Transcript PowerPoint Presentation - Therapeutic Uses of Botulinum

Therapeutic Uses of Botulinum
Toxin in Neuro-ophthalmology
Janette I. Lindley, MD FRCSC
St. Paul’s Hospital
University of British Columbia
Overview
1.On label uses:
 hemifacial spasm
 blepharospasm
injection techniques
 other: cervical dystonia
strabismus
wrinkles (glabella)
Overview
2. Off label uses:
 headache (chronic daily)
Phase II Trial Results
injection technique
 crocodile tears, protective ptosis
 other: writer’s cramp, hyperhydrosis,
head tremor, focal spasticity,
drooling
Botulinum Toxin
in Neuro-ophthalmology
neurotransmission inhibition (ACH, other)
at NMJ
 chemical denervation striated muscle
peaks @ 2 weeks
 Neuronal sprouting heralds return of
function @ 3 – 6 mos.

Botulinum Toxin
 Serotype A (Botox
 Serotype
, Dysport)
B (Myobloc)
Hemifacial spasm
Unilateral
 Periocular and lower facial
+/-platysma
stapedius (clicking at hs)
 R/O facial nerve compression
(MRI)

Hemifacial spasm movie
Click here
Blepharospasm
tonic/ clonic lid closure
 may present unilaterally
 uncontrollable
 functional cause for visual loss
 (apraxia of lid opening)

Blepharospasm movie
(Click here)
Blepharospasm
Pathological Pain Inhibition

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

observed (Binder et al) after Rx
hyperfunctional facial lines
inhibition of neuromuscular activity
and
substance P, glutamate, & calcitonin
peptide release
results in analgesic effect
Headache Disorders
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heterogeneous group of conditions
recent results Phase II trials in
chronic daily headache (CDH)/
transformed migraine
randomized, double blind
placebo controlled
75% completion at 11 mos.
CDH or Transformed Migraine
HA15 d/m > 1(3)m
 each HA 4 h/d
 no primary cause
 H/O episodic migraine (>50% pr migr)
 4% of pop ~1.2-1.5 million in Canada
 significant disability/resource use

Chronic Daily Headache Studies
-Common Design
Primary
analysis
Placebo NonResponder
(PNR)
BoNTA*
BoNTA*
BoNTA*
Placebo
Placebo
Placebo
BoNTA*
BoNTA*
BoNTA*
Placebo
Placebo
Placebo
Baseline
Placebo
Responder
(pr)
-60
Final
analysis
-30
*Allergan, Botox®, USA
0
Placebo
Day
90
180
270
Chronic Daily Headache Injection Patterns:
Fixed Site-Fixed Dose (FSFD) 75,150,225 U
Modified Follow-the-Pain (mFTP) 105-260 U. 190
Procerus, Corrugator, Frontalis,
Temporalis, Masseter (optional),
Occipitalis
Trapezius, Semispinalis,
Splenius capitis
X
X
X
X
X
X
X
X
Chronic Daily Headache Studies - Design
Silberstein et al, Headache 2005. Mathew et al, Headache 2005.
Silberstein
(n=702)
Concurrent HA
Prophylaxis
Mathew
(n=355)
Allowed
Randomization to
Active Treatment
Injection
Paradigm
Dose
3:1
1:1
FSFD
mFTP
0, 75, 150, 225U
0, 105 – 260U
Safety
 Safe
and well-tolerated
 Safe
Results
- HA-Free Days – N.S.
 1° - HA-Free Days – N.S.
 2° - Responder Rate –
P<0.05
 2° - Responder Rate – N.S.
 %  50% HA d/m
 1°
*Allergan, Botox®, USA
and well-tolerated
Chronic Daily Headache – Efficacy Measures
Mathew et al, Headache 2005.
Efficacy Measures
Outcome Measure
Day 180
Not
significant
1o
Number of HA-Free Days/month
2o
Responder Rate
(% Patients with ≥ 50% decrease HAdays/month)
p < 0.05
Number of Headaches/month
p < 0.05
Additional


Additional
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
*Allergan, Botox®, USA
Proportion of patients with ≥50%
decrease in HA frequency
Number of days of acute HA med use
Number of intakes of acute meds
MIDAS
Headache Specific QOL
Not
significant
Chronic Daily Headache – Adverse Events
Mathew et al, Headache 2005.
Treatment-Related Adverse Event
BoNTA*
Placebo
p-value
Neck Pain
23 (13.3%)
1 (0.5%)
<0.001
Arm Pain
7 (4%)
1 (0.5%)
0.033
Injection Site Hemorrhage
2 (1.2%)
9 (4.9%)
0.039
Muscular Weakness
38 (22%)
0 (0%)
<0.001
Skin Tightness
8 (4.6%)
0 (0%)
0.003
Blepharoptosis
12 (6.9%)
1 (0.5%)
<0.001
No
significant difference: Headache, neck rigidity, pain, face pain, dysphagia,
hypertonia, hyperesthesia, dizziness, pharyngitis, visual disturbance
Majority of AE's were mild to moderate in severity and transient in nature
*Allergan, Botox®, USA
Chronic Daily Headache – Safety & Results
Mathew et al, Headache 2005.
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*Allergan, Botox®, USA
Repeat treatment (up to 3 treatment cycles) with BoNTA* is
safe and well-tolerated at doses up to 260U
No neutralizing antibodies
No benefit of placebo run-in  pool PNR and PR groups
Although the 1° endpoint was not met, significant &
clinically meaningful improvements were seen following
BoNTA* vs placebo:
 Responder rates
 Headache frequency
No significant change in proportion of patients with ≥50%
Decrease in HA Frequency, Number of Days of Acute HA
Med Use, Number of Uses of Acute Meds, MIDAS, Headache
Specific QOL
CDH – 1° Outcome Measure
Mathew et al, Headache 2005.
Number of Headache-Free Days
Mean Change in Number of Days
16
PNR BoNTA*
(n=134)
14
PNR PBO
(n=145)
12
10
PR BoNTA*
(n=39)
8
PR PBO
(n=37)
6
4
Δ = 1.5 HA-free
days at Day 180
2
0
0
30
60
90
120
150
180
Days After Placebo Run - In
*Allergan, Botox®, USA
210
240
270
Blinded
Treatment
CDH – 2° Outcome Measure
Mathew et al, Headache 2005.
Responder Rate
% Patients with > 50% Decrease Headache Days
100
PNR BoNTA*
(n=134)
*p<0.027
% of Patients
75
50
PNR Placebo
(N=145)
Blinded
Treatment
*
33
25
15
0
0
30
60
90
120
150
180
Days After Placebo Run - In
*Allergan, Botox®, USA
210
240
270
CDH – Number of HA’s
Pooled
Mathew et al, Headache 2005.
(PNR + pr)
Number of Headaches – Change from Baseline
0
*p<0.05
Mean Change in
Number of Headaches
per Month
-2
§ p=0.001
-4
* *
-6
-8
*
§
-10
* * *
-12
0
30
60
90
120
150
180
Days After Placebo Run - In
*Allergan, Botox®, USA
Placebo
(n=182)
Blinded
Treatment
3.4
*
BoNTA*
(n=173)
210
240
270
Baseline
BoNTA* = 13.5
Placebo = 12.7
– % Decrease HA Frequency
CDH
Dodick et al, Headache 2005.
Subgroup Analysis - No Concomitant Prophylaxis
% Decrease in Number of Headaches
≥30%
≥50%
100
90
*p<0.05
* *
*
% of Patients
80
70
* *
60
50
100
*p<0.05
90
80
70
*
60
50
40
40
30
30
20
20
*
10
10
0
0
0
30
60
90
120
150
180
210
240
270
Days After Placebo Run - In
BoNTA*
*Allergan, Botox®, USA
0
30
60
90
120
150
180
210
Days After Placebo Run - In
Placebo
Blinded Treatment
240
270
Chronic Daily Headache
mFTP
 HA free days - NS
  50%  in HA d/m - S
 #HA/mo - S
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Protective ptosis
15 – 20 units
 into levator
ab externo
via flipped upper lid

Autonomic Nerve Inhibition –
Ach Release Blocked
glands
 lumen post injection (Swartling)
 smooth muscle

Injection
of BTX-A
Conclusions

Onset of effect occurred within 2 – 3 days
following injection and lasted for 3 - 4 months.
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Side effects are infrequent, mild and transient.
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Subjective and objective evidence for reduction in
tear production.
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Effectiveness needs to be established with a
randomised clinical trial.
Thanks to:
SPH Staff:
Cynchia, Maureen, Kathy
Residents:
Leah, Paul, Briar
Allergan: Botox Therapeutic Div
G. Davidovic
D. Hoppenbrouwer