Faculty CHAIR David Dodick, MD, FAHS, FRCPC, FACP Professor of - - PDF document

12/21/16 1

Faculty

CHAIR

David Dodick, MD, FAHS, FRCPC, FACP

Professor of Neurology Mayo Clinic Phoenix, AZ

FACULTY

Deborah I. Friedman, MD, MPH, FAHS

Professor, Neurology and Neurotherapeutics and Ophthalmology University of Texas Southwestern Medical Center Dallas, TX

Stewart J. Tepper, MD, FAHS

Geisel School of Medicine at Dartmouth Professor of Neurology Hanover, NH

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Activity Description

Target Audience This activity is designed for clinicians involved in the care and treatment of patients with migraine pain. Statement of Need Patients with frequent migraines and/or who experience functional disability need preventative migraine

• treatment. However, studies have shown that of the 38% of patients who stand to benefit from

prophylactic therapy, only 3‐13% of them actually receive it. Calcitonin gene‐related peptide (CGRP) monoclonal antibodies are under clinical investigation and constitute a new prophylactic migraine therapy class. Increased physician attention when individualizing treatment plans to maximize therapy efficacy and minimize side effects as well as managing headache triggers and existing comorbidities continue to be vital strategies as new agents emerge and when maximizing patient function. Support This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.

Barriers in the Treatment of Chronic Migraine

David W. Dodick, M.D. Professor Department of Neurology Mayo Clinic Phoenix, Arizona

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Migraine 7th most disabling MOH 20th most disabling

Lancet 2016; 388: 1545–602

MOH = Migraine overuse headache

Only 45% see an HCP Only 39% diagnosed by an HCP Of 775 patients meeting EM criteria Only 26% receive treatment Only 41% see an HCP Only 11% diagnosed by an HCP Of 1254 patients meeting CM criteria Only 4.5% receive treatment

Diagnosis and Management of Migraine (episodic and chronic) in United States

Lipton RB, et al. Headache 2013;51:81-92. Dodick DW, Headache 2016;56:821-834

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Migraine Still Undertreated!

Adults with Migraine¹

50% of those diagnosed get prescription treatment

36M

Fewer than 5 in 100 persons with migraine receive prescription treatment. Many diagnosed, yet untreated patients have cardiovascular conditions or risks, or they have stopped treatments due to lack of adequate response

Diagnosis of Migraine2

3.7M Patients

Scale: figure = 1M people

1.9M

No Prescription Treatment

1.8M

Receive Treatment2 3 out of 4 Treated Patients Receive Triptans2

• 1. www.americanmigrainefoundation.org; 2. IMS Health, PharMetrics Plus, January – December 2013 Cohort Projected to U.S.

Insured Patient Population, 2015 CVD=cardiovascular disease Kurth et al. BMJ 2016;353:i2610

Cardiovascular Risk in Migraine Women’s Health Study

• A prospective cohort study of 115,541 female nurses aged 25–42

followed from 1989-2011

• Migraine was associated with increased risk of:

– Major CVD – Myocardial infarction – Stroke – Angina/coronary revascularisation procedures – Significant increased risk for CVD mortality

• Women with migraine should be evaluated for vascular risk

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Serious and unexpected

• Ischemic

cardiovascular events

• Aneurysms/dissections
• Pregnancy‐related

vascular events Coronary artery spasm (adj ROR 21.6; 16.1–23.9) Arterial dissection (ROR 12.24; 4.42–32.25) Placental infarction (ROR 12.68; 3.23–42.70)

Roberto G, et al. Cephalalgia 2013

2600/7800 adverse events attributed to triptans fell under the cardiac category

• 2H-PF = 18-50%
• 24HSPF = 13-33%

Cameron C, et al. Headache 2015 HR=headache relief PF=pain free SHR=sustained headache relief SPF=sustained pain free

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Optimal Treatment Strategy of CM associated with medication overuse is not known

• Survey of 95 AHS members

– I think that a well‐designed clinical trial that compares different strategies of treating chronic migraine with medication overuse is needed – 92 clinicians – 3 migraine researchers

• 88.4% agreed that the most effective tx

strategy is unknown

Studies Evidence Class Early discontinuation 3 III Early discontinuation with preventive medication 19 III Preventive medication 17 II Strongly agree Somewhat agree Somewhat disagree Disagree

9.5% 87.4% 1.1% 2.1%

Closer Look at Preventive treatment Underutilized, adherence poor

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Closer look at prevention

13% Prevention Candidates Treated 40%

Migraine Sufferers

Lipton RB et al. Neurology 2007. Bigal et al. Neurology 2008;71:559‐66.

Treated 33% Chronic Migraine Sufferers

Adherence to oral migraine preventive medications in patients with chronic migraine

Hepp Z., et al. Cephalalgia 2015;35:478-488

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1 9 % 2 1 % 3 1 % 2 9 % 3 3 % 2 3 % 3 6 % 2 4 % 2 9 % 2 4 % 2 8 % 2 0 % 2 6 % 1 0 % 1 0 % 1 7 % 1 4 % 1 7 % 1 0 % 1 9 % 1 3 % 1 8 % 1 2 % 2 1 % 1 6 % 1 6 % 8 % 1 1 % 1 4 % 5 % 0 % 1 0 % 1 5 % 2 0 % 2 5 % 3 0 % 3 5 % 4 0 %

Amitriptyline N=1,164 Nortriptyline N=653 Citalopram N=1,150 Sertraline N=622 Fluoxetine N=421 Paroxetine N=190 Venlafaxine N=277 Propranolol N=699 Metoprolol N=395 Nadolol N=110 Atenolol N=195 Topiramate N=2,604 Gabapentin N=860 Divalproex N=292 Total N=9,632

Antidepressants Beta Blockers Anticonvulsants All Cla sse s

Proportionof Patients Persistent

Persistent At 6 M o n t h s 3 2 % Persistent at 1 2 M o n t h s

86% discontinue at 12 months

Hepp Z., et al. Cephalalgia 2015;35:478-488

An even higher percentage discontinue drugs after switching

Start a Prophylactic N=9,632 Persist14% Discontinue86% Switch 23% Discontinue87% Switch 27% Discontinue90% Reinitiate 32% Discontinue100% Reinitiate 43% Discontinue92% Untreated34%

2nd Prophylactic 1st Prophylactic 3rd Prophylactic

Hepp Z., et al. Cephalalgia 2015;35:478-488

18

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Summary

Enormous disability associated with migraine, chronic migraine and medication overuse headache EM and CM are poorly recognized and under‐treated in clinical practice There remains a large unmet acute treatment need with drugs that are more effective, lack safety concerns, and do not induce MOH Prophylactic therapies for migraine are under‐utilized and lack the efficacy and tolerability to enable patients to persist

Curr Curren ent and and Em Emer ergin ging Ther Therapies apies

Stewart J Tepper, MD, FAHS Professor of Neurology Geisel School of Medicine at Dartmouth Hanover, New Hampshire

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Episodic Migraine (EM) Prophylaxis: Anti‐Epilepsy Drugs

• Topiramate
• FDA‐approved for migraine prevention with Level A/Class 1 evidence and 2 large RCTs (studied up to 200 mg/day)
• Commonly reported side effects: paresthesia, weight loss, cognitive dysfunction, mood change, kidney stones
• Contraindicated in pregnancy due to teratogenicity
• Multiple mechanisms include anti‐glutamate effects and inhibition of cortical spreading depression (CSD)
• Also 2 RCTS showing effectiveness in prevention of Chronic Migraine (not FDA approved for this)
• Divalproex sodium, sodium valproate
• Level A/class I evidence
• 500‐1000 mg/day, significant reduction in 4‐week migraine headache rate as compared with PBO
• AEs: weight gain, alopecia, nausea, tremor, hepatotoxicity, polycystic ovaries
• Contraindicated in pregnancy due to teratogenicity
• Gabapentin
• Level U evidence
• Cochrane meta‐analysis found ineffective in migraine prophylaxis

Silberstein SD, et al. Neurology. 2012;78:1337-1345. Linde M, et al. Cochrane Database Syst Rev. 2013;(6):CD010609. doi: 10.1002/14651858.CD010609.

Episodic Migraine Prophylaxis: Anti‐hypertensives

• Beta Blockers
• Level A evidence: propranolol, timolol (both FDA approved), also metoprolol
• Level B evidence: atenolol, nadolol
• Contraindicated in patients with asthma, COPD, emphysema, pre‐existing

bradycardia, partial AV block, hypotension, and hypoglycemia associated with diabetes treatment

• Beta blockers inhibit CSD and central neuronal hyperexcitability
• The ARB candesartan now has Level A evidence and is equal to

(directly compared) propranolol

Silberstein SD, et al. Neurology. 2012;78:1337-1345. Barbanti P, et al. Neurol Sci. 2011;32(suppl1):S111-115. Stovner E, et al. Cephalalgia. 2014;34:523-532.

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Onabotulinumtoxin A for Prevention of Chronic Migraine (CM): Pooled Analysis of the PREEMPT Trials

• Design
• Two trials that were double‐blind, randomized, 24‐week, placebo‐controlled

identically designed trials of Chronic Migraine (CM) patients

• Followed by a 32‐week open label trial
• Primary endpoint
• Onabot (155‐195U) injections q 12 weeks for 2 cycles (n=688), placebo n=

3,696

• At week 24, there was a significant decrease in frequency of headache days

for the experimental (‐8.4 days, onabot) vs the pbo group (‐6.6 days, P<.001)

• Few treatment AEs
• Only 3.8% of onabot pts discontinued due to AEs (vs 1.2% of pbo patients)

Dodick DW, et al. Headache. 2010;50:921-936.

AAN Practice Guidelines for OnabotulinumtoxinA

• Class A evidence: Safe and effective for reducing the number of

headache days in CM (2 Class I studies)

• Probably effective for improving QOL (1 Class I study)
• Insufficient evidence to compare onabot with oral topiramate (no

direct comparison)

• Ineffective for EM and not recommended
• Probably ineffective for treating CTTH

Simpson DM et al. Neurology 2016;86:1818‐26

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As As we we mov move to to the the man many new new classes, classes, form rmula ulations, ions, and and devices devices in in dev developm lopmen ent fo for em emer ergin ging ther therapie apies, s, how how ca can we we bes best assess assess their their utility utility fo for our

• ur pa

patien tients? ts?

Patient‐Reported Outcomes (PROs)

• 5 questions can be condensed to one: How

many days was the patient at least 50% disabled at work, home, school, or recreational activities in the last 3 months?

• The domain collected is time loss reported
• The more time lost the higher the score,

intuitively understood, e.g. 20 days in the last 90 days with at least 50% disability due to migraine

• Validated for data collection Q3 months

Stewart WF, et al. Pain. 2000;88:41-52.

Migraine Disability Assessment Scale: MIDAS

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The Headache Impact Test (HIT‐6)

• 6 domains, validated for monthly data collection
• Social functioning
• Role functioning
• Vitality
• Cognitive functioning
• Psychological distress
• Severity of headache pain
• Scores range between 36 and 78; >60 severe impact
• Both MIDAS and HIT‐6 used to follow therapy effects as

PROs

• HIT‐6 scale not intuitive, but 6 domains may have an

advantage over one domain

• 2‐3 point change likely clinically meaningful

Yang M, et al. Cephalalgia. 2011;31:357-367. Kosinski M, et al. Qual Life Res. 2003;12:963-974.

The FDA, 2009‐ 40 pages of Requirements for a New Validated PRO: Since this Guidance, not a single validated PRO has been approved for therapy evaluation in any medical area, too bureaucratic, complicated, and costly

US Dept of HHS, FDA, CDER, CBER,

• CDRH. December, 2009.

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Current and Future Acute Therapies

• Triptans and Ergots
• Migraine‐specific (also work for some TACs)
• Usage at 10 days or more per month associated with chronification
• Vasoconstrictive
• Non‐vasoactive migraine‐specific acute medications in development:
• 5HT1F receptor agonists: Lasmiditan
• Phase 3 study completed & presented at EHMTIC meeting Sept 2016, Glasgow
• Established efficacy of 2 hour pain freedom and elimination of “most bothersome symptom”
• Centrally acting, no vasoconstriction
• Phase 3 adverse event profile: dizziness and fatigue at approximately the same rates as

rizatriptan (not directly compared)

• CGRP receptor antagonists (“Small molecules”), gepants: Ubrogepant‐ more later
• Prevent vasodilation, don’t vasoconstrict

Tfelt-Hansen PC, Olesen J. J Headache Pain. 2012;13:271-275. EHMTIC presentations. Glasgow, Scotland. Sept 2016.

Neuromodulation

• Targets: occipital cortex, occipital nerves, vestibular nerves,

supraorbital nerves, vagus nerve, and sphenopalatine ganglion

Proposed Mechanisms of Action

• Transcranial magnetic stimulation inhibits cortical spreading

depression

• Some neuromodulation devices may modulate central pathways such

as thalamocortical pathways to gradually down‐regulate pain systems

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• Delivers an electric current to supraorbital and supratrochlear

nerves1

• Sham controlled, randomized trial for the prevention of EM

(n=67)

• Worn 20 mins/day, above the procerus, for 3 months
• Poor adherence in this study
• Patients had at least 2 migraine attacks/month (n=67)
• Only one of two primary endpoints were positive:
• Change in monthly migraine days negative vs placebo
• 50% responder rate was significantly greater in the active vs the sham

group (38.1% vs 12.1%, p=0.23)

• AEs: Dysphoric paresthesias/dysesthesias, drowsiness2
• FDA approved for prevention of EM as a minimal risk device

1. Schoenen J. Neurology. 2013;80:1-8. 2. Magis D, et al. The Journal of Headache and Pain. 2013;14:95.

FDA Approved Devices: Transcutaneous Supraorbital Neurostimulator (tSNS)

FDA Approved Devices: Single Pulse Transcortical Magnetic Stimulation

• sTMS1‐2
• Sham controlled trial to

evaluate if 2 pulses could terminate a migraine in patients with aura

• Inhibits rat cortical spreading

depression

1. Lipton RB, et al. Lancet Neurol. 2010;9(4):373-80. 2. Bhola R, et al. J Headache Pain. 2015;16:51.

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• N=449 (140 analyzed), 9000 attacks, women in 2nd trimester of pregnancy included
• Mean baseline frequency 15 attacks per month
• PRN instructions:
• 2 consecutive pulses at onset of migraine attack
• Continue with 2 pulses every 15min for 1-2h or pain relief
• Evaluate after 1st month, increase the number of pulses if needed:
• Increase to 3 pulses every 15min for 1-2h or pain relief
• Evaluate after 2nd month, increase the number of pulses if needed:
• Increase to 4 pulses every 15min for 1-2 hours or pain relief
• For frequent migraine attack pattern: Daily treatment, 4 pulses BID

Bhola R, et al. J Headache Pain. 2015;16:51.

sTMS for Episodic Migraine: UK Post Market Pilot Program

• Pain relief (62%) in >9,000 attacks
• EM: reduction in headache days/month
• 12 (median, 8-13 IQR) to 9 (4-12 IQR)
• CM: reduction headache days/month
• 24 (median, 16-30 IQR) to 16 (10-30 IQR)
• Nausea, photophobia, phonophobia relief
• Decreased use of acute medication use in 119

(Average 8.5 day reduction)

• AEs: Lightheadedness (20%)
• Discontinuation rate: 55% (n=105)
• Ineffective, inconvenient, cost

Bhola R, et al. J Headache Pain. 2015;16:51.

UK Post Market Pilot Program: Results

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• US Open Label ESPOUSE Study
• 8 U.S. Headache Centers, N=132 migraine patients with 5‐25 headache days/month
• 4 pulses BID + prn up to 17 pulses/day
•  average 9 headache days/month at baseline to 6 days/month at 3 months of

treatment

• No serious adverse events

Presented EHMTIC meeting, Glasgow, Scotland 9/7/16.

sTMS US ESPOUSE Study : Acute & Preventive, MO & MA, EM & CM

• Tested under acute and preventive conditions for
• Episodic and Chronic Cluster, Episodic and Chronic Migraine, acute and preventive
• 5 RCTs not all published or presented
• ACT1 study: Showed acute effectiveness to provide relief by 15 minutes in episodic

cluster headaches but not chronic cluster headaches

• Acute regimen: 2 pulses lasting 2 mins each; used at the beginning of a cluster attack
• Preventive regimen: Two 90‐120 second pulses, TID for prevention of cluster and

migraine

• Handheld device delivers electrical stimulation to the vagus nerve
• Evidence for effectiveness
• Approved for use in Europe
• Approved and available in Canada but not used much
• Before the FDA for acute treatment of cluster headache

Gaul C, et al. Cephalalgia 2016;36:534‐46. Clinicaltrials.gov. NCT01792817. Clinicaltrials.gov. NCT02378844. Silberstein SD, et al. Headache. 2016;56:1317‐1332. https://www.nice.org.uk/guidance/ipg552, accessed 4-14-16.

Devices in Development: Non‐invasive Vagal Nerve Stimulator (nVNS)

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• Delivers controlled time‐varying thermal waveforms
• Heats and cools the vestibular system
• 3rd mechanism of centrally modulating migraine
• Pilot study to treat Episodic Migraine
• 6 wks of treatment, 4 weeks of follow‐up
• Per protocol: active (n = 28); placebo (n = 18)
• Used 2x daily; sessions 18 min in length
• Primary endpoint +:migraine days/ 3rd mo
• 2°: RR, acute meds, mood, cognition, balance
• Will likely be submitted to the FDA soon for prevention of EM

Black RD, et al. IEEE J Transl Eng Health

• Med. 2016;4:2000310.

Devices in Development: Caloric Vestibular Stimulation

• Implantable microstimulator for SPG neuromodulation of cluster headache
• Implanted through the mouth in <15 minutes
• EU RCT for Chronic Cluster, Sham‐controlled, n=28
• Acute treatment of chronic cluster attacks: Pain relief at 15 mins following SPG

stimulation

• 55% of attacks with pain relief 15 minutes vs 6% sham
• 89% reduction of attack preventive response seen in 40% of patients
• Transient, mild‐moderate loss of sensation within distinct maxillary nerve

regions

• 65% of events resolved within 3 months

Schoenen J, et al. Cephalalgia. 2013;33:816-830.

Devices in Development: Implanted Sphenopalatine Ganglion (SPG) Stimulation

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Sphenopalatine Ganglion Stimulation (cont)

• Long‐term device benefit1
• n=33
• 45% of patients demonstrated an acute response
• Approved in Europe, reimbursable; >400 patients now implanted world‐wide
• Long‐term responder rate (acute and preventive) 61% at 2 years
• Registration study in the US underway
• Safety data2
• n=96
• Perioperative surgical sequelae: sensory disturbances, pain, swelling
• Follow‐up: placement of a second stimulator on the opposite side, adjustment of lead location,

replacement after initial, unsuccessful placement, or removal

• 25/29 patients indicated that surgical effects were tolerable
• 90% of them would make the same decision again

1. Jürgens TP, et al. Cephalalgia. 2016;May 9. 2. Assaf AT, et al. Int J Oral Maxillofacial Surg. 2016;45:245-254.

Not Everything Works: Negative Data

• Orexin 1 and 2 (receptor) antagonist1
• Filorexant (MK‐6096), 10 mg nightly for 3 months vs PBO
• Patients with 4‐14 days of migraine/month
• Nitric oxide synthase nitric oxide
• NO is a gaseous vasodilator that may activate trigeminovascular fibers

triggering the release of CGRP

• Nitric oxide synthase inhibitor, GW274150, given daily for 12 weeks was no

different than PBO with respect to migraine prophylaxis2

1. Chabi A, et al. Cephalalgia. 2015;35:379-388. 2. Høivik HO, et al. Cephalalgia. 2010;30:1458- 1467.

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A Fo Focus on

• n CG

CGRP Mo Monoc noclona

• nal

An Antibod tibodies es

Deborah I. Friedman, MD, MPH, FAHS University of Texas Southwestern Medical Center Dallas, Texas

Calcitonin Gene‐Related Peptide

• CGRP is a 37 amino acid peptide
• Vasodilator and key mediator of neurogenic inflammation
• Regulates immune and inflammatory cells within the skin

(psoriasis)

• Derived from mouse (100%), chimeric (65% human),

humanized (90% human) or humanized (100% human)

Russell FA et al. Physiol Rev 2014:1099-1142 Granstein RD et al. Acta Physiol (Oxf) 2015;213:586-94

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Targets of Monoclonal Antibodies Dictate On and Off‐Target Toxicities

~50 mAbs currently on the market, most for oncology and rheumatology

• CD20 – modulates immune system (rituximab)
• Increased risk of opportunistic infection
• VEGF –inhibits angiogenesis and reduces tumor growth (bevacizumab)
• Can do so in healthy tissue leading to GI perforation and poor wound healing
• CGRP ‐‐ inhibits vasodilator effect
• May potentially cause ulcers or diarrhea

Monoclonal Antibodies Against CGRP

• Block CGRP, a vasodilator, without causing vasoconstriction
• CGRP mAbs have very low CNS penetration
• Reduce the bioavailability of CGRP; high receptor specificity
• Eliminated through reticuloendothelial system, similarly to endogenous antibodies

(not liver or kidney)

• Monoclonal antibodies against the CGRP ligand
• Galcanezumab (LY‐2951742)
• ALD‐403
• Fremanezumab (LBR‐101/TEV‐48125)
• Monoclonal antibodies against the receptor
• Erenumab (AMG334)

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Erenumab (AMG 334)

• Investigating for EM and CM
• PBO controlled, Phase 2 (n=483)
• Patients had 4‐14 migraine days/month
• 3 doses investigated

7 mg (n=108) PBO, n=160 21 mg (n=108) 70 mg (n=107)

• Primary endpoint
• Change in monthly migraine days from

baseline to the last 4 weeks of the 12‐week double‐blind treatment phase

• 70 mg dose → 3.4 migraine day/month

reduction vs. 2.3 days for PBO

• P value is for PBO vs 70 mg dose group

Sun H et al. Lancet Neurol. 2016;15:382-390

‐0.5 ‐1.0 ‐1.5 ‐2.0 ‐2.5 ‐3.0 ‐3.5 ‐4.0 ‐‐4.5 Baseline Week 4 Week 8 Week 12

PBO AMG334, 7 mg AMG334, 21 mg AMG334, 70 mg p=0.029 p=0.029 p=0.021

Change in migraine days

Proportion of Patients with ≥ 50% Reduction From Baseline in Monthly Migraine Days at Week 12 (AMG 334)

*p<0.001

5 10 15 20 25 30 35 40 45 PBO 70 mg 140 mg

OR 2.18 OR 2.34

23.5% * 39.9% * 41.2%

≥50% Responder Rate

n=281 n=188 n=187

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• 5
• 4
• 3
• 2
• 1

PBO LY2951742

1

3

2

Months Mean change from baseline in the number of migraine days

Galcanezumab (LY‐2951742)

• 4‐14 headache days/month (episodic

migraine)

• Galcanezumab n=107; PBO n=110
• 150 mg SC q2 weeks, for 12 weeks
• Primary endpoint
• Mean change in the number of

migraine headache days per 28‐ day period assessed at 9‐12 weeks

• Reduction of 4.2 migraine days

compared with 3.0 days in the PBO group (p=0.0030)

• 70% vs 45% response rate in

experimental vs PBO group

Dodick DW, et al. Lancet Neurol. 2014;13:885-892.

Fremanezumab (TEV‐48125) High‐frequency, Episodic Migraine

• Phase 2b
• Subcutaneous injection q 28 days
• Subjects had 8‐14 days of migraine/month
• Fremanezumab, 225 mg n= 95
• Fremanzeumab, 675 mg n=96
• PBO, n=104
• Primary endpoint
• Change from baseline in migraine days during

the third treatment cycle (weeks 9‐12)

• The least square mean (LSM) change in

number of migraine‐days from baseline to weeks 9–12 was

• ‐3.46 days (SD 5.40) in the placebo group,
• ‐6.27 days (5.38) in the 225 mg dose group,
• and ‐6.09 days (5.22) in the 675 mg dose

group

Bigal ME, et al. Lancet Neurol. 2015;14:1081-1090.

• 2
• 4
• 6
• 8

Least square mean change in number of migraine days

Baseline Weeks 1-4 Weeks 5-8 Weeks 9-12

PBO 225 mg 675 mg

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Fremanezumab (TEV‐48125): Chronic Migraine

• Phase 2b, SC injection every 28 days
• Treatment groups:
• Fremanizumab 675/225 mg (n=88)
• Fremanizumab 900 mg (n=87)
• PBO (n=89)
• Primary endpoints: change in baseline in headache hours

during 3rd treatment cycle; safety and tolerability

Bigal ME, et al. Lancet Neurol. 2015;14:1091-1100.

Fremanezumab for Chronic Migraine (Post‐hoc Analysis)

• High (900 mg, n=86) and low doses

(675/225 mg, n=88) studied.

• PBO, n=89
• Injections taken once a month, for 3

months

• Patients had a history of CM
• Primary endpoint: Change from

baseline in the number of headache hours in month 3

• Three‐seven days post‐injection (ie,

within one week of use), the number

• f headache hours decreased (early

timepoint efficacy)

• These results endured throughout

the study (month 3)

Bigal ME, et al. Neurology. 2016;87:41-48.

* ** * ** *** *** 10 20 30 40 Baseline Week 1 Week 2 Week 3 PBO 675/225 mg 900 mg Decrease in hours from baseline

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ALD403 Chronic Migraine

• Phase 2b 15‐28 headache days monthly (> 8 migraine days)
• Dose finding study with single IV dose ALD403
• 300 mg, 100 mg, 30 mg, 10 mg, PBO (n=120 per group)
• Primary outcome: 75% responder rate weeks 1‐12 reduction in

migraine days)

Time Period Reduction in MMD per month 300 mg IV N=114 100 mg IV N=118 30 mg IV N=117 10 mg IV N=123 PBO IV N=116 Weeks 1-12 50% decrease 65 (57%)** 64 (54%)* 64 (55%)* 54 (44%) 47 (41%) 75% decrease 38 (33%)* 37 (31%)* 33 (28%) 33 (27%) 24 (21%) 100% decrease 9 (8%) 6 (5%) 5 (4%) 10 (8%) 3 (3%)

1-sided p value vs. PBO: *p<0.05; **p<0.01 Dodick et al. EHMTIC 2016

ALD‐403

• Phase 2 trial
• Included patients who experienced 5‐

14 migraine days every 28 day period (episodic)

• IV formulation: 1000 mg
• ALD‐403, n=81; PBO, n=82
• Primary endpoint: Change from

baseline to weeks 5‐8 in the frequency of migraine days as recorded in patient electronic diaries

• Mean change in migraine days

between baseline and weeks 5‐8:

• ‐5.6 days (SD 3.0) for ALD403

compared with ‐4.6 (SD 3.6) for PBO (p=0.0306)

Dodick DW, et al. Lancet Neurol. 2014;13:1100-1107.

ALD‐403 PBO Time (weeks) 4 8 12 ‐2 ‐4 ‐6 ‐8 ‐10 Mean change from baseline

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Common Adverse Events Reported in Clinical Trials with CGRP mAbs

• Injection site pain
• Upper respiratory tract infection
• Nausea
• Erythema
• Arthralgia
• UTI
• Some reports of abdominal, back pain
• All treatment‐emergent adverse events were not different than those
• ccurring with the placebo injections
• All adverse events appeared to be tolerability, not safety issues

Key Challenges to Introduction of CGRP mAbs

• Long biological half-life

– Risk in patients who experience adverse events (e.g. hypertension) – Pregnancy (planned and unplanned)

• Uncertainty in patients with atherosclerotic and vasospastic (e.g.

Raynauds) vascular disease, multiple vascular risk factors, hypertension.

• Patient access and physician burden related to ‘step-edits’ and prior

authorization

• Reserved for OnabotulinumtoxinA failures
• Small molecule CGRP receptor antagonists for prevention

– Upside: short half-life – Downside: Daily oral medication

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Small Molecule vs. Monoclonal Antibodies

Small Molecules Monoclonal Antibodies Target specificity lower Target specificity high Clearance (Liver, kidney) Clearance RES Size < 1kD Size ~150kD Oral Parenteral Many enter cells and cross BBB Do not enter cells or cross BBB** Half-life minutes to hours Half-life 1-4 weeks Immunogenicity (No) Immunogenicity (yes)

CGRP Small Molecules May Offer Relief When Used Acutely

• 1. Voss T, et al. Cephalalgia. June 6, 2016.
• Ubrogepant (MK‐1602)
• CGRP receptor antagonist
• Phase IIb study
• Primary endpoint: pain freedom and headache response at 2 hrs
• N=527
• 100 mg of ubrogepant was significantly superior to PBO for 2‐hr pain

freedom but not 2‐hr headache response

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Atogepant (AGN‐241689, MK‐8031)

• Oral, small molecule CGRP receptor antagonist
• Currently in double‐blind, Phase 2, PBO‐controlled trials examining efficacy

in episodic migraine

• Characterization of the dose‐response relationship
• 10 mg QD
• 30 mg QD
• 30 mg BID
• 60 mg QD
• 60 mg BID
• Primary outcome: change from baseline in the mean number of

migraine/probable migraine headache days at month 3 (ie, last 28 days of the treatment period ending with week 12)

Clinicaltrials.gov. NCT02848326.

Summary

• Current preventive therapies are effective for many patients with

migraine, but adverse events and lack of efficacy create a need for

• ther options
• CGRP has a demonstrated role in the generation of migraine
• Targeted therapies against CGRP
• Are promising thus far in clinical trials for migraine prevention
• Do not cause vasoconstriction
• Appear safe regarding side effect profile
• Do not require daily administration (vs. oral preventives)
• Offer treatment alternatives for EM and CM patients

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