BOTOX®
The Real Facts
David H. Hammett, M.D.
Neurology
March 26, 2012
4540 Trenholm Road
Columbia, SC 29206
(803) 790-4700
Presentation Overview
Introduction to BOTOX®
How does BOTOX® Work?
BOTOX® in the Treatment of Blepharospasm
BOTOX® in the Treatment of Cervical Dystonia
BOTOX® for Severe Primary Axillary Hyperhidrosis
BOTOX® in the Treatment of Spasticity
BOTOX® in the Treatment of Chronic Migraine
Important Information About BOTOX®
History
In the 1820s, the biological basis for food
poisoning was not understood.
Studies began on a batch of improperly
prepared sausages responsible for the
death of several dozen people in
Germany.
First suggestion that there was something
in the spoiled sausages that brought
on the disease.
These experiments led to a better
understanding of the neurological
symptoms of food-borne botulism
(ptosis, dysphagia, muscle weakness,
and, if left untreated, paralysis and
respiratory failure).
History
More than 70 years later, Dr.
Emile Pierre van Ermengem
of Belgium was asked to
investigate an outbreak of
botulism following a funeral
dinner where three people
died and 23 were paralyzed.
Van Ermengem was able to make
a connection between
botulism and a spore-forming
bacterium he named Bacillus
botulinus (now known as
Clostridium botulinum). Many
scientific studies followed,
and seven strains of
botulinum toxin were
eventually identified (A-G).
History
In 1978, an Opthalmologist (Dr.Scott)
received approval to inject minute
amounts of botulinum toxin into
human volunteers.
In the early 1980s, he published a
number of studies including a 1981
paper in the Transactions of the
American Ophthalmological Society
that asserted botulinum toxin
“appears to be a safe and useful
therapy for strabismus.”
Additional research showed the drug’s
benefits went beyond
ophthalmology, providing patients
with temporary relief from facial
spasms, neck and shoulder spasms,
even vocal cord spasms.
History
In 1988, drugmaker Allergan
acquired the rights to
distribute Scott’s batch of
botulinum toxin type A (or
Oculinum, as it was then
known) and a year later, the
FDA approved botulinum
toxin type A for the treatment
of both strabismus and
blepharospasm.
Shortly thereafter, Allergan
acquired Scott’s company
and changed the drug’s
name to the compact, catchy
“Botox.”
Timeline – Development and FDA
1950s
Scientists discover that botulinum toxin can
reduce muscle spasms.
1960s/1970s
Studies explore botulinum toxin as a treatment
for strabismus (crossed eyes).
1988
Allergan researches other medical uses of
botulinum toxin.
1989
Allergan introduces BOTOX®, the first botulinum
toxin approved by the FDA to treat blepharospasm
(eyelid spasms) and strabismus.
2000
FDA approves BOTOX® for cervical dystonia
Timeline – Development and FDA
2002
FDA approves BOTOX® Cosmetic, (same formulation
as BOTOX®) for moderate to severe frown lines
between the brow.
2004
FDA approves BOTOX® for severe underarm sweating
2009
20-year anniversary of BOTOX®.
2010
FDA approves BOTOX® for upper limb spasticity.
2010
BOTOX® is approved by the FDA specifically for the
prevention of headaches in adults with Chronic
Migraine (15 or more days each month with headache
lasting 4 or more hours each day)
2011
FDA approval for neurogenic urinary incontinence
Glabellar Frown Lines
Glabellar frown lines
are the most
common reason for
cosmetic injection
of botulinum toxin.
BOTOX® (onabotulinumtoxinA) for
Chronic Migraine Patients:
A Prophylactic Treatment Paradigm
Please see Indication, Important Limitations, and Important Safety
Information, including Boxed Warning, throughout this deck.
Indication
BOTOX® (onabotulinumtoxinA) for injection is indicated for the
prophylaxis of headaches in adult patients with chronic migraine
(≥15 days per month with headache lasting 4 hours a day or longer).
Important limitations
Safety and effectiveness have not been established for the
prophylaxis of episodic migraine (14 headache days or fewer per
month) in seven placebo-controlled studies.
47
IMPORTANT SAFETY INFORMATION,
INCLUDING BOXED WARNING
Distant Spread of Toxin Effect
Postmarketing reports indicate that the effects of BOTOX® and all
botulinum toxin products may spread from the area of injection to
produce symptoms consistent with botulinum toxin effects. These may
include asthenia, generalized muscle weakness, diplopia, ptosis,
dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing
difficulties. These symptoms have been reported hours to weeks after
injection. Swallowing and breathing difficulties can be life threatening,
and there have been reports of death. The risk of symptoms is
probably greatest in children treated for spasticity, but symptoms can
also occur in adults treated for spasticity and other conditions,
particularly in those patients who have an underlying condition that
would predispose them to these symptoms. In unapproved uses,
including spasticity in children, and in approved indications, cases of
spread of effect have been reported at doses comparable to those
used to treat cervical dystonia and at lower doses.
48
Please see additional Important Safety Information
throughout this deck.
Please
Please
see
see
Important
Important
Safety
Safety
Information,
Information,
including
including
Boxed
Boxed
Warning,
Warning,
throughout
on slides this
14-20.
deck.
Diagnostic Criteria for Chronic Migraine
Chronic Migraine is a defined condition1-3
15 or more headache days per month
• Headaches lasting 4 hours per day or more
• At least 8 headache days classified as migraine days
• With or without medication overuse
What are migraine characteristics1?
Patients should experience at least 2 of these
pain characteristics:
And at least 1 of:
Unilateral
Nausea and/or vomiting
Migrainous, pulsating quality
Photophobia and
phonophobia
Moderate to severe intensity
Aggravated by routine
physical activity
49
1. Headache Classification Committee; Olesen J et al. Cephalalgia. 2004;24:9-160.
2. Headache Classification Committee; Olesen J et al. Cephalalgia. 2006;26:742-746.
3. Lipton RB. Headache. 2011;51(S2):77·83.
Please
Please
see
see
Important
Important
Safety
Safety
Information,
Information,
including
including
Boxed
Boxed
Warning,
Warning,
throughout
on slides this
14-20.
deck.
Case Study: Emily
Patient History:
• 43-year-old woman is seen for a
main complaint of headache
• She has had headaches since her
teens
• She reports 8 migraine attacks per
month, each lasting 2–3 days
• She has migraine features (nausea,
photophobia, and phonophobia) on
all headache days
• She has tried multiple preventive
medications
Case Studies do not involve actual patients
50
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Study Design of Two Phase 3 Studies of
Chronic Migraine Patients1,2
• Large clinical program of Chronic Migraine sufferers (1384 patients)
Open-Label Phase
Double-Blind Phase
Weeks
BOTOX® vs Placebo
Baseline
Randomization
-4
Day
0
4
1
BOTOX® vs
Placebo (saline)
8
12
16
2
BOTOX® vs
Placebo (saline)
20
Primary
Time
Point
24
All Patients on BOTOX®
28
3
BOTOX®
32
36
40
44
4
BOTOX®
Phone Interview
48
52
56
5
BOTOX®
Treatment
• Headache symptoms and medications were recorded in a daily telephone diary
51
1. Aurora SK et al. Cephalalgia. 2010;30:793-803.
2. Diener HC et al. Cephalalgia. 2010;30:804-814.
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Efficacy of BOTOX® at Week 24
for Study 1 and Study 2
Study 1
Study 2
BOTOX®
(n=341)
Placebo
(n=338)
BOTOX®
(n=347)
Placebo
(n=358)
Change from baseline in
frequency of headache
days
-7.8*
-6.4
-9.2*
-6.9
Change from baseline in
total cumulative hours of
headache on headache
days
-107*
-70
-134*
-95
Efficacy per 28 days
*Significantly different from placebo (p≤0.05)
52
BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011.
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Adverse Reactions Reported by 2% of Patients Treated With BOTOX
(More Frequent Than Placebo) in Two Chronic Migraine Double-Blind,
Placebo-Controlled Clinical Trials1
BOTOX® (n=687)
155 Units-195 Units
Placebo (n=692)
Nervous system disorders
• Headache
• Migraine
• Facial paresis
32 (5%)
26 (4%)
15 (2%)
22 (3%)
18 (3%)
0 (0%)
Eye disorders
• Eyelid ptosis
25 (4%)
2 (<1%)
Infections and infestations
• Bronchitis
17 (3%)
11 (2%)
Musculoskeletal and connective tissue disorders
• Neck pain
• Musculoskeletal stiffness
• Muscular weakness*
• Myalgia
• Musculoskeletal pain
• Muscle spasms
60 (9%)
25 (4%)
24 (4%)
21 (3%)
18 (3%)
13 (2%)
19 (3%)
6 (1%)
2 (<1%)
6 (1%)
10 (1%)
6 (1%)
General disorders and administration site conditions
• Injection site pain
23 (3%)
14 (2%)
Vascular disorders
• Hypertension
11 (2%)
7 (1%)
Adverse Reactions by Body Systems
Severe worsening of migraine requiring hospitalization occurred in approximately 1% of patients treated with BOTOX ® in
Study 1 and Study 2, usually within the first week after treatment, compared to 0.3% of placebo-treated patients.
53
*Aurora et al 2011 reported n=38 (5.5%); 2.2% of the incidences of muscular weakness were facial paresis. 2
1. BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011. 2. Aurora SK et al. Headache. 2011;51:1358-1373.
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Discontinuation Rates
BOTOX®
(n=687)
Placebo
(n=692)
Discontinuation rate
12%
10%
Discontinuations related to
adverse events*
4%
1%
*The most frequent adverse events leading to discontinuation in the BOTOX®
group were neck pain, headache, worsening migraine, muscular weakness,
and eyelid ptosis.
Please see Adverse Reactions table on slides 12 and 24.
54
BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011.
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Injection Paradigm
• The phase 3 BOTOX® pivotal studies for Chronic Migraine
patients has established a treatment paradigm1
• The patient population, recommended dose, and injection
paradigm were established based on 10 years of studies
assessing various patient types, muscle groups, and doses2-6
• 155 Units of BOTOX® are administered as 31 fixed-site, fixeddose injections across 7 specific head/neck muscle areas1
• For each injection site, the injection volume will be 0.1 mL
(5 Units)1
• Each muscle has a fixed1:
• Total dose
• Number of injection sites
• Location of injection sites
1. Blumenfeld AM et al. Headache. 2010;50:1406-1418. 2. Mathew NT et al. Headache.
2005;45:293-307. 3. Silberstein SD et al. Mayo Clin Proc. 2005;80:1126-1137. 4. Silberstein
SD et al. Headache. 2000;40:445-450. 5. Binder WJ et al. Otolaryngol Head Neck Surg.
2000;6:669-676.6. Freitag FG et al. Headache. 2008;48:201-209.
55
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Case Study: Emily’s Response to
Treatment 2 Weeks Post-Injection
Follow-up visit 2 weeks postinjection:
• Emily is still experiencing headaches due to
Chronic Migraine
• She also now has neck pain
• She feels dissatisfied and hopeless and is
not sure if she wants to continue with
BOTOX® treatments
In PREEMPT 1 and 2, the first
evaluation was 4 weeks post-injection.
Case Studies do not involve actual patients
56
Please see Important Safety Information, including Boxed Warning, throughout this deck.
Case Study: Monitoring Emily’s Response
to Treatment
Second Injection Cycle:
Follow-up with the patient
• Emily has returned for her
second BOTOX® treatment
• You continue to monitor and
document Emily’s response to
treatment
Case Studies do not involve actual patients
57
BOTOX®: The Real Facts
Summary
Questions