003)inpatientstreatedwith

NACcombinedwithprednisoloneandazathioprineafter52 weeks.16 _{Although the trial had some methodological} pit-falls,thistripletherapybecamethenewstandardtreatment forIPF.

Aroundthesametime,pirfenidone,anorallybioavailable synthetic compound with antifibrotic, anti-inflammatory, and antioxidant effects, wasbeing studied in clinical tri-als in Japan.17,18 _{Althoughthe exact mechanism ofaction} of pirfenidone in IPF is not yet completely understood, its anti-inflammatory effects are believed to result from thesuppressionof tumornecrosisfactor ␣(TNF-␣), inter-leukin(IL)-6,IL-12,andIL-8,19 _{whileitsanti-fibroticeffect} is thought to result primarily from inhibition of expres-sion of transforming growth factor beta --- a profibrotic cytokine--- althoughotherpathwayshavebeensuggested.20 The firstJapanese trial, a phase II, multicenter, random-ized, double-blind trial, showed no significant treatment effectfor pirfenidoneontheprimaryendpoint,whichwas achangefrombaselineinthelowestoxygensaturationby pulseoximetry[SpO2]duringa6-min exercisetest.Itdid, however,showthatthehigh-dosetreatment(1800mg/day) had apositive effectin reducing VCdecline, asecondary endpoint, at 9months.17 _{Inaddition, acuteexacerbations} wereonly observedin theplacebo groupduringthe same period.Asubsequentmulticenter,randomized,double-blind phaseIIIclinicaltrialof275IPFpatientsrandomlyassigned to pirfenidone 1800mg/day, pirfenidone 1200mg/day, or placebofor52weeks,showedasignificantlyslowerdecline inFVCandbetterprogression-free survivalinthetwo pir-fenidone groups compared with placebo.18 _{Based on the} resultsofthesetwostudies,pirfenidonewasapprovedfor IPFtreatmentbytheJapaneseauthoritiesin2008.

Meanwhile,pirfenidonewasalsobeingstudiedinEurope and in the United States of America (USA) in the CAPAC-ITYtrials.21_{Theplacebo-controlledphaseIIItrials,CAPACITY} 004and006,showedcontradictoryresults,andtheprimary endpoint ofasignificantreductioninFVCdeclineatweek 72 wasonly met instudy 004. However,the pooled anal-ysis revealed a significant reduction in the mean decline of absolute and percent predicted FVC and the number of patients with an FVC decline ≥10% at week 72 in the 2403mg/daypirfenidonegroup.21_{Inrelationtothe} second-aryendpoints,thepatients inthe2403mg/daygroupalso had longer progression-free survival and a lower rate of declineinmean6-minwalkdistance(6MWD)thanpatients intheplacebogroup.21_{Theresultsofthispooledanalysisled} totheapprovalofpirfenidoneforIPFtreatmentbythe Euro-peanMedicinesAgency(EMA)in 2011,althoughtheywere

notsufficienttoconvincetheUSFoodandDrug Administra-tion(FDA).

DespitetheapprovalofpirfenidoneinJapanandEurope, the triple therapy persisted as the treatment regimen of choiceinmany countriesuntiltheresultsofthePANTHER studywerepublished.11 _{ThePANTHERstudywasa} random-ized clinical trial with threearms: a triple therapy arm, an NAC arm, and a placebo arm. The triple therapy arm wasstoppedafterameanfollow-upof32weeksbecauseof highermortalityandhospitalizationratesthanintheother twogroups.11

Despitesomeinitialcontroversy,thiseventmarkedthe endoftripletherapy.Moreover,oncompletionofthe PAN-THERstudyin2014,nosignificantdifferencesweredetected betweenNACandplaceboforchangesinFVC(primary end-point)orfordeathratesorfrequencyofacuteexacerbations (secondary endpoints).22 _{Recent publications describing a} therapeutic effect for NAC in a subgroup of IPF patients expressing the TOLLIP gene polymorphism rs375092023 and a potential benefit of inhaled acetylcysteine,24 _have rekindled the discussion about the potential therapeutic role of NAC and antioxidants as a therapeutic group in IPF.

AftertheevaluationoftheCAPACITYtrials,19_theASCEND trial, which included 555 patients from the USA, Europe, and Australia randomly assigned to receive 2403mg/day of pirfenidone or placebo for 52 weeks showed that the treatment group hada significantlyreduced absolute FVC decline,fewerpatients withanFVC decline≥10%, better progression-freesurvival(definedasthetimetooccurrence ofaconfirmedabsolutedecreaseof≥10percentagepoints inpercentpredictedFVC,aconfirmeddecreaseof≥50min the6MWD, ordeath), andfewerpatients witha decrease of ≥50m in the 6MWD.25 _{Moreover,pooled datafrom the} CAPACITYandASCEND trialsevidencedareductioninboth all-causeandIPF-relatedmortalityafteroneyear.25 _These resultsfurthersupportedtheefficacyofpirfenidoneinIPF andledtoFDAapprovalin2014.

Inthesameyear,nintedanibalsoreceivedFDAapproval aftertheINPULSIS trials.26 _{Nintedanibisa smallmolecule} tyrosine kinase inhibitor that targets the receptors of platelet-derived growth factor, fibroblast growth factor, andvascular endothelial growth factor.Blockage of these receptors may inhibit downstream signaling cascades of fibroblastsandmyofibroblasts,attenuatingthedevelopment ofaberrantfibrosis.27

In the phase II nintedanib trial TOMORROW, which included432IPFpatientsrandomizedtooneoffourdoses ofnintedanib(50mgod,50mgbid,100mgbid,and150mg bid)orplacebo,asignificantreductioninFVCdeclineafter 52weekswasseeninthe150mgbidgroupcomparedwith placebo.28 _{This subgroup ofpatients alsohad significantly} feweracuteexacerbationsandasmallermeandecreasein theSt.George’sRespiratoryQuestionnairescore.Two sub-sequentlarge phaseIIItrials,INPULSIS1and2,comparing 150mg bid of nintedanib with placebo in 1066 patients, showeda reductionintheannual rateof declinein abso-lute and percent predicted FVC (primary endpoint) and an increase in time to the first acute exacerbation for nintedanib.26 _{Withtheseresults,theEMAfewmonthsafter} the FDA approved nintedanib for the treatment of IPF in January2015.

A new era emerged for patients with IPF following the INPULSIS26 _{and ASCEND}25 _{trials and the approval of} nintedanibandpirfenidone.29_{Thetwodrugswereidentified} innationalandinternationalguidelinesonthediagnosisand treatmentofIPF asbeingefficaciousinslowingfunctional declineanddiseaseprogressioninIPFpatients.1,30---33

The nintedanib and pirfenidone trials showed similar efficacy results but raised logical questions related to how the drugs would perform in the real world, outside therestrictions of thetrials. The inclusion criteriavaried somewhatbetweentheINPULSIS(nintedanib) andASCEND (pirfenidone) trials. The pirfenidone trials21,25 _included patients with percent predicted FVC 50---90%, predicted DLCO 30---90% and high-resolution computed tomography (HRCT) images indicating either definite or possible UIP, however with confirmation by surgical lung biopsy. The nintedanib trials,26,28 _{by contrast, included patients with} percentpredictedFVC>50%, predictedDLCO30---79%,and HRCTimages indicatingdefinite or possible UIP. Following publicationofthetrials,severalpost-marketingsurveillance studiesandsubgroupanalysesinvestigatingeffects accord-ingtoageorstageofdiseasewereundertakeninorderto answerseveral questions:Ifthesedrugsareefficacious in slowingtheprogressionofIPF,shouldtheybeusedearlier? Howwilltheybehaveinpatientswithmoreseveredisease? Willtheireffectsextendbeyondthetrialperiod?29,34

When

should

IPF

treatment

be

started?

The mostcontroversial question currently surroundingIPF treatmentisprobablywhenitshouldbestarted.Weknow thatIPFis aprogressivediseaseandthatbothpirfenidone and nintedanib slow functional decline. However, some patientsremainstableforseveralmonthsandit hasbeen arguedthatinastablepatientwithmilddisease,treatment shouldbepostponed until functionaldecline begins. Nev-ertheless,itisimpossibletopredicttherateorseverityof diseaseprogressionineach patientor toknowwhen they willexperienceanacuteexacerbation.Moreover,wecannot be sure that deleterious subclinical changes are not tak-ingplaceinpatientswithoutsignsofsignificantfunctional deterioration.

In a recent post hoc subgroup analysis of pooled data fromtheINPULSIStrials,Kolbetal.describedsimilarrates ofFVCdeclineinnintedanib-treatedpatientswithpercent predictedFVC>90%and≤90%(Fig.1).35_{Otherpre-specified} subgroupanalyses have shownsimilarresults, witha con-sistenteffectobservedfornintedanibinpatientswithFVC ≤70%and>70%.36

InaposthocanalysisofpooleddatafromtheCAPACITY and ASCEND trials, Albera et al.37 _{showed similar} clini-callysignificantdiseaseprogression(declineinFVC,6MWD, anddyspneameasuredbytheUniversityofCalifornia,San Diego Shortness ofBreath Questionnaire)at 12months in pirfenidone-treatedpatientswithmorepreservedlung func-tion (FVC ≥80% or GAP stage I) and less preserved lung function(FVC<80%orGAPstageII---III)atbaseline.TheGAP indexisamultidimensionalIPFstagingmodelthattakesinto accountgender (G),age (A),and 2lung physiology varia-bles (P) (FVC and DLCO); it distinguishes between stages I,II,andIII.38 _{Themagnitudeofthepirfenidonetreatment}

Treatment-by-time-by-subgroup interaction

P = 0.5300

Adjusted annual rate (SE) of decline in

FVC (ml/year) Nintedanib Placebo 0 -50 -100 -150 -200 -250 -300 FVC >90% predicted n = 166 Δ133.1 mL (95% CI: 68.0, 198.2) n = 108 -91.5 -224.6 Δ102.1 mL (95% CI: 61.9, 142.3) n = 472 n = 315 FVC _{≤90% predicted}

A

B

-1.0

Favors placebo Favors pirfenidone

1.0 -0.5 0.0 0.5 FVC Standardized treatment effect Treatment effect p-value Interaction p-value

Figure1 EvidencethatfavorstheuseofantifibroticsinIPFpatientswithearlydisease.(A)Nintedanib(adaptedfrom35),(B) Pirfenidone(adaptedfrom37).

effectwascomparablebetweenthesubgroups,regardless ofwhetherlungfunctionwasclassifiedasusingFVCorthe GAPmodel(Fig.1).37

Theabovedatasuggestthatpatientsdiagnosedinearly stages of diseaseexperience significant functional deteri-oration and that both nintedanib and pirfenidone have a positiveeffectintermsofslowingprogressionintheseearly stages(Fig.2), clearlysupporting the recommendationto initiatetreatmentimmediatelyafterIPFdiagnosisand high-lightingtheimportanceofpromptdiagnosis.

Severe

disease

PercentpredictedFVC<50%isusuallyassociatedwithsevere disease.Asstatedearlier,thiswasanexclusioncriterionin both the pirfenidone and nintedanib trials.21,25,26,28 Infor-mation about the potential effects of antifibrotic agents inpatientswithseverediseaseisthusscarce,andoverall, thetreatmentindicationsoutlinedbythehealthauthorities excludepatientswiththisgradeoffunctionalimpairment.

Some interesting data in this respect, however, have emerged from post-marketing surveillance studies. In the open-label INPULSIS-ON extension trial, patients who started treatment with nintedanib 150mg bid with per-centpredictedFVC≤50%(n=24)showedasimilarabsolute

Favors

IPF patients with FVC 50% - 90% 21, 25, 26, 28, 36

IPF patients with early disease 35, 37 Patients with severe IPF (FVC < 50%) 39, 40, 42 Against Not favorable Favorable Use of antifibrotics Level of evidence

Figure 2 Schematic synthesis of the level of evidence of antifibroticuseindifferentIPFpatientsubgroups.

meanchangeinFVCfrombaselinetoweek48asthosewith FVC >50% at baseline(−62.3mLvs. −87.9mL),39 suggest-ingthatnintedanibmayhaveasimilartherapeuticeffectin advancedformsofthedisease.

Ina real-liferetrospective studyof pirfenidone in sev-eralItalian interstitiallungdiseasecenters,Hararietal.40

evaluated128 IPFpatientsstratifiedaccordingtoFVCand GAPstage,andreportedagreater reductionindeclinein percentpredictedFVCinpatientswithmoderatetosevere disease.

InJapan,aretrospectiveevaluationof1371patientswho began pirfenidone in the first year after its approval for IPFtreatment detectedfunctionalandsymptomatic stabi-lization, regardless of degree of functional impairment.41 Two-thirdsofthepatientswereconsideredtohaveadvanced disease(stageIII---IV,accordingtoafour-stageJapaneseIPF stagingmodel basedonpartialpressureof arterialoxygen atrestandSpO2duringthe6MWtest).41

Attherecent2016EuropeanRespiratoryCongress, Costa-belandcolleagues42_{reportedontheresultsofacomparison} of 54patients withpercentpredictedFVC ≤50% with530 patients withFVC >50% in the RECAP trial, which wasan extensionof theCAPACITYtrials.Although ahigher treat-ment discontinuation rate was observed in the subgroup withmoreadvanceddisease,long-termtreatmentwith pir-fenidoneresulted in asimilar rateof FVCdecline inboth groups.

Despite the relatively small number of patients, the above data suggest that both nintedanib and pirfenidone haveapositiveeffectinpatientswhohaveadvanceddisease atdiagnosis(Fig.2).

Is

the

treatment

effect

maintained

after

52

weeks?

Anotherquestion thatpost-marketing surveillance studies and extensiontrials such asRECAP43 _{and INPULSIS-ON}44,45 have attempted toanswer is whether or not the positive effectobservedfornintedanibandpirfenidone intermsof slowingFVCdeclineismaintainedafter52weeks.

In2014,Valeyreetal.46_{publishedtheresultsofa} long-termsafetyassessmentofpatientstreatedwithpirfenidone intheCAPACITYtrials.Althoughsafetywastheprimaryfocus ofthestudy,theauthorsdemonstratedthattreatmentwith pirfenidoneforupto7.7years(median,2.6years;range,1 week---7.7years)wasnotonlywelltoleratedbutalsoshowed apersistentpositivetherapeuticeffect.46

More recently, in an oral communication at the 2016 ERSCongress(London,3---9September2016),Nobleetal.47 presenteddatafromtheRECAPextensionstudyonthe long-termeffectsof pirfenidoneonpercentpredicted FVCand showedthatthedrugmaintaineditseffectovermorethan 3years.

Finally, in a recent presentation of results from the INPULSIS-ON extension study, Crestani showed that FVC declinewassimilartothatobservedintheoriginal INPUL-SIStrials,suggesting thatlikepirfenidone, nintedanibalso maintaineditseffectforover3years.44,45

What

should

be

done

once

disease

progression

is

confirmed?

DiseaseprogressioninIPFisdefinedasasustaineddeclineof morethan10%inFVCand/orof15%inDLCO.Lungfunction isusuallyevaluatedevery6 monthsfollowinginitiationof treatment.Oncediseaseprogressionhasbeenestablished,

the treating physician(s) can choose to suspend the drug andadministerpalliative care only;suspend thedrugand switchtoanalternativetherapy;addanalternativetherapy; orcontinuethedrugdespitethefunctionaldecline.There isinsufficient evidence, however,to supportany ofthese options.InMay2016,Nathanetal.48_{publishedtheresultsof} apooledanalysisofpatientsfromtheCAPACITYandASCEND trialsshowingthatinthesubgroupofpatientswho experi-encedafunctionaldeclineinFVC>10%after6months,those whocontinuedto receive pirfenidone had alower risk of subsequentFVCdeclineordeath.Theseresultssuggestthat maintainingantifibrotic therapy mayconfer benefits even afterdiseaseprogressionisconfirmed.

Bonella et al., 49 _{in a German multicenter} obser-vational study of nintedanib in IPF, reported that a subgroup of patients who had shown disease progression underpirfenidone,achievedclinical andfunctional stabil-ity when switched to nintedanib. A combination regimen of pirfenidone and nintedanib has also been proposed, as theoretically it would allow synergistic activity in differentfibroticpathways.Onesafetyand pharmacokine-tics study reported acceptable tolerability for nintedanib administered alone or with pirfenidone and also showed thatnintedanib bioavailability may decreasewith the co-administration of pirfenidone.50 _{Despite these findings,} moredataandstudiesareneededtoguidetreatment strat-egiesinpatientswithdiseaseprogression.

What

is

the

impact

of

adverse

events

induced

by

nintedanib

or

pirfenidone?

Themostcommonadverseeventsreportedfornintedanibin theTOMORROW28_{andINPULSIStrials}26_{werediarrhea,} nau-sea,andvomiting,whichweremoreprevalentinthe150mg dosegroup.Although60%ofpatientsintheINPULSIStrials developeddiarrhea,only4%discontinuedtreatmentforthis reason.InapooledanalysisfromtheTOMORROWand INPUL-SIStrials, Richeldietal.51 _{foundthat 20.6%of patientsin} thenintedanib group prematurelydiscontinued treatment duetooveralladverse eventsversus 15.0%in theplacebo group.Nearly 30%of patients in both groups experienced oneormoreseriousadverseevents.Adverseeventsdueto nintedanib,however,areusuallymildormoderateandcan beeasilymanagedinmostpatients.

AninterimsafetyanalysisoftheINPULSIS-ONextension study44,45 _{showed that patients who completed 96 weeks} ofnintedanibtreatmentexperiencedfeweradverseevents (316.8eventsper100patient-years) thanthosewho com-pleted the initial 52-week evaluation (632.6 events) and thosewhoinitiated treatment after52 weeks onplacebo (550.6 events). A similar situation was observed for seri-ous adverse events (33.9 vs. 36.7 and 38.3 events per 100patient-years)andeventsleadingtotreatment discon-tinuation (14.6 vs. 21.4 events per 100 patient-years in the other two groups). The author concluded that these interimresultsfromtheINPULSIS-ONtrialsupportthe long-term efficacy and safety of nintedanib in patients with IPF.

Themostcommonadverseeventsduringthepirfenidone CAPACITY19_{andASCENDtrials}25_{weregastrointestinalevents} (nausea, dyspepsia, vomiting, and anorexia) and skin

disorders(rash,photosensitivity). The events were gener-allymildormoderate,reversiblewithdosereductions,and withoutclinicallysignificantconsequences.

Inacomprehensiveanalysisofsafetyacrossfourclinical trialsevaluatingpirfenidoneinpatientswithIPF,themore frequent adverse eventsreported werealsomild to mod-erate nausea(40%), dyspepsia (21%), vomiting (18%), and rash(26%).Theseeventsrarelyledtotreatment discontin-uation,despitethelongermediandurationof exposureto pirfenidone(2.6years).46_{Thisstudyalsoshowedthatwhile} gastrointestinal and skin-related adverse events are rela-tivelycommonatthebeginningoftreatment,theydecrease considerablyafterthefirst6monthsandremainlowduring thecourseoftreatment.

Oguraetal.,41 _{inaprospectivepost-marketing} surveil-lance studyof patients withIPF administered pirfenidone inthe firstyear afteritslaunchin Japan,found a similar safetyprofiletothatreportedintheJapanesephaseIIand IIItrials,with64.6% of patientsexperiencing at leastone adverse event.The most commonevents were decreased appetite,photosensitivity,andnausea,andtheseresolved orimprovedinthemajorityofcases.

The resultsoftheRECAPopen-labelextensionstudyof pirfenidoneshowedthatthetypeandfrequencyofadverse eventsafter 60weeks oftreatment were similartothose observed in the initial 72-week phase III CAPACITY trials and rarely resulted in early discontinuation of therapy.43 The incidence of nausea and photosensitivity was 35.4% and11.9%intheCAPACITYtrialsversus32.0%and11.8%in theRECAPstudy.Rashanddiarrhea,bycontrast,wereless commonin RECAP(18.0% and16.9% vs. 31.0% and27.0%, respectively).21,43

Conclusions

Basedontheavailabledatafromclinical trialsand exten-sion studies, we can conclude that both pirfenidone and nintedanibhaveasignificanteffectonFVCdecline, regard-lessofdiseasestageassessedbyFVCorGAP.Moreover,the RECAP and INPULSIS-ON extension trials showed that the effectwasmaintainedovertime.Bothnintedaniband pir-fenidonewerefoundtoprolongsurvival,withareductionin bothIPF-relatedandall-causemortality.

Despitetherelativelyhighratesofadverseevents,which aremostlygastrointestinalinnature,theexistingdata sup-port therecommendation thattreatment withnintedanib orpirfenidoneshouldbeconsideredwhenIPFisdiagnosed, regardlessofdiseasestage.SinceIPF isaprogressivelung disease,earlydiagnosisandtreatmentarecrucialfor slow-ingfunctionaldecline, reducingsymptoms,and improving qualityoflife.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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