Making Migraine Treatment a Priority

Making Migraine Treatment A Priority

Linda Davis, MD Director and Founder Kolvita Family Medical Group Mission Viejo, CA

Learning Objectives

▪ Review the diagnosis and impact of migraine ▪ Identify current and emerging treatment options for migraine, focusing on CGRP targeted therapies

Why Are We Talking About Migraine in Primary Care?

Prevalence of Migraine

▪ 13% prevalence in US (approx. 39 million Americans) ▪ 18% women; 6-7% men ▪ Most common neurologic disease seen in primary care ▪ Most common type of primary headache seen in primary care ▪ Not enough neurologists or headache specialists

GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2017;390(10100):1211-1259.

The Prevalence of Migraine in Primary Care

Population 12%

Primary Care Waiting Room 29%

Out-Patient with a 94% Complaint of Headache

Lipton RB, et al. Neurology. 2007;68: 343-349. Couch J, et al. Headache. 2003;43:570-571. Tepper SJ, et al. Headache. 2004;44:856-864.

Migraine – Most Common Headache in Clinical Practice

▪ Patients seen in primary care ▪ IHS diagnosis based on diary review

94% Migraine-type Episodic Tension-type Unclassifiable

N = 377 IHS = International Headache Society 3% 3%

Tepper SJ, et al. Headache. 2004;44(9):856-864.

They’re Here… (In My Waiting Room That Is)

▪ >37% of women of reproductive age in a physician’s waiting room have migraine ▪ People with episodic tension headache rarely seek medical advice ▪ Other primary headache disorders infrequently appear in a primary care office ▪ Chronic condition – they will need a lifetime of care, they will need a good primary care provider ▪ Only 706 certified headache specialists in the United States1

Couch JC, et al. Headache. 2003;43(5):570-571. 1https://www.ucns.org/Online/Diplomate_Directory/Online/Diplomate_Directory

Should Addressing Migraine Be A Priority? (After All, It’s Not A “Metric”)

Disability of Migraine

▪ One of leading causes of disability world-wide ▪ 3rd cause of YLDs (years lived with disability) ▪ Close 3rd to depression ▪ #1 in women <50 ▪ Peaks in ages 22-55 for men and women

GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2017;390(10100):1211-1259. Steiner TJ, et al. Migraine is the first cause of disability in under 50's: will health politicians now take notice? J Headache Pain. 2018;19(1):17. Steiner, T.J., Stovner, L.J., Jensen, R. et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain 21, 137 (2020). https://doi.org/10.1186/s10194-020-01208-0

Burden of Migraine

▪ Affects 1 in every 4 households in US1 ▪ High socio-economic burden ▪ Annual total cost (US) estimated $36 Billion2 ▪ Annual direct + indirect costs is $9K more in patients diagnosed w/ migraine than “similar” patients w/o migraine3 ▪ Impacts patient, family, employer

1GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2017;390(10100):1211-1259. 2Bonafede M, Sapra S, Shah N, Tepper S, Cappell K, Desai P. Direct and indirect healthcare resource utilization and costs among migraine patients in the United States [published online February 15, 2018]. Headache. doi: 10.1111/head.13275. 3Bonafede M et al. Headache. 2018;58(5):700-714.

When Is A Headache A “Migraine”?

Diagnosis of Migraine without Aura

At least 5 attacks lasting During the headache at 4-72 hours with at least least one of the following: 2 of the following: 1. Nausea and/or vomiting 1. Unilateral location 2. Photophobia and 2. Pulsating quality phonophobia 3. Moderate to severe pain 3. Not better accounted for by 4. Aggravation or avoidance another ICHD-3 diagnosis of physical activity

The International Classification of Headache Disorders. 3rd ed. Cephalalgia. 2013;33(9).

Migraine with Aura

At least 2 attacks with 1 or more At least 3 of the following: of the following fully reversible 1. At least 1 aura symptom spreads aura symptoms: gradually over >5 minutes 1. Visual 2. 2 or more occur in succession 2. Sensory 3. Each aura symptom lasts 3. Speech and/or language 5-60 minutes 4. Motor 4. At least one aura symptom 5. Brainstem is unilateral 6. Retinal 5. At least one aura symptom is positive 6. Aura accompanied or followed by headache within 60 minutes

The International Classification of Headache Disorders. 3rd ed. Cephalalgia. 2013;33(9).

ID Migraine

During the last 3 months, did you have the following with your headaches? You felt nauseated or sick to ❑ YES ❑ NO ➢ 2/3 for migraine your stomach? ➢ Sensitivity: 0.81 Light bothered you (a lot ➢ Specificity: 0.75 more than when you don’t ❑ YES ❑ NO have headaches)? Your headaches limited your ability to work, study, or do ❑ YES ❑ NO what you needed to do?

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

Classification of Migraine

▪ Episodic (EM) less than 15 days per month of headache ▪ Infrequent Episodic <4 headache days/month ▪ Frequent Episodic 4 to <15 migraine headache days/month ▪ HFEM (high freq EM) 8 or more but <15 ▪ Chronic (CM) 15 or more headache days per month of which 8 or more meet criteria for migraine for at least 3 months ▪ Migraine may or may not be associated with medication overuse

Evolution of Chronic Migraine (CM) from Episodic Migraine (EM)

Low/ Chronic High- migraine moderate- frequency No migraine frequency episodic with/without episodic migraine headache-free migraine periods 0-9 d/mo 10-14 d/mo ≥15 d/mo ▪ Patients may transition among these 3 migraine states in the direction of increasing and decreasing frequency ▪ Transitions occur over weeks to months ▪ CM develops in individuals with EM at the rate of 2.5% per year

Lipton RB. Neurology. 2009;72(5 suppl):S3-S7.

Current Theory of Migraine Pathophysiology

Vascular Theory1 Neurovascular Theory3 Pain caused by: Pain caused by ▪ Constriction of blood combination of: vessels in the cranium ▪ Cortical spreading ▪ Rebound vasodilation depression (cortex) ▪ Trigeminal system ▪ Cranial vascular Neurogenic Theory2 changes brought Pain caused by about by release of interaction between: neuropeptides and proinflammatory ▪ Cortical spreading substances depression (cortex) ▪ Trigeminal system

1. Shevel E. Headache. 2011; 51(3):409-417. 2. Gasparini CF, et al. Curr Genomics. 2013; 14:300-315. 3. Ferrari MD, et al. Lancet Neuro. 2015;14(1):65-80.

Migraine is a Complex Disease With Peripheral and Central Components

Peripheral components1: • Trigeminal afferents (CGRP) • Meningeal vasculature • Resident immune cells

Central components1: • Trigeminal efferent (CGRP) • Trigeminal cervical complex • Thalamus • Cortex

CGRP = calcitonin gene related peptide

1. Ferrari, MD. Lancet Neurology. 2015; 14(1);65-80; Figure Ferrari, MD. Lancet Neurology. 2015; 14(1);65-80.

What is CGRP?

▪ Calcitonin gene-related peptide – a 37 amino acid polypeptide in neurons and glial cells (universally present) ▪ Receptors to CGRP are located throughout the trigeminal system and multiple brain regions (as well as other locations throughout the body) ▪ CGRP is a vasodilator and causes neurogenic inflammation ▪ CGRP modulates pain signaling

Role of CGRP in Other Selected Systems

Respiratory System1 Wound Healing1 • CGRP is abundant in lungs and vasodilates • CGRP produces vasodilation and inflammation pulmonary arterioles in the skin • CGRP protects against pulmonary • Depletion of CGRP, by capsaicin, reduced hypertension in animal models wound healing in rats • Impaired wound healing, angiogenesis and enhanced inflammation in CGRP KO mice

Diabetes and Obesity1 Ischemia1 • Potential for protective and causative roles for • CGRP plays a protective role against ischemia CGRP in diabetes in the gut, kidney, brain, and heart • CGRP dampens insulin release and CGRP KO • CGRP KO mice are more susceptible to mice are resistant to diet-induced obesity ischemic injury and have impaired recovery • Possible connection between lower CGRP and • Endogenous but not exogenous CGRP impaired wound healing, neuropathy and protects against myocardial infarction cardiovascular disease common in diabetes

KO=knockout 1. Russell FA, et al. Physiological Reviews. 2014; 94 (4):1099-1142.

CGRP and Migraine: Where is the Evidence?

▪ CGRP levels elevated during migraine attack (measured external jugular vein)1 ▪ Infusion of CGRP in migraine patients can cause migraine2 ▪ Infusion of CGRP blocking medication can resolve a migraine attack in a migraine individual3 ▪ Development of new targeted CGRP blocking molecules show promise in migraine treatment (including large monoclonal antibodies and small molecule oral medications called “gepants”)

1. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183-187. 2. Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61. 3. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:38-56.

Role of CGRP in Migraine Pathophysiology

CGRP causes vasodilation and mast cell degranulation Neurogenic indirectly activating Inflammation nociceptors* Felt as initial head pain

CGRP stimulates cytokine release, thereby Peripheral stimulating trigeminal Sensitization neurons2 Felt as throbbing pain and sensitivity to movement3

* To date, dural mast cell CGRP enhances synaptic degranulation has not excitability4 been observed in humans Central Sensitization Felt as cutaneous allodynia and photophobia3

1. Ramanchandran R Sem Immunopath 2018:40:301-314. 2. Edvinsson L et al Nat Rev Neurol 2018; 4(6):338-350. 3. Schain A &Burstein R. (2017) Neurobiological Basis of Migraine. Hoboken, New Jersey: Wiley-Blackwell. 4. Russo AF. Annu Rev Pharmacol Toxicol. 2015; 55:533-552.

Meet Beth

▪ 38-year-old office manager with 20-year history of migraine without aura ▪ Takes oral Sumatriptan 100 mg for acute treatment ▪ Does not work well if nauseated or wakes up with severe headache as is typical when on her menses ▪ Tried Sumatriptan 6 mg injection but caused flushing, chest tightness, and headache seemed to get worse before it got better ▪ Would like other options for acute treatment ▪ Has no medication allergies ▪ No cardiac disease

Beth’s Journey

▪ Migraine attacks are now 1-2 times per week ▪ Missing 1 day of work per month due to migraine ▪ Topiramate caused cognitive impairment and fatigue ▪ Amitriptyline caused dry mouth, constipation and weight gain ▪ Anti-hypertensives not ideal due to low blood pressure ▪ Has 2 children, ages 8 and 10 ▪ Husband had vasectomy ▪ Asks, “What is new for acute and preventive treatment” ▪ She states, “I want my life back”

Treatment of Migraine

Acute Migraine Treatment Goals

▪ Rapid relief of headache pain ▪ Relief of “most bothersome symptoms” (MBS) including nausea, photophobia and phonophobia ▪ Sustained pain freedom ▪ No need to rescue or take a 2nd dose ▪ Return to full function ▪ Little to no side-effects from acute medication

Current, New and Emerging Acute Migraine Treatment Options

▪ Triptans (5 HT-1B and 1D receptor agonists) ▪ Ergots/Dihydroergotamine ▪ NSAIDS ▪ Non-specific options (Analgesics, Butalbital, Narcotics) ▪ Non-invasive devices ▪ Oral CGRP receptor antagonists ▪ Ditan (Lasmiditan - selective 5 HT-1F receptor agonist)

Triptans – What is New?

▪ Seven triptans (Sumatriptan, Rizatriptan, Zolmitriptan, Almotriptan, Eletriptan, Naratriptan, Frovatriptan) ▪ Sumatriptan has oral, injectable, nasal, breath-powered formulations ▪ New: 3 mg injectable Sumatriptan in auto-injector Key feature: Tolerability and ease of use, dose is 3 mg subcutaneous injection may repeat 1 hour; max is 12 mg in 24 hours (Zembrace) ▪ Breath-powered nasal delivery of Sumatriptan powder to posterior nasal cavity-1 nosepiece each nostril 11 mg per nosepiece, total dosage 22 mg; may repeat 2 hours; max 44 mg in 24 hours (Onzetra Xsail) ▪ DFN-02 (Nasal Sumatriptan 10 mg combined with an absorption enhancement agent to increase bioavailability)1 (Tosymra)

1. Munjal S, Brand-Schieber E, Allenby K, et al. A multi-center, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine. J Headache Pain. 2017 Dec; 18(1) 31. Data on file. 2018. Promius Pharmaceutical. Data on file. 2018. Avanir Pharmaceutical.

Safety Concerns of Acute Migraine Prescription Treatment Options

▪ Triptans and Ergots/Dihydroergotamine are all contraindicated in patients with coronary artery disease, peripheral vascular disease, uncontrolled high blood pressure and those at high risk of cardiac disease ▪ Triptans and Ergots/Dihydroergotamine should not be taken in the same 24-hour period due to risk of vasoconstriction ▪ Risk of medication overuse with triptans ▪ Narcotics and Butalbital are non-specific in treatment of acute migraine, can lead to medication overuse, overdose, sedation, abuse, and can cause preventives to be less effective ▪ NSAIDs contraindicated in many patients due to GI issues or those at risk for GI bleeding and those with certain kidney conditions

Oral CGRP Receptor Antagonists “Gepants”

Ubrogepant

▪ FDA approval December 2019 ▪ Approved for acute treatment of migraine with or without aura in adults ▪ Oral CGRP receptor antagonist ▪ Oral tablet 50 & 100 mg ▪ May be repeated in 2 hrs (max daily dose 200 mg) ▪ 5-7 hours half-life; T max is 1.5 hours

Ubrogepant (cont.)

▪ No cardiac contraindications ▪ Concomitant use of CYP3A4 inhibitors contraindicated; caution with CYP3A4 inducers ▪ Most common side-effects were nausea and dizziness in less than 2.5% of patients enrolled in the clinical trials. Four cases of abnormal liver enzymes reported, but none felt to be related to the study drug ▪ Brand name: Ubrelvy

Data on file. 2018. Allergan.

Ubrogepant Clinical Trials

▪ Two pivotal phase 3 clinical trials: ▪ ACHIEVE I - 1327 adults, single migraine attack treatment for moderate to severe migraine looking at 50 and 100 mg dose Ubrogepant vs placebo. Statistically significant difference in pain- freedom vs placebo as well as absence of most bothersome symptom (MBS) and most common MBS photophobia

▪ ACHIEVE II - 1686 patients ages 18-75 and looked at 25 and 50 mg dose Ubrogepant vs placebo. Both doses superior to placebo for pain-freedom. The 50 mg dose superior in relief of MBS vs placebo

Data on file. 2018. Allergan.

Ubrogepant Trial Results

Hutchinson, S., Dodick, D.W., Treppendahl, C. et al. Ubrogepant for the Acute Treatment of Migraine: Pooled Efficacy, Safety, and Tolerability From the ACHIEVE I and ACHIEVE II Phase 3 Randomized Trials. Neurol Ther (2021). https://doi.org/10.1007/s40120-021-00234-7

Ubrogepant Trial Results

Rimegepant

▪ FDA approved February 2020 ▪ Approved for acute treatment of migraine with and without aura in adults ▪ Oral CGRP receptor antagonist ▪ Available as an orally dissolving 75 mg tablet ▪ Tmax 30 minutes sooner with ODT vs standard oral tablet (1.5 hrs vs 2 hrs) ▪ Dose is 75 mg in 24-hour period ▪ Half-life is 10 hours

Rimegepant (cont.)

▪ No cardiac contraindications ▪ Well-tolerated with 1.4% nausea compared to 1.1% placebo

▪ Brand name: Nurtec ODT

Rimegepant Clinical Trials

▪ Dosage in phase 3 trials is 75 mg ▪ Primary end-points of pain-freedom and relief of most bothersome symptom (MBS) ▪ Study 301: 1084 adults ▪ 19.2% pain-free at 2 hours vs 14.2% placebo ▪ 36.6% relief of MBS vs 27.7% placebo ▪ 2-24 hours sustained pain relief 38.9% vs 27.9% placebo ▪ Study 302: 1072 patients ▪ 19.6% pain-free at 2 hours vs 12.0% placebo ▪ 37.6% relief of MBS vs 25.2% placebo ▪ 2-24 hour sustained pain relief was 42.6% active drug vs 26.5% placebo

Lipton RB. Presentation 4/22/18. Studies 301 and 302 Pivotal Trial Data Presentation. Los Angeles, CA. Data on file. 2018. Biohaven Pharmaceutical.

Rimegepant Trial Results

Rimegepant ODT 75mg Rimegepant ODT 75mg Placebo Placebo

Rimegepant ODT 75mg

Data on file: Rimegepant PI Biohaven Pharmaceuticals, Inc. New Haven, CT 06510 USA.

Rimegepant for Prevention?

▪ Approved by the FDA in May 2021 for the prevention of episodic migraines in adults ▪ More to come when we discuss migraine prevention!

Lasmiditan

▪ FDA approved October 2019; DEA scheduled January 2020 ▪ FDA approved for acute treatment of migraine with or without aura in adults ▪ First in class “ditan” - Oral 5-HT 1F serotonin receptor agonist ▪ No vasoconstriction - unlike triptans which target 5-HT 1B/1D receptors ▪ Available as a 50 & 100 mg tablet

▪ Dose is 50 or 100 or 200 mg taken as a single dose in a 24-hour period

▪ CNS side-effects including dizziness, paresthesia, somnolence, and fatigue ▪ No driving for 8 hours ▪ Schedule V controlled medication

Lasmiditan Single Attack Trials Samurai and Spartan ▪ Samurai and Spartan: phase 3 randomized, DB, PC studies (Single Attack Trials) ▪ At 2 hours Lasmiditan 200mg: ▪ Pain freedom: 32-39% vs 15-21% placebo ▪ MBS free 41-49% vs 30-34% with placebo ▪ Pain relief: efficacy endpoint (post HOC) 60-65% vs 40% with placebo ▪ With 200mg dose separation from placebo noted for pain FREE as early as 1 hour ▪ 100mg and 200mg separated from placebo for MBS at 0.5 hours

Positive Pivotal Trials. Family Practice News. August 2018; Vol 48 (12); 1, 4, 6. Kuca B, et al. Neurology. 2018 Dec;91(24):e2222-e2232. Goadsby P, et al. Brain. 2019 July; 142(7):1894-1904.

Lasmiditan Trial Results Samurai and Spartan

% Patients with Pain Freedom at 2 hours % Patients with Freedom from MBS at 2 hours

Lasmiditan 200 mg Lasmiditan 200 mg Lasmiditan 100 mg Lasmiditan 100 mg Lasmiditan 50 mg Lasmiditan 50 mg Placebo Placebo

Lasmiditan PI Indianapolis, IN: Lilly USA, LLC. 1/2021; Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0002

Lasmiditan Multi-Attack Trial Centurion ▪ Centurion: phase 3 randomized, DB, PC Multi-Attack Consistency Trial (required for EU approval) ▪ Consistency was defined as achieving pain freedom in 2 out of the first 3 treated attacks ▪ Co-primary Endpoints: ▪ Pain freedom at 2 hours after treatment of 1st attack ▪ Pain freedom at 2 hours in 2 out of the first 3 attacks ▪ Secondary Endpoint: ▪ Pain relief at 2 hours after treatment of 1st attack

Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0026

Lasmiditan Trial Results Centurion

% Pain Freedom – Single Attack % Pain Relief – Single Attack

Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0026; Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0028

Lasmiditan Trial Results Centurion

% Pain Freedom at 2 hours in at least 2 out of 3 attacks

Data on File. Indianapolis, IN: Lilly USA, LLC. DOF-LM-US-0027

Driving & Medications

▪ Medications can impair driving/operating machinery ▪ Needs to be addressed with patients ▪ Needs to be something we consider when prescribing ▪ Document!!

Impaired Driving Evaluation

https://www.fda.gov/media/90670/download Verster JC and Roth T. Int J Gen Med 2011;4:359-71.

Preventive Medications Old and New

Current Preventive Landscape

▪ Anti-depressants ▪ Anti-epileptics ▪ Anti-hypertensives ▪ Onabotulinum Toxin A ▪ Non-invasive neurostimulators ▪ Herbal Preventives ▪ Hormonal Approaches

FDA Approved Oral Medications for Prevention of Episodic Migraine

▪ Divalproex sodium ▪ Topiramate ▪ Timolol ▪ Propanolol

Note: Others commonly used but not FDA approved include Amitriptyline, Venlafaxine, Metoprolol, Naldolol, Atenolol, Nortriptyline, Duloxetine, Verapamil, Gabapentin, Candesartan, Fluoxetine, Escitalopram, Cyproheptadine

Short-term prevention menstrual migraine: Frovatriptan, Naratriptan, Sumatriptan, Zolmitriptan, Rizatriptan. All have shown efficacy in clinical trials but not FDA approved for prevention

Non-Pharmacologic Treatment Options

▪ Herbal treatments ▪ Magnesium 500mg (may cause diarrhea) ▪ Riboflavin (vitamin B2) – dietary: 1.6-3.8 mg, supplement: 400mg ▪ Co Q 10 150mg ▪ Butterbur 75mg ▪ Acupuncture ▪ Biofeedback, CBT*, stress-reduction ▪ Psychological counseling ▪ Yoga, exercise, meditation ▪ Non-invasive nerve stimulators (both acute and preventive – require Rx) ▪ Class IV Laser (photobiomodulation – “aka cold laser”) – not FDA approved for migraine but has been shown to reduce inflammation and pain in musculoskeletal and peripheral neurologic conditions – safe, non-invasive…

Slavin M. Headache. 2019;Jun;59(S1):1-208, Abstract LB0R04. *CBT = cognitive behavioral therapy

Onabotulinum Toxin A (Botox)

▪ FDA approved for chronic migraine only (not EM) ▪ Approved protocol is 155 units injected in 31 individual sites every 12 weeks ▪ Sites include procerus, corrugators, frontalis, temporalis, occipitalis, upper paracervicals, and upper trapezius ▪ FDA approved for chronic migraine in 2010 ▪ MOA includes inhibition of release of neuropeptides including CGRP from peripheral nervous system

Anti-CGRP Monoclonal Antibodies ”mAbs”

Specifically designed to target migraine prevention

Anti-CGRP Monoclonal Antibodies for Migraine Prevention

▪ Target specific: ▪ Block CGRP receptor or bind the CGRP ligand ▪ Net effect: ▪ Block CGRP activity ▪ Lessen the migraine cascade of inflammatory activity ▪ Prevent transmission of pain signals to travel to higher order neurons ▪ Anti-CGRP mABs are large monoclonal antibodies and cannot cross the blood-brain barrior to any significant degree ▪ Anti-CGRP mAbs work on the peripheral nervous system (PNS)

Key Features Anti-CGRP mAB’s

▪ Work on peripheral nervous system ▪ No data in pregnancy and breast- (PNS) feeding ▪ No central nervous system side- ▪ Not available in oral tablet effects (CNS) ▪ Expensive to make (grown in ▪ No effect on liver or kidney cell cultures) ▪ No drug-drug interactions ▪ CGRP is a vasodilator – CV ▪ Degraded by enzymatic proteolysis considerations? ▪ Stable CV in trials – no “red flags” ▪ Favorable side-effect profile in clinical trials ▪ Immunogenicity is possible – impact unclear ▪ Approved for migraine prevention in adults ▪ More similar than different

Erenumab-aooe

▪ FDA approved May 2018 for the preventive treatment of migraine in adults ▪ Fully humanized immunoglobulin (IgG2) selectively targets and blocks the CGRP receptor ▪ Competes with the binding of CGRP and inhibits its function at the CGRP receptor site ▪ Half-life is 28 days ▪ Dose is 70 or 140 mg monthly subcutaneous injection into upper arm, abdomen or thigh with auto-injector ▪ Brand name Aimovig (Amgen/Novartis)

Erenumab Clinical Trial

▪ STRIVE ▪ Multi-center, PC, DB, 24-week study erenumab vs placebo in EM ▪ Mean Migraine Frequency Baseline 8 MMD: ▪ 3.7 reduction in 140 mg-arm erenumab ▪ 3.2 reduction in 70-mg arm; 1.8 reduction in placebo arm ▪ Statistically significant (months 4-6 compared to baseline) ▪ Exploratory analysis 22% in 140 mg-arm, 20.8% in 70 mg-arm, and 7.9% in placebo arm 75% or greater reduction MMD ▪ CM study ▪ Multi-center, PC, DB, 12-week study in CM reduction in MMD by 6.6 compared to 4.2 placebo group ▪ Post-hoc analysis 21% (140 mg-arm), 17% (70 mg-arm), 8% (placebo arm) 75% or greater reduction in MMD

MMD = monthly migraine days

Aimovig (erenumab-aooe) prescribing information. 2018. Amgen Inc.

Erenumab Trial Results

Goadsby PJ et al. N Engl J Med. 2017; 377:2123-2132.

Safety Concerns

▪ 2,537 patients with migraine who received at least 1 dose of Erenumab ▪ 2,057 were exposed to Erenumab (70 or 140 mg monthly) for 6 or more months ▪ Adverse Events (incidence >3%) ▪ Injection site reaction: 3% in the placebo group, 6% in the 70 mg group, 5% in the 140 mg group ▪ Constipation: 1% of the placebo group, 1% in the 70 mg group, 3% in the 140 mg group ▪ Immunogenicity: ▪ 6.2% of patients receiving 70 mg monthly developed anti-erenumab antibodies ▪ 2.6% of patients receiving 140 mg monthly developed anti-erenumab antibodies ▪ No impact on efficacy or safety was noted in these patients but data too limited to make a definitive conclusion

Aimovig (erenumab-aooe) prescribing information. 2018. Amgen Inc. Thousand Oaks, CA.

Safety Concerns (cont.)

▪ Updated label USPI October 8, 2019: ▪ Revised warning and precautions to include language on constipation with serious complications ▪ Updated label USPI April 30, 2020: ▪ Post marketing reports of new or worsening hypertension – most occurred within 7 days and after first dose. There were cases requiring pharmacological treatment and, in some cases, hospitalization ▪ Limitations of “post marketing reports” ▪ Often self reported ▪ Limited history/additional information ▪ No “control” arm – so no statistical analysis

Aimovig (erenumab-aooe) prescribing information. 2020. Amgen Inc. Thousand Oaks, CA.

Fremanezumab-vfrm

▪ FDA approved 9/14/18 for the prevention of migraine in adults ▪ Fully humanized immunoglobulin (IgG2a) binds to the CGRP ligand ▪ Half-life is 31 days ▪ Dose is 225 mg monthly or three 225 mg subcutaneous injections quarterly ▪ Available in a pre-filled syringe (1.5 ml) or an autoinjector ▪ May be injected in upper arm, abdomen, or thigh ▪ Brand name Ajovy (Teva)

Ajovy (Fremanezumab-vfrm) prescribing information. 2018. Teva.

Fremanezumab EM Phase 3 Trial

▪ Halo EM - 875 patients randomized to 225 mg monthly dose of Fremanezumab, a single dose of 675 mg followed by placebo, or placebo for 12 weeks ▪ Reduction in Mean Monthly Migraine (MMD) days ▪ 8.9 to 4.9 in monthly dosing group ▪ 9.2 to 5.3 in the single-higher dose group ▪ 9.1 to 6.5 in placebo group ▪ Patients with at least 50% reduction in headache days per month ▪ 48% in quarterly group ▪ 44% in monthly group ▪ 28% in placebo group

Dodick D, et al. Effect of Fremanezumab Compared with Placebo for Prevention of Episodic Migraine A randomized Clinical Trial. JAMA. 2018;319(19):1999-2008.

Fremanezumab EM Trial Results

Dodick D, et al. Effect of Fremanezumab Compared with Placebo for Prevention of Episodic Migraine A randomized Clinical Trial. JAMA. 2018;319(19):1999-2008.

Fremanezumab CM Phase 3 Trial

▪ Halo CM - 1130 patients randomized to Fremanezumab quarterly dosing, monthly dosing, or placebo in a 23-week study ▪ Primary endpoint was mean change in number of headache days from baseline ▪ 4.3 in quarterly dosing group ▪ 4.6 with monthly dosing group ▪ 2.5 with placebo group ▪ Patients with at least 50% reduction in headache days per month ▪ 38% in quarterly group ▪ 41% in monthly group ▪ 18% in placebo group

Silberstein SD, et al. Fremanezumab for the Preventive Treatment of Migraine. The New England Journal of Medicine. 2017;377(22):2113-2122.

Fremanezeumab CM Trial Results

Reduction in Migraine Days Reduction in Headache Days

Silberstein SD, et al. Fremanezumab for the Preventive Treatment of Migraine. The New England Journal of Medicine. 2017;377(22):2113-2122.

Safety Concerns

▪ 2512 patients who received at least one dose of Fremanezumab ▪ Adverse Events (incidence at least 5% and greater than placebo) ▪ Injection site reactions including injection site pain, induration, and erythema ▪ 43% of the 225 mg monthly dose group, 45% of the 675 mg quarterly group, and 38% in placebo group. Total of 1% discontinued in the clinical trial ▪ Fremanezumab contraindicated in patients with serious hypersensitivity to Fremanezumab or to any of the excipients (EDTA, L-histidine, polysorbate, sucrose) ▪ Hypersensitivity reactions (rash, pruritus, urticaria) ▪ Mild to moderate in most cases and were reported from hours to 1 month after administration in the clinical trials. A few cases required corticosteroid treatment. No cases of anaphylaxis were reported ▪ Potential for immunogenicity. In 3-month placebo-controlled studies, development of anti-fremanezumab antibodies as observed in .4% of treated patients. No conclusions can be made on any impact of ADA on safety of efficacy

ADA = anti-drug antibodies Fremanezumab-vfrm prescribing information. 2018. Teva Pharmaceuticals USA.

Galcanezumab-gnlm

▪ FDA approval 9/27/18 for the prevention of migraine in adults ▪ FDA approval June 2019 for treatment of Episodic Cluster Headache at 300mg (given as 3 100mg SC injections) monthly until the end of the cluster period ▪ Fully humanized immunoglobulin (IgG4) binds to the CGRP ligand ▪ IgG4 less innate immune response compared to IgG2 ▪ Half-life is 27 days ▪ Approved dose is loading dose of 240 mg subcutaneous injection (given as two 120 mg auto-injectors or prefilled syringe) followed by monthly 120 mg injection ▪ Brand name Emgality (Lilly) (available as autoinjector or syringe)

Data on File 2019. Indianapolis, IN: Lilly USA, LLC.

Galcanezumab EM Phase 3 Trials

▪ EVOLVE-1 and EVOLVE-2 DB, PC, 6-month clinical trials with 120 mg dose (after the 240 mg loading dose) vs placebo ▪ Primary endpoint was changed in monthly migraine days over months 1-6 ▪ Evolve-1: 4.7 MMD vs 2.8 placebo ▪ Evolve-II: 4.3 MMD vs 2.3 placebo ▪ Baseline was 9 MMD in these EM trials ▪ Secondary endpoint – responder rates (in at least 1 out of 6 months) ▪ 50% reduction: 59-62% vs 36-39% placebo ▪ 75% reduction: 34-39% vs 18-19% placebo ▪ 100% reduction: 12-16% vs 6% in placebo

Data on File 2019. Indianapolis, IN: Lilly USA, LLC.

Galcanezumab EM Trial Results

Stauffer VL, et al. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial JAMA Neurol. Published online. Skljarevski V, et al. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454.

Galcanezumab EM Trial Results

Galcanezumab CM Clinical Trial

▪ REGAIN: DB, PC, 3-month study for CM ▪ Propanolol or Topiramate was continued in 15% of study participants. The 240 mg dose was not superior to the 120 mg in this study ▪ Baseline MMHD was 20 ▪ 4.3 fewer MMHD vs 2.7 in placebo group ▪ 50% responders hit statistical significance: 28% vs 15% placebo

Data on File 2019. Indianapolis, IN: Lilly USA, LLC.

Galcanezumab CM Trial Results

Detke HC, et al. Presented at: IHC 2017. Abstract PO-01-195. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Galcanezumab CM Trial Results

Detke HC, et al. Presented at: IHC 2017. Abstract PO-01-195. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Galcanezumab Open Label Trial

▪ GLADIATOR: Open label-extension study for safety/tolerability with secondary endpoint of sustained efficacy

▪ No placebo arm – open label trial

▪ No new treatment emergent adverse events

▪ (80% EM, 20% CM) demonstrated

▪ 6.4 fewer MMHD from baseline of 10 at 12 months

Stauffer VL, et al. Presented at: IHC 2017. Abstract PO-01-184. Data on file, Eli Lilly and Company.

Safety Concerns

▪ 2500+ patients in clinical trials ▪ Galcanezumab is contraindicated in patients with hypersensitivity to Galcanezumab or any of its excipients (L-histidine, polysorbate) ▪ Adverse Events: >2% of patients and >2% placebo ▪ Injection site reactions seen in 18% of patients receiving Galcanezumab compared to 13% in placebo group ▪ Rash, urticaria and dyspnea were reported ▪ Hypersensitivity reactions occurred in the clinical trials. Post marketing reports of angioedema and anaphylaxis ▪ Immunogenicity: 3-6 month trials, 4.8% of patients developed antibodies to Galcanezumab. In the 12-month trial, up to 12.5% developed ADA. No affect was seen on pharmacokinetics. No conclusions can be made on any impact of ADA on safety of efficacy

Emgality Prescribing Information. 2018. Data on File Lilly, USA. ADA = anti-drug antibodies

Eptinezumab

▪ FDA approved February 2020 for the prevention of migraine in adults ▪ Fully humanized immunoglobulin (IgG1) binds to the CGRP ligand ▪ Quarterly dosing (100mg or 300mg) given intravenously ▪ Half-life of 27 days ▪ Features include quick onset of action and high bioavailability. Reduction in migraine seen first 24 hours post-infusion in Promise-2 Study ▪ Drawback is the need for access for infusion and added cost of infusion ▪ Brand name Vyepti (Lundbeck Seattle BioPharmaceuticals, Inc.)

Vyepti (Eptinezumab) prescribing information. 2020. Lundbeck Seattle BioPharmaceuticals, Inc.

Eptinezumab Phase 3 Trials

▪ Study-1: 665 patients with EM ages 18-71 enrolled and received either 100 or 300 mg Eptinezumab or placebo IV infusion every 3 months for 12 months ▪ Reduction of 3.9 (100mg) and 4.2 (300mg) MMDs vs 3.2 in placebo group over week 1-12 ▪ 29.7% of patients achieved 75% or greater reduction in MMDs in week 1-12 in the 300mg group vs 16.2% in placebo group ▪ Study-2: 1072 patients with CM ages 18-65 enrolled and received either 100 or 300 mg Eptinezumab or placebo ▪ Reduction of 7.7 (100mg) and 8.2 (300mg) MMDs vs 5.6 in placebo group over week 1-12 ▪ 26.7% (100mg) and 33.1% (300mg) of patients achieved 75% or greater reduction in MMDs in week 1-12 vs 15% in placebo group

Vyepti (Eptinezumab) prescribing information. 2020. Lundbeck Seattle BioPharmaceuticals, Inc. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine PROMISE-2. Neurology. Mar 2020, 94 (13) e1365-e1377.

Eptinezumab CM Trial Results

Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine PROMISE-2. Neurology. Mar 2020, 94 (13) e1365-e1377.

Eptinezumab CM Trial Results

Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine PROMISE-2. Neurology. Mar 2020, 94 (13) e1365-e1377.

Safety Considerations

▪ 2076 patients in clinical trials ▪ Eptinezumab is contraindicated in patients with hypersensitivity to eptinezumab or any of its excipients ▪ Adverse Events: >2% of patients and >2% placebo ▪ Nasopharyngitis ▪ Hypersensitivity ▪ Hypersensitivity reactions included: angioedema, urticaria, facial flushing, and rash ▪ Immunogenicity can occur: 18%-20.6% developed antibodies to eptinezumab in clinical trials with 39%-43% of these neutralizing antibodies – clinical effect unknown

Vyepti (Eptinezumab) prescribing information. 2020. Lundbeck Seattle BioPharmaceuticals, Inc.

Important Points About Anti-CGRP mAB’s

▪ No head-to-head comparator trials ▪ Long-term safety trials on going ▪ To date no major “red flags” but: ▪ Could there be a downside of long-term CGRP suppression? ▪ Insufficient data on safety during pregnancy and lactation ▪ All companies forming Pregnancy Registries ▪ Only FDA approved for 18 and over in US ▪ Pediatric trials ongoing

Who is a Candidate for an Anti-CGRP mAB? ▪ Adults with migraine who have 4 or more monthly migraine headache days ▪ Migraines are disabling ▪ Current or past standard preventives have either not been tolerated or have been ineffective (most insurance companies will require trial of 2 preventives prior to approval of CGRP mAB) ▪ If adult has chronic migraine, insurance company may require failure of 4-6 month trial with Onabotulinum Toxin A

Atogepant

▪ Oral CGRP Receptor Antagonist for the prevention of migraine – submitted to FDA for review March 2021 ▪ Phase 3 trial “Advance”: MC, DB, PC, RT ▪ Dosing: 10 mg, 30 mg, 60 mg QD vs placebo ▪ 12-week trial ▪ Primary efficacy end-point of reduction from baseline in mean migraine/probable migraine days per month (10mg/30mg/60mg 3.69/3.86/4.2 days vs 2.48 placebo p=<.0001) ▪ Secondary end-point 50% responder rates (10mg/30mg/60mg 55.6%/58.7%/60.8% vs 29.0% placebo p=<.0001) ▪ Side-effects: constipation (6.9-7.7% across all doses vs. 0.5% for placebo), nausea (4.4- 6.1% across all doses vs. 1.8% for placebo) and URI (3.9-5.7% across all doses vs. 4.5% for placebo) NO sign of hepatotoxicity ▪ Has a 10-hour half-life ▪ Potential option for patients who prefer oral daily preventive for migraine as opposed to injection or IV administration of an anti-CGRP mAB

Data on file. 2018. Allergan Pharmaceutical.

Rimegepant Prevention EM

▪ 12-week trial MC, DB, randomized, PC (episodic migraine) ▪ 747 patients (373 rimegepant 75mg QOD vs 374 placebo) ▪ Primary endpoint: reduction in MMDs (weeks 9-12) ▪ -4.3 with Rimegepant vs -3.5 with placebo ▪ Secondary endpoint: 50% or more reduction in MMDs (weeks 9-12) ▪ Side effects similar to placebo

Croop R, Lipton RB, Kudrow D, Stock DA, Kamen L, Conway CM, Stock EG, Coric V, Goadsby PJ. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021 Jan 2;397(10268):51-60. doi: 10.1016/S0140-6736(20)32544-7. Epub 2020 Dec 15. PMID: 33338437. Data on file – biohaven US-RIMODT-2100251 05/10/2021.

Adding on to Onabotulinum Toxin A?

▪ For chronic migraine patients not adequately controlled with onabotulinum toxin A . . . Can we add a mAB or a preventive gepant? ▪ Some retrospective data suggests benefit of onabotulinum toxin A with mAB ▪ Cephalgia article 2021, Vol. 41(1) 17–32: Combined onabotulinum toxin A / atogepant treatment blocks activation/sensitization of high-threshold and wide-dynamic range neurons

Summary of Treatment Options

▪ CGRP is a neuropeptide that plays a key role in migraine pathogenesis ▪ Anti-CGRP Monoclonal Antibodies represent a new category for migraine prevention for adults in the US and 4 Anti-CGRP mAB’s are now FDA approved ▪ New and emerging acute migraine treatment options include new formulations for Sumatriptan and an oral 5-HT 1F agonist ▪ Oral CGRP receptor antagonists show promise for both acute and preventive treatment of migraine ▪ Knowledge of how to incorporate new acute and preventive migraine treatments in our migraine patients can reduce the burden of migraine in our patients lives

Back to Beth

Prevention for Beth

▪ Migraine attacks are now 1-2 times per week ▪ Missing 1 day of work per month due to migraine ▪ Topiramate caused cognitive impairment and fatigue ▪ Amitriptyline caused dry mouth, constipation and weight gain ▪ Anti-hypertensives not ideal due to low blood pressure ▪ Has 2 children, ages 8 and 10 ▪ Husband had vasectomy ▪ Asks, “What is new for preventive treatment” ▪ She states, “I want my life back”

Treatment Options – Beth

▪ Acute: ▪ Non-oral options include Sumatriptan 3 and 4 mg injection for potentially less side- effects she had with the 6 mg dose and/or a nasal formulation of a triptan and/or nasal dihydroergotamine (DHE) ▪ “New” oral acute medications: gepants or ditan ▪ AVOID NARCOTICS ▪ Prevention: ▪ One of the Anti-CGRP Monoclonal Antibodies based on tolerability issues with 2 standard oral preventives tried in the past (Topiramate and Amitriptyline) ▪ Onabotulinum Toxin A an option if she transforms to CM (her current pattern is 1-2 migraine headache days per week) ▪ Non-pharmacologic treatment including exercise, healthy eating, adequate sleep, stress-reduction, keeping a headache diary, and close follow-up

Summary

▪ Migraine is prevalent: 30+ million adults in US ▪ Migraine is in our office! 94% with headache complaint ▪ Migraine is disabling: #1 YLD in women <50 ▪ New CGRP targeted therapies ▪ Safe ▪ Effective ▪ Acute and preventive treatment options