Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: PIERRE FABRE MEDICAMENT, Les Cauquillous, 81500 Lavaur, France
Pharmacotherapeutic group: Urologicals, Drugs for urinary frequency and incontinence
ATC code: G04BD15
Vibegron is a selective and potent human beta-3 adrenergic receptor agonist over β1-AR and β2-AR. Activation of the beta-3 adrenergic receptor located in the bladder detrusor muscle increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling.
The efficacy of vibegron 75 mg was evaluated in a phase 3, 12-week, double-blind, randomised, placebo-controlled, and active-controlled trial (EMPOWUR) in OAB patients with symptoms of urgency and urinary frequency with or without urge urinary incontinence (UUI). Patients were randomised 5:5:4 to receive either vibegron 75 mg, placebo, or tolterodine ER 4 mg orally, once daily for 12 weeks. For study entry, patients had to have symptoms of OAB for at least 3 months with an average of 8 or more micturitions per day and at least 1 UUI per day, or an average of 8 or more micturitions per day and an average of at least 3 urgency episodes per day. UUI was defined as leakage of urine of any amount because the patient felt an urge or need to urinate immediately. The study population included OAB medicinal product-naïve patients as well as patients who had received prior therapy with OAB medicinal product. A total of 1 518 patients were randomised: 547 subjects were randomised to the vibegron group, 540 to the placebo group, and 431 to the tolterodine group. Of these 1 518 patients, 54 patients (10.0%) administered with placebo and 45 patients (8.2%) in the vibegron 75 mg group discontinued from the study. The main reason for study discontinuation was consent withdrawal (3.9% in the placebo group and 2.6% in the vibegron group).
The co-primary endpoints were change from baseline in average daily number of micturitions and average daily number of UUI episodes at Week 12. Important secondary endpoints included change from baseline in average daily number of urgency episodes, average daily number of total incontinence episodes, average volume voided per micturition, % of patients with ≥75% and 100% reduction in the average daily number of UUI episodes, and Overactive Bladder Questionnaire Long Form (OAB-q LF) coping domain score.
A total of 1 515 patients received at least one daily dose of placebo (n=540), vibegron 75 mg (n=545), or active control (n=430). The majority of patients were Caucasian (78%) and female (85%) with a mean age of 60 (range 18 to 93) years, 77% patients presenting with UUI (OAB Wet). The percentage of patients at baseline over 65 years of age was 42.6% and over 75 years of age was 12.1%.
Vibegron 75 mg was effective in treating the symptoms of OAB within 2 weeks and efficacy was maintained throughout the 12-week treatment period (results are presented below in Table 2).
Table 2. Mean baseline and change from baseline at week 12 for frequency of micturition, urge urinary incontinence episodes, urgency episodes, total incontinence episodes, and volume voided per micturition:
| Parameter | Placebo | Vibegron 75 mg | Tolterodine ER 4 mg |
|---|---|---|---|
| Average daily number of micturitionsa | |||
| Baseline mean (n) | 11.8 (520) | 11.3 (526) | 11.5 (417) |
| Change from baselineb (n) | -1.3 (475) | -1.8 (492) | -1.6 (378) |
| Difference from placebo | -0.5 | -0.3 | |
| 95% Confidence Interval | -0.8, -0.2 | -0.6, 0.1 | |
| p-value | <0.001d,e | 0.0988 | |
| Average daily number of UUI episodesc | |||
| Baseline mean (n) | 3.5 (405) | 3.4 (403) | 3.4 (319) |
| Change from baselineb (n) | -1.4 (372) | -2.0 (383) | -1.8 (286) |
| Difference from placebo | -0.6 | -0.4 | |
| 95% Confidence Interval | -0.9, -0.3 | -0.7, -0.1 | |
| p-value | <0.0001d,e | 0.0123 | |
| Average daily number of “need to urinate immediately” (urgency) episodesa | |||
| Baseline mean (n) | 8.1 (520) | 8.1 (526) | 7.9 (417) |
| Change from baselineb (n) | -2.0 (475) | -2.7 (492) | -2.5 (378) |
| Difference from placebo | -0.7 | -0.4 | |
| 95% Confidence Interval | -1.1, -0.2 | -0.9, 0.0 | |
| p-value | 0.002d,e | 0.0648 | |
| Average daily number of total incontinence episodesc | |||
| Baseline mean (n) | 4.2 (405) | 4.1 (403) | 4.1 (319) |
| Change from baselineb (n) | -1.6 (372) | -2.3 (383) | -2.0 (286) |
| Difference from placebo | -0.7 | -0.5 | |
| 95% Confidence Interval | -1.0, -0.4 | -0.8, -0.1 | |
| p-value | <0.0001d,e | 0.0074 | |
| Average volume voided (mL) per micturitiona | |||
| Baseline mean (n) | 148 (514) | 155 (524) | 147 (415) |
| Change from baselineb (n) | 2 (478) | 24 (490) | 16 (375) |
| Difference from placebo | 21 | 13 | |
| 95% Confidence Interval | 14, 28 | 9, 22 | |
| p-value | <0.0001d,e | <0.001 | |
a FAS-population: Full analysis set. All randomised patients with OAB who took at least 1 dose of double-blind study treatment and had at least one evaluable change from baseline micturition measurement.
b Least squares mean adjusted for treatment, baseline, OAB type (only for analyses on FAS), gender, geographical region, study visit, and study visit by treatment interaction term.
c FAS-I population: used for incontinence endpoints and included patients in the FAS population with OAB Wet at study entry who had at least 1 evaluable change from baseline UUI measurement.
d Statistically significant.
e Parameters included in the multiple testing procedure. Hypothesis testing was only performed for vibegron-placebo.
Additional key secondary endpoints included the proportion of patients with a reduction at week 12 compared to baseline in average daily number of UUI episodes of ≥75% or 100%. Results are presented below (Table 3).
Table 3. Secondary efficacy analysis: urge urinary incontinence 75% and 100% responder analysis at week 12 – FAS-I (included patients in the FAS population with OAB Wet at study entry who had at least 1 evaluable change from baseline UUI measurement):
| Statistic | Placebo N=405 | Vibegron 75 mg N=403 | Tolterodine ER 4 mg N=319 |
|---|---|---|---|
| Subjects with at least 75% reduction in UUI from baseline at week 12 | |||
| Estimated* n (%) | 133 (32.8) | 199 (49.3) | 135 (42.2) |
| Active-Placeboa | |||
| CMH Difference | 16.5 | 9.4 | |
| 95% CI | [9.7; 23.4] | [2.1; 16.7] | |
| p-value | <0.0001b,c | 0.0120 | |
| Patients with 100% reduction in UUI from baseline at week 12 | |||
| Estimated* n (%) | 77 (19.0) | 102 (25.3) | 67 (20.9) |
| Active-Placeboa | |||
| CMH Difference | 6.3 | 1.9 | |
| 95% CI | [0.4; 12.1] | [-4.1; 7.8] | |
| p-value | 0.0360b,c | 0.5447 | |
Notes: MI was used to impute values missing for any reason at the weeks analysed.
Presented frequencies and the denominator used for percentage were based on subjects in the FAS-I and randomised treatment.
* The estimated proportion uses the SAS procedure MIANALYZE with standard multiple imputation effect estimation.
a The difference in proportion and corresponding CI and p-value was calculated using the Cochran-Mantel-Haenszel risk difference estimate stratified by sex (female vs male), with weights proposed by Greenland and Robins.
b Statistically significant.
c Comparisons included in the multiple testing procedure. Comparisons between tolterodine ER and placebo are considered descriptive.
The long-term safety and efficacy of vibegron 75 mg was evaluated for up to 52 weeks in a phase 3 extension study in 505 patients who had completed the 12-week phase 3 study (EMPOWUR).
The European Medicines Agency has deferred the obligation to submit the results of studies with Obgemsa in one or more subsets of the paediatric population in the treatment of neurogenic detrusor overactivity (see section 4.2 for information on paediatric use).
Mean vibegron Cmax and AUC increased in a greater than dose-proportional manner up to 600 and 400 mg after single and repeated dose, respectively. Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (Rac) was 1.7 for Cmax and 2.4 for AUC0-24hr. Median vibegron Tmax is approximately 1 to 3 hours.
Oral administration of vibegron 75 mg film-coated tablet crushed and mixed with 15 mL of applesauce resulted in no clinically relevant changes in vibegron pharmacokinetics when compared to administration of an intact vibegron 75 mg film-coated tablet. Therefore, vibegron can be crushed for administration in soft food.
Co-administration of a 75 mg tablet with a high-fat meal reduced vibegron Cmax and AUC by 63% and 37%, respectively. The effect of food appeared to be smaller at steady state (unchanged AUC and 30% lower Cmax). In the phase 3 studies demonstrating efficacy and safety, vibegron was administered with or without food. Therefore, vibegron can be taken with or without food.
The mean apparent volume of distribution following oral administration is 9 120 litres. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9.
Vibegron is metabolised via oxidation and direct glucuronidation but metabolism is not a major route of elimination. Vibegron is the major circulating component following a single dose of 14C-vibegron. One major metabolite was observed in human plasma being a phase II glucuronide representing 12 to 14% of total exposure. All the recombinant UGT enzymes evaluated in vitro demonstrated some metabolism of vibegron (mainly UGT1A3, UGT1A4, UGT1A6, UGT2B10, UGT2B15). Although in vitro studies suggest a role for CYP3A4 in the oxidative metabolism of vibegron, in vivo results indicate that these isozymes play a limited role in the overall elimination.
The mean terminal half-life (t½) values following multiple-dose administration ranges from 59 to 94 hours in young and elderly subjects, and the effective half-life is approximately 31 hours across all populations.
Following the oral administration of 100 mg 14C-vibegron to heathy volunteers, approximately 59% of the radiolabeled dose was recovered in faeces and 20% in urine. Unchanged vibegron accounted for the majority of the excreted radioactivity (54 and 19% of the radiolabelled in faeces and urine, respectively). Most of the dose recovered in faeces is likely unabsorbed substance. Urinary excretion of unchanged substance is a major route of elimination (around 50% of the absorbed vibegron). Biliary excretion of unchanged substance may also contribute to the elimination while hepatic metabolism appears to play a minor part.
Relative to volunteers with normal renal function (GFR ≥ 90 mL/min), administration of 100 mg single dose of vibegron increased mean Cmax and AUC by:
No dose adjustment for vibegron is recommended for patients with mild, moderate, or severe renal impairment (15 mL/min < GFR < 90 mL/min and not requiring dialysis). Vibegron has not been studied in patients with end stage renal disease (GFR < 15 mL/min with or without haemodialysis) and is therefore not recommended in these patients.
Relative to volunteers with normal hepatic function, administration of 100 mg single dose of vibegron increased mean Cmax and AUC by 1.3- and 1.3-fold, respectively in volunteers with moderate hepatic impairment (Child-Pugh Class B).
No dose adjustment for vibegron is recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B). Vibegron has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is therefore not recommended in this patient population.
No pharmacokinetic data are available in children below 18 years of age.
No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (studied range: 18 to 93 years), gender or race/ethnicity.
Weight (studied range: 39 to 161 kg) had a modest effect on clearance and central volume of distribution in the population pharmacokinetic analysis. The increase in vibegron exposures resulting from differences in weight are not considered clinically significant.
Vibegron showed 9 and 78-times lower in vitro β3-AR potency for rabbits and rats, respectively, when compared to humans. Therefore, safety margins for potential β3-AR-mediated effects on development or reproduction are accordingly lower than for non-β3-AR-related effects.
In animal studies no effects on embryo-foetal development were observed following oral administration of vibegron during the period of organogenesis at exposures (AUC) approximately 275-fold and 285-fold greater than clinical exposure at the recommended human dose (RHD) of 75 mg/day vibegron, in rats and rabbits, respectively. Delayed foetal skeletal ossification and reduced foetal body weights were observed in rabbits at approximately 898-fold clinical exposure (AUC) at the RHD, in the presence of maternal toxicity. In rats treated with vibegron during pregnancy and lactation, no effects on offspring were observed at 89-fold clinical exposure at the RHD. Developmental toxicity was observed in offspring at approximately 458-fold clinical exposure (AUC) at the RHD, in the presence of maternal toxicity.
When a single oral dose of radiolabeled vibegron was administered to postnatal nursing rats, radioactivity was observed in milk.
No effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (AUC) at least 275-fold higher than in humans at the RHD of 75 mg/day. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1 000 mg/kg/day, associated with estimated systemic exposure 1 867-fold higher (AUC) than in humans at the RHD of 75 mg/day.
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