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Friday General Session

Focus on : A Fine‐Tuned Approach to Attain Outcome Targets

Scott A. MacDiarmid, MD, FRCPSC Director of the Bladder Control and Pelvic Pain Center Alliance Specialists Greensboro, North Carolina

Educational Objectives By completing this educational activity, the participant should be better able to: 1. Proactively evaluate and screen at‐risk individuals for overactive bladder (OAB). 2. Utilize communication strategies aimed to evaluate the impact of OAB on quality of life and educate patients on appropriate treatment options and expectations. 3. Select patients with OAB who would benefit from combination therapy to maximize efficacy and tolerability.

Speaker Disclosure Dr. MacDiarmid has disclosed that he is on the advisory committee and speaker’s bureau for Allergan, Astellas, and Urovant.

Supporter Disclosure This educational activity is supported by an educational grant from Astellas. It has been planned and produced by VemCo MedEd with Texas Academy of Family Physicians strictly as an accredited continuing medical education activity.

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FACULTY AND DISCLOSURE Jointly proved by Center for Independent Healthcare Education and Vemco MedEd Supported by an educational grant from Astellas Scientific and Medical Affairs, Inc. Scott A. MacDiarmid, MD, FRCPSC Alliance Urology Specialists Clinical Associate Professor Department of Urology University of North Carolina Chapel Hill, NC

Scott MacDiarmid, MD has relevant financial relationships with ineligible companies to disclose: Speaker’s Bureau: Astellas Pharm, Urovant Sciences Consultant: Astellas Pharm, Urovant Sciences, Allergan All relevant financial relationships have been mitigated. Dr. MacDiarmid does not intend to discuss the off-label use of a product.

No (other) speakers, authors, planners or content reviewers have any relevant financial relationships to disclose. Content review confirmed that the content was developed in a fair, balanced manner free from commercial bias. Disclosure of a relationship is not intended to suggest or condone commercial bias in any presentation, but it is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

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ACTIVITY DESCRIPTION Audience Polling Question #1

Target Audience How often do you ask your adult patients about urinary symptoms? This educational initiative is designed as a comprehensive approach to address the practice needs of primary care providers, including primary care physicians, osteopathic physicians, physician assistants, nurse practitioners, and allied healthcare professionals, who are at the 1. Always forefront of caring for adult patients who may be suffering from OAB. 2. Frequently 3. Seldomly Learning Objectives Upon completing this activity, participants will be able to: 4. Never . Proactively screen and evaluate at-risk individuals for overactive bladder (OAB) . Utilize communication strategies aimed to evaluate the impact of OAB on quality of life and educate patients on appropriate treatment options and expectations . Identify patients with OAB who would benefit from combination therapy to maximize efficacy and tolerability

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Audience Polling Question #2 Audience Polling Question #3

How confident are you in talking to your patients about overactive How confident are you in screening and diagnosing patients for bladder? overactive bladder?

1. Very confident 1. Very confident 2. Confident 2. Confident 3. Somewhat confident 3. Somewhat confident 4. Not confident 4. Not confident

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1 Overactive Bladder Defined Prevalence of OAB Symptoms in Adults

OAB is equally prevalent in men and women and increases with age International Continence Society Definition OAB is a more prevalent condition than chronic sinusitis or heart disease • Presence of urinary urgency, usually accompanied by frequency and 35 Men , with or without urgency (UUI) 30 Women • No proven infection or other obvious pathology 25 Four components of OAB symptoms: 20 • Urgency 15 10 Prevalence* Prevalence* (%)

• Frequency Prevalence* (%) 5 •Nocturia 0 *Overall prevalence, with and without urgency incontinence < 25 25-34 35-44 45-54 55-64 65-74 ≥ 75 • Urgency urinary incontinence N = 5204, P = NS women vs. men Age (years)

Abrams P, et al. Neurourol Urodyn. 2002;21:167-178. Wein AJ, et al. Urology. 2002;60(suppl 5A):7-12. Adapted from Stewart WF, et al. World J Urol. 2003;20:327-336. Pleis JR, et al. Summary Health Statistics for U.S. Adults: National Lightner DJ, et al. J Urol. 2019;202:558. Health Interview Survey, 1998. National Center for Health Statistics. Vital Health Stat. 2002:10(209). 78

OAB Negatively Impacts Many Quality-of-Life Aspects OAB – A Major Cause of Concern for Many Patients1

Physical Psychological . Limitations/cessation . Depression . Disturbed sleep . Lack of self-esteem Wear dark, baggy . Difficulties concentrating . Lacking bladder control clothes to hide wet . Tiredness Quality – Urine odor spots or wear . Overeating diapers2 Use diapers or of Bathroom Social other absorbent mapping2,3 2,3 . Reduction in social products life interaction To cope with symptoms Sexual of OAB, many patients employ . Avoidance of sexual . Rely on toilet accessibility elaborate behaviors aimed at contact hiding and managing urine loss2 Domestic Occupational Carry extra Restrict fluid . Specialized underwear, . Absence from work clothes in case intake2,3 bedding . Decreased productivity of wetting 2 Try to urinate . Precautions with . Early retirement accident clothing on a schedule3

1. Rosenberg MT. Curr Urol Rep. 2008;9:428-32. Adapted from Tubaro A. Urology. 2004:64(suppl 6A):2-6. 2. Abrams et al. Am J Manag Care. 2000 Jul;6(11 Suppl):S580-S590. Irwin DE, et al. BJU Int. 2005;97:96-100. Muller N. Urol Nurs. 2005;25:109-115. 3. Ricci JA, et al. Clin Ther. 2001;23:1245-1259. 910

Key Populations: Patients With Diabetes and Obesity Effective Questioning to Detect OAB

The first complaint may not be the chief complaint • Survey of 1359 patients with T2DM who were screened at a dedicated diabetes center1 • What brings you here today? What are your concerns? – 22.5% had OAB • What is your most distressing symptom? – 48.0% of those with OAB had incontinence • How are you handling your urinary symptoms? – What do you mean you urinate frequently? • Overweight and obese women with T2DM: high prevalence of UI – How long have you experienced these symptoms? – Higher than other complications commonly associated with diabetes • What have you tried to solve your problems? (retinopathy, 7.5%; microalbuminuria, 2.2%; neuropathy, 1.5%)2 • When asking these questions: • Important implications for screening for bladder dysfunction – Respect the patient’s situation – Consider a treatment plan – Aim for patient-centered medicine T2DM, type 2 diabetes mellitus. 1. Liu RT, et al. Urology. 2011;78:1040-1045. 2. Phelan S, et al; Action for Health in Diabetes Research Group. Diabetes Care. 2009;32:1391-1397. Marschall-Kehrel D, et al. Urology. 2006;68(suppl 2A):29-37. 11 12

2 Useful Questions to Direct the Diagnosis of OAB AUA/SUFU OAB Guidelines: Diagnostic Workup

Do you have to rush to go to the toilet? Optional Additional Tests for Complicated or Initial Diagnostic Process Do you do this because of a sudden intense feeling Urgency Diagnostic Measures Refractory Patientsa so you have to urinate IMMEDIATELY?

Do you feel that you urinate Urodynamics Frequency Urine culture too often during the day? History Postvoid residual Cystoscopy Physical Exam assessment Renal/bladder ultrasound Do you have to get up during the night to urinate? Nocturia Urinalysis Bladder diaries (should not be used in the Does the urge to urinate wake you? initial workup of Symptom questionnaires uncomplicated patients) When you feel the urge to go to the bathroom, do Urgency urinary you have leaks or wetting accidents? incontinence

aPatients who failed multiple treatments Rosenberg MT, et al. Cleve Clin J Med. 2005;72:149-156. Lightner DJ, et al. J Urol. 2019;202:558. Irwin DE, et al. Eur Urol. 2006;50:1306-1315. 13 14

Differential Diagnosis of OAB AUA/SUFU OAB Treatment Guidelines

• Behavioral therapies for all patients 1st Line • May be combined with pharmacologic management

• Oral antimuscarinics or 3- • ER formulations of antimuscarinics preferred over immediate-release • Transdermal may be offered nd • Dose modification or switch to different antimuscarinic or 3-agonist if inadequate 2 Line efficacy or poor tolerability with an antimuscarinic • Combination therapy with an antimuscarinic and 3-agonist can be considered for those refractory to monotherapy

• Sacral nerve stimulation • Peripheral tibial nerve stimulation 3rd Line • Intradetrusor onabotulinum toxin A

OAB, overactive bladder; SUI, stress urinary incontinence; UTI, Gormley EA, et al. J Urol. 2015;193:1572-80. Lightner DJ, et al. J Urol. 2019;202:558. 15 16

Behavioral Modification OAB Pharmacotherapy: Different Receptor Pathways

Acetylcholine Antimuscarinics – Timed ACH Diet voiding M3 muscarinic receptor

Weight Loss (contraction)

Quit smoking 3 agonist + Behavioral Detrusor smooth muscle Modification (relaxation) NE

Pelvic floor Delayed AR exercises voiding 3

Reinforcement Takeda M, et al. J Pharmacol Sci. 2010;2110:121-127. Fowler CJ, et al. Nat Rev Neurosci. 2008;8:453-466. 17 18

3 Antimuscarinics Used in OAB Treatment Antimuscarinics – Leader of the Pack? Immediate Release Drug Dose Dosing • Review of randomized trials revealed no Oxybutynin IR 5 mg 2–4 times per day compelling evidence for differential efficacy across IR 1–2 mg Twice per day medications 20 mg Twice per day • The choice of medication for a particular patient Extended Release depends on the patient's history of: 7.5 mg, 15 mg Daily – Prior antimuscarinic use 4 mg, 8 mg Daily – Adverse events impact on the patient Oxybutynin ER 5–30 mg Daily – Patient preferences Oxybutynin TDS 3.9 mg Twice per week – Comorbidities Oxybutynin 10% gel 100 mg Daily – Use of other medications 5 mg, 10 mg Daily – Availability of and resources to acquire specific Tolterodine ER 2, 4 mg Daily medications Trospium chloride XR 60 mg Daily AUA/SUFU. Available at: https://www.auanet.org/education/guidelines/overactive-bladder.cfm. Amended 2014. Physicians’ Desk Reference. www.pdr.net. 19 20

High Discontinuation Rate with Antimuscarinics Cognitive Impairment and Antimuscarinic Use

Bladder ACHs in Study Journal Authors Conclusions N Oxybutynin Fesoterodine Welk ACH medications significantly increased risk of Tolterodine Trospium BJU International 47,324 McArthur dementia 100 Solifenacin Darifenacin 80 92.0 Oxybutynin Fesoterodine 83.7 87.5 Tolterodine Trospium Strong ACHs associated with increased risk of Discontinuation Rate 77.2 JAMA Internal Coupland 284,343 71.0 Solifenacin Darifenacin dementia (%) From 60 Favoxate 58.8 for Oxybutynin Trospium 40 52.5 Higher cumulative ACH exposure is associated with OAB (95% CI)* Tolterodine Favoxate BMC Geriatrics Wang 16,412 41.6 increase in risk of dementia Solifenacin 20 Oxybutynin ACH drugs are linked to future dementia persisting up BMJ Richardson 40,770 0 Tolterodine to 20 years after exposure 0 4 5 6 9 12 18 24 36 Darifenacin Tolterodine ACH medication associated with increased brain Months to Discontinuation Oxybutynin Trospium JAMA Neurology Risacher atrophy and clinical decline; should be discouraged 402 Solifenacin among older adults • 3 out of 4 episodes of OAB drug treatment were discontinued by first year of treatment Oxybutynin Fesoterodine Tolterodine Trospium Dementia and Alzheimer’s were associated with 10-year • ~60% of OAB treatment episodes were discontinued at 6 months, 77% by 1 year, and 92% by 3 years JAMA Internal Gray 3,434 Solifenacin Darifenacin cumulative dose of ACHs • Study Design: UK study. Overall drug discontinuation for all women prescribed medications (N=29,369). Favoxate Unadjusted cumulative incidence of discontinuation (95% CI). *Cumulative incidence of discontinuation was determined using the Kaplan-Meier method. Welk B, McArthur E. BJU Int. 2020;126:183-190. Coupland CAC, et al. JAMA Intern Med. 2019;179:1084-93. Wang Y-C, et al. BMC Geriatr. 2019;19:380. Richardson K, et al. BMJ. 2018;361:k1315. Gopal M, et al. Obstet Gynecol. 2008;112:1311-1318. Risacher SL, et al. JAMA Neurol. 2016;73:721-32. Gray SL, et al. JAMA Intern Med. 2015;175:401-7. 21 22

Mirabegron Reduces the Mean Number of 3- for OAB Treatment Incontinence Episodes per 24 Hours

Mirabegron Adjusted Mean Change From Baseline to Final Visit (12 weeks) • First FDA-approved 3-Adrenergic Agonists to treat:

– Overactive bladder in adult patients with symptoms of urge urinary incontinence, urgency, and urinary Study 1 Study 2 Study 3 Mirabegron Mirabegron frequency, either alone or in combination with the solifenacin succinate Placebo Mirabegron 50 mg Placebo Mirabegron 50 mg Placebo 25 mg 50 mg (n=291) (n=293) (n=325) (n=312) (n=262) (n=254) (n=257) Baseline 2.67 2.83 Baseline 3.03 2.77 Baseline 2.43 2.65 2.51 • Selective β3-agonist relaxes detrusor muscle and increases bladder capacity 0 0 0 – Avoids activation of β1 and β2- receptor (no adverse effects such as increased heart rate and muscle tremors) -0.5 -0.5 -0.5 – Also approved to treat neurogenic detrusor overactivity in pediatric patients (≥3 years) -1 -1 -1 • Available in 2 extended-release doses (25 and 50 mg) -0.96 0.40 0.34 0.42 -1.17 0.41 -1.13 Episodes per 24 Hours 24 per Episodes -1.5 -1.5 -1.5 * * -1.36 -1.38

Vibegron Mean Numberof Incontinence -1.47 * * -1.57 • Newly FDA-approved 3-agonist approved for: -2 -2 -2 – The treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults • Available in one dose (75 mg) For incontinence episodes per 24 hours, the analysis population is restricted to patients with at least 1 episode of incontinence at baseline. *Statistically significant improvement vs placebo at the 0.05 level with multiplicity adjustments. Myrbetriq™ (mirabegron) prescribing information, Astellas Pharma US, Inc. April 2021. Gemtesa® (vibegron) prescribing information, Urovant Sciences, Inc., Irvine, CA. December 2020. Myrbetriq™ (mirabegron) prescribing information, Astellas Pharma US, Inc. April 2021. 23 24

4 Mirabegron Long-term Safety Data: Vibegron Reduces Urge Incontinence Episodes and 52-week Active Controlled Trial Micturition Frequency Over 12 Weeks

Percent of Patients With Adverse Reactions, Derived From All Adverse Events, Reported by >2% of Patients Treated With Mirabegron 50 mg Once Daily Mirabegron 50 mg Tolterodine ER 4 mg Urge Incontinence Episodes per 24 hours Micturition Frequency per 24 hours at 12 weeks (%) (%) Among Incontinent Patients (at 12 weeks) 0 0.0 Vibegron 75mg (n=526) No. of patients 812 812 Vibegron 75mg (n=403) Hypertension 9.2 9.6 -0.2 -0.2 Placebo (n=520) -0.4 Placebo (n=405) -0.5 Urinary tract infection 5.9 6.4 -0.4 -0.6 -0.8 -0.6 -0.7 Headache 4.1 2.5 -0.8 -1.0 -0.9 -0.8 -1.0 Nasopharyngitis 3.9 3.1 -1 -1.2 -1.0 -1.2 Back pain 2.8 1.6 -1.2 -1.4 -1.4 -1.2 -1.3 -1.4 Constipation 2.8 2.7 -1.7 Fast results -1.6 -1.8 -1.4 -1.6 Dry mouth 2.8 8.6 in 2 weeks -1.8 -2.0 -1.6 -1.8 Dizziness 2.7 2.6 Fast results

Mean Change from Baseline -2 in 2 weeks -1.8 Mean Change from Baseline Sinusitis 2.7 1.5 -2.2 -2.0 Influenza 2.6 3.4 0 2 4 8 12 0 2 4 8 12 Week Arthralgia 2.1 2.0 Week Cystitis 2.1 2.3

Myrbetriq® (mirabegron extended-release tablets) prescribing information, Astellas Pharma US, Inc., April 2021. Staskin D, et al. J Urol. 2020;204:316-324. Chapple CR, et al. Eur Urol. 2013;63:296-305. 25 26

Vibegron Efficacy is Durable Over 52 Weeks Vibegron Safety Profile: (EMPOWUR) 12-Week Data

Urge Urinary Incontinence Episodes Adverse events reported ≥2.0% of patients taking vibegron 75 mg for up to 12 weeks Week 0 1216244452 Vibegron 75 mg Placebo 0 n (%) n (%) Vibegron 75 mg Tolterodine 4 mg Number of patients 545 540 -0.5 Headache 22 (4.0) 13 (2.4) Nasopharyngitis 15 (2.8) 9 (1.7) -1 Diarrhea 12 (2.2) 6 (1.1) -1.5 Nausea 12 (2.2) 6 (1.1) Upper respiratory tract infection 11 (2.0) 4 (0.7) -2

LS MeanBaseline Change LS from -2.5

Staskin D, et al. J Urol. 2021;205:1421-29. Gemtesa® (vibegron) prescribing information, Urovant Sciences, Inc., Irvine, CA. December 2020. 27 28

3-Agonists and Hypertension Patient Case

Results from 12-week phase III placebo- Results from 52-week double-blind, active- • 55-year-old woman with long history of type 2 diabetes mellitus controlled study1 controlled study2 2 Vibegron (n=545) Placebo (n=540) Mirabegron 50 mg Tolterodine ER 4 mg • BMI = 32 kg/m n (%) n (%) (n=812) (n=812) • At today’s visit, she complains of urgency urinary incontinence Hypertension 9 (1.7) 9 (1.7) Hypertension 9.2% 9.6%

BP increase 4 (0.7) 5 (0.9) • Has experienced incontinence episodes for over 2 years but has been reluctant to talk about it • Cannot sit through a two-hour movie • Experiences 2–3 daily incontinence episodes • Uses diapers when going out • Restricts travel and fluid intake • Experiences anxiety in unfamiliar settings (must be aware of nearest bathroom) 1. Staskin D, et al. J Urol. 2020;204:316-324. 2. Myrbetriq® (mirabegron extended-release tablets) Prescribing Information. Astellas Pharma US, Inc., Northbrook, IL. April 2021.

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5 Patient Case: Discussion Points Patient Case: Discussion Points

In addition to behavioral therapy, which of the following would How would your treatment selection change if the patient: you recommend? • Was a 77-year-old female with OAB? • Antimuscarinic • Was a 59-year-old man with BPH? • 3-agonist • Partially benefited from previous antimuscarinic monotherapy? • Combination therapy • None of the above

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Tailoring OAB Therapy: Considerations When Treating Utilizing a Treat-to-Target Approach OAB in the Elderly

• OAB prevalence of ~30% among those 65 years and older (compared to ~16% in general adult • Communicate with patients to set and manage treatment population) o As high as 50% among elderly in LTCF expectations Aging Polypharmacy Multiple • Monitor regularly for efficacy and tolerability population + Concerns + Comorbidities • Adjust therapy when needed Optimal OAB • Dosage, add-on, combination = Treatment in the • Manage adverse effects Geriatric Population? • Consider patient factors (age, comorbidities, etc.) • Because of the potential risk for dementia with prolonged use of anticholinergics, caution should be used in patients over 65 years. Rutman MP, et al. Clin Drug Invest. 2021;41:293-302. MacDiarmid SA. Rev Urol. 2008;10:6-13. 33 34

Mirabegron Significantly Reduces the Number of Mirabegron Add-On Therapy Improves OAB Symptoms Incontinence Episodes in the Elderly (PILLAR) in Men Receiving for BPH (PLUS)

No. incontinence episodes/24 hours Mean Change in TUFS • Compared mirabegron vs placebo in (Total Urgency and Frequency Score) • Compared mirabegron vs. placebo among men taking tamsulosin for underlying elderly OAB patients (≥65 years of age) BPH • Patients treated with mirabegron had a • Mirabegron add-on resulted in statistically significant: significant improvement in: o Reduction in mean incontinence episodes o Mean number of micturitions per day per 24 hr o Mean volume voided per micturition o Micturitions per 24 hr o Urgency episodes per day o Improved mean volume per micturition o Total urgency and frequency score (TUFS) There were no changes in mental status over 12 weeks with mirabegron

Kaplan SA, et al. J Urol. 2020;203:1163-71. Wagg A, et al. Eur Urol. 2020;77:211-220. 35 36

6 Adjusting Pharmacologic Therapy for OAB: Mirabegron + Solifenacin Combination Improves Balancing Efficacy and Tolerability Outcomes Over Monotherapy (SYNERGY)

No. of Incontinence Episodes at 12 Weeks • Consider the goals of the individual • A 12-week, 6-arm, randomized, double- MIR 25 mg + MIR 50 mg + Placebo MIR 25 mg MIR 50 mg SOL 5 mg SOL 5 mg SOL 5 mg blind trial comparing monotherapy with • Balance efficacy and tolerability 0 combination therapy in adults with wet OAB − Start with the lowest dose -0.5 • Combination therapy provided − Monitor medication adherence, lifestyle and behavioral therapy consistent improvement in efficacy -1 compared to respective monotherapies − Titrate the dose if response to treatment not meeting patient’s goals and across most outcome parameters adverse effects are safe and tolerable EoT to Baseline -1.5 including: o Urgency − Consider add-on/combination therapy if adequate response is not achieved from Change Mean Adjusted -2 Urinary incontinence episodes/24 h with monotherapy o -2.5 • Combination therapy was well tolerated − If possible, manage adverse effects before stopping an effective therapy without any new safety concerns

Herschorn S, et al. BJU Int. 2017;120:562-75.

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Mirabegron Add-on to Solifenacin Reduces Incontinence Episodes Compared to Solifenacin Monotherapy (BESIDE) The Importance of the Primary Care Provider

• Assessed safety and efficacy of adding mirabegron 50 mg to low-dose solifenacin 5 • Vital member in the OAB management pathway mg in patients with inadequate response to solifenacin monotherapy • Screen and identify, especially high-risk patients • Patients on maximum-dose solifenacin (10 • Efficiently diagnose OAB vs. other lower urinary tract mg) had higher rates of treatment-emergent adverse events vs. combination therapy disorders • Subgroup analysis in older adults found no difference in incontinence episodes with • Effectively manage a number of OAB patients combination therapy vs. maximum-dosed solifenacin • Knowing when to refer to a specialist Combination therapy reduces overall • Encourage, cheerlead, manage expectations anticholinergic burden without losing effectiveness Drake MJ, et al. Eur Urol. 2016;70:136-45.

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When to Consider Referral Conclusions

• Hematuria • OAB is highly prevalent in men and women and substantially impacts quality of life • Recurrent urinary tract infections • Communicate with patients to set goals and manage • Pelvic pain expectations • Pelvic organ prolapse • Utilize a treat-to-target approach that involves regular • Neurogenic bladder assessment and treatment adjustments • Partial and non-responders

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7 Q&A

Evaluation Link: https://www.surveymonkey.com/r/OAB2021

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8 Notes