Migraine Diagnosis and Treatment. Merle Diamond, MD President, Managing Director, Diamond Headache Clinic Chicago, Illinois

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2 Migraine Diagnosis and Treatment Merle Diamond, MD President, Managing Director, Diamond Headache Clinic Chicago, Illinois

3 Disclosure: Merle L. Diamond, MD Consultant Advisory Boards Speaker Bureau Alder BioPharmaceuticals Allergan Amgen Depomed Lilly Supernus Pharmaceuticals Avanir Pharmaceuticals Lilly Pernix Therapeutics Avanir Pharmaceuticals Depomed Pernix Therapeutics Teva Pharmaceutical Industries 3

4 Background Treatment guidelines recommend preventive treatments for people with frequent and disabling headaches Only one-third of people with migraine who meet guidelines for preventive treatments receive them1 Of those who start preventive treatment, 80% lapse over the course of 1 year2 Why aren t preventive treatments being more widely utilized? How can we optimize the appropriate use of preventive treatments? 1. Blumenfeld AM, et al. Cephalalgia. 2011;31(3): Hepp Z, et al. Cephalalgia. 2015;35(6):

5 Migraine Is a Global Problem 30 to 39 years3 Affects >10% of population (959 million globally)1 Prevalence peaks in middle life during prime years3 >44 million individuals ~20% to 35% of people with migraine have 4 days per month3 affected in the United States2 2 to 3x more common in women vs men5-7 Global prevalence4 Lifetime prevalence % 6-8% 43% 18% 1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2016;388(10053): GBD Results Tool. GBD 2015 Data Resources. Accessed March 28, Lipton RB, et al. Neurology. 2007;68(5): Russo AF. Annu Rev Pharmacol Toxicol. 2015;55: Gasparini CF, et al. Curr Genomics. 2013;14(5): Marketscan data on file; March 24, Silberstein SD. Continuum (Minneap Minn). 2015;21(4 Headache):

6 Migraine Frequency Exists on a Spectrum Frequency of Headache Days in Migraine (N=8281)1 Traditional criteria for preventive treatment are defined in part by headache days 60 Episodic % of Patients One-third of people with migraine have headache on 4 days per month, and 6% have headache on 15 or more days per month1 40 Chronic <15 headache days per month can be classified as episodic migraine2 15 headache days per month for >3 months can be classified as chronic migraine Headache Days per Month 1. Blumenfeld AM, et al. Cephalalgia. 2011;31(3): Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):

7 Migraine Frequency Is Dynamic Frequency of Headache Days in Migraine (N=8281)1 Migraine can also transition from chronic to episodic2 60 Episodic Chronic 50 3% over 1 year % of Patients Migraine frequency can increase over time and may transition from episodic to chronic, a process termed chronification % over 2 years Headache Days per Month 1. Blumenfeld AM, et al. Cephalalgia. 2011;31(3): Bigal ME, Lipton RB. Headache. 2008;48(1): Manack A, et al. Neurology. 2011;76(8):

8 Migraine Is Usually Associated With Severe Impairment or Need for Bed Rest Migraine-related impairment was common in the American Migraine Prevalence and Prevention (AMPP) study of >18,000 individuals with migraine.1 Respondents were asked how they are usually affected by severe headaches with the following response options:2 Able to work/function normally Working ability or activity impaired to some degree Working ability or activity severely impaired Severe Impairment or Bed Rest Required Some Impairment 39% 54% Function Normally 7% Bed rest required 1. Lipton RB, et al. Neurology. 2007;68(5): Buse DC, et al. Headache. 2013;53(8):

9 Disability Increases Progressively With Increasing Number of Headache Days International Burden of Migraine Study (N=8281) <15 headache days/month (n=7812) 15 headache days/month (n=469) 100 Level of disability based on Migraine Disability Assessment (MIDAS) score 90 % of Patients 80 Little or no disability (score 0-5) 70 Mild disability (score 6-10) 60 Moderate disability (score 11-20) 50 Severe disability (score 21-40) 40 Very severe disability (score ) Headache Frequency (Days per Month) Blumenfeld AM, et al. Cephalalgia. 2011;31(3):

10 What Can We Offer This Patient? Abortive Medical Toolbox Real case.

11 NSAIDs (nonsteroidal anti-inflammatory drugs) Block cyclooxygenase (COX) enzymes Reduce prostaglandins 1899 (introduced in)

12 1926 (introduced in) Ergots 5-HT 1B/1D agonist Prolonged interaction with 5-HT 1A, 5-HT 5, 5-HT 2, 5-HT 7, α-adrenoceptors, and dopamine (DA) D2 receptors

13 Triptans 5-HT 1B/1D agonist 5-HT 2A receptors in peripheral arteries 1992 (FDA approval)

14 2008 (FDA approval) Triptan/NSAID 5-HT 1B/1D agonist + NSAID

15 Recent (FDA approval) Neuromodulatory devices Transcranial magnetic stimulation (stms, eneura) Supraorbital external trigeminal nerve stimulation (TENS, Cefaly) Noninvasive vagus nerve stimulator (nvns, gammacore)

16 Consider Prevention When Significant Interference With routine activities despite use of acute treatment Elevated Risk Medication overuse Uncommon Subtypes Present Hemiplegic Brainstem Prolonged aura Migrainous infarction Attack Frequency > 1/week Acute Medications Ineffective Contraindicated Troublesome AEs Overused Patient Preference 16

17 Migraine Prevention Is Underused The AMPP study surveyed 18,968 individuals with migraine and found that ~39% ~29% ~12% were candidates for or should be considered for prophylactic treatment1 had received prophylactic medication for migraine in the past but discontinued treatment2 were current users of prophylactic medication for the treatment of migraine1 Data from the AMPP study suggest that approximately two-thirds of individuals with migraine who qualify for prophylaxis do not receive it2 1. Lipton RB, et al. Neurology. 2007;68(5): Diamond S, et al. Headache. 2007;47(3):

18 Adherence to Current Migraine Preventives Is Poor Retrospective Claims Database Analysis: Insured Patients With Migraine and 15 Headache Days/Month (N=8688)* % of people with migraine discontinue preventive treatment over 1 year % of Patients Adherent to Oral Prophylaxis Months 12 Months *Oral prophylactic medications analyzed in this retrospective study were limited to specific antidepressants, β-blockers, and anticonvulsants. Adherence rates were reported as the proportion of patients with a proportion of days covered 80%. Hepp Z, et al. Cephalalgia. 2015;35(6):

19 Reasons Patients Discontinue Prophylactic Medication International Burden of Migraine Study-II Assessed Prophylactic Therapy Patterns in 1165 Patients With Migraine % of Patients Patient-Reported Reasons for Discontinuation of Prophylactic Medication Antidepressants (n=205) Antiepileptics (n=125) Beta blockers (n=120) Calcium channel blockers (n=59) Satisfactory Resolution Lack of Efficacy Side Effects Cost Other Lack of efficacy and medication side effects are the most common reasons for discontinuation of prophylactic medications Blumenfeld AM, et al. Headache. 2013;53(4):

20 Defining Success in Migraine Prevention 1. Standard definition of success is a 50% headache response rate (50% reduction in migraine days from baseline to weeks 9 to 12 or later). 2. This definition is predicated on the art of the possible or on what available treatments deliver. 3. Patients would prefer greater reductions in migraine days that would be achieved more quickly. 4. High discontinuation rates on current therapies may reflect unmet and inadequately managed patient expectations. 20

21 What Can We Offer This Patient? Preventive Medical Toolbox Real case.

22 (FDA approval) Tricyclic antidepressants Increase levels of norepinephrine (NE) and 5-HT Block histaminic, cholinergic, and α1-adrenergic receptor sites mid- 1960s (case reports showing benefit)

23 1979 (FDA approval) Beta blockers Noradrenergic receptor antagonists

24 Antiepileptics Enhance gamma-aminobutyric acid (GABAergic) inhibitory neurotransmission Decrease glutamatergic excitatory neurotransmission 1996 (FDA approval)

25 2010 (FDA approval) OnabotulinumtoxinA Block acetylcholine release May act in part through blocking CGRP release

26 Neuromodulatory devices Supraorbital external trigeminal nerve stimulation (TENS, Cefaly) Transcranial magnetic stimulation (stms, eneura) Caloric vestibular stimulation (CVS, Scion NeuroStim) Recent (FDA approval)

27 2018 (FDA approval) anti-cgrp MAB therapy Targets the CGRP receptor

28 Addressing the Unmet Need in Preventive Treatment Approximately 80% of patients discontinue oral preventive therapy after 1 year of treatment1 80% More than 40% of patients receiving therapy still experience at least one migraine-related issue, including headache-related disability, treatment dissatisfaction, and/or excessive opioid use2 Up to 13% of patients with migraine receiving acute or preventive therapy still have at least 1 emergency department visit a year3 1. Hepp Z, et al. Cephalalgia. 2015;35(6): Lipton RB, et al. Headache. 2013;53(8): Bonafede M, et al. J Manag Care Spec Pharm. 2015;21(suppl10):S48-S49. 40% 13% 28

29 All Approved Oral Drugs Share Similar Efficacy to Prevent Migraine 215 publications of RCTs provided mostly low-strength evidence because of the risk of bias and imprecision Approved Drugs Off-Label Drugs Topiramate (9 RCTs) Metoprolol (4 RCTs) Captopril (1 RCT) Divalproex (3 RCTs) Atenolol (1 RCT) Lisinopril (1 RCT) Timolol (3 RCTs) Nadolol (1 RCT) Candesartan (2 RCTs) Propranolol (4 RCTs) Topiramate and antidepressants result in more adverse events No significant differences in treatment discontinuation due to adverse events between labeled drugs Angiotensin-converting enzyme inhibitors and beta blockers most tolerable and effective Long-term evidence is lacking (>3-month duration) RCTs=randomized, controlled trials. Shamliyan T. J Gen Int Med. 2013;28(9):

30 Communication Establish goals Headache toolbox Check in Calendar/diary 30

31 Q & A 31

32 New and Emerging Headache Therapies Stewart J. Tepper, MD Director, Dartmouth Headache Center Professor of Neurology, Geisel School of Medicine at Dartmouth Lebanon, New Hampshire

33 Disclosures Stewart J. Tepper, MD Alder BioPharmaceuticals Allergan Amgen ATI Dr. Reddy s Acorda Therapeutics Alder Alexsa BioPharmaceuticals Allergan Alexsa Alphasights Amgen ATI Axsome Therapeutics Cefaly Charleston Laboratories DeepBench Stock Options ATI Royalties Springer Salary Dartmouth-Hitchcock Medical Center American Headache Society Grants/Research Support (No Personal Compensation) Consultant/ Advisory Boards ElectroCore eneura Scion NeuroStim Teva Pharmaceutical Industries Zosano Pharma Dr. Reddy s ElectroCore Lilly eneura GLG Guidepoint Global Magellan Rx Management Neurolief Nordic BioTech Pfizer Scion NeuroStim Slingshot Insights Supernus Pharmaceuticals Teva Pharmaceutical Industries Zosano Pharma 33

34 New Horizons in Headache Treatment! 34

35 Overview New formulations of existing medications, FDA-approved and in development Pathophysiology leads to pharmacology and neuromodulation: translational research made real New classes of acute medication in development Gepants, serotonin (5-HT1F) agonists [ditans] New classes of preventive medication in development Anti-calcitonin gene-related peptide (CGRP) or anti-cgrp receptor monoclonal antibodies (MABs) Neuromodulation Noninvasive, FDA approved: Transcutaneous supraorbital neurostimulation (tsns), single pulse transcranial magnetic stimulation (stms), non-invasive vagal nerve stimulation (nvns), and caloric vestibular stimulation (CVS) Noninvasive in development: Remote nonpainful electrical upper arm skin stimulation and combined occipital and supraorbital transcutaneous nerve stimulation (OS-TNS) Minimally invasive in development: Sphenopalatine ganglion stimulation (SPG) 35

36 Pathophysiology and Neurotransmitter Targets 36

37 Pathophysiology Peripheral pain mechanisms: CGRP, pituitary adenylate cyclaseactivating polypeptide (PACAP) Dura Pain perception Sensitized peripheral neuron (trigeminal ganglion) Cutaneous allodynia Throbbing pain Meningeal blood vessel Activated central neuron (thalamus) Central generator? Pain processing: Sensitized central neuron (trigeminal cervical complex) Neck muscle tenderness Tepper SJ. Adapted from C79, Comprehensive Migraine Education Program 1 presented at AAN 2017; Boston. 37

38 New Devices for Delivering Medications 38

39 Devices for Delivering Medications FDA-approved and available1 Sumatriptan autoinjectors (Sun Pharma, Dr. Reddy s, Zembrace) Sumatriptan breath-powered dry nasal powder (ONZETRA Xsail) In development2 Phase 3 RCTs completed Zolmitriptan skin patch (ADAM) DFN-02 sumatriptan nasal spray In development New Acute Treatment Classes Oxytocin nasal spray, T1-001 Sumatriptan skin patch (Sofusa platform), KC5010 Zolmitriptan oral inhalation, CVT-427 Sumatriptan oral spray, SUD-001 DHE HFA nasal spray, powder nasal spray, novel autoinjectors RCT=randomized, controlled trial Accessed June 11, Accessed June 11,

40 New Acute Treatment Classes 40

41 Serotonin (5-HT) Mechanisms in Migraine Anti-migraine targets: 5-HT1B/1D receptors 5-HT1F receptors 5-HT1F 5-HT1B 5-HT1D 5-HT1D (CGRP) Adapted from Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl3):S12-S19. 41

42 Lasmiditan: A 5-HT 1F Agonist (ditan) 42

43 Data From 2 Phase 3 Lasmiditan Trials for Acute Treatment of Episodic Migraine 2-Hour Pain Freedom: 100 mg % 200 mg % Placebo- 15.3%-21.3% For comparison, rizatriptan 10 mg prescribing information: Dizziness 20% greater than lasmiditan Somnolence + fatigue 15% greater than lasmiditan Both doses also eliminated the Most Bothersome Symptom Conclusions for lasmiditan acute treatment: (MBS), chosen by the patient from nausea, photophobia, Efficacy and side effects similar to rizatriptan or phonophobia at 2 hours Central adverse events probably due to central 5-HT1F activity and likely no Adverse events in the Phase 3 RCTs: vasoconstrictive effects Dizziness + vertigo =100 mg average 15.5% 200 mg average 16.8% Somnolence + fatigue + lethargy =100 mg average 10.4% 200 mg average 12% 1. Kuca B, et al. Presented at Diamond Headache Clinic Research & Educational Foundation Headache Update 2017; Lake Buena Vista, FL. 2. Wietecha LA, et al. Abstract PO presented at IHC 2017; Vancouver. 43

44 Gepants: Small-Molecule CGRP Receptor Antagonists 44

45 CGRP Neuropeptide belonging to calcitonin family Calcitonin Amylin Adrenomedullin Intermedin Present at all migraine pathogenesis sites Increases in migraine, decreases with treatment CGRP receptors Cortex RAMP1 CGRP CLR adenylyl cyclase RCP camp Gs camp=cyclic adenosine monophosphate. CLR=calcitonin receptor-like receptor. NS=nervous system. RAMP=receptor activity modifying protein. RCP=receptor component protein. 1. Naot D, Cornish J. Bone. 2008;43(5): Benarroch EE. Neurology. 2011;77:

46 Gepants Are Small Molecule CGRP Receptor Antagonists: They Have Never Failed on Efficacy Acute Treatment of Episodic Migraine 6 gepants effective in acute migraine treatment: olcegepant, BI TA, telcagepant, MK-3207, rimegepant, and ubrogepant BI TA, telcagepant, and MK-3207 all reportedly liver toxic Efficacy: Ubrogepant Phase 3 acute treatment of episodic migraine: 2-hour pain freedom: 50 mg 19.2%; 100 mg 21.2%; placebo 11.8%; Also relieved 2-hour MBS Conclusions for gepants acute treatment: Efficacy and side effects similar to naratriptan Tolerability is excellent Liver safety will still need to be explored Prevents vasodilation; no expectation of vasoconstriction Efficacy: Rimegepant Phase 3 acute treatment of episodic migraine: 2-hour pain freedom: 75 mg %; placebo 12%-14.2%; also relieved 2-hour MBS Adverse events 1. Liver, Ubrogepant: 6 cases with ALT >3x ULN, one of which was 10X ULN; 1 case with placebo >3x ULN; Rimegepant: one case each from active and placebo with >3x ULN 2. Tolerability, Ubrogepant: nausea, somnolence, dry mouth in <5% of patients; Rimegepant: nausea in <2% of patients Preventive Treatment of Episodic Migraine Telcagepant had liver toxicity when given daily Atogepant vs placebo positive phase 2 for migraine prevention, no liver signal; Rimegepant to be tested 1. Tfelt-Hansen P. Headache. 2011;51: Tfelt-Hansen P, Do TP. Abstract PO presented at IHC 2017; Vancouver. 3. Allergan press release. February 6, Accessed April 26, Biohaven press release. March 26, Accessed April 26, Accessed June 13,

47 Prevention: MABs 47

48 The New England Journal of Medicine November 30,

49 MABs to CGRP or the CGRP Receptor for Migraine Prevention How will they be different than what we have now? MABs are big molecules that do not cross the blood brain barrier1,2 MABs are eliminated by the reticuloendothelial system, so no risk for hepatotoxicity, as long as the gepant liver problem was metabolic degradation and not mechanism-based so far, MABs are safe1 Because they work, it means that peripheral, not central, CGRP action is sufficient to trigger migraine Will they be an improvement?3 All 4 Work to prevent episodic migraine, chronic migraine, and medication-overuse headache Have quick onset, separating from placebo within 1 week Show clinically meaningful response by 1 month Have favorable responder rates for 50% and higher Have safety and tolerability similar to placebo Decrease acute medication use days, and improve impact, disability, and/or quality of life 1. Yu YJ, Watts RJ. Neurotherapeutics. 2013;10(3): Lipton RB, et al. US Neurology. 2018;14(suppl 4):S3-S Tepper SJ. Headache. 2018;58:in press. 49

50 4 Injectable MABs to CGRP or Its Receptor in Development Terms: N=neurologic; umab=fully human; zumab=humanized, 90-95% human Erenumab-aooe (fully human) Galcanezumab (90% humanized) Fremanezumab (95% humanized) Eptinezumab (90% humanized) Studied for EM, CM EM, CM, ech, cch EM, CM, ech, cch EM, CM Dosing Monthly SC Monthly SC Monthly or quarterly SC; IV load for CH Q3 month IV Target CGRP receptor CGRP peptide or ligand CGRP peptide or ligand CGRP peptide or ligand FDA approved May 17, 2018; EM & CM registration studies fully published Submitted to FDA for migraine prevention; Presented (+) phase 3 EM & CM; One EM trial fully published; Announced (+) ech trial, (-) cch trial Submitted to FDA for migraine prevention; Both pivotal trials (EM & CM) fully published Announced (-) cch trial Presented (+) phase 3 EM & CM RCTs Regulatory status July 2018 cch=chronic cluster headache. CM=chronic migraine. ech=episodic cluster headache. EM=episodic migraine. SC=subcutaneous. RCT=randomized controlled trial. Tepper SJ. Headache. 2018;58:in press. 50

51 Clinical Utility of the 4 MABs All data announced to date for EM and CM have shown a reduction in mean monthly migraine days (MMDs) with a magnitude of 1-3 days drop over placebo, similar to the registration studies for onabotulinumtoxina Using MMDs is necessary from a regulatory standpoint However, MMDs are not a useful clinical endpoint for estimating value, as the clinical effect is underestimated due to inclusion of placebo More useful is the drop from baseline and the secondary endpoints, such as responder rates Erenumab in CM prevention showed a 6.7-day reduction in MMDs in the pivotal trial, which would represent 79 fewer migraine days/year1; for eptinezumab, an 8-day reduction from baseline would be 96 fewer migraine days per year The 50% responder rates (secondary endpoints) in the galcanezumab EM registration studies were 50%, in the eptinezumab CM study 61%, and the 75% responder rates for both were about 1/3 of patients2,3 Erenumab 140 mg worked in patients who had failed 2-4 preventive medications in a prospective randomized placebo-controlled trial4 1. Tepper SJ, et al. Lancet Neurol. 2017;16: Oakes TM, et al. Abstract PS-19 presented at AHS 2017; Boston. 3. Alder press release. Jan 8, Accessed April 27, Goadsby P et al. Poster IOR08. Headache 2018;;58(Supplement 2):77 (presented at American Headache Society 60th Scientific meeting 2018 ;San Francisco. 51

52 How Are They Given? Erenumab and galcanezumab: Self-inject monthly Fremanezumab: Self-inject monthly or every 3 months Eptinezumab: Receive an IV infusion every 3 months Autoinjector Used for erenumab, etanercept for rheumatoid arthritis, and one of the generic sumatriptans. 52

53 How Could This Change the Future? Situation Before MABs Current preventive medications Were designed for other therapeutic areas Have numerous adverse events Take 2-4 months to be effective Have 50% responder rates of <50% May lose effectiveness in medication overuse headache (MOH) MABs Potential Specificity: designed for primary migraine prevention Wide therapeutic targets: EM, CM, MOH, and ech Speed time to onset: <1 week to 1 month Tolerability: similar to placebo If current safety is confirmed, one could potentially use these specific preventive biologics first line Safety: no safety signal Improved responder rates, even at 75% or more Lower acute medication use The potential for this paradigm shift will depend on cost and access! Sometimes don t even lower acute medication use 53

54 Q & A 54

55 Neuromodulation FDA-approved In development 1 Transcutaneous supraorbital neurostimulation (tsns, e-tns, Cefaly) 2 Single Pulse Transcranial Magnetic Stimulator (stms, SpringTMS) 3 Noninvasive vagal nerve stimulator (nvns, gammacore) 4 Noninvasive caloric vestibular stimulation (CVS, Scion NeuroStim) 5 Remote, nonpainful stimulation for acute treatment of migraine (Nerivio Migra) 6 Combined occipital and supraorbital transcutaneous nerve stimulation (OS-TNS, Relievion) 7 Sphenopalatine ganglion stimulation (SPGs, Pulsante) 55

56 Transcutaneous Supraorbital Neurostimulation for Acute and Preventive Treatment of Migraine (tsns, e-tns, Cefaly) Preventive RCT: Turn it on and wear it 20 minutes/day; N=67 Acute RCT: turn on in different setting for acute attack for 1 hour; N=57 Migraine days/month in third month: not significant Mean change in visual analog (VAS) 1-hour pain score reported as statistically significant in active vs placebo 50% reduction in migraine days/month, 38.2% vs sham (P=0.023) FDA approved in 2017 for preventive and acute treatment of migraine as nonsignificant risk device Cost: $550 (initial) Change in HA days (NS) P= Active Sham Cost: $25 (3 electrodes every 3 months) % Responder Rates P= Active Sham HA=headache. NS=non-significant 1. Schoenen J, et al. Neurology. 2013;80; Tepper D. Headache. 2014;54(8): Chou DE, et al. Abstract OC-LB-005 presented at IHC 2017; Vancouver. 56

57 Single Pulse Transcranial Magnetic Stimulation (stms, SpringTMS) Magnetic pulses disrupt cortical spreading depression (CSD), the basis for aura, and down-regulate thalamocortical pain pathways 1 RCT for acute treatment of migraine with aura, N=167 2 hours pain-free: 39% stms vs 22% sham (P=0.0179) 2 studies for prevention of migraine with prn extra pulses, N= headache days for inclusion; 4 pulses BID with extra prn up to 17 pulses per day FDA-approved in 2017 as nonsignificant risk device for preventive and acute treatment of migraine Rental cost $225/month 1. Andreou AP, et al. Brain. 2016;139: Lipton RB, et al. Lancet Neurol. 2010;9: Bhola R, et al. J Headache and Pain. 2015;16: Starling A, et al. Abstract S presented at AAN 2017; Boston. 57

58 Noninvasive Vagal Nerve Stimulator (nvns, gammacore) Handheld, patient-controlled device, which preferentially activates afferent A and large B fibers, not C or efferent pathways that mediate bradycardia and bronchoconstriction1 Inhibits CSD2 and central trigeminovascular and thalamocortical pathways3,4 2 RCTs showed effectiveness in terminating attacks of episodic cluster headache, but not chronic cluster headache5,6 2 RCTs failed primary endpoints in prevention and acute treatment of migraine, but showed suggestive secondary endpoints7,8 FDA-approved as nonsignificant risk device for acute treatment of episodic cluster headache attacks and acute treatment of migraine $575/month for loaded stimulation package 1. Mourdoukoutas AP, et al. Neuromodulation. 2018;21(3): Chen SP, et al. Pain. 2016;157: Hawkins JL, et al. Presented AAN 2016; Vancouver. 4. Akerman S, et al. Neurobiol Dis. 2017;102: Silberstein SD, et al. Headache. 2016;56: Goadsby PJ, et al. Presented at Clinical Trials Plenary Session, AAN 2017; Boston. 7. Silberstein SD, et al. Neurology. 2016;87: Tassorelli C, et al. Abstract OC-LB-002 presented at IHS 2017; Vancouver. 58

59 Caloric Vestibular Stimulation (CVS, Scion NeuroStim) Prevention RCT: Significantly Migraine Frequency 6-site, placebo-controlled, blinded, home-use protocol 4-14 HA days/month 1 endpoint: migraine d, 3rd month Per protocol: active (n=28); placebo (n=18) Active: -3.6 HA days vs baseline (P <0.0001) Active vs sham: -2.7 HA days (P=0.012) 2 endpoints also positive Approved by FDA in March 2018 for prevention of EM ages 12 and above; not commercially available yet Wilkinson D, et al. Headache. 2017; 57: Trigeminocervical complex Normalized monthly migraine days (%) of baseline 2 : RR, acute meds, mood, cognition, balance ITT V, Neck VIII, Vestibulo-cochlear input AEs >1 patient: nausea, dizziness, ear sx, tinnitus. Placebo dizziness= Active dizziness (4 in each). 59

60 Remote Nonpainful Electrical Upper Arm Skin Stimulation for Acute Migraine Treatment (Nerivio Migra) Prospective, double-blinded, randomized, crossover, sham-controlled trial Migraineurs applied electrical patch to upper arm soon after attack onset for 20 minutes, at various pulse widths, for up to 20 attacks 50% pain reduction for 64% of participants based on best of 3-pulse width stimuli per individual vs 26% sham, N=71 patients, 299 treatments Second study underway in US 1. Yarnitsky D, et al. Neurology. 2017; 88(13): Nir RR, et al. Eur J Pain. 2011;15: Goadsby PJ. Ann Indian Acad Neurol. 2012;15(suppl1):S15-S22. 60

61 Combined Occipital and Supraorbital Transcutaneous Nerve Stimulation (OS-TNS, Relievion) Randomized, sham-controlled trial for acute treatment of migraine attack, N=30, treatment duration 45 minutes Decreased pain VAS score in the treatment group vs increased pain VAS score in the control group (-79.2% vs %, P=0.0002) 2-hour pain-free: active OS-TNS vs sham (P=0.0031) Hering-Hanit. Cephalalgia. 2017;37(suppl1):73. 61

62 Sphenopalatine Ganglion Stimulation (SPGs, Pulsante) The SPG is the final switching station for cluster and migraine The SPG is a wireless device with a minimally invasive oral procedure The device is powered by a programmable remote control 1 RCT showed efficacy for acute and preventive treatment of chronic cluster headache Around 2/3 of cluster patients have relief after stimulation within 15 minutes and/or at least a 50% reduction in cluster attack frequency The US randomized controlled trial for acute treatment of chronic cluster headache was announced as positive in 6/18 1. Edvinsson L, Goadsby PJ. Cephalalgia. 1994;14: Burstein R, Jakubowski M. J Comp Neurol. 2005;493: Schoenen J, et al. Cephalalgia. 2013;33: Jurgens TP, et al. Cephalalgia. 2017;37: Late Breaking Abstract, 60th Scientific American Headache Society meeting, San Francisco, June

63 Summary New formulations of existing medications, FDA-approved, and in development Pathophysiology leads to pharmacology and neuromodulation: translational research made real New classes of acute medication in development Gepants, serotonin (5-HT1F) agonists [ditans] New classes of preventive medication in development Anti-CGRP or CGRP receptor MABs Neuromodulation Noninvasive, FDA-approved: Transcutaneous supraorbital neurostimulation (tsns, e-tns, Cefaly), single pulse transcranial magnetic stimulation (stms, SpringTMS), noninvasive vagal nerve stimulation (nvns, gammacore), Caloric vestibular stimulation (CVS, Scion NeuroStim) Noninvasive, in development: Remote nonpainful stimulation (Nerivio Migra), combined occipital and supraorbital transcutaneous nerve stimulation (OS-TNS, Relievion) Minimally invasive, in development: Sphenopalatine ganglion stimulation (SPGs, Pulsante) 63

64 Q & A Session For valuable resources related to this activity, please visit forefrontcollabactivities.com /Diamond