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 year 1 Discontinuation after first prescription 2 Most common reasons for switching are lack of effectiveness and side effects 3 *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. 100 80

Percentage of patients remaining on each anticholinergic over 12 months 4

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 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

•

Pharma

Mirabegron • multiple therapy • Oestrogens • Desmopressin

Other options

•

Non pharma

BOTOX • PTNS • SNS • Clam/diversion [email protected]

Botulinum toxin type A: A large three dimensional protein

BoNT-A (core) 149,500 Da 1,2 C 6763 H 10452 N 1744 O 2011 S 33 Zn Compound

Acetylsalicylic acid

MW

180 Da 3 Trospium chloride Tamsulosin 430 Da 3 445 Da 3 Sildenafil citrate BOTOX ® complex (botulinum toxin type A) 667 Da 3 ~900,000 Da 4

Atorvastatin 3 559 Da C 33 H 35 FN 2 O 5 Ibuprofen 3 206 Da C 13 H 18 O 2

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 another

1

BOTOX ® Ipsen toxin Merz toxin

~900 kDa

Batch release assay:

Cell-based potency assay

~400 kDa 150 kDa

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 bioassay 2 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 3a. Receptors delivered to membrane insertion sites 3b. Neurotransmitter released Synaptobrevin (VAMP) SNARE proteins 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 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 M M M M

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

BOTOX

®

: An innovative treatment for OAB with a dual mechanism of action

1–3

BOTOX ® targets both the afferent and efferent pathways Efferent pathway Afferent pathway

Blocks peripheral release of neurotransmitter at presynaptic cholinergic nerve terminals Acetylcholine Muscle contraction BOTOX ® Targets both the efferent and afferent pathway 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 Blocks release of neurotransmitters and down regulates expression of receptors associated with sensory afferent pathway Sympathetic nervous system activity maintained as bladder fills Treatment benefit:

Reduced urgency

2005

OAB clinical development programme

Idiopathic overactive bladder (OAB) BOTOX ® development programme 2006 2007 2008

Phase II: Study 077 1 (N=313) Began: July 2005 Ended: June 2008 RELAX study 200 u BOTOX vs palcebo 320 patients randomised 1:1

2009 2010 2011

Phase III: EMBARK 2,3 Pivotal study 095 (N=557) 72 sites; Canada and USA Began: Sept 2009 Ended: July 2011

2012

Phase III: EMBARK 3,4 Pivotal study 520 (N=548) 64 sites; Belgium, Czech Republic, Germany, Poland, Russia, UK, USA Began: Oct 2009 Ended: Aug 2011

2013

Phase III: 096 EMBARK long-term extension 5 (N=839) Began: Feb 2010 Ends: Sept 2014

2014

1.

2.

3.

4.

5.

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.

EMBARK: phase III trials

BOTOX ® 100 U Placebo Study 095 (N=557) BOTOX ® 100 U Placebo Study 520 (N=548) Primary endpoint Earliest time for re-treatment –3 0 Pre-screen/ randomisation 2* 6* *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

Weeks

12* 18 Efficacy and safety assessment: Weeks 2, 6, 12 Quality-of-life assessment: Week 12 24 Long-term extension: Study 096 Up to 3 additional years

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

Primary Secondary • •

Measure

Number of urinary incontinence episodes Proportion of patients with positive treatment response on the Treatment Benefit Scale • • • • • 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 paradigm

1 • 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

Parameter

Demographics and baseline characteristics

1

BOTOX ® 100 U (N=557)

60.6

Age (years) Sex (%) Male Female Race (%) Caucasian Non-Caucasian BMI (mean, kg/m 2 ) Duration of OAB (years) Number of prior anticholinergics used (mean) Urinary incontinence episodes (per 24 hours) Urgency episodes (per 24 hours) Micturition episodes (per 24 hours) Nocturia episodes (per 24 hours) Volume voided per micturition (mL) 11.0

89.0

89.8

10.2

29.9

6.04

2.4

5.49

8.82

11.99

2.17

150.4

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

095/520 Pooled Placebo (N=548)

60.1

13.5

86.5 92.0

8.0

30.9

6.14

2.5

5.39

8.31

11.48

2.04

156.9

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 –2 –1.05

–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 –2.97** –0.95

–2.74** 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 ≥50% reduction ≥75% reduction 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 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)

Week 2

Daily micturition frequency and nocturia

Daily micturition frequency 1

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) Nocturia 2 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.

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 ** **

Subjective outcomes

Significantly more BOTOX ® patients reported their symptoms as “Greatly improved” or “Improved” 095/520 Pooled

** ** ** 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 ® based on patient request for re-treatment, was 166 days (~24 weeks) treatment,

Adapted from: BOTOX ® Summary of Product Characteristics, Allergan

Urinary tract infection Urinary retention

Adverse events

1

EMBARK study

Bacteriuria count of >10 5 >5/HPF CFU/mL and leukocyturia of 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 (%)

Urinary tract infection Dysuria Urinary retention Bacteriuria Haematuria Residual urine volume Sinusitis Leukocyturia

First 12 weeks BOTOX ® 100 U (N=552)

99(17.9) 50 (9.1) 31 (5.6) 24 (4.3) 17 (3.1) 17 (3.1) 12 (2.2) 11 (2.0)

Placebo (N=542)

30 (5.5) 36 (6.6) 2 (0.4) 11 (2.0) 16 (3.0) 1 (0.2) 2 (0.4) 2 (0.4)

Any time in treatment cycle 1 BOTOX ® 100 U (N=552)

141 (25.5) 60 (10.9) 32 (5.8) 44 (8.0) 18 (3.3) 19 (3.4) 18 (3.3) 18 (3.3)

Placebo (N=542)

52 (9.6) 38 (7.0) 2 (0.4) 19 (3.5) 18 (3.3) 2 (0.4) 6 (1.1) 2 (0.4) 1. Allergan Data on File Adverse Events

Post void residuals

Patients with absolute PVR at different thresholds at Week 12

® PVR, post-void residual.

Adapted from Allergan Data on File PVR Tables

PVR

1.3% 2.5% 0.4%

Self Cath rates

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

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

280 5 (1.8%) 4 (1.4%)

095 Study Placebo

277 4 (1.4%) 2 (0.7%)

Total

557 9 (1.6%) 6 (1.1%)

BOTOX ® 100 U

277 6 (2.2%) 4 (1.4%)

520 Study Placebo

271

Total

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%) 1 (0.4%) 1 (0.4%) 7 (1.3%) 5 (0.9%) 1.

2.

Data on File-004 – BOTOX ® Cumulative Patient Disposition by Scheduled Visit 191622-095 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

** ** ** ** ** *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).

** ** * **

Clinically important difference = –5 points

®

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) Overall incidence of adverse events (%)

65.6 58.4

Incidence of individual adverse events ≥5% in any cycle (%)

Urinary tract infection 25.2

21.8

Dysuria Bacteriuria 8.8

6.9

PVR, urinary retention and use of CIC

Mean change in PVR (at Week 2, mL) 45.8

2nd BOTOX (N=546)

7.1

6.4

44.4

®

Urinary retention (%) Patients using CIC (%) 4.1

4.7

3.1

3.8

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

.

1. BOTOX ® Summary of Product Characteristics, Allergan 2. Allergan Data on File Summary of clinical Safety

3rd BOTOX ® (N=253)

51.0

19.4

4.0

2.4

53.4

2.8

4.3

4th BOTOX ® (N=88)

52.3

18.2

3.4

3.4

62.7

3.4

5.7

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 ®

• •

Neurostimulation

Peripheral tibial nerve stimulation Sacral nerve stimulation

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 • • •

Pharmacotherapy

Antimuscarinics Beta-3 adrenoreceptor agonists Flavoxate, Imipramine, Oestrogens

More invasive

• •

Surgery

Augmentation cystoplasty Urinary diversion