Migraine Immunotherapy

6 Mar 2019

พ.อ. เจษฎา อุดมมงคล รพ. พระมงกุฎเกล้า Migraine: the MOST common neurological disorder

15 12.1%

10 6.7%

5

0.96% 1% Disease prevalence, % prevalence, Disease 0.71% 0.09% 0 MS Epilepsy PD+HD Stroke AD Migraine

MS = multiple sclerosis; PD+HD = Parkinson disease + Huntington disease; AD = Alzheimer’s disease.

National Institute of Neurological Disorders and Stroke. Available at: www.ninds.nih.gov. Accessed May 17, 2007 Hirtz D. et al. Neurology. 2007;68:326–337 Symptoms of Migraine Migraine phases and associated symptoms 1,2,3,4

Prodrome Aura HEADACHE Postdrome † (20% of cases)

Other symptoms may include: ▪ Unusual sensitivity to light, sounds, and smells ▪ Changes in vision ▪ Lightheadedness and fainting ▪ Skin sensations/tingling ▪ Nausea and vomiting ▪ Language problems

▪ Repetitive yawning ▪ Head pain ▪ Repetitive yawning ▪ Food cravings ▪ Often unilateral ▪ Food cravings ▪ Neck stiffness/ pain ▪ Neck stiffness/pain ▪ Fatigue ▪ Tends to have a pulsating quality ▪ Fatigue ▪ Can be aggravated by routine physical activity

Intensity Intensity of Symptoms or Phases ▪ Can be associated with cutaneous allodynia Few hours Few hours to few days 5-60 min‡ 4-72 hours to few days Proportion Time of patients ~30%-40% ~30% 100% ~70% † Illustrative only. ‡ Duration per symptom. 1.Headache Classification Committee of the International Headache Society (IHS). 3. Figure adapted from Blau JN. Lancet. 1992;339:1202-7. Cephalalgia. 2013;33:629-808. 4. Charles A. Headache. 2013;53:413-9. 2.Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533-52. Migraine classification by ICHD-3 20181,2

Diagnosis ICHD-3

1 Migraine

1.1 Migraine without aura 1.2.1 Migraine with typical aura 1.2.1.1 With headache 1.2.3.1.1 Type 1 CACNA1A 1.2.2 Migraine with brainstem aura 1.2.1.2 Without headache 1.2 Migraine with aura 1.2.3.1.2 Type 2 ATP1A2 1.2.3 Hemiplegic migraine 1.2.3.1 Familial hemiplegic migraine 1.2.3.1.3 Type 3 SCN1A 1.2.4 Retinal migraine 1.2.3.2 Sporadic hemiplegic migraine 1.3 Chronic migraine 1.2.3.1.4 Other loci 1.4.1 Status migranosus

1.4.2 Persistent aura without infarction 1.4 Complications of migraine 1.4.3 Migrainous infarction

1.4.4 Migraine aura-triggered seizure 1.5.1 Probable migraine with aura 1.5 Probable migraine 1.5.2 Probably migraine without aura 1.6.1.1 Cyclical vomiting syndrome 1.6.1 Recurrent gastrointestinal disturbance 1.6 Episodic syndromes that 1.6.1.2 Abdominal migraine may be associated with 1.6.2 Benign paroxysmal vertigo migraine 1.6.3 Benign paroxysmal torticollis

ICHD-3 = International Classification of Headache Disorders, 3rd edition 1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2018;38:1-211.. 2. Lipton RB and Silberstein SD. Headache. 2015;55(Suppl 2):103-122. Migraine begins with ‘abnormal’ activation of the TGVS

▪ The cause of migraine is unclear but involves abnormal activation of the TGVS

▪ TGVS activation causes Trigeminal nerve release of various neuropeptides at the meninges: Calcitonin • CGRP • Neurokinin A • Substance P

▪ These peptides can induce neurogenic inflammation Smooth muscle cell / postsynaptic neuron

▪ Inflammation and dysregulation contribute to a feed-forward loop, causing migraine

CGRP = calcitonin gene-related peptide; TGG = trigeminal ganglion; TGVS = trigeminovascular system

1. Burgos-Vega C, et al. Prog Mol Biol Transl Sci. 2015;131:537-64. 2. Raddant AC, Russo AF. Expert Rev Mol Med. 2011;13:e36. 3. Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533-52. 4. Pietrobon D, Moskowitz MA. Annu Rev Physiol. 2013;75:365-91. 5. Demarquay G, Mauguière F. Headache. 2016;56:1418-38. CGRP is a neuropeptide involved in migraine pathophysiology

CGRPα is a 37-amino acid neuropeptide encoded by the calcitonin gene1,2 Widely distributed in both the central and the peripheral nervous system3 CGRP is a sensory neurotransmitter released by nociceptive fibers of the trigeminal system3 Activation of the trigeminal nerve causes CGRP to be released from perivascular nerve endings4 Calcitonin CGRP plays a role in neurogenic inflammation gene-related peptide and is a potent dilator of peripheral and cerebral (CGRP) blood vessels4 Ala-Cys-Asp-Thr-Ala-Thr-Cys-Val-Thr-His- During migraine attacks, CGRP serum levels Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly- are elevated1,5,6 Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr- Asn-Val-Gly-Ser-Lys-Ala-Phe-NH28 Selective antagonists to CGRP and its receptor effectively treat migraine4,7

Right image: Ref.9 Left image: Novartis. CGRP = calcitonin gene-related peptide 1. Goadsby PJ, et al. Ann Neurol. 1990;28:183-187. 2. Amara SG, et al. Nature. 1982;298:240-244. 3. Ho TW, et al. Nat Rev Neurol. 2010;6:573-582. 4. Durham PL. Headache. 2006;46:S3-S8. 5. Edvinsson L, Goadsby PJ. Eur J Neurol. 1998;5:329-341. 6. Cernuda-Morollón E, et al. Neurology. 2013;81:1191-1196. 7. Giamberardino MA, Martelletti P. Expert Opin Emerg Drugs. 2015;20:137-147. 8. Russell FA, et al. Physiol Rev. 2014;94:1099-1142. 9. Breeze AL, et al. Biochemistry. 1991;30:575-582. Structure of CGRP receptor

The CGRP receptor has 3 components and belongs to the family of G protein-coupled receptors (GPCRs):1,2 ▪ Calcitonin receptor-like receptor (CLR) ▪ Receptor activity-modifying protein (RAMP1) ▪ Receptor component protein (RCP)

The most common effector pathway is through cAMP and protein kinase A1

Ion channels CGRP Receptors

R Adenylate eNOS A C M L P R Cyclase Transcription 1 Etc.

RCP

Gβγ Gαs Figure with permission from Russel FA76. Image adapted from original. cAMP = cyclic adenosine monophosphate; CGRP = calcitonin gene-related peptide; eNOS = endothelial nitric oxide synthase.

1. Russell FA, et al. Physiol Rev. 2014;94:1099-42. 2. Poyner DR, et al. Pharmacol Rev. 2002;54:233-46. Physiological functions of other calcitonin-family ligand-receptor interactions

Amylin1, 2 ▪ Secreted from pancreatic islets (β-cells) into the blood* ▪ Plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial increases in blood glucose levels* ▪ Functions as a synergistic partner to insulin*

Amylin81 ▪ Acts in bone metabolism, along with the related peptides CT and CGRP†

AM and PAMP83 ▪ Act as inhibitors of gastric acid secretion and gastric emptying* ▪ Contribute to the mucosal host defense system by regulating gut microbiota† ▪ Protect the gastric mucosa from injury* ▪ Accelerate healing in diseases such as gastric ulcer and IBD†

Calcitonin84,85 ▪ Receptors for CT are located on bone cells* ▪ CT promotes bone formation by inhibiting osteolytic activity and stimulating osteoblasts† * in vivo; † in vitro. AM = adrenomedullin; CGRP = calcitonin gene-related peptide; CT = calcitonin; IBD = inflammatory bowel disease; PAMP = proadrenomedullin.

1. Pittner RA, et al. J Cell Biochem. 1994;55 Suppl:19-28. 2. Hieronymus L, Griffin S. Diabetes Educ. 2015;41(1 Suppl):47S-56S. 83. Martínez-Herrero S, Martínez A. Domest Anim Endocrinol. 2016;56 Suppl:S66-S83. 84. Zaidi M, et al. Bone. 2002;30:655-663. 85. Costoff A. "Sect. 5, Ch. 6: Effects of CT on Bone". Medical College of Georgia. Essentials of Human Physiology. https://web.archive.org/web/20080622221510/http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_24.htm. accessed on 01 Feb 2017. CGRP & CLR/RAMP1 receptors are distributed throughout the trigeminal system

Dural vessel Cerebral vessel Dural vessel Cerebral vessel To thalamus Hypothalamus To thalamus Hypothalamus

C-fibers PAG A-fibers PAG TG TG Cerebellum Cerebellum LC LC PC SSN SSN SPG SPG PC IV IV

FN TNC FN TNC MRN MRN CLR CGRP RAMP1 STN STN Cellular localization Cellular localization Fiber localization Fiber localization

IV = fourth ventricle; CGRP = calcitonin gene-related peptide; CLR = calcitonin receptor-like receptor; FN = fastigial nucleus; LC = locus coeruleus; MRN = magnus raphe nucleus; PAG = periaqueductal grey region; PC = Purkinje cell; RAMP1 = receptor activity-modifying protein 1; SPG = superior sphenopalatine ganglion; SSN = superior salivatory nucleus; STN = spinal trigeminal nucleus; TG = trigeminal ganglion; TNC = trigeminal nucleus pars caudalis.

Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-98. Image courtesy of Lars Edvinsson. CGRP and CGRP receptor antagonists do not act centrally for clinical effect

• Telcagepant has low receptor occupancy in the CNS at clinically effective doses in both healthy subjects and migraine patients

• While a higher does of telcagepant displaces the tracer from the CGRP receptor, there is no additional clinical benefit

Baseline Telcagepant 140 & 1120 mg Positron emission tomography (PET) of the human brain showing uptake of the CGRP PET CNS tracer [11C]MK-4232 at baseline and after administration of telcagepant, a potent, selective CGRP-receptor antagonist 140 mg, 1120 mg

Hostetler ED et al. J Pharmacol Exp Ther 2013;347:478-86 CGRP Agonists: Gepants

Neurotherapeutics 2018;15:304–12 ▪ Evidenced-base ▪ Nonspecific ▪ Side effects ▪ Low adherence ▪ Availability

Neurology 2012;78:1337-45 Low adherence with current preventive therapy

Retrospective claims analysis of a US claim database for 8,688 chronic migraine patients Regardless of medication used, adherence was low among oral migraine-preventive medications

Hepp Z et al. Cephalalgia 2015;35:478 Reasons for poor adherence

Side-effects and lack of efficacy are the key drivers of suboptimal adherence

Reasons reported by patients for discontinuation of preventive medication

Blumenfeld AM et al. Headache 2013;53:644 CGRP Monoclonal Antibodies: Precision Medicine for migraine

▪ Developed for migraine-specific targets ▪ Good efficacy in episodic and chronic migraine, with a subgroup of patients showing 75% response rates ▪ Tolerability data to date are promising, although long-term safety needs to be established ▪ Offer potential to tailor acute or preventive migraine therapy to individual patients ▪ Provide new hope for migraine patients for whom current options are either ineffective or poorly tolerated Anti CGRP Comparison of Structure and Function of Mabs

Fremanezumab Erenumab Galcanezumab Eptinezumab i.v. infusion ROA s.c. injection s.c. injection s.c. injection s.c. injection (Phase I) Dosing Monthly, Quarterly Monthly Monthly Quarterly IgG Subtype IgG2Δa IgG2 IgG4 IgG1

Human Fully humanized Human Humanized Humanized sequences (>95% human) (100% human) (>90% human) (>90% human)

Expression Chinese hamster ovary Chinese hamster Chinese hamster Yeast system (CHO) ovary (CHO) ovary (CHO) (Pichia pastoris) Target CGRP ligand CGRP receptor CGRP ligand CGRP ligand t½ 31 days 21 days ~25–30 days ~32 days *Potential for reformulation to subcutaneous (s.c.) injection. †Alternative dosing regimens are currently under investigation. ‡Fully human sequence-derived or humanized, with the replacement of mouse constant regions and V framework regions for human sequences2.

CGRP, calcitonin gene-related peptide; IgG, immunoglobulin G; ND, not disclosed; ROA, route of administration; t½, half-life.

1. Bigal ME et al. Br J Clin Pharmacol 2015;79:886–895. 2. Harding FA et al. MAbs 2010;2:256–265. 3. Data on File (Teva Pharmaceuticals) Silberstein S et al. , Headache 2015;55:1171 Silberstein Practical neurology 2019 Foltz I N et al. Circulation. 2013;127:2222-2230 Silberstein S et al. , Headache 2015;55:1171 Structure–Function Comparisons

IgG Subtype Half-life

Eptinezumab is subtype IgG1, All four mAbs have long terminal erenumab and fremanezumab are T1/2 (>20 days), but IgG2, and galcanezumab is IgG41,2 fremanezumab and eptinezumab have the longest, which supports their quarterly dosing:1,2,4 Route of Administration Fremanezumab 3 Eptinezumab is the Erenumab 21 only anti-CGRP mAb for migraine administered by i.v. Galcanezumab 28 infusion3 Eptinezumab 32

Immediate bioavailability of the i.v. infusion may 0 10 20 30 40 contribute to a rapid onset of efficacy; however, subcutaneous injections will likely be preferred by patients Half-life (days)

CGRP, calcitonin gene-related peptide; IgG, immunoglobulin G; i.v., intravenous.

1. Bigal ME et al. Br J Clin Pharmacol 2015;79;886–895. 2. Harding FA et al. MAbs 2010;2:256–265. 3. Mitsikostas DD, Reuter U. Curr Opin Neurol 2017;30:272-280. 4. Data on File (Teva Pharmaceuticals) Direction on episodic & chronic migraine

EPISODIC CHRONIC

• Less information in actual guidelines • More information in actual guidelines • In literature, information only available for Onabotulinumtoxin A; recommendation is 6–12 • In clinical trials from 8–24 weeks months of treatment to prove failure • In clinical trials: treatment failure, 2–3 months • No clinical trials or randomized studies on how long to • Guidelines recommend: 3–6 months of treatment maintain treatment when there is a good response (longer than previous guidelines) • Open label information: - Onabotulinumtoxin A • No clinical trials or randomized studies on when to - CGRP Mabs stop preventive treatment in EM • General trend to maintain preventive treatment as long • Clear trend to maintain treatment for longer periods as necessary; ‘forever’ in some cases

CGRP, calcitonin gene-related peptide; Mab, monoclonal antibody Exploratory and Post Hoc Analyses: Comorbid Patients

Fremanezumab Erenumab Galcanezumab Eptinezumab

EM CM EM CM EM CM EM CM

Response in Depressed ✓ ✓ Patients

Response in Patients With ✓ or without Aura

Menstrual Migraine ✓

Medication Overuse Headache ✓ ✓

Cardiovascular Risk Factors ✓ ✓ ✓ ✓

Change in Days With Nausea and/or Vomiting ✓ ✓ Change in Days With Photophobia or ✓ ✓ Phonophobia

CM, chronic migraine; EM, episodic migraine. Exploratory and Post Hoc Analyses: Difficult-to-treat Patients

Fremanezumab Erenumab Galcanezumab Eptinezumab

EM CM EM CM EM CM EM CM

Response in Patients Taking ✓ ✓ Concomitant Preventive

Response in Patients Who ✓ ✓ ✓ ✓ ✓ ✓ Failed Preventives

Response in Patients Who ✓ ✓ ✓ Failed OnabotulinumtoxinA

Acute Med in Patients Who Failed Preventives ✓ ✓ ✓ ✓ ✓ ✓

CM Reversion to EM ✓ ✓

CM, chronic migraine; EM, episodic migraine Patient-Reported Outcomes (PROs)

Fremanezumab Erenumab Galcanezumab Eptinezumab

EM CM EM EM CM EM CM

mMIDAS; HIT-6;

Disability MIDAS HIT-6 MPFID-PI MIDAS – Endpoints Secondary QoL MSQ-RFR, -RFP, -EF MSQ-RFR, -RFP, -EF MSQ-RFR, -RFP, -EF SF-36

Productivity/ Activity WPAI MPFID-EA – –

Satisfaction PGIC – – –

Health Status EQ-5D – PGI-S –

Exploratory Exploratory Endpoints Depression PHQ-2, -9 – – –

CM, chronic migraine; EF, emotional function; EM; episodic migraine; EQ-5D, EuroQoL-5 Dimension; HIT-6, Headache Impact Test; MFPID, Migraine Physical Function Impact Diary; MIDAS, Migraine Disability Assessment; MSQ, Migraine-Specific Quality of Life; PHQ, Patient Health Questionnaire; QoL, quality of life; RFP, role function-preventive; RFR, role function-restrictive; SF-36, Short Form Health Survey; WPAI, Work Productivity and Activity Impairment. EM Patient Disposition

Number of Patients (%) Fremanezumab Erenumab Galcanezumab Eptinezumab

HALO EM1 ARISE2 STRIVE3 EVOLVE-14 EVOLVE-25 PROMISE-16 Randomized 875 (100) 577 (100) 955 (100) 862 (100) 922 (100) Received study drug 874 (99.9) 572 (99.1) 952 (99.7) 858 (99.5) 915 (99.2) 888 (99) Discontinued intervention 84 (10) 31 (5) 97 (10) 155 (18) 129 (14) 193 (22) Withdrew consent 26 (3) 24 (4) 76 (8) 60 (7) 64 (7) 141 (16)a Protocol violation/deviation 12 (1) – – 6 (<1) 8 (<1) – Adverse event 16 (2) – – 26 (3) 22 (2) 27 (3) Lost to follow-up 25 (3) 5 (<1) 18 (2) 32 (4) 17 (2) – Pregnancy 3 (<1) – – 6 (<1) 3 (<1) – Decision by sponsor/physician – 2 (<1) 3 (<1) 12 (1) 7 (<1) – Lack of efficacy – – – 13 (2) 8 (<1) – Other 2 (<1) – – – – 21 (2) Completed trial 791 (90) 546 (95) 858 (90) 703 (82) 785 (85) 771 (86)

aWithdrew consent or lost to follow-up. EM, episodic migraine.

1. Data on file (Summary table 15.1, Teva Pharmaceuticals). 2. Dodick D et al. Cephalalgia 2018;38:1026–1037. 3. Goadsby P et al. N Engl J Med 2017;377:2123–2132. 4. Stauffer VL et al. JAMA Neurol 2018; doi:10.1001/jamaneurol.2018.1212. 5. Skljarevski V et al. Cephalalgia 2018; doi: 10.1177/0333102418779543. 6. Silberstein S et al. Poster P4.108 presented at the American Academy of Neurology meeting, Los Angeles, CA; April 21–27, 2018. CM Patient Disposition

Number of Patients (%) Fremanezumab Erenumab Galcanezumab Eptinezumab HALO CM1 Phase 22 REGAIN3 PROMISE-24 Randomized 1130 (100) 667 (100) 1117 (100) 1121 (100) Received study drug 1130 (100) 660 (99) 1113 (99.6) 1072 (96) Discontinued intervention 96 (8) 23 (3) 75 (7) 55 (5) Withdrew consent 33 (3) 9 (1) 29 (3) 36 (3) Protocol violation 6 (<1) – 7 (<1) – Adverse event 20 (2) 4 (<1) 11 (1) 14 (1) Lost to follow-up 25 (2) 4 (<1) 15 (1) – Pregnancy 2 (<1) – 4 (<1) – Death 1 (<1) – – – Physician decision/ineligibility determined – 5 (<1) 4 (<1) – Non-compliance – 1 (<1) – – Lack of efficacy – – 5 (<1) – Other 5 (<1) – – 5 (<1) Completed treatment 1034 (92) 637 (96) 1037 (93) 1049 (94)

CM, chronic migraine.

1. Data on file (Summary table 15.1, Teva Pharmaceuticals). 2. Tepper S et al. Lancet Neurol 2017;16:425–434. 3. Detke H et al. Poster PS89LB presented at the American Headache Society meeting, Boston, MA; June 8–11, 2017; 4. Lipton R et al. Poster PF110LB presented at the American Headache Society meeting, San Francisco, CA; June 28–July 1, 2018. Primary Endpoint Comparison

EPISODIC Study Primary Endpoint Time Frame MIGRAINE Fremanezumab HALO1 Months 1–3 ARISE2 Weeks 9–12 Erenumab STRIVE3 Months 4–6 Monthly Migraine Days EVOLVE-14 Months 1–6 Galcanezumab EVOLVE-25 Months 1–6 Eptinezumab PROMISE-16 Months 1–6 CHRONIC Study Primary Endpoint Time Frame MIGRAINE Headache Days Fremanezumab HALO7 (at least moderate severity) Months 1–3 8 Erenumab Phase 2 (erenumab from Galcanezumab REGAIN9 Monthly Migraine Days 9-12 week analysis) Eptinezumab PROMISE-210

1.Dodick DW et al. JAMA 2018;319:1999–2008. 2. Dodick DW et al. Cephalalgia 2018; doi:10.1177/0333102418759786. 3. Goadsby PJ et al. N Engl J Med 2017;377:2123–2132. 4. Stauffer VL et al. JAMA Neurol 2018; doi:10.1001/jamaneurol.2018.1212. 5. Skljarevski V et al. Cephalalgia 2018; doi: 10.1177/0333102418779543. 6. Silberstein S et al. Poster PF108LB presented at the American Headache Society meeting, San Francisco, CA; June 28–July 1, 2018. 7. Silberstein SD et al. N Engl J Med 2017;377:2113–2122. 8. Tepper S et al. Lancet Neurol 2017; 16: 425–434. 9. Detke H et al. Poster PS89LB presented at the American Headache Society meeting, Boston, MA; June 8–11, 2017. 10. Winner P et al. Presentation IOR03 presented at the American Headache Society meeting, San Francisco, CA; June 28–July 1, 2018. EM Secondary Endpoints

Fremanezumab Erenumab Galcanezumab Eptinezumab STRIV EVOLVE HALO EM1 ARISE2 EVOLVE-14 PROMISE-16 E3 -25 Mean change in monthly migraine days at Wk 4 ✓ ≥50% reduction in migraine days ✓ ✓ ✓ ✓ ✓ ✓ ≥50% reduction in migraine days at Wk 4 ✓ ≥75% reduction in migraine days ✓ ✓ ✓ ≥75% reduction in migraine days at Wk 4 ✓ 100% reduction in migraine days ✓ ✓ ✓ 100% reduction in migraine days at Wk 4 ✓ Acute headache medication days ✓ ✓ ✓ ✓ ✓ MIDAS ✓ ✓ ✓ MSQoL ✓ ✓ MPFID ✓ ✓ PGI-S ✓ ✓ Headache hours ✓ ✓ ADAs ✓ ✓ Other safety measures (laboratory, ECG, ✓ adverse events)

ADAs, anti-drug antibodies; ECG, electrocardiogram; MIDAS, Migraine Disability Assessment; MPFID, Migraine Physical Function Impact Diary; MSQoL, Migraine-Specific Quality of Life; PGI-S, Patient Global Impression-Severity. CM Secondary Endpoints vs Competitors

Fremanezumab Erenumab Galcanezumab Eptinezumab

HALO CM1 Phase 22 REGAIN3 Phase 24 Headache days (at least moderate severity) at Week 4 ✓ ≥50% reduction in migraine days ✓ ✓ ✓ ✓ ≥50% reduction in migraine days at Week 4 ✓ ≥75% reduction in migraine days ✓ ✓ ≥75% reduction in migraine days at Week 4 ✓ 100% reduction in migraine days ✓ ✓ 100% reduction in migraine days at Week 4 ✓ Acute headache medication days ✓ ✓ ✓ HIT-6 ✓ MSQoL ✓ PGI-S ✓ Headache hours ✓ ✓ ADAs ✓ Other safety measures (laboratory, ECG, adverse events) ✓ ADAs, anti-drug antibodies; ECG, electrocardiogram; HIT-6, Headache Impact Test; MSQoL, Migraine-Specific Quality of Life; PGI-S, Patient Global Impression-Severity. Migraine Disability Assessment (MIDAS)1,2

– MIDAS is a validated questionnaire designed to evaluate migraine-related disability over the previous 3 months – MIDAS contains five patient-reported items that quantify the number of days, over the last 3 months, with reduced performance of: – Work or school – Household work – Family, social, and leisure activities – Higher scores indicate greater disability MCID has not been reported

MCID, minimum clinically important difference; MIDAS, Migraine Disability Assessment.

1. Peng K-P, Wang S-J. Acta Anaesthesiologica Taiwanica 2012;50:69–73. 2. Blumenfeld AM et al. Cephalalgia 2011;31:301–315. Utility of MIDAS in Episodic Migraine1,2

MIDAS scoring allows for stratification of patients at the low range of disability scores 0–5 points Grade I Little or no disability 6–10 points Grade II Mild disability 11–20 points Grade III Moderate disability >21 Grade IV Severe disability

▪ This severity banding works well for EM patients, who have lower levels of disability and lower mean scores than patients with CM ▪ A very high proportion of CM patients fall within the Grade IV (severe) band; therefore, this stratification is not sensitive enough to categorize the disability of CM patients

CM, chronic migraine; EM, episodic migraine; MIDAS, Migraine Disability Assessment.

1. Blumenfeld AM et al. Cephalalgia 2011;31:301–315. 2. Yang M et al. Cephalalgia 2011;31:357–367. Headache Impact Test (HIT-6)

▪ The HIT-6 is a validated instrument for measuring headache-related disability1,2 ▪ HIT-6 is composed of six items assessing, over the previous month, the impact of headache on several HRQoL domains:1–3

– Pain (headache severity) – Vitality (fatigue and desire to lie down) – Social functioning – Cognitive functioning (concentration) – Role functioning (including work, school, and – Psychological distress (irritability) household work) ≤49 Little or no impact 50–55 Some impact MCID has been reported to be 56–59 Substantial impact 2.3 points1,2 ≥60 Severe impact

Scores range from 36–78, with larger scores indicating greater impact:1,2 HRQoL, health-related quality of life, MCID, minimum clinically important difference.

1. Rendas-Baum R et al. Health Qual Life Outcomes 2014;12:117. 2. Peng K-P, Wang S-J. Acta Anaesthesiologica Taiwanica 2012;50:69–73. 3. Yang M et al. Cephalalgia 2011;31:357–367. Comparison of Analysis Periods for Primary Endpoints in Phase 3 Trials

Teva: Fremanezumab Amgen & Novartis: Erenumab

HALO EM 3 months ARISE EM 2 months 1 month

HALO CM 3 months STRIVE EM 3 months 3 months CM phase 2 analyzed last month ( week 9-12)

Eli Lilly: Galcanezumab Alder: Eptinezumab

EVOLVE-1 and 6 months EVOLVE-2 EM 6 months PROMISE-1 EM REGAIN CM 3 months PROMISE-2 CM 3 months

EHF guidelines mAbs EHF Guidelines mAbs

▪ CGRP mAbs are promising migraine prevention drugs:

Eptinezumab Erenumab Fremanezumab Galcanezumab Quarterly Monthly Monthly Monthly Quarterly Monthly Monthly (1000 mg) (70 mg) (140 mg) (225 mg) (675 mg) (120 mg)† (240 mg) Episodic Quality of Low High Medium High Medium Medium Medium migraine evidence Recommendation Weak Strong Strong Strong Strong Strong Strong ? Chronic Quality of - Medium Medium High* Medium Medium Medium migraine evidence Recommendation - Strong Strong Strong* Strong Strong Strong

▪ Symbols depict the strength of recommendation according to the GRADE system ▪ EHF guidelines will be updated based on real-world data reflecting the use of those drugs from clinical practice *With 675 mg loading dose †With 240 mg loading dose CGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies Recommendation for mabs in Prevention of EM & CM Headache 2019;59:1-18 Continuation of CGRP Ab

Headache 2019;59:1-18 Immunogenicity (EM)

Study ADAs NAbs • 4 (0.5%) patients developed ADAs Fremanezumab HALO1 • 1.4% in the fremanezumab monthly group • One patient developed NAbs at wk • 4.3% of erenumab-treated patients ARISE2 developed ADAs 4, but tested negative at each subsequent time point Erenumab • 5.6% of patients developed ADAs • One patient in 70 mg group STRIVE3 • 8% in the 70 mg group • 3.2% in the 140 mg group developed NAbs • 3% of patients developed ADAs • 3.5% in the 120 mg group • All but one of the ADA-positive EVOLVE-14 • 5.2% in the 240 mg group patients developed NAbs • 1.7% in the placebo group Galcanezumab • 3.5% of patients developed ADAs • 8.6% in the 120 mg group • 29 of the ADA-positive patients EVOLVE-25 • 5.1% in the 240 mg group developed NAbs • 0.5% in the placebo group Eptinezumab PROMISE-1 Data not available Data not available ADA, anti-drug antibody; EM, episodic migraine; NAb, neutralizing antibody

1.Dodick DW et al. JAMA 2018;319:1999–2008. 2. Dodick DW et al. Cephalalgia 2018; doi:10.1177/0333102418759786; 3. Goadsby PJ et al. N Engl J Med 2017;377:2123–2132. 4. Stauffer VL et al. JAMA Neurol 2018; doi:10.1001/jamaneurol.2018.1212. 5. Skljarevski V et al. Cephalalgia 2018; doi: 10.1177/0333102418779543. Immunogenicity (CM)

Study ADAs NAbs • 2 (0.2%) patients developed 1 ADAs Fremanezumab HALO • 0.5% in the fremanezumab quarterly group • 2.1% of patients developed ADAs 2 No NAbs were observed at any time Erenumab Phase 2 • 5.8% in the 70 mg group • 1.6% in the 140 mg group Galcanezumab REGAIN No info available Eptinezumab PROMISE-2 No info available

ADA, anti-drug antibody; CM, chronic migraine; NAb, neutralizing antibody

1. Silberstein SD et al. N Engl J Med 2017;377:2113–2122. 2. Tepper S et al. Lancet Neurol 2017; 16:425–434. Fremanezumab

Erenumab

Galcanezumab

Eptinezumab