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

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 What’s wrong with anticholinergic medication *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– 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 months 4 Solifenacin (n=1,381) Tolterodine ER (n=1,758) Tolterodine IR (n=482) Oxybutynin ER (n=590) Oxybutynin IR (n=1,371) Patients (%) Months 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

CompoundMW Acetylsalicylic acid180 Da 3 Trospium chloride430 Da 3 Tamsulosin445 Da 3 Sildenafil citrate667 Da 3 BOTOX ® complex (botulinum toxin type A) ~900,000 Da 4 Botulinum toxin type A: A large three- dimensional protein BoNT-A (core) 149,500 Da 1,2 C 6763 H N 1744 O 2011 S 33 Zn Ibuprofen Da C 13 H 18 O 2 Atorvastatin Da C 33 H 35 FN 2 O 5 BoNT-A, botulinum toxin type A; MW, molecular weight. 1. Lacy DB, et al. Nat Struct Biol 1998;5:898– Lacy DB, Stevens RC. J Mol Biol 1999;291:1091– DrugBank. Available from Last accessed February Schantz EJ, Johnson EA. Perspect Biol Med 1997;40:317–27.

Botulinum toxins are non-interchangeable from one product to another 1 Cell-based potency assayLethal 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 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 ~900 kDa~400 kDa150 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 animals 1.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 expression 2. 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 form a complex MM 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 SNARE complex does not form 1. Botulinum toxin binds to receptor 2. Botulinum toxin endocytosed MM 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 sensitisation Central sensitisation BOTOX ® : An innovative treatment for OAB with a dual mechanism of action 1–3 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 both the efferent and 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, Allergan 2. Purves D, et al. Autonomic Regulation of the Bladder. Neuroscience. 2nd edition Apostolidis A, et al. Eur Urol 2006;49:644–50.

Idiopathic overactive bladder (OAB) BOTOX ® development programme OAB clinical development programme Phase II: Study (N=313) Began: July 2005 Ended: June 2008 Phase III: EMBARK 2,3 Pivotal study 095 (N=557) 72 sites; Canada and USA Began: Sept 2009 Ended: July 2011 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 Phase III: 096 EMBARK long-term extension 5 (N=839) Began: Feb 2010 Ends: Sept Fowler CJ, et al. Eur Urol Jul;62(1): Epub 2012 Mar Nitti VW, et alJ Urol Jun;189(6): BOTOX ® Summary of Product Characteristics, Allergan 4. Chapple C, et al. Eur Urol Aug;64(2): ClinicalTrials.gov. Identifier: NCT Available from Last accessed July RELAX study 200 u BOTOX vs palcebo 320 patients randomised 1:1

EMBARK: phase III trials Efficacy and safety assessment: Weeks 2, 6, 12 Quality-of-life assessment: Week 12 Primary endpoint Earliest time for re-treatment Pre-screen/ randomisation BOTOX ® 100 U Placebo BOTOX ® 100 U Placebo –302*6*12*1824 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;189:1388–95 2. BOTOX ® Summary of Product Characteristics, Allergan 3. Chapple C, et al. Eur Urol 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 Jun;189(6): Chapple C, et al. Eur Urol Aug;64(2):249-56

Study endpoints EndpointMeasure 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 Jun;189(6): Chapple C, et al. Eur Urol Aug;64(2):249-56

Randomised in a 1:1 ratio: – BOTOX ® 100 U – Placebo Re-treatment permitted: – after ≥12 weeks Treatment paradigm 1 PVR, post-void residual. 1.. BOTOX ® Summary of Product Characteristics, Allergan

Demographics and baseline characteristics 1 095/520 Pooled Parameter BOTOX ® 100 U (N=557) Placebo (N=548) 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) 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 values Placebo: 5.39/day BOTOX ® 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 in UI 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’)* Patients (%) ≥50% reduction Placebo (n=548) 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. Adapted from: BOTOX ® Summary of Product Characteristics, Allergan

urgency episodes Baseline values Placebo: 8.31/day BOTOX ® 100 U: 8.82/day **p<0.001 vs. placebo. At Week 12, BOTOX ® led to a 37% reduction from baseline in daily urgency episodes versus 15% with placebo (p<0.001) Placebo (n=548) BOTOX ® 100 U (n=557) Adapted from: BOTOX ® Summary of Product Characteristics, Allergan

Daily micturition frequency and nocturia Week 2 Week 6 Week 12 Placebo (n=548) BOTOX ® 100 U (n=557) Baseline values: Placebo: 11.48/day BOTOX ® 100 U: 11.99/day ** * Baseline values: Placebo: 2.04/day BOTOX ® 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, Alleragan 2. Data on File-003 – BOTOX ® Daily Average Frequency of Nocturia Episodes During Treatment Cycle 1 Daily micturition frequency 1 Nocturia 2 Mean change from baseline (episodes/day)

Subjective outcomes 095/520 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” 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 events 1 EMBARK study Urinary tract infection Bacteriuria count of >10 5 CFU/mL and leukocyturia of >5/HPF Urinary retentionElevated 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 weeksAny time in treatment cycle 1 BOTOX ® 100 U (N=552) Placebo (N=542) BOTOX ® 100 U (N=552) Placebo (N=542) Urinary tract infection99(17.9)30 (5.5)141(25.5)52 (9.6) Dysuria50 (9.1)36 (6.6)60 (10.9)38 (7.0) Urinary retention31 (5.6)2(0.4)32 (5.8)2 (0.4) Bacteriuria24 (4.3)11(2.0)44 (8.0)19 (3.5) Haematuria17 (3.1)16 (3.0)18 (3.3) Residual urine volume17 (3.1)1(0.2)19 (3.4)2 (0.4) Sinusitis12 (2.2)2(0.4)18 (3.3)6 (1.1) Leukocyturia11 (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 ® Patients (%) 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 Study520 Study BOTOX ® 100 U PlaceboTotal BOTOX ® 100 U PlaceboTotal Randomised (N) Discontinued Any reason Full treatment cycle 1 1st 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 events Full treatment cycle 1 1st 12 weeks 5 (1.8%) 4 (1.4%) 2 (0.7%) 9 (1.6%) 6 (1.1%) 6 (2.2%) 4 (1.4%) 1 (0.4%) 7 (1.3%) 5 (0.9%) 1. Data on File-004 – BOTOX ® Cumulative Patient Disposition by Scheduled Visit Data on File-005 – BOTOX ® Cumulative Patient Disposition by Scheduled Visit

Change in I-QOL scores Week 12 Clinically important difference = + 10 points ** Adapted from Data on File Incontinence Quality of Life Domain & Total summary Score (2). **p< 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 study 1st BOTOX ® (N=814) 2nd BOTOX ® (N=546) 3rd BOTOX ® (N=253) 4th BOTOX ® (N=88) Overall incidence of adverse events (%) Incidence of individual adverse events ≥5% in any cycle (%) Urinary tract infection Dysuria Bacteriuria PVR, urinary retention and use of CIC Mean change in PVR (at Week 2, mL) Urinary retention (%) Patients using CIC (%) BOTOX ® Summary of Product Characteristics, Allergan 2. 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 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 Available from: Last accessed July BOTOX ® Summary of Product Characteristics, Allergan Less invasiveMore invasive Neurostimulation Peripheral tibial nerve stimulation Sacral nerve stimulation Surgery Augmentation cystoplasty Urinary diversion Assisted emptying Voiding by abdominal straining Triggered reflex voiding Containment Urinary incontinence products 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