Disclosure. Learning Objectives 11/10/2017. The Best and Most Interesting Research from Last Year Cephalalgia

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1 The Best and Most Interesting Research from Last Year Cephalalgia David W. Dodick, M.D. Department of Neurology Mayo Clinic Scottsdale Arizona Disclosure Consulting services: Acorda, Allergan, Amgen, Alder, Promius, eneura, Eli Lilly & Company, Insys therapeutics, Autonomic Technologies, Teva, Xenon, Tonix, Trigemina, Nocira, Colucid, Zosano, Laydenburg Thalmann, Biocentric, Biohaven, Magellan, Charleston Laboratories. Royalties: Oxford University Press and Cambridge University Press (Book Royalty). Editorial/honoraria: UpToDate, Chameleon Communications, Medscape, WebMD, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, HealthLogix, Academy for Continued Healthcare Learning, MeetingLogiX, Wiley Blackwell, Oxford University Press, Cambridge University Press. Stock/options: Nocira, Epien, Healint, Theranica, and Mobile Health. Consulting use agreement: NAS. Board position: King-Devick, Epien. Learning Objectives At the conclusion of this presentation, participants should be better able to: Discuss the advances in the basic and clinical science of headache as published in Cephalalgia in 2017 Describe the translational implications of scientific advances and the clinical implications of the treatment advances in headache as published in Cephalalgia in 2017 Develop a patient-specific diagnostic plan based on differential diagnosis 1

2 432 pregnant women exposed to triptans in German Embryotox System Compared to a non-migraine cohort no increase in: major birth defects (OR adj 0.84; 95% CI ) Spontaneous abortions (OR adj 1.20; 95% CI ), preterm delivery (OR adj 1.01; 95% CI ), preeclampsia (OR adj 1.33; 95% CI ) Triptans are not major teratogens. Sumatriptan best studied triptan appears acceptable treatment option. A detailed fetal ultrasound should be offered in cases of first trimester exposure to less well-studied triptans. Trigeminal Autonomic Cephalalgias 2

3 LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. Increased parasympathetic outflow is not sufficient to induce CH attacks in patients. Activation of afferent or efferent arms of trigeminal-autonomic reflex is insufficient to trigger CH Brain drives CH Does not exclude therapeutic actions being either outside or inside CNS. Responder rate: 77% 3

4 100 patients (35 CM, 33 CCH, 20 SUNCT and 12 HC) Response rate of the cohort was 48%. Multivariate analysis: SUNCT (OR 6.71; 95% CI ; p 0.013) and prior response to GON block (OR 4.22; 95% CI ; p 0.013) were associated with increased likelihood of response. Presence of occipital pain (OR 0.27; 95% CI ; p 0.014) and the presence of severe anxiety and/or depression at time of implantation (OR 0.32; 95% CI ; p 0.032) were associated with reduced likelihood of response. 4

5 Research with promising translational implications 5

6 Migraine, Stroke and White Matter Hyperintense Lesions WMHs are more common in patients with migraine than in healthy controls. Increased aortic stiffness or central systolic blood pressure in the presence of low intracranial artery resistance may predispose patients with migraine to WMH formation 6

7 Headache/Migraine: Biomarkers and Natural History 7

8 Female sex, no overuse of pain medication and lower headache frequency were associated with remission. 8

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10 Cephalalgia Abstracts Presented at 2017 International Headache Congress Increased Odds of 50% Response in Patients With Prior Treatment Failure Achievement of 50% reduction in monthly migraine days from baseline Odds ratio Odds ratio Odds ratio Odds ratio 3.06 Odds ratio 2.89 Odds ratio 4.54 Overall population 1 prior treatment failures 2 prior treatment failures Goadsby et al. Cephalalgia 2017;37 A Randomized, Double-Blind, Placebo- Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients with Stable Angina Christophe Depre, 1 Lubomir Antalik, 2 Amaal Starling, 3 Michael Koren, 4 Osaro Eisele, 1 Yumi Kubo, 1 Robert A Lenz, 1 Daniel D Mikol 1 1 Amgen Inc., Thousand Oaks, CA, USA; 2 Regional Hospital, Cardiological Department, Slovakia; 3 Mayo Clinic, Scottsdale, AZ; 4 Jacksonville Center for Clinical Research, Jacksonville, FL 10

11 Multicenter, Randomized, Double-blind, Placebo-controlled Study ClinicalTrials.gov #NCT Key Inclusion Criteria History of ischemic heart disease History of chronic stable angina for 3 months prior to screening, with 1 angina episode/month, on average Primary endpoint Change from baseline in exercise duration as measured by TET Secondary endpoints Time to onset of 1 mm ST-segment depression Time to onset of exercise-induced angina during the ETT Mikol D, et al. IHC 2017, Vancouver Canada, Sept 2017 Erenumab in Patients with Cardiovascular Disease Placebo (N = 44) Erenumab 140 mg (N = 45) Age (years), median (Q1, Q3) 65.0 (58.5, 69.5) 64.0 (56.0, 70.0) Female, n (%) 11 (25) 9 (20) White, n (%) 37 (84) 43 (95) Cardiovascular history, n (%) Coronary artery disease (CAD) 44 (100) 45 (100) Myocardial infarction 20 (46) 16 (36) Coronary artery bypass 15 (34) 14 (31) Percutaneous coronary artery intervention 28 (64) 27 (60) Cerebrovascular or peripheral arterial disease 10 (23) 11 (24) Transient ischemic attack 2 (5) 2 (4) Cerebrovascular accident 2 (5) 1 (2) Carotid or vertebra-basilar artery disease 2 (5) 6 (13) Other cerebrovascular conditions 3 (7) 2 (4) Peripheral artery disease 5 (11) 4 (9) Data represent mean (SD) unless otherwise indicated. Randomization analyses set; all patients randomized. Mikol D, et al. IHC 2017, Vancouver Canada, Sept 2017 No Difference in Total Treadmill Exercise Time Time to Onset of 1 mm ST-segment Depression Mikol D, et al. IHC 2017, Vancouver Canada, Sept

12 Time to Onset of Exercise-induced Angina Mikol D, et al. IHC 2017, Vancouver Canada, Sept 2017 Summary of Adverse Events 12-week Follow Up Adverse events, n (%) Placebo (N = 44) Erenumab 140 mg (N = 44) Any 14 (32) 12 (27) Serious 1 (2) 0 (0) Leading to discontinuation of study drug 0 (0) 0 (0) Fatal 0 (0) 0 (0) Mikol D, et al. IHC 2017, Vancouver Canada, Sept 2017 Summary and Conclusion Erenumab did not adversely affect exercise capacity, a surrogate of underlying myocardial ischemia Compared to placebo: Change from baseline in total exercise time was non-inferior in the erenumab group No difference was observed in the time to onset of 1 mm STsegment depression No difference was observed in the time to onset of exercise-induced angina No difference in adverse events reported These results support that inhibition of the CGRP receptor does not aggravate myocardial ischemia in an at-risk population of patients with stable angina Mikol D, et al. IHC 2017, Vancouver Canada, Sept

13 Episodic Migraine & CGRP Monoclonal Antibodies: Phase 3 Results 50% responders (%) N = Dose: 100/300mg, iv 70/140mg, sc 70mg, sc 120/240mg, sc 120/240mg, sc 225/675mg, sc (1) (2) (3) (4) (5) (6) Statistically significant difference vs placebo 1. Saper et al. IHC 2017 poster 2. Goadsby et al. Headache 2017; 57 (Suppl 3): 128, abs IOR04 3. Dodick et al. Headache 2017; 57 (Suppl 3): 191, abs PS21 4. Stauffer et al. Headache 2017; Conley et al. Headache 2017; Aycardi et al. IHC 2017 Chronic Migraine and CGRP mabs Phase II/III Results Compared to Current Therapy 50% response migraine days N = Dose- 300mg, IV (1) 140mg, sc (2) 675//225mg 240mg, sc (4) PREEMPT (5) 100mg daily (6) (3) Statistically significant difference vs placebo 1. Baker et al. Headache 2017; 57: late breaking abstract 2. Tepper et al. Lancet Neurol : Aycardi et al. Headache 2017; 57: late breaking abstract 4. Detke et al. Headache 2017; 57: 5. Dodick et al. Headache 2010; 51: Silberstein et al. Headache 2009;46:1153 Lasmiditan in Acute Migraine SAMURAI: Aurora et al. Headache 2017; in press (late-breaking AHS abstract) SPARTAN: Wietecha et al. Cephalalgia 2017; 37: in press (late-breaking IHC abstract) Poster P Pain Free 2 hr Patients (%) N = N = Treatment- Emergent Adverse Events - Dizziness, paresthesia, and somnolence All doses significant vs placebo 13