179

European Journal of Endocrinology -18-0616 (IGFI) due to a GH-secreting pituitary adenoma ( (IGFI) due to a GH-secreting pituitary growth hormone(GH)and insulin-likegrowthfactorI Acromegaly isararedisease causedbyhypersecretionof Introduction patients withacromegaly. Conclusions: their follow-upwasreportedin3%. both. InpatientswithnormallivertestsatPEGVstart,an ALT orASTelevationof (72.2%) hadnochangeintumorsizerelativetothepriorscan;16.8%adecrease,6.8%anincreaseand4.3% in 22%ofpatients,which2.3%wereconsideredtreatmentrelated.LocallyreportedMRIsshowedmostpatients patients (54.4%),ofwhich570wereconsideredtreatmentrelatedin337(16.1%).SeriousAEsreported PEGV increasedfrom12.8 of patientswithnormalIGFIlevelsincreasedfrom53%atyear1to73%10,andtheaveragedailydose of of those.AtstartPEGV, 89%ofpatientshadIGFIlevelsabovetheupperlimitnormal(ULN).Thepercentage Results: performed. Methods: of May12,2016. study thelong-termsafetyandefficacy ofPEGV. Thisreportcomprisesthesecondinterimanalysisof2090patientsas pegvisomant (PEGV),agrowthhormonereceptorantagonistandhasbeenconductedsince2004in15countries to Objectives: Abstract Sollentuna, Sweden Global ClinicalAffairs, Pfizer Inc.,Collegeville,Pennsylvania,USA,and Turin, Italy, Medicine, CharitéUniversitätsmedizin,CampusMitte,Berlin,Germany, Hôpital delaConception,Marseille,France, Barcelona, Spain, USA, MC, Rotterdam,theNetherlands, 1 Peter Jönsson Christian J Strasburger Michael Buchfelder in ACROSTUDY observations from 2090acromegaly patients Long-term treatment withpegvisomant: Department ofNeurosurgery, UniversityofErlangen-Nürnberg,Erlangen,Germany, https://doi.org/ https://eje.bioscientifica.com Clinical Study 4 Endocrinologia (MalaltiesdelaHipòfisi),HospitalSantPau,UniversitatAutònomaBarcelona(UAB), PriortostartingPEGV, 96%ofpatientshadreportedsurgery, radiation,medicaltherapyoranycombinations 8 Descriptiveanalysesofsafety, pituitary imagingandoutcomesonPEGVtreatmentupto12 yearswere Endocrine CareGlobalMedicalAffairs, PfizerInc.,New York City, New York, USA, ACROSTUDYisaninternational,non-interventionalstudyofacromegalypatientstreatedwith 10.1530/EJE Thissecondinterimanalysisconfirmsthatlong-termuse ofPEGVisaneffective andsafetreatmentin 5 Department ofEndocrinology, CentredeRéférencedesMaladiesRaresd’OrigineHypophysaire, 10 and -18-0616 1 Juliana H Hey-Hadavi , Aart-Jan van der Lely 6 , Ezio Ghigo

mg (year1)to18.9 3 6 Neuroendocrine Unit,MassachusettsGeneralHospital,Boston,Massachusetts, © 2018EuropeanSociety ofEndocrinology M Buchfelderandothers 6 Department ofMedicineforEndocrinology, DiabetesandNutritional 7 , Cecilia Camacho-Hubner Printed inGreatBritain 8

mg (year10).Atotalof4832adverseevents(AEs)werereportedin1137 2 , Beverly M K Biller 10 1 7 Endocrine Care,PfizerHealthAB, ). University HospitalCittàSaluteeScienza,

and the substitution of glycine for alanine at position amino acidsubstitutionsingrowth hormone–bindingsite1 Pegvisomant (PEGV)isapegylated GHanalogwitheight in ACROSTUDY Findings frompegvisomantuse Published byBioscientifica Ltd. 2 8 Department ofMedicine,ErasmusUniversity 3 , Kaijie Pan , Susan M Webb 9 Endocrine Care 9 , Joanne Lavenberg > 3 × 4 Downloaded fromBioscientifica.com at09/25/202102:39:54PM ULNatanytimepointduring , Thierry Brue (2018) Endocrinology European Journal of uk-erlangen.de Michael.Buchfelder@ Email to MBuchfelder should beaddressed Correspondence 179 179 5 9 , :6 , , 419–427

419 –427 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com that contributedlargerpatient cohortshasresultedin 13 with somatostatinanalogsand/or dopamineagonists( monotherapy andmostrecently ofPEGVincombination of subgroupsinACROSTUDY focused onPEGV use as enzymes and lipodystrophy. Subsequent publications tumorsize,elevated liver low ratesofincreasedpituitary enrolled asofDecember31,2009( and includeddatacollectedon1288patientswhowere performed fiveyearsafterthestartofACROSTUDY ( understanding ofPEGVtreatmentinclinicalpractice additional patientenrolmentwouldprovideabetter trials. Itwasconcludedthatlonger-termfollow-upand inthe pivotalclinical was lowerthanthatobserved seen, butitwasnotedthattheIGFInormalizationrate In theseanalyses,nounexpectedsafetyconcernswere reported ondatafromthestudyatyears4and5( report forms.ThefirsttwopublicationsfromACROSTUDY reported datafromfollow-upvisitsinelectroniccase in the study on an ongoing basis and the investigators patients with acromegaly ( the long-termsafetyandoutcomeofPEGVtreatmentin with PEGV. Themainstudyobjectivewasto monitor study and was open to all patientswith acromegaly treated international, post-authorization,safetysurveillance the long-termfollow-updata. have beenincludedintoACROSTUDYandaddedto global ACROSTUDY( information andcontributedtothedevelopmentof over 300patients( (GPOS), initiatedin2003,whichreporteddatafrom Study from theGermanProspectiveObservational clinical setting. developed to provide these long-term data in a real-world profile ofPEGVinacromegalypatients.ACROSTUDYwas program tobetterunderstandthesafetyandefficacy to collectadditionaldataoutsideoftheclinicaltrial of actionasaGHreceptorantagonist,therewasneed 97% ofpatients( in reliefofsymptomsandnormalizationIGFIupto acromegaly and demonstrated that PEGV was effective studies includedapproximately200patientswith years.Theinitial pivotal acromegaly for morethan15 ( receptor signaling.PEGVactsasaGHantagonist receptor and prevention of functional growth hormone– 120, resultinginbothenhancedaffinityfortheGH 2 9 , ). Ithasbeenavailableforthemedicaltreatmentof Clinical Study ). Inaddition,theavailability ofdatafromcountries ACROSTUDY was initiated in 2004 to serve asan ACROSTUDY wasinitiatedin2004toserve The firstreal-worlddataonPEGVtreatmentcame 10 ). Thefirstinterimanalysisofthisstudywas 3 , 4 5 ). Becauseoftheuniquemechanism , 5 , 6 6 ). Itprovidedvaluableclinical , 8 7 , ). Mostpatients from GPOS 9 , 10 M Buchfelderandothers ). Patients were enrolled 11 ). Thisanalysisnoted 9 , 10 12 ). ,

procedures beyondroutineclinicalpracticewererequired of assessments,noadditional diagnostic ormonitoring protocol maderecommendationsforthetimingandtype in areal-worldclinicalpracticesetting.Althoughthe treatment onalargegroupofpatientswithacromegaly to monitorthelong-termsafetyandoutcomesofPEGV studywasconducted This open-label,global,observational Study design Methods the patientswhowerepartoforiginalcohort. and reportsthelong-termexperienceforupto12 years in describes theresultsofPEGVtreatmentinACROSTUDY on allpatientsinthemainstudyasofMay12,2016.It and Spain( publicationsfromFrance,Italy several country-specific the reportingperiodencompassed thedateofinformed (MedDRA) version14.1.For serious adverseevents(SAEs), Activities ofRegulatory terms fromtheMedicalDictionary imaging. Adverseevents(AEs) wereclassifiedaccordingto history, testing andpituitary physicalexams,laboratory included findings from baseline and follow-up medical when theywereenrolled( study; asnoted,somepatientswerealreadytakingPEGV of PEGV start forms usingaWeb-based tool. Baselinewasdefined as The parameterswerecapturedonelectroniccasereport each routineclinicalvisitwasthenaddedlongitudinally. the medicalrecordsatbaseline;informationgathered at countries exceptforItalyandtheUnitedStates. patients ( hypertension, werenoteligibleforenrolment.Pediatric palsiesorintracranial of visualfieldloss,cranialnerve decompress the tumor or non-medical therapy because investigational trialsforacromegaly, to requiredsurgery exclusion criteria.Patientswhowereparticipatinginother on anongoingbasisaftermeetingallinclusionand Patients withacromegalytreatedPEGVwereenrolled Patients anddatacollection have beenpublishedpreviously( and localpractice.Descriptionsofthestudymethods determined bytheinvestigatorbasedonclinicaljudgment the study, PEGVdosing,frequencyandtitrationwere as partofthestudy. natureof Duetotheobservational in ACROSTUDY Findings frompegvisomantuse This report comprises the second interim analysis Data werecollectedbythesiteinvestigatorsfrom < 14 8 yearsofage)couldbeincludedinall 18 , regardless of time of enrolment into the , 15 , 16 ). Downloaded fromBioscientifica.com at09/25/202102:39:54PM i. 1 Fig. 8 ). Reportedinformation , 9 , 179 10 :6 , 11 ). 420 via freeaccess European Journal of Endocrinology point oroveraspecifiedtime frame.Descriptiveanalyses measure of interest at a specified time with an observed percent, which were based on the total number of patients summarized bypresentingthe frequencydistributionand and yearlyvisitsthereafter. Categoricalvariableswere after PEGV start), month 6,12 before and 1 day year PEGV start,exceptforMRIscanswhichallowed1 after beforeto1 day reporting: Baseline(from6 months treatment. Thefollowingvisitlabelswereusedfordata order tocaptureasmuchinformationpossibleduring data reportedatbaselinewereincludedintheanalysis in could bepriortoenrolmentintoACROSTUDY, clinical baseline wasdefinedasthestartofPEGVtreatment,which received at least one PEGV dose. Importantly, because defined as all patients who enrolled in ACROSTUDY and and summarizeddescriptively. Thefullanalysissetwas andinfollow-upafterPEGVstarttobeevaluated history in thisstudy, withalldatacollectedregardingacromegaly There werenopre-specifiedstatisticalhypothesestested Statistical methods capture. informed consent signature and process prior to any data andethicalrequirements,including local legal,regulatory investigator sitesandconductedinaccordancewithall approved byindependentlocalethicalcommitteesatthe as describedinapreviouspublication( decrease), thescansweretobesentforcentralassessment tumorsize(increaseor indicated achangeinpituitary additional informationifnecessary. IflocalMRIreports according tolocalpoliciesandsiteswereaskedprovide PEGV. Remoteand/oron-sitemonitoringwasperformed consent through28calendardaysafterthelastdoseof Data collectionandflow. Figure 1 • • • Star Before Pegvisomant Clinical Study Co La Pi tu t bo mo itar ra rb to y Im idies ry T ag ests in Start (Baseline) Pegvisomant g • • • Treatmen Pegvisomant Co-morbidies La Pi tu bo itar rato t y Imag ry T ests in g M Buchfelderandothers Start ACROSTUDY • • • • enrollment ACROSTUDY Ad Co-morbidies La Pi tu bo 11 ve itar rato rse ). Thestudywas y Imag Ev ry en T ests ts ( in g AE May 12,2016 Freeze Database s) Country distribution(%). Figure 2 (22.3%) werestillongoingsubjectsatthetimeofdata Among the2090patientsenrolledinACROSTUDY, 466 from 14 European countries and the United States ( As of May 12, 2016, data from 2090 patients were available Participants Results shift analysis. during thecourseofPEGVtreatmentwereincludedin either ASTorALT measuredatbaselineandanytime times theupperlimitofnormal(ULN).Patientswhohad abnormal; abnormalwasdefinedasASTorALT levels results shiftedbetweennormal,mildlyelevatedor a ‘shiftanalysis’wasperformedtodeterminehowmany patients with liver tests (AST/ALT) reported at baseline, patients treatedwithPEGVwereperformed.Amongthe of safety, tumorstatusandtreatmentoutcomesforall .,rne –91 years). Patients were followed in 8.1, range:0–19.1 (median Mean PEGVtreatmentdurationwas7.6 years Patient characteristics imaging. for pituitary data recordedand2045patients(97.8%)wereevaluated causality. Atotalof2080(99.5%)patientshadlaboratory for analysisofAEsincludingduration,severityand (100%) patientswereincludedinthesafetypopulation deceased. There were 78 (3.7%) deaths reported. All 2090 due toclosureofstudysites,exitingorbeing concluded theirparticipationpriortothistimepoint freeze inMay12,2016,and1624(77.7%)subjectshad in ACROSTUDY Findings frompegvisomantuse 10 20 25 30 15 0 5 25.3 20.8 14.9 9. 6 7. 87 .8 Downloaded fromBioscientifica.com at09/25/202102:39:54PM 2. 7 2. 3 2. 2 1. 179 71 https://eje.bioscientifica.com :6 .7 1. 5 0. 8 0. Fig. 2 421 6 0. > via freeaccess 3 ). 3 European Journal of Endocrinology https://eje.bioscientifica.com more thanoneco-morbidity reported.Ofthesepatients, reported beforestartingPEGV andpatientscouldhavehad of patients( during enrolment in ACROSTUDY( start ofPEGVbutbeforeACROSTUDY start,aswell during threetimeperiods:beforePEGVstart,afterthe Acromegaly-associated co-morbiditieswerecaptured Co-morbidities had stereotacticradiation. received radiationafterinitiationofPEGV, most(77%) Among the13.1%ofthosewhowerereportedtohave (TSS in98%ofthesecases). surgery subsequent pituitary 49% andstereotacticin51%ofcases. patients whohadradiation,conventionalwasreportedin (TSS).Amongthe26%of had trans-sphenoidalsurgery the 76% of patients who had surgery, most (96.4%) medical therapyoranycombinationsofthose.Among PEGV, 96%ofpatientshadundergonesurgery, radiation, in thepatientspriortoinitiationofPEGV. Priorto starting Figure 3 Acromegaly treatment after theageof70 years. years,while166patients(7.9%)startedPEGV age 70 spectrum, therewere47patients(2.2%)diagnosedafter years.Onthe othersideofthe before theageof18 while15patients(0.7%)startedPEGV age of18 years, patients (2.2%)diagnosedwithacromegalybeforethe of acromegalyaswellstartPEGV. There were 46 based on the age at diagnosisgrouped by age category same timeasenrolmentinACROSTUDY. Patientswere The remaining subjects started PEGV treatment at the days(median 345.5;range 598 start ofPEGVtreatmenttoACROSTUDY enrolment intoACROSTUDYwiththemeantimefrom were 1572patients(75%)whostartedPEGVpriorto years).There yearsvs50.8 slightly youngerage(48.3 years)andwerealsostartedonPEGVat vs 43.3 years Males wereslightlyyoungeratdiagnosis(40.8 years). yearsmedian49.8,range:3.9–85.6 was 49.5 and themeanageatstartofPEGV(baseline) years) years(median41.1,range: 1.7–83.7 was 42.1 (51 vs49%).Themeanageatdiagnosisofacromegaly and theproportionofmalesfemaleswassimilar − ACROSTUDY for a mean of 6.3 years (median 6.8, range 0.1 to+12.1 years). MostpatientswereCaucasian(93%) Clinical Study After PEGVstart,8.6%ofpatientsreported summarizesthemaintreatmentparadigmsused n

= 1827, 87.4%)atleastoneco-morbidity was M Buchfelderandothers − Fig. 4 7 o+94 days). 970 to+3944 ). Inthemajority

and beforeenrolmentintoACROSTUDYafter co-morbidities before PEGV start, after PEGV start co-morbidities combinedandthemostcommon dopamine agonist. combination withanothermedication,inmostcases,a 31% werereportedtohavebeentreatedwithSSAin as theonlymedicationpriortostartingPEGV, while 66% hadbeentreatedwithasomatostatinanalog(SSA) Treatment foracromegalypriortoinitiationofPEGV. Figure 3 Most commonlyreportedacromegaly-related co-morbidities. Figure 4 in ACROSTUDY Findings frompegvisomantuse

Percentage of paents The overallpercentage ofpatientswithall n= 1(0%) Radiation only 87. 4 30.3 7. 2 n=42 (2%) Radiation Medical 51. 1 12.4 12 & 39. n=376 (18% Medical Therapyonly 2 28. Downloaded fromBioscientifica.com at09/25/202102:39:54PM n=35 (1.7%) Surgery Radiation & n=464 (22.2% & Radiatio Medical, Surgery 2 17.3 33. ) 3 15.9 n 13.3 ) ( Surgery n=1000 Medical 32 47.8% 179 10.5 14 A ACROSTUDY Between PEGVstartan Befo :6 ) .7 er & n=90 (4.3%) Surgery onl re AC 20.3 PE RO 6. GV ST 1

2. st UD 7 ar Y t y 17.2 st ar 422 7. t d 1 3. via freeaccess 3 European Journal of Endocrinology recently reported( combination therapywas increasinglyemployedas treatment, overtimethat percentage decreased and the medicationasmonotherapy atthestartofPEGV year 12( patients receiving We a steady increase inthenumber of also observed 18.7% received 20 to received 15to doses wereup-titrated.Forexample,atyear1,20.6% remained initiallythemostcommon,overtime, dose of 10to patients ( between 2and6timesperweek( prescribed PEGVeitheronceweekly( administered PEGVoncedaily, whiletheotherswere At PEGVstart,most( Efficacy andsafety syndromes (46patients,2.2%). acromegaly (9patients,0.4%)orotherassociated McCune Albrightsyndrome(20patients,1%),familial endocrine neoplasia(MENtype1)(24patients,1.1%), syndrome in4.9%ofpatients;theseincludedmultiple Acromegaly wasreportedinassociationwithaninherited disorders werenotedonlyinasmallnumberofpatients. associated withthediagnosisofacromegaly, andsuch common. ( of 420patients,2%).Inpreviouslyirradiatedpatients (156 of551patients;28.3%)anddiabetesinsipidus(8 function (185of635 patients; 29.1%),adrenal function (230 of 607 patients; 37.9%), followed by thyroid function forpituitary–gonadal commonly observed function, deficienciesatPEGVstartweremost In patientswithinformationreportedaboutpituitary Pituitary deficiencies (2.3, 2.5,1.3%)andbreast(3.2,1.7,0.7%). in thyroid(18,7.3,6.7%),colon(14.9,9.6,7.3%);prostate malignant tumorsatthethreetimeperiods(respectively) and diabetesinalmostone-thirdofpatients. hypertension wasreportedinmorethanhalfofpatients ACROSTUDY startareshownin n Clinical Study

= 542, 26%), multiple pituitary deficiencieswere542, 26%),multiplepituitary Most patients (88.8%) had no genetic syndromes Included under‘Tumors’ arebothbenignand ≥ 30 Fig. 5 < mg. Althoughdailydosingof10to n 15

= 1439, 68.9%)hadastartingdailydose mg, while57patients(2.7%)startedata ). Whilemostpatients(55.5%) received < 20 13 mg dailyvs7.3%atPEGVstartand ≥ 30 ). < mg/days from2.7 to 20.6%at n 25

= mg vs 5.8% at PEGV start. 1734, 83%)patientswere M Buchfelderandothers Fig. 4 n 6, .%. Most 7.8%). =164, . BeforePEGVstart n 8, .% or 8.6%) =180, < 15 mg with thediagnosisofacromegaly. Thenextmost increased’ (10.5% of patients), which was associated (54.4%), andthemostcommonAEreportedwas‘IGFI A totalof4832AEswasreportedin1137patients Safety PEGV from12.8 accompanied by an increase in the mean daily dose of at year10( normal IGFIlevelsincreasedfrom53%atyear1to73% in thenormalrange.Thepercentage ofpatientswith At thestartofPEGV, only11%ofpatientshadIGFIlevels Efficacy Pegvisomant treatmentbyyear(dailydose). Figure 5 IGF-I normalizationovertime. Figure 6 in ACROSTUDY Findings frompegvisomantuse 10 20 30 40 50 60 70 80 0 IG IG Star F- F- Peg I> I no UL t rm N Percentage of patients (% al 100

(% 10 20 30 40 50 60 70 80 90 123456789 ) 0 ) n=1450 S 88. 11. tart i. 6 Fig. 54 45 n=1188 YR1 mg atyear1to18.9 44 35 ). Thisincreasedlevelofcontrolwas n=1182 YR2 0. 7. 23 45 n=1039 Downloaded fromBioscientifica.com at09/25/202102:39:54PM YR3 8. 8. 9 26 n=880 37. YR4 06 83 n=686 YR5 5. 2. 43 46 n=516 mg atyear10. 179 YR6 4. 4 https://eje.bioscientifica.com 3 :6 n 37. 60. YR7 =343 93 66 30 25 20 15 10 <1 0m mg -< -< -< -< n YR8 =232 30 25 20 15 10 4. 4. or g 13 26 mg mg mg mg > n=157 YR9 11 0. 5. 6 6 423 n=105 YR10 25. 73. 12 via freeaccess 7 3 European Journal of Endocrinology https://eje.bioscientifica.com nine patients (0.4%). Of the 1094 patients with normal related. Drugwithdrawalfor thisreasonwasreportedin of patients,which4.2% wereconsideredtreatment patients, therewasnochange. reading confirmedanincrease in29patients;while23 had anincreaseasperlocalreading( centralized re-assessment( MRIs showingasignificantchangeweretobesentfor drug withdrawn.Aspreviouslyreported,anypituitary as treatmentrelated, eight patients (0.4%) had study (1%) wereconsideredtreatmentrelated.Ofthoselisted were reportedasAEsfor90patients(4.3%)ofwhich21 had both an increase and decrease. Changes in tumor size decrease intumorsize,6.8%hadanincreaseand4.3% change in tumorsize relative tothe prior scan; 16.8% had assessed MRIsshowedthatmostpatients(72.2%)hadno reported in follow-up after PEGV start. Reports of locally imagingresult 1712 patientshadatleast1localpituitary for thisstudy. non-serious AEsandtheseverityofwerenotcaptured site conditions.Thenumberofdiscontinuationsdueto reaction, death,diseaseprogression)andadministration recorded as generaldisorders (i.e. asthenia, adverse drug The mostcommonSAEsresultingindiscontinuationwere Different typesofcancerwerereportedineightpatients. acute MI( disorders suchascardiacfailure( due to variety of reasons, most commonly cardiac considered unrelatedtothetreatment.Deathsoccurred of deathwascardiovasculardisordersandalldeathswere due totreatment-relatedSAEs.Themostcommoncause 78 patientsduetodeathand24discontinuing discontinued fromACROSTUDYduetoSAEs,including (1%) anddeath(1%).Overall,146patients(7%)were tumorrecurrence(1%),osteoarthritis SAEs werepituitary considered treatmentrelated.Themostfrequentlyreported were experiencedin22%ofpatients,which2.3% fatigue ( ( erythema conditions (lipohypertrophy ( intestinal disorders( increase ( increased ( (in patients (16.1%).Amongthesetreatment-relatedAEs considered treatmentrelatedwereexperiencedby337 deficiency (4.6%)andarthralgia(3.7%).Intotal,570AEs commonly reportedAEswereheadache(4.9%),vitamin-D Clinical Study ≥ Hepatobiliary-related AEswerereportedfor9.8% Hepatobiliary-related imaging, Of the2045patientsanalyzedforpituitary 2 patients)werelivertestelevations(transaminases n

n =

= n n 6) and pituitary tumorrecurrence( 6) andpituitary 4

) lpdsrpy ( lipodystrophy =3), 18), ASTincrease( = ), cardiacarrest/suddendeath( 30), hepaticenzymeincrease( n 6, shna ( asthenia =26), 10 n ). Amongpatientswho n 5

1, ecin ( reactions =31), = M Buchfelderandothers ), myocardialinfarction/ n 5)), followedbygastro- ), edce ( headache =5)), n n 1) te central the =119), ) ijcin site injection =9), n n 8, ALT =18), ) SAEs =9). n n =16), =7), 4 ). follow-up, whilein3%atleastoneASTorALT value continued tohavenormalASTandALT valuesduring baseline ASTandALT measurements,most(62%), of adosetitrationscheme (as typicallydoneinclinical the useofdifferentcriteriafor IGFInormalization,absence control betweenclinicaltrials andACROSTUDYinclude 16 reported as‘co-morbidities’andnotadverseevent. an additionalfourpatients,injectionsitereactionswere One caseoflipohypertrophywasreportedasaSAE.In considered bytheinvestigatortobetreatmentrelated. (3.4%) and the majority (65 patients, 3.1%) were ULN whileonPEGVtreatment. (between 1and3 three shiftedtonormal,mildlyabnormal entering thestudywithanASTorALT value3–5 while 10% had ALT or AST (46%) remainedwithintheirbaselinemeasurementrange, AST andALT duringfollow-uponPEGVtreatment,41 3 with amildly elevated AST or ALT valuesbetween 1 and ULN wasreported.Ofthe89patientsenteringstudy ACROSTUDY publications ( inthefirstinterim analysis andother what wasobserved lower thanwhatwasseeninclinicaltrials,itissimilar to time (upto73%inyear10).Whilethisrateissomewhat year. Serum IGFI normalization rate increased over 1 being treatedwithPEGVforamediandurationofalmost IGFI control.Mostpatientsentered ACROSTUDY after which inthemajority(89%)didnotresultadequate radiation, medicaltherapyorcombinationsofthose, to starting PEGV, 96% of subjects had undergone surgery, testswereperformed locally.required andlaboratory Prior practice with no specificprotocolprocedures orvisitdates of PEGVtreatment.Patients were treatedaccordingtolocal ‘real-world’ data set ( acromegaly provided an opportunity to evaluate a large studyoftreatmentwithPEGVin This observational Discussion ACROSTUDY havebeenpreviouslyreported( resulted inanormaloutcome.Datafrompregnancies and threeunknown.Allchildbirthswerereportedtohave pregnancies included nine childbirths, three abortions patient’s partner) were reported. The outcomes of these total of15pregnancies(threewhichoccurredinthe in ACROSTUDY Findings frompegvisomantuse × ). Possibleexplanationsfor thediscrepancyinIGFI ULN,30patients(34%)shifteddownwardtoanormal Injection site reactions were reportedfor 71 patients Despite the requirement ofadequatebirth control, a × ULN)andonepatientshiftedto n

= 2090) over an average of 7.6 years Downloaded fromBioscientifica.com at09/25/202102:39:54PM > 3 3 , × 4 ULN. Of the seven patients , 9 , 10 179 , 11 :6 , 12 , 17 13 ). , × 14 ULN, 424 , > > 15 5 3 via freeaccess × × ,

European Journal of Endocrinology of Japanesepatientswith acromegaly, Shimatsu elevations ofliverenzymes.Inareport and transitory in 2oftheir27patients(7.4%) mild(1.5and2.3 pegvisomant inasingleBrazilian centerandobserved of PEGV. Kasuki 4 patientstransaminasesnormalizeddespitecontinuation with PEGV, 5casescould be attributedtogallstonesandin patients withtransaminaseselevationsduringtreatment earlier studybyBiering transient andtherewerenoreportsofliverfailure.Inan due tolivertestelevations.Notably, mostelevations were subjects. In ninepatients (0.4%), PEGV was withdrawn their follow-upinACROSTUDYwasreported3% of ALT orAST elevationof and hypertension. patient withmetabolicco-morbiditiessuchasdiabetes that PEGVmayhavebeenmorecommonlyprescribedin acromegaly in anoldercohort,butanother possibility is These differencescouldbeduetothelongerdurationof and hypertensionin51%ofpatientsatthestartPEGV. co-morbidities werereportedhigherwithdiabetesin32% diagnosis ofacromegaly. Inthecurrentstudy, those and hypertensionin28.8%ofpatientsatthetime al et Database of3173patientswithacromegaly, Petrossians common. InananalysisoftheLiègeAcromegalySurvey IGFI initial normalization. of any‘escape’phenomenon, i.e. elevationofIGFIafter disease ( who neededhigherdosesofPEGVhavemoreaggressive that patients treatment in 56 patients, it was observed a recentanalysisofACROSTUDYlookingathigh-dose more patientsweretreatedwithdoses limiting doseescalations.Itwasalsonotedthatovertime adherence, possibleadverseeffectsandeconomicreasons included insufficient dosetitration, inadequate patient proposed potentialreasonsforthisdiscrepancy which inclinicaltrials.Tritosobserved normalization ratemethodsarenotcomparabletothose of adherencewerenotpartthisstudy. Therefore, world settingadherencemayfluctuate andmeasurements outcomeinclinicaltrials.Inreal- typical fortheprimary basis inthisdatabaseratherthanatonlyonetimepoint and thatthenormalizationratewasassessedonayearly the maximalalloweddailydoseaccordingtolabel, of patientswithanelevatedIGFIwerenottitratedupto trials), useofavarietyIGFIassays,thefactthatnumber Clinical Study In subjectswithnormallivertestsatPEGVstart,an At the time of PEGV start 89% of patients had . ( >

ULN and co-morbidities at PEGV start were 21 20 ) describedthepresenceofdiabetesin27.5% ). InACROSTUDY, there wasnoindication et al . ( et al > 23 3 ) reported the experience with × . ( ULNatanytimepointduring 22 ), it was observed thatin12 ), itwasobserved M Buchfelderandothers t al et . ( 19 ≥ ) alsorecently gdy In 30 mg/day. × ULN) t al et . retrospective analysis of75patientsintwocenters in ( data clinical trialsandpriorlong-termobservational from the initial analysis are consistent with observations discontinuation ofpegvisomant.Theresultsthis moderate) of16patients(16.7%),whichresolvedafter ( period andasignificantdecrease offastingbloodglucose amean weightincreaseof3 they observed similar findingsasreported inthisanalysis;however, entered intoACROSTUDY were evaluated.Theyfound by Chanson patients anddatathanothers( global database,certaincountrieshavecontributedmore countries. AlthoughACROSTUDYismaintainedas a long-term datainavarietyofclinicalsettingsacross15 central reading. not allscansthatshowedachangeweresubmittedfor imagingassessment wasthat limitation ofthepituitary after SSAwithdrawal.Aswaspreviouslyreported( the changeofmedicationandreflectedreboundgrowth or iftheymayhavebeentemporallyassociatedwith volumeincreasespredatedthePEGVtreatment pituitary assessments, wewerenotabletodeterminewhetherthe natureofourstudyandtimingMRI the observational another treatment (most cases dopamine agonist). Due to with SSAonly, while31.3%weretreatedwithSSAplus prior toPEGVinitiation, 65.9% ofpatients were treated treatment withdrawnpriortoPEGV. InACROSTUDY, first yearofenrolment.Allthreepatientshadoctreotide volume increase tumor during PEGVtreatmentbyMRI.Theyobserved examining the long-term course of adenoma volumes published theresultsofaGermanprospectivestudy growing priortoPEGVtreatment( significant tumorsizeincrease;however, thistumorwas the UnitedKingdom,onepatientwasreportedtohave ACROSTUDY ( consistent withthepreviouslyreporteddatafor not havebeentreatedwithPEGV. the visitsandpatientspronetolivertestelevationsmay natureofthestudy,non-interventional thefrequencyof early monthsoftherapymayhavebeenmissedduetothe occur. However, transientelevationsespeciallyinthe Monitoring of liver test during PEGV treatment should worsening oflivertestsatanytimeduringfollow-up. mild elevationsofALT orAST(1–3 of thelivertestresults,majoritypatientswith in ACROSTUDY Findings frompegvisomantuse 3 24 , ) reportedALT andASTincreasesin3(2mild1 8 The pituitary MRIfindings inthis analysis were The pituitary ACROSTUDY providedanopportunitytoevaluate , 10 , 11 , t al et 12 5 > , , . ( 25% in 3 of 61 patients (4.9%) during the 13 9 , 14 , 10 14 ), thedataof292Frenchpatients , , Downloaded fromBioscientifica.com at09/25/202102:39:54PM 15 11 , , 22 12 ). Inthecurrentanalysis i. 2 Fig. , 13 × 17 ULN)didnotreport 179 , ). Inapublication https://eje.bioscientifica.com ). Buhk 14 :6 , kg over5-year 15 , t al et 16 ). Ina 11 . ( 425 ), a 25 via freeaccess )

European Journal of Endocrinology https://eje.bioscientifica.com patients inwhichPEGViseffective) cannotbeexcluded. Finally, any bias in reporting or in patient selection (i.e. or tocaptureanypossible reasonfordiscontinuation. stopped becausetheydidnot responsetoPEGVtreatment current studydidnotallowustodeterminepatientswere also discontinuedparticipationinACROSTUDY. The After discontinuationofPEGVforanyreasonmostpatients depended onthepatient’s visitsandleveloffollow-up. to individualclinic/physicianpracticeanddataentry captured routineclinicalcarethatwasprovidedaccording regarding enrolledpatients.ThisisbecauseACROSTUDY additional limitation was possible underreporting of data study, and therefore never enrolled in ACROSTUDY. An who stoppedPEGVbeforebeingconsideredforthe early sideeffectswouldhavebeenobtainedforpatients to enrolmentinACROSTUDY. Inaddition,nodataabout who hadalreadybeentakingPEGVforalongtimeprior have beenmissedearly in treatmentthosepatients the source documents, when available.Safetydatamay relevant clinicalinformation,suchasco-morbiditiesfrom addressed by retrospective collection of additional entered before starting the medication. This was partially meant thatmanypatientsdidnothavebaselinedata PEGV treatment(i.e.didnotneedtobenaive) enrolled intothestudyregardlessofwhentheystarted have limitations.Forexample,thefactthatpatientswere studieslikeACROSTUDY surveillance observational, and along-termpatientfollow-upperiod.Nevertheless, large patient numbers, wide geographic representation, patients inACROSTUDYwereWestern Europe. analysis; thecountriesthatcontributedmajorityof care andaccesstomedicationsmayhaveinfluencedthis separately. Differencesintreatmentpractice,standardsof datawerenotexamined current analysis,country-specific of thepatientsreceivedcombinationtreatment( However, PEGVdosingwaslowerinthatreport,and52% showed similarIGFIcontrolasreportedglobally( also confirmedafavorablesafetyandefficacyprofile year 6.ThepublicationofSpanishdatafrom199patients 70.9% ofpatientswerefoundtohavenormalIGFIlevelsat treatment modalities.Nonethelesstheyreportedthat in patientswhohadfailedtonormalizeIGFIwiththese orradiotherapyandSSAfailure)therefore surgery In Italy, PEGV is available as third-line therapy (after high efficacyandsafetysimilartotheglobalcohort( ACROSTUDY, reportedthattreatmentwithPEGVshowed 341 patientsfrom25centersincludedatthattimein over time.ThepreviouslyreportedItalianexperiencein Clinical Study There are many strengths of ACROSTUDY, including M Buchfelderandothers 16 ). Inthe 16 15 ). ). investigators ( real-world outcomes of PEGV treatment and numerous ACROSTUDY providesarobustglobalperspectiveon Conclusions follow-up, allowedforabetterunderstandingofoverall enrolment inclinicaltrials,andthelongerdurationof including those who may not have been eligible for from clinicaltrials.Thelargernumbersofsubjects, information thatcomplementsthesafetydataobtained reassuring. liver test elevationsand site administration reactions was tumorenlargement,new The lowoccurrenceofpituitary effective andsafetreatmentinpatientswithacromegaly. patients, confirmsthatlong-termuseofPEGVcanbean a decadeofACROSTUDYenrolment,performedon2090 database. Thissecondinterimanalysis,aftermorethan information fromtheirclinicpatientstothisrobust References ACROSTUDY. ThisstudyhasbeensponsoredbyPfizerInc. coordinators and patients for their participation and contributions to The authors sincerely thank all investigators, sub-investigators and study Acknowledgements the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding Pfizer employeeatthetimeofstudycompletion. C Camacho-Hubner, KPan,JLavenberg,HHey-Hadavi.PJönssenwasa B MKBiller, SMWebb, TBrue,CJStrasburger, EGhigo.PfizerEmployees: ACROSTUDY SteeringCommitteeMembers:MBuchfelder, A-JvanderLely, Declaration ofinterest use andthesafetyprofileofPEGV. in ACROSTUDY Findings frompegvisomantuse 4 3 2 1 Trainer PJ, Drake WM,Katznelson L, Freda PU,Herman-Bonert V, Van derLely AJ,Hutson RK, Trainer PJ, Besser GM,Barkan AL, Kopchick JJ, Parkinson C,Stevens EC&Trainer PJ. Growthhormone Melmed S. Medicalprogress:acromegaly. et al van derLely AJ,Dimaraki EV, Stewart PM, Friend KE,Vance ML (https://doi.org/10.1016/S0140-6736(01)06844-1) growth hormonereceptorantagonist. et al Katznelson L, Klibanski A,Herman-Bonert V, Melmed S,Vance ML org/10.1210/er.2001-0022) with acromegaly. receptor antagonist:discovery, development,anduseinpatients NEJMra062453) of Medicine ACROSTUDY hasprovidedlong-termsafety . Treatment ofacromegaly withthegrowthhormone–receptor . Long-termtreatmentofacromegalywithpegvisomant,a 2006 > 200) in15countrieshavecontributed 355 Endocrine Reviews 2558–2573. Downloaded fromBioscientifica.com at09/25/202102:39:54PM (https://doi.org/10.1056/ 2002 Lancet 23 New England Journal New EnglandJournal 179 623–646. 2001 :6 358 (https://doi. 1754–1759. 426 via freeaccess European Journal of Endocrinology

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Accepted 1October2018 Revised versionreceived25September2018 Received 20July2018

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