Vibegron, sold under the brand name Gemtesa, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

for the treatment of

overactive bladder Overactive bladder (OAB) is a common condition where there is a frequent feeling of needing to urinate to a degree that it negatively affects a person's life. The frequent need to urinate may occur during the day, at night, or both. Loss of bl ...

. Vibegron is a selective

beta-3 adrenergic receptor The beta-3 adrenergic receptor (β3-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it. Function Actions of the β3 receptor include *Enhancement of lipolysis in adipose tissue. *The ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

. The most common side effects include headache,

urinary tract infection A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...

common cold The common cold, or the cold, is a virus, viral infectious disease of the upper respiratory tract that primarily affects the Respiratory epithelium, respiratory mucosa of the human nose, nose, throat, Paranasal sinuses, sinuses, and larynx. ...

, diarrhea, nausea, and

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat ...

. Vibegron was first discovered by scientists at Merck & Co. Inc. and was later developed in Japan by Kyorin Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co., Ltd, and Urovant Sciences. It was approved for medical use in Japan in September 2018, in the United States in December 2020, and in the European Union in June 2024.

Efficacy

Vibegron, once daily 75 mg provided significant reduction in micturition, urgency episodes and urge incontinence, and increased the volume per micturition.

Medical uses

Vibegron is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of

with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

Safety

Generally, the introduction of β3 adrenergic receptors agonists such as vibegron has improved overactive bladder (OAB) management by minimizing anticholinergic-related adverse effects. Monotherapy with a β3 adrenergic agonist may be preferred in older patients, those with high anticholinergic burden, and older adults with multiple comorbidities. An ambulatory blood pressure monitoring study showed that treatment with vibegron was not associated with clinically meaningful effects on blood pressure or heart rate. Treatment with vibegron was also associated with improvements in patient-reported measures of quality of life. Vibegron was generally effective, safe and well tolerated, thus represents a valuable treatment option for patients with OAB.

Adverse effects

The most common side effects of vibegron are dry mouth, constipation, headache, nasopharyngitis, diarrhea, nausea,

bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

and

. In case of urinary retention, the patient should stop using the drug. Risk assessment for the drug in pregnant people has yet to be evaluated.

Interactions

Vibegron is, in contrast to other OAB drugs, very selective and leads to a lesser degree of unwanted side effects. Vibegron is found to be a substrate for CYP3A4 in vivo, but does not actually induce or inhibit any of the cytochrome P450 enzymes and is thus less likely to take part in drug–drug interactions (DDI). Here vibegron differs from the previous overactive bladder drug mirabegron, which was known to be associated in various drug–drug interactions by inhibiting

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

or inducing CYP3A4, CYP2D6 and

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

in the liver. Using vibegron only (monotherapy) has positive effects on OAB and UUI, but a combination with other drugs can have additional effects. In a study with

antimuscarinic A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...

drugs, more DDIs were investigated using a model of rhesus monkeys. Dose combinations of vibegron and

tolterodine Tolterodine, sold under the brand name Detrol among others, is a medication used to treat frequent urination, urinary incontinence, or urinary urgency. Effects are seen within an hour. It is taken by mouth. Common side effects include head ...

showed increased bladder capacity, the effects of both drugs at low doses strengthened each other, known as synergism. The addition of darifenacin to vibegron created greater bladder relaxation only when used at high doses. Additionally, co-administration with imidafenacin shows an increase in bladder capacity and voided volume in comparison to monotherapy. Possibly, a widely adapted treatment will be the combination of beta-3-adrenergic agonist with a nonselective M2/ M3 antagonist as the most prevalent option. Clinical studies show no significant drug–drug interaction, aside from a serum concentration increase of digoxin when taken with vibegron. Maximal concentrations and systemic exposure (Cmax and area under the curve (AUC)) of digoxin are both increased as a result of DDI. Apart from the no to little DDIs, vibegron has an additional safety quality in that it does not cross the blood-brain barrier and therefore does not induce cognitive impairment. Furthermore, vibegron can be taken with or without food, this does not have an effect on vibegron plasma concentrations.

Pharmacology

Mechanism of action

Vibegron is a selective agonist for the beta-3 adrenergic receptor. The receptors are located in the kidneys, urinary tract and bladder tissue. Upon binding, the β3 receptor undergoes a conformational change. This induces the activation of adenylate cyclases via G proteins and thereby promotes the formation of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP). The consequence of this cascade is an increased intracellular cAMP concentration, which triggers activation of cAMP-dependent

protein kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

and causes a reduction of Ca2+ concentration in the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

. The kinase then

phosphorylates In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

chains and thereby inhibits muscle contraction. The final effect of vibegron is muscle relaxation in the bladder. Due to this muscle relaxation, bladder capacity increases and symptoms of overactive bladder are relieved.

Pharmacokinetics

The two main metabolic pathways are the

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

and

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

of vibegron. Two oxidative metabolites and three glucuronide metabolites can be formed. The exact structure of these metabolites have not been studied yet. In vitro,

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

is the enzyme responsible for the metabolism of vibegron, facilitating oxidative metabolism. Eventually, still a large part of the unmodified drug is excreted through feces and urine.

History

The

(beta3AR) was discovered in the late 1980s and initially, beta3AR

s were investigated as treatment for obesity and diabetes. A number of compounds were tested in clinical trials but didn't show sufficient benefits in these areas. A phase IIb global trial completed in 2013 of 1395 patients, of which 89.7% were women and 63.3% had not been treated previously, demonstrated a significant decrease in daily

micturition Urination is the release of urine from the bladder through the urethra in placental mammals, or through the cloaca in other vertebrates. It is the urinary system's form of excretion. It is also known medically as micturition, voiding, ures ...

s and urgent urinary incontinence episodes upon administration of vibegron. An international phase III trial of 506 participants completed in 2019 found statistically significant efficacy of vibegron after two weeks of daily administration. The adverse effect rates in participants treated with vibegron were comparable to those in participants who received a placebo. Vibegron was evaluated in patients with OAB in several clinical studies. A large active-controlled study, called Empower, showed the beneficial effects of the drug to treat the condition and UUI. Primary outcomes of different clinical trials showed there was an overall increase in efficacy. These outcomes concluded that there was a reduction in urgency to urinate, a decrease in micturitions and an increase in average volume voided per micturition. There is also an improvement observed of the symptoms when vibegron is administered over a longer period (52 weeks) concluding that it is effective and safe for longer use. In severe patients, increasing the dose was accompanied by similar beneficial effects when there was first a lack of these.

Quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

of the patients is improved, including a reduction of

nocturia Nocturia is defined by the International Continence Society (ICS) as "the complaint that the individual has to wake at night one or more times for voiding (''i.e., to urinate'')". The term is derived from Latin ''nox'' – "night", and Greek '' ...

Society and culture

Legal status

Vibegron was developed in Japan by Kyorin Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co., Ltd, and Urovant Sciences. It was approved for medical use in Japan in September 2018, and in the United States in December 2020. In April 2024, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Obgemsa, intended for the symptomatic treatment of adults with overactive bladder (OAB) syndrome. The applicant for this medicinal product is Pierre Fabre Medicament. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Vibegron was approved for medical use in the European Union in June 2024.

Names

Vibegron is the international nonproprietary name.

Veterinary uses

Pregnant rats were given very high daily oral doses of vibegron during the period of

organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...

and showed no embryo-fetal developmental toxicity up to 300 mg/kg/day. Similar data was found in rabbits. Maternal toxicity was observed when doses exceeded 100 mg/kg/day in lactating rats. Clinical studies show that vibegron is not toxic, safe and well-tolerated in patients.

References

External links

* {{Authority control Beta-Hydroxyamphetamines Beta3-adrenergic agonists