Overactive Bladder beyond antimuscarinics Marcus Drake Bristol Urological Institute Conflicts of interest; Allergan, AMS, Astellas, Ferring, Pfizer
Getting the diagnosis right Improving treatment Improving efficacy, reducing adverse effects Long-term management Matching treatment to the individual patient New drug class
Storage phase LUTS Urgency: sudden compelling desire to pass urine which is difficult to defer Increased Daytime Frequency: the complaint by a patient who considers that he/she voids too often by day Nocturia: the complaint that the individual has to wake at night 1 or more times to void Abrams P et al Neurourol Urodyn 2002;21:167-178
Spectrum of OAB OAB; urgency, with or without urgency incontinence, usually with frequency and nocturia. Exclude other causes SUI Mixed Symptoms URGENCY Mixed Incontinence UUI OAB Symptoms Urgency: a sudden compelling desire to pass urine, which is difficult to defer Urgency: the only symptom a patient must have to be described as having OAB Wein AJ. Rackley RR. J Urol 2006;175:s5-10; Abrams P et al Neurourol Urodyn 2002;21:167-178;Abrams P BJU Int 2005; 96 (Suppl 1)1-3
Prevalence % Prevalence of OAB symptoms Comparison of data from the SIFO study 1997 and the EPIC study 2005 40 35 30 25 20 15 Men SIFO 1997 Women SIFO 1997 Men EPIC 2005 Women EPIC- 2005 16.6 11.8 (n= 16,776) (n= 19,165) SIFO conducted in 6 European countries 10 5 0 18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ EPIC conducted in Europe and Canada using ICS terminology standards of 2002 Age, years Adapted from Milsom I et al. BJU Int. 2001;87:760-766 Adapted from Milsom I &Irwin D. Eur Urol Suppl. 2007;6:4-9 SIFO = Sifo/Gallup telephone survey
Unmet needs; diagnosis Selective diagnosis; OAB is not a dustbin Professional consensus Due prioritisation Screen for OAB Offer treatment
Currently available treatments Treatment options currently used in OAB include: 1 Conservative therapies 1 Lifestyle intervention Physical therapies Behavioural therapies Use of appropriate drug treatment (i.e. antimuscarinics) Surgical management 1 e.g. sacral nerve stimulation, augmentation cystoplasty, urinary diversion, botulinum toxin A injection Antimuscarinic therapy has long been the main treatment for OAB 2,3 1. NICE clinical guidance CG40: Urinary incontinence, October 2006. 2. Hegde SS. Br J Pharmacol 2006;147:S80 S87. 3. Athanasopoulos A et al. Adv Urol 2011;820816. doi: 10.1155/2011/820816. Date of preparation: February 2013. BET13018UK
Median percentage reduction Antimuscarinic drug therapy improves OAB symptoms 40-week open-label extension trial with patients completing treatment in the two previous randomised, double-blind, 12-week studies Duration of solifenacin 5/10mg exposure (weeks) 0 4 8 12 16 28 40 52-20 -40-60 Frequency Nocturia -27% -50% -80-100 Urgency -89% Adapted from: Haab F et al. Eur Urol. 2005;47:376-384
Wagg A BJU Int 2012; doi:10.1111/j.1464-410x.2012.11023.x
Persistence with antimuscarinic medication: A UK experience UK prescription database; community treatment with antimuscarinics for OAB Patients commencing treatment Jan 2007 to Dec 2007 and review Dec 2008 1.2 million records reviewed 4833 patients new to treatment within 6 months Wagg A BJU Int 2012; doi:10.1111/j.1464-410x.2012.11023.x
Darifenacinn Flavoxate Oxybutynin ER Oxybutynin IR Propiverine Solifenacin 5 mg Solifenacin 10 mg Tolterodine ER Tolterodine IR Trospium Patients % Persistence with antimuscarinic medication: A UK experience Twelve-month persistence with each prescribed antimuscarinic therapy analyzed by individual drug 100 90 80 70 60 50 40 30 20 10 0 n=23 n=89 n=590 n=1371 n=97 n=1258 n=332 n=1758 n=482 n=352 40 49 years 50 59 years 60 69 years 70 79 years >80 years Wagg A BJU Int 2012; doi:10.1111/j.1464-410x.2012.11023.x
Symptom change after discontinuation of successful antimuscarinic treatment 65% of patients required recommencement of treatment by three months A longer course of treatment would have been beneficial Long term treatment may be the best option 35% of patients remained satisfied after a short course of treatment A longer course may have been unnecessary Symptoms did not deteriorate despite stopping treatment Treatment persistence would have been unnecessary Lee et al. Int J Clin Pract. 2011, 65, 9, 997 1004
Percentage of Patients General willingness to try new medication Dissatisfied patients are more likely to try a new medication. 7 in 10 lapsed patients would be willing to re-start Rx treatment for their OAB symptoms 100% 90% 80% 70% Dissatisfied patients did not receive this question 85% 76% 73% 70% 67% 60% 50% 50% 52% 40% 30% 20% 10% 0% Likelihood to try new product upon becoming aware of it General willingness to try new medication Likelihood to try new medication suggested by physician Dissatisfied patients (top 3) Lapsed patients (top 3) Likelihood to consult physician regarding dissatisfaction wtihin the next 6 months Astellas Market Research, GfK Healthcare. Dec 2011; p.78
Unmet needs Diagnosis Selective diagnosis; OAB is not a dustbin Professional consensus and prioritisation Screen for OAB and offer treatment Treatment Improved balance of efficacy: adverse effects Short- and long-term maintenance Refractory OAB management options Difficult subgroups; voiding dysfunction, extremes of age, mixed urinary incontinence, increased filling sensation
Therapy Antimuscarinics
Mirabegron is a novel treatment for OAB that works differently to antimuscarinics 1,2 Mode of action of OAB treatments 1,3 Adapted from Betmiga Summary of Product Characteristics, December 2012 1 and Chu et al., 2006. 3 1. Betmiga Summary of Product Characteristics, December 2012. 2. Gras J. Drugs of Today 2012;48(1):25-32. 3. Chu F, Dmochowski R. Am J Med 2006;119(3A):3S 8S. Date of preparation: February 2013. BET13018UK
Relaxation effects of beta-agonists on carbachol-induced contractions of muscle strips from patients
SCORPIO: A key European-Australian, 12-week, Phase III trial in patients with OAB 1 SCORPIO trial design 1 A randomised, double-blind, placebo- and active-controlled, 12-week Phase III trial of 1978 patients with OAB 1 Mirabegron 50mg (n=493) Adapted from Khullar et al., 2013. 1 *Evaluation of adverse events and concomitant medication by telephone or visit for a period of 30 days. Tolterodine ER (extended-release) 4mg was included as an active control in this study. 1. Khullar V et al. Eur Urol 2013;63(2):283 295. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO: Improvements in incontinence episodes/24h (co-primary endpoint) 1 Incontinence episodes/24h (FAS-I) Adapted from Khullar et al., 2013. 1 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS-I = all full analysis set patients who had 1 incontinence episode at baseline. ns = no statistically significant difference vs. placebo. *Statistically significant improvement vs. placebo (p<0.05). Mean difference vs. placebo (95% two-sided CI: -0.72, -0.09). 1. Khullar V et al. Eur Urol 2013;63(2):283 295. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO: Improvements in micturitions/24h (co-primary endpoint) 1 Micturitions/24h (FAS) Adapted from Khullar et al., 2013. 1 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS = full analysis set ns = no statistically significant difference vs. placebo. *Statistically significant improvement vs. placebo (p<0.05). Mean difference vs. placebo (95% two-sided CI: -0.90, -0.29). 1. Khullar V et al. Eur Urol 2013;63(2):283 295. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO: Most common TEAEs ( 2% in any treatment group) 1 In the three, 12-week Phase III studies, the most common adverse reactions reported for mirabegron 50mg were tachycardia and urinary tract infections (1.2% and 2.9% respectively). Serious adverse reactions included atrial fibrillation (0.2%) 2 In SCORPIO, rates of drug discontinuation due to TEAEs were low and comparable in the active groups (<5%) 1 Adverse events % Incidence of most common ( 2%) TEAEs 1 Placebo (n=494) Mirabegron 50mg (n=493) Tolterodine ER 4mg active control (n=495) Dry mouth 2.6% 2.8% 10.1% Constipation 1.4% 1.6% 2.0% Hypertension 7.7% 5.9% 8.1% Nasopharyngitis 1.6% 2.8% 2.8% Headache 2.8% 3.7% 3.6% Urinary tract infection 1.4% 1.4% 2.0% For the full list of adverse events refer to the SmPC. 2 Tolterodine ER 4mg was included as an active control therefore direct statistical comparisons cannot be made between mirabegron and tolterodine ER 4mg. Table adapted from Khullar et al., 2013. 1 Data not shown for the unlicensed 100mg dose of Mirabegron. TEAEs, treatment-emergent adverse events. 1. Khullar V et al. Eur Urol 2013;63(2):283 295. 2. Betmiga Summary of Product Characteristics, December 2012. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO post hoc analysis: Patients who discontinued previous OAB therapy due to lack of effect 1,2 Incontinence episodes/24h (FAS-I) Adapted from Khullar et al., 2012 1 and Betmiga Summary of Product Characteristics, December 2012. 2 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS-I = all full analysis set patients who had 1 incontinence episode at baseline. *Mean difference vs. placebo (95% two-sided CI: -1.32, -0.19). 1. Khullar V et al. Poster presented at the 27th Annual Congress of the European Association of Urology, 24 28 February 2012, Paris, France (Poster 684). 2. Betmiga Summary of Product Characteristics, December 2012. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO post hoc analysis: Patients who discontinued previous OAB therapy due to lack of effect 1,2 Micturitions/24h (FAS) Adapted from Khullar et al., 2012 1 and Betmiga Summary of Product Characteristics, December 2012. 2 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS = full analysis set. Mean difference vs. placebo (95% two-sided CI: -1.15, -0.04). 1. Khullar V et al. Poster presented at the 27th Annual Congress of the European Association of Urology, 24 28 February 2012, Paris, France (Poster 684). 2. Betmiga Summary of Product Characteristics, December 2012. Date of preparation: February 2013. BET13018UK Prescribing information
SCORPIO: Conclusions Mirabegron 50mg, over 12 weeks, demonstrated superior efficacy compared with placebo for co-primary endpoints of micturitions and incontinence episodes/24 hours 1 Mirabegron 50mg is an effective treatment for OAB in treatment-naïve patients and previously treated patients 1 Mirabegron 50mg is effective in patients who discontinued antimuscarinic therapy due to lack of effect 2 Mirabegron 50mg was generally well tolerated 1 1. Khullar V et al. Eur Urol 2013;63(2):283 295. 2. Khullar V et al. Poster presented at the 27 th Annual Congress of the European Association of Urology, 24-28 February 2012, Paris, France (Poster 684). Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: 12-month extension study looking at the safety and efficacy of mirabegron 1 TAURUS trial design: long-term safety and efficacy of mirabegron A multi-centre, 12-month, double-blind study of 2444 patients with OAB 1 Tolterodine ER 4mg was an active control Mirabegron 50mg (n=812) Adapted from Chapple et al., 2013. 1 Eligible patients who completed Phase III, 12-week mirabegron studies could be enrolled, but required a minimum 30-day drug washout. The study was not designed to demonstrate a statistically significant difference in efficacy between treatment groups. Tolterodine ER 4mg was an active control. No direct statistical comparisons can be made between tolterodine ER 4mg and mirabegron 50mg. 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: 12-month extension study 1 In the three, 12-week Phase III studies, the most common adverse reactions reported for mirabegron 50mg were tachycardia and urinary tract infections (1.2% and 2.9% respectively). Serious adverse reactions included atrial fibrillation (0.2%) 2 The long-term safety and tolerability profile of mirabegron 50mg was demonstrated in a multi-centre, 12-month, doubleblind study (n=2444) 1 The incidence and severity of TEAEs (primary endpoint) was similar across the active treatments in this study 1 Most TEAEs were mild to moderate in severity 1 TEAE, treatment-emergent adverse event. 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. 2. Betmiga Summary of Product Characteristics, December 2012. Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: Most frequent ( 2% in any group) TEAEs 1 Adverse event Mirabegron 50mg (n=812) n (%) Tolterodine ER 4mg active control (n=812) n (%) Hypertension 75 (9.2%) 78 (9.6%) Urinary tract infection 48 (5.9%) 52 (6.4%) Headache 33 (4.1%) 20 (2.5%) Nasopharyngitis 32 (3.9%) 25 (3.1%) Back pain 23 (2.8%) 13 (1.6%) Constipation 23 (2.8%) 22 (2.7%) Dry mouth 23 (2.8%) 70 (8.6%) Sinusitis 22 (2.7%) 12 (1.5%) Dizziness 22 (2.7%) 21 (2.6%) Influenza 21 (2.6%) 28 (3.4%) Cystitis 17 (2.1%) 19 (2.3%) Arthralgia 17 (2.1%) 16 (2.0%) Diarrhoea 15 (1.8%) 16 (2.0%) Tachycardia 8 (1.0%) 25 (3.1%) For full list of side effects, please consult the SmPC 2 Safety Analysis Set (SAF) all randomised patients who took 1 dose of double-blind study drug; TEAE, treatment-emergent adverse event. 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. 2. Betmiga Summary of Product Characteristics, December 2012. Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: Efficacy variables over 52 weeks (secondary endpoint) Mean number of incontinence episodes/24h (FAS-I) 1 Adapted from Chapple CR et al., 2013. 1 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS-I = all full analysis set patients who had 1 incontinence episode at baseline. 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: Efficacy variables over 52 weeks (secondary endpoint) Mean number of micturitions/24h (FAS) 1 Adapted from Chapple CR et al., 2013. 1 Tolterodine ER (extended-release) 4mg was included as an active control in this study. FAS = full analysis set. 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. Date of preparation: February 2013. BET13018UK Prescribing information
TAURUS: Conclusions The TAURUS study supports the 12-month safety and tolerability of mirabegron 50mg for OAB 1 The incidence and severity of TEAEs (primary endpoint) was similar across the active treatments in this study 1 Mirabegron 50mg was generally well tolerated over 12-months 1 Incidence of dry mouth, a common side effect associated with antimuscarinics, was more than three-fold higher in the tolterodine ER 4mg group than in the mirabegron 50mg group 1 Improvements in the secondary endpoints of micturition frequency and incontinence episodes noted at 4 weeks were maintained over the duration of the study 1. Chapple CR et al. Eur Urol 2013;63(2):296 305. Date of preparation: February 2013. BET13018UK Prescribing information
Summary OAB; Getting the diagnosis right Improving treatment Improving efficacy, reducing adverse effects Long-term management Matching treatment to the individual patient Beta-3 agonist Mirabegron 50mg has a novel mode of action, effective in treatment-naïve and previously treated OAB patients, generally well tolerated Prescribing information
Prescribing Information Presentation: Betmiga TM prolonged-release film-coated tablets containing 25mg or 50mg mirabegron. Indication: Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Dosage: Adults (including the elderly): Recommended dose: 50mg once daily. Children and adolescents: Should not be used. Contraindications: Hypersensitivity to active substance or any of the excipients. Warnings and Precautions: Should not be used in patients with end stage renal disease (or patients requiring haemodialysis), severe hepatic impairment and severe uncontrolled hypertension. Not recommended in patients with severe renal impairment and/or moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors. Dose adjustment to 25mg is recommended in patients with; mild/moderate renal and/or mild hepatic impairment receiving strong CYP3A inhibitor concomitantly and in patients with severe renal and/or moderate hepatic impairment. Caution in patients with a known history of QT prolongation or in patients taking medicines known to prolong the QT interval. Not recommended during pregnancy and in women of childbearing potential not using contraception. Not recommended during breastfeeding. Interactions: Clinically relevant drug interactions between Betmiga TM and medicinal products that inhibit, induce or are a substrate for one of the CYP isozymes or transporters are not expected, except for inhibitory effect on the metabolism of CYP2D6 substrates. Betmiga TM is a moderate and time-dependent inhibitor of CYP2D6 and weak inhibitor of CYP3A. No dose adjustment needed when administered with CYP2D6 inhibitors or CYP2D6 poor metabolisers. Caution if co-administered with medicines with a narrow therapeutic index and significantly metabolised by CYP2D6. When initiating in combination with digoxin, the lowest dose for digoxin should be prescribed and serum digoxin should be monitored and used for titration of digoxin dose. Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Betmiga TM. No dose adjustment is needed for Betmiga TM when administered with therapeutic doses for rifampicin or other CYP3A or P-gp inducers. The potential for inhibition of P-gp by Betmiga TM should be considered when combined with sensitive P-gp substrates. Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate. Adverse Effects: Urinary tract infection, tachycardia, vaginal infection, cystitis, palpitation, atrial fibrillation, dyspepsia, gastritis, urticaria, rash, rash macular, rash papular, pruritus, joint swelling, vulvovaginal pruritus, blood pressure increase, liver enzymes increase, eyelid oedema, lip oedema, leukocytoclastic vasculitis and purpura. Prescribers should consult the Summary of Product Characteristics in relation to other side effects. Pack and prices: Betmiga TM 25mg and Betmiga TM 50mg pack of 30 tablets 29.00. Legal Category: POM. Product Licence Number: Betmiga TM 25mg EU/1/12/809/001-007; Betmiga TM 50mg EU/1/12/809/008-014. Date of Preparation: January 2013. Further information available from: Astellas Pharma Ltd, 2000 Hillswood Drive, Chertsey, Surrey, KT16 0RS, UK. Betmiga TM is a Registered Trademark. For full prescribing information please refer to the Summary of Product Characteristics. For Medical Information phone 0800 783 5018. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Astellas Pharma Ltd. Please contact 0800 783 5018 Date of preparation: February 2013. BET13018UK BACK Prescribing END PRESENTATION information