Chronic Migraine. Pain BC Conference October 25, 2014

Chronic Migraine Pain BC Conference October 25, 2014 1

2 Advisory boards - Allergan Canada Supported speaker - Allergan Canada Financial interests - none

Learning objectives: 3 1. Understand the diagnosis of Chronic Migraine 2. Recognize the burden of illness associated with this condition 3. Describe the components of comprehensive Chronic Migraine management 4. Discuss future treatments for Chronic Migraine

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Headache Disorders ICHD-3 5 1. Migraine 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine

Headache Disorders ICHD-3 6 1. Migraine 1.1 Migraine without aura 1.2 Migraine with aura 1.3 Chronic migraine

7 Chronic migraine Recognition, diagnosis and burden of illness

Migraine progression 8 Transformation is often gradual and can evolve over several 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 No migraine Lowfrequency episodic migraine Highfrequency episodic migraine Chronic migraine 1. Lipton RB. Neurology. 2009;72:S3-S7. 2. Bigal ME, Lipton RB. Curr Opin Neurology 2008;21:301-308.

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Chronic migraine: current state of classification and diagnosis 11 ICHD-2R ± Medication Overuse Combined Criteria 2 Headache on 15 days per month for 3 months 1 5 prior migraine attacks 1 On 8 days per month, headache fulfills criteria for migraine 1 Has 2 of the following: a) unilateral b) throbbing c) moderate or severe d) aggravated by physical activity and 1 of the following: a) nausea and/or vomiting b) photophobia and phonophobia OR Treated or relieved with triptans or ergotamine Not attributed to another causative disorder Subclassified as with or without medication overuse 1,2 Simplified diagnosis* Diagnose chronic headache syndrome Diagnosis migraine With or without medication overuse *GMAP recommendation 1. Headache Classification Committee; Olesen J et al. Cephalalgia. 2006;26:742-746. 2. Silberstein SD et al; International Headache Society. Cephalalgia. 2005;25:460-465..

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Risk factors for migraine progression 14 Age Gender Not readily modifiable Low education/ socioeconomic status Head injury Modifiable Attack frequency Obesity Medication overuse Stressful life events Caffeine overuse Snoring Other pain syndromes Putative, currently being investigated Allodynia Pro-inflammatory states Prothrombotic states Specific genes Bigal ME, Lipton RB. Curr Opin Neurol 22:269 276.

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Chronic migraine and MOH 17 Nearly 50% do not overuse medication Medication withdrawal may not result in improvement Two hypotheses: - Chronification driven by another factor - Chronification caused by overuse, but now reversible

18 Chronic migraine Pathophysiology

Activation of trigeminal sensory afferents 19 1. Central disinhibition 2. Stimulation of meningeal sensory nerve (trigeminal) 6. PAIN Vessel dilation Nerve Peptide release Inflammation 3. Release of painenhancing neuropeptides, such as CGRP Trigeminal Nerve Trigeminal Ganglion Spinothalamic tract Thalamus TNC 5. Activation of cortical pain centers via thalamus CGRP = calcitonin gene-related peptide; TNC = trigeminal nucleus candalis. 1. Pietrobon D et al. Nat Rev Neurosci. 2003;4:386-398. 2. Pietrobon D. Neuroscientist. 2005;11:373-386. 4. Activation of trigeminal nucleus caudalis can result in central sensitization

Communication between sensory nerves outside and inside of the skull 20 Extracranial origin of intracranial pain Unmyelinated C-fibers Activation Release of pro-inflammatory neuropeptides Kosaras B et al. J Comp Neurol. 2009;515:331-348.

Fundamental biology of attacks in episodic migraine 21 Intermittent central sensitization in episodic migraine 1. Aurora SK. Cephalalgia. 2009;29:597-605. 2. Dodick D, Silberstein S. Headache. 2006;46(Suppl 4):S182-S191.

Chronic migraine pathophysiology overview 22 Primary disorder of the brain Often occurs after repeated attacks of episodic migraine Believed to be a disorder of cortical hyperexcitability and dysfunctional brainstem pain modulating centers Persistent central sensitization 1. Goadsby PJ et al. N Engl J Med. 2002;346:257-270. 2. Aurora SK. Cephalalgia. 2009;29:597-605. 3. Pietrobon D. Neuroscientist. 2005;11:373-386.

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24 Chronic migraine Patient management and treatment options

Chronic migraine: multifaceted approach to therapy 25 Lifestyle modifications, behavioral therapy Education, support, managing expectations, and close follow-up Pharmacologic therapy Chronic migraine management Dodick DW. N Engl J Med. 2006;354:158-165.

Chronic migraine: medication overuse 26 Drug withdrawal Break headache cycle and treat withdrawal Behavioural modification Acute treatment plan Prophylaxis Follow-up is critical

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Clinical trials of pharmacotherapy in CM 28 Treatment Evidence for Use in Chronic Migraine Valproate Topiramate Gabapentin Levetiracetum Pregabalin Small double-blind, placebo-controlled in CM Double-blind, placebo-controlled trials in CM One double-blind, placebo-controlled trial in CDH One double-blind, placebo controlled trial in CM Small open-label trial in CM Amitriptyline Fluoxetine Tizanidine Beta-blockers Calcium channel blockers ACE inhibitors and ARBs OnabotulinumtoxinA Small open-label trial in TM Small double-blind, placebo-controlled trial in CDH Small double-blind, placebo-controlled trial in CDH No evidence that they are effective in CM No evidence that they are effective in CM No evidence that they are effective in CM Double-blind, placebo-controlled trials in CM TM = transformed migraine. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Clinical trials of pharmacotherapy in CM 29 Treatment Evidence for Use in Chronic Migraine Valproate Topiramate Gabapentin Levetiracetum Pregabalin Small double-blind, placebo-controlled in CM Double-blind, placebo-controlled trials in CM One double-blind, placebo-controlled trial in CDH One double-blind, placebo controlled trial in CM Small open-label trial in CM Amitriptyline Fluoxetine Tizanidine Beta-blockers Calcium channel blockers ACE inhibitors and ARBs OnabotulinumtoxinA Small open-label trial in TM Small double-blind, placebo-controlled trial in CDH Small double-blind, placebo-controlled trial in CDH No evidence that they are effective in CM No evidence that they are effective in CM No evidence that they are effective in CM Double-blind, placebo-controlled trials in CM TM = transformed migraine. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Topiramate US trial: Efficacy outcomes 34 Topiramate (n = 153) Placebo (n = 153) Trial completers 55.8% 55.2% Final dose (mean) 56.0 mg/d N/A Mean duration of therapy (days) 91.7 90.6 Mean reduction of migraine headache days -6.4* -4.7 Silberstein SD, et al. Headache. 2007; 47(2):170-80. *p=0.010

Topiramate US trial: Adverse events 35 Topiramate (n = 160), % *Generally mild or moderate in severity. *Adverse events reported by at least 5% of subjects in any treatment group. Silberstein SD, et al. Headache. 2007; 47(2):170-80. Placebo (n = 161), % Subjects with adverse event, % 82.5 70.2 Paresthesia 28.8 7.5 Upper respiratory tract infection 13.8 12.4 Fatigue 11.9 9.9 Hypoesthesia 9.4 0 Dry mouth 9.4 3.1 Difficulty with concentration/attention 9.4 2.5 Taste perversion 9.4 2.5 Nausea 8.8 8.1 Difficulty with memory, not other specified 6.9 6.2 Somnolence 5.6 4.3 Injury 5.0 1.2 Anorexia 5.0 5.6 Sinusitis 4.4 5.0 Dizziness 3.8 7.5

Topiramate US trial: Adverse events 36 Topiramate (n = 160), % *Generally mild or moderate in severity. *Adverse events reported by at least 5% of subjects in any treatment group. Silberstein SD, et al. Headache. 2007; 47(2):170-80. Placebo (n = 161), % Subjects with adverse event, % 82.5 70.2 Paresthesia 28.8 7.5 Upper respiratory tract infection 13.8 12.4 Fatigue 11.9 9.9 Hypoesthesia 9.4 0 Dry mouth 9.4 3.1 Difficulty with concentration/attention 9.4 2.5 Taste perversion 9.4 2.5 Nausea 8.8 8.1 Difficulty with memory, not other specified 6.9 6.2 Somnolence 5.6 4.3 Injury 5.0 1.2 Anorexia 5.0 5.6 Sinusitis 4.4 5.0 Dizziness 3.8 7.5

OnabotulinumtoxinA

Hyperfunctional facial lines BEFORE AFTER

Fixed site injections: 155 units 43 The anatomic injection sites follow distributions and areas innervated by the trigeminal nerve complex Supine Sitting A. Corrugator: 5 U each side B. Procerus: 5 U (one site) C. Frontalis: 10 U each side D. Temporalis: 20 U each side E. Occipitalis: 15 U each side F. Cervical paraspinal: 10 U each side G. Trapezius: 15 U each side 0.1 ml = (5 U/site). Blumenfeld AM et al. Presented at AAN 2010.

Pooled efficacy of onabotulinumtoxina at week 24 (primary time point) 44 Endpoint Change from baseline OnabotulinumtoxinA 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). *p values are adjusted for baseline and for medication overuse stratification. HA = headache; HIT = Headache Impact Test. Dodick DW et al. Headache. 2010;50:921-936. OnabotulinumtoxinA (n=688) Baseline (±SD) Final Baseline (±SD) Placebo (n=696) Final p Value* Frequency of HA days (±SD) 19.9 (3.7) -8.4 19.8 (3.7) -6.6 <0.001 Frequency of migraine days (±SD) Frequency of moderate/severe HA days (±SD) Total cumulative HA hours on HA days (±SD) % patients with severe ( 60) HIT-6 score 19.1 (4.0) -8.2 18.9 (4.1) -6.2 <0.001 18.1 (4.12) -7.7 18.0 (4.3) -5.8 <0.001 295.9 (116.9) -119.7 281.2 (114.7) -80.5 <0.001 93.5% 67.6% 92.7% 78.2% <0.001 Total HIT-6 score 65.5-4.8 65.4-2.4 <0.001 % patients overusing acute HA pain medication 64.8-3.2 66.1-2.1 <0.001

Pooled efficacy of onabotulinumtoxina at week 24 (primary time point) 45 Endpoint Change from baseline OnabotulinumtoxinA 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). *p values are adjusted for baseline and for medication overuse stratification. HA = headache; HIT = Headache Impact Test. Dodick DW et al. Headache. 2010;50:921-936. OnabotulinumtoxinA (n=688) Baseline (±SD) Final Baseline (±SD) Placebo (n=696) Final p Value* Frequency of HA days (±SD) 19.9 (3.7) -8.4 19.8 (3.7) -6.6 <0.001 Frequency of migraine days (±SD) Frequency of moderate/severe HA days (±SD) Total cumulative HA hours on HA days (±SD) % patients with severe ( 60) HIT-6 score 19.1 (4.0) -8.2 18.9 (4.1) -6.2 <0.001 18.1 (4.12) -7.7 18.0 (4.3) -5.8 <0.001 295.9 (116.9) -119.7 281.2 (114.7) -80.5 <0.001 93.5% 67.6% 92.7% 78.2% <0.001 Total HIT-6 score 65.5-4.8 65.4-2.4 <0.001 % patients overusing acute HA pain medication 64.8-3.2 66.1-2.1 <0.001

PREEMPT pooled analysis: OnabotulinumtoxinA reduced cumulative headache hours on headache days 46 Week: 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Cumulative Hours of HA on HA Days (Mean Change From Baseline) -20-40 -60-80 -100-120 -140-160 -180 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 OnabotulinumtoxinA Placebo p=0.005 p=0.001 p=0.004 p=0.018 p=0.012 p=0.007 p=0.018-200 Double-Blind Phase Open-Label Phase Mean ± standard error. The double-blind phase included 688 subjects in the onabotulinumtoxina group and 696 in the placebo group. Cumulative hours of headache at baseline: 295.9 onabotulinumtoxina group vs 281.2 placebo group, p=0.021. HA = headache. Aurora et al. Headache. 2011 51(9):1358-7

PREEMPT: OnabotulinumtoxinA is a welltolerated treatment for chronic migraine 47 No new treatment-related AEs were identified Most AEs were mild or moderate in severity and resolved without sequelae OnabotulinumtoxinA n = 687 (%) Placebo n = 692 (%) (%)Neck pain 60 (8.7) 19 (2.7) Muscular weakness 24 (5.5) 2 (0.3) Headache 32 (4.7) 22 (3.2) Migraine 26 (3.8) 18 (2.6) Musculoskeletal stiffness 25 (3.6) 6 (0.9) Eyelid ptosis 25 (3.6) 2 (0.3) Injection-site pain 23 (3.3) 14 (2.0) Myalgia 21 (3.1) 6 (0.9) Musculoskeletal pain 18 (2.6) 10 (1.4) Facial paresis 15 (2.2) 0 (0.0) Data on file. Allergan, Inc.

Mechanism of Action Reversible binding preventing transmitter release

Rat formalin pain model 250 200 Phase I Phase II Saline 7 g/kg 150 100 15 g/kg 30 g/kg 50 0 0-5 5-10 10-15 15-20 20-2525-30 30-3535-4040-45 45-50 50-55 55-60 Time after formalin injection (min) Aoki KR. J Neurol. 2001;248(suppl 1):3-10.

Peripheral sensitization 51 Reduced threshold for stimulation of the peripheral neurons Inflammatory mediators (CGRP, glutamate, and others) promote sensitization of meningeal trigeminal sensory afferents Trigeminal afferents CGRP = calcitonin gene-related peptide. 1. Dodick D, Silberstein S. Headache. 2006;46(Suppl 4):S182-S191. 2. Strassman AM et al. Nature. 1996;384:560-564. 3. Hargreaves R. Headache. 2007;47(Suppl 1):S26-S43. 4. Aoki KR. Neurotoxicology. 2005;26:785-793.

OnabotulinumtoxinA: Mechanism of action in CM 52 Acts as an inhibitor of inflammatory neurotransmitters release Inhibits peripheral sensitization which indirectly reduces central sensitization 1. BOTOX (onabotulinumtoxina) product monograph. Allergan, Inc. Markham, ON. Oct 18, 2011.

Chronic migraine evolving therapies 58 Neurostimulation - occipital nerve stimulation - trans-cranial Magnetic Stimulation - non-invasive Vagal Nerve Stimulation

Efficacy of Occipital Nerve Stimulation for the Management of Intractable, Chronic Migraine: Results from a Prospective, Multicenter, Double-blinded, Controlled Study Stephen Silberstein, MD; Jefferson Headache Center, Philadelphia, PA David Dodick, MD; Mayo Clinic Hospital, Phoenix, AZ Joel Saper, MD; Michigan Head Pain & Neurological Institute, Ann Arbor, MI Billy Huh, MD, Ph.D.; Duke Pain & Palliative Clinic, Durham, NC Ken Reed, MD; Ascendant Neuro, Dallas, TX Samer Narouze, MD; Summa Western Reserve Hospital, Cuyahoga Falls, OH Nagy Mekhail, MD, Ph.D.; Cleveland Clinic, Cleveland, OH This work was supported by St. Jude Medical Neuromodulation Division through a sponsored clinical research study. Drs. Silberstein, Saper, Huh, Bacon, Slavin, Deer, and Levy are paid consultants and Dr. Mekhail is a consultant of St. Jude Medical Neuromodulation Division.

Results: Pain Relief Headache Pain Relief at 12 Weeks Post-Implant

Results: MIDAS MIDAS Scores at Baseline and 12 Weeks Post-Implant

Chronic migraine evolving therapies 62 Calcitonin Gene Related Peptide (CGRP) - small molecule receptor CGRP antagonists - Anti-CGRP mono-clonal antibodies

Calcitonin Gene-Related Peptide in Migraine: The Evidence CGRP released during and triggers migraine attacks CGRP infusion triggers migraine CGRP levels normalized by triptans CGRP blockade at key sites (TNC, PAG, thalamus) effective in preclinical models of migraine pain Goadsby PJ, et al Ann Neurol 1988 Feb;23(2):193-6. Lassen LH, et al. Cephalalgia 2002 Feb;22(1):54-61 Juhasz G, et al. Cephalalgia 2005 Mar;25(3):179-83. Durham, P. NEJM 2004; 350(11): 1073-1075

Benefits of Therapeutic mabs No toxic metabolites: (breakdown to constituent amino acids) Restricted distribution Pharmacokinetics ideally suited for chronic diseases prevention (t1/2 >14 days) No off-target toxicity and overall tolerability is usually good (although dependent on mechanism-of-action)

Responder Rates 100.0% Percentage of Responders 80.0% 60.0% 40.0% 20.0% 70.4% (n=69) 45.2% (n=47) 49.0% (n=48) 26.9% (n=28) 31.6% (n=31) 17.3% (n=18) LY2951742 Placebo 0.0% >50% Reduction >75% Reduction* 100% Reduction* OR estimate on the proportion of responders: >50% [2.88], >75% [2.54], 100% [2.16] *Exploratory posthoc analysis Dodick DW, et al. Lancet Neurol 2014; Published Online August 11, 2014: http://dx.doi.org/10.1016/s1474-4422(14)70128-0

Responder Rates (weeks 1-12) 100 80 p<0.001 Placebo i.v. (n=82) ALD403 1000mg i.v. (n=81) % patients 60 40 33 60 p<0.001 32 p<0.001 20 0 16 9 0 50% response 75% response 100% response Dodick DW, et al. Lancet Neurology 2014; in press

Summary CGRP plays a crucial role in the pathogenesis of migraine Appear safe and effective for the preventive treatment of migraine Phase III studies soon underway

QUESTIONS