9/14/20

Next Generation Therapies:

BrainWeekEnd 2020

September 19, 2020 L. Charleston IV, MD, MSc, FAHS Chief Consultant- Charleston Health, Neurology & Head Pain Consultants, PLLC Associate Professor of Neurology- Headache Medicine Department of Neurology, University of Michigan @LCharlestonIVMD

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Disclosures

• Consultant/Advisory Board: Biohaven, Abbvie/Allergan • AHS Migraine Education Program Presenter • BrainWeekend Faculty/Advisory Board • Co-founder & CEO Charleston International (in partnership with Amway Corporation (IBO) and Leadership Team Development) • Chief Consultant & CEO, Charleston Health Neurology & HPC • Some treatments are off-label, some are not FDA approved

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Learning Objectives

EXPLAIN the goals of acute “abortive” and preventive migraine therapy.

EXAMINE strategies to optimize abortive and preventive migraine care

ASSESS evidence-based abortive and preventive for the treatment of migraine

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Learning Objectives

DISCUSS devices used in the treatment of migraine

APPRAISE new abortive and preventive treatment for migraine care

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Comprehensive Plan: The Elements

• Abortives – Rescue • Preventives • “Non-pharmacological” (i.e. Behavioral Modalities, Headache Healthiness)

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Case History

• 27-year-old man • Migraine diagnosed in his teens • Lapsed consulting ~1 year • New insurance provider • Needs prescription override for –Limit of 6 tablets/month –3 attacks/month –Each lasts 2–3 days

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Coping Strategies

OTC naproxen at the beginning of the month so he doesn't run out of “the good stuff”

½ tablet per attack to increase doses/month

Outcome: ED 4x in 3 months • Ran out of • Became dehydrated

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Acute Treatment: ARS Question 1

Why is this patient no longer responding to treatment? a. Delayed treatment b. Took incorrect dose of medication c. Developed tolerance to his triptan d. All of the above e. A and B

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Goals of Acute Treatment

• Treat attacks quickly and consistently avoiding recurrence • Restore patient function in personal, social, and work environment • Optimize self-care and reduce subsequent need for resource use (e.g. UC, ED) • Minimize the use of back-up/rescue medications: –Rescue: An acute therapy very seldom used if headache continues after appropriate acute therapy measures.

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Factors affect Acute Medication Choice: “3 PACD FiSHES”

Patient Preference Previous Response Peak Time

Age Associated Symptoms AEs

Coexistent illnesses Cost “Comebacks” Recurrence

Diagnosis/Type of Duration Disability Migraine

Frequency Severity Health Status

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What Do Patients With Headache Disorders Want From Acute Treatment? 10 0 87% 86% 83% 79% 80 76%

60 56%

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0 Complete relief No recurrence Rapid onset No side Effects Relief of Route of associated administration symptoms N=688

Lipton RB et al. Headache. 1999;39(suppl 2):S20-S26. 11

Optimizing abortive care

A. SAME DRUG AND ROUTE — USE TREATMENT DIFFERENTLY • Treat early with primary medication – Improves onset and consistency of response – Prevents disability and recurrence – Reduces need for rescue – May reduce risk of allodynia • Optimize the dose to improve response consistency • Provide advice on secondary treatment and rescue – Secondary: recurrence – Rescue: treatment failure

Caution: Guard against overuse

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Optimizing Abortive Care For Migraine

A. Same drug and route — use treatment differently B. SAME DRUG, SWITCH ROUTES

Nasal Spray

Injections Consider non-oral therapy Inhaler

Suppository

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When Allodynia and Nausea Are Present. . .

Circumvent the gut: • Injectables Consider • Nasal sprays (some) treatments with a faster onset of action • Suppositories • Intranasal delivery system • Powdered NSAID

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When Allodynia and Nausea Are Present

Treat Early

Optimize Minimize benefits risk of MOH

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Medication Overuse Headache

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8.2 Medication-overuse headache (MOH)

Days/month for 3 months MOH Medication criteria

Simple Analgesics 15 days/month Multiple Drugs not individual overused 10 days/month Opioids* 10 days/month

Combination Analgesics (≥2 classes)* 10 days/month

Ergotamine 10 days/month 10 days/month

ICHD-3rd Edition. Cephalalgia 2018; 38(1) 1-211

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Consequences of acute medication overuse Adverse Events

Triptans CDH, increased vascular risk?

Ergots Muscle cramps, ergotism (gangrene), nausea, fibrotic disorders, CDH NSAIDs Ulcers, renal disease, easy bruising

Opioids Constipation, dependence, addiction, CDH, multiple comorbid associations

Barbiturates Sedation, dependence, CDH

Neuroleptics/Antiemetics Sedation, weight gain, tardive dyskinesias, p arkin so n ism

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Strategies Once on Triptans

A. Same drug and route — use treatment differently B. Same drug, switch routes C. SWITCH DRUGS 1. Within class: triptans o Onset: or o Recurrence: eletriptan or ; add NSAID* to triptan o Tolerability: or almotriptan 2. Among classes o Failure of two or more trials of triptans o Consider other acute treatments—DHE, lidocaine nasal spray, dopamine blockers, fast NSAIDs

*Use with caution — NSAIDs increase risk of heart attack and stroke

http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm 19

Addressing Unmet Needs: Acute Treatment Strategies

A. Same drug and route—use treatment differently B. Same drug, switch routes C. Switch drugs 1. Within class 2. Among classes D.RATIONAL POLYPHARMACY/COMPANION THERAPY E. ADDRESS SECONDARY TREATMENT AND RESCUE F. OTHER MODALITIES

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Choosing Acute Treatment

Primary Acute Secondary Acute Rescue

First-line treatment, Recurrence after No response to primary usually early in the attack an initial response or secondary treatment

Consider: • Severity and degree of disability (stratified care) • Duration of headache condition pre-treatment • Presence of nausea, vomiting, or gastroparesis • Prior pattern of response • Patient preference

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Acute Treatments for Migraine

Established Efficacy Probably Effective Triptans aandand other other forms forms of of DHE DHE Ergotamine derivatives IV magnesiumab NSAIDs: aspirin, diclofenac, ibuprofen, NSAIDs: ketoprofen, IV and IM ketorolac, flurbiprofen naproxen Opioids: butorphanolc Isometheptene-containing compounds Combination medications Combinations: codeine/acetaminophen, tramadol/acetaminophentramadol/acetaminophenbd Antiemetics: prochlorperazine, promethazine, droperidol, chlorpromazine, metoclopramide DHE, ; IV, intravenous; IM, intramuscular; NSAID, nonsteroidal anti-inflammatory drug aDo not give with other sympathomimetics, macrolides, , nicotine bConsider neuromodulation if patients prefer nondrug treatments or if drug treatment is ineffective, intolerable, or contraindicated. cNot recommended dMigraine with aura

AHS. Headache. 2019;59:1-18; Marmura MJ et al. Headache. 2015;55:3-20. 22

Serotonin 5-HT1B/1D Agonists (Triptans)

Medication Formulations Doses (mg) Tmax Half-life (hours) (hours) Almotriptan PO 6.25, 12.5 2.1 3.1 Eletriptan PO 20, 40 1.8 5 PO 2.5 ~2.5 ~26 Naratriptan PO 1, 2.5 2 6 Rizatriptan Tablet or 5, 10 2-3 2 dissolvable (ODT)

Sumatriptan PO 25, 50, 100 1.5 2 NS 20 1.5 1.8 SC 4, 6 0.17 2 /naproxen PO 85/500 Tablet or ODT 2.5, 5 NS 5 3 3 23

Treatment Efficacy Within the Class

Secondary Drug Class Primary Acute Rescue FDA Approved? Acute Simple Over-the-Counter Yes Yes – Yes Prescription NSAIDs Yes Yes Ketorolaca Yes Combination analgesics Rarely Rarely Rarely Yes Triptans Yes Yes Yes Yes Dihydroergotamine Yes Yes Yes Yes Lidocaine nasal spray Yes Yes Yes No Muscle relaxant – – Yes No Dopamine antagonists Yes Yes Yes No Corticosteroid – – Yes No Opioids – – Rarely No NSAID, nonsteroidal anti-inflammatory drug aParenteral

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Acute Treatment: ARS Question 2

How would you optimize his treatment strategy? a. Use oral triptan early in the attack b. Increase dose of NSAID c. Switch to a long-acting triptan (naratriptan or frovatriptan) to prevent recurrence d. Begin prevention e. All of the above

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Newer Acute Treatments in Practice

For patients who have contraindications, poor tolerance, or inadequate response to at least 2 oral triptans

Small Molecule Neuromodulation CGRP Receptor Selective serotonin (5- HT1F) receptor agonist Antagonists Transcranial magnetic stimulation Vagus nerve stimulation Trigeminal nerve stimulation

No constriction of blood vessels — role in patients with cardiovascular contraindications to triptans

AHS. Headache. 2019;59:1-18. 26

Newer Acute Treatments in Practice

Onabot-A = onabotulinumtoxinA. Edvinsson L, et al. Nat Rev Neurol. 2018;14:338-350. 27

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Lasmiditan

• First (and only) FDA-approved (10/2019) Ditan - a High-Affinity 5HT1F Receptor Agonist

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Lasmiditan

• Evaluated in 2 Randomized, Double-Blind, Placebo-Controlled, Single-Attack Trials (SPARTAN/SAMURI) – 4439 patients age 18 and older were dosed (Lasmiditan: 3177; placebo: 1262), including those with: o ≥2 cardiovascular risk factors (41%)

o Concomitant use of migraine preventive drugs (22%) o Concomitant use of medication (22%) o Prior triptan exposure within the past 3 months (37%) Shapiro RE, et al. J Headache Pain. 2019;20:90 – All patients had: REYVOW [Prescribing Information]. Indianapolis, IN: Lilly USA, o History of migraine for at least 1 year LLC. Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0018 o 3-8 migraine attacks/month Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0005 Kuca B et.al. Neurology. 2018;91:e2222-e2232 o MIDAS* score ≥11 (pooled median was 25) Goadsby PJ, et al. Brain. 2019;142:1894–1904 Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0012

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Lasmiditan

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Lasmiditan

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Lasmiditan

• Dizziness was the most common side effect after first dose

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Lasmiditan Safety Continued

• Driving Impairment: – Advise patients not to drive or operate machinery for 8 hours after taking Lasmiditan – Patients who can't follow this advice should not take Lasmiditan – Patients may not be able to assess their own driving competence and degree of impairment • Lasmiditan is a Schedule V controlled substance. – Schedule V represents the lowest abuse potential categorization from the DEA.

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Brief Overview of Calcitonin Gene Related Peptide (CGRP) in Migraine Pathophysiology

• CGRP family- CGRP, Calcitonin (CT), Adrenomedullin (AM), Amylin (AMY) • Alpha/Beta based on splicing of Calcitonin gene- Alpha main subtype in Trigeminal neurons • CGRP receptor: 3 parts – Calcitonin-like receptor (CLR) – Receptor activity-modifying protein type-1 (RAMP-1) – A receptor component protein • Amylin receptors are created by linking calcitonin receptor (CTR) with RAMP (1-3 respectively with each other) • Amylin 1 receptor (CTR with RAMP1) responds to CGRP

Silberstein SD, CNS Spectrums. 2017 34

Brief Overview of Calcitonin Gene Related Peptide (CGRP) in Migraine Pathophysiology

• CGRP receptors on trigeminal ganglia, primary sensory afferents, periaqueductal gray, meningeal blood vessels. • CGRP infusion trigger attacks of migraine headache • Triptans inhibit CGRP release • Migraine pain relief parallels decline in circulating CGRP • CGRP levels increased in attack

Silberstein SD, CNS Spectrums. 2017 Image Headache pathophysiology www.memorangapp.com 35

Ubrogepant

• FDA Approved (December 2019) oral CGRP receptor antagonist • Evaluated in multicenter DB-RCT of 1686 participants

Lipton RB, et al JAMA. 2019 Nov 19;322(19):1887-1898 36

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Ubrogepant

• Two co-primary endpoints absence of migraine associated MBS and pain freedom – Several secondary endpoints • Rates of pain freedom at 2 hours were significantly greater with ubrogepant 50 mg (21.8%) or 25 mg (20.7%) than with placebo (14.3%). • Rates of freedom from the most bothersome migraine- associated symptom at 2 hours were significantly greater with the 50-mg (38.9%) dose but not the 25-mg (34.1%) dose vs placebo (27.4%) Lipton RB, et al JAMA. 2019 Nov 19;322(19):1887-1898 Dodick DW, et al. N Engl J Med. 2019 Dec 5;381(23):2230-2241

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Ubrogepant

• In a Phase IIb DBRCT with co-primary endpoints 1) pain freedom and 2) headache response at two hours – Ubrogepant 100mg was significantly superior to placebo for pain freedom (25.8% versus 8.9%), but not for headache response at 2 hours

Voss T, et al. Cephalalgia. 2016 Aug: 36(9):887-98

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Ubrogepant

• The most common side effects that patients in the clinical trials reported were nausea, tiredness and dry mouth. • Avoid use in end-stage renal disease • Ubrogepent is contraindicated for co-administration with strong CYP3A4 inhibitors – (e.g. Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir)

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https://www.ebmconsult.com/articles/ https://www.rxlist.com/ubrelvy- medications-inhibitors-cyp3a4-enzyme drug.htm#indications 40

Rimegepant

• CGRP Receptor Antagonist (Gepant) – Rimegepant • Small molecule CGRP receptor antagonist studied in DB-RCT • Three Phase 3 Trials, 1-Year Safety

– Over 3100 Subjects Treated and >113,000 Rimegepant Doses Delivered • FDA approved February 2020 Croop R. et al. Lancet. 2019 Aug 31;394(10200):737-745 • Has been used concomitantly Lipton RB, et al. N Engl J Med. 2019 Jul 11;381(2):142-149 with CGRP-Mab Mullin K, et al. Neurology. 2020 Jan 13 epub ahead of print

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Rimegepant

• Two Phase 3 trials with 75 mg oral tablet and one Phase 3 trial with 75 mg ODT – ODT and tablet formulations are bioequivalent; ODT has shorter Tmax4 • Primary endpoints achieved in three pivotal Phase 3 trials – Pain freedom at two hours – Freedom from most bothersome symptom (MBS) at two hours • Rimegepant 75 mg ODT: early onset of pain relief and return to normal function at 60 minutes

Croop R. et al. Lancet. 2019 Aug 31;394(10200):737-745 Lipton RB, et al. N Engl J Med. 2019 Jul 11;381(2):142-149 Mullin K, et al. Neurology. 2020 Jan 13 epub ahead of print

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Rimegepant

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Rimegepant

• Superior to placebo on 21 consecutive, pre-specified, hierarchically-tested efficacy outcome measures • Achieved multiple secondary endpoints – Majority of patients achieved pain relief within two hours – Sustained pain freedom and pain relief vs. placebo from 2 out to 48 hours – ~80-85% of patients did not require rescue meds up to 24 hours • Safety and tolerability similar to placebo • Consistent results across endpoints and efficacy trials Croop R. et al. Lancet. 2019 Aug 31;394(10200):737-745 Lipton RB, et al. N Engl J Med. 2019 Jul 11;381(2):142-149 Mullin K, et al. Neurology. 2020 Jan 13 epub ahead of print

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Rimegepant

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Celecoxib Oral Solution

• Inhibition of prostaglandin syntheses via cyclooxygenase-2 (COX-2) • FDA approved for Acute Migraine (May 2020) • 2 randomized, double-blind, placebo-controlled clinical trials • Both studies reported a significant percentage of patients with freedom from the most bothersome symptom at 2 hours compared with placebo, and in Study 1, a markedly greater percentage achieved pain freedom at 2 hours post-dose

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212157s000lbl.pdf Lipton RB, et al Headache. 2019 epub Oct 24

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Celecoxib Oral Solution

Lipton RB, et al Headache 2019 epub Oct 24 47

Celecoxib Oral Solution

Lipton RB, et al Headache 2019 epub Oct 24 48

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Celecoxib Oral Solution

• Dosing 120mg oral • Similar warnings and black box warning of NSAIDs • Contraindicated – in the setting of coronary artery bypass graft (CABG) surgery. – History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs – Known hypersensitivity to celecoxib, any components of the drug product, or sulfonamides

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212157s000lbl.pdf Lipton RB, et al Headache. 2019 epub Oct 24 49

Neuromodulation in Migraine

Transcranial magnetic Vagus nerve Trigeminal nerve Remote electrical stimulation stimulation stimulation neuromodulation

Acute/Preventive Acute Acute/Preventive Acute

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Devices for Migraine Abortive Treatment

Image from www.google.com search 51

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Devices for Abortive Treatment

• Single pulse Transcranial Magnetic Stimulator: – Spring TMS- FDA approved for acute treatment of Migraine with aura

Image from www.google.com search 52

Transcranial Magnetic Stimulation

• Inhibits cortical spreading depression? • Modulates cortical excitability

Superior to sham stimulation (N = 82) • Pain-free at 2 hours: 39% vs 22% (P = 0.018) • Sustained pain-free: – 24 hours: 29% vs 16% (P < 0.040) – 48 hours: 27% vs 13% (P < 0.033) • Treatment-related adverse events: 5% vs 2%

Lipton RB et al. Lancet Neurology. 2010;9:373–380. 53

Vagal Nerve Stimulation

• Innervates multiple anatomical structures • Inhibits cortical spreading depression involved in migraine • Reduces allodynia and glutamate release – Active autonomic–somatic inhibitory interaction • Effective for migraine and cluster headache

N=27; 80 attacks treated 2-Hour Response Rates (%) N=50a; 131 attacks treated Response Rates (%) Baseline pain Pain-free Pain relief Pain-free Pain relief Moderate to severe 22 43 1 hour postdose 17.6 38.2 Mild 38 - 2 hours postdose 22.9 51.1 Relevant AEs: Neck twitching (1), Raspy voice (1) aChronic/High-frequency: 36/14

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Abortive Therapeutic Devices

• Non-invasive vagus nerve stimulation with GammaCore Device – (safety also demonstrated in adolescents)

Grazzi L. et al. Neurol Sci. 2017 Puledda F. and Goadsby PJ. Headache 2017 Image from www.google.com search 55

External Trigeminal Nerve Stimulation

• Prospective, open-label clinical trial Cefaly® • Subjects (N=30) experiencing an acute migraine attack with or without aura • Treated with a 1-hour session • Pain intensity scored on VAS at baseline and at 1 hour and 2 hours after the initiation of treatment • Mean pain intensity significantly reduced: • Manual control of intensity – 57.1% at 1 hour (-3.22 ± 2.40; P < 0.001) • Rechargeable – 52.8% at 2 hours (-2.98 ± 2.31; P < 0.001) battery • No AEs or subjective complaints reported • Pocket-sized

Chou DE et al. Neuromodulation. 2017;20:678-683 56

Nerivio Device • Novel, FDA-cleared non- pharmacological, non-invasive remote electrical neuromodulation (REN) device for the acute treatment of migraine • A wireless, wearable, noninvasive stimulation device applied to the lateral upper arm between the bellies of the lateral deltoid and the triceps for

45 minutes Rapoport AM and Lin T. Expert Rev Med Devices. 2019 Dec;16(12):1017-1023 Yarnitsky D. et al. Headache 2019 Sep; 59(8): 1240–1252 57

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Nerivio Device

• Relieves migraine headache using a descending endogenous analgesic mechanism termed conditioned pain modulation • CPM involves the inhibition of pain in remote body regions by sub-threshold conditioning stimulation. • REN stimulates upper arm peripheral nerves to activate descending inhibition pathways that originate in the periaqueductal gray (PAG) and in the rostral ventromedial medulla (RVM)

Rapoport AM and Lin T. Expert Rev Med Devices. 2019 Dec;16(12):1017-1023 Yarnitsky D. et al. Headache 2019 Sep; 59(8): 1240–1252 58

Nerivio Device

Yarnitsky D. et al. Headache 2019 Sep; 59(8): 1240–1252 59

Nerivio Device

Efficacy endpoints. (A) Pain response at 2 and 48 hours post-treatment. (B) MBS response at 2 hours post-treatment. The error bars represent 95% confidence intervals. ***P < .001, **P < .005, *P < .05. MBS = most bothersome symptom. Yarnitsky D. et al. Headache 2019 Sep; 59(8): 1240–1252 60

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Nerivio Device

• Therapeutic gain of 27.9% for pain relief and 19% for pain freedom, both at 2 hour • Controlled by a user-friendly app, induces a global pain inhibition mechanism in which pain in the arm inhibits pain in other areas of the body. • Indicated for acute treatment of migraine with or without aura in patients 18 years of age or older who do not have chronic migraine • Should not be used by people with congestive heart failure, severe cardiac or cerebrovascular disease, uncontrolled epilepsy, or by anyone with active implantable medical devices (eg, pacemaker, hearing aid implant) Rapoport AM and Lin T. Expert Rev Med Devices. 2019 Dec;16(12):1017-1023 Yarnitsky D. et al. Headache 2019 Sep; 59(8): 1240–1252 61

Clinical Pearls

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TREAT EARLY in the Attack

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For best efficacy, use the. . . HIGHEST EFFICACIOUS & TOLERABLE DOSE FIRST

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Use NON-ORAL ROUTES of administration. . .

in patients with NAUSEA AND/OR VOMITING 65

Use fast-acting formulations when attacks peak quickly

or awaken patients from sleep

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Patients Should Leave the Office With a Plan

PRIMARY ACUTE TREATMENT

SECONDARY ACUTE TREATMENT

RESCUE MEDICATION

Mamura MJ et al. Headache. 2015;55(1):3-20. 67

“My last Hope”: Meet Mr. I. Love 41y/o M

• “You are my last hope” • Husband & father of 3 young children • Bilateral severe throbbing h/a attacks assoc. w N/V, Sensitivity to light & smells, • Severity range 5-9/10, lasting ~2 days, 14-16 days/month getting worse • Missing at least 7 days of work per month over last 2 months, fearful of losing job • No aura but lots of yawning before attack, fatigue & difficulty concentrating after attack. • Migraine since early college years • 4 ED visits in the last 3 months

Image from www.google.com search

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“My last Hope”: Meet Mr. I. Love 41y/o M

• “Nothing has worked.” “Triptans don’t work. I’ve tried Sumatriptan, Rizatriptan, Zolmitriptan pills & I think I’m extremely sensitive to pills” Takes Excedrin and Ibuprofen “as needed” • Has tried Gabapentin, , Valproic Acid, , Magnesium, all for about 3-6 weeks • Referred to Headache specialist but there’s a 10-month wait • Oxycodone is the only thing that help but hates the way they make him feel + sedated. • Normal exam & MRI of brain • “Help me please” Image from www.google.com search

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Nearly 40% of Patients Should Be Offered or Considered for Migraine Preventive Therapy

Lipton RB et al. Neurology. 2007;68:343–349. 70

Goals of Migraine Prevention

DECREASE IMPROVE PREVENT • Migraine days • Response to acute • Disease Progression • Headache days treatment • Intensity of symptoms • Functional ability • Duration of attacks • Disability

Benefits Occur Over Time

Silberstein SD. Neurology. 2000;55:754–762. 71

General Principles of Migraine Prevention

Start with low dose and increase slowly

Allow enough time on an adequate dose (2–3 months)

Monitor medication usage • Avoid acute medication overuse • Limit/Eliminate interfering drugs

Silberstein SD. Neurology. 2000;55(6):754-762; Diener HC et al. J Neurol. 2004;251:943–950. 72

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General Principles of Migraine Prevention

Evaluate preventive therapy • Use calendar/diary • Consider taper/discontinue if controlled at 6 months Manage communications • Ask about patient preference • Discuss contraception Optimize medication use • Best efficacy • Fewest AEs Consider Comorbid and Concomitant Conditions • Cardiovascular, Asthma, Mood, Sleep, CNS disorders, GI orders • Individualize Prevention Selection Silberstein SD. Neurology. 2000;55(6):754-762; Diener HC et al. J Neurol. 2004;251:943–950. 73

Prevention: ARS Question

All of the following are general principles of migraine preventive therapy except: a. Start with low dose and increase slowly b. Allow for adequate trial (2-3 months) c. Discuss comorbidities d. If controlled at 3 months then rapidly taper dose

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Preventive Treatments for Migraine LEVEL A — ESTABLISHED AS EFFECTIVE; SHOULD BE OFFERED Divalproex sodium* Topiramate Metoprolol Propranolol LEVEL B — PROBABLY EFFECTIVE; SHOULD BE CONSIDERED

Memantine NSAIDs Riboflavin Amitriptyline Nadolol Magnesium

Venlafaxine Atenolol Fenoprofen Ketoprofen Mig 99 (feverfew) Ibuprofen Naproxen Histamine (SQ) LEVEL C — POSSIBLY EFFECTIVE; MAY BE OFFERED Lisinopril Candesartan CoQ10 Cyprohepatadine LEVEL U — WEAK/NO EVIDENCE Gabapentin Fluoxetine Fluvoxamine

*Contraindicated in women of childbearing potential Level A -- Established Ineffective: Lamotrigine

Silberstein SD et al. Neurology. 2012;78:1337-1345. 75

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Preventive Treatments: Evidence in Chronic Migraine

Choice Based on Evidence in Chronic Migraine and Chronic Daily Headache

Treatment Evidence Topiramate • Double-blind placebo-controlled trials in chronic migraine Gabapentin • One double-blind, placebo-controlled trial in chronic daily headache • Small placebo-controlled and comparator trials in chronic migraine and chronic daily headache Antidepressants

Amitriptyline • Small open-label trial in transformed migraine Fluoxetine • Small double-blind, placebo-controlled trial in chronic daily headache Tizanidine • Small double-blind, placebo-controlled trial in chronic daily headache (adjunctive) Neurotoxins OnabotulinumtoxinA* Double-blind placebo-controlled trials in chronic migraine *FDA approved for chronic migraine

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WHAT’S NEW(ER) IN PREVENTIVE TREATMENT?

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Neuromodulation in Migraine

Transcranial magnetic Vagus nerve Trigeminal nerve Remote electrical stimulation stimulation stimulation neuromodulation

Acute/Preventive Acute Acute/Preventive Acute

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Newer FDA-Approved CGRP Monoclonal Antibodies

Drug Indication(s) Dosing Examples of Common Adverse Events EM, CM IV, quarterly URI, nasopharyngitis, fatigue, diarrhea, oropharyngeal pain

Erenumab EM, CM SC, monthly Injection site reactions, constipation

Fremanezumab* EM, CM SC, monthly Injection site reactions or quarterly * EM, CM SC, monthly Injection site reactions

*Has also been studied for cluster headache. CM = chronic migraine; EM = episodic migraine; SC = subcutaneous; URI = upper respiratory infection; UTI = urinary tract infection. ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03855137. Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02605174. Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03732638. Accessed Apr 13, 2020; Edvinsson L, et al. Nat Rev Neurol. 2018;14:338-350. 79

CGRP/CGRP-R mAbs: Phase 3 Trials

Ep ti nez u m ab: E M Ep ti nez u m ab: C M Er en um ab: EM Er en um ab: CM Fr em an ezum ab : EM Fr em an ezum ab : C M Galcanezu mab:EM Galcanezu mab:CM 0

-1 -1.8 -2 -2.2 -2.5 -2.8 -2.7 -3 -3.2 -3.7 -3.7 -4 -4.3 -4.2 -4.6 -4.7 -4.8 -5 -5.6

-6 -6.6 Mo st e ffe cti vedo se Placebo -7 All statistically significant

-8 -8.2 Reduction in Monthly Migraine HeadacheDaysMigraine Monthly in Reduction

-9

Holland C et al, Neurology. 2018;91:e2211-e2221; Stauffer VL. JAMA Neurol. 2018;75:1080-1088; Dodick DW et al, JAMA 2018;319:5-14; VanderPluym J et al. Neurology. 2018;91:e1152-e1165; Goadsby PJ et al, N Engl J Med. 2017;377:2123-2132; Lipton et al. Neurology. 2019;92: e2250-e2260; Ashina M et al. Cephalalgia. 2020;40: 241-254; Silberstein SD, et al. N Engl J Med. 2017;377:2113-2122; Stauffer VL et al, JAMA Neurol. 2018;75:1080-1088; Sklijarveski V et al, Cephalagia 2018;38:1442-1454. 80

Indications for Initiating Treatment With Monoclonal Antibodies to CGRP or its Receptor

b Use is approved when ALL of the following are met: Recommended Preventive Treatments A. Prescribed by a licensed medical provider 1. Topiramate B. Patient is ≥18 years of age 2. Divalproex sodium/valproate sodiumc C. ICHD-3 migraine (4-14 monthly headache days) AND: 3. Beta-blocker a. Poor tolerability or inadequate response to a 6-week trial of ≥2 preventive treatments 4. b. At least moderate disability 5. Serotonin-norepinephrine reuptake inhibitor c. ≥2 quarterly injections of onabotulinumtoxinAa 6. Other treatments with established efficacy

CGRP, calcitonin gene-related peptide;AAN-AHS, American Academy of Neurology-American Headache Society aChronic migraine only bAccording to AAN-AHS guideline cNot for use in women of childbearing potential

AHS. Headache. 2019;59:1-18; Marmura MJ et al. Headache. 2015;55:3-20. 81

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Emerging Preventive Medications

• CGRP Receptor Antagonist “Gepants” – Atogepant (oral)

o Phase 3 ADVANCE trial evaluating atogepant meets primary endpoint of statistically significant reduction from baseline in mean monthly migraine days, compared to placebo, for all doses evaluated across a 12-week treatment period • Patients treated in the 10 mg/30 mg/60 mg atogepant arms experienced a decrease of 3.69/3.86/4.2 days, respectively, all compared to patients in the placebo arm, who experienced a decrease of 2.48 days (all dose groups vs. placebo, p=<.0001) o Phase 2b/3 RCT

• Decrease Monthly Migraine days compared to placebo -3.55 to-4.23 vs.-2.85 • Most common AE: Nausea, fatigue, constipation, nasopharynitis, UTI • No Increase in AST/ALT vs. placebo

Allergan Data: 2019 AHS Scientific Meeting, Google Scholar AbbVie Press Release (July 29, 2020)

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Clinical Pearls

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Ask patients. . .

how many days they are entirely pain-free

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Remind patients it takes time...

for most prevention to work.

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Summary: Preventive Treatment Strategies

• Goals of preventive therapy – Decrease migraine days, headache days, intensity of symptoms, duration of attacks, disability – Improve response to acute treatment and functional ability – Prevent disease progression • Select preventive medication based on level of evidence, comorbidities and side effects • General principles – Start with low doses, increase slowly – Monitor medication usage – Avoid overuse of acute agents – Limit/Eliminate interfering drugs – Allow for an adequate trial (2–3 months)

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Comprehensive Migraine Treatment Plan: The Elements

• Abortives – Rescue • Preventives • “Non-pharmacological” (i.e. Behavioral Modalities, Headache Healthiness)

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Thank you for your attention! Questions?

@LCharlestonIVMD [email protected]

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Supplemental Slides

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Consider Prevention When. . .

SIGNIFICANT INTERFERENCE ATTACK ELEVATED RISK: with routine activities — FREQUENCY Medication overuse despite use of acute treatment >1/week Chronic Daily Headache

ACUTE MEDICATIONS UNCOMMON SUBTYPES PRESENT Ineffective Hemiplegic PATIENT Contraindicated Brainstem PREFERENCE Troublesome AEs Prolonged Aura Overused Migrainous Infarction

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Supraorbital Transcutaneous Stimulator for Prevention of Episodic Migraine Double-blind, randomized, sham-controlled trial (N = 67) • Neurostimulation for 20 mins/day • 250 us, 16 mA, 60 Hz • First FDA device approved for migraine prevention

Approved by the FDA

Schoenen J et al. Neurology. 2013;80:697–704. 92

From: Who Should Try New Antibody Treatments for Migraine?

JAMA Neurol. Published online May 21, 2018. doi:10.1001/jamaneurol.2018.1268

Table Title: Guidance for the Use of Calcitonin Gene–Related Peptide Antibody Treatments for Migraine Copyright 2018 American Medical Association. All Rights Reserved. 93

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