Botox® for the overactive bladder -The evidence Philip Toozs-Hobson Consultant Urogynaecologist.

Botox® for the overactive bladder -The evidence

Philip Toozs-HobsonConsultant 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

• Almost 70–90% of patients stop their treatment within 1 year1

• Discontinuation after first prescription2

• Most common reasons for switching are lack of effectiveness and side effects3

What’s wrong with anticholinergic medication

*Not all anticholinergic treatments listed may be licensed in IrelandER, 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.

Propiverine (n=97)Trospium (n=352)Darifenacin (n=23)Flavoxate (n=89)

Percentage of patients remaining on each anticholinergic over 12 months4

Solifenacin (n=1,381)Tolterodine ER (n=1,758)Tolterodine IR (n=482)Oxybutynin ER (n=590)Oxybutynin IR (n=1,371)

100

80

60

20

0

40

Patie

nts

(%)

1 2 3 4 5 6 7 8 9 10 11 12Months

Adapted from: Wagg A, et al. BJU Int 2012;110:1767–1774

Other options

Pharma• Mirabegron

• multiple therapy

• Oestrogens

• Desmopressin

Non pharma• BOTOX

• PTNS

• SNS

• Clam/diversion

[email protected]

Compound MW

Acetylsalicylic acid 180 Da3

Trospium chloride 430 Da3

Tamsulosin 445 Da3

Sildenafil citrate 667 Da3

BOTOX® complex(botulinum toxin type A) ~900,000 Da4

Botulinum toxin type A: A large three-dimensional protein

BoNT-A (core)149,500 Da1,2

C6763H10452N1744O2011S33Zn

Ibuprofen3

206 DaC13H18O2

Atorvastatin3

559 DaC33H35FN2O5

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.

Botulinum toxins are non-interchangeable from one product to another1

Cell-based potency assay Lethal dose 50 Lethal dose 50

Batch release assay:

• 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

~900 kDa ~400 kDa 150 kDa

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 animals1.BOTOX® Summary of Product Characteristics , Allergan 2.Fernandez-Salas E, et al. PLoS One 2012;7:e49516.

SNARE proteins

Synaptobrevin (VAMP)

SNAP-25

Syntaxin

SYNAPTIC CLEFT

PRE-SYNAPSE

Receptor requires SNARE complex for membrane

expression2. Vesicle and terminal

membranes fuse

3a. Receptors delivered to membrane insertion sites

3b. Neurotransmitter released

4. Mediators (e.g. SP) bind to inserted receptors

1. SNARE proteins forma complex

M M

M M

Neurotransmitter release requires interaction of synaptic vesicles with nerve terminal membranes

SP, substance P.Adapted from Arnon SS, et al. JAMA 2001;285:1059–70.

3. Light chain cleaves specific SNARE proteins

Types B, D, F, G: VAMP

Types A, C, E:SNAP-25

4. SNARE complex does not form

1. Botulinum toxin binds to receptor

2. Botulinum toxin endocytosed

M M

M M

Inhibition of interaction of synaptic vesicles with nerve terminal membranes is key to the sensorimotor action of BOTOX®

Adapted from Arnon SS, et al. JAMA 2001;285:1059–70.

Muscle contraction Peripheral sensitisationCentral sensitisation

BOTOX®: An innovative treatment for OAB with a dual mechanism of action1–3

Blocks peripheral release of

neurotransmitter at presynaptic

cholinergic nerve terminals

Blocks release of neurotransmitters

and down regulates expression of

receptors associated with sensory afferent

pathway

BOTOX® Targets boththe efferentand afferent pathway

Treatment benefit:Detrusor muscle relaxation Treatment benefit:

Reduced urgency

BOTOX® targets both the afferent and efferent pathways

Acetylcholine Sensory neuropeptides and receptors

Sympathetic nervous system activity maintained as bladder

fills

Reduced parasympathetic nervous system activity in

response to bladder distension

Efferent pathway Afferent pathway

OAB, overactive bladder.

1. BOTOX® Summary of Product Characteristics, Allergan2. Purves D, et al. Autonomic Regulation of the Bladder. Neuroscience. 2nd edition. 2001.3. Apostolidis A, et al. Eur Urol 2006;49:644–50.

Idiopathic overactive bladder (OAB) BOTOX® development programme

OAB clinical development programme

20112005 201220102009200820072006 2013 2014

Phase II: Study 0771

(N=313)Began: July 2005 Ended: June 2008

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

1. Fowler CJ, et al. Eur Urol. 2012 Jul;62(1):148-57. Epub 2012 Mar 14. 2. Nitti VW, et alJ Urol. 2013 Jun;189(6):2186-93 3. BOTOX® Summary of Product Characteristics, Allergan4. Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-565. ClinicalTrials.gov. Identifier: NCT00915525. Available from www.clinicaltrials.gov. Last accessed July 2013.

RELAX study 200 u BOTOX vs palcebo320 patients randomised 1:1

EMBARK: phase III trials

Efficacy and safety assessment: Weeks 2, 6, 12Quality-of-life assessment: Week 12

Primary endpoint Earliest time for re-treatment

Pre-screen/randomisation

BOTOX® 100 U

Placebo

BOTOX® 100 U

Placebo

–3 0 2* 6* 12* 18 24

Study 095 (N=557)

Study 520 (N=548)

Long-term extension: Study 096

Up to 3 additional years

Weeks

Study exit unless

re-treatment occurred

*Placebo-controlled comparison period.

1. Nitti VW, et al. J Urol 2013;189:1388–952. BOTOX® Summary of Product Characteristics, Allergan3. Chapple C, et al. Eur Urol. 2013 Aug;64(2):249-56

• 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

Inclusion criteria

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

• Randomised in a 1:1 ratio:– BOTOX® 100 U– Placebo

• Re-treatment permitted:– after ≥12 weeks

Treatment paradigm1

PVR, post-void residual.

1. . BOTOX® Summary of Product Characteristics, Allergan

Demographics and baseline characteristics1

095/520 Pooled

ParameterBOTOX® 100 U

(N=557)Placebo(N=548)

Age (years) 60.6 60.1Sex (%)

Male Female

11.089.0

13.586.5

Race (%)Caucasian Non-Caucasian

89.810.2

92.08.0

BMI (mean, kg/m2) 29.9 30.9Duration of OAB (years) 6.04 6.14Number of prior anticholinergics used (mean) 2.4 2.5Urinary incontinence episodes (per 24 hours) 5.49 5.39Urgency episodes (per 24 hours) 8.82 8.31Micturition episodes (per 24 hours) 11.99 11.48Nocturia episodes (per 24 hours) 2.17 2.04Volume voided per micturition (mL) 150.4 156.9

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

Baseline valuesPlacebo: 5.39/dayBOTOX® 100 U: 5.49/day

0

–1.13–0.95

–2.66**–2.97**

–2.74**

Placebo (n=548)BOTOX® 100 U (n=557)

At Week 12, BOTOX® led to a 51% reduction from baseline inUI episodes versus 18% with placebo (p<0.001)

**p<0.001 vs. placebo.UI, urinary incontinence.

Adapted from: BOTOX® Summary of Product Characteristics, Allergan

–1

–2

–3

–4

–1.05

Patient response

76%

Patients with ≥50% or ≥75%decrease in urinary incontinence

≥75% reduction

Patients with 100% decrease in urinary incontinence (‘DRY’)*

Patie

nts

(%)

Patie

nts

(%)

≥50% reduction

Placebo(n=548)

BOTOX® 100 U(n=557)

BOTOX® 100 U

(n=557)

Placebo(n=548)

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.


urgency episodes

Baseline valuesPlacebo: 8.31/dayBOTOX® 100 U: 8.82/day

**p<0.001 vs. placebo.

At Week 12, BOTOX® led to a 37% reduction from baseline in dailyurgency episodes versus 15% with placebo (p<0.001)



Daily micturitionfrequency and nocturia

Week 2 Week 6 Week 12


Baseline values:Placebo: 11.48/dayBOTOX® 100 U: 11.99/day

***

**Baseline values:Placebo: 2.04/dayBOTOX® 100 U: 2.17/day

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)

*p≤0.05; **p<0.001 vs. placebo.

1. Adapted from BOTOX® Summary of Product Characteristics, Alleragan2. Data on File-003 – BOTOX® Daily Average Frequency of Nocturia Episodes During Treatment Cycle 1

Daily micturition frequency1

Nocturia2

Mea

n ch

ange

from

bas

elin

e(e

piso

des/

day)

Subjective outcomes095/520 Pooled

** ****

BOTOX® 100 U (n=557)

Placebo (n=548)

**p<0.001 vs. placebo.

Significantly more BOTOX® patients reported their symptoms as “Greatly improved” or “Improved”


Median time to patient requestfor 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)


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

Adverse event ≥3%,n (%)

First 12 weeks 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

Patients with absolute PVR at different thresholds at Week 12

Post void residuals

®

Patie

nts

(%)

PVR

Adapted from Allergan Data on File PVR Tables

PVR, post-void residual.

2.5%

1.3%

0.4%1.4%

0.9%

Self Cath rates

% of Patients

6.5%CIC = 6.5% (36/552 patients)*

Adapted from: BOTOX® Summary of Product Characteristics, Allergan and Allergan Data on File Summary of Clinical Safety.

*Patients requiring CIC at any point during treatment cycle 1.CIC, clean intermittent catheterisation.

Discontinuation due to adverse events

Parameter

095 Study 520 Study

BOTOX®

100 UPlacebo Total

BOTOX® 100 U

Placebo Total

Randomised (N) 280 277 557 277 271 548

DiscontinuedAny reasonFull treatment

cycle 11st 12 weeks

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%)

Due to adverse eventsFull treatment cycle 11st 12 weeks

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 191622-0952. 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

****

**

**

Adapted from Data on File-001 - Incontinence Quality of Life Domain & Total summary Score (2).

**p<0.0001 vs. placebo.I-QOL, Incontinence quality-of-life questionnaire.

®

Change in KHQ scores Week 12

**

**

** ****

**

**

**

*

Clinically important difference = –5 points

®

Adapted from Data on File-002 – BOTOX® King’s Health Questionnaire (KHQ).

*p≤0.005; **p≤0.001 vs. placebo.KHQ, King’s Health Questionnaire; OAB, idiopathic overactive bladder.

Repeat treatment

Adapted from: BOTOX® Summary of Product Characteristics, Allergan.

Proportion of patients with positive treatment response on treatment benefit scale

Repeat treatment

Adapted from: BOTOX® Summary of Product Characteristics, Allergan.

Long term study1st BOTOX®

(N=814)2nd BOTOX®

(N=546)3rd BOTOX®

(N=253)4th BOTOX®

(N=88)

Overall incidence of adverse events (%)

65.6 58.4 51.0 52.3

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

.

1. BOTOX® Summary of Product Characteristics, Allergan2. Allergan Data on File Summary of clinical Safety

CIC, clean intermittent catheterisation; PVR, post-void residual.

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

NDO, neurogenic detrusor overactivityNB: 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

Less invasive More invasive

Neurostimulation•Peripheral tibialnerve stimulation•Sacral nerve stimulation

Surgery•Augmentation cystoplasty•Urinary diversion

Assisted emptying•Voiding by abdominal straining•Triggered reflex voiding

Containment•Urinary incontinenceproducts•Intermittent self-catheterisation

Pharmacotherapy•Antimuscarinics•Beta-3 adrenoreceptor agonists•Flavoxate, Imipramine, Oestrogens

Spectrum of treatments for NDO

BOTOX®

Lifestyle advice/behavioural approaches•Regular voiding schedule•Pelvic floor muscle exercises

Botox® for the overactive bladder -The evidence Philip Toozs-Hobson Consultant Urogynaecologist.

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Transcript of Botox® for the overactive bladder -The evidence Philip Toozs-Hobson Consultant Urogynaecologist.