Supported by an educational grant from Teva Pharmaceuticals - PowerPoint Presentation

Supported by an educational grant from Teva Pharmaceuticals Provided by MediCom Worldwide, Inc.

Faculty David W. Dodick, MD – Chair Professor of NeurologyDepartment of NeurologyMayo Clinic Phoenix, Arizona    Deborah I. Friedman, MD, MPH, FAANProfessor of Neurology & Neurotherapeutics Professor of Ophthalmology University of Texas Southwestern Medical Center Dallas, Texas Andrew C. Charles, MD Professor of Neurology UCLA School of Medicine Los Angeles, California

Agenda 4:30 pm Registration and Dinner5:00 pm Moderator’s Welcome5:10 pm The Patient’s Story; Meet LK 5:15 pm Panel Presentations/Interaction/ Discussion with LK and Audience

Three-month self-report prevalence in adults Children and adolescents Migraine is Highly Prevalent… 1 in 6 Americans1 in 4 women Prevalence of migraine or severe headache highest in American Indian or Alaskan Natives - Lowest prevalence in Asians Higher burden in: - Ages 18-44 (17.9%) - Unemployed (21.4%) - Family income X $35,000/year (19.9%) - Elderly and disabled (16.4%) Third leading cause of ED visits in reproductive aged women 7.7-9.1% overall 9.7% of girls 6.0% of boys Burch R, et al. Headache . 2018;58:496-505.; Özge A, et al. Curr Pain Headache Rep . 2016;20;14.

Headache is the 2 nd leading cause of years lived with disability (YLD) worldwideHeadache disorders are the cause of more than three-quarters of all neurological TLDs (6.5% of all YLDs) Migraine is the 3rd among people ages 15-49 years (GBD 2016)Migraine is the 2nd cause of disability in both sexes and all ages (#1 is low back pain)And the first cause of disability in persons under age 50 …and Highly Disabling Global Burden of Disease StudySaylor D, et al. Semin Neurol. 2018;38:182-190.; GBD 2015. Lancet. 2016;388:1545-1602.; Steiner TJ, et al. J Headache Pain. 2018;19(1):17.

% Agree Migraine Impacts Work Productivity – Most migraneurs, and more than half of those with 4+ MHD, believe they’ve missed opportunitiesBase: Migraine sufferers who work (n=227); total migraine for changed job and career goals (n=518) agree is top 3 box agreement on a 6-point scale Q15. Using the scale shown below, please indicate how much you agree or disagree with the following statements.Q10. Thinking about the overall impact migraines have had on your life, to what extent do you believe that migraines have negatively impacted your… Missed out on opportunities at work (promotions, etc.) Chose to turn down opportunities at work (promotions, etc.) Missed out on additional earning potential at work Changed jobs to minimize the likelihood of getting a migraine 4+ MHD: 52% 4+ MHD: 53% 55% say migraine has impacted career goals Migraine impacts work productivity for 68% of migraineurs Some also have career-changing impact

CaMEO Study (web based, 2012-2013) assessed Family Burden Module in EM and CM (ICHD-3b) 13,064 respondents (65.7% response rate)4,022 migraineur-spouse dyads including 2,275 dyads with children EM (91.2%), CM (8.8%)48-57% reported reduced participation in family activities due to migraine at least once monthlyMany perceived that their spouse/partner did not believe the severity and impact of their migraines (EM 34-40%, CM 44%)1/3 worried about long-term financial security for themselves or their families because of their headachesMany felt that they would be better parents without migraine (EM 30-58%, CM 72%)Spouses agreed to a lesser extentFamily Impact of Migraine Buse DC, et al . Mayo Clin Proc. 2016;91:596-611.

CaMEO Study (1,411 parent-adolescent dyads) Highly statistically significant (P<.001) responses related to:Loss of parental support/reverse caregiving (cooking, chores, taking care of parent) Emotional experiences (arguing, taking advantage of parent, angry at parent, parent is “needy,” would get along with parent better if they didn’t have migraine)Interference with school (missing events, parent can’t participate like other parents do) Adolescent Perspectives of a Parent’s MigraineBuse DC, et al. Headache. 2018;58:512-524.

Missed group activities (family, school, sports, performance)Missed social activities (movie, party, friends visiting, friends had to leave) Missed major events (vacation, holidays, celebrations) Anxiety and depression rates among adolescents whose parent had migraineBuse DC, et al. Headache. 2018;58:512-524.

German Health Interview Study (n=7341) Screened for severe headaches in the previous 12 months12-month prevalence 60% (women 66%, men 53%) Diagnosed with migraine using ICHD-2 criteria12-month prevalence 10.6% (women 15.6%, men 5.3%)“Do you believe that your headaches were, at least in part, due to migraine?” 70% of patients with migraine regarded their headaches as migraine41% had consulted a physician for headache in 12 months-65% of those had received a diagnosis of migraineRate of Self-Awareness of the Diagnosis is Low Radtke A, et al. Cephalalgia. 2012;32:1023-1030.; Lipton RB, et al. Neurology. 2002;58:885-894.

Most common misdiagnoses by physicians: Tension-type headache (55.6%)Sinus headache (9.1%) Other (35.4%)Factors predicting higher self-awareness:Greater headache intensityGreater number of headache daysPhotophobia and photophobia, nausea or vomiting, unilateral pain, throbbing pain, visual aura Sex and having a medical consultation were NSIn a 2002 U.S. study, only 53% of patients correctly diagnosed their own migrainesRadtke A, et al. Cephalalgia. 2012;32:1023-1030.; Lipton RB, et al. Neurology. 2002;58:885-894.

1. Consulted a healthcare professional 2. Diagnosed accurately 3. Prescribed appropriate treatment 45.5% of entire cohort (n=353) 39.5% of entire cohort (n=306) (87% of previous) 26.3% of entire cohort (n=204) (67% of previous) Most Migraine Patients Do Not Successfully Traverse Barriers to Care CM Patients from CaMEO Study (n=1254) 40.8% of entire cohort (n=512) 10% of entire cohort (n=126) (25% of previous) 4.5% of entire cohort (n=56) (44% of previous) EM Patients from AMPP Study (n=775) Dodick DW, et al. Headache . 2016;56:821-834.; Lipton RB, et al. Headache . 2013;53:81-92.

Retrospective cohort study using research databases Identified adults with migraine diagnosis who initiated preventive treatment (index event) with topiramate, beta- blockers, TCAs in years 2008-2011Patients had 12 months of pre- and post-index enrollment Assessed gaps in therapy, treatment changes, additions of index medications and acute medication usageN=107,122Mean age 4183% female Adherence to Preventive Treatment is PoorTopiramateBeta BlockersTCA 49% (52,275) 21% (22,658) 30% (32,189) Woolley JM, et al. Headache. 2017;57:1399-1408.

81% had gaps of >90 days in the first year Gaps occurred early in therapy (mean 95 days)Only 10% restarted preventive therapy within that yearSwitching meds (13%) or adding another preventive medication (5%) was uncommon After one year, 65% were not on preventive treatment81% used acute treatmentsOpioids 53%, of whom 40% did not have another pain conditionTriptans 48% Woolley JM, et al. Headache. 2017;57:1399-1408.

Both EM and CM Have a Significant Impact on Patients’ Lives Of the employed patients:13% with HFEM (10+ days per month) and 11% with CMmissed at least one day per week in the preceding 2 weeks(AMPP, n=6,204)Buse DC, et al. Mayo Clin Proc. 2016;91:596-561.; Stewart WF, et al. J Occup Environ Med. 2010;52:8-14.

Retrospective cohort study using Research Databases Adults with CM who initiated an oral preventive in 2008-2012: TCAs, SSRIs, beta blockers, gabapentin, topiramate, divalproex Index date determined by first pharmacy claimExcluded patients whose claim occurred within 12 months after a diagnosis of CHF, HTN, depression or seizureCalculated medication possession ratio (MPR and proportion of days covered (PCD) Adherence to Oral Preventives in Chronic MigraineHepp Z, et al. Cephalalgia. 2015;35:478-488.

74,870 patients with CM identified 49% initiated a preventive medication 8,688 met inclusion/exclusion criteria Most were female, average age 40; 59% working full-timeBased on medication possession(MPR ≥80%): 29% were adherent at the end of 6 months 20% were adherent at 12 months Based on proportion of days covered (PCD ≥80%): 26% were adherent at the end of 6 months 17% were adherent at 12 monthsHepp Z, et al. Cephalalgia. 2015;35:478-488.

Topiramate was most the commonly prescribed preventive Amitriptyline, nortriptyline, gabapentin and divalproex had lower odds of patient adherence compared to topiramate Hepp Z, et al. Cephalalgia. 2015;35:478-488.

Study of EM (n=123), CM (n=123) and epilepsy (n=62) patients using the Stigma Scale for Chronic Illness CM patients reported more stigma than epilepsy and EM patientsEM and CM patients had higher rates of internalized stigma than those with epilepsy Stigma was correlated with inability to work in all groupsAge, income and education did not affect stigma scoresStigma of Migraine Young WB, et al. PLoS One. 2013;8(1):e54074.

368 French neurologists, of whom 48.6% had migraine 92.3% claimed to be very or quite interested in migraine 96.5% considered it a “real” illness 96.6% considered it very or quite disabling About half considered it challenging to treat because of: Unrealistic patient expectations (46.2%) Time-consuming treatment (48.9%) Complications of co-existing anxiety and depression (59.5%) Medical nomadism (47.0%) No difference between those who did and did not have migraine How Do Neurologists Perceive Migraine?Donnett A, et al. Headache. 2010;50:1115-1125.

Currently 475 UCNS-certified headache medicine specialists in the US and Canada One specialist for every 80,000 patients Marked geographic disparityBest patient ratio: DC, NH, NY, NBIn 2014, six states had no headache specialistMost located in urban and higher income areasLong wait times for appointments Headache Medicine Fellowship programs are largely unfilledThere is a Shortage of Headache Specialists to Care for Migraine PatientsRosen NR, et al. International Headache Congress, 2013.; Rizzoli P, et al. Headache. 2014;54:1591-1600.; Minen MT, et al. Headache . 2015;55:1092-1101.

State by State Breakdown of UCNS-Certified Headache Specialists www.theraspecs.com

What is a Neuropeptide? Small chains of amino acids released by neural cells (neurons or glial cells) to signal to other cells Multiple properties that set them apart from classical neurotransmitters

Hökfelt T, et al. Lancet Neurol . 2003;2(8):463-472.Examples of Neuropeptides Calcitonin gene-related peptidePituitary adenylate cyclase activating peptideVasoactive intestinal peptideOrexinsSubstance PHypothalamic hormones (eg, GnRH, oxytocin)Endogenous opioids (endorphins, enkephalins)MelanocortinBradykinin

Summary Compared to neurotransmitters (like glutamate, GABA) neuropeptides: Are produced and packaged differently by cellsTake more activation to releaseBind more tightly to receptorsHave a more sustained effectCan be released away from a synapseOnce released can travel to more distant locationsCan cause more diffuse effects on glia, vascular cells, endocrine cells, etc.

Calcitonin Gene Related Peptide (CGRP) 37 amino acid polypeptideAlpha-CGRP believed to be primary active form in nervous system Beta-CGRP (3 amino acids different from Alpha CGRP) believed to be primarily active form in GI tractActivates CGRP receptor and may also activate other types of receptors

Evidence of a Key Role for CGRP in Migraine CGRP is Released During a Migraine Attack CGRP Levels areElevated in Chronic Migraine CGRP Administration Triggers Migraine Small Molecule CGRP Antagonists Abort Migraine Antibodies to CGRP or its Receptor Prevent Migraine Goadsby PJ, et al. Ann Neurol . 1990;28:183-187.; Goadsby PJ, et al . Brain. 1994;117( Pt 3):427-434.; Hansen JM, et al. Cephalalgia. 2010;30(10):1179-1186.; Cernuda-Morollon E, et al. Neurology. 2013;81(14):1191-1196.; Olesen J, et al. N Engl J Med . 2004;350:1104-1110.; Ho TW, et al. Neurology. 2008;70:1304-1312.

CGRP Release in Migraine Goadsby PJ, et al. Ann Neurol .1990;28:183-187.; Goadsby PJ, et al. Ann Neurol. 1993;33(1):48-56.; Cernuda-Morollon E, et al. Neurology. 2013;81(14):1191-1196. CGRP but not neuropeptide Y, VIP, or substance P released during attacks of migraine with and without aura Elevated CGRP levels were observed in jugular but not antecubital venous blood on same side as pain Greater elevation in CGRP observed in migraine with aura CGRP levels normalize upon treatment with sumatriptan Serum CGRP levels reported to be chronically elevated in patients with chronic migraine

CGRP Administration Triggers Migraine Intravenous administration of CGRP evokes migraine in those with a history of migraine, but not in controls Hansen JM, et al. Cephalalgia. 2010;30(10):1179-1186.; Schytz HW, et al. Curr Opin Neurol. 2010;23(3):259-265.

Small Molecule CGRP Receptor Antagonists (“Gepants”) Abort Migraine Karsan N, et al. Curr Opin Neurol. 2015;28(3):250-254.; Voss T, et al. Cephalalgia. 2016;36(9):887-898.; Marcus R, et al. Cephalalgia. 2014;34(2):114-125. Drug Pain free at 2 h (%) Verum Placebo Side effects reportedStatus in pharmacological trialsOlcegepant44; 2.5 mg 220% reported adverse effects Discontinued development — poor oral bioavailability Telcagepant 27; 300 mg 10 Transaminitis Discontinued — hepatotoxic concerns MK3207 69; 200 mg 39.1 Transaminitis Discontinued — hepatotoxic concerns BI44370 27.4; 400 mg 8.6 1.4  9.4% reported adverse effects, dose dependent Phase IIa complete BMS-927711 32.9; 150 mg 15.3 18% reported adverse effects, dose dependentPhase IIa complete

What Do Clinical Trials of CGRP-related Therapies Tell Us About Pathophysiology?

CGRP Antibody Clinical Trials What Do They Tell Us About Migraine Biology? Specificity of antibodies to targets definitively proves primary role for CGRP and CGRP receptor in migraineEfficacy of antibodies, which presumably do not cross blood- brain barrier, indicates mechanism of action that is either peripheral, or in brain regions outside of BBBIndividual patient responses represent an opportunity to markedly increase our understanding of basic mechanisms

CGRP and Receptor Localization Related to Migraine Peripheral and Central Nervous System CGRP peptide is localized in neurons and glial cells CGRP receptors are localized in neurons, glial cells, dural arteries, and mast cellsCGRP and its receptors are localized throughout the trigeminal nociceptive pathway, including peripheral afferents, trigeminal ganglion, and trigeminal-cervical complexCGRP receptors are localized in multiple brain regions including:Trigeminal nucleus caudalis, dorsolateral pons/midbrain, thalamus, hypothalamus, cortex, cerebellum, amygdala, vestibular nuclei Karsan N, et al. Curr Opin Neurol. 2015;28(3):250-254.; Kaiser EA, et al. Neuropeptides . 2013;47(6):451-461.

19 patients with spontaneous migraine No extracranial artery dilation during attackSlight intracranial artery dilation during attackEffective treatment with sumatriptan caused no intracranial vasoconstriction The Paradigm Shift from the Vascular Hypothesis of Migraine

If the Vascular Hypothesis of Migraine is not Correct, How Do You Explain the Role of CGRP, Which is a Vasodilator? The fundamental tenet of the vascular hypothesis is that the dilation of blood vessels is responsible for headacheWhile CGRP is indeed a vasodilator, it is also separately involved in pain transmissionThus, while CGRP may dilate blood vessels, it is the parallel effect of CGRP on pain transmission that is responsible for headache, and not the dilation of blood vessels

GENES >38 Migraine associated gene polymorphisms ENVIRONMENT Barometric pressure Stress HORMONES Menstrual cycle Pregnancy DRUGS Exacerbating medications METABOLISM Diet Neuroendocrine function Hypothalamic activation Alteration in thalamocortical circuits Altered brain connectivity Hormonal and metabolic state Migraine genes Variable Attack Symptoms and Severity Premonitory Aura Headache Postdrome Brainstem Activation CSD CGRP PACAP Release Cervical nerve anatomy Drugs Adapted from Charles AC. Lancet Neurol. 2018.

Neuromodulation Single pulse transcranial magnetic stimulation (sTMS) Non-invasive vagal nerve stimulation (n-VNS) External trigeminal nerve stimulation (e-TNS) Biologics Anti CGRP/CGRP-R monoclonal antibodies (mAbs) OnabotulinumtoxinA Practical Strategies for Navigating Today’s New Era in Preventive Treatment of Migraine

CGRP Monoclonal Antibodies ( mAbs ) in Development for Migraine Prevention Edvinsson L. Headache. 2018;58:33-47. ALD403 eptinezumab AMG334 erenumab LY2951742 galcanezumab TEV-48125 fremanezumab Antibody-IgG 1 2 4 2a Type Humanized Human Humanized Humanized Target CGRP CLR/RAMP1 CGRP CGRP Route/frequency of administration IV (quarterly) SQ (monthly) SQ (monthly) SQ (monthly/quarterly) Efficacy EM/CM EM/CM EM/CM EM/CM Serious treatment -related adverse events None None None None Status Completing phase 3 FDA approved May 17, 2018 BLA submitted BLA submitted

40 Goals of Preventive Treatment Reduce attack frequency, severity, and disability Avoid escalation in use of acute headache medication Reduce reliance on poorly tolerated, ineffective, or unwanted acute treatments Enable patients to manage their disease to enhance a sense of personal control Improve health-related quality of life Reduce headache-related distress and psychological symptoms

Indications for Pharmacologic Migraine Prevention Attacks significantly interfere with patients’ daily routines despite acute treatment Frequent attacks (≥4 MHDs) Contraindication to, adverse events with, failure, or overuse of acute treatmentsPatient preference MHD=migraine headache days

Prevention should be. . .Headache days/month Degree of disability requiredOffered6 or moreNone 4 or more Some 3 or more Severe Considered 4 or 5 None 3 Some 2 Severe Lipton RB, et al. Neurolog y. 2007;68(5):343-349. Practical Strategies for Navigating Today’s New Era in Preventive Treatment of Migraine Candidates for prevention

Initiating Treatment With Novel Emerging Therapies Prescribed by a licensed medical provider who is authorized to practice and performing within the scope of practice Patient is at least 18 years of ageDiagnosis of ICHD-3 episodic migraine ( 4-7 MHDs) and A and BContraindication for use, inadequate response, or inability to tolerate a 6-week trial of at least 2 of the following:TopiramateDivalproex sodium/valproate sodium Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol Tricyclic antidepressant: amitriptyline, nortriptyline Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine Other Level A or B medications according to AAN-AHS guideline At least moderate disability (MIDAS>11, HIT-6>50)

AAN-AHS Level A/B Drugs Established efficacy Probably effective Antiepileptic drugsAntidepressantsDivalproex sodium Amitriptyline Valproate sodium Venlafaxine Topiramate Beta-blockers Beta-blockers Atenolol Metoprolol Nadolol Propranolol Angiotensin receptor blockers Timolol  Candesartan OnabotulinumtoxinA*   *Indicated only for chronic migraine

Diagnosis of ICHD-3 frequent episodic migraine ( 8-14 MHDs) and contraindication for use, inadequate response, or inability to tolerate a 6-week trial of at least 2 of the following:TopiramateDivalproex sodium/valproate sodium Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadololTricyclic antidepressant: amitriptyline, nortriptylineSerotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetineOther Level A or B medications (established efficacy or probably effective) according to AAN-AHS guideline At least moderate disability (MIDAS>11, HIT-6>50) Initiating Treatment With Novel Emerging Therapies

Diagnosis of ICHD-3 chronic migraine and EITHER A or B:Contraindication for use, inadequate response, or inability to tolerate a 6-week trial of ≥2 of the following:Topiramate Divalproex sodium/valproate sodium*Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadololTricyclic antidepressant: amitriptyline, nortriptylineSerotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetineOther Level A or B medications (established efficacy or probably effective) according to AAN-AHS guideline Inadequate response or inability to tolerate a minimum of 2 injection cycles of onabotulinumtoxinA (6 months) Initiating Treatment With Novel Emerging Therapies * Initial authorization: 6 months; re-authorization: indefinite

Practical Considerations Adjunctive treatment: many patients will be on preventive treatment Add, then subtract if response is strong (new therapies have favorable tolerability profile and no drug interactions)Track outcomesPGIC (Patient Global Impression of Change)MSQv2.1 (Migraine Specific Quality of Life) Migraine HIT-6 (Headache Impact Test)MIDAS (Migraine Disability Assessment Score)MPFID (Migraine Physical Function Impact Diary)AIM-D (Activity In Migraine Impairment-Diary) 47 Dodick DW, et al. Headache. 2007;47(10):1398-1408.; Mannix S, et al. Health Qual Life Outcomes. 2016;14(1):143.; Bagley CL, et al.. Headache. 2012;52(3):409-421.; Kawata AK, et al. Headache. 2017;57(9):1385-1398.; Lipton RB, et al. Cephalalgia. 2009;29(7):751-759.; Stewart WF, et al. Neurology. 2001;56(6 Suppl 1:S20-28.; Kala ML, et al. [abstract] Presented at AHS San Francisco, June 2018.

Reauthorization after initial use** is approved when EITHER A or B are met:Reduction in mean MMDs or headache days of at least moderate severity of ≥50% relative to the pretreatment baseline (diary documentation is recommended but not required) A clinically meaningful improvement in ANY of the following validated migraine-specific patient-reported outcome measures: MIDASReduction of ≥5 points when baseline score is 11-20Reduction of 30% when baseline scores >20MPFIDReduction of ≥5 pointsHIT-6 Reduction of ≥5 points * Exceptions to these criteria may be made under circumstances when deemed medically indicated **Initial authorization: 6 months; re-authorization: indefinite Continuing Treatment With Novel Emerging Therapies *