巴克莱-欧洲-制药业-偏头痛：头痛很快就会过去-2019.10.25-50页.pdf

Equity Research 25 October 2019 FOCUS Barclays Capital Inc.and/or one of its affiliates does and seeks to do business with companies covered in its research reports.As a result,investors should be aware that the firm may have a conflict of interest that could affect the objectivity of this report.Investors should consider this report as only a single factor in making their investment decision.This research report has been prepared in whole or in part by equity research analysts based outside the US who are not registered/qualified as research analysts with FINRA.PLEASE SEE ANALYST CERTIFICATION(S)AND IMPORTANT DISCLOSURES BEGINNING ON PAGE 46.Restricted-Internal Migraine The headaches will soon be over One of the notable therapeutic class innovations of recent years has been the discovery of the novel CGRP of medications for migraine:a class relevant for Novartis via its shared ownership of the leading asset(Aimovig)in the space with Amgen and now Lundbeck following its recent$2bn deal to acquire Alder and its asset eptinezumab.In this report,we present a detailed review of the migraine therapeutic space and our proprietary market model(available upon request).For implications for Novartis/Lundbeck please see our respective separate company notes also out today,and we also include some perspectives from Balaji Prasad,who covers Teva/Allergan,respective owners of two additional key assets in the space.We think market potential is significant,noting triptans peaked at$2bn despite CV contraindication and modest efficacy,whilst therapeutic Botox sales for chronic migraine are$1.5bn.We model a total$6bn late 2020s global CGRP class opportunity($8bn total market,including Botox/Reyvow,of which$5bn is in the US),and splitting c.25/45/30%across acute/episodic/chronic migraine,respectively;we expect CGRP mAbs/orals to capture$4.4/1.6bn,respectively,with Aimovig retaining clear leadership but near-blockbuster opportunities for Emgality/Ajovy/eptinezumab.We think the latters inconvenient formulation and modest episodic data is compensated for by arguably best-in-class chronic data,longer dosing intervals(Q12W)and rapid onset of action,though we see a likely stiff battle with Tevas quarterly Ajovy dosage ahead.We think the acute migraine opportunity for oral CGRPs and lasmiditan is likely to be somewhat handicapped by modest efficacy/difficult labelling,respectively,coupled with a lack of H2H triptan data and likely payor obstruction(e.g.step edits)given generic triptans,though even there,CV contraindication in 20%of patients and a large refractory population should see a blockbuster opportunity.CGRP mAb data has looked far more compelling,with solid benefits seen in the prophylactic(episodic/chronic)setting,particularly amongst refractory patients,which amount to several million individuals in the US alone.In episodic P3 trials all assets have shown PBO-adjusted MHD(monthly migraine headache days)reductions of 1.5-2.5 days,with 10-20%of patients typically achieving a 50%PBO-adjusted reduction in MHD.Data has looked even better in the chronic setting,with 2-2.5 days MHD reduction and 15-20%of patients achieving PBO-adjusted 50%MHD reduction(all of which is somewhat better than Botox).Unique insight from BrandImpact survey data shows that in the neurologist setting the class has quickly risen to challenge triptan volume share at 30%in total migraine,with Emgality providing a stiff challenge to Aimovigs early lead but Ajovy continuing to lag somewhat and Botox holding share.Critically,the data shows that CGRP usage remains confined to 2L(.continued on page 2)INDUSTRY UPDATE European Pharmaceuticals POSITIVE Unchanged European Pharmaceuticals Emmanuel Papadakis,PhD CFA+44(0)20 3134 1246 Barclays,UK Emily Field,CFA+44(0)20 7773 6263 Barclays,UK Jameel Bakhsh,CFA+44(0)20 7116 7038 Barclays,UK Brian Balchin,ACA+44(0)20 3134 0137 Barclays,UK Sidhartha Modi+91(0)22 6175 1326 Barclays,UK U.S.Specialty Pharmaceuticals Balaji Prasad,MD+1 212 526 4160 BCI,US Barclays|Migraine 25 October 2019 2(continued from page 1)and the severe setting,where it has begun to heavily displace triptan/topiramate/other therapies for share.In the primary care setting,uptake has lagged the specialist setting but continues to build,with CGRP share now up to 20%,albeit also heavily focused on 2L.Switching data shows physician sampling remains dynamic.Uptake to date for subcut CGRP mAbs Aimovig/Emgality/Ajovy has been a promising indicator of class potential and we do not think a slight recent slowdown in US script growth heralds an early cap on class potential,but rather a natural transition to a fully commercial market post an initial bolus driven by heavy free sampling we expect to see solid continued volume growth going forward,which should translate into the class annualising at over$1bn by late 2019,barely the second year of launch,with utilisation focused on the refractory prophylactic population(i.e.episodic/chronic patients experiencing 4 and 15 MHD,respectively).CGRP recap:by reminder early oral small molecule CGRP antagonists were marred by hepatotoxicity issues,leaving three assets that have shown very modest benefit in P3 studies:rimegepant(Biohaven;acute,PDUFA Q120),and Allergans atogepant(episodic,P3)and ubrogepant(acute,PDUFA Q419).Subcutaneous CGRP mAbs have greater potency and been approved in the prophylactic FE/chronic settings:erenumab(Aimovig),fremanezumab(Ajovy),and galcanezumab(Emgality),with i.v.eptinezumab due a Q120 PDUFA.Oral triptan follow-ons target an alternative subreceptor(5-HT1F)lasmiditan was approved earlier this month for acute usage but despite solid efficacy uptake could be somewhat handicapped by a tough label contraindication on driving.Barclays|Migraine 25 October 2019 3 CONTENTS MIGRAINE REVIEW.4 Brief summary:condition,data and asset status.4 Migraine primer.6 Market epidemiology.7 Drugs in development.9 Pipeline of all ph.2 and ph.3 drugs for Migraine.12 Clinical Data:CGRP class,5-HT1F agonists&other novel targets.13 Sales,Pricing and Rx data.28 BrandImpact data.32 Perspectives from our US colleagues on TEVA/AGN .35 Barclays EU pharma migraine market model.37 Barclays|Migraine 25 October 2019 4 MIGRAINE REVIEW Brief summary:condition,data and asset status Migraine is a common,debilitating neurological disease that impacts around 12%of the US population(39 million people).Patients are stratified by the frequency of their migraines-measured by the number of migraine headache days(MHD)per 28-day period:acute(415 days).Of the 39 million patients,65%(25m)are classed as acute migraine patients while 25%(10m)and 10%(4m)are episodic and chronic migraine patients,respectively.Currently,patients with acute migraines are treated with non-prophylactic treatments;triptans(serotonin-5HT1B/D receptor agonists)and/or NSAIDs(over the counter pain medicines such as ibuprofen or acetaminophen),with the goal of near-term relief,while patients with episodic and chronic migraines are treated with prophylactic treatments:topiramate and Botox,respectively.As such,in the US,around 25m acute migraine patients are candidates for non-prophylactic treatments while 14m patients(episodic(10m)and chronic(4m)are candidates for prophylactic treatments.In the acute setting,the current standard of care(SoC),triptans,are contraindicated in patients with cardiovascular or cerebrovascular disease,which has led to the development of three key novel therapies in this setting:lasmiditan,ubrogepant,and rimegepant,all of which are administered orally and suitable for patients with cardiovascular(CV)risk factors.Lasmiditan is a 5-HT1F receptor agonist developed by Eli Lilly,while both ubrogepant(Allergan)and rimegepant(Biohaven)are small molecule calcitonin gene-related peptide(CGRP)antagonists.In terms of positioning,all therapies could be used in 1L in patients with CV risk factors or as a 2L treatment in patients that fail on triptans(up to 20%of patients).Safety is comparable across all treatments but lasmiditan is the most efficacious and is likely to be first to market given it is the first to be FDA approved(10th October 2019)vs.ubrogepant and rimegepant,which are awaiting PDUFA decisions expected in December 19 and Q1 20,respectively.As such,lasmiditan seems best positioned to out-compete the current SoC and see good uptake in the acute migraine market though the label will likely be a handicap;uptake this would further depend on the number of triptans insurers require patients to step through prior to lasmiditan prescription.In the episodic and chronic setting,clinical development efforts have been largely focused on anti-CGRP monoclonal antibodies administered by subcutaneous injection/IV infusion.The four key novel therapies in this space are:Novartis/Amgens Aimovig(70mg/140mg-monthly SC),Eli Lillys Emgality(120mg/240mg-monthly SC),Tevas Ajovy(225mg monthly or 675mg quarterly SC),and Alders eptinezumab(IV infusion Q12w).In terms of clinical data,all CGRPs exhibited largely undifferentiated efficacy and comparably benign safety profiles in both episodic and chronic settings.Of note,eptinezumab showed more competitive efficacy data in the chronic vs.episodic setting and a fast onset of action,reducing the risk of migraine by 50%in both episodic and chronic patients in 24 hours.In terms of approvals and launches,Aimovig(FDA/EU approved in May/Jul 18),Emgality(FDA/EU approved in Sep/Nov 18),and Ajovy(FDA/EU approved in Sep 18/Apr 19)are all currently on the market,while a PDUFA date of 21st February 2020 is scheduled for eptinezumab.Barclays|Migraine 25 October 2019 5 FIGURE 1 Overview of CGRP assets in development Source:Barclays Research;company presentations DrugCompanyMechanismStatusFormAdministration schedule&doseSettingUbrogepant Allergansmall molecule CGRP receptor antagonistPDUFA:Acute,December 19oral 25mg/50mg/100mg,2-48hrs after initial dose if neededAcuteAtogepantAllergansmall molecule CGRP receptor antagonistP3oral10mg/30mg/60mg-QD&BIDEpisodicRimegepantBiohaven small molecule CGRP receptor antagonistPDUFA:Acute,Q1 20P3:Episodic,topline results Q4 19oral75mg,2-48hrs after initial dose if neededAcuteEpisodicErenumab(Aimovig)Novartis/AmgenCGRP receptor antagonisthumanised IgG2 mAbFDA Approved:May 18EU Approved:July 18SCMonthly,70mg/140mgEpisodic and ChronicGalcanezumab(Emgality)Eli LillyCGRP ligand antagonisthumanised IgG4 mAb FDA Approved:Sep 18EU Approved:Nov 18SC Monthly,120mg/240mgEpisodic and ChronicFremanezumab(Ajovy)TevaCGRP ligand antagonisthumanised mABFDA Approved:Sep 18EU Approved:Apr 19SCMonthly(225mg)or Quarterly(675mg)Episodic and ChronicEptinezumab AlderCGRP ligand antagonisthumanised mABP2:Acute(P3 to begin H2 20)PDUFA:Episodic/Chronic,Q1 20IVQ12WAcute,Episodic and ChronicBarclays|Migraine 25 October 2019 6 Migraine primer Migraine is a common,debilitating neurological disease.It is generally described as a neurovascular disorder in which the dilation of blood vessels and pain are triggered by neural signals.The trigeminovascular system plays a key role and innervations from the trigeminal ganglion help control blood flow and provide nearly all of the pain site innervations.Migraine often begins with premonitory symptoms hours or days before the onset of pain with the most characteristic symptoms being photophobia(sensitivity to light),phonophobia(sensitivity to sound),cutaneous allodynia,dizziness,and gastrointestinal symptoms such as nausea and emesis.This is then followed by the migraine headache,which is reported by patients to be a throbbing pain that is aggravated by physical activity or head movement.The headache can change sides during or between attacks and the pain intensity is at least moderate or severe.The duration of a migraine headache can range from 4 to 72 hours in adults and 2 to 48 hours in children.The pain can involve any part of the head and often involves the posterior cervical and trapezius regions.In about one-third of people with migraine,reversible neurological symptoms known as migraine aura can occur before the onset,during,or in the absence of pain.Migraine with aura is characterised by visual,sensory,language,or disturbances associated with brainstem dysfunction that usually last between 5 and 60 minutes before the headache.Migraines are differentiated from cluster headaches,which are characterised by a strictly unilateral severe pain,localised in or around the eye and accompanied by ipsilateral autonomic symptoms such as lacrimation,rhinorrhoea,and nasal congestion.As opposed to migraines,cluster headaches are far less common and symptoms are short-lived,lasting anywhere between 15-180 minutes in regular bouts(up to eight attacks a day).Headaches occur daily for a cluster of weeks followed by a period of remission.On average,a cluster can span 6-12 weeks and remissions can last up to 12 months.The cause of the severe unilateral pain is likely mediated by activation of the first(ophthalmic)division of the trigeminal nerve,whereas the autonomic symptoms such as lacrimation are due to activation of the cranial parasympathetic outflow from the seventh cranial nerve.See the table below outlining the diagnostic criteria for migraines and cluster headaches as defined by the International Classification of Headache Disorders.Barclays|Migraine 25 October 2019 7 FIGURE 2 Diagnostic Criteria:Migraine vs.Cluster Headache Source:Barclays Research;International Classification of Headache Disorders,Lancet Market epidemiology 12%of the US population is impacted by migraines,which amounts to 39 million people.The WHO ranks migraine as the third most prevalent medical condition and the second most disabling neurological disorder in the world with a greater prevalence of migraine noted in females vs.males.Migraine is most prevalent between the ages of 25 and 55 years,and the prevalence rises through early adult life and then falls after midlife i.e.55 years.For patient management,clinical trial,and regulatory purposes,migraine patients are stratified by the frequency of their migraines-measured by the number of migraine headache days(MHD)per 28-day period:low or acute(4 and 15).Of the 39 million patients,65%(25m)are classed as acute migraine patients while 25%(10m)and 10%(4m)are episodic and chronic migraine patients,respectively.As such,around 14m patients(episodic and chronic)are candidates for preventive treatments.See the figure below.MigraineCluster Headache1)At least five attacks fulfilling criteria 2-4A)At least five headache attacks fulfilling criteria B-D2)Headache attacks lasting 4-72h(untreated or successfully treated)(B)Severe or very severe unilateral orbital,supraorbital,and/or temporal headache attacks,which last untreated for 15180 min.During part(but less than half)of the time course of the cluster headache,attacks may be less severe,less frequent,or of shorter or longer duration3)Headache has at least two fo the following characteristics:unlateral location,pulsating quality,moderate or severe pai