Thinking Ahead: New Treatment Options for Migraine Preventioncongress.cnsfederation.org/course-notes/2018_Course_Notes/CNSF_… · Thinking Ahead: New Treatment Options for Migraine

Thinking Ahead: New Treatment Options for

Migraine Prevention

Satellite Symposium Sunday, June 24th, 2018

Halifax, Nova Scotia

This program was developed by the CNSF, Hc3 Communications and Novartis and was planned to achieve scientific integrity, objectivity and balance. It has been approved for 1.5 hours of Royal College MOC Section 1 credits.

Faculty

Suzanne N. Christie, MD, FRCPC Neurologist Director, Ottawa Headache Centre Assistant Professor, University of Ottawa Ottawa, ON Richard Leckey, MD, B.Sc., FRCPC Neurologist Division of Neurology Dalhousie University, Halifax, NS

Faculty Disclosures

I, Suzanne Christie, MD, FRCPC, have received Consultant, Speaker, Investigator, Scientific Officer, Steering Committee, Advisory Board, Publication Committee honoraria from the following companies: Allergan, Amgen, Eli Lilly, Novartis and Teva

Faculty Disclosures

I, Richard Leckey, MD, FRCPC, have received Consultant, Speaker, Investigator, Scientific Officer, Steering Committee, Advisory Board, Publication Committee honoraria from the following companies: Allergan, Genzyme, Novartis and Pfizer

Learning Objectives

Upon completion of this program, participants will be able to: Recognize the importance of migraine and its significant burden to patients Describe the pathophysiology underlying migraine and the role of the calcitonin gene-related peptide (CGRP) pathway Identify unmet needs with currently available treatments for migraine Review recent data from evolving research and upcoming treatments for migraine prevention including CGRP antagonists

Program Outline

1 Introduction: Migraine in 2018

2 Migraine Pathophysiology

3 Migraine Treatment: Old & New

4 Practical Tips: Guidance to discuss the new treatments with patients

5 Q & A Period

Migraine in 2018: Burden of Disease and Treatment Challenges

* Migraine patients may not experience all phases and symptoms shown, and not all possible symptoms are listed. † Illustrative only. ‡ Duration per symptom.

Adapted from: Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2013;33:629-808.

Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533-552. Figure adapted from Blau JN. Lancet. 1992;339:1202-1207. Charles A. Headache. 2013;53:413-419.

Inte

nsity o

f S

ym

pto

ms o

r P

ha

se

s†

Repetitive yawning Food cravings Neck stiffness/pain Fatigue

Changes in vision Skin sensations/tingling Language problems

Head pain Often unilateral Tends to have a pulsating quality Can be aggravated by routine physical activity Can be associated with

cutaneous allodynia

Repetitive yawning Food cravings Neck stiffness/pain Fatigue

Other symptoms may include: Unusual sensitivity to light, sounds, and smells Lightheadedness and fainting Nausea and vomiting

Postdrome Prodrome Headache Aura (20% of cases)

Few hours to few days 4-72 hours 5-60 min‡

Few hours to few days

Time

Migraine Phases and Associated Symptoms*

• Classification by attack frequency (< or ≥ 15 HD/months)1,2

• EM may evolve into CM: EM progresses to CM at the rate of 2.5% per year, and CM often remits to EM (2-year transition rate of 26%)1,3

Adapted from: 1. Katsarava Z et al. Curr Pain Headache Rep 2012; 16:86–92. 2. The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia 2013; 33(9) 629–808. 3. Lipton RB, Headache 2015;55;S2:103-122. 4. Buse DC, et al. Headache 2012;52(10):1456-1470.

Approximately 92% of migraineurs have EM (<15 HD/month) and 8% have CM (≥15 HD/month)4

Episodic Migraine (EM) Chronic Migraine (CM)

• Headaches (untreated or unsuccessfully treated) occur <15 days/month1

• Headaches (tension-type and/or migraine) occur ≥15 days/month for ≥3 months1

• Headache has features of migraine without aura for ≥8 days/month1

Highest frequency → Highest unmet need - Increasing patient and societal burden1,3

Episodic and Chronic Migraine are Considered as Part of the Spectrum of Migraine Disorders

9 CM: chronic migraine; EM: episodic migraine; HD: headache days

Polling Question

Migraine attacks account for approximately

what percentage of an average person’s life?

1. 1%

2. 3%

3. 5 %

4. 10%

5. 15%

Migraine: Burden of Disease

The 2016 Global Burden of Disease Study found migraine to have

the highest amount of years lived with disability of the neurologic

disorders and second highest of all diseases studied following

low back pain

The 2015 Global Burden of Disease Study found that migraine is

the 3rd cause of disability in under 50s

Adapted from: GBD 2016. Lancet 2017; 390:1211-59. Steiner TJ et al. J Headache Pain 2016; 17(1): 104.

Migraine: Burden of Disease

Contributors to annual costs: • Hospitalizations and emergency department visits

• Primary care and specialist visits

• Procedures and diagnostic tests

• Medication

• Loss of productivity

Treatments that reduce headache frequency could reduce the clinical

and economic burden

Adapted from: Linde M, et al. Eur J Neurol. 2012;19:703-711. Munakata J, et al. Headache. 2009;49:498-508. Stokes M, et al. Headache. 2011;51:1058-1077. Bloudek LM, et al. J Headache Pain. 2012;13:361-378.

Migraine is Disabling

Real-world data from the Adelphi

Migraine US Disease Specific

Program (2014) show that pain,

nausea and photophobia were

the key symptoms reported

by patients as impacting their

work and lifestyle

Adapted from: Ford J et al. EHMTIC 2016, Glasgow 15-18 September 2016. Abstract 173.

0 10 20 30 40 50 60

Light-headedness

Muscle weakness/fatigue

Pain worsened by activity

Phonophobia

Vomiting

Photophobia

Nausea

Bilateral pain

Unilateral pain

Pulsating/throbbing pain

Percent of patients

Chronic N=137

Episodic N=1,350

Most bothersome symptoms associated with migraine that impacted lifestyle or work in ≥10% of patients

*p<0.05

*

*

*

*

*

*

*

*

Migraine is Disabling

Migraine attacks account for

about 5% of an average person’s

life; the percentage is substantially

higher in those with severe

chronic migraine

Depression is 3 times more

common in people with migraine

or severe headaches than in

healthy individuals

Adapted from: Steiner TJ et al. J Headache & Pain 2013, 14:1. Burch RC et al. Headache 2015;55:21.

In the USA, headache or pain in the head is the 4th leading cause of visits to the emergency department

Migraines/headaches account for 3.1% of all visits to emergency departments

3.1%

Migraine Negatively Impacts Personal Activities

Personal impact of migraine assessed as headache-attributed lost work, housework and social days in preceding 3 months: Eurolight project

In the preceding 3 months, migraine patients lost 3.2 workdays, 4.6 housework days and 2.1 social days

Adapted from: HALT, Headache attributed lost time (including work days lost, days of household work or days on which family, social or leisure activities were lost). Steiner TJ, et al. J Headache Pain. 2014;15:31.

2.9 3.4 3.2 3.3

5.2 4.6

1.7 2.3 2.1

0

1

2

3

4

5

6

Males Females Overall

Workdays Housework Days Social Days

Me

an d

ays

lost

in

pre

ced

ing

3 m

on

ths

Disability Associated with Migraine Headache MIDAS

In 2009, the International Burden of Migraine Study (IBMS) collected data on headache-related disability with MIDAS • Assessed the extent to which the following

activities were missed as a result of headache over the previous 3 months:

• Schoolwork/paid employment • Household work or chores • Non-work activities • Total scores ranged from 0 (no disability) to

270 (very severe disability)

0%

10%

20%

30%

40%

50%

60%

70%

Episodic (N=8,227) Chronic (N=499)

Perc

enta

ge o

f p

arti

cip

ants

Migraine Frequency

Migraine frequency and severity of disability

Grade I Grade II Grade III Grade IV-A Grade IV-B

23.3% of EM and 78.0% of CM patients, reported severe (grade IV-A) or very severe (grade IV-B) headache-related disability

MIDAS = Migraine Disability Assessment test; EM: Episodic migraine; CM: Chronic migraine Adapted from: Blumenfeld AM, et al. Cephalalgia. 2011;31:301-315. MED/AMG/0013

Migraine is Costly

EuroLight Project • Cross-sectional survey in 8

countries (55% of European adult population)

• Mean per-person annual costs were €1222

• Total annual cost of migraine in EU: €111 billion

Adapted from: Linde M et al. Eur J Neurol 2012;19:703; Steiner TJ et al. Cephalalgia 2003;23:519; Headache Disorders – not respected, not resourced. All-Party Parliamentary Group on Primary Headache Disorders. 2010; Shapiro RE & Goadsby PJ. Cephalalgia 2007;27:991-4.

In the UK • 25 million days are lost from work or

school each year because of migraine, costing £2.25 billion

• The cost to the NHS is £150 million per year

• Despite its economic impact, migraine is the least publicly funded of all neurological illnesses

Current Challenges: Migraine is Underdiagnosed

• World-wide, 60% of individuals with migraine are not professionally diagnosed

• About 50% of patients consult a clinician

• There is a lack of professional training: ~ 4 hours are allocated to undergraduate training ~ 10 hours are allocated for specialist training

Adapted from: WHO Atlas of headache disorders and resources in the world 2011; Pavone E et al. Cephalalgia. 2007;27:1000-4; Diamond S et al. Headache 2007;47:355.

Current Challenges: Migraine in Undertreated

Worldwide, about 50% of people with migraine are self-medicating

In the AMPP study of migraine treatment: • 49% used OTC medication only • 29% used prescription and OTC

medication • Only 1 in 8 received preventive

therapy

AMPP: American Migraine Prevalence & Prevention; OTC: Over the counter Adapted from: WHO Atlas of headache disorders and resources in the world 2011; Diamond S et al. Headache 2007;47:355.

Treatment of migraine

0% 10% 20% 30% 40% 50%

Others

Alternative

Neurologist

PCP

Self

Percentage of patients

Preventive Strategies are Being Underused

Migraine patients who consulted a HCP received a diagnosis and received treatment

HCP: Healthcare professional Adapted from: Lipton RB et al. Headache 2013; 53:81-92; Dodick DW et al. Headache 2016; 56:821-34

0

5

10

15

20

25

30

Episodic Migraine (N=775)

Chronic Migraine (N=1,254)

Pati

ents

, %

Persistence to the initial treatment was 25% at 6 months and 14% at 12 months

Preventive Strategies are Being Underused

Adapted from: Hepp Z et al. Cephalalgia 2017; 37:470-85

Antidepressants Anticonvulsants Beta-blockers

0 25 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400

0

0.25

0.50

0.75

1.00

Pro

po

rtio

n o

f Pe

rsis

ten

t Pa

tien

ts

Analysis Time, Days

Reasons for Poor Adherence Side-effects and lack of efficacy are

the key drivers of suboptimal adherence

Adapted from: Blumenfeld AM et al. Headache 2013;53:644.

Reasons reported by patients for discontinuation of preventive medication

Antidepressants (N=205)

Anti-epileptics (N=125)

β-blockers (N=130) Calcium-channel blockers(N=59)

0 5

10 15 20 25 30 35

40 45 50

Pati

ents

%

Satisfactory Resolution

Lack of Efficacy

Side-Effects Cost Other

Clinical Challenges: Episodic Migraine

• On average 4 moderate-to-severe migraines per month

• Takes OTC medications often combined with a triptan

• Migraines still take 2-3 days to resolve

• She is struggling with continuing with her university studies due to all these unplanned absences and impact on her productivity

Sophie 24 year-old female Student

Clinical Challenges: Chronic Migraine

• On average 16 headache days per month

• Has tried multiple preventive treatments for migraines, which have only had a minor impact on her migraine frequency and duration

• She is struggling with keeping her employment and large amount of sick days and has needed to bring in extra help with her children, which has all contributed to increased financial and emotional stress

Marie 32 year-old female Mother of 2 children

Summary: Current Challenges with Migraine Treatment • Underdiagnosis and undertreatment

• Current prophylactic drugs are repurposed from other conditions

• Issues with available preventive strategies, specifically efficacy and tolerability

• Long-term adherence can be problematic due to tolerability issues and modest efficacy

• Acute treatments do not demonstrate efficacy in a high percentage of cases; patients

respond to acute treatment for some, but not necessarily all, attacks of migraine

• Comorbidities can restrict treatment choice

Adapted from: Pringsheim T, et al. CMAJ. 2010;182:E269-E276. Lipton RB, et al. Headache. 2013;53:1300-1311.

Migraine Pathophysiology

Migraine: Pathophysiology Introduction

• Current thinking is that migraine is a complex condition which is thought to involve the vasculature, central and peripheral neuronal pathways involved in pain signalling, as well as inflammation

• While the events that actually initiate a migraine attack remain unknown, activation of the trigeminovascular system is considered key

Adapted from: Amara SG et al. Nature 1982;298:240.

CGRP = calcitonin gene-related peptide

Polling Question

The most abundant neuropeptide in the trigeminal system is: 1. Substance P

2. CGRP

3. Calcitonin

4. Neurokinin A

Migraine headache is thought to involve the trigeminal

system

While the brain lacks pain receptors

(nociceptors) they are present in the dura and pia of

the meninges

Migraine pain is transmitted from the meninges through the

trigeminal nerve

CGRP is the most abundant neuropeptide in the trigeminal system and is associated with migraine

attacks

The Neurological Basis for Migraine Pain

CGRP = calcitonin gene-related peptide. Adapted from: Burgos-Vega C, et al. Prog Mol Biol Transl Sci. 2015;131:537-564. Moskowitz MA. Neurology. 1993;43:S16-S20. Goadsby PJ, et al. N Engl J Med. 2002;346:257-270. Messlinger K. Exp Brain Res. 2009;196:179-193. Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398. Eftekhari S, et al. Neuroscience. 2010;169:683-696.

Skull bone

Cerebrum

Blood vessel Cerebrum

Pia mater

Skull bone

Arachnoid mater

Dura mater Cranial meninges

Subarachnoid Space

(contains cerebrospinal

fluid)

Figure adapted from Burgos-Vega C, et al. Prog Mol Biol Transl Sci. 2015;131:537–564.

MED/AMG/0016

Neurogenic inflammation and vessel dilation

2. Trigeminal ganglion Activation of pain signaling

1. Meninges Neuropeptides

4. Headache pain

TNC

3. Second-order brainstem neurons

Pathophysiology includes:

Trigeminovascular activation

1. Peripheral vasodilation and neurogenic inflammation

2. Peripheral afferent signals to trigeminal ganglion (TGG)

3. CNS pain signals relay to higher order structures (i.e. TNC and cortex)

CGRP neuropeptide is enriched in the migraine pathway

Migraine Involves Activation of Peripheral and Central Components of the Trigeminal System

The key pathway for pain in migraine Trigeminovascular input from the meningeal vessels passes through the trigeminal ganglion and synapses on second-order neurons in the brainstem before being relayed to the sensory cortex.

Image adapted from Bigal ME, et al. Arq Neuropsiquiatr. 2009;67(2-B):559-569.

CGRP = calcitonin gene-related peptide; CNS = central nervous system; TGG = trigeminal ganglion; TNC = trigeminal nucleus caudalis. Adapted from: Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533-552. Bigal ME, et al. Arq Neuropsiquiatr. 2009;67(2-B):559-569. MED/AMG/0016

Trigeminal nerve

Smooth muscle cell / postsynaptic neuron

Migraine Pain Starts with ‘Abnormal’ Activation of the TGVS The cause of migraine is unclear but involves abnormal activation of the TGVS

CGRP = calcitonin gene-related peptide; TGG = trigeminal ganglion; TGVS = trigeminovascular system. Adapted from: Burgos-Vega C, et al. Prog Mol Biol Transl Sci. 2015;131:537-564. Raddant AC, Russo AF. Expert Rev Mol Med. 2011;13:e36. Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533-552. Pietrobon D, Moskowitz MA. Annu Rev Physiol. 2013;75:365-391. Demarquay G, Mauguière F. Headache. 2016;56:1418-1438.

TGVS activation causes release of various neuropeptides at the meninges: Calcitonin CGRP Neurokinin A Substance P

These peptides can induce

neurogenic inflammation

Inflammation and dysregulation contribute to a feed-forward loop, causing migraine65

MED/AMG/0016

A Feed-forward Loop in the TGVS Creates a State of Hypersensitivity and Sustained Pain

TGN = trigeminal nerve; TGVS = trigeminovascular system; TNC = trigeminal nucleus caudalis. Adapted from: Demarquay G, Mauguière F. Headache. 2016;56:1418-1438. Akerman S, et al. Br J Pharmacol. 2002;137:62-68. Capuano A, et al. Mol Pain. 2009;5:43.

Meninges

4. Meningeal nociceptive receptors transmit signal back to TGN

1. Activation of TNC of the brainstem

2. Signal transmitted to the trigeminal ganglion

3. Collateral axons release pro-inflammatory peptides to meninges and vessels

MIGRAINE

5. Feed-forward loop creates hypersensitivity

Inflammation

Cortex

Thalamus

Trigeminal nerve fiber

MED/AMG/0016


Polling question:

Which of the following statements is FALSE? 1. CGRP is a 37-amino acid neuropeptide derived from

the gene encoding calcitonin

2. CGRP functions as a messenger in nerve cells and as a vasodilator

3. In the trigeminocervical complex, CGRP acts on second-order neurons to activate spinothalamic pathways

4. CGRP levels are decreased in migraine sufferers

5. Triptans suppress CGRP release from trigeminal nerves

What is Calcitonin-related Gene Peptide (CGRP)?

CGRP is a 37-amino acid neuropeptide derived from the gene encoding calcitonin. It functions as a messenger in nerve cells and as a vasodilator.

Adapted from: Amara SG et al. Nature 1982;298:240

CGRP is found in the peripheral and central nervous systems. This is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11.

CGRP is found in the enteric nervous system. This differs in 3 amino acids.

CGRP exists in two forms in humans: the α form predominates


Where are CGRP and their Receptors Located?

CGRP and CGRP receptors are widely expressed throughout the body. Of importance to migraine, CGRP and CGRP receptors are found in the central nervous system (CNS) and throughout the trigeminovascular system. Binding studies showed: • Co-expression of CLR and RAMP-1 in smooth muscle of human cranial vessels • CGRP and CGRP receptor expression in the dura mater and the trigeminal ganglion • In the spinal cord, CGRP expression in un-myelinated fibres (C-fibres); CGRP receptor expression

in myelinated fibres (A-delta-fibres) • In humans, CGRP binds densely in the cerebellum

Adapted from: Giamberardino MA et al. Intern Emerg Med 2016; 11:1045-57. Tso AR et al. Curr Treat Options Neurol 2017; 19-27.

CGRP Plays a Pivotal Role in Migraine

Adapted from: Russell FA et al. Physiol Rev 2014;94:1099.


Vasodilation

CGRP antibodies/antagonists

Dural mast cell degranulation leading to neurogenic inflammation

Dura mater Arachnoid mater Subarachnoid space

Pia mater

Vasodilation

CGRP antagonists

CGRP antibodies/antagonists

CGRP antagonists?

Trigeminal ganglion

Trigeminal nerve caudalis

Pial vessel

Trigeminal nerve fibers

CGRP PAIN PHOTOPHOBIA PHONOPHOBIA

White matter

Cortex

CGRP

Skull

Meningeal vessel

CGRP and the Trigeminovascular System

Adapted by: Walker CS and Hay DL. Brit J Pharmacol 2013;170 :1293–1307

In the trigeminocervical complex, CGRP acts on second-order neurons to activate spinothalamic pathways


Cranial vasculature

Trigeminal ganglia

Spinal trigeminal nuclei

Trigeminal neuron

Trigeminal neuron

Neuron

To thalamus Receptors

CGRP

AM1

AM2

AMY1

Cell types Hormones

CGRP

AM

Satellite glia

Endothellial

Vascular smooth muscle

Other glial

Direction of release

Trigeminal Ganglion Stimulation Increases CGRP in the Cranial Circulation

• Activation of the trigeminal ganglion increased levels of substance P-like and CGRP-like immunoreactivity.

• These findings suggested a putative

role of these peptides in the pathophysiology of migraine.

Adapted from: Goadsby PJ et al. Ann Neurol 1988;23:193-6.


120

100

80

60

40

20

0 CGRP Substance P CGRP Substance P

Cat Human

(pm

ol/

l)

TG Stimulation Control

CGRP Levels are Increased in Migraine Sufferers

• During migraine attacks (with or without aura) CGRP levels increase in the extracerebral circulation (external jugular blood)

• Only CGRP levels are elevated; there is no change in other peptides thought to be involved in pain transmission

Adapted from: Goadsby PJ et al. Ann Neurol 1990;28:183-7.

CGRP = calcitonin gene-related peptide; CONT = Control

100

80

60

40

20

0 Cont Rest Attack Cont Rest Attack

CG

RP

pm

ol/

l ju

gula

r

Migraine without Aura Migraine with Aura *

*

* p<0.001

Sumatriptan Suppress CGRP Release from Trigeminal Nerves

Adapted from: Goadsby PJ et al. Ann Neurol 1993;33:48-56. Edvinsson L & Linde M. Lancet 2010;376:645-55.

Treatment with sumatriptan normalized the increase in CGRP levels seen in acute migraine, with relief of headache pain

Sumatriptan acts via presynaptic 5-HT1B/D receptors to suppress CGRP release from trigeminal nerves

CGRP = calcitonin gene-related peptide: 5-HT = serotonin; VIP: vasoactive intestinal peptide; SP: substance P

80

60

40

20

0 CGRP

pm

ol/

l

VIP SP

Control

Migraine

Post-Sumatriptan

BOTOX Inhibits CGRP Release

Clinical and preclinical studies demonstrated that BOTOX acts via direct and indirect peripheral and central nociceptive pathways through the inhibition of the release of neuropeptides including CGRP

Adapted from: Szok D et al. Toxins 2015; 7:2659-73.

CGRP = calcitonin gene-related peptide; OBOT-A = Onabotulism toxin A; NK = Neurokinin; SP = Substance P; SNAP = synaptosomal-associated protein

CGRP SP Synaptic vesicle

Nerve terminal

OBOT-A OBOT-A SNAP-25 SNAP-25 (-) (-)

Synaptic cleft

CGRP receptor NK1 receptor

Do CGRP-targeted Agents Need to Cross the Blood-brain Barrier?

The trigeminal ganglion is a key site of action for CGRP in migraine • CGRP and CGRP receptors are

expressed in the trigeminal ganglion. As the trigeminal ganglion is expressed outside the blood-brain barrier (BBB), therapeutic agents do not need to penetrate the BBB to act.

Adapted from: Eftekhari S et al. Brain Res 2015; 1600:93.


Satellite glial cells

Large neuron CLR/RAMP1

Vessel, CLR/RAMP1 expression in smooth muscle cell layer

Small to medium-sized neurons

Lumen

CGRP expression

Co-expression CLR/RAMP1

Targeting CGRP or the CGRP Receptor? Therapeutic monoclonal antibodies have been developed that inhibit the activity of CGRP at the CGRP receptor. However, the cross-talk inhibition is different. Monoclonal antibodies to the CGRP receptor • Only inhibit function at the CGRP receptor • Leaving other calcitonin-family receptors functionally intact • To date, only one monoclonal antibody therapeutic targets the CGRP receptor:

Erenumab Monoclonal antibodies to the CGRP ligand • Inhibit the function of CGRP at all calcitonin-family receptors • To date, 3 monoclonal antibodies to the CGRP ligand are in development:

Eptinezumab, Fremanezumab, Galcaenzumab


Pellesi L, et al. Clin Pharmacol Drug Dev. 2017; 6(6):534-47.

Therapeutic Monoclonal Antibodies vs. Small Molecule Therapies

Adapted from: Silberstein S et al. , Headache 2015;55:1171.

Monoclonal antibodies Small molecule therapies

Larger (~150 kD); mainly extracellular Smaller (<1 kD); able to enter cells and cross blood-brain barrier

Target-specific Less specific

Parenteral administration Oral administration possible

Longer dosing interval (half-life: days to weeks) Shorter dosing interval (half-life: hours)

Not eliminated via hepatic, renal or biliary routes Elimination via hepatic, renal and/or biliary routes

Lower risk of drug-drug interactions Drug-drug interactions possible

Benefits of Therapeutic Monoclonal Antibodies

• No toxic metabolites (broken down to constituent amino acids)

• Restricted distribution

• Pharmacokinetics allow for longer dosing intervals (half-life days to weeks)

• Do not have a high degree of off-target toxicity

Adapted from: Wang W, et al. Clin Pharmacol & Therapeutics. 2008;84:548-558. Tabrizi MA, et al. Drug Discov Today. 2006;11:81-88. Foltz IN, et al. Circulation. 2013;127:2222-2230. Silberstein S et al. Headache 2015;55:1171.

Summary: Migraine Pathophysiology

• Migraine is a complex condition which is thought to involve the vasculature, central and peripheral neuronal pathways involved in pain signalling, as well as inflammation

• Activation of the trigeminovascular system is considered key and leads to the release of neuropeptide, induction of neurogenic inflammation contributing to a feed-forward loop, causing migraine

• Growing evidence suggests that CGRP plays a pivotal role in migraine prevention and treatment

• Based on this, small molecules and monoclonal antibodies have been developed to inhibit CGRP and its receptor


Migraine Treatment: Old and New

Polling Question Which of the following classes of medications do you use most often for migraine prophylaxis? 1. Antihypertensive

2. Antidepressant

3. Antiepileptic

4. Vitamins/minerals

5. Other

Migraine is a Neurologic Condition with Recurrent Attacks Varying in Frequency, Duration, and Disability

Establish a diagnosis

Educate migraine sufferers about their condition

Set realistic patient goals; discuss expected benefits of

therapy Empower patients to be actively engaged in their

treatment; track their progress

Develop formal management plan, individualize treatment, and consider comorbidities

Encourage patients to identify and avoid

migraine triggers

General principles of management

Adapted from: AAN = American Academy of Neurology. Silberstein SD. Neurology. 2000;55:754-762.

Migraine Treatment Goals (AAN/ASH Guidelines)

1. Marmura MJ, et al. Headache. 2015;55:3-20. 2. Silberstein SD. Neurology. 2000;55:754-762. 3. Silberstein SD. Continuum. 2015;21:973-989.

Adapted from: AAN = American Academy of Neurology; AHS = American Headache Society.

AAN and AHS treatment goals for acute and prophylactic therapy

Acute1,2 Prophylatic2,3

1. Treat attacks rapidly and consistently without recurrence

2. Restore the patient’s ability to function

3. Minimize the use of back-up and rescue medications

4. Optimize self-care and reduce subsequent use of resources

5. Be cost-effective for overall management

6. Have minimal or no adverse events

1. Reduce frequency, duration, or severity of attacks

2. Enhance responsiveness to acute therapy

3. Improve the patient’s ability to function

4. Reduce disability

5. Reduce healthcare costs

The goals of acute and prophylactic therapies are distinct but complementary

Acute Treatment Strategies (CHS)

Adapted from: Worthington et al., Can J Neurol Sci 2013;40:S1-S80

Acetaminophen Ibuprofen

ASA diclofenac potassium for oral solution

diclofenac potassium tablets naproxen sodium ± metoclopramide

Mild to Moderate Attack

• NSAID ± metoclopramide

• Triptan ± metoclopramide • Sumatriptan, SC injection,

nasal, oral • Zolmitriptan, nasal, oral, wafer • Rzatriptan, oral, wafer • Naratriptan, oral

Moderate to Severe Attack / NSAID Failure

+ a Triptan later for rescue if

necessary

• Eletriptan, oral • Almotriptan, oral • Frovatriptan, oral

Triptan NSAID w Triptan Rescue

ASA: acetylsalicylic acid; NSAID: non-steroidal anti-inflammatory drug; SC: subcutaneous

Adapted from Worthington et al., Can J Neurol Sci 2013;40:S1-S80

Refractory Migraine: Rx treatment Strategies (CHS)

Triptan + NSAID Triptan + NSAID (simultaneously) ± metoclopramide

Triptan + NSAID w/ rescue • Triptan + NSAID (simultaneously)

± metoclopramide + ≥1 for rescue later (as necessary) of:

Ketorolac

Indomethacin

Prochlorperazine

Chlorpromazine

Dexamethasone or prednisone

Opioid combination analgesic (last resort)

Dihydroergotamine Dihydroergotamine (nasal, or SC, IM self inj.) ± metoclopramide

Refractory Migraine

SC: subcutaneous; IM: intramuscular; NSAID: non-steroidal anti-inflammatory drug

How Do Physicians Choose Between Treatment Options?

• It can be difficult to decide between treatment options

• Decisions are made on a case-by-case basis and taking into account any

comorbidities, the patient’s age and history of side effects and response to previous medications

• Goal is to choose the most efficacious and best tolerated option for each patient

• Other considerations: • When selecting a triptan, choose a non oral route (NS or SC) for patients that vomit • If patients wake up with a migraine that is already severe, SC sumatriptan as a good option • For patients that are sensitive to side effects, choose almotriptan or naratriptan which

have a better side effect profile than the other triptans

NS = nasal spray; SC = subcutaneous

Adapted from: Expert Opinions

New Treatment Strategies: Targeting CGRP

• Small molecules (gepants) were developed specifically for migraine prevention

• These small molecules are orally administered and can cross the blood brain barrier

• Six gepants were found to be effective in acute migraine treatment

• Two of these were found to be associated with elevated transaminase levels when used for prevention in some patients

• There are currently newer gepants in clinical development (e.g. ubrogenpant, rimegepant)

Adapted from: Diener HC et al Lancet Neurol 2015; 14:1010-22 Silberstein S et al. Headache 2015; 55:1171-82.


4 mABs are currently in development for migraine prevention: Eptinezumab / Erenumab /Fremanezumab / Galcaenzumab All have CGRP targeted mABs were statistically superior to placebo in: 1. Primary endpoint:

• Reducing monthly migraine days (MMD)

2. Secondary endpoints may include: • 50% responder rates • Disability • Change in moderate/severe headache days • Change in monthly cumulative hours of headache

CGRP Target in Migraine: Monoclonal Antibodies

Adapted from: Giamberardino MA et al. Intern Emerg Med 2016; 11:1045-57.

mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide

All have shown: • A quick onset with a meaningful clinical effect in the first month

• Short-term safety and tolerability comparable to placebo

• Most common treatment-related adverse event was injection site reaction of mild to moderate severity with subcutaneous injections.

CGRP Target in Migraine: Monoclonal Antibodies

Adapted from: Giamberardino MA et al. Intern Emerg Med 2016; 11:1045-57. Tso AR et al. Curr Treat Options Neurol 2017; 19-27.

CGRP mABs Significantly Decrease the Number of Migraine Days

Adapted from: Bigal ME, et al. Lancet Neurology 2015; 14: 1081.

Fremanezumab for prevention of episodic

migraine:

Primary endpoint analysis (Weeks 9-12)


1

0

-1

-2

-3

-4

-5

-6

-7 Placebo

p<0.0001

p<0.0001

p<0.001

p<0.0001

p<0.0001

p<0.001

-6.27

-6.09

-3.46

Baseline Month 1 Month 2 Month 3

Dec

reas

e in

th

e N

um

ber

o

f M

igra

ine

Day

s

Baseline mean migraine days: 11.5 (placebo), 11.5 (225 mg), 11.3 (675 mg)

225 mg 675 mg

CGRP mABs Significantly Increase Responder Rates (short-term)

Galcanezumab for prevention of

migraine: Responder rates at 12

weeks

Adapted from: Dodick DW, et al. Lancet Neurol 2014; 13: 885.


70%

49%

32%

45%

27%

17%

0%

25%

50%

75%

100%

>50% Reduction >75% Reduction 100% Reduction

Galcanezumab Placebo

Secondary (OR 2.88)

Exploratory post-hoc analysis (OR 2.54)

Exploratory post-hoc analysis (OR 2.16)

Perc

enta

ge o

f R

esp

on

der

s

*Exploratory post hoc analysis

CGRP mABs Significantly Increase Responder Rates (long-term)

Adapted from: Goadsby PJ et al. NEJM. 2017;377:2123-32.


100

90

80

70

60

50

40

30

20

10

0 1 2 3 4 5 6

Months

Perc

enta

ge o

f Pa

tien

ts w

ith

≥5

0%

Red

uct

ion

in

Mig

rain

e D

ays

per

Mo

nth

Percentage of patients with ≥50% reduction at months 4-6 Placebo, 26.6% Erenumab, 70 mg, 43.3% (odds ratio vs. placebo, 2.1) Erenumab, ,140 mg, 50.0% (odds ratio vs. placebo, 2.8)

Placebo Erenumab, 70 mg Erenumab, 140 mg

CGRP mABs Improved Impact of Migraine on QoL Measures (MPFID)

Adapted from: Goadsby PJ et al. NEJM. 2017;377:2123-32.

Change from baseline at month 6

mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptid; MPFID = Migraine Physical Function Impact Diary

0

-1

-2

-3

-4

-5

-6

-4.2 -4.8

-2.4

P<0.001 for both

Poin

ts

Erenumab 70 mg Erenumab 140 mg Placebo

Change in Mean Physical Impairment Score (N=955)

0

-1

-2

-3

-4

-5

-6 -5.5 -5.9

-3.3

P<0.001 for both

Poin

ts

Erenumab 70 mg Erenumab 140 mg Placebo

Change in Impact on Everyday Activities Scores (N=955)

-7

Erenumab 70 mg and 140 mg reduced impact of migraine on QoL measures.

CGRP mABs Improved Impact of Migraine on QoL Measures (HIT-6)

Adapted: Lipton R et al. AAN 2017. Abstract 165.

mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide; HIT = Headache Impact Test

Change in HIT-6 scores for patients with chronic migraine achieving 75%, response rate following infusion of eptinezumab or placebo (N=616)

70

60

50

40

30

20

10

0 Baseline Week 4 Week 12

-13.6

-12.3

Ave

rage

HIT

-6 S

core

s

for

75

% R

esp

on

der

s

Wit

h A

ny

Stu

dy

Do

se

CGRP mABs Significantly Decreased Monthly Migraine Days in Chronic Migraine

Adapted from: Tepper S et al. Lancet Neurol 2017; 16:425-34.


Baseline Week 4 Week 8 Week 12

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.0

-4.5

-5.0

-5.5

-6.0

-6.5

-7.0

-7.5

-5.1

-5.0

-6.2

-6.5 -6.6 -6.6

-4.2

-3.6

-2.7

Placebo (n=281) Erenumab 70 mg (n=188) Erenumab 140 mg (n=187)

Ch

ange

in m

on

thly

mig

rain

e d

ays

CGRP mABs: Clinical Trial Results: Tolerability Summary No clinically significant change seen in vitals or ECGs

No change in hepatic enzymes judged to be treatment related

AEs in similar proportion to placebo group

Most common AE was injection site reaction of mild to moderate severity for SC injections

No SAEs reported

Long term safety remains unknown (trials were usually 3 months duration), further study needed

SAE: Serious adverse event; AE: Adverse event; SC: sub-cutaneous Adapted from: Tso AR et al. Curr Treat Options Neurol 2017; 19-27.

Polling Question

Do you talk to your patients about new medications that are coming to market?

1. Yes

2. No

3. It depends

Practical Tips: Guidance to discuss the new treatment

with patients

Practical Guidance for Talking to Your Patients about New Medications

Discussion points with patients can include: • Purpose of medication • Treatment options • How the medication works • How the medication is administered • Duration of therapy, reminder that this is a long-term disorder and the patient

needs to be involved in their own management • Goals of therapy • How effectiveness will be monitored • Adverse effects and how to deal with them - drug specific issues

New options are coming…

…providing hope for your patients like Sophie and Marie

Sophie Episodic Migraine

Marie Chronic Migraine

Key Points • Migraine greatly impacts patients quality of life and impacts them personally and professionally

• Current unmet needs remain in terms of finding treatments that are effective, tolerable and patients will continue to take.

• CGRP monoclonal antibodies were developed for migraine-specific targets and have demonstrated good efficacy in episodic and chronic migraine

Key Points

• Tolerability data to date are promising, although long-term safety needs to be established

• These new treatment options provide hope for migraine patients for whom current options are either ineffective or poorly tolerated

Q & A

Documents

Thinking Ahead: New Treatment Options for Migraine Preventioncongress.cnsfederation.org/course-notes/2018_Course_Notes/CNSF_… · Thinking Ahead: New Treatment Options for Migraine