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4 PREVALENCE AND BURDEN OF HEADACHE Patient with CDH IHS migraine Recurrent severe headache Severe headache Episodic headache Have had headache Entire population CDH=chronic daily headache. IHS=International Headache Society. Lipton R, et al. Headache. 2001;41:

5 EPIDEMIOLOGIC DATA Chronic Migraine (CM) % consult an HCP 10 % receive diagnosis of CM Cluster headache Average 5-year diagnostic delay 2 21 % receive correct diagnosis 3 Episodic Migraine (EM) % are dissatisfied with regimen 26.2 % have a history of cardiovascular (CV) events Migraine 4 In migraine, ~4 years between diagnosis and initiation of preventive medication 38 % of migraineurs meet criteria for preventive medication; only 11 % obtain it HCP=healthcare professional. 1. Dodick DW, et al. Headache. 2016;56(5): Voiticovschi-Iosob C, et al. J Headache Pain. 2014;15: Rozen TD, Fishman RS. Headache. 2012;52(1): Lipton RB, et al. Headache. 2013;53(8): Minen M, et al. Headache. 2016;56(4):

6 FDA-APPROVED MEDICATIONS FOR HEADACHE: ACUTE TREATMENT 1 Device Triptans Ergots NSAID Triptan/ NSAID Triptan Ergot Device Sumatriptan Transcranial magnetic stimulation 3 Zolmitriptan Naratriptan Rizatriptan Almotriptan Frovatriptan Ergotamine/ caffeine Diclofenac potassium powder Sumatriptan/ naproxen Sumatriptan Dihydroergotamine Dihydroergotamine Noninvasive nerve vagal stimulation 2 Eletriptan FDA=U.S. Food and Drug Administration. NSAID=nonsteroidal anti-inflammatory drug. 1. Dodick DW, et al. Headache. 2016;56(5): Voiticovschi-Iosob C, et al. J Headache Pain. 2014;15: Rozen TD, Fishman RS. Headache. 2012;52(1):

7 FDA-APPROVED MEDICATIONS FOR HEADACHE PROPHYLAXIS 1,2 Beta blockers Propranolol Timolol Antiepileptic drugs Divalproex Topiramate Device Transcutaneous electrical nerve stimulation (TENS) device 3 Injection Onabotulinumtoxin A 4 Nothing currently 1. Med Lett Drugs Ther. 2017;59(1514): Med Lett Drugs Ther. 2017;59(1514):e31-e Accessed March 26, Accessed March 26,

8 EXAMPLE CASE COMORBID CONDITIONS Depression Migraine PRIOR TREATMENT FAILURES OF Amitriptyline Fluoxetine BUILDING AN INDIVIDUALIZED TREATMENT PLAN Try to treat both problems with a single agent but may have to treat separately 8

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10 PAIN-SENSITIVE STRUCTURES IN THE HEAD PORTIONS OF THE MENINGES Basal dura mater Venous sinuses and tributaries NEURAL STRUCTURES Trigeminal cranial nerves Glossopharyngeal nerves Vagus nerves SCALP AND SUPERFICIAL STRUCTURES VASCULAR STRUCTURES Dural arteries Carotid/vertebral arteries Proximal portions of the cerebral vessels 1. Stewart WA, King RB. J Comp Neurol. 1963;121: Strassman AM, et al. Nature. 1996;384(6609):

11 AA K + NO CGRP NKA SP AA=amino acid. K + =potassium. NO=nitric oxide. CGRP=calcitonin gene-related peptide. NKA=neurokinin A. SP=substance P. 1. Bolay H, et al. Nat Med. 2002;8(2): Russo AF. Annu Rev Pharmacol Toxicol. 2015;55: Edvinsson L, Ho TW. Neurotherapeutics. 2010;7(2):

12 CGRP G-PROTEIN COUPLED RECEPTOR COMPLEX 1. Accessed November 10, Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:

13 PATHOPHYSIOLOGY IN 3D 3D=three dimensions. 13

14 1. Bolay H, et al. Nat Med. 2002;8(2): Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:

15 Walker CS, Hay DL. Br J Pharmacol. 2013;170(7):

16 Walker CS, Hay DL. Br J Pharmacol. 2013;170(7):

17 Walker CS, Hay DL. Br J Pharmacol. 2013;170(7):

18 PATHOPHYSIOLOGY IN 3D THE END 18

19 WHY DO WE CARE ABOUT CGRP FOR MIGRAINE? VIP SP CGRP Circulating CGRP is high in migraine and other primary headache disorders Other neuropeptides do not follow the same pattern Migraine without aura ±0 ±0 Migraine with aura ±0 ±0 Trigeminal neuralgia ±0 ±0 Cluster headache ±0 Chronic paroxysmal headache ±0 ±0=no change from before headache. =significant increase in neuropeptide level. Adapted with permission from Edvinsson L, Uddman R. Brain Res Rev. 2005;48: VIP=vasoactive intestinal peptide. 1. Edvinsson L, Uddman R. Brain Res Brain Res Rev. 2005;48(3): Lassen LH, et al. Cephalalgia. 2002;22(1):

20 WHY DO WE CARE ABOUT CGRP FOR MIGRAINE? (CONT.) CGRP declines as migraine is diminished with treatment 1 In participants whose migraine improved with sumatriptan Injecting CGRP induces headache and migraine 2 Number of participants to develop a headache over the course of 12 hours hα-cgrp 8/9 Plasma CGRP decreased placebo 1/9 α=alpha. 1. Edvinsson L, Uddman R. Brain Res Brain Res Rev. 2005;48(3): Lassen LH, et al. Cephalalgia. 2002;22(1):

21 PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP) RECEPTOR Perivascular space of cranial vessels are mediators of nociceptive input PACAP-38 infusions induce dilation of extracranial vessels and delayed migraines in migraineurs PACAP activates PAC1 receptor: dilation of extracranial vessels PAC 1 mab being evaluated for CM mab=monoclonal antibody. Edvinsson, L. Br, J Pharmacol. 2015;172(19):

22 LATE-STAGE EMERGING THERAPIES: ACUTE HEADACHE TREATMENT 1 Pharmacologic Noninvasive neuromodulatory device Invasive neuromodulatory device Invasive neuromodulatory device Pharmacologic Intranasal sumatriptan and 1-O-n-Dodecyl-beta- D-Maltopyranoside 2 Vagus nerve stimulation Ditan (5-HT 1F agonist) Remote nonpainful electrical upper arm skin stimulation Sphenopalatine ganglion stimulation Sphenopalatine ganglion stimulation Intranasal oxytocin Gepant (CGRP receptor antagonist) TENS 5-HT 1F =serotonin 1F receptor Munjal S, et al. J Headache Pain. 2017;18(1):31. 22

23 UBROGEPANT (PHASE 2B) TRIAL P=.003 Percent (95% CI) P=.344 P=.211 P=.013 P= Placebo (n+113) Ubrogepant 1 mg (n=107) Ubrogepant 10 mg (n=108) Ubrogepant 25 mg (n=104) Ubrogepant 50 mg (n=106) Ubrogepant 100 mg (n=112) Overall side effects similar between ubrogepant and placebo 1. Voss T et al. Cephalalgia. 2016;36:

24 RIMEGEPANT (PHASE 2B) 812 patients Significantly better than placebo for Pain Nausea Photophobia Phonophobia 2-24 hour pain freedom statistically better than placebo Middle dose decreased pain and associated symptoms for a sustained amount of time No SAES DB/PC=double-blind placebo-controlled. SAE=serious adverse event. Accessed June

25 CLINICAL IMPLICATIONS OF GEPANTS SAFETY IS AN ISSUE Investigation with olcegepant and telcagepant discontinued Liver toxicity with extended, regular use SMALL MOLECULE RECEPTOR ANTAGONISTS AGAINST CGRP Ubrogepant, rimegepant, and others THEY HAVE A ROLE IN ACUTE MIGRAINE TREATMENT Study is under way for the prevention of migraine Bigal ME, et al. Headache. 2013;53:

26 LASMIDITAN (PHASE 3) 100-mg and 200-mg doses increased pain freedom at the 2-hour time point Well tolerated No significant difference in cardiovascular AEs (in patients dosed with lasmiditan vs placebo) 100 mg 200 mg Placebo TEAE LASMIDITAN 100 mg (n=630) LASMIDITAN 200 mg (n=609) Placebo (n=617) Primary endpoint Migraine headache pain free at 2 hours 28.2 P<.001 % of Patients 32.2 P< Dizziness 75 (11.9%) 94 (15.4%) 19 (3.1%) Paresthesia 36 (5.7%) 46 (7.6%) 13 (2.1%) Somnolence 33 (5.2%) 32 (5.3%) 14 (2.3%) Nausea 16 (2.5%) 29 (4.8%) 9 (1.5%) Secondary endpoint Most bothersome associated symptom free at 2 hours 40.9 P< P< Fatigue 24 (3.8%) 18 (3.0%) 1 (0.2%) Lethargy 12 (1.9%) 14 (2.3%) 1 (0.2%) Vertigo 6 (1.0%) 2 (0.3%) 0 AE=adverse event. TEAE=treatment-emergent adverse event. Secondary-Endpoints-in-the-SAMURAI-Phase-3-Pivotal-Trial-of-Lasmiditan-in-Migraine.html. Accessed June 19,

27 mabs WITH HUMAN SEQUENCES REDUCE THE IMMUNOLOGIC RESPONSE POTENTIAL Murine (0% human) Generic suffix: -omab Chimeric (65% human) Generic suffix: -ximab Humanized (>90% human) Generic suffix: -zumab Fully Human (100% human) Generic suffix: -umab Silberstein S, et al. Headache. 2015;55(8):

28 LATE-STAGE EMERGING THERAPIES FOR HEADACHE PROPHYLAXIS Monoclonal Antibodies Receptor Antagonist Galcanezumab Erenumab Fremanezumab Eptinezumab Atogepant* Migraine Cluster headache Migraine Migraine Cluster headache Migraine Migraine Humanized Human Humanized Humanized SC injection SC injection SC injection IV infusion SC=subcutaneous. IV=intravenous. *See Additional Resources for more information. 28

29 LATE-STAGE EMERGING THERAPIES FOR HEADACHE PROPHYLAXIS (CONT.) Vagus nerve stimulation* Migraine Chronic cluster headache Caloric vestibular stimulation* Episodic and vestibular migraine *See Additional Resources for more information. 29

30 EPTINEZUMAB/ALD403 (PHASE 2) CHRONIC MIGRAINE WITH SINGLE IV INFUSION EFFICACY 75% reduction in migraine days for the entire 12 weeks with single IV infusion 1 Number of patients self-reporting a migraine was reduced in the first full day (24 hours) following infusion 2 SAFETY Well-tolerated with no serious related AEs reported *Statistically significant, P< Smith J, et al. Presented at: 58 th Annual Scientific Meeting American Headache Society; June 9-12, 2017; Boston, MA. Abstract #IOR Smith J, et al. Presented at: 58 th Annual Scientific Meeting American Headache Society; June 9-12, 2017; Boston, MA. Abstract #PF87. 30

31 GALCANEZUMAB/LY (PHASE 3) EVOLVE 1 IN EPISODIC MIGRAINE DB/PC 240 mg initially, then 120 or 240 mg monthly vs placebo for 6 months Decrease monthly migraine headache days with acute medication over 6-month treatment period REGAIN IN CHRONIC MIGRAINE DB/PC 240 mg initially, then 120 or 240 mg monthly vs placebo for 3 months Decrease monthly migraine headache days with acute medication over 3-month treatment period Accessed June 19,

32 FREMANEZUMAB/TEV (PHASE 3) PREVENTION OF EPISODIC MIGRAINE 1 Improved number of migraine days relative to baseline over 12 weeks PREVENTION OF CHRONIC MIGRAINE 2 Reduced number of monthly headache days of at least moderate severity over 12 weeks Dosing Monthly: 225 mg 225 mg 225 mg Quarterly: 675 mg placebo placebo Dosing Monthly: 675 mg 225 mg 225 mg Quarterly: 675 mg placebo placebo 1. regimens_in_phase_iii_study_in_episodic_migraine_prevention_06_17.aspx. Accessed June 19, positive_results_for_phase_iii_study_of_fremanezumab_for_the_prevention_of_chronic_migraine_05_17.aspx. Accessed June 19,

33 ERENUMAB/AMG334 (PHASE 2, 3) STRIVE AND ARISE: PHASE 3 TRIALS IN EM 1,2 6-month study, 955 subjects Reduction in migraine days PHASE 2 TRIALS IN CM 3 Reduced monthly migraine days during weeks 9-12 compared to baseline 50% reduction in migraine days Safety/tolerability profile of erenumab was similar to placebo, with nasopharyngitis, upper respiratory tract infection, and sinusitis being most frequently reported 1. Goadsby PJ, et al. Presented at: 58th Annual Scientific Meeting American Headache Society; June 9-12, 2017; Boston, MA. Abstract #IOR Dodick DW, et al. Presented at: 58th Annual Scientific Meeting American Headache Society; June 9-12, 2017; Boston, MA. Abstract #IPS Tepper SJ, et al. Presented at: 58th Annual Scientific Meeting American Headache Society; June 9-12, 2017; Boston, MA. Abstract #IOR07. 33

34 SUMMARY Recent clinical trials have shown safety and efficacy of blocking CGRP to treat migraine without apparent significant CV risk Emerging therapies target migrainespecific pathophysiologic mechanisms CGRP=calcitonin gene related peptide. 34

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37 Advisory Board: Alder Biopharmaceuticals, Allergan, Amgen, Avanir, Depomed, Lilly, Supernus Consultant: Avanir, Lilly, Pernix Speaker s Bureau: Avanir, Depomed, Pernix, Teva 37

38 CLASSIFICATION CLASSIFICATION Why is it important? History Limitations ICHD-3 BETA CGRP=calcitonin ICHD=International gene Classification related peptide. of Headache Disorders. 38

39 MIGRAINE DIAGNOSTIC CRITERIA Unilateral Pulsating Lasts 4-72 hours Untreated or unsuccessfully treated Moderate/ severe pain >2 attacks >1 attacks Aggravated by/avoidance of routine physical activity Nausea and/or vomiting Photophobia and phonophobia Not better accounted for by another ICHD-3 diagnosis Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9): >1 attacks fully reversible symptoms Visual Sensory Speech and/or language 2 attacks First 2 criteria for migraine without aura >2 attacks Motor Brainstem Retinal 1 aura symptom spreads gradually over 5 minutes and/or 2 in succession Each aura symptom lasts 5-60 minutes 1 aura symptom is unilateral Aura accompanied/followed, within 60 minutes, by headache Not better accounted for by another ICHD-3 diagnosis and transient ischemic attack excluded 39

40 MIGRAINE DIAGNOSTIC CRITERIA (CONT.) 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine 1.4 Complication of migraine 1.5 Probably migraine 1.6 Episodic syndromes that may be associated with migraine Migraine with typical aura Typical aura with headache Typical aura without headache Migraine with brainstem aura Hemiplegic migraine Familial hemiplegic migraine (FHM) FHM FHM FHM FHM, other loci Sporadic hemiplegic migraine Retinal migraine Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

41 MIGRAINE DIAGNOSTIC CRITERIA (CONT.) 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine 1.4 Complication of migraine 1.5 Probably migraine Status migrainosus Persistent aura without infarction Migrainous infarction Migraine aura-triggered seizure 1.6 Episodic syndromes that may be associated with migraine Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

42 MIGRAINE DIAGNOSTIC CRITERIA (CONT.) 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine 1.4 Complication of migraine 1.5 Probably migraine Probable migraine without aura Probable migraine with aura 1.6 Episodic syndromes that may be associated with migraine Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

43 MIGRAINE DIAGNOSTIC CRITERIA (CONT.) 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine 1.4 Complication of migraine 1.5 Probably migraine 1.6 Episodic syndromes that may be associated with migraine Recurrent gastrointestinal disturbance Cyclical vomiting syndrome Abdominal migraine Benign paroxysmal vertigo Benign paroxysmal torticollis Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

44 MIGRAINE FREQUENCY EXISTS ON A SPECTRUM One-third of people with migraine have headache on 4 days per month and 6% on 15 or more days per month 1 Traditional criteria for preventive treatment are defined in part by headache days % of Patients Episodic <15 headache days per month can be classified as episodic migraine Chronic 15 headache days per month >3 months can be classified as chronic migraine Headache days per month 1. Blumenfeld AM, et al. Cephalalgia. 2011;31(3): Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):

45 CONSIDER PREVENTION WHEN SIGNIFICANT INTERFERENCE with routine activities despite use of acute treatment ATTACK FREQUENCY >1/week ELEVATED RISK: Medication overuse ACUTE MEDICATIONS Ineffective Contraindicated Troublesome AEs Overused UNCOMMON SUBTYPES PRESENT Ineffective Contraindicated Troublesome AEs Overused PATIENT PREFERENCE 42

46 MIGRAINE PREVENTION IS UNDERUSED The AMPP study surveyed 18,968 individuals with migraine and found that: were candidates for or should be considered for prophylactic treatement 1 had received prophylactic medication for migraine in the past but discontinued treatment 2 were current users of prophylactic medication for the treatment of migraine 1 AMPP=American Migraine Prevalence and Prevention. 1. Lipton RB, et al. Neurology. 2007;68(5): Diamond S, et al. Headache. 2007;47(3):

47 TENSION-TYPE HEADACHE 2.1 Infrequent episodic tension-type headache 2.2 Frequent episodic tension-type headache Infrequent episodic tension-type headache associated with pericranial tenderness Infrequent episodic tension-type headache not associated with pericranial tenderness 2.3 Chronic tension-type headache 2.4 Probable tension-type headache Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

48 TENSION-TYPE HEADACHE 2.1 Infrequent episodic tension-type headache 2.2 Frequent episodic tension-type headache Frequent episodic tension-type headache associated with pericranial tenderness Frequent episodic tension-type headache not associated with pericranial tenderness 2.3 Chronic tension-type headache 2.4 Probable tension-type headache Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

49 TENSION-TYPE HEADACHE 2.1 Infrequent episodic tension-type headache 2.2 Frequent episodic tension-type headache 2.3 Chronic tension-type headache 2.4 Probable tension-type headache Chronic tension-type headache associated with pericranial tenderness Chronic tension-type headache not associated with pericranial tenderness Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

50 TENSION-TYPE HEADACHE 2.1 Infrequent episodic tension-type headache 2.2 Frequent episodic tension-type headache 2.3 Chronic tension-type headache 2.4 Probable tension-type headache Probable infrequent episodic tension-type headache Probable frequent episodic tension-type headache Probable chronic tension-type headache Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

51 TRIGEMINAL AUTONOMIC CEPHALALGIAS 3.1 Cluster headache Episodic cluster headache Chronic cluster headache 3.2 Paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.4 Hemicrania continua 3.5 Probable trigeminal autonomic cephalalgia Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

52 TRIGEMINAL AUTONOMIC CEPHALALGIAS 3.1 Cluster headache 3.2 Paroxysmal hemicrania Episodic paroxysmal hemicrania Chronic paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.4 Hemicrania continua 3.5 Probable trigeminal autonomic cephalalgia Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

53 TRIGEMINAL AUTONOMIC CEPHALALGIAS 3.1 Cluster headache 3.2 Paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.4 Hemicrania continua 3.5 Probable trigeminal autonomic cephalalgia Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) Episodic SUNCT Chronic SUNCT Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) Episodic SUNA Chronic SUNA Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

54 TRIGEMINAL AUTONOMIC CEPHALALGIAS 3.1 Cluster headache 3.2 Paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.4 Hemicrania continua 3.5 Probable trigeminal autonomic cephalalgia Probable cluster headache Probable paroxysmal hemicrania Probable short-lasting unilateral neuralgiform headache attacks Probable hemicrania continua Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33(9):

55 PIN THE DIAGNOSIS ON THE MIGRAINE SUFFERER ID MIGRAINE SCREENER VALIDATED IN PRIMARY CARE SETTING 3 items (any 2 of the 3 items) Photophobia Impact (headache-related disability) Nausea Sensitivity 0.81, specificity 0.75 Positive predictive value=93.3% Lipton R, et al. Neurology. 2003;61:

56 ACUTE RX 1. Buse DC, et al. J Neurol. 2013;260(8): Buse DC, et al. Headache. 2012;52(10):

57 APPROACH ONE AND DONE Large single dose is best to prevent or avoid central sensitization PAIN-FREE ASAP ASAP=as soon as possible. 48

58 TOOLBOX 49

59 PREVENTIVE RX INDICATIONS Frequent or long-lasting migraine Significant disability Contraindications to acute therapy AEs with acute therapy Risk of MOH Menstrual-related migraine (MRM) 1. Buse DC, et al. J Neurol. 2013;260(8): Buse DC, et al. Headache. 2012;52(10):

60 RISK OF CHRONIFICATION Caffeine Butalbitals Opioids Triptans 51

61 PRINCIPLES REDUCE frequency and disability IMPROVE acute therapy response START LOW DOSE and increase AVOID MOH MANAGE patient expectations DISCUSS lifestyle changes Katsarava Z, et al. Neurology. 2004;62(5):

62