Botulinum toxin in the treatment of chronic migraine. Gregory P. Hanes, MD Neuroscience Summit 5/14/15

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1 Botulinum toxin in the treatment of chronic migraine Gregory P. Hanes, MD Neuroscience Summit 5/14/15

2 Primary Headache Disorders: Frequency Classification After Secondary Causes Are Ruled Out Short-Duration Chronic Daily Headache Duration <4 Hours or Multiple Discrete Episodes Primary Headache Disorders Chronic Headache Frequency 15 Days/Month Episodic Headache Frequency <15 Days/Month Chronic Daily Headache (Long Duration) Daily or Near-daily Headache Lasting 4 Hours With or Without Medication Overuse 1. Silberstein SD et al. Neurology. 1996;47; Dodick DW. N Engl J Med. 2006;354:

3 Diagnostic Criteria for Chronic Migraine Chronic Migraine is a defined condition 1-3* 15 or more headache days per month Headaches lasting 4 hours per day or more At least 8 headache days that are linked to migraine 2,3 With or without medication overuse What are migraine characteristics 1*? Patients Should Experience at Least 2 of These Pain Characteristics: Unilateral Pulsating quality And at Least 1 of: Nausea and/or vomiting Photophobia and phonophobia Moderate to severe intensity Aggravated by routine physical activity * Multiple headache phenotypes are possible. 1,2 1. Headache Classification Committee. Cephalalgia. 2004;24(suppl 1): Headache Classification Committee; Olesen J et al. Cephalalgia. 2006;26: Lipton RB. Headache. 2011;51(S2):77-83.

4 2 Activation of Trigeminal Sensory Stimulation of meningeal sensory nerve (trigeminal) 1 Afferents Central disinhibition PAIN 6 Vessel dilation Inflammation Nerve Peptide release 3 Release of neuropeptides, CGRP Trigeminal Nerve Trigeminal Ganglion Spinothalamic track Thalamus TNC 5 Activation of cortical pain centers via thalamus 4 Activation of TNC can result in central sensitization CGRP = calcitonin gene-related peptide; TNC = trigeminal nucleus candalis. 1. Pietrobon D et al. Nat Rev Neurosci. 2003;4: Pietrobon D. Neuroscientist. 2005;11:

5 Prevalence of Chronic Migraine Chronic migraine is the most common form of chronic daily headache in headache specialty clinics 1 Approximately 2%* of the global population suffers from chronic migraine 2 Chronic migraine prevalence estimates are 2.5 to 6.5 times higher in women (1.7% 4.0%) than in men (0.6% 0.7%) 2 * According to broad criteria (migraine with 15 headache days/month). 1. Dodick D. N Engl J Med 2006;354: Natoli J et al. Cephalalgia. 2010;30(5):

6 Common Comorbidities with Significant Differences Between Episodic and Chronic Migraine * % * * * * 26 * * * * * 34 * (392) (5374) (296) (3926) (160) (1827) (126) (1370) (270) (2718) (206) (1599) (198) (1993) (221) (2951) (224) (2713) (167) (2223) (220) (2354) Allergies or Hay Fever Sinusitis Asthma Bronchitis Depression Chronic Pain Anxiety High Blood Pressure High Cholesterol Obesity Arthritis Chronic Migraine Episodic Migraine * p<0.05. Data from the American Migraine Prevalence and Prevention (AMPP) study. Buse D et al. J Neurol Neurosurg Psychiatry. 2010; 81(4):

7 Migraine Progression No Migraine Low-Frequency Episodic Migraine High-Frequency Episodic Migraine Chronic Migraine Progression is often gradual and can evolve over months or years 1,2 Transformation is neither inexorable nor irreversible; spontaneous or induced remissions are possible 1,2 Transformation happens in some but not all episodic patients (~3% of episodic migraine sufferers in 1 year, n=18,968) 2 1. Lipton RB. Neurology. 2009;72:S3-S7. 2. Bigal ME, Lipton RB. Curr Opin Neurology. 2008;21:

8 Severe Migraine is Ranked in the Highest Disability* Class by WHO 7 Severe Migraine Active Psychosis Dementia Quadriplegia Increasing Disability Below-the-Knee Amputation Deafness Mild Mental Retardation Down Syndrome Unipolar Major Depression Blindness Paraplegia 3 Disability Class 4 Disability Class 5 Disability Class 6 Disability Class 7 Menken M. Arch Neurol. 2000;57:

9 70% 60% Impact of Chronic Migraine on Daily Activities Over a 3-Month Period p<0.001 p< % 40% 30% 20% p<0.001 p< % p= % 5 Days of Missed Work or School 5 Days with Reduced Productivity at School or Work 5 Days of Missed Household Work 5 Days of Reduced Productivity at Houshold Work 5 Days of Missed Family Activities Chronic Migraine Episodic Migraine n= n= 8,542-9,135 Data from the American Prevalence and Prevention (AMPP) Study. Bigal ME et al. Neurology. 2008;71;

10 Treatment of Chronic Migraine Oral Medications Prophylactic medications Abortive Injections botulinum toxin Trigger point Occipital nerve blocks Facet Alternative Medicine Acupuncture Massage Heat/cold biofeedback

11 Oral Medications Abortive Triptans sumatriptan (Immitrex) rizatriptan (Maxalt) NSAIDS naproxen (Aleve) ibuprofen (Advil) Opiates Prophylactic BP meds B-blockers (propranolol) CCBs (verapamil) ACE/ARB (Avapro, Atacand) Anticonvulsants topiramate (Topamax) valproic acid (Depakote) Antidepressants fluoxetine (Prozac) duloxetine (Cymbalta) NSAIDS Natural supplements CoQ10, feverfew, Mg, butterbur

12 botulinum toxin Type A, Botox Only FDA-approved toxin for chronic migraine Blocks pre-synaptic acetylcholine release Weakens muscles by blocking NMJ Interrupts synaptic communication between nerves

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14 PREEMPT Study Design PREEMPT consisted of two phase 3 studies of CM patients Largest clinical program on CM sufferers (1384 patients) Global study across 122 sites in North America and Europe 24-week randomized, double-blind, placebo-controlled phase 32-week open-label phase Phone Interview Treatment Double-Blind Phase Open-Label Phase Baseline Randomization Primary Time Point Weeks -4 Day BOTOX vs. Placebo (saline) BOTOX vs. Placebo (saline) BOTOX BOTOX BOTOX Headache symptoms and medications were recorded in a daily telephone diary Dodick DW et al. Headache. 2010; 50(6): American Headache Society. Published by Wiley Periodicals, Inc. Reprinted by permission of John Wiley and Sons.

15 Dosing and Administration Supine Sitting C D E A F B G A) Corrugator: 5 U each side D) Temporalis: 20 U (each side) E) Occipitalis: 15U (each side) F) Cervical paraspinal: 10 U (each side) B) Procerus: 5 U (1 site) C) Frontalis: 10 U each side Allowed additional FTP* site of injection: 10 U (up to 2 sites) Allowed additional FTP site of injection: 10 U (up to 2 sites) G) Trapezius: 15 U (each side) Allowed additional FTP site of injection: 20 U (up to 4 sites) * FTP = Follow the Pain Dodick DW et al. Headache. 2010;50: Pictures by AlphaMedica for Allergan 2010

16 Injection Paradigm: Required Dose Using a Fixed-Site, Fixed-Dose Paradigm Order Muscle Number of Units (U) A Corrugator 10 (5 each side) B Procerus 5 C Frontalis 20 (10 each side) D Temporalis 40 (20 each side) E Occipitalis 30 (15 each side) F Cervical paraspinal 20 (10 each side) G Trapezius 30 (15 each side) Total number of units (U) 155 Dosing and results in these studies are specific to the formulation of BOTOX manufactured by Allergan, Inc. (Irvine, CA). The Allergan, Inc., formulation is not interchangeable with other botulinum toxin products and cannot be converted using a dose ratio. Blumenfeld Headache 2010;50:

17 Pooled Efficacy of BOTOX at Week 24 (Primary Time Point) Endpoint, Mean Change From Baseline BOTOX (n=688) Placebo (n=696) p Value Frequency of HA days <0.001 Frequency of migraine days <0.001 Frequency of moderate/severe HA days <0.001 Total cumulative HA hours on HA days <0.001 % Patients with severe ( 60) HIT-6 score <0.001 Total HIT-6 score <0.001 Frequency of HA episodes Frequency of migraine episodes Frequency of acute HA pain medication intake (all categories) Frequency of triptan use <0.001 BOTOX was statistically significantly more effective than placebo in reducing mean frequency of headache days at every visit in the double-blind phase starting at the first post-treatment study visit (Week 4) HA = headache; HIT = Headache Impact Test. Dodick DW et al. Headache. 2010; 50(6): American Headache Society. Published by Wiley Periodicals, Inc. Reprinted by permission of John Wiley and Sons.

18 PREEMPT Pooled Analysis Mean Change from Baseline in Cumulative Headache Hours on Headache Days Mean ± standard error. The double-blind phase included 688 subjects in the BOTOX group and 696 in the placebo group. Cumulative hours of headache at baseline: BOTOX group vs placebo group, p= Aurora SK, et al. Headache 2011; 51: American Headache Society. Published by Wiley Periodicals, Inc. Reprinted by permission of John Wiley and Sons.

19 PREEMPT Pooled Analysis Mean Change from Baseline in Total HIT-6 Scores Weeks BOTOX Change from Baseline in Total HIT-6 Score p<0.001 p<0.001 p<0.001 p<0.001 p< * p<0.001 p=0.002 Placebo p=0.002 p=0.022 p= Double-Blind Phase Open-Label Phase * Between-group difference exceeded the minimally important difference (MID) for HIT-6 (2.3 units) indicating a clinically significant effect of BOTOX treatment. 1 The double-blind phase included 688 subjects in the BOTOX group and 696 in the placebo group. Total HIT-6 scores at baseline: 65.5 BOTOX group vs placebo group; p= DB phase - Lipton RB et al. Neurology 2011;77(15): OL Phase - Data on file, Allergan, Inc.

20 PREEMPT: Summary of Adverse Events Pooled Data, Double-Blind Phase (%) BOTOX (n=687) Placebo (n=692) All adverse events (AEs)* Treatment-related AEs Serious AEs Treatment-related, serious AEs Discontinuations related to AEs Deaths *All AEs include all reported events, regardless of relationship to treatment. Treatment-related AEs are those that in the investigator s opinion may have been caused by the study medication with reasonable possibility. Migraine requiring hospitalization. The most frequently reported AEs leading to discontinuation in the BOTOX group were neck pain (0.6%), muscular weakness (0.4%), headache (0.4%), and migraine (0.4%). Dodick DW et al. Headache. 2010; 50(6): American Headache Society. Published by Wiley Periodicals, Inc. Reprinted by permission of John Wiley and Sons.

21 PREEMPT: Treatment-Related AEs Reported in 2% of Patients Pooled Data, Double-Blind Phase (%) BOTOX (n=687) Placebo (n=692) Total treatment-related AEs Neck pain Muscular weakness Eyelid ptosis Musculoskeletal pain Injection-site pain Headache Myalgia Musculoskeletal stiffness Most AEs were mild or moderate in severity and resolved without sequelae. Only neck pain and muscular weakness were reported in 5% of patients Dodick DW et al. Headache. 2010; 50(6): American Headache Society. Published by Wiley Periodicals, Inc. Reprinted by permission of John Wiley and Sons.

22 Botox vs Topamax Allergan-sponsored Randomized, prospective, phase 4 trial Open label 36 week study Topamax dropouts can roll into Botox arm at any point before 36 weeks

23 Summary Chronic migraine is a separately classifiable headache syndrome CM has very high associated disability Abortive and prophylactic treatment options Botulinum toxin injections (Botox) is a efficacious and well-tolerated prophylactic Ongoing studies of Botox vs topiramate