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Report
Botox® for the overactive
bladder -The evidence
Philip Toozs-Hobson
Consultant Urogynaecologist
Declaration
• I was sponsored by Allergan to travel to and
attend this meeting
• I work as a consultant for Allergan and Astellas
• I was an author on the RELAX study
• I have been involved in Allergan and Astellas
sponsored trials
• I undertake private practice
What’s wrong with anticholinergic medication
• Almost 70–90% of patients
stop their treatment within 1
year1
Percentage of patients remaining on each
anticholinergic over 12 months4
100
• Discontinuation after first
prescription2
80
Patients (%)
• Most common reasons for
switching are lack of
effectiveness and side
effects3
Solifenacin (n=1,381)
Tolterodine ER (n=1,758)
Tolterodine IR (n=482)
Oxybutynin ER (n=590)
Oxybutynin IR (n=1,371)
Propiverine (n=97)
Trospium (n=352)
Darifenacin (n=23)
Flavoxate (n=89)
60
40
20
0
*Not all anticholinergic treatments listed may be licensed in Ireland
ER, extended release; IR, immediate release.
1.D'Souza AO, et al. J Manag Care Pharm 2008;14:291–301.
2.Kelleher C, et al. B J Obstet Gynecol. 1997;104:988–93.
3.Castro D, et al. Acta Urol Esp 2011;35:73–9.
4.Wagg A, et al. BJU Int 2012;110:1767–74.
1 2
3 4 5 6 7 8 9 10 11 12
Months
Adapted from: Wagg A, et al. BJU Int 2012;110:1767–1774
Other options
Pharma
• Mirabegron
Non pharma
• BOTOX
• multiple therapy
• PTNS
• Oestrogens
• SNS
• Desmopressin
• Clam/diversion
[email protected]
Botulinum toxin type A: A large threedimensional protein
BoNT-A (core)
Compound
149,500 Da1,2
C6763H10452N1744O2011S33Zn
Acetylsalicylic acid
180 Da3
Trospium chloride
430 Da3
Tamsulosin
445 Da3
Sildenafil citrate
667 Da3
BOTOX® complex
(botulinum toxin type A)
Atorvastatin3
Ibuprofen3
559 Da
C33H35FN2O5
206 Da
C13H18O2
BoNT-A, botulinum toxin type A; MW, molecular weight.
1. Lacy DB, et al. Nat Struct Biol 1998;5:898–902.
2. Lacy DB, Stevens RC. J Mol Biol 1999;291:1091–104.
3. DrugBank. Available from http://www.drugbank.ca/drugs/DB01076. Last accessed February 2013.
4. Schantz EJ, Johnson EA. Perspect Biol Med 1997;40:317–27.
MW
~900,000 Da4
Botulinum toxins are non-interchangeable
from one product to another1
BOTOX®
Ipsen toxin
Merz toxin
~900 kDa
~400 kDa
150 kDa
Batch release assay:
Cell-based potency assay
•
•
•
•
Lethal dose 50
Lethal dose 50
It is the first cell-based potency assay (CBPA) using an
established cell-line to measure the biological activity of
BOTOX®2
This assay has sensitivity equal or superior to the mouse
bioassay2
This ensures the quality and consistency of neurotoxic activity
in the product that is delivered to the clinic
Approved by the FDA and Irish Medicines Board for the
potency testing of BOTOX ®2
FDA, United States Food and Drug Administration.
*LD50 is the amount of a material, given all at once, which causes the death of 50% of a group of test animals
1.BOTOX® Summary of Product Characteristics , Allergan
2.Fernandez-Salas E, et al. PLoS One 2012;7:e49516.
Neurotransmitter release requires interaction of
synaptic vesicles with nerve terminal membranes
Receptor requires
SNARE complex for membrane
expression
1. SNARE proteins form
a complex
2. Vesicle and terminal
membranes fuse
PRE-SYNAPSE
Synaptobrevin
(VAMP)
SNARE
proteins
3a. Receptors delivered to membrane
insertion sites
3b. Neurotransmitter released
4. Mediators (e.g. SP) bind to inserted
receptors
Syntaxin
SNAP-25
SYNAPTIC CLEFT
SP, substance P.
Adapted from Arnon SS, et al. JAMA 2001;285:1059–70.
M
M
M
M
Inhibition of interaction of synaptic vesicles with nerve terminal
membranes is key to the sensorimotor action of BOTOX®
2. Botulinum toxin
endocytosed
1. Botulinum toxin
binds to receptor
Types B, D, F, G: VAMP
3. Light chain cleaves
specific SNARE proteins
Types A, C, E:
SNAP-25
4. SNARE complex
does not form
M
M
Adapted from Arnon SS, et al. JAMA 2001;285:1059–70.
M
M
BOTOX®: An innovative treatment for OAB with a
dual mechanism of action1–3
BOTOX® targets both the afferent and efferent pathways
Afferent pathway
Efferent pathway
Blocks peripheral
release of
neurotransmitter at
presynaptic
cholinergic nerve
terminals
Acetylcholine
BOTOX®
Targets both
the efferent
and afferent
pathway
Muscle contraction
Reduced parasympathetic nervous
system activity in response to
bladder distension
Treatment benefit:
Detrusor muscle relaxation
OAB, overactive bladder.
1. BOTOX® Summary of Product Characteristics, Allergan
2. Purves D, et al. Autonomic Regulation of the Bladder. Neuroscience. 2nd edition. 2001.
3. Apostolidis A, et al. Eur Urol 2006;49:644–50.
Sensory neuropeptides and
receptors
Peripheral sensitisation
Central sensitisation
Sympathetic nervous system
activity maintained as bladder
fills
Treatment benefit:
Reduced urgency
Blocks release of
neurotransmitters
and down regulates
expression of
receptors
associated with
sensory afferent
pathway
OAB clinical development programme
Idiopathic overactive bladder (OAB) BOTOX® development programme
2005
2006
2007
2008
2009
Phase II: Study 0771
(N=313)
Began: July 2005 Ended: June 2008
RELAX study 200 u BOTOX vs palcebo
320 patients randomised 1:1
1.
2.
3.
4.
5.
2010
2011
2012
2013
Phase III: EMBARK2,3
Pivotal study 095
(N=557)
72 sites; Canada and USA
Began: Sept 2009
Ended: July 2011
Phase III: EMBARK3,4
Pivotal study 520
(N=548)
64 sites; Belgium, Czech
Republic, Germany,
Poland, Russia, UK, USA
Began: Oct 2009
Ended: Aug 2011
Phase III: 096 EMBARK long-term extension5
(N=839) Began: Feb 2010 Ends: Sept 2014
Fowler CJ, et al. Eur Urol. 2012 Jul;62(1):148-57. Epub 2012 Mar 14.
Nitti VW, et alJ Urol. 2013 Jun;189(6):2186-93
BOTOX® Summary of Product Characteristics, Allergan
Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-56
ClinicalTrials.gov. Identifier: NCT00915525. Available from www.clinicaltrials.gov. Last accessed July 2013.
2014
EMBARK: phase III trials
BOTOX® 100 U
Long-term
extension:
Study 096
Study 095 (N=557)
Placebo
Up to 3
additional years
BOTOX® 100 U
Study 520 (N=548)
Placebo
Primary endpoint
Earliest time for re-treatment
Weeks
–3
0
2*
6*
Pre-screen/
randomisation
12*
18
Efficacy and safety assessment: Weeks 2, 6, 12
Quality-of-life assessment: Week 12
*Placebo-controlled comparison period.
1. Nitti VW, et al. J Urol 2013;189:1388–95
2. BOTOX® Summary of Product Characteristics, Allergan
3. Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-56
24
Study exit
unless
re-treatment
occurred
Inclusion criteria
• Population of patients with OAB
– ≥3 urinary urgency incontinence episodes in 3-day
diary
– ≥8 micturitions/day
– Post-void residual urine ≤100 mL
– Inadequately managed by anticholinergics
• Washout period 2 weeks
• No anticholinergic use permitted during the trial
1 . Nitti VW, et alJ Urol. 2013 Jun;189(6):2186-93
2. Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-56
Study endpoints
Endpoint
Measure
Primary
• Number of urinary incontinence episodes
• Proportion of patients with positive treatment response on the Treatment Benefit
Scale
Secondary
•
•
•
•
•
Number of urgency episodes
Number of micturition episodes
Volume voided per micturition
I-QOL total summary score
KHQ domains (role limitations and social limitations)
1 . Nitti VW, et alJ Urol. 2013 Jun;189(6):2186-93
2. Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-56
Treatment
1
paradigm
• Randomised in a 1:1 ratio:
– BOTOX® 100 U
– Placebo
• Re-treatment permitted:
– after ≥12 weeks
PVR, post-void residual.
1. . BOTOX® Summary of Product Characteristics, Allergan
Demographics and baseline
characteristics1
095/520 Pooled
Parameter
BOTOX® 100 U
(N=557)
Placebo
(N=548)
Age (years)
60.6
60.1
11.0
89.0
13.5
86.5
89.8
10.2
92.0
8.0
BMI (mean, kg/m2)
29.9
30.9
Duration of OAB (years)
6.04
6.14
Number of prior anticholinergics used (mean)
2.4
2.5
Urinary incontinence episodes (per 24 hours)
5.49
5.39
Urgency episodes (per 24 hours)
8.82
8.31
Micturition episodes (per 24 hours)
11.99
11.48
Nocturia episodes (per 24 hours)
2.17
2.04
Volume voided per micturition (mL)
150.4
156.9
Sex (%)
Male
Female
Race (%)
Caucasian
Non-Caucasian
Groups were well balanced with no significant differences between treatment groups.
BMI, body mass index; OAB, idiopathic overactive bladder; OAB, overactive bladder.
1. Allergan Data on File Baseline Patient Characteristics
Incontinence episodes
At Week 12, BOTOX® led to a 51% reduction from baseline in
UI episodes versus 18% with placebo (p<0.001)
0
–1
–1.05
–2
–0.95
–1.13
–3
–2.66**
–4
Baseline values
Placebo: 5.39/day
BOTOX® 100 U: 5.49/day
**p<0.001 vs. placebo.
UI, urinary incontinence.
Adapted from: BOTOX® Summary of Product Characteristics, Allergan
–2.74**
–2.97**
Placebo (n=548)
BOTOX® 100 U (n=557)
Patient response
Patients with 100% decrease in
urinary incontinence (‘DRY’)*
Patients with ≥50% or ≥75%
decrease in urinary incontinence
76%
Placebo
(n=548)
BOTOX® 100 U
(n=557)
*Patients must have had no incontinence episodes in the 3 days preceding the 12-week time point.
Adapted from: BOTOX® Summary of Product Characteristics, Allergan
≥75% reduction
Patients (%)
Patients (%)
≥50% reduction
Placebo
(n=548)
BOTOX®
100 U
(n=557)
Placebo
(n=548)
BOTOX®
100 U
(n=557)
urgency episodes
At Week 12, BOTOX® led to a 37% reduction from baseline in daily
urgency episodes versus 15% with placebo (p<0.001)
Baseline values
Placebo: 8.31/day
BOTOX® 100 U: 8.82/day
**p<0.001 vs. placebo.
Adapted from: BOTOX® Summary of Product Characteristics, Allergan
Placebo (n=548)
BOTOX® 100 U (n=557)
Daily micturition
frequency and nocturia
Daily micturition frequency1
Week 2
Week 6
Week 12
At Week 12, BOTOX® led to a 20%
reduction from baseline in daily
micturition frequency versus 8% with
placebo (p<0.001) and a 21%
reduction from baseline in nocturia
versus 12% with placebo (p<0.05)
Baseline values:
Placebo: 11.48/day
BOTOX® 100 U: 11.99/day
Placebo (n=548)
BOTOX® 100 U (n=557)
*p≤0.05; **p<0.001 vs. placebo.
Mean change from baseline
(episodes/day)
Nocturia2
1. Adapted from BOTOX® Summary of Product Characteristics, Alleragan
2. Data on File-003 – BOTOX® Daily Average Frequency of Nocturia
Episodes During Treatment Cycle 1
*
Baseline values:
Placebo: 2.04/day
BOTOX® 100 U: 2.17/day
**
**
095/520 Pooled
Subjective outcomes
Significantly more BOTOX® patients reported their symptoms as
“Greatly improved” or “Improved”
**
**
**
Placebo (n=548)
BOTOX® 100 U (n=557)
**p<0.001 vs. placebo.
Adapted from: BOTOX® Summary of Product Characteristics, Allergan
Median time to patient request
for re-treatment is ~6 months
The median duration of response following BOTOX® treatment,
based on patient request for re-treatment,
was 166 days (~24 weeks)
Adapted from: BOTOX® Summary of Product Characteristics, Allergan
Adverse events1
EMBARK study
Urinary tract infection
Bacteriuria count of >105 CFU/mL and leukocyturia of
>5/HPF
Urinary retention
Elevated PVR ≥200 mL requiring CIC
CIC to be initiated either:
• If PVR between ≥200 mL and <350 mL and patient has
associated symptoms that require CIC
• PVR ≥350 mL (regardless of symptoms)
CFU, colony-forming units; CIC, clean intermittent catheterisation;
HPF, high-power field; PVR, post-void residual; UTI, urinary tract infection.
1.
Allergan Data on File Summary of clinical Efficacy
Adverse events
First 12 weeks
Adverse event ≥3%,
n (%)
Any time in treatment cycle 1
BOTOX® 100 U
(N=552)
Placebo
(N=542)
BOTOX® 100 U
(N=552)
Placebo
(N=542)
Urinary tract infection
99(17.9)
30 (5.5)
141 (25.5)
52 (9.6)
Dysuria
50 (9.1)
36 (6.6)
60 (10.9)
38 (7.0)
Urinary retention
31 (5.6)
2 (0.4)
32 (5.8)
2 (0.4)
Bacteriuria
24 (4.3)
11 (2.0)
44 (8.0)
19 (3.5)
Haematuria
17 (3.1)
16 (3.0)
18 (3.3)
18 (3.3)
Residual urine volume
17 (3.1)
1 (0.2)
19 (3.4)
2 (0.4)
Sinusitis
12 (2.2)
2 (0.4)
18 (3.3)
6 (1.1)
Leukocyturia
11 (2.0)
2 (0.4)
18 (3.3)
2 (0.4)
1.
Allergan Data on File Adverse Events
Post void residuals
Patients with absolute PVR at different thresholds at Week 12
Patients (%)
®
PVR
PVR, post-void residual.
Adapted from Allergan Data on File PVR Tables
Self Cath rates
0.4%
1.3%
2.5%
1.4%
0.9%
6.5%
CIC = 6.5% (36/552 patients)*
% of Patients
*Patients requiring CIC at any point during treatment cycle 1.
CIC, clean intermittent catheterisation.
Adapted from: BOTOX® Summary of Product Characteristics, Allergan and Allergan Data on File Summary of Clinical Safety.
Discontinuation due to adverse events
095 Study
Parameter
Randomised (N)
Discontinued
Any reason
Full treatment
cycle 1
1st 12 weeks
Due to adverse events
Full treatment cycle 1
1st 12 weeks
BOTOX®
100 U
Placebo
280
520 Study
Total
BOTOX®
100 U
Placebo
Total
277
557
277
271
548
31 (11.1%)
13 (4.6%)
34 (12.3%)
21 (7.6%)
65 (11.7%)
34 (6.1%)
20 (7.2%)
11 (4.0%)
24 (8.9%)
16 (5.9%)
44 (8.0%)
27 (4.9%)
5 (1.8%)
4 (1.4%)
4 (1.4%)
2 (0.7%)
9 (1.6%)
6 (1.1%)
6 (2.2%)
4 (1.4%)
1 (0.4%)
1 (0.4%)
7 (1.3%)
5 (0.9%)
1. Data on File-004 – BOTOX® Cumulative Patient Disposition by Scheduled Visit 191622-095
2. Data on File-005 – BOTOX® Cumulative Patient Disposition by Scheduled Visit 191622-520
Change in I-QOL scores Week 12
**
**
**
**
®
Clinically important
difference = + 10
points
**p<0.0001 vs. placebo.
I-QOL, Incontinence quality-of-life questionnaire.
Adapted from Data on File-001 - Incontinence Quality of Life Domain & Total summary Score (2).
Change in KHQ scores Week 12
Clinically important
difference = –5
points
*
**
**
®
**
**
**
*p≤0.005; **p≤0.001 vs. placebo.
KHQ, King’s Health Questionnaire; OAB, idiopathic overactive bladder.
Adapted from Data on File-002 – BOTOX® King’s Health Questionnaire (KHQ).
**
**
**
Repeat treatment
Adapted from: BOTOX® Summary of Product Characteristics, Allergan.
Repeat treatment
Proportion of patients with positive treatment response on treatment benefit scale
Adapted from: BOTOX® Summary of Product Characteristics, Allergan.
Long term study
1st BOTOX®
(N=814)
2nd BOTOX®
(N=546)
3rd BOTOX®
(N=253)
4th BOTOX®
(N=88)
58.4
51.0
52.3
Overall incidence of adverse events (%)
65.6
Incidence of individual adverse events ≥5% in any cycle (%)
Urinary tract infection
25.2
21.8
19.4
18.2
Dysuria
8.8
7.1
4.0
3.4
Bacteriuria
6.9
6.4
2.4
3.4
PVR, urinary retention and use of CIC
Mean change in PVR
(at Week 2, mL)
45.8
44.4
53.4
62.7
Urinary retention (%)
4.1
3.1
2.8
3.4
Patients using CIC (%)
4.7
3.8
4.3
5.7
CIC, clean intermittent catheterisation; PVR, post-void residual.
.
1. BOTOX® Summary of Product Characteristics, Allergan
2. Allergan Data on File Summary of clinical Safety
Our data
• Voiding difficulties reproducible (90%)
• OP flexible injections well tolerated
• Not using exponentially
– Moderating effect?
Conclusions
• Embark programme comprehensive
– Results consistent with previous studies
– Lower dosage than initial (RELAX) studies
• BOTOX® adds to our treatment options
• Long term data reassuring
Spectrum of treatments for NDO
Lifestyle advice/behavioural
approaches
• Regular voiding schedule
• Pelvic floor muscle exercises
BOTOX®
Less invasive
Assisted emptying
• Voiding by abdominal straining
• Triggered reflex voiding
Containment
• Urinary incontinence
products
• Intermittent self-catheterisation
NDO, neurogenic detrusor overactivity
NB: Not all treatments mentioned here are licensed for NDO in Ireland
Pannek J. European Association of Urology. Guidelines on neurogenic lower urinary tract dysfunction. 2011.
Available from: http://www.uroweb.org/gls/pdf/17_Neurogenic%20LUTS.pdf. Last accessed July 2013.
BOTOX® Summary of Product Characteristics, Allergan
Neurostimulation
• Peripheral tibial
nerve stimulation
• Sacral nerve stimulation
More invasive
Pharmacotherapy
• Antimuscarinics
• Beta-3
adrenoreceptor
agonists
• Flavoxate,
Imipramine,
Oestrogens
Surgery
• Augmentation cystoplasty
• Urinary diversion

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