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ChinookTherapeuticsInc:TooLittle,TooLate

MuddyWatersisshortChinookTherapeuticsInc(NASDAQ:KDNY)becausewebelieveitishighlyunlikelythatatrasentan,itsleadproductcandidate,willbeapprovedbytheFDA.Weconcludethatatrasentanisinefficaciousforchronickidneydisease.1Wealsoconcludethatatrasentanhasbeenshowntobeharmfultopatients’cardiovascularhealth.2AbbVie3andChinookseemtohavesystemicallymanipulatedresearchfindingsandpresentationonatrasentantoobscurethesetrialresults.Evenifatrasentanwereefficaciousandsafe,itwouldbeunlikelytogainapprovalbecauseacompetingdrug,sparsentan,hasreceivedacceleratedandexclusiveorphandrugapprovalbytheUSFDAforIgAnephropathy,theconditiontargetedinChinook’sonlyPhase3trial,theALIGNstudy.4

Fromtrialdata,atrasentanappearsinefficaciousforchronickidneydisease.Inthelargestavailablestudy,atrasentanhadnostatistically-significanteffectonadvancementtoend-stagerenaldisease,showingonlyaminornumericaldifferencebetweendrugandplacebogroups.5AlldifferencesinUACRandsystolicbloodpressurebetweenatrasentanandplacebopatientsdisappearedaftertrialcessation,whichsuggeststherewasnoactualimprovementintherateofrenaldecline.6,7,8ScientificliteraturerespondingtoSONARalsonotesthatthedrug’sreportedeffectsonUACRmaybeimplausiblyhigh.9HadtheRADARandSONARtrialperiodsfullyreportedhematocrit,webelievetheywouldhaveshownthatatrasentan’sprimaryeffectwasblooddilution–i.e.,ahemodynamiceffect.10,11Thisprobablehemodynamiceffectwasnotonlylikelyresponsibleforthetemporarilyimprovedbiomarkersobservedduringthetrial,butalsowouldposeserioushealthrisks.

Atrasentanisalsoharmfultopatients’health,especiallyolderandmorefragilepatientssuchasthosewithdiabetickidneydisease,thelargestpotentialpatientpopulation.12Thenumericaldifferenceinheartfailurebetweenatrasentanandplacebowasgreaterthanthenumericaldifferenceinpatients’progressiontoend-stagerenaldisease.13Acutekidneyinjurywashigher

1https://repo.dma.dp.ua/6035/1/SONAR.pdf

2https://repo.dma.dp.ua/6035/1/SONAR.pdf,

/ct2/show/results/NCT01858532?term=atrasentan&draw=2&rank=4

3FromwhichChinookin-licensedatrasentanin2019:2021KDNY10-K,pg.5.

4/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=6144175https://repo.dma.dp.ua/6035/1/SONAR.pdf,Table2.

6https://repo.dma.dp.ua/6035/1/SONAR.pdf,Figure2.

7https://repo.dma.dp.ua/6035/1/SONAR.pdf,Figure2.KDNY10-K2021.

8https://repo.dma.dp.ua/6035/1/SONAR.pdf,Figure2,Figure3.

9“SONAR:DoaNewStudyDesignandStatisticallySignificantResultsTranslatetoReliability?”,ClinicalJournaloftheAmericanSocietyofNephrology.

10/jasn/Fulltext/2014/05000/The_Endothelin_Antagonist_Atrasentan_Lowers.27.aspx,“ClinicalStudyProtocol”forSONAR.

11/jasn/Fulltext/2014/05000/The_Endothelin_Antagonist_Atrasentan_Lowers.27.aspx12“IndividualAtrasentanExposureisAssociatedWithLong-termKidneyandHeartFailureOutcomesinPatientsWithType2DiabetesandChronicKidneyDisease”,ClinicalPharmacologyandTherapeutics:“ERAsalsocausefluidretention,whichcanleadtoedemaandheartfailureinhigh-riskpatients.

13https://repo.dma.dp.ua/6035/1/SONAR.pdf

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intheatrasentangroupthanintheplacebogroup.14,15,16SONARdatareflectsanincreaseinbrainnatriureticpeptideinpatientstreatedwithatrasentaninSONAR.BNPwasnormalforallpatientsenteringtreatment,butquicklybecameelevatedinatrasentanpatients.17Atrasentanisalsoassociatedwithastatistically-significantlyelevatedrateofanemia.18AnemiaisaseriousriskfactorfordiseaseprogressioninIgAN,animportantpatientpopulationforChinook.19,20,21Reportedmortalityonatrasentanwasnumericallyhigherthanreportedmortalityonplacebointhedouble-blindperiodoftheSONARtrial.22Thismortalityincreaseintheatrasentangroupisalsopresentintheenrichmentperiod.23Avosentan,adrugwithasimilarmechanismtoatrasentan,hadaclinicaltrialabruptlystoppedbecauseofanincreasedriskofheartfailure.24Studiesdoneonatrasentanandsimilardrugsshowthattheyraiseheartfailurerisk.25AsumofcardiaceventsfromtheFDAreportedadverseeffectsgives136heartfailureeventsonatrasentanand93onplacebo.26Averysmallstudyusinganarguablysuperiorbiomarker,inulin,tomeasureGFR,foundthatatrasentanseeminglymadeGFRworse.27Asdiscussedinfra,sparsentan,whichhasexclusiveorphandrugapprovalforreducingproteinuriainIgAN,islikelysafer,showingalessalarmingeffectonheartfailureandanemia.28

BothAbbVieandChinookappeartohavemanipulatedfactsandfigurestoconcealdangersassociatedwithatrasentan.AbbVieappearstohavemanipulatedgraphstomodifytheapparenteffectofatrasentanbyvisuallydistortingenrichmentandpost-treatmentperiods,therebymodifyingtheslopeofthedrugeffect.29AbbVieusedcompositeendpointsinitsdatathatconflatedpositiveandnegativeoutcomesfromatrasentan,whichrunscontrarytobestclinicalpractice.30TheSONARauthorsthenlabeltheseendpointsinamisleadingwayandincludequestionableendpointsincomposites,includingnon-fatalstrokefiguresthatentirelyreversethemeaningofcriticalendpoints.31Chinookappearstohavemisledinvestorsaboutthenumberofpatientsinwhichatrasentanwastrialed,likelytogiveafalseimpressionofdrugsafety.32Chinookhasalsomisrepresentedatrasentan’ssafetyprofilebyclaimingnoSAEsassociatedwith

14https://repo.dma.dp.ua/6035/1/SONAR.pdf.

15“SupplementaryAppendix”totheSONARtrial.

16/ct2/show/results/NCT01858532?term=atrasentan&draw=2&rank=5.17“SupplementaryAppendix”toSONAR,https://repo.dma.dp.ua/6035/1/SONAR.pdf.

18https://repo.dma.dp.ua/6035/1/SONAR.pdf

19/pmc/articles/PMC6340464/

20/pmc/articles/PMC3514188/

21/ajn/article-abstract/51/8/624/41630/The-Association-of-Low-Hemoglobin-Levels-with-IgA?redirectedFrom=fulltext

22https://repo.dma.dp.ua/6035/1/SONAR.pdf

23/ct2/show/results/NCT01858532?term=atrasentan&draw=2&rank=5

24https://repo.dma.dp.ua/6035/1/SONAR.pdf

25https://repo.dma.dp.ua/6035/1/SONAR.pdf

26SeeAppendix.

27/co-

nephrolhypertens/Fulltext/2021/07000/Endothelin_receptor_antagonists_for_the_treatment.13.aspx

28/journals/lancet/article/PIIS0140-6736(23)00569-X/fulltext

29https://repo.dma.dp.ua/6035/1/SONAR.pdf

30/pmc/articles/PMC2923692/

31https://repo.dma.dp.ua/6035/1/SONAR.pdf,

/ct2/show/results/NCT01858532?term=atrasentan&draw=2&rank=5

.

32SeeAppendix.

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itorevidenceofsignificantfluidretention,neitherofwhichisaccurate.33ChinookhasmisleadinglypresenteddatabysuggestingthathemodynamicfactorsplayednoroleintheUACRresultsitshowed.34WhenChinookreportedonthisstudy,itmisleadinglygavepercentagesforpatientbenefitandadverseeffectratesdrawnfromdifferentsub-groupingsofthesample.35Theonlyplacebo-matcheddataonatrasentanfromChinookhasbeendelayedbyrequestoftheFDA,sothereisnoreasontoexpectthatthesafetyissuessuprahavebeen

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overcome.

Introduction:OnStudyMethodology

Despitebeingdesignedtoreducetheoddsofseriousadverseeffects,theSONARtrialwasabruptlyhalted.37Weseeitastellingthatdespitethedesign,thedataindicatesincreasedriskofseriouscardiovasculareventsfromatrasentan.SONARmadeuseofanenrichment-basedstudydesign,inwhichpatientswerestratifiedinto“responder”and“non-responder”drugpopulationsfollowingasix-week“enrichment”periodonatrasentan.38Patientswereexcludedfromconsiderationiftheyhadaprevioushospitaladmissionforheartfailure,ahistoryofpulmonaryhypertension,anyknownnon-diabetickidneydisease,ahistoryofsevereperipheralorfacialoedema,orother-than-normallevelsofbrainnatriureticpeptide(amongothercriteria).39Patientswererequiredtoentertreatmentwithanangiotensinreceptorblockeroranangiotensin-convertingenzymeinhibitorandadiuretic,bothofwhichmeasureswereintendedtomakeheartfailurelesslikelyandrenalrepairmorelikely.40Then,alleligiblepatientsweregivenasix-weekroundofatrasentan,afterwhichtheywerestratifiedintoresponderandnon-responderpopulations.41Responderswerethosepatientswhoshoweda30%reductioninurinealbumin-to-creatinineratio,whodidnothavesubstantialfluidretention,anddidnotshowanincreaseinserumcreatinineduringtheenrichmentperiod—again,allmeasuresintendedtoensurethatthepopulationthatcontinuedinthetrialwouldbeaslikelyaspossibletobenefitfromthetreatment,andasunlikelyaspossibletosuffercardiovascularcomplications.42Only3,666patients—theresponderpopulationandabout1,000non-responders—enteredthedouble-blindtreatmentperiod,andonly2,648patientscompletedthestudy.43Aswenotesupra,thetrialwasthenabruptlyhalted.

Atrasentan:NoStructuralRepair

Weconcludethatthetrialdatashowedthatatrasentanisinefficaciousforchronickidneydisease.Thestudydatashowsthattherewasnostatisticallysignificantimprovementinadvancementto

33/file.cfm/52/docs/era_2022-atrasentan_affinity_igan-fc052.pdf,Slides8,12.34SeeAppendix.

35/file.cfm/52/docs/era_2022-atrasentan_affinity_igan-fc052.pdf,Slide8.36/chinook-delays-topline-kidney-condition-data-eluminex-ropes-in-40m-in-a-series-b/37/news/media-statements/abbvie-statement-on-sonar-study-closure.htm38https://repo.dma.dp.ua/6035/1/SONAR.pdf39https://repo.dma.dp.ua/6035/1/SONAR.pdf40https://repo.dma.dp.ua/6035/1/SONAR.pdf41https://repo.dma.dp.ua/6035/1/SONAR.pdf42https://repo.dma.dp.ua/6035/1/SONAR.pdf

43https://repo.dma.dp.ua/6035/1/SONAR.pdf;“Atrasentaninpatientswithdiabetesandchronickidneydisease”responseletter,LancetJanuary25,2020,VincenzoSepe,CarmeloLibetta.

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end-stagerenaldiseaseintheatrasentanversustheplacebocohort,onlyanumericaldifferenceof14patientsandap-valueof0.06withapercentagedifferenceof5.1%to6.1%ofpatients.Aftercessationoftreatment,measurementsofthesurrogatebiomarkersconvergedbetweenthetreatmentandplaceboarms.Systolicbloodpressureconvergedbeforethetreatmentperiodwascomplete.Expertsinvolvedintheatrasentantrialswithwhomwespokeexplainedthattheeffectwas“functional”,not“structural”,maintainingthat,intheiropinions,therewassomepossibilityofastructuraleffectbecomingevidentinthefuture.

NoStatisticallySignificantImprovementinAdvancementtoEnd-StageRenalDisease

Atrasentan’sdirecteffectonratesofadvancementtoend-stagekidneydisease,asthebelowtabletakenfromtheSONARanalysisshows,doesnotreachstatisticalsignificance.Itisonlybyconflatingend-stagekidneydiseasewithotherrenalendpoints,atechniquewewilldiscussinfra,thatrenaloutcomescanbemadetoappearsignificant.44Differenceinend-stagekidneydisease,inthebelowtablefromtheSONARstudy,achievedap-valueof0.06.45Thenumericaldifferenceinadvancementtoend-stagerenaldiseasebetweenatrasentanandplacebogroupsamongresponderswasonly14patients,afigureovershadowedbytheexcesscardiovasculareventsexperiencedbypatientsinthetreatmentarmofSONAR.ThenumbersreportedtotheFDAreflectanevensmallerbetween-groupsdifferenceof8patients,withalowertotalnumberofeventsreported;it’snotobviouswhytheSONARauthorsgivedifferentESKDnumbersindifferentplaces.46

44https://repo.dma.dp.ua/6035/1/SONAR.pdf

45https://repo.dma.dp.ua/6035/1/SONAR.pdf

46/ct2/show/results/NCT01858532?term=atrasentan&draw=2&rank=5

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AllDifferencesBetweenGroupsDisappearAfterTrial

FigurefromboththeRADARandSONARanalysesshowthatimportantsurrogatebiomarkersconvergebetweenatrasentanandplacebogroupsveryshortlyaftertreatmentcessation.47Thisisnottheresultweshouldexpectifatrasentanisslowingrenaldecline,becausebytheendofthetreatmentperiodthereshouldbesomelastingdifferenceinkidneyfunctionbetweenthegroups.Instead,theresultsweseearemuchmoreconsistentwithaconfoundingeffectofatrasentanonthesurrogatebiomarkersusedbythetrial,whichwouldnotreflectanyrealrenalbenefit.

Thebelowfigure,fromtheRADARtrial,48showsthatpatienturinealbumin-creatinineratios(UACR)convergedonly30daysaftertreatmentcessation(possiblysoonersincethiswastheonlyposttreatmentendpoint),withthelowerdosageatrasentangroup(whichusedthedoserecommendedtoavoidcardiovascularcomplications)actuallyshowinganincreaseinUACRoverplacebobytheendofthetrial:

ItisknownthatUACRisacorrelate,notadirectindicator,ofdiseaseseverity.49ButifUACR

returnstonormalimmediatelyafterdrugcessation,weseethatishasnotbeenareliablecorrelate,becauseitsinitialreductionevidentlyhasnotreflectedarealchangeinkidneyfunctionbutlikelyadirecthemodynamicchangeonthecorrelateitself.

47/jasn/Fulltext/2014/05000/The_Endothelin_Antagonist_Atrasentan_Lowers.27.aspx,

https://repo.dma.dp.ua/6035/1/SONAR.pdf

.

48/jasn/Fulltext/2014/05000/The_Endothelin_Antagonist_Atrasentan_Lowers.27.aspx.Thestudypoolstwotrials,oneofwhichwastheRADARtrial.

49/cjasn/pages/articleviewer.aspx?year=2020&issue=06000&article=00023&type=Fulltext.Emphasisadded:“SONARwasdesignedonthebasisoftheobservationthatriskofprogressivekidneydiseaseiscorrelatedtoalbuminuria…Therearecaveatstotheusefulnessofthisdesign.Mostimportantly,thebiologicresponseismostlikelytopredictaclinicaltreatmentresponseifthebiologicresponseliesonthecausalpathway.

Historytellsusthatourassumptionsthatassociationsbetweenbiologicresponsesandclinicalresponse,nomatterhowconsistentandstrong,arecausal,arefrequentlyincorrect.”

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Theabovetableshowsaremarkablyrapideffectonalbuminuriaatthebeginningandendofthetreatmentperiod.Ifalbuminuriais,inthiscase,tobetakenasanindicatorofrenalhealth,weshouldexpectthealbuminuriato(1)declineslowlyafterdruginitiation,asthekidneyimproves,and(2)remainlowerthanatbaselineafterdrugcessation.Aswesee,neitherofthesearethecase:albuminuriadeclinessharplyassoonastreatmentisinitiated,andthen,moreimportantly,differencesbetweengroupsdisappearafterdrugcessation.Asthestudyfound(emphasisadded):50

Attheendofthe30-dayfollow-upperiodwithoutstudymedication,themedianUACRswere737±912mg/g,1051±1206mg/g,and727±821mg/gfortheplacebo,0.75mg/d,and1.25mg/dgroups,respectively.Thegeometricmeanchangesfrombaselinetorecoverywere?5.3%,+4.3%,and?7.8%fortheplacebo,0.75mg/d,and1.25mg/dgroups,respectively,thusshowingthatUACRvalu