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Subpopulation Analysis from the EMPOWUR Randomized, International, Phase III Study

Efficacy and Safety of Once-Daily Vibegron for Treatment of Overactive Bladder in Patients Aged 65+ and 75+

Jonny Nguyen, PharmD

Overactive Bladder (OAB): a condition that causes frequent and sudden urge to urinate, although the bladder isn't at full capacity- Other symptoms can include waking up more at night, not making it to the bathroom in timeOAB has affected the general population causing more than half of women between aged 40-45 to report OAB symptoms and more than 85% of women aged 71-75 to report symptoms- For men, the percentage of men seeking treatment for OAB has a significant correlation with increasing ageThe American Urological Assoication has recommended oral anticholingergic or B₃-adrenergic receptor agonist for treatment of OAB- Considered first-line if used in combination with behavioral therapy- Second-line if treated after behavioral therapyIn this Phase III study, the following medication were provided:- Tolterodine 4mg ER : M2 and M3 subtype antimuscarinic antagonist- Side effect: anticholinergic side effect (dry mouth, dementia, blurred vision, urinary retention, xerostomia, confusion, etc.) - Vibegron 75mg : Highly-selective B₃-adrenergic receptor agonist- Does not inhibit cytochrome P450 CYP2D6- Have not been associated with drug-related cognitive side effects- SIde effect: infrequently causes dry mouth

INTRODUCTION

KEY POINTS

In patients with OAB aged 65+ and 75+, treatment with vibegron was generally safe and well tolerated and demonstrated a safety profile consistent with that of the overall population

Within each age group and to those in the overall study population, rates of adverse events with Vibegron were generally comparable

In a subpopulation analysis of the phase III, 12-week EMPOWUR trial of patients with overactive bladder, patients (grouped by age; 65+ and 75+) receiving Vibegron showed significant improvement from baseline in average daily micturitions and in average daily number of urge urinary incontinence (UUI) and daily urgency episodes

SBP: systolic blood pressure DBP: diastolic blood pressure

With baseline hypertension: An average of three readings showing increases from baseline of ≥20mmHg SBP or ≥10 mmHg DBP at two consecutive visits, increased dosing or initiation of any medication to treat hypertension

Without baseline hypertension: SBP ≥140 or DBP ≥ 90mmHg at two consecutive visits

Treatment-emergent AEs:Occurring during the period of time from the first dose through 28 days after the last dose of study medication

Key secondary efficacy measure: change from baseline to week 12 in average number of urgency episodes per day

Coprimary efficacy endpoint were changes from baseline to week 12 in the frequency of micturition and frequency of UUI episodes per day

Data were collected from a 7-day event and 1-day volume diary completed by patients at baseline, week 2,4,8, and 12

METHOD: EFFICACY AND SAFETY

• Subpopulation analysis assessed efficacy and safety in patient aged 65+ and 75+
• Full analysis set was used for all non-incontinence efficacy endpoint
• Defined as all randomized patients who received at least one dose of double-blind study treatment and had at least one evaluable change from baseline micutrition frequency assessment
• Full analysis set for incontinence

• Defined as randomized patient who had wet OAB at study entry who received at least one dose of double-blind study treatment and had at least one evaluable change from baseline UUI measurement
• Mixed model for repeated measure (MMRM) with restricted maximum likelihood estimation was used to evaluate changes from baseline for continuous efficacy endpoints
• Included data from weeks 2,4,8, and 12
• Covariates for all patients and patient aged >65+, included study visit, age group, sex, region, OAB type (full analysis set only), baseline, and interaction terms
• For patients aged ≥ 65 years, post hoc responder analyses were performed to determine the proportion of patients with ≥ 50% reduction from baseline in the average number of daily urgency episodes and ≥ 75% or 100% reduction in average number of daily UUI episodes.
• Model used for patient 75+ was a post hoc analysis and did not include sex or region because of the small sample size

• Estimated differences in the proportion of responder (vibegron or tolterodine vs placebo) were analyzed using the Cochran-Mantel-Haenszel risk difference estimate and were stratified by OAB type and sex
• Missing data were imputed using multiple imputations
• Safety data were summarized for all patients who received at least one dose of double-blinded study treatment (safety set)

METHOD: STATISTICAL ANALYSES

In the overall study, 1518 patients were enrolled, 1515 patients received at least one dose of study treatment. Furthermore, Of these patients, 1463 were included in the full analysis set

RESULTS: PATIENT AND EFFICACY ENDPOINT

LS least square, SE standard error *P < 0.05, **P <0.01, ***P < 0.001 vs placebo using mixed model for repeated measures

RESULTS: EFFICACY ENDPOINT CONT.

Data are presemted as n (%) unless otherwise inndicated.AE adverse event, TEAE treatment-emergent AE, URTI upper respiratory tract infection, UTI urinary tract infection

Table 3: Summary of adverse events by age subgroup and treatment (safety set)

A. Full analysis se t for incontience (placebo, N=168; vibegron, N=192; tolterodine, N=128)*P <0.05; **P<0.001 vs placebo

Table 2: Responder analysis in patients aged ≥65 years

RESULTS: RESPONDER AND SAFETY

• Statistically significant benefits with vibegron versus placebo were seen in both age groups in the coprimary endpoints of change in frequency of micturition and UUI episodes and in the key secondary endpoint of urgency episodes
• Compared with tolterodine, numerical difference favoring vibegron were seen in older patients for change in the frequency of micturition and urgency episodes
• Efficacy finding in the subpopulation analysis of older age groups are consistent with those in the EMPOWUR study population
• Compared with the overall population, patients who received vibegron had generally similar rates of AEs versus placebo for both age subgroups
• Dry mouth was consistently more common with tolterodine vs vibegron
• Rates of cardiovascular-associated AEs were low across all age subgroups of patient receiving vibegron and were similar to those with placebo
• Among patient who received vibegron, rates of both hypertension and increased BP among adults were similar to or lower than those in patient who received placebo or tolterodine
• Vibegron may provide important safety advantages in older patient with OAB as polypharmacy service is common among older patient.
• Furthermore, 74% of patients in long-term care facilities are receiving CYP2d6 substrates
• EMPOWUR stuffy was limited to not detect difference within subgroups and is therefore limited by the small size, particularly 75+.
• Safety results for vibegron observed in both age subgroups were consistent with those seen in the overall EMPOWUR population

Once-daily Vibegron 75mg is efficacious across all symptoms of OAB and is generally safe and well tolerated for treatment of OAB due to the result of the subpopulation analysis aged 65+ and 75+ in the EMPOWUR study aligning with the result of the overall population

DISCUSSION AND CONCLUSION