1、FOCUSMigraineThe headaches will soon be overINDUSTRY UPDATEEquityResearch25October2019Oneofthenotabletherapeuticclassinnovationsofrecentyearshasbeenthe discoveryofthenovelCGRPofmedicationsformigraine:aclassrelevantfor Novartisviaitssharedownershipoftheleadingasset(Aimovig)inthespacewith AmgenandnowL

2、undbeckfollowingitsrecent$2bndealtoacquireAlderandits asseteptinezumab.Inthisreport,wepresentadetailedreviewofthemigraine therapeuticspaceandourproprietarymarketmodel(availableuponrequest).For implications for Novartis/Lundbeck please see ourrespective separate company notesalsoouttoday,andwealsoinc

3、ludesomeperspectivesfromBalajiPrasad,who coversTeva/Allergan,respectiveownersoftwoadditionalkeyassetsinthespace.is at aisWe aWethinktheacutemigraineopportunityfororalCGRPsandlasmiditanislikelyto besomewhathandicappedbymodestefficacy/difficultlabelling,respectively, coupledwithalackofH2Htriptandataan

4、dlikelypayorobstruction(e.g.stepedits) givengenerictriptans,thougheventhere,CVcontraindicationin20%ofpatientsand alargerefractorypopulationshouldseeablockbusteropportunity.CGRPmAbdata has looked far more compelling, with solid benefits seen in theprophylactic (episodic/chronic)setting,particularlyam

5、ongstrefractorypatients,whichamount toseveralmillionindividualsintheUSalone.InepisodicP3trialsallassetshaveshown PBO-adjustedMHD(monthlymigraineheadachedays)reductionsof1.5-2.5days,with 10-20% of patients typically achieving a 50% PBO-adjusted reduction in MHD.Data haslookedevenbetterinthechronicset

6、ting,with2-2.5daysMHDreductionand15- 20%ofpatientsachievingPBO-adjusted50%MHDreduction(allofwhichissomewhat better thanBotox).UniqueinsightfromBrandImpactsurveydatashowsthatintheneurologistsetting theclasshasquicklyrisentochallengetriptanvolumeshareat30%intotal migraine,withEmgalityprovidingastiffch

7、allengetoAimovigsearlyleadbutAjovy continuingtolagsomewhatandBotoxholdingshare.Critically,thedatashowsthat CGRPusageremainsconfinedto2L(.continuedon page2)European PharmaceuticalsPOSITIVEUnchangedEuropean Pharmaceuticals Emmanuel Papadakis, PhD CFA+44 (0)20 3134 1246 HYPERLINK mailto:emmanuel.papada

8、kis emmanuel.papadakis Barclays, UKEmily Field, CFA+44 (0)20 7773 6263 HYPERLINK mailto:emily.field emily.field Barclays, UKJameel Bakhsh, CFA+44 (0)20 7116 7038 HYPERLINK mailto:jameel.x.bakhsh jameel.x.bakhsh Barclays, UKBrian Balchin, ACA+44 (0)20 3134 0137 HYPERLINK mailto:brian.balchin brian.ba

9、lchin Barclays, UKSidhartha Modi+91 (0)22 6175 1326 HYPERLINK mailto:sidhartha.modi sidhartha.modi Barclays, UKU.S. Specialty Pharmaceuticals Balaji Prasad, MD+1 212 526 4160 HYPERLINK mailto:balaji.prasad balaji.prasad BCI, USal n rteal n rten I-d e tc itr sReofandtodoAsabethathaveathattheofasahasi

10、northeUSasPLEASE SEE ANALYST CERTIFICATION(S) AND IMPORTANT DISCLOSURES BEGINNING ON PAGE 46.(continuedfrompage1)andtheseveresetting,whereithasbeguntoheavilydisplace triptan/topiramate/othertherapiesforshare.Intheprimarycaresetting,uptakehaslagged thespecialistsettingbutcontinuestobuild,withCGRPshar

11、enowupto20%,albeitalso heavilyfocusedon2L.Switchingdatashowsphysiciansamplingremainsdynamic.UptaketodateforsubcutCGRPmAbsAimovig/Emgality/Ajovyhasbeenapromising indicatorofclasspotentialandwedonotthinkaslightrecentslowdowninUSscript growthheraldsanearlycaponclasspotential,butratheranaturaltransition

12、toafully commercialmarketpostaninitialbolusdrivenbyheavyfreesamplingweexpecttosee solid continued volume growth going forward, which should translate into the class annualisingatover$1bnbylate2019,barelythesecondyearoflaunch,withutilisation focused on the refractory prophylactic population (i.e. epi

13、sodic/chronicpatients experiencing4and15MHD,respectively).CGRP recap: by reminder early oral small molecule CGRP antagonists were marred by hepatotoxicityissues,leavingthreeassetsthathaveshownverymodestbenefitinP3 studies: rimegepant(Biohaven;acute,PDUFAQ120),andAllergansatogepant(episodic, P3) and

14、ubrogepant (acute, PDUFA Q419). Subcutaneous CGRP mAbs have greater potency and been approved in the prophylactic FE/chronic settings: erenumab (Aimovig), fremanezumab(Ajovy),andgalcanezumab(Emgality),withi.v.eptinezumabdueaQ120 PDUFA.Oraltriptanfollow-onstargetanalternativesubreceptor(5-HT1F)lasmid

15、itanwas approvedearlierthismonthforacuteusagebutdespitesolidefficacyuptakecouldbe somewhathandicappedbyatoughlabelcontraindicationondriving.CONTENTSTOC o 1-2 h z u HYPERLINK l _TOC_250010 MIGRAINEREVIEW4 HYPERLINK l _TOC_250009 Briefsummary:condition,dataandassetstatus4 HYPERLINK l _TOC_250008 Migra

16、ineprimer6 HYPERLINK l _TOC_250007 Marketepidemiology7 HYPERLINK l _TOC_250006 Drugsindevelopment9 HYPERLINK l _TOC_250005 Pipelineofallph.2andph.3drugsforMigraine12 HYPERLINK l _TOC_250004 ClinicalData:CGRPclass,5-HT1Fagonists&othernoveltargets13 HYPERLINK l _TOC_250003 Sales,PricingandRxdata28 HYP

17、ERLINK l _TOC_250002 BrandImpactdata32 HYPERLINK l _TOC_250001 PerspectivesfromourUScolleaguesonTEVA/AGN35 HYPERLINK l _TOC_250000 BarclaysEUpharmamigrainemarketmodel37MIGRAINE REVIEWBrief summary: condition, data and asset statusMigraineisacommon,debilitatingneurologicaldiseasethatimpactsaround12%o

18、ftheUS population(39millionpeople).Patientsarestratifiedbythefrequencyoftheirmigraines- measuredbythenumberofmigraineheadachedays(MHD)per28-dayperiod:acute(415days).Ofthe39millionpatients,65% (25m)areclassedasacutemigrainepatientswhile25%(10m)and10%(4m)are episodic and chronic migraine patients, res

19、pectively. Currently, patients with acute migrainesaretreatedwithnon-prophylactictreatments;triptans(serotonin-5HT1B/D receptoragonists)and/orNSAIDs(overthecounterpainmedicinessuchasibuprofenor acetaminophen),withthegoalofnear-termrelief,whilepatientswithepisodicandchronic migrainesaretreatedwithpro

20、phylactictreatments:topiramateandBotox,respectively.As such,intheUS,around25macutemigrainepatientsarecandidatesfornon-prophylactic treatmentswhile14mpatients(episodic(10m)andchronic(4m)arecandidatesfor prophylactictreatments.Intheacutesetting,thecurrentstandardofcare(SoC),triptans,arecontraindicated

21、in patientswithcardiovascularorcerebrovasculardisease,whichhasledtothedevelopment ofthreekeynoveltherapiesinthissetting:lasmiditan,ubrogepant,andrimegepant,allof whichareadministeredorallyandsuitableforpatientswithcardiovascular(CV)riskfactors. Lasmiditanisa5-HT1F receptoragonistdevelopedbyEliLilly,

22、whilebothubrogepant (Allergan)andrimegepant(Biohaven)aresmallmoleculecalcitoningene-relatedpeptide (CGRP)antagonists.Intermsofpositioning,alltherapiescouldbeusedin1Linpatients withCVriskfactorsorasa2Ltreatmentinpatientsthatfailontriptans(upto20%of patients).Safetyiscomparableacrossalltreatmentsbutla

23、smiditanisthemostefficacious andislikelytobefirsttomarketgivenitisthefirsttobeFDAapproved(10thOctober2019) vs.ubrogepantandrimegepant,whichareawaitingPDUFAdecisionsexpectedinDecember 19andQ120,respectively.Assuch,lasmiditanseemsbestpositionedtoout-competethe currentSoCandseegooduptakeintheacutemigra

24、inemarketthoughthelabelwilllikely beahandicap;uptakethiswouldfurtherdependonthenumberoftriptansinsurersrequire patientstostepthroughpriortolasmiditanprescription.Intheepisodicandchronicsetting,clinicaldevelopmenteffortshavebeenlargelyfocused onanti-CGRPmonoclonalantibodiesadministeredbysubcutaneousi

25、njection/IVinfusion. Thefourkeynoveltherapiesinthisspaceare:Novartis/AmgensAimovig(70mg/140mg- monthlySC),EliLillysEmgality(120mg/240mg-monthlySC),TevasAjovy(225mg monthlyor675mgquarterlySC),andAlderseptinezumab(IVinfusionQ12w).Intermsof clinicaldata,allCGRPsexhibitedlargelyundifferentiatedefficacya

26、ndcomparablybenign safetyprofilesinbothepisodicandchronicsettings.Ofnote,eptinezumabshowedmore competitiveefficacydatainthechronicvs.episodicsettingandafastonsetofaction, reducingtheriskofmigraineby50%inbothepisodicandchronicpatientsin24hours.In termsofapprovalsandlaunches,Aimovig(FDA/EUapprovedinMa

27、y/Jul18),Emgality (FDA/EUapprovedinSep/Nov18),andAjovy(FDA/EUapprovedinSep18/Apr19)are allcurrentlyonthemarket,whileaPDUFAdateof21st February2020isscheduledfor eptinezumab.FIGURE 1Overview of CGRP assets in developmentDrugCompanyMechanismStatusFormAdministrationschedule & doseSettingUbrogepantAllerg

28、ansmall molecule CGRP receptor antagonistPDUFA: Acute, December 19oral48hrsafterinitialdoseAcuteAtogepantsmall molecule CGRP receptor antagonistQD&BIDErenumabantagonist humanisedIgG2FDAMay18SCMonthly,EUJuly18Episodic and ChronicGalcanezumabEli(Emgality)Fremanezumab(Ajovy)ligand antagonist humanisedI

29、gG4ligand antagonist humanised mAB ligandFDA18EU18FDA18EUApr19P2: Acute (P3 to begin H2 20)Monthly, MonthlyQuarterlyand Chronicand ChronicAcute, Episodic andEptinezumabantagonist humanisedPDUFA: Episodic/Chronic, Q1 20IVQ12WChronicAcute Episodic2-48hrs after initialdoseAcute Episodic2-48hrs after in

30、itialdoseoralPDUFA: Acute, Q1 20resultsQ4 19smallantagonistBiohavenRimegepantMigraine primerMigraineisacommon,debilitatingneurologicaldisease.Itisgenerallydescribedasa neurovasculardisorderinwhichthedilationofbloodvesselsandpainaretriggeredby neuralsignals.Thetrigeminovascularsystemplaysakeyroleandi

31、nnervationsfromthe trigeminal ganglion help control blood flow and provide nearly all of the pain site innervations.Migraineoftenbeginswithpremonitorysymptomshoursordaysbeforethe onsetofpainwiththemostcharacteristicsymptomsbeingphotophobia(sensitivityto light), phonophobia (sensitivity to sound), cu

32、taneous allodynia, dizziness, and gastrointestinal symptoms such as nausea and emesis. This is then followed bythe migraineheadache,whichisreportedbypatientstobeathrobbingpainthatisaggravated byphysicalactivityorheadmovement.Theheadachecanchangesidesduringorbetween attacksandthepainintensityisatleas

33、tmoderateorsevere.Thedurationofamigraine headachecanrangefrom4to72hoursinadultsand2to48hoursinchildren.Thepaincan involveanypartoftheheadandofteninvolvestheposteriorcervicalandtrapeziusregions. In about one-third of people with migraine, reversible neurological symptoms known as migraineauracanoccur

34、beforetheonset,during,orintheabsenceofpain.Migrainewith aura is characterised by visual, sensory, language, or disturbances associated with brainstemdysfunctionthatusuallylastbetween5and60minutesbeforetheheadache.Migrainesaredifferentiatedfromclusterheadaches,whicharecharacterisedbyastrictly unilate

35、ralseverepain,localisedinoraroundtheeyeandaccompaniedbyipsilateral autonomicsymptomssuchaslacrimation,rhinorrhoea,andnasalcongestion.Asopposed tomigraines,clusterheadachesarefarlesscommonandsymptomsareshort-lived,lasting anywherebetween15-180minutesinregularbouts(uptoeightattacksaday).Headaches occu

36、rdailyforaclusterofweeksfollowedbyaperiodofremission.Onaverage,acluster canspan6-12weeksandremissionscanlastupto12months.Thecauseofthesevere unilateralpainislikelymediatedbyactivationofthefirst(ophthalmic)divisionofthe trigeminal nerve, whereas the autonomic symptoms such as lacrimation are due to a

37、ctivationofthecranialparasympatheticoutflowfromtheseventhcranialnerve.Seethe tablebelowoutliningthediagnosticcriteriaformigrainesandclusterheadachesasdefined bytheInternationalClassificationofHeadacheDisorders.MigraineClusterHeadacheDiagnostic Criteria: Migraine vs. Cluster HeadacheMigraineClusterHe

38、adacheAtleastfiveattacksfulfillingcriteria2-4A)AtleastfiveheadacheattacksfulfillingcriteriaB-D(B) Severe or very severe unilateral orbital, supraorbital, and/or temporal headache attacks, which lastHeadacheattackslasting4-72h(untreatedor successfullytreated)Headache has at least two fo the following

39、 characteristics:unlaterallocation,pulsatingquality, moderateorseverepaininensity,aggravationbyor causingavoidanceofroutinephysicalactivity(e.g. walkingorcllimbingstairs)untreatedfor15180min.Duringpart(butlessthan half) of the time course of the cluster headache, attacksmaybelesssevere,lessfrequent,

40、orofshorter or longerdurationTheheadacheisaccompaniedbyatleastoneof thefollowingsymptomsipsilateraltothepain:Conjunctivalinjectionorlacrimationcongestionand/orrhinorrhoeaEyelidoedemaForeheadandfacialsweatingMiosis and/orptosisAsenseofrestlessnessandagitation4)4)Duringheadacheatleastoneofthefollowing

41、:nausea Theattackshaveafrequencyfromoneeveryother orvomiting,orboth;orphotophobiaandphonophobia daytoeightperday5)Notattributedtoanotherdisorder-e.g.meningitisor brainhemorrhageHistoryandphysicalandneurologicalexamination donotsuggestanyotherdisorder,ortheyareruled outbyappropriateinvestigationsSour

42、ce: Barclays Research; International Classification of Headache Disorders, LancetMarket epidemiology12%oftheUSpopulationisimpactedbymigraines,whichamountsto39millionpeople. TheWHOranksmigraineasthethirdmostprevalentmedicalconditionandthesecond mostdisablingneurologicaldisorderintheworldwithagreaterp

43、revalenceofmigraine notedinfemalesvs.males.Migraineismostprevalentbetweentheagesof25and55years, andtheprevalencerisesthroughearlyadultlifeandthenfallsaftermidlifei.e.55years.Forpatientmanagement,clinicaltrial,andregulatorypurposes,migrainepatientsare stratified by the frequency of their migraines-me

44、asured by the number of migraine headachedays(MHD)per28-dayperiod:loworacute(4 and15).Ofthe39millionpatients,65%(25m)areclassedasacute migrainepatientswhile25%(10m)and10%(4m)areepisodicandchronicmigraine patients,respectively.Assuch,around14mpatients(episodicandchronic)arecandidates forpreventivetre

45、atments. Seethefigurebelow.FIGURE 3USA: Percentage distribution of patients across acute, episodic and chronic settings41.4EpisodicChronic23.7 4 and 15 MHD/month 15 MHD/month41.4EpisodicChronic23.7 4 and 15 MHD/month 15 MHD/month 50Source:Cephalagia,BarclaysResearchMigraine headach

46、e days per monthPatientswithlowfrequencyoracutemigrainesaretypicallytreatedwiththestandardof care,triptans(serotonin-5HT1B/Dreceptoragonists)and/orNSAIDs(overthecounterpain medicines such as ibuprofen or acetaminophen), with the goal of near-term relief. Migrainestreatedwithtriptans,however,havebeen

47、knowntoreoccurwithin24hours. Further,useoftriptansisalsocontraindicatedinpatientswithcardiovascularor cerebrovasculardiseaseaswellasthosewithuncontrolledhypertension.Assuch,current guidelinesrecommendfirstadministrationinamedicalcentresupervisedwithanECG. Migraineisaprogressivediseasewith2.5%ofhighf

48、requencyepisodicmigrainepatients transitioningtochronicmigrainepatientsonanannualbasis,whichunderscoresthe importanceofdevelopingeffectiveprophylacticorpreventivetreatments.Inprophylacticsetting,standardofcareoptionsincludetopiramateforepisodicmigraine andAllergansonabutlinumtoxinA(Botox),approvedin

49、2010forchronicmigraine. Adherencetotheseprophylactics,however,particularlyinchronicmigraines,ispoorwith30% at 6 months and 50% monthly migraine-headache days (MHD) reduction, Alders anti-CGRP monoclonal antibody eptinezumab (IV infusion, Q12W) achieved8.8%to13.9%,whichislesscompetitivethanotheranti-

50、CGRPmAbsEmgality (120mg/240mg, monthly SC), Aimovig (70mg/140mg, monthly SC), and Ajovy (675mg/225mg,monthlySC),allofwhichachievedundifferentiatedefficacydata rangesof20.5%-23.7%,10.2%-23.4%,and16%-19.7%,respectively.Onplacebo-adjustedmonthlymigraine-headachedays(MHD)reduction,atogepant (oralanti-CG

51、RP)wasthemostefficaciousatthe60mgBIDdose,achievinga4.14day reduction, while eptinezumab, Aimovig, Emgality, and Ajovy achieved largely undifferentiatedMHDreductionof0.7to1.2days,1.77to1.99days,1.1daysto2.4 days,and1.2daysto1.5days,respectively.Intermsofsafety, alltreatmentswerelargelycomparablewithl

52、owSAEsobserved across alloptions.Chronic SettingOn percentage of patients with 50% monthly migraine-headache days (MHD) reduction,Ajovywasthemostcompetitive,achieving20%to23%vs.eptinezumab (18.3% to 22.1%) and Emgality (12.6-12.7%). Notably, eptinezumab is more competitiveonthisdatapointinchronicvs.

53、episodicmigraine.On placebo-adjusted monthly migraine-headache days (MHD) reduction, eptinezumabachieved2.1to2.6daysreduction,whichislargelycomparablewith monthlySCoptions;Emgality(-1.9daysto-2.1days)andAjovy(-1.8daysto-2.1days).Intermsofsafety,alltreatmentsexhibitedsimilartoxicityprofileswithlowSAE

54、s.Acute Onset Migraine SettingAllstudiesintheacutemigrainesetting(1,000).Inthegraph belowwehavesummarisedallkeyefficacydatapointsachievedbyubrogepant,rimegepant andlasmiditan.Thedetailedacutemigraineclinicaldatatableisattheendofthissection.FIGURE 6AcuteMigraineSetting:Cross-trialcomparisonPBO adjust

55、ed % pain free 2 hours20.0%18.0%16.0%14.0%12.0%10.0%8.0%6.0%4.0%2.0%0.0%PBO adjusted % absence of MBS16.0%14.0%12.0%10.0%8.0%6.0%4.0%2.0%0.0%50mg100mg25mg50mg75mg75mg75mg100mg200mg100mg200mgACHIEVE IACHIEVEUbrogepantStudy301 Study302 StudyRimegepantSAMURAILasmiditanSPARTANPBOadjusted%painfree2hoursP

56、BO-adjusted%AbsenceofMBSSource: Barclays Research; company presentationsAcute Migraine: Trial ComparisonAcute Migraine: Trial ComparisonB-jued % pin-ree t 2 hrs: the mt ffcacus s amdtn (73%- 17.5%)withubrogepant(6.4%-9.4%)andrimegepant(5.4%-7.6%)seenasmore comparable.B-jued % ence f BS:Lmdtnisthemtf

57、fcacus(107%-152), thoughthegepantsareslightlymorecompetitiveonthisdatapoint;rimegepant (8.9%-12.4%)andubrogepant(6.7%-11.5%).Safety: All three treatments were well tolerated with minimal SAEs and no hepatotoxicity signal.Giventhatgepants(ubrogepant,rimegepant)andditan(lasmiditan)donotconstrict crani

58、alarteries,theycouldallbeusedasa1LtherapyinpatientswithCVriskfactors orasa2Ltreatmentinpatientsthatfailontriptans.Intermsofdelivery,allthese optionsoffertheconvenienceofanoralrouteofadministrationwhilerimegepantalso offersanODTformulationforthosewithdysphagia.Acute Migraine: Notable Label WarningsAc

59、ute Migraine: Notable Label WarningsLasmiditan (REYVOW): Driving impairment-patients are advised not to drive or operate machinery until at least 8 hours after taking REYVOW.Biohaven (not covered)linicl Dta o de: To ph3 tas ntgatd al CP cptor antgnt, rimegepant (75mg) for acute migraine treatment. I

60、n the first trial (Study 301, NCT03235479, n=1485) preliminary results showed percentage of patients with 2-h painfreedomwas19.2%vs.14.2%forplacebo(p=0.0298)whilefreedomfromMost BothersomeSyndrome(MBS)at2-hwas36.6%vs.27.7%forplacebo(p=0.0016).In thesecondtrial(Study302,NCT03237845,N=1499)thepercenta