Beova Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Vibegron selectively stimulates β₃-adrenergic receptors present in bladder smooth muscles, and by relaxing bladders, it promotes urine accumulation function, and improves urinary urgency, urinary frequency and urge incontinence in overactive bladder patients.
Effects on β-adrenergic receptors: In cells stably expressing the human β₃-adrenergic receptors, Vibegron increased concentrations of intracellular cAMP in a concentration-dependent manner, but in cells expressing human β₁- or β₂-adrenergic receptors it hardly increased concentrations of intracellular cAMP (in vitro).
Effects on bladder tissues (in vitro): Vibegron suppressed contraction in a concentration-dependent manner in human bladder tissues contracted by electrical stimulation.
Effects on bladder functions: Vibegron increased the bladder capacity in rhesus monkeys under anesthesia in a dose-dependent manner.
Vibegron increased the bladder capacity in crab-eating monkeys without anesthesia in a dose-dependent manner.
CLINICAL STUDIES: Clinical Studies for Efficacy and Safety: Japan phase III double-blind placebo-controlled study (KRP114V-T301): Vibegron 50 mg, 100 mg^note), or Placebo was orally administered to 1107 patients with overactive bladder once daily after a meal for 12 weeks. Following tables show change in mean urination frequency per day (primary endpoint), change in mean urinary urgency frequency per day and change in mean number of urge incontinence per day (secondary endpoints). Significant improvements were observed in each item evaluated in both treatment groups (Vibegron 50 mg and Vibegron 100 mg) compared with the placebo group.
Adverse reactions occurred in 7.6% (28/370 patients) in the Vibegron 50 mg group, 5.4% (20/369 patients) in the Vibegron 100 mg group and 5.1% (19/369 patients) in the placebo group. Common adverse reactions were constipation in 1.6% (6/370 patients) and dry mouth in 1.4% (5/370 patients) in the 50 mg group. (See Tables 1, 2 and 3.)

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Japan phase III long-term study (KRP114V-T302): Vibegron at the dose of 50 mg was orally administered to 166 patients with overactive bladder once daily after a meal for 52 weeks. After initial administration of Vibegron at the dose of 50 mg for 8 weeks, dosage was increased from 50 mg to 100 mg^note) once daily only in subjects who met the following: insufficient in efficacy, investigator judged no problem in safety, and the subject wished to increase dosage. Following tables show changes at Week 8 and 52 in mean urination frequency per day, mean urinary urgency frequency per day, and mean number of urge incontinence per day. In both the Vibegron 50 mg dose-maintained group and the Vibegron 100 mg dose-increased group, improvement from the baseline (before administration) was observed in every endpoint, which was maintained without attenuation over the duration of 52 weeks.
Adverse reactions occurred in 18.1% (21/116 patients) in the Vibegron 50 mg dose-maintained group, and 11.8% (6/51 patients) in the Vibegron 100 mg dose-increased group. Common adverse reactions were increased residual urine volume in 4.3% (5/116 patients), dry mouth and cystitis both in 2.6% (3/116 patients), and constipation in 1.7% (2/116 patient) in the Vibegron 50 mg dose-maintained group, and constipation and dry mouth both in 3.9% (2/51 patient), and rheumatoid arthritis and pruritus both in 2.0% (1/51 patient) in the Vibegron 100 mg dose-increased group. (See Tables 4, 5 and 6.)

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Note): Approved dose of this drug is 50 mg.
Pharmacokinetics: Blood Level: Single administration: After single oral administration of 10-300 mg^note) of Vibegron to 6 healthy adult males under fasted conditions, C_max and AUC_inf rose more than proportional to dose increase, but t_max and t_½ were constant regardless of the dose. (See figure and Table 7.)

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Repeated administration: After repeated oral administration of 50 mg, 100 mg or 200 mg^note) of Vibegron once daily for 14 days to 6 healthy adult males under fasted conditions, AUC_0-24 was ranging from 1.84 to 2.29 times higher than those on Day 1. The steady state of plasma concentrations of Vibegron was achieved by the 7th day of administration. (See Table 8.)

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Absorption: Effect of meal: After single oral administration of 50 mg of Vibegron to 8 healthy adult males after a meal, pharmacokinetic parameters were as shown as follows. C_max and AUC_inf under fasted conditions were 1.73 and 1.40 times higher, respectively, than those under fed conditions, but there were no effect on T_max and t_½. (See Table 9)

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Distribution: The plasma protein binding rate of Vibegron was approximately 49.6%-51.3%. The blood-to-plasma concentration ratio of Vibegron was measured to be 0.8-1.0 (in-vitro).
Metabolism: Vibegron mostly remains as unchanged form in human plasma after oral administration, and three different glucuronides and two different oxidative metabolites were identified as metabolites.
Excretion: In the mass balance study of single oral administration of 100 mg^note) of ¹⁴C labeled Vibegron to 6 healthy adult males, 20.3% of the dose was recovered as radioactivity in urine and 59.2% in feces by Day 20. Unchanged form accounted for 92.7% of radioactivity in urine and 91.0% in feces.
Patients with Specific Backgrounds: Patients with renal impairment: Among patients with renal impairment, C_max and AUC_inf after single oral administration of 100 mg^note) of Vibegron compared with those of healthy adult subjects were 1.96 and 1.49 times higher in mild (eGFR <90 - ≥60 mL/min/1.73 m²), 1.68 and 2.06 times higher in moderate (eGFR <60 - ≥30 mL/min/1.73 m²), and 1.42 and 1.83 times higher in severe (eGFR less than 30 mL/min/1.73 m², not on dialysis) renal impairment patients, respectively.
Patients with hepatic impairment: After single oral administration of 100 mg^note) of Vibegron in patients with moderate hepatic impairment (Child-Pugh Classification score of 7-9 points), C_max and AUC_inf were 1.35 and 1.27 times higher, respectively, than those of healthy adult subjects [see Precautions].
Geriatric use: After repeated oral administration of 100 mg^note) of Vibegron once daily for 14 days to healthy elderly males (65 to 74 years, 6 cases), C_max and AUC_0-24 was 1.88 and 1.45 times higher, respectively, than those of healthy non-elderly adult males (23 to 39 years, 5 cases) [see Precautions].
Note): Approved dose of this drug is 50 mg.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No carcinogenicity was observed in long-term studies conducted in mice and rats treated with daily oral doses of Vibegron for approximately 2 years. In the mouse carcinogenicity study, CD-1 mice were treated with daily oral doses of Vibegron up to 90 mg/kg/day in males and up to 150 mg/kg/day in females, corresponding to estimated systemic exposures (AUC) 21- and 55-fold higher, respectively, than in humans treated with the recommended daily dose of Vibegron. In the rat carcinogenicity study, Sprague Dawley rats were treated with daily oral doses of Vibegron up to 30 mg/kg/day in males and up to 180 mg/kg/day in females, corresponding to systemic exposures (AUC) 18- and 117-fold higher, respectively, than in humans treated with the recommended daily dose of Vibegron.
Mutagenesis: Vibegron was not mutagenic in in vitro microbial reverse mutation assays, showed no evidence of genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay.
Impairment of Fertility: In fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day Vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day Vibegron. 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 274-fold higher than in humans treated with the recommended daily dose of Vibegron. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of Vibegron.