A CME/CE-certified Activity

This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com.

Jointly provided by:

Steering CommitteeM. Susan Burke, MD, FACP – Speaking FacultyClinical Associate Professor of MedicineSidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphia, PASenior Advisor, Lankenau Medical AssociatesLankenau Medical CenterWynnewood, PA

Teshamae Monteith, MD, FAHSChief, Headache DivisionFellowship Program DirectorAssociate Professor of Clinical NeurologyDepartment of NeurologyUniversity of Miami, Miller School of MedicineMiami, FL

DisclosuresFaculty and Steering Committee Disclosures

The faculty and steering committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

M. Susan Burke, MD, FACP: Nothing to disclose

Teshamae Monteith, MD, FAHS: Advisory Board: Biohaven, Teva

Brian E. McGeeney, MD, MPH, MBA, CME Course Director: Consultant: Amgen, XOC Pharma; Stockholder: Pfizer

Non-faculty DisclosuresNon-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

Chad Williamson, MS, MBA, CMPP; Blair St. Amand; Elizabeth Drury; Natalie Sanfratello, MPH; PIM Planners and Managers: Nothing to disclose

Educational ObjectivesAt the conclusion of this activity, participants should be able to:• Recognize the signs and symptoms of migraine to differentiate it from other

types of headache • Describe the pathophysiology of migraine, specifically the role of calcitonin

gene-related peptide (CGRP)• Develop a migraine management plan utilizing pharmacologic and

nonpharmacologic treatments, along with preventive therapies, to individualize therapy

• Examine clinical-trial data on the efficacy/safety of new and emerging therapeutic agents for the prevention of migraine

Please rate your confidence in your ability to differentiate migraine from other types of headache:

1. Not confident 2. Slightly confident3. Confident4. Highly confident5. Expert

Polling Question 1

Migraine Impact and Epidemiology

1. Migraine.com/migraine-statistics. 2. GBD 2016. Lancet Neurol. 2018;17:954-976.3. Saylor D, Steiner TJ. Semin Neurol. 2018;38:182-190. 4. Minen MT et al. Cephalgia. 2015;36:358-370.

• One in five US adults has migraine1

– 38-50 million persons have migraine each year in the US• Prevalence

– Women 25% (lifetime); Men 8% (lifetime)– ~ 70% of migraineurs have positive family history in first-degree relative– Almost half have not been diagnosed!

• From the 2016 Global Burden of Disease Study– Migraine second leading cause of disability worldwide after low back pain2

• 5–9 million PCP office visits per year in US due to migraines3

• 5 million headache annual visits to US EDs4

• Associated with ~ $35 billion/year in direct and indirect healthcare costs1

Differentiating Migraine from Other Types of Headache

Jamal, a 31-year-old CPA• Has had occasional migraine without aura 1-2 x/month since his

early 20s. Naproxen and/or a triptan usually provided relief.• Started new job 6 months ago, requiring him to work long hours.• His headaches now occur several days a week, especially on most

weekend days for the last few months.• They start posteriorly on his neck and spread to his temples and

forehead. He goes to the chiropractor frequently now and is taking an abortive medication most days a week.

Several Types of Headaches (HAs)

• Migraine• Tension type• Cluster

• Infectious (meningitis, sinusitis)• Space occupying lesion (abscess, mass)• Bleeding (SAH)• Vascular (cerebral venous thrombosis, cervical artery

dissection)• Rheumatologic (giant cell arteritis)• Ophthalmological (angle-closure glaucoma, optic neuritis)• Neurological (trigeminal neuralgia, post-herpetic neuralgia)• Idiopathic intracranial hypertension• Others (acute hypertension, CO poisoning)

Primary Examples Secondary Examples

Ahmed F. Br J Pain. 2012;6:124-132.

Remember the History and Physical!Evaluate:• Perform fundoscopic exam!• Assess symmetry of cranial nerves,

motor, sensory, coordination, deep tendon reflexes

• Palpate head, arteries, trigger points• Examine neck for stiffness and range

of motion• Examine oral cavity/

temporomandibular joint

Inquire about:• Timing/frequency• Exacerbating factors/triggers

– What meds have been tried– Use/overuse of meds

• Location • Intensity• Nature of pain• Any associated symptoms?

– Visual, motor, sensory, GIDiagnosis and Treatment of Headache. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); 2009.

Episodic Migraine (EM) Recognition by ICHD CriteriaMigraine without Aura (1.1)

At Least FIVE Attacks with:• At least two of the following

– Unilateral– Pulsating– Moderate to severe pain – Aggravated by or avoidance

of routine physical activity • At least one of the following

– Nausea and/or vomiting– Photo and phonophobia

• No organic disease

Migraine with Aura (1.2.1-6)At Least TWO Attacks with:• At least one fully reversible symptom without motor

– Visual + and/or -– Sensory + and/or -– Speech or language dysfunction

• At least two of the following– At least one aura symptom develops gradually

over ≥5 min or different symptoms occur in succession over ≥5 min

– Each symptom lasts ≥5 and ≤60 min• 1.1 begins with aura or in ≤60 min• No organic disease

ICHD3 = International Classification of Headache Disorders. International Headache Society. Cephalalgia. 2018;38:1-211.

• Headache ≥15 days/month AND duration ≥4 hours/day x >3 mo

• ≥ 8 days/month are migrainous• Not just “more” episodic migraine!• Evolves as complication of EM (2.5%/year) • More disabling with higher costs• Risk factors include:

– Comorbidities (anxiety, depression, obesity)– Iatrogenic factors (medication type and frequency of use)

• Can be reversed; goal is reversion back to episodic migraine

• Pharmacologically maintained HA• >15 d/mo with HA• Regular acute drug use >10 d/mo (>15 d for

simple analgesics) for >3 moHA worsens over time of overuse

• ANY abortive medication can cause medication overuse headache!!

• Not better accounted for by another ICHD-3 diagnosis

Chronic Migraine (CM) Medication Overuse Headache (MOH)

Other Headache Definitions

Natoli JL et al. Cephalalgia. 2010;30:599-609. International Headache Society. Cephalalgia. 2018;38:1-211.Buse DC et al. J Neurol Neurosurg Psychiatry. 2010;81:428-432. Blumenfeld AM et al. Cephalalgia. 2011;31:301-315. CDCP. Census projections request (http://wonder.cdc.gov/population-projections.html). Accessed 10/9/17. American Headache Society. http://www.americanheadachesociety.org/assets/1/7/Stephen_Silberstein_-_Medication_Overuse_Headache.pdf.

Link to app for identifying CM

Ong JJY et al. Drugs. 2018;78:411.

Phases of Migraine

Pitfalls in DiagnosisNeck and Sinus Pain During Migraine

ICHD=International Classification of Headache Disorders.1 - 2 -3. 4 -

. Schreiber CP et al. Arch Intern Med. 2004;164:1769 1772. . Barbanti P et al. Cephalalgia. 2002;22:256 259. Kaniecki R. Neurology. 2002;58(suppl 6):S15-S20. . Eross E et al. Headache. 2007;47:213 224.

75% of patients with migraine experience neck pain

Migraine Misdiagnosis as Sinus Headache1,2

• 86-88% with self-diagnosis of sinus headache actually have ICHD migraine or probable migraine headache2,3

• ≥80% report ≥1 cranial autonomic symptom, i.e. nasal congestion > rhinorrhea > lacrimation4

• ≤50% of patients report their headacheis influenced by weather4

Migraine Misdiagnosis as Tension-type Headache• 82% had previously been given a diagnosis of

tension-type headache3

The ID Migraine screening tool evaluates for all of the following EXCEPT:

1. Associated nausea and vomiting2. Photophobia3. Sinus pain4. Limitation of work or activities5. They are all part of the ID Migraine tool

Polling Question 2

ID Migraine™ – A Validated Screener Closing the Headache Diagnosis Gap Choose “Yes” or “No”

• When you have a headache, do you feel nauseated or sick to your stomach?• When you have a headache, does light bother you (a lot more than when you don’t have a

headache)?• During the last 3 months, have your headaches limited your ability to work, study, or do what

you needed to do?

Lipton RB et al. Neurology. 2003;61:375-382.

2/3 “Yes” for migraine:• Sensitivity: 0.81 • Specificity: 0.75

Positive predictive value of 93% in primary care setting=

Indications for Diagnostic Testing Green Flags• Stable pattern >6 months• Long-standing HA history• Family history of similar HA• Normal exams• Consistently triggered by

– Hormonal cycle– Specific sensory input– Weather changes

Diagnostic testing NOT indicated if only green flags present

Adapted from Dodick D. Semin Neurol. 2010;30:74-81.

Red Flags (SNOOP4)• Systemic: fever, weight loss,

immunosuppression, cancer • Neurologic symptoms or signs• Onset sudden: abrupt or split-

second • Onset older, especially >50 years• Pattern change, precipitated by

Valsalva, postural aggravation, papilledema

Diagnostic testing indicated if ANY red flags are present

Insights into Migraine Pathophysiology

Charles A et al. Lancet Neurol. 2018;17:174-182.

Migraine PathophysiologyFactors

Mechanisms

Attack

HormonesGenes Environment

Hypothalmic activationAlteration in

thalamo-cortical circuitsAltered brain connectivity

Brainstem activationCortical spreading

depolarization

Release of CGRP and

PACAP

Variable attack symptoms and severity; premonitory aura, headache, and postdrome phases

DrugsMetabolism

Migraine genesHormonal and metabolic state

Cervical nerve anatomyDrugs

CortexTarget for neuromodulation

ThalamusTarget for neuromodulation Release of CGRP and PACAP

Target for small-molecule antagonists and antibodies

Trigemino-cervical complexTarget medications and

neuromodulationHypothalamusTarget for hypothalamic peptides and modulators

Upper cervical nervesTarget for local injections and

neuromodulation

Naot D, Cornish J. Bone. 2008;43:813-818. Benarroch EE. Neurology. 2011;77:281-287.

Calcitonin Gene-related Peptide (CGRP)• Present at all migraine pathogenesis sites• Increases in migraine, decreases with treatment

Cortex

CGRP receptorsCLR=calcitonin receptor-like receptor. RAMP=receptor activity modifying protein. RCP=receptor component protein

Neuropeptide belonging to calcitonin family• Calcitonin• Amylin

• Adrenomedullin• Intermedin

Treating Migraines Current, New, and Emerging Therapies

Maritza, a 31-year-old Woman• She visits you because of sinus headaches; she has been getting them

2-3x/month for several years, but now they are occurring almost daily• Predominantly frontal and maxillary in location; not throbbing• Past medical history: asthma, eczema• Current medications: albuterol prn; acetaminophen almost daily; pseudoephedrine

preparations and occasional loratadine when she has watery eyes and nasal congestion

• She wants to get pregnant• How do you approach a patient who presents like Maritza?• What treatments could be offered?

• Education!• Acute (abortive)

– Taken after attack has begun to relieve pain and disability and stop progression

• Preventive– Taken to reduce attack frequency, severity, and duration of

attacks• Non-pharmacologic (behavioral, neuromodulation,

complementary/alternative)

Headache Treatment

Principles of Management for the Patient • Establish realistic expectations

– ≥70% relief with acute treatment– ≈50% reduction with prevention; may be higher with monoclonal antibodies

• Encourage patients to participate in their care– Keep a headache diary, identify triggers– Accept that some Rx side effects are inevitable; may be few or zero with newer

antibody-based medications – Optimize behavioral management– Acute: administer treatment early; do not use more than 2-3x/week or 9 days/month– Prevention: follow guidelines for drug/complementary/alternative treatments – Regular patient follow-up with dose/drug/combination changes as needed– If fails on current treatment modalities, utilize newer specific treatments

Silberstein SD. Neurology. 2000;55:754-762.

Behavioral Strategies1. Sleep – 6 to 8 hours, consistent within 1 hour to

bed/rise (even weekends!)2. Regular Exercise 3. Stress management 4. Substance use – Taper caffeine to maximum 1-6 oz cup

– Eliminate sweeteners, decongestants, smoking5. Diet – Fresh, non-processed, healthy meals/snacks

Keeping a headache diary can help identify possible triggers

Ha H, Gonzalez A. Am Fam Physician. 2019;99:17-24.

Acute (Abortive) Migraine Medications1

Non-specific• NSAIDs• Combination analgesics• Neuroleptics/antiemetics• CorticosteroidsSpecific • Triptans• Ergotamine/DHE• 5-HT1F receptor agonist (lasmiditan)5

NSAID = non-steroidal antiinflammatory drug; DHE = dihydroergotamine

New Formulations (FDA-approved)• Breath-powered intranasal sumatriptan dry powder2

• New sumatriptan autoinjectors3

• Sumatriptan nasal spray with permeation enhancer4

New Formulations and Classes (In Development)• Microneedle array skin patch (zolmitriptan)• New DHE intranasal deliveries: HFA propellant, dry powder• Gepants• New combinations: meloxicam-rizatriptan; promethazine-

sumatriptan

1. Silberstein S. Expert Opin Pharmacother. 2012;13:1961-1968. 2. Tepper SJ. Headache.2016;56:817. 3. Landy S et al. J Headache Pain. 2018;19:69. 4. Munjal S et al. J Headache Pain. 2017;18:17. 5. Kuca B et al. Neurology. 2018;91:e222-e2232.

CHOOSING WISELYDon’t recommend prolonged or frequent

use of OTC pain meds for headache

Which of the following suggest(s) a patient should start preventive strategies?

1. Nine or more headaches per month2. Symptoms interfere with daily life3. Use of acute medications more than two times per week4. Patient request5. All of the above

Polling Question 3

Guidelines for Initiating Migraine Prevention Therapy• Goals: reduce disability and medication overuse • Many migraineurs qualify for prevention, few are offered it• Institute preventive strategies if:

– 2 attacks/mo with disability totaling >3 d/moRecurring HA significantly interfering with patient’s daily routine despite acute Rx

– Presence of uncommon migraine conditions: hemiplegic migraine, prolonged aura, migrainous infarction

– Patient preference, cost considerations, med intolerance– Acute medications overused >2 d/wk, ineffective, intolerable side effects, or

contraindicatedSimpson DM et al. Neurology. 2016;86:1818-1820. Silberstein SD et al. Neurology. 2012;78:1337-1345.

How long should you advise a patient it may take for non-specific preventive medications to be fully effective?

1. 1 week2. 2 weeks3. 1 month4. 2-3 months5. 6 months

Polling Question 4

Oral Preventive Therapies for Episodic Migraine Before mAbs (Nonspecific): US Classification / Level of Evidence

Level of Evidence/Efficacy Drug Class/Agent

Level AEstablished Efficacy

Antiepileptic drugs: Divalproex sodium*, sodium valproate*, topiramate*Beta blockers: Metoprolol, propranolol*, timolol*Triptans: Frovatriptan (for menstrual-related migraine)Angiotensin receptor blockers: Candesartan (studies now suggest level A efficacy)**

Level BProbably Effective

Antidepressants/TCA/SNRI: Amitriptyline, venlafaxineBeta blockers: Atenolol, nadolol Triptans: Naratriptan, zolmitriptan (for menstrual-related migraine)

Level CPossibly Effective

ACE inhibitors: Lisinopril Antiepileptic drugs: CarbamazepineBeta blockers: Nebivolol, pindolol Alpha agonists: Clonidine, guanfacine Antihistamines: Cyproheptadine

Silberstein SD et al. Neurology. 2012;78;1337-1345. * FDA-approved ** Not in original paper

Start low and go slow. Allow 2-3 months for full effect.

The First Approved Treatment for Chronic Migraine• Specific FDA-approved medication:

OnabotulinumtoxinA– Approved for prophylaxis of chronic migraine

(≥15 headache days/month)– 8-9 fewer HA compared to 6-7 with placebo– 31 injection sites into head/neck Q 3 mo– Boxed warning: possibility for spread causing

weakness in distant area(s)• OnabotulinumtoxinA blocks the presynaptic

release of neurotransmitters, such as calcitonin gene-related peptide (CGRP)

Blumenfeld AM. Headache. 2017;57:766-777. Linzmeyer TA. J Spinal Med. 2013;36:402-419.

Sphenopalatine Ganglion and Greater Occipital Nerve Blocks

Kin HS et al. Sci Rep. 2018;8:870.

Considerations with Conception and Pregnancy1,2

• Best to discuss medication options before conception

• Most with migraine note decreased headache frequency after first trimester

• New-onset migraines in pregnancy warrant workup to rule out secondary causes

• Avoid topiramate and valproic acid without adequate contraception

• Because of their long half-life, consider stopping mAbs 5-6 months before conception

1. Afridi SK. Obstet Med. 2018;11:154-159. 2. American Migraine Foundation. https://americanmigrainefoundation.org/resource-library/pregnancy-lactation-migraine-management.

• Optimize nonpharmacologic treatments– Massage, relaxation, exercise, trigger

avoidance, neuromodulation device• Considered relatively safe

– Acetaminophen, diphenhydramine, caffeine, metoclopramide, triptans, NSAIDs (before third trimester)

– Propranolol, memantine, cyproheptadine(but not when nursing)

– Neuromodulation, nerve blocks• Use medications where benefits > risks

New, Emerging, and Alternative Approaches to

Treating Migraine Headaches

A 22-year-old female with a history of migraines is having more frequent headaches despite compliance with treatment (topiramate 50 mg BID, a triptan PRN) and behavioral modifications. Which would be an appropriate next step?

1. Calcitonin gene-related peptide inhibitor (CGRP)2. Gabapentin3. Verapamil4. Lamotrigine

Polling Question 5

Which of the following statements about CGRP is/are true?1. Elevation of CGRP is associated with acute migraine attacks2. CGRP monoclonal antibodies have similar side effects to placebo with

the exception of injection site reactions3. Similar to valproate and topiramate use, women of childbearing age

should be counseled to use adequate birth control when taking a CGRP antagonist

4. CGRP antagonists do not cause vasoconstriction5. 1 and 2 6. All of the above

Polling Question 6

CGRP in Migraine• Potent vasodilator of cerebral arteries• Released into jugular venous system during migraine• Serum CGRP levels elevated in CM • CGRP infusion evokes migraine• Small-molecule CGRP-receptor antagonists (gepants) in development effectively

abort migraine attacks and can be administered daily for migraine prevention• Large molecule anti-CGRP and anti-CGRP-receptor monoclonal antibodies (mAbs)

prevent EM and CM– Because of large size, potential to cross blood-brain barrier limited – mAb activity likely peripheral

Adapted from AHS CMEP. Edvinsson L et al. Neurosci Lett. 1985;58:213-217. McCulloch J et al. Proc Natl Acad Sci USA. 1986;83:5731-5735. Edvinsson L et al. Ann Neurol. 1987;21:431-437. Lassen LH et al. Cephalalgia. 2002;22:54-61. Goadsby PJ, Edvinsson L. Brain. 1994;117:427-434. Olesen J et al. N Engl J Med. 2004;350:1104-1110. Ho TW et al. Neurology. 2008;70:1304-1312. Voss T et al. Cephalalgia. 2016;36:887-898.

Small Molecule ApproachCGRP-Receptor Antagonists: The Gepants• Development of older gepants stopped because of liver toxicity• Newer, safer gepants in development:

– For acute treatment of episodic migraine Ubrogepant: first FDA approved gepant Rimegepant: effective vs placebo in phase III; submitted to the FDA in 2019 Vazegepant: to be studied as nasal spray for acute treatment

– For preventive treatment of episodic migraine Atogepant vs placebo: effective vs placebo in phase II; currently in phase III trial Rimegepant: phase II/III: effective vs placebo in phase III study

– 7 gepants tested have NEVER failed on EFFICACYCroop R et al. Lancet. 2019;394:737-745; Olesen J et al. N Engl J Med. 2004;350:1104-1110; Diener HC et al. Cephalalgia. 2011;31:573-584; Ho TW et al. Lancet. 2008;372:2115-2123; Marcus R et al. Cephalalgia. 2014;34:114-125; Voss T et al. Cephalalgia. 2016;36:887-898. Allergan press release. June 11, 2018. Allergan press release. March 11, 2019. FDA press release. FDA approves new treatment for adults with migraine. Dec 23, 2019.

mAbs to CGRP or Receptor for Migraine Prevention• How are they different than our current migraine preventive medications?

– Big molecules that do not cross the blood-brain barrier,1,2 so action likely peripheral – Eliminated by the reticuloendothelial system—so far, safe with zero hepatotoxicity1, 3,4

• Are they an improvement?3,4 All four:– Prevent episodic migraine, chronic migraine, medication-overuse

headache; galcanezumab also prevents episodic cluster headache– Quick onset: separate from placebo within 1 week– Clinically meaningful response by 1 month– Unprecedented responder rates of ≥75%– Safety and tolerability similar to placebo– Decrease acute medication use days; improve impact,

disability, and/or quality of life– Cumulative functional benefits and tolerability have been shown in long term open-label studies

1. Yu YJ, Watts RJ. Neurotherapeutics. 2013;10:459-472. 2. Lipton et al. US Neurology. 2018;14 (Supplement 4):S3-S10. 3. Tepper SJ. Headache. 2018;58(Supp 3):238 275. 4. Tepper SJ. Headache. 2018;58(Supplement 3):276 290. - -

Four Injectable mAbs to CGRP or Its ReceptorNow FDA Approved

Tepper SJ. Headache. 2018;58 (Suppl 3):238 275. Tepper SJ. Headache. 2018;5(Suppl 3):276 290. Edvinsson L. Headache. 2018;58(suppl 1):33-47. US FDA news release, June 4, 2019.

- -

Erenumab-aooe(fully human)

Fremanezumab-vfrm(fully humanized)

Galcanezumab-gnlm(humanized)

Eptinezumab(humanized)

Studied for EM, CM EM, CM, eCH EM, CM, eCH EM, CM

Route and Dosing

Monthly SC70, 140 mg

Monthly or quarterly SC;225 mg monthly, or 675 mg

quarterly

Monthly SC; 240 mg loading dose, then 120 mg SC monthly

thereafterQ3 month IV

Target CGRP receptor CGRP peptide or ligand CGRP peptide or ligand CGRP peptide or ligand

T1/2 (days) 28 31 27 30-31

Regulatory Status

FDA approved 5/17/18 for migraine

preventionFDA approved

9/14/18 for migraine preventionFDA approved

9/26/18 for migraine prevention;6/4/19 for eCH

FDA approved migraineprevention 2/21/20

n=neurologic; umab=fully human; zumab=humanized; Human= 100%; humanized= 90%-95%; US suffixes added to differentiate biosimilarsCM = chronic migraine; eCH = episodic cluster headache; EM = episodic migraine; IV= intravenous; SC= subcutaneous

Four mAb Phase III RCTs for EM: Primary Endpoint Reduction Monthly Migraine Days (MMDS)

-2.81 days*

-4.73 days*-4.57 days*

<0.0001

<0.0001

<0.0001

<0.0001

0.0003

<0.0001

<0.0001

<0.0001

0.0009

<0.0001

0.0013

0.0002

TEV-48125 675 mg/Placebo/Placebo

TEV-48125 225/225/225 mg

Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3Visit:

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

LS M

ean

(+/-

SE) C

hang

e fr

om B

asel

ine

**P<0.0001*P=0.0179

Placebo: -2.2 days-3.4, P=0.0013

-3.7, P<0.0002

Fremanezumab was equally effective in preventing EM and CM whether administered subcutaneously monthly or quarterly (primary endpoints)

Galcanezumab EVOLVE-1 EM3 Eptinezumab PROMISE 1 EM4

1. Goadsby PJ et al. N Engl J Med. 2017;377:2123-2132. 2. Dodick DW et al. JAMA. 2018;319:1999-2008. 3. Stauffer VL et al. JAMA Neurology. 2018;75:1080-1088. 4. Saper et al. IHC poster presentation, September 2017 (abstract).

Mean

chan

ge in

mon

thly m

igrain

e da

ys

from

base

line

Mean

chan

ge in

mon

thly m

igrain

e da

ys

from

base

line

LS M

ean

(+/-

SE) C

hang

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om B

asel

ine

TEV-48125 225/225/225 mgTEV-48125 675 mg/Placebo/PlaceboPlacebo

1-12

Fremanezumab Halo EM2Erenumab STRIVE EM1

Galcanezumab REGAIN2

-2.7

-4.8-4.6

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

0.0007

<0.0001

TEV-48125 675 mg/Placebo/Placebo

TEV-48125 675/225/225 mg

Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3Visit:

-5.5

-5.0

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

LS

Mea

n (+

/- S

E)

Cha

nge

from

Bas

elin

e

PBOFr 675/pbo/pbo (Quarterly)Fr 675/225/225 (Monthly)

Three Pivotal CM RCTs: Same 1° Endpoints

Fremanezumab HALO CM3

P<0.001-2.5

-4.6

-4.3

LS

Mea

n (+

/- S

E)

Cha

nge

from

Bas

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P<0.001

Erenumab1

1. Tepper S et al. Lancet Neurol. 2017;16:425-434. 2. Detke HC et al. Neurology. 2018;91:e2211-e2221. 3. Silberstein SD et al. N Engl J Med. 2017;377: 2113-2122.

Fremanezumab was equally effective in preventing EM and CM whether administered subcutaneously

monthly or quarterly (primary endpoints)

Who Should Receive the mAbsAmerican Headache Society Consensus Statement 20191. Lower frequency EM (≥4-7 headache days/month)

– Lack of success with two antiepileptics (valproate, topiramate), TCAs (amitriptyline, nortriptyline), beta blockers, SNRIs, other Level A or B migraine preventive meds

– Documented at least moderate disability or impact by the migraines2. High frequency EM (≥8-14 days/month)

– Same requirements as 1, but no need to document disability, as they are clearly impacted

3. CM (≥15 days/month)– Same requirements as 1, with onabotulinumtoxinA as an additional choice, and no need

to document disability, as they are clearly impacted

American Headache Society. Headache. 2019;59:1-18.

LasmiditanFirst FDA Approved Serotonin (5-HT)1F Agonist

(ditan)

The Role of Serotonin (5-HT) in Migraine Pathophysiology

Lasmiditan

• Novel, centrally acting serotonin (5-HT1F) agonist

• Lacks vasoconstrictive activity• Approved by the FDA in October 2019

for acute treatment of migraine with a warning not to engage in potentially hazardous activities for at least 8 hours

1. Adapted from Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(Suppl 3):S12-S19; 2. Kuca B et al. Neurology. 2018;91:e222-e2232; 3. Wietecha LA et al. American Academy of Neurology 2018 Annual Meeting (AAN 2018). Abstract S50.008; 4. Oswald JC, Schuster NM. J Pain Res. 2018;11:2221-2227; 5. US FDA news release, Oct 11, 2019; https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-patients-migraine .

Trigeminal nerve fibers

SAMURAI and SPARTAN1-3

Phase III RCTs of Lasmiditan for Acute Treatment of Migraine

1. Kuca B et al. Neurology. 2018;91:e222-e2232. 2. Wietecha LA et al. AAN 2018. Abstract S50.008. 3. Oswald JC, Schuster NM. J Pain Res. 2018;11:2221-2227.

Pain–Free at 2 Hours

15.328.2 32.2

21.328.6 31.4

38.8

0

20

40

60

80

100

Placebo Lasmiditan100 mg

Lasmiditan200 mg

Placebo Lasmiditan50 mg

Lasmiditan100 mg

Lasmiditan200 mg

P<0.001

SAMURAI SPARTAN

P=0.003P<0.001

P<0.001 P<0.001

Patie

nts, %

Most Bothersome Symptom-FreeSAMURAI

Placebo 29.5%

Lasmiditan 100 mg 40.9%; P<0.001

Lasmiditan 200 mg 40.7%; P<0.001

SPARTAN

Placebo 33.5%

Lasmiditan 50 mg 40.8%; P=0.009

Lasmiditan 100 mg 44.2%; P<0.001

Lasmiditan 200 mg 48.7%; P<0.001

Neuromodulation/Complementary and Alternative Treatments

Neuromodulation for Headache

Single Pulse Transcranial Magnetic Stimulator (sTMS) 2

Transcutaneous supraorbital neurostimulation (tSNS, e-TNS)1

Noninvasive vagal nerve stimulator (nVNS)3 Noninvasive caloric vestibular stimulation

(CVS)7Remote Electrical Neuromodulation (REN)*

Combined occipital and supraorbital transcutaneous nerve stimulation (OS-TNS)5

Sphenopalatine ganglion stimulation (SPGs)6

FDA-approved and Non-significant Risk Devices

In Development

Tepper SJ, Tepper DE. Practical Neurology. 2018;17:42-45.

4

* Approved May 2019

FDA-Approved Noninvasive, Nonsignificant Risk NeurostimulatorsExternal Trigeminal Stimulation (eTNS)• FDA approved for acute and preventive migraine

treatment• Ordered online to own for $550• Little or no insurance coverage• Preventive: Wear nightly for 20 minutes• Acute: Use different program for 60 minutes

• FDA approved for acute and preventive migraine treatment

• Rent for $220/month• Little or no insurance coverage• 4 pulses twice daily, with extra pulses as-

needed, up to 17 pulses/day

Tepper SJ, Tepper DE. Practical Neurology. 2018;17:42-45.

Single Pulse Transcranial Magnetic Stimulation (sTMS)

• FDA approved for acute treatment of migraine, acute treatment of episodic cluster headache, and adjunctive preventive treatment of cluster headache

• Being studied for migraine prevention• Turn on for 2 min cycles, up to 3x in a row, up to 3x/day• $575/month to recharge

FDA-Approved Noninvasive, Nonsignificant Risk NeurostimulatorsNon-invasive Vagal Nerve Stimulation (nVNS)

• FDA approved for acute treatment in patients who do not have chronic migraine

• Worn on upper arm with an armband

• Utilizes Conditioned Pain Modulation (CPM)

• Controlled thru smartphone

• $99 to treat 12 migraines

Remote Electrical Neuromodulation (REN)

Tepper SJ, Tepper DE. Practical Neurology. 2018;17:42-45. Migraineagain.com/armband-for-migraines. Accessed June 7, 2019.

Complementary and Alternative Considerations• Riboflavin• Magnesium• Acupuncture • Coenzyme Q10• Feverfew• Melatonin• Ginger • Lavender• Butterbur

• Cognitive behavioral therapy• Relaxation therapy • Cold therapy/menthols • Massage • Biofeedback• Physical therapy• Aerobic exercise • Yoga

Wells RE et al. Curr Pain Headache Rep. 2019;23:10. Deiner HC et al. Cephalalgia Rep. 2018; doi:10.1177/2515816318759304.

Migraine and Management:The Impact of Decision Making with PCPs

©HEALTH UNION, LLC. 54

Patient Doctor Relationships & MigraineManagement

Source: Health Union – Migraine In America Survey 2018

Opportunity to improve the patient experience with treatment

Only half reported being satisfied with care from HCP

Only half reported having an HCP who regularly discussed QoL on current treatment plan

N= 4,356

Perceptions of the HCP Relationship

Source: Health Union – Migraine In America Survey 2018N= 3,975. *Top 2 StronglyAgree/Agree

58%* 46%*

My HCP clearly explains treatment options

My HCP regularly discusses my QOL with my current treatment plan

My HCPs communicate effectively with each other about my condition/health concerns

39%*

Key Takeaways• If a patient self diagnoses their headache, don’t assume they’re right!!• Migraine is the most common cause of headache that brings a

patient to the doctor1

• Recurring moderate to severe headache is migraine until proven otherwise

• Successful treatment of migraines includes a comprehensive approach of patient education, behavioral strategies, pharmacologic therapies, and non-pharmacologic interventions

1 Tepper SJ, et al. Headache. 2004;44:856-864.

Key Takeaways (2)• These are exciting times in migraine treatment!• Older, nonspecific medications, with adverse events and poor adherence, are

giving way to new designer medications and neuromodulators• New medication classes, devices, formulations, and combinations offer

opportunities to match patient needs to treatments• Monoclonal antibodies are specific for migraine, injected monthly or quarterly,

well tolerated and safe, start working within 1-4 weeks and improve QoL• The 2019 AHS Consensus statement highlights the importance of documenting

prescriptions and drug failures so appropriate patients can qualify for these agents

Post-activity Questions

The ID Migraine screening tool evaluates for all of the following EXCEPT:

1. Associated nausea and vomiting2. Photophobia3. Sinus pain4. Limitation of work or activities5. They are all part of the ID Migraine tool

Post-activity Question 1

Which of the following suggest(s) a patient should start preventive strategies?

1. Nine or more headaches per month2. Symptoms interfere with daily life3. Use of acute medications more than two times per week4. Patient request5. All of the above

Post-activity Question 2

How long should you advise a patient it may take for non-specific preventive medications to be fully effective?

1. 1 week2. 2 weeks3. 1 month4. 2-3 months5. 6 months

Post-activity Question 3

A 22-year-old female with a history of migraines is having more frequent headaches despite compliance with treatment (topiramate50 mg BID, a triptan PRN) and behavioral modifications. Which would be an appropriate next step?

1. Calcitonin gene-related peptide inhibitor (CGRP)2. Gabapentin3. Verapamil4. Lamotrigene

Post-activity Question 4

Which of the following statements about CGRP is/are true?1. Elevation of CGRP is associated with acute migraine attacks2. CGRP monoclonal antibodies have similar side effects to placebo with the

exception of injection site reactions3. Similar to valproate and topiramate use, women of childbearing age should be

counseled to use adequate birth control when taking a CGRP antagonist4. CGRP antagonists do not cause vasoconstriction5. 1 and 2 6. All of the above

Post-activity Question 5

Questions?

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Migraine ManagementNew Therapeutic Options to Reduce Migraine Pain