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

(1)

Botulinum toxin in the treatment

of chronic migraine

Gregory P. Hanes, MD

Neuroscience Summit

(2)

1. Silberstein SD et al. Neurology. 1996;47;871-875. 2. Dodick DW. N Engl J Med. 2006;354:158-165.

Primary Headache Disorders:

Frequency Classification

After Secondary Causes

Are Ruled Out

Episodic Headache

Frequency

<15 Days/Month

Short-Duration Chronic

Daily Headache

Duration <4 Hours or

Multiple Discrete

Episodes

Chronic Daily Headache

(Long Duration)

Daily or Near-daily Headache

Lasting ≥4 Hours

Chronic Headache

Frequency

≥15 Days/Month

Primary Headache

Disorders

With or Without

Medication Overuse

(3)

Unilateral

Pulsating quality

Moderate to severe intensity

Aggravated by routine

physical activity

Nausea and/or vomiting

Photophobia and phonophobia

Diagnostic Criteria for Chronic

Migraine

* Multiple headache phenotypes are possible.1,2

1. Headache Classification Committee. Cephalalgia. 2004;24(suppl 1):9-160. 2. Headache Classification Committee; Olesen J et al. Cephalalgia. 2006;26:742-746. 3. Lipton RB. Headache. 2011;51(S2):77-83.

• Chronic Migraine is a defined condition

1-3*

–

15 or more headache days per month

–

Headaches lasting 4 hours per day or more

–

At least 8 headache days that are linked to migraine

2,3

–

With or without medication overuse

• What are migraine characteristics

1*

?

Patients Should Experience at Least

(4)

1. Pietrobon D et al. Nat Rev Neurosci. 2003;4:386-398. 2. Pietrobon D. Neuroscientist. 2005;11:373-386.

Activation of Trigeminal Sensory

Afferents

Central disinhibition

1 Stimulation of meningeal

sensory nerve (trigeminal)

2 Vessel

dilation

Nerve

Peptide

release

Inflammation

Release of

neuropeptides,

CGRP

3 Activation of TNC can result

in central sensitization

Spinothalamic

track

Trigeminal

Nerve

Trigeminal

Ganglion

TNC

4

CGRP = calcitonin gene-related peptide; TNC = trigeminal nucleus candalis.

Activation of

cortical pain

centers via

thalamus

5 Thalamus

PAIN

6

(5)

Prevalence of Chronic Migraine

* According to broad criteria (migraine with ≥15 headache days/month). 1. Dodick D. N Engl J Med 2006;354:158-165.

2. Natoli J et al. Cephalalgia. 2010;30(5):599-609

• Chronic migraine is the most common form of

chronic daily headache in headache specialty

clinics

1

• Approximately 2%* of the global population

suffers from

chronic migraine

2 –

Chronic migraine prevalence estimates are 2.5 to

6.5 times higher in women (1.7%–4.0%) than in

(6)

60

45

24

19

41

31 ₃₀

34

26

34

51

37

17

13

26

15

19

28

26

21

22

0

10

20

30

40

50

60

70 Allergies or

Hay Fever

Sinusitis

Asthma Bronchitis Depression Chronic

Pain

Anxiety High Blood

Pressure

Cholesterol

High

Obesity

Arthritis

%

Chronic Migraine

Episodic Migraine

* p<0.05.

Data from the American Migraine Prevalence and Prevention (AMPP) study. Buse D et al. J Neurol Neurosurg Psychiatry. 2010; 81(4):428-432

Common Comorbidities with Significant Differences

Between Episodic and Chronic Migraine

*

(392) (5374) (296) (3926) (160) (1827) (126) (1370) (270) (2718) (206) (1599) (198) (1993) (221) (2951) (224) (2713) (167) (2223) (220) (2354)

(7)

Migraine Progression

1. Lipton RB. Neurology. 2009;72:S3-S7.

2. Bigal ME, Lipton RB. Curr Opin Neurology. 2008;21:301-308.

• Progression is often gradual and can evolve over months or years

1,2

• Transformation is neither inexorable nor irreversible; spontaneous or

induced remissions are possible

1,2

• Transformation happens in some but not all episodic patients (~3% of

episodic migraine sufferers in 1 year, n=18,968)

2

(8)

Menken M. Arch Neurol. 2000;57:418-420.

Severe Migraine is Ranked in the

Highest Disability* Class by WHO

3

4

5

6

7 Disability

Class 4

Disability

Class 5

Disability

Class 6

Disability

Class 7

In

cr

ea

sin

g D

isa

bili

ty

Below-the-Knee

Amputation

Deafness

Mild Mental Retardation

Down Syndrome

Unipolar Major Depression

Blindness

Paraplegia

Severe Migraine

Active Psychosis

Dementia

Quadriplegia

(9)

Data from the American Prevalence and Prevention (AMPP) Study. Bigal ME et al. Neurology. 2008;71;559-566.

Impact of Chronic Migraine on Daily

Activities Over a 3-Month Period

0%

10%

20%

30%

40%

50%

60%

70%

≥5 Days of Missed

Work or School

Reduced Productivity

≥5 Days with

at School or Work

≥5 Days of Missed

Household Work

≥5 Days of Reduced

Productivity at

Houshold Work

≥5 Days of Missed

Family Activities

Chronic Migraine

Episodic Migraine

p=0.0012

p<0.001

(10)

Treatment of Chronic Migraine

• Oral Medications

–

Prophylactic medications

–

Abortive

• Injections

–

botulinum toxin

–

Trigger point

–

Occipital nerve blocks

–

Facet

• Alternative Medicine

–

Acupuncture

–

Massage

–

Heat/cold

–

biofeedback

(11)

Oral Medications

Abortive

• Triptans

–

sumatriptan (Immitrex)

–

rizatriptan (Maxalt)

• NSAIDS

–

naproxen (Aleve)

–

ibuprofen (Advil)

• Opiates

Prophylactic

• BP meds

–

B-blockers (propranolol)

–

CCBs (verapamil)

–

ACE/ARB (Avapro, Atacand)

• Anticonvulsants

–

topiramate (Topamax)

–

valproic acid (Depakote)

• Antidepressants

–

fluoxetine (Prozac)

–

duloxetine (Cymbalta)

• NSAIDS

• Natural supplements

–

CoQ10, feverfew, Mg,

butterbur

(12)

botulinum toxin

• Type A, Botox

• Only FDA-approved toxin for chronic migraine

• Blocks pre-synaptic acetylcholine release

• Weakens muscles by blocking NMJ

• Interrupts synaptic communication between

(13)

(14)



PREEMPT consisted of two phase 3 studies of CM patients

–

Largest clinical program on CM sufferers (1384 patients)

–

Global study across 122 sites in North America and Europe

–

24-week randomized, double-blind, placebo-controlled phase

–

32-week open-label phase



Headache symptoms and medications were recorded in a daily telephone diary

PREEMPT Study Design

12

32

36

40

44

48

52

4

8

16

20

56 -4

Day ₀

24

28 Open-Label Phase

Baseline

W

eek

s

Primary

Time Point

Randomization

Double-Blind Phase

1

2

3

4

5 BOTOX® vs.

Placebo (saline)

BOTOX®_vs.

Placebo (saline) BOTOX

® _BOTOX® _BOTOX®

(15)

* FTP = Follow the Pain

Dodick DW et al. Headache. 2010;50:921-936. Pictures by AlphaMedica for Allergan 2010

Dosing and Administration

A

C

D

B

A) Corrugator: 5 U each side B) Procerus: 5 U (1 site) C) Frontalis: 10 U each side

D) Temporalis: 20 U (each side)

Allowed additional FTP* site of injection: 10 U (up to 2 sites)

G

E

F

E) Occipitalis: 15U (each side) F) Cervical paraspinal: 10 U _{(each side)} Allowed additional FTP site of

injection: 10 U (up to 2 sites)

G) Trapezius: 15 U (each side) Allowed additional FTP site of

injection: 20 U (up to 4 sites)

(16)

Dosing and results in these studies are specific to the formulation of BOTOX® manufactured by Allergan, Inc. (Irvine, CA). The Allergan, Inc., formulation is not interchangeable with other botulinum toxin products and cannot be converted using a dose ratio.

Blumenfeld Headache 2010;50:1406-1418.

Injection Paradigm: Required Dose

Using

a Fixed-Site, Fixed-Dose Paradigm

Order

Muscle

Number of Units (U)

A

Corrugator

10 (5 each side)

B

Procerus

5 C

Frontalis

20 (10 each side)

D

Temporalis

40 (20 each side)

E

Occipitalis

30 (15 each side)

F

Cervical paraspinal

20 (10 each side)

G

Trapezius

30 (15 each side)

(17)

BOTOX® was statistically significantly more effective than placebo in reducing mean frequency of headache days at every visit in the double-blind phase starting at the first post-treatment study visit (Week 4)

HA = headache; HIT = Headache Impact Test.

Pooled Efficacy of BOTOX

®

_{at Week 24}

(Primary Time Point)

Endpoint, Mean Change From Baseline

BOTOX

_(n=688)

®

Placebo

_(n=696)

p Value

Frequency of HA days

-8.4

-6.6

<0.001

Frequency of migraine days

-8.2

-6.2

<0.001

Frequency of moderate/severe HA days

-7.7

-5.8

<0.001

Total cumulative HA hours on HA days

-120

-80.5

<0.001

% Patients with severe (≥ 60) HIT-6 score

67.6

78.2 <0.001

Total HIT-6 score

-4.8

-2.4

<0.001

Frequency of HA episodes

-5.2

-4.9

0.009 Frequency of migraine episodes

-4.9

-4.5

0.004 Frequency of acute HA pain medication intake (all categories)

-10.1

-9.4

0.247

(18)

Mean Change from Baseline in Cumulative Headache Hours on Headache Days

PREEMPT Pooled Analysis

Mean ± standard error.

The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group. Cumulative hours of headache at baseline: 295.9 BOTOX® group vs. 281.2 placebo group, p=0.021.

(19)

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

4

8

12

16

20

24

28

36

48

56 Mean Change from Baseline in Total HIT-6 Scores

* Between-group difference exceeded the minimally important difference (MID) for HIT-6 (2.3 units) indicating a clinically significant effect of BOTOX® treatment.1

The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group. Total HIT-6 scores at baseline: 65.5 BOTOX® group vs. 65.4 placebo group; p=0.638.1

1_{DB phase - Lipton RB et al. Neurology 2011;77(15):1465-72.} 2_{OL Phase - Data on file, Allergan, Inc.}

PREEMPT Pooled Analysis

Ch

an

ge

fro

m

B

as

elin

e in

To

tal H

IT

-6 Sc

or

e

p<0.001 p<0.001 p<0.001 p<0.001 _p<0.001 p<0.001 p=0.002 p=0.002 p=0.022 p=0.069

Weeks

2.4*

BOTOX

®

Placebo

(20)

*All AEs include all reported events, regardless of relationship to treatment. †_{Treatment-related AEs are those that in the investigator’s opinion may have been}

caused by the study medication with reasonable possibility. ‡_{Migraine requiring hospitalization.}§_{The most frequently reported AEs leading to discontinuation in}

the BOTOX®_{group were neck pain (0.6%), muscular weakness (0.4%), headache (0.4%), and migraine (0.4%).}

PREEMPT: Summary of Adverse Events

Pooled Data, Double-Blind Phase (%)

BOTOX

®

(n=687)

Placebo

(n=692)

All adverse events (AEs)*

62.4

51.7 Treatment-related AEs

†

_29.4

_12.7

Serious AEs

4.8

2.3 Treatment-related, serious AEs

†

_0.1

‡

_0.0

Discontinuations related to AEs

§

_3.8

_1.2

(21)

Most AEs were mild or moderate in severity and resolved without sequelae. Only neck pain and muscular weakness were reported in ≥5% of patients