thinking ahead: new treatment options for migraine...
TRANSCRIPT
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
CGRP = calcitonin gene-related peptide
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
CGRP = calcitonin gene-related peptide
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.
CGRP = calcitonin gene-related peptide
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
CGRP = calcitonin gene-related peptide
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.
CGRP = calcitonin gene-related peptide
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.
CGRP = calcitonin gene-related peptide
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
CGRP = calcitonin gene-related peptide
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
CGRP = calcitonin gene-related peptide
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.
CGRP = calcitonin gene-related peptide
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)
mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide
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.
mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide
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.
mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide
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.
mABs = monoclonal antibodies; CGRP = calcitonin gene-related peptide
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