RECENT ADVANCES IN MIGRAINE THERAPY:

MY HEAD HURTS REMEMBERING THE

NAMES

Donna Beall, Pharm.D., FCCP, CPP

Disclosures

• I have no disclosures to report

Objectives

• At the conclusion of the presentation, participants will be

able to:

• Distinguish between migraine and other types of headache utilizing

criteria from the International Headache Society

• Recognize the clinical efficacy and safety of new and emerging

therapeutic agents for the prevention of migraines

Historical Perspective

• “The physician shall

bind a crocodile made

of clay, with an eye of

a faience, and straw in

its mouth . . .And he

shall pray”

• 2500 BC Temple in Egypt

CASE 1

• HA, a 25-year-old female patient is seen in the student health clinic with a chief complaint of “headaches.” During the interview the following was ascertained: This particular headache started 24 hours ago and she has vomited twice during the course. On a pain scale of 1-10, she rates his headaches as an “8.” She took Naproxen 500mg, but vomited about 45 minutes later. The characteristics of this headache are similar to the ones she has had in the past - throbbing pain on the left temple, associated with nausea and vomiting. The headaches generally last 24-48 hours. NSAIDs are sometimes effective. Rest in a dark room is what she usually does to get rid of them. She has never seen a health care provider for them. Her headaches cause her to miss time from school as well as work (she is a bartender at the Tamarac). She has experienced 6-8 headaches over the past 3 months. They are never preceded by visual changes; although she relates some with the onset of menses. Past medical history includes EIB (Exercise Induced Bronchospasms), which is relieved with albuterol MDI. Social History – Single, is a first year graduate student studying modern dance, drinks socially (~2 drinks 2-3 times a week), non-smoker and does not use illicit drugs. She has student insurance.

Common Primary Headaches

• Classification system developed by IHS,3rd edition

(beta version)Cephalagia 2015 33 (9) 629-808

• Major primary subtypes• Migraine

• Without aura

• Pure menstrual migraine

• Menstrually related migraines

• With aura

• Chronic Migraine

• Tension Type headache

Episodic Migraine without Aura

• At least 5 attacks• 4 to 72 hours

• Pain (2 of 4)

• unilateral

• Throbbing/pulsating

• mod to severe

• aggravated with activity

• In addition (1 of 2)

• Nausea +/or vomiting

• Photophobia and phonophobia

• Less than 15 attacks/month

Episodic Migraine with aura

• HA pain presentation similar

• One or more of the following REVERSIBLE symptoms- visual, sensory, speech and/or language, motor, brainstem. Retinal

• Lasts 5 to 60 minutes

• Aura accompanied or followed within 60 minutes by headache

• Less than 15/month

Pure Menstrual Migraines

• Attacks fulfilling criteria of migraines without aura AND

• Documented evidence over at least 3 consecutive cycles

the attacks occur EXCLUSIVELY on day 1 + 2 of

menstruation in at least 2 out of 3 cycles and at NO

OTHER times of the cycle

Chronic Migraine

• Headache occurring >15 days of the month for

more than 3 months

• Features of migraine HA on at least 8

attacks/month

• Most common cause is Medication-overuse HA

Episodic Tension-Type HA

• Pain (2 of 4)

• bilateral

• pressing/tightening

• mild to moderate

• not aggravated by activity

• In addition:

• No nausea

• Photophobia OR phonophobia

• Fewer than 15 days/month

What type of headaches is HA suffering

from?• 1.) Episodic Migraine without Aura

• 2.) Episodic Migraine with Aura

• 3.) Chronic Migraine

• 4.) Pure Menstrual Migraine

Impact-based Recognition of Migraine

• Do your HAs interfere with your ability to work or engage in family and social functions?• MIDAS

• HIT

• Has the pattern of your HAs changed over the last 6 months?

• How frequently do you have any kind of HAs?

• What are you doing to treat your HAs?

• Bedell AW, Cady RK, Diamond ML et al. Patient-centered strategies for effective management of migraine. Primary

Care Network, 2000

Managing the

Migraine Patient

Nonpharmacologic Treatment

• Educate

• HA Diary ***

• Identify and eliminate triggers

• Stress-management

• Biofeedback

• Other

Goals of Migraine Prophylaxis

• Reduce frequency by >50% and/or decrease severity

• Improve function and quality of life

• Improve responsiveness to and avoid escalation in use of

acute treatment

• Reduce overall costs associated with migraine treatment

• Reduce headache-related distress and psychological

symptoms

Prophylactic - General Guidelines

• Consider preventative treatment

• Attacks significantly interfere with patients’ daily routines even with

acute treatment

• Migraine attacks are frequent (> 4 migraine headaches per month)

• There is a contraindication to, failure, or overuse of acute treatment

• Acute treatments lead to adverse events

Low Adherence with Current Therapy

Reasons for Poor Adherence

CGRP Monoclonal Antibodies

• Erenumab (AimovigTM) – May 2018 (Amgen/Novartis)

• Dose – 70mg SQ once monthly

• Works on the CGRP receptor

• Galcabezumab (Emgality TM)-September 2018 (Lilly)

• Dose: 240mg SQ Loading Dose; 120mg monthly

• Works on the CGRP ligand

• Fremanezumab-vfrm (AjovyTM)- September 2018 (Teva)

• Dose: 225mg SQ monthly or 675mg SQ Quarterly

• Works on the CGRP ligand

Erenumab (AimovigTM) • Targets the CGRP receptor

• LIBERTY, ARISE and STRIVE studies

• LIBERTY trial

• 12 week – double-blind, placebo controlled, multi-centered study

• 246 “difficult to treat subjects” – failed 2-4 previous therapies; 4-14

HA days/month for at least 3 months

• Episodic migraines

• End point – reduction of migraines by 50% or more – 30% vs 14%

in placebo

ARISE Trial

• Double blind, placebo controlled Phase 3 study of 577

patients. 3 month study using 70mg erenumab

• Primary endpoint change in monthly migraine days

• Secondary outcomes >50% reduction in monthly migraine

days, change in acute migraine-specific medication

treatment days and change on Physical Impact Score

• Results: -2.9 days change vs -1.8 days with placebo;

almost 40% achieved a 50% reduction compared to 30%

in placebo; statistical improvement with regard to impact

scores

• Adverse events – injection site reaction; URI infections

STRIVE Trial

• Double blind, placebo

controlled Phase 3 study

of 9555 patients. 6 month

study using 70mg and

140mg erenumab

• Same primary and

secondary outcomes as

ARISE

Figure 1

Figure 2

Postmarketing Adverse Event Data

• ISMP QuarterWatch 2018-2019

• Quarter 1 2019 – 277,400 prescriptions written

• Striking – sheer number of adverse events reported in first

12 months – 10,508 case reports, including 1,458 with a

serious outcome

• “signal” for Constipation (n=1,169)

• “signal” for Alopecia (n=376)

• Possible “signal” for cardiac arrhythmias (n=225) –

increased HR, palpitations, and loss of consciousness

https://www.ismp.org/resources/quarterwatchtm-includes-new-data-quarter-4-

2018-and-quarter-1-2019-focus-four-new-drugs

Galcabezumab (Emgality TM)• EVOLVE trials

• Double blind placebo controlled 6 month study comparing 120mg and

240mg vs placebo subq/monthly

• Primary Endpoint- number of migraine days/month,

• Secondary endpoint - at least 50%, 75% and 100% in monthly

migraine headaches, medication use, migraine qol measures

Fremanezumab (Ajovy)

• HALO study

• Episodic migraine patients (fewer than 15/month) Pts who

failed 2 classes of migraine-preventative therapies were

EXCLUDED

• Double blind placebo controlled dosing of fremanezumab

studied was either a single sub q dose of 225mg monthly;

or 675mg quarterly vs placebo

• Primary outcome was mean change in number of

migraine days during the 12 week period after the first

dose

• Results – difference of 1.3-1.5 migraine days/month vs

placebo

Measuring response to anti-CRPGs

• Benefits of anti-CGRP monoclonal antibodies be

assessed after 3 months of treatment for those

administered monthly and 6 months after the start of the

quarterly treatment

• 50%(or more) reduction in monthly headache days

• A clinically meaningful improvement in validated migraine-specific

tools

• A reduction of at least 5 points in MIDAS when baseline is 11-20 or

>30% when baseline scores >20

• A reduction of at lest 5 points on the HIP

• Other documented benefits reported by clinician

AHS POSITION STATEMENT ON CGRP

INHIBITORS (JAN 2019)• Prescribed by a licensed medical prescriber

• Patients at least 18 years of age

• Diagnosis of migraine with or without aura

• Must have failed 6 weeks of at least 2 therapies

• Moderate disability (defined by MIDAS score >11 or HIT

score of >50

• https://www.neurologylive.com/clinical-focus/ahs-statement-cgrp-inhibition-clinical-

practice

European Headache Federation (EHF)

• The European Headache Federation (EHF) in March

2019 sought to create an expert- and evidence-

based guideline for the treatment of migraine with

monoclonal antibodies. However, in reviewing available

research, the EHF found that there was not enough

evidence to provide a guideline based on the Grading of

Recommendation, Assessment, Development, and

Evaluation (GRADE) approach.

• https://www.ajmc.com/newsroom/insufficient-evidence-for-

anticgrp-treatment-guideline-for-migraine

What About Acute Therapies??

Ubrogepant (UbrelvyTM)

• Allergan – received FDA approval in December 2019

• Oral small molecule CGRP receptor antagonist for the

treatment of acute migraine in adults with or without aura

• Studies - ACHIEVE 1 and ACHIEVE II

• Double blinded, placebo controlled studies

• End points - 2 hour pain free and most bothersome

symptoms relief

• ACHIEVE I 1300 patients results 19%(50mg) and 21%

(100mg) vs 12% (Placebo)

Lasmiditan (Reyvow)

• Lasmiditan (Reyvow) – Eli Lilly approval in late October

• 50mg and 100mg tablets

• New class – Ditan

• High affinity 5-HT 1f Receptor Agonist

• NOT a triptan

• Does not cause vasoconstriction

• Schedule V

• Dizziness and somnolence. Do not drive for 8 hours after

taking

• Studies - GLADIATOR

References• The American Headache Society Position Statement On Integrating New Migraine Treatments Into

Clinical Practice Headache 2019;59:1-18

• Reuter U, Goadsby P, Lanteri-Minet M, Ferrari M, Wen S, Klatt J. Efficacy and safety of erenumab in episodic migraine patients with 2-4 prior preventive treatment failures: Results from the Phase 3b LIBERTY study. Presented at the American Academy of Neurology 2018 Annual Meeting. Emerging Science Abstract 009. April 24, 2018. Los Angeles, CA.

• Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018 May. 38 (6):1026-1037. [Medline].

• Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017 Nov 30. 377 (22):2123-2132. [Medline]

• Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol. 2018 Sep 1. 75 (9):1080-1088

• Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017 Nov 30. 377 (22):2113-2122

• Bedell AW, Cady RK, Diamond ML et al. Patient-centered strategies for effective management of

migraine. Primary Care Network, 2000

• https://www.ismp.org/resources/quarterwatchtm-includes-new-data-quarter-4-2018-and-quarter-1-

2019-focus-four-new-drugs