What’snewinIPFdrugs?

KatyBlack,MDOctober5,2017

ClinicalTrialterms

• PhaseI:SAFETY(20-100normalvolunteer)– Focusonsideeffectsanddosing

• PhaseII:Diseasespecific– Focusondosingandsideeffectsintargetpopulation

• 2a:isitdoingwhatwethink• 2b:what’sthebestdose

• Phase3:EFFICACY(300-3,000)– Doesitwork?– Primaryandsecondaryendpoints

https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm

https://clinicaltrials.gov

LookforNCTnumberonalltrials

Notethatanyonecanregisteratrial,sobeingontheclinicaltrial.govwebsitedoesn’tproveit’slegitimate!Trytonoticewhoissponsoringthetrial– academiccenter?Pharmacompany?Willalsolistinclusioncriteria:Howold?WhatPFTs?

https://pulmonaryfibrosisnews.com/

• Treatment->>experimental

“News”frompharmaceutical– sobeingmentionedheredoesnotimplyendorsementfromscientificcommunity- butcanfindpublishedreferencesetc.

Epithelial CellStress and Death

CapillaryEpithelium

Macrophage

Innate Immune Activation and

Polarization

Fibrin Clot

Vascular Leak and ExtravascularCoagulation

Fibroblast Recruitment,

Invasion, Proliferation,

and Persistence

Fibroblast Activation and MyofibroblastDifferentiation

Myofibroblast

Matrix Accumulation and Cross-Linking

Alveolar Collapseand Re-Epithelialization

ALVEOLUSLungInjury

Fibroblast

How can we cure IPF?

NACNOX4 Inhibitor

Aeol 1050

Endostatin?nintedanib

PirfenidoneLPA1 antagonist

Autotaxin inhibitorAnti-CTGF mAb

Nintedanib

PirfenidoneAnti-anb6 mAb

Nintedanib

Anti-LOXL2 mAb

Anti-IL-13 mAbPentraxin-2Anti CXCR4

cotrimixazole

AhluwaliaN,SheaBS,TagerAM.AmJRespir Crit CareMed.2014

Mora..SelmanNatRevDrugDiscov.2017Nov;16(11):755-772.

ReviewofrecentstudiesinIPF

TakeHome

• Lotsofpromisingdrugsinthepipeline• Clinicaltrials.govshouldlistallpotentialtrialsandrelevantdetails– Locationsofstudy– Inclusion/exclusion

• Localresearchcoordinatorswillhelpyoulookatreal-worlddetails

• IfnotregisteredwithPFFregistryandwanttobe,contactme!kblack1@partners.org

Specificdrugs

• Looselyorganizedbythewaythesciencesuggeststheywouldwork

• Informationfromliteratureorthecompany’swebsite

• Noendorsementimplied!

Targetingthescar

• BMS986020• GLPG1690

• FG-3019/pamrevlumab

• Simtuzumab

FG3019- PamrevlumabBasic:Antibodytoconnectivetissuegrowthfactor(CTGF)Science:CTGFactivatesfibroblastsPriorstudies:PhaseIRecentPhaseII– Pts 40-80withIPF<6years;FVC>-55%– Outcome:changein%predictedFVCover48weeks– Otheroutcomes:death,QOL,changeinDLCO,hospitalization

– Companysaysresultspromising– stabilization,someimprovement

NCT01890265– sponsor =Pharma

FG3019:Pamrevlumab

• Substudy inpatientsonpirfenidoneornintedanib:“PRAISE”study– ReportedatERSconferencethisyear– 2.85%declineinpamrevlumab vs 7%placebo– Nowawaitingresultsinpatientsonactivedrugs

BMS986020

• Intro:LysophosphatidicAcidreceptor1(LPA1)Antagonist

• Science:DiscoveredbyAndyTagertobecriticalinfibroblastmovementandactivation

BMS986020

• PhaseIcompletedinJan• PhaseIIcompletedFeb2016

included:IPF40-90,noasthma,noimprovementover1yearRateofchangeinforcedvitalcapacity(FVC) over26weeks,HRCTchanges6mwtTime FrameSamedrughadliversideeffectsinscleroderma,sostoppedstudy

GLPG1690

• Intro:inhibitstheenzyme“autotaxin”whichmakesLPA

• Science:Blockingautotaxin meanlessLPAtoactivatefibroblasts

• Data:someefficacyinmice– (conflictingdatausingwithotherautotaxininhibitorsinmice)

DesroyJ.Med.Chem.,2017,60(9),pp3580–3590BlackFASEBJ. 2016Jun;30(6):2435-50.

GLPG1690

• PhaseIcompleted2015• PhaseIIa Study:FLORAtrial(3/16-5/17)• 23IPFpatient(17ondrug,6onplacebo)• Primaryoutcome:safety• Accordingtopressrelease;thoseondrughadstableFVCover12weeks(reportedAugust2017)(vs.downveryslightly)

Simtuzumab GS-6624• Intro:HumanizedantibodyagainstLysl oxidase-like2

• Science:LOXL2stabilizesscartissueinIPF,soblockingthatshouldletscargetsofter

• Data:Largerandomizeddoubleblindedphase2study(272pts eachgroup;183locations);lookedatsurvivalandfunction

• Stoppedearly:Noeffect• Newdrugstargetingsamepathwaybeingdeveloped

Raghu LancetRespir Med.2017Jan;5(1):22-32.

IW-001

• Intro:OralAntibodytocollagenV• Science:normallycollagenVishiddenfromimmunesystem,butinpulmonaryfibrosisitisexposedandcouldtriggeranimmuneresponse;turningthatoffcouldhelp

• Phase1in30IPFpatients(withanticollagenantibodiescompleted2012;published2015

NCT01199887VittalPLoSOne.2013;8(10):e76451

WilkesEur Respir J.2015May;45(5):1393-402.

PBI-4050

• Intro“Antifibrotic”• Science:Testedinmiceforabilitytoreduceknownprofibroticfactors

• PhaseIItrial40ptsacrossCanada– datapresentedatATS2017

• 9PBI-4050only,15nintedanib,16pirfenidone– PirfenidoneblockedabsorptionofPBI-4050

• Seemedtostabilizepatients• PlanningPhase2/3trialsoon

NCT02538536

Targetingimmunesystem

• Lebrikizumab

• Cotrimoxazole• Valgancylovir

Lebrikizumab

• HumanizedantibodytoIL-13• Science:IL-13isproducedbysomeTcellsoftheimmunesystem,andcanactivatefibroblastsandepithelialcells,soblockingIL-13couldhelp

• Trialedinasthmaaswell• PhaseIItrialinIPF– IPFpts over40+– Skininjectionsevery4weeks+/- pirfenidone– StartedOct2013;shouldbedoneNov15,2017!

NCT01872689Hoffmann-LaRoche

Cotrimoxazole• Trimethoprim80mgandsulfamethoxazole400• (“Bactrim”)• Science:infectionsmightcontributetoprogression;changing“microbiome”mayalterdisease

• IPFpatientshavemorebacteriainlavagefluid• ?RoleoforganismcalledPneumocystics jirovecii• Priordoubleblindmulticentertrial:– 181pts Co-trimoxazole 960mg(two480mgtablets)orbid

Molyneaux PLetal.AmJRespir Crit CareMed. 2014Oct1SihulingaThorax.2013Feb;68(2):155-62

Phase3trialPrimaryOutcome:timetorespiratoryhospitalizationordeath

- Otherhospitalization,changesinPFTs,#ofinfections,QOL

Enrolling:IPF>=40,norecentantibiotics160mgtrimethoprim/800mgsulfamethoxazole(doublestrengthtwicedailyplusfolicacid5mgdailyIfallergic->doxycycline

NCT02759120– sponsoredbyWeillMedicalCollegeofCornellUniversity

Valganciclovir hydrochloride

• Antiviraldrugthatworksagainstherpesviruses,CMV

• Science:thesevirusesmabe promotingdiseases

• Phase1btrialtobeginatVanderbilt– single-center,prospective,randomized,placebo-controlled,double-blindpilotstudy

– Requiresbronchoscopytotestinfections

NCT02871401,VanderbiltandPharma

Preventingdamage

• VAS2870• Aeol 10150• PTL-202

VAS2870

• BlocksNAD(P)Hoxidases(Nox)thatcreatesreactiveoxygenspecies

• Science:BlockingNox shouldloweramountofreactiveoxygenanddecreasefibroticresponse

• PhaseIItrialofsimilarcompoundGKT137831testedindiabeteskidneydisease

• NohumandataTenFreyhausCardiovascRes. 2006Jul15;71(2):331-41..Hecker CellMol LifeSci.2012Jul;69(14):2365–2371.

Aeol 10150Basics:metalloporphyrin antioxidant,

LikenaturalenzymesuperoxidedismutaseConvertsreactiveoxygen(O2-)intoH2O2

Science:oxidativedamagetoepithelialcellsmaydriveIPFprogressionIndications:AcuteRadiationSickness,nervegasdamage,IPF,cancerDatasofar:Preclinical:testedinmiceandmacaquesagainstradiation-inducedpneumonitisClinical:PhaseItrials(safety)completed(Sep18pressrelease)

MacVittie etal.RadiationResearch187(3):298-318.2017

Tipelukast- MN001

• Oralanti-inflammatory• Testedforbladderirritation• Nowplanningtrial• (alsoinbladder,liverdisease

BJUInt.2006Aug;98(2):430-4.

PRM-151

• recombinanthumanserumamyloidP/pentraxin2protein

• Science:– pentraxin mayblockactivationofinflammatorycells

• Data:– PhaseIItrialpublishedinMarch2016– 21pts,safebutnotmucheffect.

NCT01254409,sponsorpharma.VandemBlinkEurRespirJ.2016Mar;47(3):889-97

PTL-202

• Combinationofpentoxyfilline andN-acetyl-cysteine– twoapproveddrugs

• PhaseIshowedsafe;easiertotake(only1/day)

• Noefficacydata

Newpathways

• PRM151• TD139• KD025

• RES-529

TD139

• Intro:Inhaledinhibitorofgalectin-3• Science:Galectin-3hasbeenshowntobeimportantinrecruitingfibroblastsandactivatingmacrophages

• Data:Mice• CompletedPhase1-2studyinDec2016• (requiredbronchoscopytomeasuredruglevels)

NCT02257177

KD025SLX-2119

• Intro:blocksROCK2• Science:blockingsignalingpathwaysmightwork• Mousemodelsshoweffect

• Phase2,open-label,24-weekstudyexaminesthe• IPFpatientsonpirfenidoneand/ornintedanib.• Thirty- sixpatients:24withKD025at400mgQD,12patientstreatedwithstandardofcare

NCT02688647 :SponsorPharma

RES-529

• SmallmoleculethatblocksTORC1/TORC2interaction

• PhaseIformaculardegneration• Pre-clinicalforglioblastioma• Preclinicaldataaboutmyofibroblastactivation

Fentanylforshortnessofbreath

• Fentanyl– potentopiod• Primarytrialofinhaledfentanyl:dyspnea(inOntario)

• Measurebreathing

NCT03018756

iBio-CFB03

• Basic:Endostatin derivedpeptide• Scienc:– Endostatin – fragmentofacollagensubtype;blocksbloodvesselgrowth

– Endostatin-likepeptidesaregrowninplants• Data:mouseofsclerodermaandIPF– (Dr.CarolFeghali-Bostwick )

• Nohumandata;patentinJune2016

Yamaguchi SciTransl Med.2012May 30;4(136):136ra71.

AD-114

Basicidea:newkindofantibodytoCXCR4– CXCchemokinereceptorfamilyofGPCRs,– ligandCXCL12(alsoknownasstromalcell-derivedfactor1,SDF-1

– Receptorseemstohaveroleincancers,stabilizingstemcells

– Differentantibodystructuremaybindbetter• variablenewantigenreceptors(VNARs)fromshark!

• Priordata:Noclinicaldata– Planstobetestedinmultiplediseases

Griffithsetal.JBiolChem.2016Jun10;291(24):12641–12657.

Exacerbations

• Newcasereportusednintedanib

ART-123

Underlyingidea:humanrecombinantthrombomodulin• Science:– anticlottingfactor– acceleratesthrombin’sactivationofprotein- >turnsoffthrombin

– Thrombinhasotherpro-fibroticactivity,soreducingit’sactivityhaspotentialprofibroticeffects

• Approvedin2008inJapanfortreatmentof“DisseminatedIntravascularCoagulation(“Recomodulin”)

DrugDesDevel Ther.2015;9:5755–5762.

ART-120• Datasofar:Prospectivestudy– 22patients• Nonrandomized,singlecenter• 90mortality:36%vs 90%,P=0.023;mediansurvivaltime:not

reachedvs 15.0days,P=0.019)

Abeetal.DrugDesDevel Ther.2015;9:5755–5762.

ART-120• Datasofar:Prospectivestudy– 22patients• Nonrandomized,singlecenter• 90mortality:36%vs 90%,P=0.023;mediansurvivaltime:not

reachedvs 15.0days,P=0.019)

Abeetal.DrugDesDevel Ther.2015;9:5755–5762.

ClinicalStudyofART-123fortheTreatmentofAcuteExacerbationofIdiopathicPulmonaryFibrosis

OngoingtrialinJapanmulticenter,double-blind,randomized,placebo-controlled,parallelgroupcomparisonstudyDrugvs.placebo(+standardofcare)Outcome:survivalrateonDay90astheprimaryendpointEnrolling:IPFpatients40-80Expectedtocomplete:inJuly2018Sponsor:Pharma

Lotsofreasonsforhope!